Heterocyclic compounds and use thereof

Abstract

Provided in the present invention are heterocyclic compounds, and a pharmaceutical composition and use thereof, belonging to the technical field of pharmaceutical chemistry. The series of heterocyclic compounds prepared by the present invention have effective sedative, hypnotic and / or anaesthetic effects, can control the status epilepticus, and also have an analgesic effect, thus providing a new option for clinical preparation of drugs having an analgesic effect, drugs having anaesthetic, sedative, or hypnotic effects and / or capable of controlling status epilepticus, and drugs having anaesthetic, sedative, or hypnotic effects and / or being capable of controlling status epilepticus and also having an analgesic effect.

Description

A 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 critically ill patients. Propofol is a fast-acting and short-acting intravenous general anesthetic currently used in clinical practice. It has the advantages of rapid onset of anesthetic induction, rapid recovery, perfect functional recovery, and low incidence of postoperative nausea and vomiting. However, none of the intravenous general anesthetics 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 of opioid analgesics, reduce the adverse reactions of opioid analgesics, and make the sedation, hypnotic, and / or anesthesia process more stable. At the same time, it can also reduce the use of other drugs during 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] (±)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole is an imidazole alpha-2-adrenergic receptor agonist with sedative and analgesic effects. However, the activity of (±)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole needs to be further improved. Therefore, it is of great significance 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 present application aims 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 ability to control status epilepticus, and in the preparation of a drug with anesthetic, sedative, hypnotic effect and / or ability to control 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] R B selected from substituted or unsubstituted C 1-8alkyl, phenyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocycloalkyl, 5-6 membered heteroaromatic ring; each of said substituents is independently selected from the group consisting of halogenated or non-halogenated C 1-8 alkyl, C 1-8 alkoxy, =0, halogen, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclyl, amino protecting group;

[0007] R2, R3are each independently selected from the group consisting of hydrogen, cyano, C 2-6 alkynyl, halogen, C 1-6 alkyl, non-substituted or substituted with one or two more R'; 2-6 alkenyl, 3-6 membered saturated cycloalkyl, halogenated or non-halogenated C 1-6 alkoxy, hydroxyl, or R2, R3are linked to form a 3-6 membered saturated cycloalkyl or 3-6 membered saturated heterocyclyl, or R2, R3together with the C atom in between form C(=CR h R j ), CO; R' is selected from the group consisting of halogen, C 1-6 alkyl, C 2-6 alkenyl; R h , R j are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl;

[0008] L3is selected from the group consisting of nothing, C 1-6 alkylene, OL5, L5is selected from the group consisting of C 1-6 alkylene;

[0009] A ring is selected from the group consisting of

[0010] y, z are each independently selected from the group consisting of 0, 1, 2, 3;

[0011] X' are each independently selected from the group consisting of hydrogen, halogen, halogenated or non-halogenated C 1-5 alkyl;

[0012] R k are each independently selected from the group consisting of L4(W) d R9R'9, W is selected from the group consisting of C or N; d is selected from the group consisting of 0, 1, 2; G is selected from the group consisting of O, NH;

[0013] when A ring is R k is , is

[0014] when A ring is R k is when for

[0015] when for A ring is when R k is

[0016] L4is selected from the group consisting of nothing, CO, C 2-6 alkenylene, C 1-6 alkylene which is unsubstituted or substituted by one or two or more C 1-6 alkyl groups;

[0017] R c is selected from the group consisting of hydrogen, C 1-8 alkoxy, R d is selected from the group consisting of hydrogen, C 1-8 alkoxy, or R c , R d are linked to form a 3-8 membered saturated oxacycle;

[0018] Y is selected from the group consisting of nothing, NR9, CR 10 R 11 ; R 10 is selected from the group consisting of hydrogen, C 1-8 alkyl, hydroxy, C 1-8 alkoxy, R 11 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, or R 10 , R 11 are linked to form a 3-8 membered saturated heterocycle which is unsubstituted or substituted by one or two or more R 12 groups, a 3-8 membered saturated cycloalkyl which is unsubstituted or substituted by one or two or more R 12 groups; R 12 is each independently selected from the group consisting of C 1-8 alkyl;

[0019] L, L' are each independently selected from the group consisting of nothing, NR9R'9, C 1-6 alkylene, CR9R'9;

[0020] R0, R0', R e is each independently selected from the group consisting of hydrogen, hydroxy, COOR' 10 , NR9R'9, the following groups which are unsubstituted or substituted by one or two or more R8: C 1-8 alkyl, C 1-8 alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated cycloalkyl, 3-8 membered saturated heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, R8is each independently selected from the group consisting of halogen, NR9R'9, hydroxyl, thiol, C 1-8 alkyl, C 1-8 alkoxy, C 2- 8alkenyl, C 2-8 alkynyl, COR' 10 , COOR' 10 , C=CR9R'9, 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated cycloalkyl, 3-8 membered saturated heterocyclyl, R0" is selected from the group consisting of hydrogen, hydroxyl, C 1-8 alkyl;

[0021] R9, R'9, R' 10 are each independently selected from the group consisting of nothing, hydrogen, halogen, hydroxyl, C 2-6 alkenyl, halo- or unhalo- genated C 1- 8alkyl, cyano, or R9, R'9together form a 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated heterocyclyl,

[0022] said compound is not

[0023] Further, said compound is shown as Formula II:

[0024] wherein,

[0025] X is selected from CH2, O, NR G ; R G is selected from hydrogen or an amino protecting group;

[0026] a, b are each independently selected from 1, 2, 3;

[0027] m is selected from 0, 1, 2, 3, 4;

[0028] R a are each independently selected from C 1-5 alkyl, C 1-5 alkoxy, =0, halogen, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, an amino protecting group;

[0029] R2, R3are each independently selected from hydrogen, cyano, C 2-4 alkynyl, halogen, C 1-5 alkyl unsubstituted or substituted with one or two more R', C 2-4 alkenyl, 3-6 membered saturated cycloalkyl, halo- or unhalo- genated C 1-5Alkoxy groups, hydroxyl groups, or R2 and R3 linked together to form 3-6 membered saturated cycloalkyl groups or 3-6 membered saturated heterocyclic groups, or R2 and R3 together with the C atom between them to form C(=CR) h R j ), CO; R' is selected from halogens, C 1-5 Alkyl, C 2-4 alkenyl; R h R j Each element is independently selected from hydrogen, halogens, and carbon. 1-5 alkyl;

[0030] L3 is selected from none, C 1-5 Alkylene, OL5, L5 is selected from C 1-5 Alkylene;

[0031] L is selected from None, NR9R'9, and C. 1-4 Alkylene, CR9R'9;

[0032] R0 is selected from the following groups that are unsubstituted or substituted by one or more R8 groups: C 1-5 Alkyl, C 1-5 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated cycloalkyl, 3-6 membered saturated heterocyclic group, C 2-4 alkenyl, C 2-4 acetylinyl R8 is independently selected from halogens, NR9R'9, hydroxyl groups, thiol groups, and C. 1-5 Alkyl, C 1-5 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, COR' 10 COOR' 10 C=CR9R'9, 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated cycloalkyl, 3-6 membered saturated heterocyclic group "R0" is selected from hydrogen, hydroxyl group, C 1-5 alkyl;

[0033] R9 and R'9 are each independently selected from the absence of hydrogen, halogen, hydroxyl, and C. 2-4 alkenyl, halogenated or unhalogenated C 1-5 Alkyl groups, cyano groups, or R9 and R'9 can be combined to form 3-6 membered saturated cycloalkyl groups or 3-6 membered unsaturated heterocyclic groups;

[0034] X' is selected from C(OH)₂, which is free of hydrogen, halogen, halogenated, or unhalogenated. 1-5 alkyl;

[0035] The compound is not

[0036] Furthermore, the compound is as shown in Formula III:

[0037] wherein

[0038] t is selected from 0, 1, 2, 3, 4;

[0039] R b each independently selected from C 1-5 alkyl, C 1-5 alkoxy, =0, halogen, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, an amino protecting group;

[0040] R2, R3are each independently selected from hydrogen, cyano, C 2-4 alkynyl, halogen, C 1-5 alkyl unsubstituted or substituted by one or two more R', C 2-4 alkenyl, 3-6 membered saturated cycloalkyl, halogenated or unhalogenated C 1-5 alkoxy, hydroxy, or R2, R3are linked to form a 3-6 membered saturated cycloalkyl or a 3-6 membered saturated heterocyclyl, or R2, R3together with the C atom in between form C(=CR h R j ), CO; R' is selected from halogen, C 1-5 alkyl, C 2-4 alkenyl; R h , R j are each independently selected from hydrogen, halogen, C 1-5 alkyl;

[0041] L3is selected from nothing, C 1-5 alkylene, OL5, L5is selected from C 1-5 alkylene;

[0042] A ring is selected from

[0043] y, z are each independently selected from 0, 1, 2, 3;

[0044] X' are each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-5 alkyl;

[0045] R k are each independently selected from L4(W) d R9R'9, W is selected from C or N; d is selected from 0, 1, 2; G is selected from O, NH;

[0046] when A ring is R k is , is

[0047] when A ring is R k is , is

[0048] when is A ring is , k is

[0049] L4is selected from the group consisting of nothing, CO, C 2-4 alkenylene, C 1-4 alkylene which is unsubstituted or substituted by one or two or more C 1-4 alkyl groups;

[0050] R c is selected from the group consisting of hydrogen, C 1-5 alkoxy, R d is selected from the group consisting of hydrogen, C 1-5 alkoxy, or R c , R d are linked to form a 3-6 membered saturated oxacycle;

[0051] Y is selected from the group consisting of nothing, NR9, CR 10 R 11 ; R 10 is selected from the group consisting of hydrogen, C 1-5 alkyl, hydroxy, C 1-5 alkoxy, R 11 is selected from the group consisting of hydrogen, C 1-5 alkyl, C 1-5 alkoxy, or R 10 , R 11 are linked to form a 3-6 membered saturated heterocycle which is unsubstituted or substituted by one or two or more R 12 groups, a 3-6 membered saturated cycloalkyl which is unsubstituted or substituted by one or two or more R 12 groups; R 12 is each independently selected from the group consisting of C 1-5 alkyl;

[0052] L, L' are each independently selected from the group consisting of nothing, NR9R'9, C 1-4 alkylene, CR9R'9;

[0053] R0, R0', R e is each independently selected from the group consisting of hydrogen, hydroxy, COOR' 10 , NR9R'9, C 1-5 alkyl, C 1-5alkyl, C 2-4 alkenyl, C 2-4 alkynyl, R8is each independently selected from the group consisting of halogen, NR9R'9, hydroxy, thio, C 1-5 alkyl, C 1-5 alkoxy, C 2- 4alkenyl, C 2-4 alkynyl, COR' 10 , COOR' 10 , C=CR9R'9, 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated cycloalkyl, 3-6 membered saturated heterocyclyl, R0" is selected from the group consisting of hydrogen, hydroxy, C 1-5 alkyl;

[0054] R9, R'9, R' 10 is each independently selected from the group consisting of nothing, hydrogen, halogen, hydroxy, C 2-4 alkenyl, halogenated or unhalogenated C 1- 5alkyl, cyano, or R9, R'9together form a 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated heterocyclyl,

[0055] said compound is not

[0056] Further, said compound is shown as formula IV:

[0057] t, R b , R2, R3, y, z, X', R k as described above.

[0058] Further, said compound is shown as formula IV-a, IV-b:

[0059] t, R b , R2, R3, y, z, X', R k as described above.

[0060] Further, said compound is shown as formula V-a, V-b:

[0061] t, R b , R2, R3, y, X', L4, L, R0as described above.

[0062] Further, said compound is shown as formula VI-a, VI-b:

[0063] t, R b , R2, R3, z, R k As described above.

[0064] The present application also provides a compound selected from one of the following compounds, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated derivative thereof:

[0065] Further, the pharmaceutically acceptable salt is citrate, hydrofluoride, phosphate, propionate, succinate, tartrate, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, 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.

[0066] The present application also provides a pharmaceutical composition which is a preparation prepared by adding a pharmaceutically acceptable adjuvant to the above-mentioned compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated derivative thereof as an active ingredient.

[0067] The application also provides the use of the above-mentioned compound, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, metabolite or deuterated derivative thereof in the preparation of a drug with analgesic effect, and / or with anesthetic, sedative, hypnotic effect and / or capable of controlling status epilepticus.

[0068] In the application, the use of the drug with analgesic effect, and / or with anesthetic, sedative, hypnotic effect and / or capable of controlling status epilepticus includes the following three cases: (1) analgesic effect; (2) anesthetic, sedative, hypnotic effect and / or capable of controlling status epilepticus; (3) both anesthetic, sedative, hypnotic effect and / or capable of controlling status epilepticus and analgesic effect.

[0069] In the application, the drug with both anesthetic, sedative, hypnotic effect and / or capable of controlling status epilepticus and analgesic effect means that there is no response to noxious stimuli or the response threshold to noxious stimuli is increased when the compound produces sedative, hypnotic and / or anesthetic effect.

[0070] In the application, the drug with sedative effect means 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.

[0071] In the application, the drug with hypnotic effect means a drug that can induce sleepiness and promote sleep, that is, it has an inhibitory effect on the central nervous system, a small dose causes sedation, and an overdose causes general anesthesia.

[0072] In the application, the drug with anesthetic effect means a reversible inhibition of central and / or peripheral nervous system function produced by a drug, and the main feature of this inhibition is the loss of sensation, especially pain sensation. Preferably, the anesthetic is general anesthesia.

[0073] In the application, general anesthesia, referred to as general anesthesia, means temporary inhibition of the central nervous system produced after anesthetic enters the body, and the clinical manifestations are loss of consciousness, loss of general pain sensation, amnesia, reflex inhibition and skeletal muscle relaxation.

[0074] In the application, status epilepticus means that consciousness is not completely restored between consecutive seizures, or seizures frequently recur, or seizures last more than 30 minutes and do not stop on their own. Long-term seizures, if not treated in time, can cause irreversible brain damage due to high fever, circulatory failure or neuronal excitotoxicity, resulting in a high rate of disability and mortality, so status epilepticus is a common emergency in internal medicine.

[0075] Definitions of terms used in connection with the present invention: Unless otherwise indicated, the initial definition of a group or term provided herein applies throughout the specification. For terms not specifically defined herein, a meaning that is given to them by one of ordinary skill in the art in light of the disclosure and context will be intended.

[0076] 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 refers to a straight or branched chain alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms, C 1～6 Alkyl refers to a straight or branched chain alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms, C 1～6 Alkoxy refers to a straight or branched chain alkoxy group containing 1, 2, 3, 4, 5, or 6 carbon atoms, C 1-4 Alkylene refers to a straight or branched chain alkylene group containing 1, 2, 3, or 4 carbon atoms, and the like.

[0077] The minimum and maximum number of ring atoms in a cyclic group is indicated by a prefix, e.g., 3-8 membered saturated cycloalkyl refers to a saturated cycloalkyl group containing 3, 4, 5, 6, 7, or 8 ring atoms, 3-8 membered saturated heterocyclyl refers to a saturated heterocyclyl group containing 3, 4, 5, 6, 7, or 8 ring atoms, and the like.

[0078] Amino protecting group refers to a functional group commonly used in organic chemistry to protect an amino group from reacting under certain conditions. Amino protecting groups include, but are not limited to, Boc group (tert-butyloxycarbonyl), Cbz group (benzyloxycarbonyl), Fmoc group (pivaloyloxycarbonyl), Bn group (benzyl).

[0079] "Substituted" herein refers to the replacement of one, two, or more hydrogen atoms in a molecule with other different atoms or molecules, including one, two, or more substitutions of isotopic or isotopic atoms in the molecule.

[0080] "Substituted" herein refers to the replacement of one, two, or more hydrogen atoms in a molecule with other different atoms or molecules, including one, two, or more substitutions of isotopic or isotopic atoms in the molecule.

[0081] "Heteroaromatic ring" refers to a heteroaromatic group containing one to multiple heteroatoms. Heteroatoms referred to herein include, but are not limited to, oxygen, sulfur, nitrogen. Examples include furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrimidinonyl, pyridinonyl, indolyl, tetrazolyl, and the like.

[0082] In some preferred technical solutions, the heteroaromatic ring is a 5-6 membered heteroaromatic ring.

[0083] A heterocyclic compound is a cyclic compound composed of carbon atoms and non-carbon atoms (heteroatoms) combined to form a ring. Among the atoms combined to form the ring, the non-carbon atoms other than carbon atoms are referred to as "ring heteroatoms".

[0084] Halogen is fluorine, chlorine, bromine or iodine.

[0085] 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 subject.

[0086] In the present application, "salt" is an acid and / or base salt formed by a compound or its stereoisomer 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 directly obtained 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 after being precipitated in a solution, or recovered after evaporation of a solvent, or prepared by freeze-drying after reaction in an aqueous medium. In the present application, the salt of the compound 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.

[0087] "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.

[0088] "Stereoisomer" means that in molecules of compounds having the same molecular formula, the order of connection of atoms or atom groups is the same, but the spatial arrangement is different.

[0089] Benzene sulfonate is 2,4-dimethylbenzene sulfonate.

[0090] Compared with the prior art, the compound of the present application has the following beneficial effects:

[0091] The compound provided by the present application has a sedative, hypnotic and / or anesthetic effect, and can control status epilepticus, thereby providing a new choice for preparing a drug with a sedative, hypnotic and / or anesthetic effect and control of status epilepticus in a clinic.

[0092] In addition, the present application also first discovers that the compound of the present application not only has high efficiency of sedation, hypnosis and / or anesthesia, and can control status epilepticus, but also has analgesic effect, and when used clinically, can reduce or not use opioid analgesic drugs such as fentanyl, alfentanil, sufentanil or remifentanil, thereby reducing the occurrence of adverse reactions such as circulatory depression, respiratory depression, urinary retention and skin itching of opioid analgesic drugs.

[0093] 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, replacements or changes can be made without departing from the above basic technical idea of the present application.

[0094] 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

[0095] 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.

[0096] 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, and the determination solvent is deuterated dimethyl sulfoxide (d6-DMSO), deuterated methanol (CD3OD) or deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0097] The determination of LCMS is carried out by using (Agilent LCMS 1260 Infinity II-6125B) (API-ES), column: Waters Agilent Eclipse Plus C18 (4.6mm x 50mm x 3.5μm); column temperature: 45℃; flow rate: 2.0mL / min; mobile phase: gradient from 95% [water+0.1% TFA] and 5% [CH3CN+0.1% TFA] to 0% [water+0.1% TFA] and 100% [CH3CN+0.1% TFA] in 2.5 minutes, under this condition for 0.5 minutes, and then gradient to 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] in 0.05 minutes, and then keep this condition for 0.45 minutes.

[0098] 1) Reagents and materials

[0099] Thin layer chromatography silica gel plate: HSGF254 silica gel plate with a thickness of 1 mm from Yantai Xinuo Chemical Co., Ltd.

[0100] Thin layer chromatography (TLC) was performed using a product from Yantai Jiangyou Silica Gel Development Co., Ltd. with a specification of 0.2 ± 0.03 mm.

[0101] Column chromatography silica gel: 100-200 mesh or 200-300 mesh silica gel from Rushan Taiyang Desiccant Co., Ltd. (Weihai, Shandong) was used as a carrier.

[0102] 2) Main instruments

[0103] Electronic balance JA2003N (Shanghai Youke Instrument and Meter Co., Ltd.);

[0104] 98-2 magnetic stirrer (Shanghai Sile Instrument Co., Ltd.);

[0105] DF-101S heat collecting constant temperature heating magnetic stirrer (Zhengzhou Setlis Biological Technology Co., Ltd.);

[0106] ZF-2 three-purpose ultraviolet instrument (Shanghai Anting Electronic Instrument Factory);

[0107] RE-2000B rotary evaporator (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

[0108] SHB-III circulating water type vacuum pump (Zhengzhou Hui Cheng Science and Technology Trade Co., Ltd.);

[0109] DLSK-5 / 20 low-temperature cooling liquid circulating pump (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

[0110] DGJ-10C vacuum freeze dryer (Shanghai Bodeng Biological Technology Co., Ltd.);

[0111] KQ5200 ultrasonic cleaner (Kunshan Ultrasonic Instrument Co., Ltd.);

[0112] 2XZ-2 type rotary vane vacuum pump (Linhai Tan Vacuum Equipment Co., Ltd.);

[0113] Biotage Isolera One (Biotage Sweden AB)

[0114] Example 1, Preparation of the compounds MA-1 to MA-9 of the present application

[0115] 1, Preparation of the compounds MA-1 to MA-3 of the present application

[0116] To a solution of compound MA-1.1 (4.72 g, 20.0 mmol) and triphenylmethyl chloride (7.23 g, 26.0 mmol) in CH2Cl2(100 mL) was added triethylamine (5.10 g, 50.0 mmol) dropwise at 0 °C under ice-water bath. The mixture was stirred at room temperature for 3 h. After the reaction was completed by TLC, H2O (100 mL) was added to the reaction mixture, which was extracted with EtOAc (3 x 50 mL). The combined organic phase was 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 / 20 ~ 1 / 5), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the fraction with Rf= 0.5 ~ 0.6 was collected to give compound MA-1.2 (7.16 g, yield 81.0%) as a white solid. ESI [M+H] + = 443.3.

[0117] To a solution of compound MA-1.2 (7.16 g, 16.2 mmol) in THF (100 mL) was added n-BuLi (18.7 mL, 24.3 mmol, 1.3 M in THF) dropwise at -70 °C under dry ice-ethanol bath. The mixture was stirred for 1 h. Ethyl chloroformate (2.62 g, 24.3 mmol) was added to the reaction mixture by syringe. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC, the reaction mixture was poured into ice-water and 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 a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 20 ~ 1 / 5), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the fraction with Rf= 0.4 ~ 0.5 was collected to give compound MA-1.3 (7.0 g, yield 84.1%) as a white solid. ESI [M+H] + = 515.3

[0118] TFA (15.5 g, 136.2 mmol) was added to a solution of compound MA-1.3 (7.0 g, 13.62 mmol) in CH2Cl2(60 mL) at 0 °C under ice-water bath, stirred at room temperature for 3 h. After the reaction was monitored to be completed by TLC, concentrated under reduced pressure, cooled to 0 °C under ice-water bath, adjusted to pH ~ 7 with saturated aqueous NaHC03solution, 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, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 2 ~ 1 / 1), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) monitoring, the fraction with Rf= 0.4 ~ 0.5 was collected to give compound MA-1 and MA-3 of the present application

[0119] Compound MA-1: 220.9 mg, white solid, ESI [M+H] + = 273.2

[0120] 1 H NMR (400 MHz, d6-DMSO) δ 13.07 (br s, 1H), 7.08 - 6.94 (m, 3H), 6.90 (s, 1H), 4.41 - 4.31 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.47 (d, J = 7.2 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0121] Compound MA-3: 100 mg, light yellow solid, ESI [M+H] + = 285.2

[0122] 1 H NMR (400 MHz, d6-DMSO) δ 12.99 (br s, 1H), 7.16 - 6.79 (m, 4H), 4.51 - 4.25 (m, 1H), 2.92 (t, J = 7.2 Hz, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.63 - 1.52 (m, 2H), 1.49 (d, J = 7.2 Hz, 3H), 1.37 - 1.25 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0123] The preparation method of compound MA-2 of the present application is similar to that of compound MA-1 of the present application, and in the preparation of MA-2, by-product MA-27 is collected.

[0124] Compound MA-2: 30 mg, colorless oil, ESI [M+H] + = 273.2

[0125] 1 H NMR (400 MHz, d6-DMSO) δ 8.94 (d, J = 37.8 Hz, 1H), 7.07 (d, J = 5.4 Hz, 1H), 7.02 (d, J = 6.3 Hz, 2H), 4.15 - 4.06 (m, 1H), 4.06 - 3.98 (m, 2H), 2.23 (s, 3H), 2.16 (d, J = 11.2 Hz, 3H), 1.23 (d, J = 6.9 Hz, 3H), 1.18 (d, J = 7.1 Hz, 3H).

[0126] Compound MA-27: 11 mg, white solid, ESI [M+H] + = 345.2

[0127] 1 H NMR (400 MHz, d6-DMSO) δ 7.17 (d, J = 0.8 Hz, 1H), 7.03 - 6.94 (m, 2H), 6.54 - 6.51 (m, 1H), 4.59 (q, J = 6.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.98 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 2.21 (s, 3H), 1.48 (d, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H).

[0128] 2, Preparation of the compound MA-4~MA-7 of the present application

[0129] LiOH (529 mg, 22.06 mmol) was added to a solution of compound MA-1 (3.0 g, 11.03 mmol) in THF / MeOH / H2O (50 mL, v / v / v = 5 / 3 / 2) at room temperature, and stirred at room temperature overnight. After the reaction was completed by TLC monitoring, the pH was adjusted to ~7 with saturated aqueous sodium bicarbonate solution, and the crude product was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 20~1 / 5), TLC (methanol / dichloromethane (v / v) = 1 / 5) monitoring, and the fraction with Rf = 0.5~0.6 was collected to obtain compound MA-5.1 (1.8 g, yield 66.9%) as a gray solid. ESI [M+H] + = 245.2.

[0130] DCC (128 mg, 0.62 mmol) and DMAP (76 mg, 0.62 mmol) were added to a solution of compound MA-5.1 (100 mg, 0.41 mmol) in CH2Cl2(10 mL) at room temperature, and stirred at room temperature for 20 min. Cyclobutanol (59 mg, 0.82 mmol) was added to the reaction system, and stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was suction 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 / 2 ~ 1 / 1), and TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) monitoring was performed. The Rf= 0.4 ~ 0.5 part was collected to obtain the compound of the application MA-5 (53 mg, yield 43.4%) in the form of a white solid. ESI [M+H] + = 299.2

[0131] 1 H NMR (400 MHz, d6-DMSO) δ 13.06 (s, 1H), 7.09 - 6.94 (m, 3H), 6.94 - 6.82 (m, 1H), 5.08 (p, J = 7.1 Hz, 1H), 4.44 - 4.27 (m, 1H), 2.38 - 2.29 (m, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 2.17 - 2.06 (m, 2H), 1.84 - 1.73 (m, 1H), 1.70 - 1.57 (m, 1H), 1.47 (d, J = 7.1 Hz, 3H).

[0132] The preparation method of the compound MA-4, MA-6 ~ MA-7 of the application is similar to that of the compound MA-5 of the application.

[0133] Compound MA-7: 44 mg, ESI [M+H] + = 285.2

[0134] 1 H NMR (400 MHz, d6-DMSO) δ 13.07 (s, 1H), 7.03 - 6.95 (m, 3H), 6.92 - 6.85 (m, 1H), 4.40 - 4.32 (m, 1H), 4.26 - 4.21 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 1.47 (d, J = 7.2 Hz, 3H), 0.77 - 0.74 (m, 4H).

[0135] 3, Preparation of the compound MA-8 ~ MA-9 of the application

[0136] To a solution of compound MA-5.1 (70 mg, 0.29 mmol) and catalytic amount of DMF in dry CH2Cl2(10 mL) was added oxalyl chloride (70 mg, 0.55 mmol) slowly dropwise using a syringe under ice water bath at 0 °C, stirred at room temperature for 1 h, concentrated under reduced pressure, added dry CH2Cl2(10 mL) solution. The reaction was cooled to 0 °C with ice water bath, added ethylamine (0.60 mmol) slowly, stirred at room temperature for 3 h. After the reaction was completed by TLC, 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 / 2 ~ 1 / 1), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) monitoring, the fractions with Rf= 0.4 ~ 0.5 were collected to give compound MA-8 of the present application.

[0137] Compound MA-8: 67 mg, white solid, ESI [M+H] + = 272.2

[0138] 1 H NMR (400 MHz, d6-DMSO) δ 12.71 (s, 1H), 8.26 (s, 1H), 7.01 - 6.95 (m, 2H), 6.92 - 6.87 (m, 1H), 4.40 - 4.28 (m, 1H), 3.26 - 3.18 (m, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H), 1.06 (t, J = 7.2 Hz, 3H).

[0139] Example 2, Preparation of compound MA-10 of the present application

[0140] To a solution of compound MA-10.1 (297 mg, 1.5 mmol) in dry THF (20 mL) was added n-BuLi (1.73 mL, 2.25 mmol, 1.3 mol / L in THF) slowly using a syringe under dry ice ethanol bath at -70 °C, stirred for 1 h. To the reaction was added ethyl chloroformate (324 mg, 3.0 mmol) using a syringe, stirred for 30 min. After the reaction was completed by TLC, the reaction was poured into ice water, extracted with EtOAc (3 x 30 mL), the organic phases were combined, 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 / 10 ~ 1 / 2), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) monitoring, the fractions with Rf= 0.5 ~ 0.6 were collected to give compound MA-10 of the present application (110 mg, yield 27.1%) as colorless oil. ESI [M+H] + = 271.2

[0141] 1 H NMR (400 MHz, d6-DMSO) δ 8.29 (d, J = 1.1 Hz, 1H), 7.17 (d, J = 7.3 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.1 Hz, 1H), 6.68 (s, 1H), 6.10 (d, J = 2.2 Hz, 1H), 5.02 (d, J = 2.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 2.04 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0142] Example 3, Preparation of the compounds of the application MA-11 to MA-14, MA-19 to MA-24, MA-28, MA-29, MA-31, MA-32, MA-34, MA-35, MA-37 and MA-38

[0143] 1, Preparation of the compound of the application MA-11

[0144] To a solution of compound MA-11.1 (320 mg, 1.5 mmol) in dry DMF (5 mL) was added sodium hydride (120 mg, 60% in mineral oil, 3.0 mmol) portionwise at 0 °C under ice-water bath, and stirred for 1 h. Ethyl chloroformate (324 mg, 3.0 mmol) was added slowly into the reaction mixture by syringe, and stirred at room temperature overnight. After the reaction was completed by TLC, the reaction mixture was poured into ice-water, extracted with EtOAc (3 x 10 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 / 10 to 1 / 5), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the fraction with Rf = 0.4 to 0.5 was collected to give the compound of the application MA-11 (127 mg, yield 29.7%) as colorless oil. ESI [M+H] = 286.2 + = 286.2

[0145] 1 H NMR (400 MHz, d6-DMSO) δ 7.40 - 7.29 (m, 1H), 7.26 - 7.12 (m, 2H), 6.41 (d, J = 3.6 Hz, 1H), 6.10 (d, J = 3.5 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 2.29 (s, 3H), 2.18 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0146] 2. Preparation of compound MA-12 of the present application

[0147] Boc20 (654 mg, 3.0 mmol) was added to a solution of compound MA-11.1 (320 mg, 1.5 mmol) and DMAP (183 mg, 1.5 mmol) in dry CH2Cl2(10 mL) at room temperature and stirred at room temperature overnight. After the reaction was completed by TLC monitoring, the reaction was poured into ice water and extracted with EtOAc (3 x 10 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the fraction with Rf= 0.4 ~ 0.5 was collected to give compound MA-12 of the present application (152.4 mg, yield 32.5%) as a white solid. ESI [M+H] + = 314.2

[0148] 1 H NMR (400 MHz, d6-DMSO) δ 7.39 - 7.27 (m, 1H), 7.18 (d, J = 6.7 Hz, 2H), 6.33 (d, J = 3.6 Hz, 1H), 6.05 (d, J = 3.4 Hz, 1H), 2.35 (s, 3H), 2.29 (s, 3H), 2.17 (s, 3H), 1.52 (s, 9H).

[0149] 3. Preparation of compound MA-13 of the present application

[0150] TBHP (135 mg, 1.5 mmol) was slowly added to a solution of compound MA-11.1 (320 mg, 1.5 mmol) and Cu(OTf)2(180 mg, 0.5 mmol) in dry DMF (20 mL) at room temperature and stirred at 80 °C overnight. After the reaction was completed by TLC monitoring, the reaction was poured into ice water and extracted with EtOAc (3 x 10 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the fraction with Rf= 0.4 ~ 0.5 was collected to give compound MA-13 of the present application (96.6 mg, yield 22.5%) as a white solid. ESI [M+H] + = 285.2

[0151] 1H NMR (400 MHz, d6-DMSO) δ 7.33 - 7.27 (m, 1H), 7.21 - 7.14 (m, 2H), 6.38 (d, J = 3.8 Hz, 1H), 6.11 (d, J = 3.7 Hz, 1H), 3.09 (s, 3H), 2.63 (s, 3H), 2.29 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H).

[0152] 4. Preparation of compound MA-14 of the present application

[0153] Ethyl isocyanate (213 mg, 3.0 mmol) was added slowly to a solution of compound MA-11.1 (320 mg, 1.5 mmol) and DIEA (387 mg, 3.0 mmol) in dry DMF (20 mL) at room temperature, and stirred at 60 °C overnight. After the reaction was completed by TLC monitoring, the reaction mixture was poured into ice water, extracted with EtOAc (3 x 10 mL), the organic phases were combined, 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 / 10 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the fraction with Rf = 0.4 ~ 0.5 was collected to give compound MA-14 of the present application (36.5 mg, yield 8.6%) as a white solid. ESI [M+H] + = 285.2

[0154] 1 H NMR (400 MHz, d6-DMSO) δ 8.67 (t, J = 5.4 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.22 - 7.13 (m, 2H), 6.29 (d, J = 3.7 Hz, 1H), 6.01 (d, J = 3.6 Hz, 1H), 3.30 - 3.22 (m, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H).

[0155] 5. Preparation of compounds MA-19 ~ MA-24 of the present application

[0156] The preparation method of compounds MA-19 ~ MA-24 of the present application is similar to that of compounds MA-11 ~ MA-14 of the present application.

[0157] Compound MA-19: 126 mg, white solid, ESI [M+H] + = 286.2

[0158] 1H NMR (400 MHz, d6-DMSO) δ 7.31 (d, J = 7.0 Hz, 1H), 7.25 (s, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 4.6 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0159] Compound MA-20: 160 mg, white solid, ESI [M+H] + = 314.2

[0160] 1 H NMR (400 MHz, d6-DMSO) δ 7.31 (d, J = 7.0 Hz, 1H), 7.25 (s, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 4.6 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0161] Compound MA-21: 24 mg, colorless oil, ESI [M+H] + = 285.2

[0162] 1 H NMR (400 MHz, d6-DMSO) δ 7.31 (d, J = 7.0 Hz, 1H), 7.25 (s, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 4.6 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0163] Compound MA-22: 161.8 mg, white solid, ESI [M+H] + = 285.2

[0164] 1 H NMR (400 MHz, d6-DMSO) δ 7.31 (d, J = 7.0 Hz, 1H), 7.25 (s, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 4.6 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0165] Compound MA-23: 34.6 mg, colorless oil, ESI [M+H] + = 283.2

[0166] 1 H NMR (400 MHz, d6-DMSO) δ 8.05 (d, J = 5.6 Hz, 1H), 7.18 (s, 1H), 7.13 (d, J = 6.3 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 7.1 Hz, 1H), 6.76 (s, 1H), 5.50 (d, J = 1.7 Hz, 1H), 4.91 (d, J = 1.7 Hz, 1H), 3.21 - 3.12 (m, 2H), 2.24 (s, 3H), 2.01 (d, J = 7.7 Hz, 6H), 1.06 (t, J = 7.2 Hz, 3H).

[0167] Compound MA-24: 70.6 mg, light yellow oil, ESI [M+H] + = 284.2

[0168] 1 H NMR (400 MHz, d6-DMSO) δ 7.14 (d, J = 6.7 Hz, 1H), 7.12 (dd, J = 2.4, 1.2 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 5.58 (d, J = 1.5 Hz, 1H), 4.98 (d, J = 1.5 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 2.02 (d, J = 1.0 Hz, 3H), 2.00 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).

[0169] 6, Preparation of compounds MA-28, MA-29, MA-34 and MA-35 of the present application

[0170] The preparation method of compounds MA-28, MA-29, MA-34 and MA-35 of the present application is similar to that of compound MA-11 of the present application.

[0171] Compound MA-28: 270 mg, white solid, ESI [M+H] + = 272.2

[0172] 1H NMR (400 MHz, d6-DMSO) δ 7.63 - 7.56 (m, 1H), 7.34 (d, J = 6.9 Hz, 1H), 7.17 (s, 2H), 6.64 - 6.58 (m, 1H), 6.33 (d, J = 3.1 Hz, 1H), 4.25 (d, J = 7.1 Hz, 2H), 2.30 (s, 3H), 2.23 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H).

[0173] Compound MA-29: 174.4 mg, colorless oil, ESI [M+H] + = 270.1

[0174] 1 H NMR (400 MHz, d6-DMSO) δ 7.27 (dd, J = 3.2, 1.8 Hz, 1H), 7.06 (d, J = 7.3 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 7.0 Hz, 1H), 6.31 - 6.22 (m, 2H), 5.54 (d, J = 1.7 Hz, 1H), 5.16 (d, J = 1.7 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 1.04 (t, J = 7.1 Hz, 3H).

[0175] Compound MA-34: 199 mg, white solid, ESI [M+H] + = 272.2

[0176] 1 H NMR (400 MHz, d6-DMSO) δ 7.44 (dd, J = 3.3, 2.1 Hz, 1H), 7.36 (t, J = 1.8 Hz, 1H), 7.32 (d, J = 6.5 Hz, 1H), 7.26 - 7.13 (m, 2H), 6.68 (dd, J = 3.3, 1.6 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 2.12 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H).

[0177] Compound MA-35: 118.9 mg, colorless oil, ESI [M+H] + = 270.1

[0178] 1H NMR (400 MHz, d6-DMSO) δ 7.27 (dd, J = 3.2, 1.8 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.33 - 6.19 (m, 2H), 5.54 (d, J = 1.7 Hz, 1H), 5.16 (d, J = 1.7 Hz, 1H), 4.04 (d, J = 7.1 Hz, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 1.04 (t, J = 7.1 Hz, 3H).

[0179] The preparation method of the compounds MA-31, MA-32, MA-37 and MA-38 of the application is similar to that of the compound MA-14 of the application.

[0180] Compound MA-31: 102 mg, white solid, ESI [M+H] + = 271.1

[0181] 1 H NMR (400 MHz, d6-DMSO) δ 7.56 (d, J = 1.1 Hz, 1H), 7.31 (d, J = 6.7 Hz, 1H), 7.21 (s, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.49 (dd, J = 3.7, 1.7 Hz, 1H), 6.25 (d, J = 2.8 Hz, 1H), 3.22 (d, J = 1.7 Hz, 2H), 2.29 (s, 3H), 2.15 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H).

[0182] Compound MA-32: 37.2 mg, white solid, ESI [M+H] + = 269.2

[0183] 1 H NMR (400 MHz, d6-DMSO) δ 7.46 - 7.33 (m, 1H), 7.14 (d, J = 6.8 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 6.75 (d, J = 1.9 Hz, 1H), 6.50 (dd, J = 3.2, 1.7 Hz, 1H), 5.64 (d, J = 1.6 Hz, 1H), 4.81 (d, J = 1.6 Hz, 1H), 3.24 - 3.11 (m, 2H), 2.26 (s, 3H), 2.03 (s, 3H), 1.12 - 1.03 (m, 3H).

[0184] Compound MA-37: 200.3 mg, colorless oil, ESI [M+H]+ = 271.1

[0185] 1 H NMR (400 MHz, d6-DMSO) δ 7.62 (t, J = 1.9 Hz, 1H), 7.49 (dd, J = 3.3, 2.2 Hz, 1H), 7.31 (d, J = 6.9 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 1.6 Hz, 1H), 6.62 (dd, J = 3.3, 1.6 Hz, 1H), 3.23 (dd, J = 7.2, 5.5 Hz, 2H), 2.29 (s, 3H), 2.11 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H).

[0186] Compound MA-38: 49.1 mg, white solid, ESI [M+H] + = 269.2

[0187] 1 H NMR (400 MHz, d6-DMSO) δ 7.37 (dd, J = 3.2, 2.3 Hz, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 6.76 (t, J = 1.9 Hz, 1H), 6.50 (dd, J = 3.2, 1.7 Hz, 1H), 5.64 (d, J = 1.7 Hz, 1H), 4.81 (d, J = 1.7 Hz, 1H), 3.23 - 3.12 (m, 2H), 2.27 (s, 3H), 2.03 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H).

[0188] Example 4, Preparation of compounds MA-40~MA-43 of the present application

[0189] 1, Preparation of compound MA-40 of the present application

[0190] Compound MA-40.1 (60 mg, 0.28 mmol), ethyl bromoacetate (125 mg, 0.75 mmol), Cs2CO3(183.7 mg, 0.56 mmol) and KI (6.23 mg, 0.04 mmol) were added into dry DMF (2 mL) at room temperature, stirred at room temperature for 12 hours. After the reaction was completed by TLC monitoring, ice water (5 mL) was added to the reaction system, extracted with EtOAc (3 x 15 mL), the combined organic phase was dried over anhydrous Na2SO4, 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 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, the Rf= 0.3 ~ 0.5 part was collected to obtain the compound MA-40 of the application (54.5 mg, yield 64.7%) in white solid. ESI [M+H] + = 300.2.

[0191] 1 H NMR (400 MHz, d6-DMSO) δ 7.27 (d, J = 7.3 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.30 (d, J = 4.0 Hz, 1H), 6.02 (d, J = 3.9 Hz, 1H), 5.23 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0192] 2, Preparation of the compound MA-42 of the application

[0193] NaOH (108.0 mg, 2.70 mmol) was added to a solution of compound MA-40 (403.6 mg, 1.35 mmol) in THF / MeOH / H2O (6 mL, v / v / v = 1 / 1 / 1) at room temperature, stirred at room temperature for 2 hours. After the reaction was completed by TLC monitoring, concentrated under reduced pressure, reduced to 0°C in ice water bath, the system was adjusted to PH ~ 7 with 1N aqueous hydrochloric acid solution, extracted with EtOAc (3 x 15 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 / 10 ~ 1 / 1), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) monitoring, the Rf= 0.2 ~ 0.4 part was collected to obtain compound MA-42.1 (359 mg, yield 98.1%). ESI [M+H] + = 272.1.

[0194] HATU (209.6 mg, 0.55 mmol) was added to a solution of compound MA-42.1 (100 mg, 0.37 mmol), 2-(tert-butyldimethylsilyloxy)ethylamine (96.1 mg, 0.55 mmol) and DIEA (142.3 mg, 1.10 mmol) in dry DMF (5 mL) at room temperature. The reaction was stirred at room temperature for 12 h. After the reaction was completed by TLC, ice water (10 mL) was added to the reaction mixture, which was extracted with EtOAc (3 x 15 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product MA-42.2 (200 mg). ESI [M+H] + = 429.1.

[0195] TBAF (0.73 mL, 1 M in THF, 0.73 mmol) was added to a solution of crude compound MA-42.2 (200 mg) in THF (5 mL) at 0 °C under an ice water bath using a syringe. The reaction was stirred at 0 °C for 1 h. After the reaction was completed by TLC, H2O (5 mL) was added to the reaction mixture, which was extracted with EtOAc (3 x 5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (CH2Cl2 / MeOH (v / v) = 20 / 1) to give compound MA-42 (55.3 mg, yield 47.7%) as a white solid. ESI [M+H] + = 315.2

[0196] 1 H NMR (400 MHz, d6-DMSO) δ 8.01 (s, 1H), 7.26 (d, J = 7.1 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.26 (d, J = 3.9 Hz, 1H), 5.98 (d, J = 3.9 Hz, 1H), 5.14 (s, 2H), 4.67 (t, J = 5.4 Hz, 1H), 3.45 (q, J = 6.1 Hz, 2H), 3.20 (q, J = 5.9 Hz, 2H), 2.29 (s, 3H), 2.23 (s, 3H), 2.10 (s, 3H).

[0197] 3. Preparation of compounds MA-41 and MA-43 of the present application

[0198] The preparation of compounds MA-41 and MA-43 of the present application is similar to that of compounds MA-40 and MA-42.2, respectively.

[0199] Compound MA-41: 58.9 mg, white solid, ESI [M+H]+ = 314.2.

[0200] 1 H NMR (400 MHz, d6-DMSO) δ 7.26 (d, J = 7.3 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.30 (d, J = 4.0 Hz, 1H), 5.99 (d, J = 4.0 Hz, 1H), 5.44 - 5.42 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.29 (s, 3H), 2.08 (s, 3H), 1.65 (d, J = 6.9 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H).

[0201] Compound MA-43: 70.0 mg, white solid, ESI [M+H] + = 329.2.

[0202] 1 H NMR (400 MHz, d6-DMSO) δ 8.10 (t, J = 5.4 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.25 (d, J = 4.0 Hz, 1H), 5.98 (d, J = 3.9 Hz, 1H), 5.14 (s, 2H), 3.39 (t, J = 5.7 Hz, 2H), 3.31 - 3.27 (m, 5H), 2.29 (s, 3H), 2.22 (s, 3H), 2.10 (s, 3H).

[0203] Example 5, Preparation of compounds MA-61, MA-66, MA-67, MA-72, MA-116, MA-121 and MA-129 of the present application

[0204] 1, Preparation of compounds MA-61 and MA-121 of the present application

[0205] Bromoacetic acid ethyl ester (139 mg, 0.84 mmol) was added to a solution of compound MA-1.1 (100 mg, 0.42 mmol) and Cs2CO3(273 mg, 0.84 mmol) in DMF (5 mL) at room temperature, and stirred at room temperature for 12 hours. After the reaction was completed by TLC monitoring, ice water (5 mL) was added to the reaction system, extracted with EtOAc (3 x 10 mL), and the combined organic phase was dried over anhydrous Na2SO4, 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 / 20 ~ 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 compound of the present application MA-61 (73.1 mg, yield 60.8%) in the form of a gray solid. ESI [M+H] + = 287.2.

[0206] 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.46 (s, 1H), 4.66 (s, 2H), 4.43 (d, J = 7.1 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 2.24 (s, 3H), 1.63 (d, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0207] The preparation method of the compound of the present application MA-121 is similar to that of the compound of the present application MA-61.

[0208] Compound MA-121: 28.7 mg, gray solid, ESI [M+H] + = 273.2

[0209] 1 H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.10 (dd, J = 7.4, 5.2 Hz, 3H), 6.44 (s, 1H), 5.00 (s, 2H), 4.54 (d, J = 7.1 Hz, 1H), 3.79 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.72 (d, J = 7.1 Hz, 3H).

[0210] 2, Preparation of the compound of the present application MA-129

[0211] LiOH (480 mg, 20 mmol) was added to a solution of compound MA-64 (2.86 g, 10.0 mmol) in ethanol (30 mL) at room temperature and stirred at room temperature overnight. After the reaction was completed by TLC monitoring, the crude product was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 20 ~ 1 / 5), TLC (methanol / dichloromethane (v / v) = 1 / 5) monitoring, and the Rf = 0.5 ~ 0.6 fraction was collected to obtain compound MA-129.1 (1.87 g, yield 72.5 %). ESI [M+H] + = 259.1.

[0212] HATU (593 mg, 1.56 mmol) was added to a solution of compound MA-129.1 (200 mg, 0.78 mmol), 2-(tert-butyldimethylsilyloxy)ethylamine (273 mg, 1.56 mmol), and DIEA (302 mg, 2.34 mmol) in DMF (5 mL) at room temperature and stirred at room temperature for 12 hours. After the reaction was completed by TLC monitoring, ice water (20 mL) was added to the reaction system, extracted with EtOAc (3 x 10 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product MA-129.2 (137 mg). ESI [M+H] + = 416.3.

[0213] TBAF (0.66 mL, 1M in THF, 0.66 mmol) was added to a solution of the crude compound MA-129.2 (137 mg) in THF (10 mL) at room temperature and stirred for 1 hour. After the reaction was completed by TLC monitoring, H2O (20 mL) was added to the reaction system, extracted with EtOAc (3 x 15 mL), and the combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC (CH2Cl2 / MeOH (v / v) = 20 / 1) to obtain the present compound MA-129 (26 mg, yield 13.1 %) as a colorless oil. ESI [M+H] + = 302.2

[0214] 1H NMR (400 MHz, d6-DMSO) δ 8.10 (s, 1H), 7.44 (s, 1H), 7.06 - 6.93 (m, 3H), 6.67 (s, 1H), 4.56 (s, 2H), 4.32 - 4.19 (m, 1H), 3.43 (q, J = 5.9 Hz, 2H), 3.16 (q, J = 5.9 Hz, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H).

[0215] 3. Preparation of the compounds MA-66, MA-67, MA-72 and MA-116 of the present application

[0216] The preparation of the compounds MA-66, MA-67, MA-72 and MA-116 of the present application is analogous to the preparation of the compound MA-129.2 of the present application.

[0217] Compound MA-66: 136 mg, colorless oil, ESI [M+H] + = 330.2

[0218] 1 H NMR (400 MHz, d6-DMSO) δ 8.10 (s, 1H), 7.44 (s, 1H), 7.06 - 6.93 (m, 3H), 6.67 (s, 1H), 4.56 (s, 2H), 4.32 - 4.19 (m, 1H), 3.43 (q, J = 5.9 Hz, 2H), 3.16 (q, J = 5.9 Hz, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H).

[0219] Compound MA-67: 173 mg, colorless oil, ESI [M+H] + = 344.2

[0220] 1H NMR (400 MHz, d6-DMSO) δ 7.46 (s, 1H), 6.99 (dd, J = 7.6, 4.4 Hz, 3H), 6.67 (s, 1H), 4.57 (s, 2H), 4.24 (dd, J = 13.2, 6.7 Hz, 1H), 3.54 (dt, J = 12.3, 6.1 Hz, 1H), 3.38 (d, J = 5.7 Hz, 2H), 3.21 (d, J = 5.8 Hz, 2H), 2.27 (d, J = 11.6 Hz, 3H), 2.23 (d, J = 5.1 Hz, 3H), 1.46 (d, J = 7.1 Hz, 3H), 1.10 (t, J = 5.5 Hz, 6H).

[0221] Compound MA-72: 13 mg, white solid, ESI [M+H] + = 316.2

[0222] 1 H NMR (400 MHz, d6-DMSO) δ 7.38 (d, J = 5.2 Hz, 1H), 7.11 - 6.90 (m, 3H), 6.60 (d, J = 5.8 Hz, 1H), 4.93 (s, 2H), 4.25 (d, J = 7.5 Hz, 1H), 3.54 (dd, J = 37.8, 5.5 Hz, 2H), 3.43 - 3.32 (m, 3H), 3.03 (s, 1H), 2.86 (s, 1H), 2.25 (s, 3H), 2.22 (s, 3H), 1.46 (d, J = 7.2 Hz, 3H).

[0223] Compound MA-116: 86 mg, yellow oil, ESI [M+H] + = 316.2

[0224] 1 H NMR (400 MHz, d6-DMSO) δ 8.29 (s, 1H), 7.99 (d, J = 31.1 Hz, 1H), 7.02 (d, J = 5.1 Hz, 2H), 6.99 - 6.91 (m, 2H), 4.69 (s, 2H), 4.34 (d, J = 7.1 Hz, 1H), 3.38 (t, J = 5.5 Hz, 2H), 3.29 (d, J = 5.6 Hz, 1H), 3.27 (s, 3H), 3.23 (dd, J = 10.8, 6.6 Hz, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 1.48 (d, J = 7.1 Hz, 3H).

[0225] Example 6, Preparation of compounds MA-63~MA-65, MA-75 and MA-124 of the present application

[0226] 1. Preparation of compounds MA-63 and MA-65 of the present application

[0227] Acrylonitrile (159 mg, 3.0 mmol), triethylamine (303 mg, 3.0 mmol) and MA-1.1 (354 mg, 1.5 mmol) were dissolved in toluene (30 mL) at room temperature, stirred at 60 °C for 3 hours. After the reaction was monitored to be completed by TLC, concentrated under reduced pressure, cooled with ice water bath, extracted with EtOAc (3 x 10 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to get the crude product, which 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 = 0.4 ~ 0.5 was collected to give compounds MA-63 and MA-65 of the present application

[0228] Compound MA-63: 138 mg, light yellow oil, ESI [M+H] + = 287.2

[0229] 1 H NMR (400 MHz, d6-DMSO) δ 7.48 (s, 1H), 7.02 - 6.93 (m, 3H), 6.76 (s, 1H), 4.23 (q, J = 7.1 Hz, 1H), 4.14 (t, J = 6.8 Hz, 2H), 3.60 (s, 3H), 2.81 (t, J = 6.8 Hz, 2H), 2.25 (s, 3H), 2.21 (s, 3H), 1.44 (d, J = 7.1 Hz, 3H).

[0230] Compound MA-65: 35 mg, light yellow oil, ESI [M+H] + = 287.2

[0231] 1 H NMR (400 MHz, d6-DMSO) δ 7.55 (s, 1H), 7.05 - 6.93 (m, 2H), 6.87 (s, 1H), 6.61 (d, J = 7.4 Hz, 1H), 4.42 (q, J = 7.0 Hz, 1H), 3.85 - 3.66 (m, 2H), 3.56 (s, 3H), 2.50 - 2.42 (m, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.27 - 2.18 (m, 1H), 1.46 (d, J = 7.0 Hz, 3H).

[0232] The preparation method of compounds MA-64 and MA-124 of the present application is similar to that of compounds MA-63 of the present application.

[0233] Compound MA-64: 33 mg, light yellow solid, ESI [M+H] + = 254.2

[0234] 1 H NMR (400 MHz, d6-DMSO) δ 7.65 (s, 1H), 7.10 - 6.96 (m, 2H), 6.93 (s, 1H), 6.61 (d, J = 7.5 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 3.96 - 3.85 (m, 1H), 3.78 - 3.65 (m, 1H), 2.66 - 2.47 (m, 2H), 2.33 (s, 3H), 2.29 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H).

[0235] Compound MA-124: 128 mg, white solid, ESI [M+H] + = 254.2

[0236] 1 H NMR (400 MHz, d6-DMSO) δ 7.57 (s, 1H), 7.02 - 6.96 (m, 3H), 6.85 (s, 1H), 4.26 (q, J = 7.1 Hz, 1H), 4.19 (t, J = 6.5 Hz, 2H), 3.02 (t, J = 6.5 Hz, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H).

[0237] The preparation method of the compound MA-75 of the application is similar to that of the compound MA-129.2 in Example 5.

[0238] Compound MA-75: 48 mg, colorless syrup, ESI [M+H] + = 330.2

[0239] 1 H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.10 (d, J = 6.9 Hz, 2H), 7.06 (s, 1H), 6.49 (s, 1H), 4.42 (d, J = 7.1 Hz, 1H), 4.26 (t, J = 6.5 Hz, 2H), 3.44 (d, J = 2.5 Hz, 4H), 3.36 (s, 3H), 2.63 (t, J = 6.5 Hz, 2H), 2.33 (s, 3H), 2.27 (s, 3H), 1.63 (d, J = 7.1 Hz, 3H).

[0240] Example 7, Preparation of the compounds MA-76~MA-78 of the application

[0241] Compound MA-76.1 (236 mg, 1.0 mmol), dry pyridine (158 mg, 2.0 mmol) and DMAP (122 mg, 1.0 mmol) in benzene (20 mL) was added ethyl chloroformate (163 mg, 1.5 mmol) slowly at room temperature with a syringe, and stirred at 50 °C for 10 min. After the reaction was monitored to be completed by TLC, the reaction mixture was poured into ice water, extracted with EtOAc (3 x 10 mL), the organic phase was combined, 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 / 10 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the fraction with Rf = 0.4 ~ 0.5 was collected to give compound MA-76 of the application (130 mg, yield 47.6%) as a white solid. ESI [M+H] + = 273.2

[0242] 1 H NMR (400 MHz, d6-DMSO) δ 8.18 (d, J = 0.8 Hz, 1H), 7.19 - 7.16 (m, 1H), 7.01 - 6.95 (m, 3H), 4.38 (q, J = 7.1 Hz, 2H), 4.29 (q, J = 7.2 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0243] The preparation method of compounds MA-77 and MA-78 of the application is similar to that of compound MA-76 of the application.

[0244] Compound MA-77: 127 mg, colorless oil, ESI [M+H] + = 273.2

[0245] 1 H NMR (400 MHz, d6-DMSO) δ 8.18 (d, J = 0.8 Hz, 1H), 7.19 - 7.16 (m, 1H), 7.01 - 6.95 (m, 3H), 4.38 (q, J = 7.1 Hz, 2H), 4.29 (q, J = 7.2 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0246] Compound MA-78: 102 mg, white solid, ESI [M+H] + = 273.2

[0247] 1H NMR (400 MHz, d6-DMSO) δ 8.15 (d, J = 1.3 Hz, 1H), 7.16 (t, J = 1.0 Hz, 1H), 7.02 - 6.94 (m, 3H), 4.38 (q, J = 7.1 Hz, 1H), 4.29 (q, J = 7.2 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0248] Example 8, Preparation of the compounds of the application MA-79, MA-80, MA-82, MA-83, MA-84, MA-86, MA-87, MA-89, MA-94, MA-114, MA-125, MA-131

[0249] 1, Preparation of the compound of the application MA-79

[0250] To a solution of dry CH2Cl2(10 mL) of dry pyridine (296 mg, 3.75 mmol) and ethylene glycol monomethyl ether (152 mg, 2.0 mmol) was added to a solution of triphosgene (223 mg, 0.75 mmol) at 0 °C under ice water bath. Stirring at 0 °C for 1 h. Concentrated under reduced pressure, the system was reduced to 0 °C with ice water bath, dry CH2Cl2(10 mL) was added, dry pyridine (296 mg, 3.75 mmol) and MA-1.1 (236 mg, 1.0 mmol) were added in turn, and stirred at room temperature overnight. TLC monitoring reaction complete, reduced to 0 °C with ice water bath, saturated sodium bicarbonate solution (20 mL) was slowly added to the reaction system, extracted with EtOAc (3 x 10 mL), the combined organic phase was dried over anhydrous Na2SO4, suction filtration, the filtrate was 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 / 20 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, the Rf= 0.4 ~ 0.5 part was collected to give the compound of the application MA-79 (74.1 mg, yield 24.5%) as colorless oil. ESI [M+H] + = 303.2.

[0251] 1 H NMR (400 MHz, d6-DMSO) δ 8.15 (d, J = 1.3 Hz, 1H), 7.16 (t, J = 1.0 Hz, 1H), 7.02 - 6.94 (m, 3H), 4.38 (q, J = 7.1 Hz, 1H), 4.29 (q, J = 7.2 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0252] 2. Preparation of the compound MA-94 of the present application

[0253] To a solution of compound MA-94.1 (146 mg, 0.36 mmol) in THF (10 mL) was added TBAF (0.72 mL, 1 M in THF, 0.72 mmol) at 0 °C under ice-water bath using a syringe. The mixture was stirred at 0 °C for 1 h. The reaction was monitored by TLC. After completion of the reaction, H2O (20 mL) was added to the reaction mixture, which was extracted with EtOAc (3 x 15 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative TLC (CH2Cl2 / MeOH (v / v) = 20 / 1) to give the compound MA-94 (72 mg, 69.9% yield) as a white solid. ESI [M+H] = 288.2 +

[0254] To a solution of compound MA-94.1 (146 mg, 0.36 mmol) in THF (10 mL) was added TBAF (0.72 mL, 1 M in THF, 0.72 mmol) at 0 °C under ice-water bath using a syringe. The mixture was stirred at 0 °C for 1 h. The reaction was monitored by TLC. After completion of the reaction, H2O (20 mL) was added to the reaction mixture, which was extracted with EtOAc (3 x 15 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative TLC (CH2Cl2 / MeOH (v / v) = 20 / 1) to give the compound MA-94 (72 mg, 69.9% yield) as a white solid. ESI [M+H] = 288.2 +

[0255] 1 H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.80 (s, 1H), 7.11 (d, J = 4.4 Hz, 2H), 7.06 (d, J = 4.5 Hz, 1H), 4.58 - 4.52 (m, 1H), 3.90 (s, 2H), 3.61 (d, J = 4.6 Hz, 2H), 2.34 (s, 3H), 2.26 (s, 3H), 1.73 (d, J = 7.1 Hz, 3H).​​

[0256] 3, The preparation method of the compound MA-80, MA-82, MA-83, MA-84, MA-86, MA-87, MA-89, MA-114, MA-125, MA-131 of the application is similar to that of the compound MA-79 of the application.

[0257] The preparation of compound MA-114 and compound MA-125 uses condition 2.

[0258] Compound MA-80: 72.0 mg, yellow oil, ESI [M+H] + = 299.2

[0259] 1 H NMR (400 MHz, d6-DMSO) δ 8.17 (s, 1H), 7.18 (s, 1H), 6.99 (s, 3H), 5.17 - 5.11 (m, 1H), 4.30 (d, J = 7.1 Hz, 1H), 2.38 - 2.33 (m, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 1.88 - 1.76 (m, 2H), 1.65 (dd, J = 18.5, 7.9 Hz, 2H), 1.47 (d, J = 7.1 Hz, 3H).

[0260] Compound MA-82: 86.0 mg, colorless oil, ESI [M+H] + = 315.2

[0261] 1 H NMR (400 MHz, d6-DMSO) δ 8.17 (d, J = 1.0 Hz, 1H), 7.21 (s, 1H), 7.03 - 6.97 (m, 3H), 4.89 - 4.82 (m, 1H), 4.31 (q, J = 7.0 Hz, 1H), 2.25 (s, 3H), 2.23 (s, 3H), 1.73 - 1.65 (m, 4H), 1.48 (d, J = 7.1 Hz, 3H), 0.90 (t, J = 7.4 Hz, 6H).

[0262] Compound MA-83: 116.1 mg, colorless oil, ESI [M+H] + = 343.2

[0263] 1H NMR (400 MHz, d6-DMSO) δ 8.21 (d, J = 1.1 Hz, 1H), 7.22 (s, 1H), 7.04 - 6.96 (m, 3H), 4.31 (q, J = 7.0 Hz, 1H), 3.70 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H), 1.62 - 1.56 (m, 2H), 1.56 - 1.50 (m, 2H), 1.48 (d, J = 7.1 Hz, 3H).

[0264] Compound MA-84: 60.0 mg, colorless oil, ESI [M+H] + = 327.2

[0265] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (d, J = 1.1 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.01 - 6.96 (m, 3H), 6.34 (dd, J = 17.5, 11.0 Hz, 1H), 5.50 (d, J = 17.4 Hz, 1H), 5.40 (d, J = 11.0 Hz, 1H), 4.94 (d, J = 7.5 Hz, 2H), 4.71 (d, J = 7.9 Hz, 2H), 4.31 (q, J = 7.3 Hz, 1H), 2.24 (s, 3H), 2.23 (s, 3H), 1.48 (d, J = 7.1 Hz, 3H).

[0266] Compound MA-86: 280.0 mg, colorless oil, ESI [M+H] + = 329.2

[0267] 1 H NMR (400 MHz, d6-DMSO) δ 8.19 - 8.15 (m, 1H), 7.22 - 7.17 (m, 1H), 7.02 - 6.94 (m, 3H), 4.84 (p, J = 7.2 Hz, 1H), 4.29 (q, J = 7.0 Hz, 1H), 3.62 (p, J = 6.8 Hz, 1H), 3.15 (s, 3H), 2.83 - 2.73 (m, 2H), 2.24 (s, 3H), 2.22 (s, 3H), 2.14 - 2.05 (m, 2H).

[0268] Compound MA-87: 209.1 mg, yellow solid, ESI [M+H] + = 345.2

[0269] 1H NMR (400 MHz, d6-DMSO) δ 8.20 (d, J = 1.2 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.01 - 6.96 (m, 3H), 4.30 (q, J = 6.9 Hz, 1H), 3.69 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 1.65 (s, 6H), 1.47 (d, J = 7.1 Hz, 3H).

[0270] Compound MA-89: 30.1 mg, colorless oil, ESI [M+H] + = 285.1

[0271] 1 H NMR (400 MHz, d6-DMSO) δ 8.20 (d, J = 1.2 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.01 - 6.96 (m, 3H), 4.30 (q, J = 6.9 Hz, 1H), 3.69 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 1.65 (s, 6H), 1.47 (d, J = 7.1 Hz, 3H).

[0272] Compound MA-114: 123.0 mg, white solid, ESI [M+H] + = 302.2

[0273] 1 H NMR (400 MHz, d6-DMSO) δ 8.20 (d, J = 1.2 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.01 - 6.96 (m, 3H), 4.30 (q, J = 6.9 Hz, 1H), 3.69 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 1.65 (s, 6H), 1.47 (d, J = 7.1 Hz, 3H).

[0274] Compound MA-125: 131.0 mg, colorless oil, ESI [M+H] + = 316.2

[0275] 1H NMR (400 MHz, d6-DMSO) δ 8.92 (d, J = 5.9 Hz, 1H), 8.17 (d, J = 1.1 Hz, 1H), 7.30 (s, 1H), 7.03 (d, J = 4.4 Hz, 3H), 4.31 (d, J = 7.1 Hz, 1H), 4.02 (d, J = 5.8 Hz, 2H), 3.69 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H), 1.50 (d, J = 7.1 Hz, 3H).

[0276] Compound MA-131 : 14 mg, colorless oil, ESI [M+H] + = 327.2

[0277] 1 H NMR (400 MHz, d6-DMSO) δ 9.67 (t, J = 1.3 Hz, 1H), 8.17 (d, J = 1.0 Hz, 1H), 7.19 (s, 1H), 7.05 - 6.89 (m, 3H), 4.34 (t, J = 6.2 Hz, 2H), 4.30 (q, J = 6.7 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 1.76 - 1.67 (m, 2H), 1.67 - 1.57 (m, 2H), 1.47 (d, J = 7.1 Hz, 3H).

[0278] Example 9, Preparation of the compound MA-88 of the present application

[0279] The preparation method of the compound MA-88 of the present application is similar to that of the compound MA-12 of the present application.

[0280] Compound MA-88: 240.0 mg, colorless oil, ESI [M+H] + = 301.2

[0281] 1 H NMR (400 MHz, d6-DMSO) δ 8.09 (d, J = 1.2 Hz, 1H), 7.13 (t, J = 1.1 Hz, 1H), 7.05 - 6.95 (m, 3H), 4.28 (q, J = 7.2 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 1.55 (s, 9H), 1.46 (d, J = 7.1 Hz, 3H).

[0282] Example 10, Preparation of the compounds MA-96, MA-97, MA-98, MA-104, MA-110 and MA-123 of the present application

[0283] 1, Preparation of the compound MA-104 of the present application

[0284] Compound MA-1.1 (640 mg, 3.0 mmol) and triethylamine (606 mg, 6.0 mmol) in CH2Cl2(20 mL) at 0 °C under ice-water bath, stirred at room temperature for 3 h, after TLC monitoring reaction was completed, the reaction was poured into ice-water, extracted with EtOAc (3 x 10 mL), combined organic phase, washed with saturated brine, dried over anhydrous Na2SO4, filtered, 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 / 10 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, the fraction of Rf= 0.4 ~ 0.5 was collected to give the compound of the application MA-104 (378.8 mg, yield 41.4%) as a white solid. ESI [M+H] + = 306.1

[0285] 1 H NMR (400 MHz, d6-DMSO) δ 8.15 (d, J = 0.9 Hz, 1H), 7.29 (s, 1H), 7.01 (t, J = 5.0 Hz, 3H), 4.28 (d, J = 6.9 Hz, 1H), 3.74 (t, J = 6.0 Hz, 2H), 3.61 - 3.50 (m, 2H), 2.25 (s, 3H), 2.21 (s, 3H), 1.47 (t, J = 6.2 Hz, 3H).

[0286] 2, Preparation of the compound of the application MA-96

[0287] Compound MA-1.1 (640 mg, 3.0 mmol) and triethylamine (606 mg, 6.0 mmol) in CH2Cl2(20 mL) at 0 °C under ice-water bath, stirred at room temperature for 3 h, after TLC monitoring reaction was completed, the reaction was poured into ice-water, extracted with EtOAc (3 x 10 mL), combined organic phase, washed with saturated brine, dried over anhydrous Na2SO4, filtered, 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 / 10 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, the fraction of Rf= 0.4 ~ 0.5 was collected to give the compound of the application MA-104 (378.8 mg, yield 41.4%) as a white solid. ESI [M+H] + = 270.2

[0288] 1H NMR (400 MHz, d6-DMSO) δ 8.05 (d, J = 1.2 Hz, 1H), 7.12 (t, J = 1.0 Hz, 1H), 7.02 - 6.95 (m, 3H), 4.57 (t, J = 9.1 Hz, 2H), 4.30 (q, J = 7.1 Hz, 1H), 3.90 (t, J = 9.1 Hz, 2H), 2.24 (s, 3H), 2.20 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H).

[0289] 3, The preparation method of the compound MA-97, MA-98, MA-110, MA-123 of the application is similar to the preparation of the compound MA-104 of the application

[0290] Compound MA-97: 60.6 mg, white solid, ESI [M+H] + = 284.2

[0291] 1 H NMR (400 MHz, d6-DMSO) δ 8.05 (d, J = 1.2 Hz, 1H), 7.12 (t, J = 1.0 Hz, 1H), 7.02 - 6.95 (m, 3H), 4.57 (t, J = 9.1 Hz, 2H), 4.30 (q, J = 7.1 Hz, 1H), 3.90 (t, J = 9.1 Hz, 2H), 2.24 (s, 3H), 2.20 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H).

[0292] Compound MA-98: 8.4 mg, white solid, ESI [M+H] + = 288.2

[0293] 1 H NMR (400 MHz, d6-DMSO) δ 8.05 (d, J = 1.2 Hz, 1H), 7.12 (t, J = 1.0 Hz, 1H), 7.02 - 6.95 (m, 3H), 4.57 (t, J = 9.1 Hz, 2H), 4.30 (q, J = 7.1 Hz, 1H), 3.90 (t, J = 9.1 Hz, 2H), 2.24 (s, 3H), 2.20 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H).

[0294] Compound MA-110: 212.9 mg, white solid, ESI [M+H] + = 300.2

[0295] 1H NMR (400 MHz, d6-DMSO) δ 8.11 (s, 1H), 7.72 (s, 1H), 7.35 (s, 1H), 7.03 - 6.93 (m, 3H), 4.26 (q, J = 7.1 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H), 1.36 (s, 9H).

[0296] Compound MA-123: 147.2 mg, white solid, ESI [M+H] + = 272.2

[0297] 1 H NMR (400 MHz, CDC13) δ 9.46 (s, 1H), 7.14 - 6.96 (m, 4H), 4.44 (d, J = 7.3 Hz, 1H), 3.47 (dd, J = 10.8, 5.2 Hz, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 1.64 (d, J = 7.1 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0298] Example 11, Preparation of the compound of the application MA-102

[0299] MA-1.1 (236 mg, 1.0 mmol) and sodium bicarbonate (168 mg, 2.0 mmol) were dissolved in dry THF (2 mL) at room temperature, stirred at room temperature for 30 minutes, suction filtered, and the filtrate was dried over anhydrous Na2S04. The filtrate was cooled to 0 °C with an ice water bath, sodium hydride (80 mg, 60% in mineral oil, 2.0 mmol) was added in portions, stirred for 10 minutes, and 2-(chloromethyl)-2-imidazoline (238 mg, 2.0 mmol) was added to the reaction system, and stirred for 30 minutes. After the reaction was completed by TLC monitoring, the reaction system was cooled to 0 °C with an ice water bath, saturated aqueous sodium chloride solution (20 mL) was added, extracted with EtOAc (3 x 10 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous Na2S04, 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 / 10 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the fraction with Rf = 0.4 ~ 0.5 was collected to obtain the compound of the application MA-102 (30.8 mg, yield 10.9%) as a white solid. ESI [M+H] + = 283.2.

[0300] 1H NMR (400 MHz, d6-DMSO) δ 7.49 (s, 1H), 7.02-6.96 (m, 3H), 6.73 (s, 1H), 4.63 (s, 2H), 4.23 (d, J = 7.1 Hz, 1H), 3.43 (s, 4H), 2.24 (s, 3H), 2.21 (s, 3H), 1.44 (d, J = 7.1 Hz, 3H).

[0301] Example 12, Preparation of the compounds MA-105, MA-127 and MA-128 of the present application

[0302] To a solution of compound MA-1.1 (236 mg, 1.0 mmol) and triethylamine (202 mg, 2.0 mmol) in CH2Cl2(10 mL) was added oxalyl chloride monoethyl ester (273 mg, 2.0 mmol) at 0 °C under ice-water bath, and stirred at room temperature overnight. After the reaction was completed by TLC monitoring, the reaction mixture was poured into ice-water, 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, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, the fraction with Rf = 0.4 ~ 0.5 was collected to give the compound MA-105 of the present application (42 mg, yield 14%) as a light yellow oil. ESI [M+H] + = 301.2

[0303] 1 H NMR (400 MHz, d6-DMSO) δ 7.40 (d, J = 2.2 Hz, 1H), 7.15 (s, 1H), 7.04 (d, J = 4.6 Hz, 1H), 7.01-6.96 (m, 1H), 6.95-6.88 (m, 1H), 4.51 (d, J = 7.1 Hz, 1H), 4.42-4.29 (m, 2H), 2.25 (d, J = 6.7 Hz, 3H), 2.22 (d, J = 4.7 Hz, 3H), 1.52 (dd, J = 16.8, 7.2 Hz, 3H), 1.29 (td, J = 7.1, 2.2 Hz, 3H).

[0304] The preparation method of the compounds MA-127 and MA-128 of the present application is similar to that of the compound MA-105 of the present application.

[0305] Compound MA-127: 89.9 mg, white solid, ESI [M+H] + = 243.1

[0306] 1H NMR (400 MHz, d6-DMSO) δ 8.29 (s, 1H), 7.29 (s, 1H), 7.03 - 6.94 (m, 3H), 4.29 (q, J = 7.2 Hz, 1H), 2.57 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H).

[0307] Compound MA-128: 86.5 mg, white solid, ESI [M+H] + = 272.2

[0308] 1 H NMR (400 MHz, CDC13) δ 8.03 (s, 1H), 7.14 - 6.97 (m, 3H), 6.78 (s, 1H), 4.43 (d, J = 6.4 Hz, 1H), 3.09 (s, 6H), 2.30 (s, 3H), 2.24 (s, 3H), 1.63 (d, J = 6.6 Hz, 3H).

[0309] Example 13, Preparation of Compounds MA-106 and MA-126 of the Invention

[0310] Compound MA-1.1 (472 mg, 2.0 mmol), bromocyanogen (421 mg, 4.0 mmol), triethylamine (303 mg, 3.0 mmol) and DMAP (61 mg, 0.5 mmol) were dissolved in CH2Cl2(20 mL) solution, stirred at room temperature overnight. After the reaction was monitored to be complete by TLC, the reaction system was poured into ice water, extracted with EtOAc (3 x 10 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous Na2S04, filtered under suction, concentrated under reduced pressure to obtain the crude product, which was purified by Prep-TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) quickly, and the fraction with Rf = 0.4-0.5 was collected to obtain Compounds MA-106 and MA-126 of the Invention.

[0311] Compound MA-106: 110 mg, white solid, ESI [M+H] + = 226.1

[0312] 1 H NMR (400 MHz, d6-DMSO) δ 8.42 (s, 1H), 7.11 (s, 1H), 7.07 - 6.98 (m, 2H), 6.67 (dd, J = 7.4, 1.0 Hz, 1H), 4.55 (q, J = 7.0 Hz, 1H), 2.27 (s, 6H), 1.49 (d, J = 7.0 Hz, 3H).

[0313] Compound MA-126: 68 mg, white solid, ESI [M+H] + = 226.1

[0314] 1 H NMR (400 MHz, d6-DMSO) δ 8.42 (d, J = 1.1 Hz, 1H), 7.62 (s, 1H), 7.03 - 6.95 (m, 2H), 6.95 - 6.87 (m, 1H), 4.31 (q, J = 7.0 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 1.45 (d, J = 7.1 Hz, 3H).

[0315] Example 14, Preparation of intermediate compounds in the application

[0316] 1, Preparation of intermediate compounds A-1~A-8 in the application

[0317] Under ice water bath 0 ℃, lithium aluminum hydride (4.56 g, 120.0 mmol) was added to the solution of cyclopropyl methyl ketone (5.0 g, 60.0 mmol) in dry THF (200 mL) in batches, and stirred for 4 hours. After the reaction was completed by TLC monitoring, excess sodium sulfate decahydrate was added to the reaction system in batches, stirred for 1 hour, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100~1 / 20), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20) monitoring, and the Rf=0.5~0.6 part was collected to obtain compound A-1 (4.16 g, yield 80.6%). ESI [M+H] + = 87.1. The preparation method of A-5 is similar to that of compound A-1.

[0318] Under ice water bath 0 ℃, ethyl magnesium bromide (215 mL, 215 mmol, 1 mol / L in THF) was slowly added to the solution of cyclopropyl methyl ketone (10.0 g, 143 mmol) in dry THF (100 mL) with a constant pressure dropping funnel, and slowly stirred to room temperature for 4 hours. After the reaction was completed by TLC monitoring, the reaction system was poured into ice water, extracted with EtOAc (3x100 mL), and the combined organic phase was 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 / 20) monitoring, and the Rf=0.5~0.6 part was collected to obtain compound A-2 (11.03 g, yield 77.2%). ESI [M+H] + = 101.1.

[0319] A-8 (1.78 g, yield 78.0%) was obtained. ESI [M+H] = 115.1. The preparation methods of A-3, A-6 and A-7 were similar to those of compounds A-2, A-4 and A-8. + = 115.1.

[0320] A-8 (1.78 g, yield 78.0%) was obtained. ESI [M+H] = 115.1. The preparation methods of A-3, A-6 and A-7 were similar to those of compounds A-2, A-4 and A-8. + = 115.1. The preparation methods of A-3, A-6 and A-7 were similar to those of compounds A-2, A-4 and A-8.

[0321] 2. Preparation of intermediate compounds B-1 to B-5

[0322] A-8 (1.78 g, yield 78.0%) was obtained. ESI [M+H] = 115.1. The preparation methods of A-3, A-6 and A-7 were similar to those of compounds A-2, A-4 and A-8.

[0323] 3. Preparation of intermediate compound C-1

[0324] To a solution of compound C-1 (244 mg, 1.0 mmol) in dry THF (10 mL) was added ethylmagnesium bromide (10 mL, 10.0 mmol, 1 mol / L in THF) dropwise at 0 °C under ice-water bath, and then the reaction mixture was allowed to warm to room temperature and stirred for 2 h. After the reaction was completed by TLC, the reaction mixture was poured into ice-water, and extracted with EtOAc (3 x 10 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 to give compound C-2 (180 mg, yield 73.2%) as colorless oil.

[0325] 4. Preparation of intermediate compound D

[0326] Compound D.3 was purchased or prepared by condensation reaction and Grignard reaction using carboxylic acid.

[0327] Compound D-A and D-B were purchased or prepared by chiral reduction / sodium borohydride reduction using compound D.3.

[0328] The preparation of intermediate compound D-A and D-B was according to the following experimental procedure:

[0329] To a solution of compound MA-531.1 (25 g, 147 mmol, 1.1 eq) and N, O-dimethylhydroxylamine hydrochloride (43 g, 439 mmol, 3.0 eq) in DMF (80 mL) was added HATU (84 g, 219 mmol, 1.5 eq) portionwise at 0 °C under ice-water bath, and then the reaction mixture was allowed to warm to room temperature and stirred overnight. After the reaction was completed by TLC, the reaction mixture was poured into ice-water, and extracted with EtOAc (3 x 100 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 / 20 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, to give compound M-531.2 (24 g, yield 76.6%) as yellow oil. ESI [M+H] = 214.1 +

[0330] ​Methylmagnesium bromide (75.1 mL, 225.4 mmol, 3.0 M in THF) was added slowly to a solution of M-531.2 (24 g, 112.7 mmol) in dry THF (100 mL) at 0 °C with a constant pressure dropping funnel. The reaction was stirred at room temperature for 4 h. After the reaction was completed by TLC, the reaction mixture was poured into ice water and extracted with EtOAc (3 x 100 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 / 100 ~ 1 / 20) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20) monitoring. The fractions with Rf = 0.4 ~ 0.5 were collected to give compound M-531.3 (16.1 g, 85.5% yield). ESI [M+H] + = 169.1

[0331] Chiral alcohol preparation Method A:

[0332] (-)-DIP-Chloride (11.55 g, 36.0 mmol) was added slowly to a solution of M-531.3 (5.04 g, 30.0 mmol) in dry THF (50 mL) at -20 °C. The reaction was stirred at -20 °C for 6 h. MeOH (12.6 mL) was added slowly to the reaction mixture at -20 °C and the stirring was continued for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was dissolved in ethyl acetate (16 mL) and ethanolamine (6.3 mL, 66.3 mmol) was added to the solution. The reaction was stirred at room temperature for 2 h. After the reaction was completed by TLC, the reaction mixture was poured into ice water and extracted with EtOAc (3 x 50 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 / 10) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring. The fractions with Rf = 0.4 ~ 0.5 were collected to give chiral compound M-531.4 (2.40 g, 47.1% yield). ESI [M+H] + = 171.1

[0333] Chiral alcohol preparation Method B:

[0334] M-531.3 (22 g, 130.5 mmol, 1.0 eq), formic acid (30 g, 651.7 mmol, 5.0 eq) and triethylamine (39.6 g, 391.3 mmol, 3.0 eq) were added to isopropanol (220 mL, 10 V) at room temperature, and stirred at 60 °C for 6 h. After the reaction was completed by TLC monitoring, it was concentrated under reduced pressure, extracted with EtOAc (3 x 50 mL), and 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 / 50 ~ 1 / 10) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the fraction with Rf = 0.4 ~ 0.5 was collected to give chiral compound M-531.4 (16.8 g, yield 75.4%).

[0335] Method C for racemic alcohol preparation:

[0336] M-531.3 (1.0 eq) was dissolved in methanol (10 V) at 0 °C in an ice water bath, and sodium borohydride (3.0 eq) was added to the above system, which was slowly warmed to room temperature and stirred for 2 h. After the reaction was completed by TLC monitoring, the reaction system was poured into ice water, extracted with EtOAc (3 x 10 V), and 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 / 50 ~ 1 / 10) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the fraction with Rf = 0.4 ~ 0.5 was collected to give compound 1-(2-chloro-3-methylphenyl)ethanol-1-ol.

[0337] 5. Preparation of intermediate compounds E-1 ~ E-3

[0338] Methyllithium (9.8 mL, 9.8 mmol, 1.0 M in THF) was slowly added to a solution of E.1 (420 mg, 4.88 mmol) in THF (100 mL) at 0 °C in an ice water bath, which was slowly warmed to room temperature and stirred for 2 h. After the reaction was completed by TLC monitoring, the reaction system was poured into ice water, extracted with EtOAc (3 x 10 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product E-1, which was used directly in the next step without purification.

[0339] To a solution of E.2 (1.0 eq) in dry THF (10 V) was added ethyl magnesium bromide (2.0 eq) slowly dropwise at 0 °C under ice-water bath, and then the reaction mixture was allowed to warm up to room temperature and stirred for 2 h. After the reaction was completed by TLC, the reaction mixture was poured into ice-water and extracted with EtOAc (3 x 10 V), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product E-2 / E3, which was used in the next step without further purification.

[0340] 6. Preparation of intermediate compounds H-1 ~ H-3

[0341] H-1.1 (3.0 g, 23.8 mmol), ethanol (30 mL) and methane sulfonic acid (6 mL) were added into a 200 mL sealed tube at room temperature, and the reaction mixture was heated at 120 °C for 10 h. After the reaction mixture was concentrated, the pH was adjusted to 8 with saturated NaHCO3 aqueous solution, and the mixture was extracted with ethyl acetate (3 x 150 mL), washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give compound H-1.2 (3.0 g, 81% yield) as a gray solid.

[0342] To a solution of intermediate compound H-1.2 (250 mg, 1.61 mmol) in 40% HBF4 was added a solution of NaNO2 (117 mg, 1.69 mmol) in water (0.15 mL) at -10 °C under ice-salt bath, and the reaction mixture was irradiated under a mercury lamp (302 nm) for 2 h. After the reaction was completed, the pH was adjusted to 7 with 1 N NaOH aqueous solution under ice-water bath, and the aqueous layer was extracted with ethyl acetate (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, which was separated by column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1) and TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) to give compound H-1 (100 mg, 39% yield).

[0343] H-2.1 (10 g, 64.45 mmol) was dissolved in 40% HBF4 in an ice-salt bath at -10 °C, and an aqueous solution of NaNO2(20.55 g, 297.9 mmol) in 25.5 mL of water was added. The reaction was irradiated by a mercury lamp (302 nm) for 10 days. After the reaction was completed, the pH was adjusted to 7 with an aqueous solution of 1 N NaOH in an ice-water bath. The aqueous layer was extracted with ethyl acetate (5 x 100 mL), and the combined organic phase was washed with saturated brine, dried, filtered, and concentrated under reduced pressure to obtain the crude product. The product was separated by column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1) and TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) monitoring. The fraction with Rf = 0.4-0.5 was collected to obtain compound H-2 (1.6 g, yield 15.7%) as a white solid.

[0344] Compound H-3.1 (4.89 g, 22.4 mmol), water (0.8 mL), and formamide (10.1 g, 224 mmol) were sequentially added to a 100 mL sealed tube at room temperature, and the reaction was performed at 150 °C for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH 8 with a dilute aqueous NaHCO3solution, extracted with ethyl acetate (3 x 150 mL), washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound H-3 (1.9 g, yield 41%) as a white solid. ESI [M+H] = 209.1 +

[0345] Example 15, Preparation of a compound of the present application

[0346] ​Ethyl 4-fluoro-1H-imidazole-5-carboxylate (875.5 mg, 5.5 mmol) was dissolved in dry THF (10 mL) at room temperature, the temperature was reduced to -30 °C with dry ice acetone bath, (S)-1-Phenylethan-1-ol (806.3 mg, 6.6 mmol) and PPh3(2.16 g, 8.25 mmol) were added into the reaction system in turn, DEAD (1.44 g, 8.27 mmol) was slowly added into the reaction system with a syringe, stirred at room temperature overnight. After the reaction was monitored to be complete by TLC, ice water was added into the reaction system, extracted with EtOAc (3 x 10 mL), the organic phases were combined, 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 / 5 ~ 1 / 1), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) monitoring, the fraction with Rf= 0.5 ~ 0.6 was collected to obtain compound M-365 (1.2 g, yield 83.2%) as colorless oil. ESI [M+H] + = 262.9.

[0347] 1 H NMR (400 MHz, d6-DMSO) δ 8.13 (d, J = 1.7 Hz, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.29 (dd, J = 8.5, 6.0 Hz, 1H), 7.20 (d, J = 7.3 Hz, 2H), 6.17 (q, J = 7.2 Hz, 1H), 4.28 - 4.10 (m, 2H), 1.85 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0348] The target compound of the application was prepared according to the preparation method of M-365:

[0349] Compound M-1RS: 89.3 mg, colorless oil, ESI [M+H] + = 209.2.

[0350] 1 H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.78 (s, 1H), 4.50 - 4.41 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.54 (d, J = 6.7 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.30 - 1.23 (m, 1H), 0.81 - 0.72 (m, 1H), 0.63 - 0.55 (m, 1H), 0.48 - 0.41 (m, 1H), 0.39 - 0.31 (m, 1H).

[0351] Compound M-1RS HCI: 352.23 mg, white solid, ESI [M+H] + = 209.2.

[0352] 1 H NMR (400 MHz, d6-DMSO) δ 9.35 (s, 1H), 8.30 (s, 1H), 4.50 - 4.42 (m, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.54 (d, J = 6.7 Hz, 3H), 1.50 - 1.42 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 0.73 - 0.67 (m, 1H), 0.54 - 0.43 (m, 2H), 0.39 - 0.31 (m, 1H).

[0353] Compound M-21: 164 mg, colorless oil, ESI [M+H] + = 233.1.

[0354] Compound M-22: 112 mg, colorless oil, ESI [M+H] + = 223.2.

[0355] 1 H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.70 (d, J = 0.8 Hz, 1H), 4.37 - 4.24 (m, 3H), 2.03 (p, J = 7.4 Hz, 2H), 1.49 - 1.31 (m, 4H), 0.90 (t, J = 7.4 Hz, 3H), 0.86 - 0.76 (m, 1H), 0.59 - 0.43 (m, 2H), 0.34 - 0.21 (m, 1H).

[0356] Compound M-25: 41 mg, colorless oil, ESI [M+H] + = 237.1.

[0357] 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.95 (s, 1H), 6.34 (dd, J = 17.4, 10.9 Hz, 1H), 5.50 - 5.36 (m, 2H), 4.98 (d, J = 7.6 Hz, 2H), 4.81 (d, J = 7.8 Hz, 2H), 4.46 (s, 1H), 1.58 (d, J = 6.6 Hz, 3H), 1.30 (s, 1H), 0.84 (s, 1H), 0.68 (s, 1H), 0.56 - 0.44 (m, 1H), 0.39 (s, 1H).

[0358] Compound M-26: 123 mg, colorless oil, ESI [M+H] + = 233.1.

[0359] 1 H NMR (400 MHz, CDC13) δ 8.10 (s, 1H), 7.78 (s, 1H), 5.98 (dd, J = 5.5, 2.4 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.89 (d, J = 2.3 Hz, 3H), 1.44 (d, J = 2.7 Hz, 1H), 1.41 (t, J = 7.1 Hz, 3H), 0.69 - 0.62 (m, 2H), 0.62 - 0.54 (m, 2H).

[0360] Compound M-27: 64 mg, colorless oil, ESI [M+H] + = 251.2.

[0361] 1 H NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.68 (d, J = 0.7 Hz, 1H), 4.45 (d, J = 10.7 Hz, 1H), 4.37 - 4.25 (m, 2H), 1.63 - 1.50 (m, 1H), 1.37 (t, J = 7.1 Hz, 3H), 1.03 (s, 9H), 1.01 - 0.89 (m, 2H), 0.65 - 0.56 (m, 1H), 0.56 - 0.46 (m, 1H).

[0362] Compound M-28: 216 mg, white solid, ESI [M+H] + = 235.1.

[0363] 1 H NMR (400 MHz, CDC13) δ 8.09 (s, 1H), 7.80 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.19 (t, J = 8.6 Hz, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.36 - 1.27 (m, 2H), 0.82 - 0.67 (m, 2H), 0.65 - 0.46 (m, 4H), 0.46 - 0.33 (m, 2H).

[0364] Compound M-29: 164 mg, colorless oil, ESI [M+H] + = 223.1.

[0365] 1H NMR (400 MHz, CD3OD) δ 7.99 (s, 1H), 7.68 (d, J = 0.7 Hz, 1H), 5.25 - 5.13 (m, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.93 - 2.77 (m, 1H), 2.27 - 2.10 (m, 1H), 2.00 - 1.78 (m, 4H), 1.75 - 1.61 (m, 1H), 1.45 - 1.33 (m, 6H).

[0366] Compound M-30: 54 mg, colorless oil, ESI [M+H] + = 225.1.

[0367] 1 H NMR (400 MHz, d6-DMSO) δ 8.11 (s, 1H), 7.66 (d, J = 0.8 Hz, 1H), 5.42 (dq, J = 10.1, 6.7 Hz, 1H), 4.72 (dd, J = 7.9, 6.4 Hz, 1H), 4.53 (dd, J = 7.7, 6.2 Hz, 1H), 4.39 (t, J = 6.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.17 (t, J = 6.2 Hz, 1H), 3.67 - 3.52 (m, 1H), 1.38 (d, J = 6.7 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0368] Compound M-33: 42 mg, white solid, ESI [M+H] + = 223.1.

[0369] 1 H NMR (400 MHz, d6-DMSO) δ 7.87 (s, 1H), 7.65 (s, 1H), 5.42 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.23 - 2.10 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.07 - 0.98 (m, 2H), 0.98 - 0.86 (m, 2H).

[0370] Compound M-34: 131 mg, colorless oil, ESI [M+H] + = 269.1.

[0371] 1H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.69 (d, J = 0.9 Hz, 1H), 4.45 (d, J = 7.5 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.16 (s, 3H), 3.16 (s, 3H), 2.61 - 2.48 (m, 1H), 2.32 - 2.19 (m, 2H), 1.94 - 1.84 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H).

[0372] Compound M-35: 190 mg, light yellow oil, ESI [M+H] + = 249.2.

[0373] 1 H NMR (400 MHz, d6-DMSO) δ 8.17 (s, 1H), 7.62 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.06 - 2.90 (m, 1H), 2.17 - 1.97 (m, 1H), 1.94 - 1.66 (m, 4H), 1.66 - 1.53 (m, 1H), 1.38 - 1.23 (m, 5H), 0.71 - 0.61 (m, 1H), 0.48 - 0.39 (m, 1H), 0.39 - 0.27 (m, 1H), 0.13 - 0.03 (m, 1H).

[0374] Compound M-42: 45 mg, white solid, ESI [M+H] + = 223.1.

[0375] 1 H NMR (400 MHz, d6-DMSO) δ 8.21 (d, J = 0.5 Hz, 1H), 7.76 (d, J = 0.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.80 - 1.69 (m, 1H), 1.52 (s, 6H), 1.30 (t, J = 7.1 Hz, 3H), 0.64 - 0.55 (m, 2H), 0.54 - 0.47 (m, 1H).

[0376] Compound M-44: 55 mg, colorless oil, ESI [M+H] + = 251.2.

[0377] 1H NMR (400 MHz, d6-DMSO) δ 8.03 (s, 1H), 7.64 (s, 1H), 4.90 (m, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.99 (m, 1H), 2.07 (m, 2H), 1.76 (m, 4H), 1.48 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H), 0.69 (d, J = 6.7 Hz, 3H).

[0378] Compound M-45: 173.3 mg, colorless oil, ESI [M+H] + = 237.2.

[0379] 1 H NMR (400 MHz, d6-DMSO) δ 8.08 (s, 1H), 7.64 (s, 1H), 4.94 (m, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.84 (m, 1H), 2.09 (m, 1H), 1.76 (m, 6H), 1.54 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.67 (t, J = 7.4 Hz, 3H).

[0380] Compound M-46: 104.7 mg, white solid, ESI [M+H] + = 251.2.

[0381] 1 H NMR (400 MHz, d6-DMSO) δ 8.17 (s, 1H), 7.64 (s, 1H), 4.83 (m, 1H), 4.26 (q, J = 7.1 Hz, 2H), 2.33 (m, 1H), 1.86 (m, 3H), 1.54 (m, 4H), 1.25 (m, 5H), 1.01 (m, 1H), 0.64 (t, J = 7.3 Hz, 3H).

[0382] Compound M-51: 114.1 mg, colorless oil, ESI [M+H] + = 235.2.

[0383] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.68 (d, J = 0.9 Hz, 1H), 4.87 (s, 1H), 4.58 (m, 2H), 4.22 (m, 2H), 1.71 (s, 3H), 1.55 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.83 (m, 1H), 0.56 (m, 2H), 0.25 (m, 1H).

[0384] Compound M-52: 399.6 mg, colorless oil, ESI [M+H] + = 249.2.

[0385] 1 H NMR (400 MHz, d6-DMSO) δ 8.02 (s, 1H), 7.66 (d, J = 0.8 Hz, 1H), 5.47 (d, J = 11.3 Hz, 1H), 4.92 (s, 1H), 4.86 (s, 1H), 4.27 (m, 2H), 3.15 (m, 1H), 2.10 (m, 1H), 1.86 (m, 4H), 1.59 (m, 1H), 1.51 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0386] Compound M-53: 272 mg, colorless oil, ESI [M+H] + = 271.1.

[0387] 1 H NMR (400 MHz, d6-DMSO) δ 8.50 (s, 1H), 7.69 (s, 1H), 7.41 - 7.31 (m, 2H), 7.31 - 7.24 (m, 1H), 7.19 (d, J = 7.2 Hz, 2H), 5.26 (d, J = 10.2 Hz, 1H), 4.25 - 4.00 (m, 2H), 1.92 - 1.70 (m, 1H), 0.87 - 0.57 (m, 3H), 0.46 - 0.28 (m, 1H).

[0388] Compound M-66: 223.1 mg, colorless oil, ESI [M+H] + = 223.1.

[0389] 1 H NMR (400 MHz, d6-DMSO) δ 8.09 (s, 1H), 7.68 (d, J = 0.9 Hz, 1H), 4.49 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.15 - 3.02 (m, 2H), 2.97 - 2.80 (m, 3H), 1.31 (t, J = 7.1 Hz, 3H).

[0390] Compound M-W: 120 mg, colorless oil, ESI [M+H] + = 297.2.

[0391] 1H NMR (400 MHz, d6-DMSO) d 8.00 (s, 1H), 7.64 (s, 1H), 4.34 (d, J = 7.5 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.38 - 3.32 (m, 4H), 2.48 - 2.37 (m, 1H), 2.22 - 2.11 (m, 2H), 1.90 - 1.77 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.16 - 1.05 (m, 6H).

[0392] Compound M-120: 33 mg, white solid, ESI [M+H] + = 305.1.

[0393] 1 H NMR (400 MHz, d6-DMSO) d 8.34 (s, 1H), 7.68 (s, 1H), 7.53 - 7.41 (m, 1H), 7.34 (s, 2H), 7.23 - 7.10 (m, 1H), 5.80 (d, J = 9.3 Hz, 1H), 4.25 - 4.07 (m, 2H), 1.79 - 1.64 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H), 0.86 - 0.72 (m, 2H), 0.69 - 0.60 (m, 1H), 0.47 (dd, J = 9.0, 4.1 Hz, 1H).

[0394] Compound M-121: 108 mg, colorless oil, ESI [M+H] + = 305.1.

[0395] 1 H NMR (400 MHz, d6-DMSO) d 8.53 (s, 1H), 7.71 (d, J = 0.8 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.27 (s, 1H), 7.13 (d, J = 7.1 Hz, 1H), 5.21 (d, J = 10.3 Hz, 1H), 4.25 - 4.05 (m, 2H), 1.93 - 1.76 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H), 0.78 (dd, J = 13.3, 5.7 Hz, 1H), 0.70 (s, 2H), 0.41 (dd, J = 11.7, 6.5 Hz, 1H).

[0396] Compound M-122: 130 mg, colorless oil, ESI [M+H] + = 305.1.

[0397] 1H NMR (400 MHz, d6-DMSO) δ 8.50 (s, 1H), 7.70 (s, 1H), 7.41 (t, J = 5.6 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 5.23 (d, J = 10.2 Hz, 1H), 4.25 - 4.06 (m, 2H), 1.81 (dd, J = 6.2, 3.9 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H), 0.81 - 0.73 (m, 1H), 0.73 - 0.61 (m, 2H), 0.40 (dd, J = 9.2, 4.2 Hz, 1H).

[0398] Compound M-123: 89 mg, white solid, ESI [M+H] + = 285.1.

[0399] 1 H NMR (400 MHz, d6-DMSO) δ 8.49 (s, 1H), 7.69 (s, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H), 6.98 (d, J = 7.8 Hz, 1H), 5.23 (d, J = 10.2 Hz, 1H), 4.26 - 4.03 (m, 2H), 2.29 (s, 3H), 1.89 - 1.73 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H), 0.76 (dt, J = 8.5, 3.6 Hz, 1H), 0.68 (dt, J = 8.9, 4.8 Hz, 1H), 0.61 (tt, J = 9.5, 4.9 Hz, 1H), 0.38 (dt, J = 9.5, 4.7 Hz, 1H).

[0400] Compound M-124: 84 mg, colorless oil, ESI [M+H] + = 285.1.

[0401] 1 H NMR (400 MHz, d6-DMSO) δ 8.47 (s, 1H), 7.68 (s, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 5.23 (d, J = 10.1 Hz, 1H), 4.24 - 4.08 (m, 2H), 2.28 (s, 3H), 1.86 - 1.74 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H), 0.75 (dd, J = 9.1, 4.6 Hz, 1H), 0.68 (dd, J = 8.0, 4.5 Hz, 1H), 0.58 (dd, J = 9.4, 4.7 Hz, 1H), 0.37 (dd, J = 9.4, 4.6 Hz, 1H).

[0402] Compound M-125: 56 mg, colorless oil, ESI [M+H] + = 331.2.

[0403] 1 H NMR (400 MHz, d6-DMSO) d 8.25 (s, 1H), 7.64 (d, J = 0.7 Hz, 1H), 7.10 - 6.97 (m, 2H), 6.80 (dd, J = 7.5, 1.5 Hz, 1H), 5.66 (d, J = 9.9 Hz, 1H), 4.28 - 4.14 (m, 2H), 3.81 (s, 3H), 3.62 (s, 3H), 1.74 (qt, J = 9.7, 4.9 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H), 0.68 (d, J = 25.1 Hz, 2H), 0.55 - 0.40 (m, 2H).

[0404] Compound M-126: 94 mg, colorless oil, ESI [M+H] + = 331.2.

[0405] 1 H NMR (400 MHz, d6-DMSO) d 8.49 (s, 1H), 7.67 (s, 1H), 6.90 (dd, J = 6.7, 5.3 Hz, 2H), 6.71 (dd, J = 8.3, 1.9 Hz, 1H), 5.22 (d, J = 10.1 Hz, 1H), 4.19 (qd, J = 7.1, 4.3 Hz, 2H), 3.73 (d, J = 2.8 Hz, 6H), 1.93 - 1.81 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H), 0.81 - 0.71 (m, 1H), 0.67 (dd, J = 7.9, 4.6 Hz, 1H), 0.58 (dd, J = 9.4, 4.7 Hz, 1H), 0.36 (dd, J = 9.3, 4.6 Hz, 1H).

[0406] Compound M-130: 200 mg, colorless syrup, ESI [M+H] + = 338.2.

[0407] 1H NMR (400 MHz, d6-DMSO) δ 8.16 (s, 1H), 7.69 (s, 1H), 5.34 - 4.98 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.00 (t, J = 8.3 Hz, 1H), 3.81 - 3.62 (m, 2H), 3.45 - 3.36 (m, 1H), 3.27 - 3.05 (m, 1H), 1.89 - 1.70 (m, 2H), 1.38 (s, 9H), 1.32 (t, J = 7.1 Hz, 3H), 0.67 (t, J = 7.3 Hz, 3H).

[0408] Compound M-131: 111 mg, colorless syrup, ESI [M+H] + = 238.1.

[0409] 1 H NMR (400 MHz, d6-DMSO) δ 8.77 (s, 1H), 8.18 (s, 1H), 7.71 (s, 1H), 5.32 - 5.05 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.13 - 3.97 (m, 1H), 3.94 - 3.73 (m, 2H), 3.70 - 3.42 (m, 2H), 1.88 - 1.62 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.66 (t, J = 7.3 Hz, 3H).

[0410] Compound M-132: 100 mg, colorless syrup, ESI [M+H] + = 352.2.

[0411] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (d, J = 9.3 Hz, 1H), 7.67 (s, 1H), 5.17 - 4.83 (m, 1H), 4.32 - 4.22 (m, 2H), 3.60 - 3.36 (m, 1H), 3.31 - 3.17 (m, 1H), 3.17 - 2.90 (m, 1H), 2.84 - 2.62 (m, 1H), 2.01 - 1.74 (m, 2H), 1.73 - 1.59 (m, 1H), 1.47 - 1.27 (m, 14H), 0.71 - 0.54 (m, 3H).

[0412] Compound M-178A: 49 mg, colorless oil, ESI [M+H] + = 235.2.

[0413] 1H NMR (400 MHz, d6-DMSO) d 7.92 (s, 1H), 7.65 (s, 1H), 4.81 (s, 2H), 4.62 - 4.47 (m, 1H), 4.30 - 4.17 (m, 2H), 1.62 (s, 3H), 1.60 - 1.42 (m, 1H), 1.32 - 1.19 (m, 3H), 0.76 - 0.67 (m, 2H), 0.29 - 0.17 (m, 2H).

[0414] Compound M-346: 45 mg, colorless oil, ESI [M+H] + = 301.1.

[0415] 1 H NMR (400 MHz, d6-DMSO) d 8.27 (s, 1H), 7.62 (s, 1H), 7.28 (t, J = 6.9 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 5.64 (d, J = 9.9 Hz, 1H), 4.17 (q, J = 6.9 Hz, 2H), 3.74 (s, 3H), 1.48 (s, 1H), 1.21 (s, 3H), 0.69 (d, J = 16.4 Hz, 2H), 0.57 - 0.36 (m, 2H).

[0416] Compound M-347: 84 mg, colorless oil, ESI [M+H] + = 301.1.

[0417] 1 H NMR (400 MHz, d6-DMSO) d 8.50 (s, 1H), 7.69 (d, J = 0.8 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 6.93 - 6.84 (m, 1H), 6.75 (t, J = 4.3 Hz, 2H), 5.22 (d, J = 10.2 Hz, 1H), 4.22 - 4.09 (m, 2H), 3.74 (s, 3H), 1.83 (td, J = 12.8, 6.4 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H), 0.82 - 0.73 (m, 1H), 0.72 - 0.58 (m, 2H), 0.39 (dt, J = 8.9, 4.3 Hz, 1H).

[0418] Compound M-348: 63 mg, colorless oil, ESI [M+H] + = 301.1.

[0419] 1H NMR (400 MHz, d6-DMSO) δ 8.46 (s, 1H), 7.67 (s, 1H), 7.15 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.23 (d, J = 10.2 Hz, 1H), 4.17 (s, 2H), 3.74 (s, 3H), 1.81 (s, 1H), 1.22 (t, J = 7.1 Hz, 3H), 0.75 (s, 1H), 0.66 (d, J = 4.7 Hz, 1H), 0.55 (dd, J = 9.3, 4.4 Hz, 1H), 0.42 - 0.28 (m, 1H).

[0420] Compound M-350: 108 mg, yellow oil, ESI [M+H] + = 259.1.

[0421] 1 H NMR (400 MHz, d6-DMSO) δ 8.13 (s, 1H), 7.72 (s, 1H), 7.24 - 7.11 (m, 3H), 6.83 - 6.70 (m, 1H), 6.34 (q, J = 7.0 Hz, 1H), 4.28 - 4.09 (m, 2H), 2.34 (s, 3H), 1.77 (d, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H).

[0422] Compound M-352: 115 mg, colorless oil, ESI [M+H] + = 263.1.

[0423] 1 H NMR (400 MHz, d6-DMSO) δ 8.27 (s, 1H), 7.72 (d, J = 0.9 Hz, 1H), 7.40 - 7.32 (m, 1H), 7.28 - 7.13 (m, 2H), 6.94 - 6.84 (m, 1H), 6.43 (q, J = 7.2 Hz, 1H), 4.25 - 4.09 (m, 2H), 1.85 (d, J = 7.2 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H).

[0424] Compound M-354: 190 mg, colorless oil, ESI [M+H] + = 279.1.

[0425] 1H NMR (400 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.75 (d, J = 0.8 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.38 - 7.27 (m, 2H), 6.80 - 6.74 (m, 1H), 6.42 (q, J = 7.1 Hz, 1H), 4.26 - 4.03 (m, 2H), 1.84 (d, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H).

[0426] Compound M-356: 101 mg, yellow oil, ESI [M+H] + = 259.1.

[0427] 1 H NMR (400 MHz, d6-DMSO) δ 8.29 (s, 1H), 7.69 (s, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.22 (q, J = 7.1 Hz, 1H), 4.28 - 4.13 (m, 2H), 2.28 (s, 3H), 1.84 (d, J = 7.2 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H).

[0428] Compound M-358: 104 mg, yellow oil, ESI [M+H] + = 279.1.

[0429] 1 H NMR (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 7.72 (s, 1H), 7.43 - 7.32 (m, 2H), 7.26 (s, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.24 (q, J = 7.2 Hz, 1H), 4.29 - 4.12 (m, 2H), 1.87 (d, J = 7.2 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H).

[0430] Compound M-363: 106 mg, white solid, ESI [M+H] + = 253.2.

[0431] 1H NMR (400 MHz, d6-DMSO) δ 8.08 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.72 (t, J = 8.8 Hz, 1H), 1.58 - 1.43 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.72 - 0.60 (m, 2H), 0.54 - 0.37 (m, 4H), 0.30 - 0.17 (m, 2H).

[0432] Compound M-366: 262 mg, white solid, ESI [M+H] + = 235.0.

[0433] 1 H NMR (400 MHz, d6-DMSO) δ 7.85 (d, J = 0.8 Hz, 1H), 7.14 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.03 (t, J = 9.1 Hz, 1H), 1.50 - 1.38 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.70 - 0.60 (m, 2H), 0.54 - 0.44 (m, 2H), 0.42 - 0.31 (m, 2H), 0.23 - 0.11 (m, 2H).

[0434] Compound M-371: 172 mg, colorless oil, ESI [M+H] + = 245.0.

[0435] 1 H NMR (400 MHz, d6-DMSO) δ 7.78 (d, J = 1.0 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.32 - 7.26 (m, 1H), 7.26 - 7.20 (m, 2H), 7.17 (d, J = 0.8 Hz, 1H), 6.49 (q, J = 7.1 Hz, 1H), 4.37 - 4.17 (m, 2H), 1.82 (d, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0436] Compound M-377: 227 mg, colorless oil, ESI [M+H] + = 253.0.

[0437] 1H NMR (400 MHz, d6-DMSO) d 8.08 (d, J = 1.8 Hz, 1H), 4.89 (s, 1H), 4.57 (s, 1H), 4.49 (d, J = 10.4 Hz, 1H), 4.31 - 4.14 (m, 2H), 1.73 (s, 3H), 1.58 - 1.44 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 0.89 - 0.79 (m, 1H), 0.65 - 0.51 (m, 2H), 0.34 - 0.22 (m, 1H).

[0438] Compound M-378: 143 mg, colorless oil, ESI [M+H] + = 263.0.

[0439] 1 H NMR (400 MHz, d6-DMSO) d 7.50 (d, J = 1.9 Hz, 1H), 7.41 (dd, J = 10.1, 4.6 Hz, 2H), 7.37 - 7.30 (m, 1H), 7.26 (d, J = 7.4 Hz, 2H), 6.46 (q, J = 7.2 Hz, 1H), 4.35 - 4.21 (m, 2H), 1.87 (dd, J = 7.2, 2.6 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0440] Compound M-380: 77 mg, colorless oil, ESI [M+H] + = 263.1.

[0441] 1 H NMR (400 MHz, d6-DMSO) d 8.31 (s, 1H), 7.69 (d, J = 0.8 Hz, 1H), 7.33 - 7.21 (m, 2H), 7.21 - 7.12 (m, 2H), 6.25 (q, J = 7.2 Hz, 1H), 4.26 - 4.15 (m, 2H), 1.85 (d, J = 7.2 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H).

[0442] Compound M-381 : 471 mg, colorless oil, ESI [M+H] + = 277.0.

[0443] 1H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H), 7.71 (d, J = 0.6 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.43 (q, J = 7.1 Hz, 1H), 4.27 - 4.08 (m, 2H), 2.25 (d, J = 1.7 Hz, 3H), 1.83 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0444] Compound M-382: 291 mg, white solid, ESI [M+H] + = 277.0.

[0445] 1 H NMR (400 MHz, d6-DMSO) δ 8.25 (s, 1H), 7.71 (d, J = 0.7 Hz, 1H), 7.19 - 7.04 (m, 2H), 6.73 (d, J = 6.0 Hz, 1H), 6.40 (q, J = 7.1 Hz, 1H), 4.25 - 4.12 (m, 2H), 2.23 (s, 3H), 1.83 (d, J = 7.2 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H).

[0446] Compound M-383: 72 mg, white solid, ESI [M+H] + = 280.9.

[0447] 1 H NMR (400 MHz, d6-DMSO) δ 8.10 (d, J = 1.8 Hz, 1H), 7.43 - 7.32 (m, 1H), 7.28 - 7.15 (m, 2H), 6.98 - 6.89 (m, 1H), 6.34 (q, J = 7.1 Hz, 1H), 4.22 - 4.11 (m, 2H), 1.84 (d, J = 7.2 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H).

[0448] Compound M-384: 69 mg, colorless oil, ESI [M+H] + = 296.9.

[0449] 1H NMR (400 MHz, d6-DMSO) d 8.04 (d, J = 1.6 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.39 - 7.30 (m, 2H), 6.85 - 6.77 (m, 1H), 6.34 (q, J = 7.0 Hz, 1H), 4.24 - 4.06 (m, 2H), 1.82 (d, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H).

[0450] Compound M-385: 59 mg, colorless oil, ESI [M+H] + = 276.9.

[0451] 1 H NMR (400 MHz, d6-DMSO) d 8.04 (d, J = 1.6 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.39 - 7.30 (m, 2H), 6.85 - 6.77 (m, 1H), 6.34 (q, J = 7.0 Hz, 1H), 4.24 - 4.06 (m, 2H), 1.82 (d, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H).

[0452] Compound M-386: 43 mg, colorless oil, ESI [M+H] + = 280.9.

[0453] 1 H NMR (400 MHz, d6-DMSO) d 8.04 (d, J = 1.6 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.39 - 7.30 (m, 2H), 6.85 - 6.77 (m, 1H), 6.34 (q, J = 7.0 Hz, 1H), 4.24 - 4.06 (m, 2H), 1.82 (d, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H).

[0454] Compound M-387: 49 mg, colorless oil, ESI [M+H] + = 286.1.

[0455] 1H NMR (400 MHz, d6-DMSO) δ 7.69 (s, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.22 (d, J = 7.7 Hz, 2H), 6.40 (q, J = 7.3 Hz, 1H), 4.23 (dt, J = 13.4, 6.7 Hz, 2H), 1.88 (d, J = 7.2 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H).

[0456] Compound M-404: 82 mg, colorless oil, ESI [M+H] + = 253.0.

[0457] 1 H NMR (400 MHz, d6-DMSO) δ 7.70 (s, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.97 (t, J = 9.4 Hz, 1H), 1.49 - 1.36 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.74 - 0.63 (m, 2H), 0.60 - 0.41 (m, 4H), 0.30 - 0.16 (m, 2H).

[0458] Compound M-405: 71 mg, colorless oil, ESI [M+H] + = 253.0.

[0459] 1 H NMR (400 MHz, d6-DMSO) δ 7.71 (s, 1H), 5.02 (s, 1H), 4.92 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.96 (d, J = 10.3 Hz, 1H), 1.72 (s, 3H), 1.60 - 1.47 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.86 - 0.75 (m, 1H), 0.66 - 0.57 (m, 1H), 0.57 - 0.48 (m, 1H), 0.39 - 0.26 (m, 1H).

[0460] Compound M-412: 162 mg, colorless oil, ESI [M+H] + = 340.8.

[0461] 1H NMR (400 MHz, d6-DMSO) δ 8.26 (s, 1H), 7.46 - 7.39 (m, 1H), 7.32 - 7.21 (m, 3H), 5.80 (q, J = 7.0 Hz, 1H), 4.32 - 4.18 (m, 2H), 1.85 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0462] Compound M-413: 135 mg, colorless oil, ESI [M+H] + = 354.8.

[0463] 1 H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H), 7.34 - 7.25 (m, 1H), 7.19 - 7.11 (m, 1H), 7.10 - 7.03 (m, 1H), 5.78 (q, J = 7.0 Hz, 1H), 4.29 - 4.20 (m, 2H), 2.25 (d, J = 1.8 Hz, 3H), 1.83 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0464] Compound M-414: 306 mg, colorless oil, ESI [M+H] + = 346.8.

[0465] 1 H NMR (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 7.59 - 7.49 (m, 1H), 7.42 - 7.34 (m, 2H), 6.99 - 6.90 (m, 1H), 5.99 (q, J = 6.9 Hz, 1H), 4.37 - 4.20 (m, 2H), 1.90 (d, J = 6.9 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0466] Compound M-415: 273 mg, light yellow solid, ESI [M+H] + = 344.9.

[0467] 1 H NMR (400 MHz, d6-DMSO) δ 8.34 (s, 1H), 7.29 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 5.92 (q, J = 7.0 Hz, 1H), 4.40 - 4.12 (m, 2H), 2.25 (d, J = 1.9 Hz, 3H), 1.90 (d, J = 7.0 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0468] Compound M-416: 322 mg, light yellow solid, ESI [M+H] + = 330.9.

[0469] 1 H NMR (400 MHz, d6-DMSO) δ 8.39 (s, 1H), 7.48 - 7.37 (m, 1H), 7.31 - 7.21 (m, 2H), 7.20 - 7.10 (m, 1H), 5.95 (q, J = 7.0 Hz, 1H), 4.37 - 4.22 (m, 2H), 1.92 (d, J = 7.0 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0470] Compound M-417: 205 mg, colorless oil, ESI [M+H] + = 360.8.

[0471] 1 H NMR (400 MHz, d6-DMSO) δ 8.35 (s, 1H), 7.37 (d, J = 7.1 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.03 (q, J = 6.8 Hz, 1H), 4.38 - 4.17 (m, 2H), 2.39 (s, 3H), 1.89 (d, J = 6.9 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0472] Compound M-418: 205 mg, white solid, ESI [M+H] + = 295.0.

[0473] 1 H NMR (400 MHz, d6-DMSO) δ 7.81 (s, 1H), 7.34 - 7.27 (m, 1H), 7.23 - 7.12 (m, 2H), 5.75 (q, J = 7.1 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.25 (d, J = 1.9 Hz, 3H), 1.86 (d, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0474] Compound M-419: 84 mg, white solid, ESI [M+H] + = 310.9.

[0475] 1H NMR (400 MHz, d6-DMSO) δ 7.80 (s, 1H), 7.39 (d, J = 7.1 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 5.85 (q, J = 7.0 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.84 (d, J = 7.0 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0476] Compound M-422: 98 mg, white solid, ESI [M+H] + = 294.9.

[0477] 1 H NMR (400 MHz, d6-DMSO) δ 8.07 (d, J = 1.6 Hz, 1H), 7.24 (t, J = 7.3 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.34 (q, J = 7.1 Hz, 1H), 4.27 - 4.06 (m, 2H), 2.25 (d, J = 1.7 Hz, 3H), 1.82 (d, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H).

[0478] Compound M-423: 167 mg, colorless oil, ESI [M+H] + = 292.9.

[0479] 1 H NMR (400 MHz, d6-DMSO) δ 7.94 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 1.1 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.25 - 7.20 (m, 1H), 5.96 (q, J = 7.0 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.84 (d, J = 7.0 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H).

[0480] Compound M-426-1: 25 mg, white solid, ESI [M+H] + = 348.8.

[0481] 1H NMR (400 MHz, d6-DMSO) δ 7.89 (s, 1H), 7.79 (dd, J = 10.5, 0.9 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 5.86 (q, J = 7.1 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H), 1.90 (d, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0482] Compound M-502: 264 mg, white solid, ESI [M+H] + = 297.1.

[0483] 1 H NMR (400 MHz, CDC13) δ 7.51 - 7.42 (m, 1H), 7.32 (d, J = 6.5 Hz, 2H), 7.01 - 6.89 (m, 1H), 6.53 (d, J = 6.9 Hz, 1H), 4.30 (dd, J = 9.2, 7.1 Hz, 2H), 1.88 (d, J = 7.0 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0484] Compound M-516: 349 mg, colorless oil, ESI [M+H] + = 278.9.

[0485] 1 H NMR (400 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.75 (d, J = 0.8 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.37 - 7.28 (m, 2H), 6.80 - 6.73 (m, 1H), 6.42 (q, J = 7.1 Hz, 1H), 4.25 - 4.06 (m, 2H), 1.84 (d, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H).

[0486] Compound M-517: 360 mg, colorless oil, ESI [M+H] + = 296.9.

[0487] 1 H NMR (400 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.75 (d, J = 0.8 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.37 - 7.28 (m, 2H), 6.80 - 6.73 (m, 1H), 6.42 (q, J = 7.1 Hz, 1H), 4.25 - 4.06 (m, 2H), 1.84 (d, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H).

[0488] Compound M-519: 90 mg, colorless oil, ESI [M+H]+ = 358.7. + = 358.7.

[0489] 1 H NMR (400 MHz, CDC13) δ 7.71 (s, 1H), 7.70 - 7.65 (m, 1H), 7.40 - 7.30 (m, 3H), 6.69 (q, J = 6.9 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.03 (d, J = 7.1 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H).

[0490] Compound M-520: 233 mg, white solid, ESI [M+H]+ = 292.9. + = 292.9.

[0491] 1 H NMR (400 MHz, d6-DMSO) δ 8.20 - 8.19 (m, 1H), 7.74 (d, J = 0.9 Hz, 1H), 7.31 (d, J = 6.8 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.59 (d, J = 6.7 Hz, 1H), 6.45 (q, J = 6.9 Hz, 1H), 4.26 - 4.06 (m, 2H), 2.38 (s, 3H), 1.82 (d, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H).

[0492] Compound M-521: 170 mg, white solid, ESI [M+H]+ = 311.1.

[0493] 1 H NMR (400 MHz, CDC13) δ 7.84 (s, 1H), 7.69 (s, 1H), 6.97 (t, J = 8.6 Hz, 1H), 6.75 (dd, J = 8.6, 5.7 Hz, 1H), 6.59 (q, J = 7.0 Hz, 1H), 4.29 (qq, J = 10.8, 7.1 Hz, 2H), 2.23 (d, J = 1.7 Hz, 3H), 1.88 (d, J = 7.0 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0494] Compound M-522: 69 mg, white solid, ESI [M+H]+ = 358.7. + = 358.7.

[0495] 1H NMR (400 MHz, CDC13) δ 7.61 (s, 1H), 7.47 - 7.42 (m, 1H), 7.35 - 7.25 (m, 2H), 6.93 (dd, J = 6.1, 3.3 Hz, 1H), 6.58 (q, J = 7.0 Hz, 1H), 4.40 - 4.23 (m, 2H), 1.89 (d, J = 7.0 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H).

[0496] Compound M-523: 62 mg, colorless oil, ESI [M+H] + = 436.6.

[0497] 1 H NMR (400 MHz, CDC13) δ 7.66 (dd, J = 7.1, 2.1 Hz, 1H), 7.41 - 7.30 (m, 3H), 6.45 (q, J = 7.0 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 2.05 (d, J = 7.1 Hz, 3H), 1.58 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0498] Compound M-524: 79 mg, colorless oil, ESI [M+H] + = 346.8.

[0499] 1 H NMR (400 MHz, CDC13) δ 7.67 - 7.61 (m, 1H), 7.41 - 7.31 (m, 3H), 6.61 (q, J = 7.1 Hz, 1H), 4.39 - 4.28 (m, 2H), 2.03 (d, J = 7.1 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0500] Compound M-527: 158 mg, white solid, ESI [M+H] + = 311.1.

[0501] 1 H NMR (400 MHz, CDC13) δ 7.85 (s, 1H), 7.74 (s, 1H), 7.13 (d, J = 9.0 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.52 (q, J = 7.0 Hz, 1H), 4.29 (qq, J = 10.8, 7.1 Hz, 2H), 2.22 (d, J = 1.7 Hz, 3H), 1.87 (d, J = 7.0 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H).

[0502] Compound M-528: 160 mg, white solid, ESI [M+H] + = 311.1.

[0503] 1 H NMR (400 MHz, CDC13) δ 7.82 (s, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.73 (t, J = 8.1 Hz, 1H), 6.53 (q, J = 7.1 Hz, 1H), 4.28 (qdd, J = 14.3, 9.0, 5.4 Hz, 2H), 2.33 (d, J = 2.3 Hz, 3H), 1.89 (d, J = 7.1 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H).

[0504] Compound M-530: 240 mg, colorless oil, ESI [M+H] + = 276.9.

[0505] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.71 (d, J = 0.9 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.70 (t, J = 6.9 Hz, 1H), 6.43 (q, J = 7.2 Hz, 1H), 4.28 - 4.08 (m, 2H), 2.25 (d, J = 1.9 Hz, 3H), 1.83 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0506] Compound M-531: 3.1 g, white solid, ESI [M+H]+ = 293.1.

[0507] 1 H NMR (400 MHz, CDC13) δ 7.84 (s, 1H), 7.70 (s, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.64 (q, J = 6.9 Hz, 1H), 4.29 (tdd, J = 10.8, 7.1, 3.7 Hz, 2H), 2.44 (s, 3H), 1.89 (d, J = 7.0 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0508] Compound M-532: 497 mg, colorless oil, ESI [M+H] + = 340.8.

[0509] 1H NMR (400 MHz, d6-DMSO) δ 7.68 (s, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.45 - 7.36 (m, 1H), 7.31 - 7.23 (m, 1H), 7.19 - 7.09 (m, 1H), 6.68 (q, J = 7.1 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.96 (d, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H).

[0510] Compound M-533: 516 mg, colorless oil, ESI [M+H]+ = 354.8. +

[0511] 1 H NMR (400 MHz, d6-DMSO) δ 7.68 (s, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.45 - 7.36 (m, 1H), 7.31 - 7.23 (m, 1H), 7.19 - 7.09 (m, 1H), 6.68 (q, J = 7.1 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.96 (d, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H).

[0512] Compound M-545: 1.62 g, colorless oil, ESI [M+H]+ = 303.1.

[0513] 1 H NMR (400 MHz, d6-DMSO) δ 7.68 (s, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.45 - 7.36 (m, 1H), 7.31 - 7.23 (m, 1H), 7.19 - 7.09 (m, 1H), 6.68 (q, J = 7.1 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.96 (d, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H).

[0514] Compound M-548: 432 mg, colorless oil, ESI [M+H]+ = 346.8. +

[0515] 1 ​​H NMR (400 MHz, d6-DMSO) d 8.37 (s, 1H), 7.55 - 7.48 (m, 1H), 7.41 - 7.31 (m, 2H), 6.97 - 6.87 (m, 1H), 6.37 (q, J = 7.0 Hz, 1H), 4.29 - 4.12 (m, 2H), 1.88 (d, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H).

[0516] Compound M-549: 315 mg, colorless oil, ESI [M+H] + = 276.9.

[0517] 1 H NMR (400 MHz, d6-DMSO) d 8.24 (s, 1H), 7.72 (d, J = 0.9 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.71 (t, J = 6.9 Hz, 1H), 6.43 (q, J = 7.1 Hz, 1H), 4.27 - 4.08 (m, 2H), 2.25 (d, J = 1.9 Hz, 3H), 1.84 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0518] Compound M-556: 259 mg, white semi-solid, ESI [M+H] + = 330.9.

[0519] 1 H NMR (400 MHz, d6-DMSO) d 8.44 (s, 1H), 7.44 - 7.34 (m, 1H), 7.29 - 7.17 (m, 2H), 7.08 - 6.89 (m, 1H), 6.36 (q, J = 7.1 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.90 (d, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H).

[0520] Compound M-557: 243 mg, colorless oil, ESI [M+H] + = 344.9.

[0521] 1H NMR (400 MHz, d6-DMSO) δ 8.40 (s, 1H), 7.26 (t, J = 7.2 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.84 (t, J = 6.9 Hz, 1H), 6.35 (q, J = 7.1 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 2.24 (d, J = 1.7 Hz, 3H), 1.88 (d, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H).

[0522] Compound M-558: 156 mg, colorless oil, ESI [M+H] + = 360.8.

[0523] 1 H NMR (400 MHz, d6-DMSO) δ 8.33 (s, 1H), 7.34 (d, J = 6.9 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.40 (q, J = 7.0 Hz, 1H), 4.29 - 4.10 (m, 2H), 2.38 (s, 3H), 1.87 (d, J = 7.0 Hz, 3H).

[0524] Compound M-562: 172 mg, colorless oil, ESI [M+H] + = 358.9.

[0525] 1 H NMR (400 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.80 (s, 1H), 7.23 (t, J = 7.3 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.44 (q, J = 7.0 Hz, 1H), 5.91 - 5.71 (m, 2H), 5.28 (ddd, J = 17.3, 4.4, 1.8 Hz, 1H), 5.10 (ddd, J = 10.8, 5.3, 1.7 Hz, 1H), 5.03 (s, 2H), 5.00 (d, J = 7.0 Hz, 1H), 4.11 - 3.88 (m, 2H), 2.30 (dd, J = 6.9, 4.1 Hz, 2H), 2.24 (s, 3H), 1.83 (d, J = 7.1 Hz, 3H).

[0526] Compound M-563: 221 mg, white solid, ESI [M+H] + = 294.9.

[0527] 1H NMR (400 MHz, d6-DMSO) δ 8.07 (d, J = 1.7 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.73 (t, J = 7.0 Hz, 1H), 6.34 (q, J = 7.1 Hz, 1H), 4.29 - 4.08 (m, 2H), 2.25 (d, J = 1.9 Hz, 3H), 1.82 (d, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H).

[0528] Compound M-564: 71 mg, white solid, ESI [M+H] + = 294.9.

[0529] 1 H NMR (400 MHz, d6-DMSO) δ 7.81 (s, 1H), 7.29 (dd, J = 10.5, 4.3 Hz, 1H), 7.24 - 7.09 (m, 2H), 5.75 (q, J = 7.1 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.24 (d, J = 1.7 Hz, 3H), 1.86 (d, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0530] Compound M-565: 230 mg, white solid, ESI [M+H] + = 314.8.

[0531] 1 H NMR (400 MHz, d6-DMSO) δ 8.15 (d, J = 1.6 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.21 (t, J = 8.0 Hz, 1H), 6.85 (t, J = 6.7 Hz, 1H), 6.31 (q, J = 7.1 Hz, 1H), 4.25 - 4.04 (m, 2H), 1.84 (d, J = 7.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H).

[0532] Compound M-566: 179 mg, white solid, ESI [M+H] + = 330.8.

[0533] 1H NMR (400 MHz, d6-DMSO) δ 8.11 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 8.0, 1.3 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 6.72 (dd, J = 7.9, 1.1 Hz, 1H), 6.32 (q, J = 7.0 Hz, 1H), 4.24 - 4.05 (m, 2H), 1.83 (d, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H).

[0534] Compound M-567: 250 mg, colorless oil, ESI [M+H] + = 366.9.

[0535] 1 H NMR (400 MHz, d6-DMSO) δ 7.77 (d, J = 1.6 Hz, 1H), 7.20 (q, J = 7.2 Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H), 4.69 (q, J = 6.4 Hz, 1H), 4.34 - 4.16 (m, 4H), 3.33 - 3.17 (m, 2H), 2.24 (s, 3H), 1.83 - 1.64 (m, 2H), 1.51 - 1.39 (m, 2H), 1.35 (d, J = 6.4 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0536] Compound M-568: 137 mg, colorless oil, ESI [M+H] + = 280.9.

[0537] 1 H NMR (400 MHz, d6-DMSO) δ 8.34 (s, 1H), 7.73 (s, 1H), 7.42 - 7.32 (m, 1H), 7.21 - 7.11 (m, 1H), 6.67 (t, J = 7.1 Hz, 1H), 6.42 (q, J = 7.1 Hz, 1H), 4.26 - 4.06 (m, 2H), 1.86 (d, J = 7.2 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H).

[0538] Compound M-569: 224 mg, white solid, ESI [M+H] + = 298.9.

[0539] 1H NMR (400 MHz, d6-DMSO) d 8.15 (d, J = 1.7 Hz, 1H), 7.54 - 7.26 (m, 1H), 7.26 - 7.13 (m, 1H), 6.80 - 6.65 (m, 1H), 6.33 (q, J = 7.1 Hz, 1H), 4.32 - 4.04 (m, 2H), 1.84 (d, J = 7.2 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H).

[0540] Compound M-570: 52 mg, white solid, ESI [M+H] + = 273.1.

[0541] 1 H NMR (400 MHz, d6-DMSO) d 8.07 (s, 1H), 7.72 (d, J = 0.8 Hz, 1H), 7.18 - 6.99 (m, 2H), 6.62 (d, J = 7.4 Hz, 1H), 6.41 (q, J = 7.0 Hz, 1H), 4.18 (tdd, J = 10.8, 7.1, 3.8 Hz, 2H), 2.27 (s, 3H), 2.21 (s, 3H), 1.75 (d, J = 7.0 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0542] Compound M-571: 124 mg, white solid, ESI [M+H] + = 291.1.

[0543] 1 H NMR (400 MHz, d6-DMSO) d 8.07 (s, 1H), 7.72 (d, J = 0.8 Hz, 1H), 7.18 - 6.99 (m, 2H), 6.62 (d, J = 7.4 Hz, 1H), 6.41 (q, J = 7.0 Hz, 1H), 4.18 (tdd, J = 10.8, 7.1, 3.8 Hz, 2H), 2.27 (s, 3H), 2.21 (s, 3H), 1.75 (d, J = 7.0 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0544] Compound M-643: 51 mg, white solid, ESI [M+H] + = 241.1.

[0545] 1H NMR (400 MHz, CDC13) δ 7.28 (d, J = 1.3 Hz, 1H), 5.07 (dq, J = 9.9, 6.7 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.80 - 2.66 (m, 1H), 2.26 - 2.11 (m, 1H), 2.03 - 1.91 (m, 2H), 1.92 - 1.80 (m, 2H), 1.79 - 1.70 (m, 1H), 1.47 - 1.35 (m, 6H).

[0546] Compound M-649: 65 mg, colorless oil, ESI [M+H] + = 323.1.

[0547] 1 H NMR (400 MHz, CDC13) δ 7.75 (d, J = 1.3 Hz, 1H), 7.30 (s, 1H), 7.28 (d, J = 9.9 Hz, 2H), 7.16 (s, 1H), 7.05 (dd, J = 6.2, 2.3 Hz, 1H), 5.41 (d, J = 9.6 Hz, 1H), 4.36 - 4.12 (m, 2H), 1.50 (ddd, J = 12.6, 8.0, 4.6 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 0.91 (td, J = 8.2, 4.5 Hz, 1H), 0.83 (ddd, J = 16.9, 8.4, 5.2 Hz, 1H), 0.66 (td, J = 9.8, 4.9 Hz, 1H), 0.54 (td, J = 10.2, 5.1 Hz, 1H).

[0548] Compound M-653: 60 mg, colorless oil, ESI [M+H] + = 303.1.

[0549] 1 H NMR (400 MHz, CDC13) δ 7.74 (d, J = 1.4 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.05 - 6.87 (m, 2H), 5.44 (d, J = 9.4 Hz, 1H), 4.33 - 4.13 (m, 2H), 2.36 (s, 3H), 1.51 (ddd, J = 12.6, 8.0, 4.6 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.93 - 0.83 (m, 1H), 0.79 (ddd, J = 17.0, 8.5, 5.1 Hz, 1H), 0.63 (td, J = 9.7, 4.8 Hz, 1H), 0.53 (dt, J = 9.8, 5.1 Hz, 1H).

[0550] Compound M-865: 140 mg, white solid, ESI [M+H] + = 299.1.

[0551] 1 H NMR (400 MHz, d6-DMSO) δ 8.10 (d, J = 1.5 Hz, 1H), 7.30 (dd, J = 9.5, 4.6 Hz, 1H), 7.27 - 7.18 (m, 1H), 6.87 - 6.78 (m, 1H), 6.30 (d, J = 7.1 Hz, 1H), 4.18 (dd, J = 7.0, 5.5 Hz, 2H), 1.83 (d, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H).

[0552] Compound M-866: 110 mg, colorless oil, ESI [M+H] + = 299.1.

[0553] 1 H NMR (400 MHz, d6-DMSO) δ 8.16 (d, J = 1.6 Hz, 1H), 7.19 (dd, J = 6.9, 4.7 Hz, 1H), 6.95 (d, J = 6.5 Hz, 2H), 6.15 (d, J = 7.2 Hz, 1H), 4.26 - 4.14 (m, 2H), 1.85 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0554] Compound M-867: 106 mg, white solid, ESI [M+H] + = 299.1.

[0555] 1 H NMR (400 MHz, d6-DMSO) δ 8.16 (s, 1H), 7.41 (s, 1H), 7.09 (t, J = 8.7 Hz, 2H), 6.22 (d, J = 7.3 Hz, 1H), 4.14 (dd, J = 7.1, 2.0 Hz, 2H), 1.91 (d, J = 7.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H).

[0556] Compound M-868: 167 mg, white solid, ESI [M+H] + = 315.1.

[0557] 1H NMR (400 MHz, d6-DMSO) δ 8.03 (d, J = 1.7 Hz, 1H), 7.53 (dd, J = 8.7, 2.6 Hz, 1H), 7.23 (td, J = 8.5, 2.7 Hz, 1H), 6.89 (dd, J = 8.8, 6.0 Hz, 1H), 6.29 (q, J = 7.0 Hz, 1H), 4.26 - 4.02 (m, 2H), 1.80 (d, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H).

[0558] Compound M-882: 207 mg, white solid, ESI [M+H] + = 317.1.

[0559] 1 H NMR (400 MHz, d6-DMSO) δ 8.16 (s, 1H), 7.20 (t, J = 9.2 Hz, 2H), 6.17 (q, J = 7.2 Hz, 1H), 4.21 - 4.10 (m, 2H), 1.89 (d, J = 7.2 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H).

[0560] Compound M-883: 218 mg, white solid, ESI [M+H] + = 315.1.

[0561] 1 H NMR (400 MHz, d6-DMSO) δ 8.13 (d, J = 1.6 Hz, 1H), 7.42 - 7.36 (m, 2H), 6.64 - 6.58 (m, 1H), 6.32 (q, J = 7.1 Hz, 1H), 4.23 - 4.06 (m, 2H), 1.82 (d, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H).

[0562] Compound M-884: 287 mg, colorless oil, ESI [M+H] + = 295.1.

[0563] 1 H NMR (400 MHz, d6-DMSO) δ 8.07 (d, J = 1.6 Hz, 1H), 7.06 (d, J = 11.7 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 8.0 Hz, 1H), 6.30 (q, J = 7.1 Hz, 1H), 4.26 - 4.09 (m, 2H), 2.30 (s, 3H), 1.81 (d, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H).

[0564] Compound M-885: 316 mg, white solid, ESI [M+H] + = 298.1.

[0565] 1 H NMR (400 MHz, d6-DMSO) δ 8.11 (d, J = 1.6 Hz, 1H), 7.36 - 7.25 (m, 1H), 7.09 (td, J = 8.5, 2.2 Hz, 1H), 7.02 (td, J = 8.6, 6.5 Hz, 1H), 6.29 (q, J = 7.2 Hz, 1H), 4.27 - 4.05 (m, 2H), 1.82 (d, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H).

[0566] Compound M-886: 287 mg, white solid, ESI [M+H] + = 280.1.

[0567] 1 H NMR (400 MHz, d6-DMSO) δ 8.30 (s, 1H), 7.68 (s, 1H), 7.47 - 7.33 (m, 1H), 7.16 - 6.96 (m, 2H), 6.31 (q, J = 7.2 Hz, 1H), 4.24 - 4.04 (m, 2H), 1.92 (d, J = 7.3 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H).

[0568] Compound M-887: 171 mg, white solid, ESI [M+H] + = 348.8.

[0569] 1 H NMR (400 MHz, d6-DMSO) δ 8.21 (d, J = 1.7 Hz, 1H), 7.76 (dd, J = 10.4, 1.1 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.34 (q, J = 7.1 Hz, 1H), 4.25 - 4.01 (m, 2H), 1.86 (d, J = 7.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H).

[0570] Compound M-888: 152 mg, white solid, ESI [M+H] + = 348.8.

[0571] 1H NMR (400 MHz, d6-DMSO) δ 8.19 (d, J = 1.7 Hz, 1H), 7.75 (t, J = 7.0 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 6.36 (q, J = 7.2 Hz, 1H), 4.24 - 4.06 (m, 2H), 1.86 (d, J = 7.2 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H).

[0572] Compound M-892: 146 mg, white solid, ESI [M+H] + = 317.1.

[0573] 1 H NMR (400 MHz, d6-DMSO) δ 8.19 (d, J = 1.7 Hz, 1H), 7.75 (t, J = 7.0 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 6.36 (q, J = 7.2 Hz, 1H), 4.24 - 4.06 (m, 2H), 1.86 (d, J = 7.2 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H).

[0574] Compound M-893: 174 mg, white solid, ESI [M+H] + = 317.1.

[0575] 1 H NMR (400 MHz, d6-DMSO) δ 8.19 (d, J = 1.7 Hz, 1H), 7.75 (t, J = 7.0 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 6.36 (q, J = 7.2 Hz, 1H), 4.24 - 4.06 (m, 2H), 1.86 (d, J = 7.2 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H).

[0576] Compound M-894: 158 mg, white solid, ESI [M+H] + = 317.1.

[0577] 1 H NMR (400 MHz, d6-DMSO) δ 8.19 (d, J = 1.7 Hz, 1H), 7.75 (t, J = 7.0 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 6.36 (q, J = 7.2 Hz, 1H), 4.24 - 4.06 (m, 2H), 1.86 (d, J = 7.2 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H).

[0578] Compound M-1000: 204 mg, light yellow syrup, ESI [M+H] + = 374.8.

[0579] 1 H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H), 7.38 - 7.23 (m, 1H), 7.17 - 6.97 (m, 2H), 6.35 (q, J = 7.0 Hz, 1H), 4.31 - 4.11 (m, 2H), 3.55 (s, 3H), 1.85 (d, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0580] Example 16, Preparation of the compound of the application

[0581] NaOH (2 eq.) was added to a solution of the ethyl ester compound (1 eq.) in EtOH / H2O (30 V, v / v = 1 / 1) at room temperature, and stirred at reflux for 2 hours. After the reaction was completed by TLC monitoring, it was concentrated under reduced pressure, cooled in an ice water bath, adjusted to pH ≈ 5 with 1N HCl, extracted with EtOAc (3 x 10 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and filtered under suction, and concentrated under reduced pressure to obtain the carboxylic acid compound.

[0582] The carboxylic acid (1.0 eq.) prepared in the previous step, DCC (1.5 eq.) and DMAP (1.5 eq.) were dissolved in dichloromethane (5 V) at room temperature, and stirred at room temperature for 5 minutes, and then the alcohol compound R 10 -OH (1.0-1.5 eq.) was slowly added to the reaction system by syringe, and stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was concentrated under reduced pressure, stirred with methyl tert-butyl ether, filtered under suction, and 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 preparative TLC or silica gel column chromatography to obtain the target compound of the application.

[0583] Compound M-20: 112 mg, white solid, ESI [M+H] + = 263.1.

[0584] 1H NMR (400 MHz, CDC13) δ 8.34 (s, 1H), 7.95 (s, 1H), 6.34 (dd, J = 17.4, 10.9 Hz, 1H), 5.50 - 5.36 (m, 2H), 4.98 (d, J = 7.6 Hz, 2H), 4.81 (d, J = 7.8 Hz, 2H), 4.46 (s, 1H), 1.58 (d, J = 6.6 Hz, 3H), 1.30 (s, 1H), 0.84 (s, 1H), 0.68 (s, 1H), 0.56 - 0.44 (m, 1H), 0.39 (s, 1H).

[0585] Compound M-75: 99 mg, white solid, ESI [M+H] + = 289.1.

[0586] 1 H NMR (400 MHz, d6-DMSO) δ 8.33 (s, 1H), 7.79 (d, J = 0.9 Hz, 1H), 6.35 (dd, J = 17.4, 10.9 Hz, 1H), 5.36 (t, J = 14.6 Hz, 2H), 4.84 (d, J = 7.8 Hz, 2H), 4.70 (d, J = 7.9 Hz, 2H), 3.71 (t, J = 9.2 Hz, 1H), 1.60 - 1.37 (m, 2H), 0.74 - 0.55 (m, 2H), 0.54 - 0.33 (m, 4H), 0.26 - 0.12 (m, J = 9.6,

[0587] 4.9 Hz, 2H).

[0588] Compound M-76: 85 mg, white solid, ESI [M+H] + = 305.2.

[0589] 1 H NMR (400 MHz, d6-DMSO) δ 8.25 (d, J = 0.7 Hz, 1H), 7.79 (d, J = 0.8 Hz, 1H), 6.33 (dd, J = 17.4, 10.9 Hz, 1H), 5.34 (dd, J = 14.1, 10.8 Hz, 2H), 4.81 (dd, J = 14.2, 7.7 Hz, 2H), 4.70 (d, J = 7.9 Hz, 2H), 4.13 (d, J = 10.8 Hz, 1H), 1.64 - 1.52 (m, 1H), 0.93 (s, 9H), 0.90 - 0.80 (m, 1H), 0.57 - 0.47 (m, 1H), 0.46 - 0.34 (m, 1H), -0.03 - -0.16 (m, 1H).

[0590] Compound M-77: 156 mg, white semi-solid, ESI [M+H] + = 277.2.

[0591] 1 H NMR (400 MHz, d6-DMSO) δ 8.28 (s, 1H), 7.80 (d, J = 0.8 Hz, 1H), 6.35 (dd, J = 17.4, 10.9 Hz, 1H), 5.36 (t, J = 14.0 Hz, 2H), 4.84 (dd, J = 7.7, 2.8 Hz, 2H), 4.70 (d, J = 7.9 Hz, 2H), 4.05 (dd, J = 16.8, 7.3 Hz, 1H), 2.03 - 1.86 (m, 2H), 1.51 - 1.34 (m, 1H), 0.78 (t, J = 7.4 Hz, 3H), 0.74 - 0.63 (m, 1H), 0.50 - 0.34 (m, 2H), 0.23 - 0.09 (m, 1H).

[0592] Compound M-78: 122 mg, colorless syrup, ESI [M+H] + = 291.2.

[0593] 1 H NMR (400 MHz, d6-DMSO) δ 8.14 (s, 1H), 7.79 (d, J = 0.7 Hz, 1H), 6.37 (dd, J = 17.4, 10.9 Hz, 1H), 5.37 (dd, J = 14.0, 12.3 Hz, 2H), 4.85 (d, J = 7.6 Hz, 3H), 4.73 (d, J = 7.9 Hz, 2H), 2.95 - 2.76 (m, 1H), 2.14 - 2.03 (m, 1H), 1.88 - 1.63 (m, 6H), 1.61 - 1.42 (m, 1H), 0.67 (t, J = 7.4 Hz, 3H).

[0594] Compound M-80: 216 mg, colorless oil, ESI [M+H] + = 319.2.

[0595] 1 H NMR (400 MHz, d6-DMSO) δ 8.29 (s, 1H), 7.67 (s, 1H), 4.20 (s, 2H), 3.77 (t, J = 8.9 Hz, 1H), 3.37 (s, 2H), 3.30 (s, 3H), 1.97 - 1.78 (m, 6H), 1.60 - 1.40 (m, 2H), 0.72 - 0.61 (m, 2H), 0.51 - 0.36 (m, 4H), 0.25 - 0.15 (m, 2H).

[0596] Compound M-82: 141 mg, colorless oil, ESI [M+H] + = 291.2.

[0597] 1 H NMR (400 MHz, d6-DMSO) δ 8.30 (s, 1H), 7.70 (d, J = 1.0 Hz, 1H), 4.45 (d, J = 5.9 Hz, 2H), 4.31 (d, J = 5.6 Hz, 4H), 3.79 (t, J = 9.1 Hz, 1H), 1.59 - 1.44 (m, 2H), 1.32 (s, 3H), 0.71 - 0.59 (m, 2H), 0.51 - 0.34 (m, 4H), 0.26 - 0.13 (m, 2H).

[0598] Compound M-83: 158 mg, white solid, ESI [M+H] + = 277.2.

[0599] 1 H NMR (400 MHz, d6-DMSO) δ 8.31 (s, 1H), 7.71 (d, J = 0.9 Hz, 1H), 4.74 (d, J = 7.2 Hz, 2H), 4.50 (d, J = 7.7 Hz, 2H), 3.74 (t, J = 9.1 Hz, 1H), 1.72 (s, 3H), 1.57 - 1.40 (m, 2H), 0.72 - 0.59 (m, 2H), 0.53 - 0.35 (m, 4H), 0.28 - 0.10 (m, 2H).

[0600] Compound M-85: 166 mg, colorless oil, ESI [M+H] + = 277.2.

[0601] 1 H NMR (400 MHz, d6-DMSO) δ 8.27 (s, 1H), 7.63 (d, J = 0.9 Hz, 1H), 4.89 - 4.77 (m, 1H), 3.78 (t, J = 9.2 Hz, 1H), 1.75 - 1.56 (m, 4H), 1.55 - 1.43 (m, 2H), 0.88 (t, J = 7.4 Hz, 6H), 0.70 - 0.60 (m, 2H), 0.52 - 0.32 (m, 4H), 0.24 - 0.11 (m, 2H).

[0602] Compound M-87: 137 mg, colorless oil, ESI [M+H] + = 301.2.

[0603] 1H NMR (400 MHz, d6-DMSO) δ 8.32 (s, 1H), 7.74 (d, J = 0.6 Hz, 1H), 5.85 (t, J = 6.6 Hz, 1H), 5.15 (d, J = 6.7 Hz, 2H), 4.84 (d, J = 7.6 Hz, 2H), 4.68 (d, J = 7.7 Hz, 2H), 3.71 (t, J = 9.3 Hz, 1H), 1.57 - 1.43 (m, 2H), 0.70 - 0.60 (m, 2H), 0.52 - 0.36 (m, 4H), 0.27 - 0.13 (m, 2H).

[0604] Compound M-88: 118 mg, colorless oil, ESI [M+H] + = 317.1.

[0605] 1 H NMR (400 MHz, d6-DMSO) δ 8.28 (s, 1H), 7.67 (s, 1H), 5.89 (t, J = 6.6 Hz, 1H), 5.18 (d, J = 6.6 Hz, 2H), 3.83 (d, J = 10.5 Hz, 2H), 3.69 (t, J = 9.0 Hz, 1H), 3.34 (d, J = 10.5 Hz, 2H), 1.53 - 1.40 (m, 2H), 0.70 - 0.57 (m, 2H), 0.51 - 0.33 (m, 4H), 0.25 - 0.13 (m, 2H).

[0606] Compound M-90: 102 mg, white semi-solid, ESI [M+H] + = 335.2.

[0607] 1 H NMR (400 MHz, d6-DMSO) δ 8.20 (s, 1H), 7.66 (s, 1H), 4.30 - 4.13 (m, 3H), 3.37 (s, 2H), 3.29 (s, 3H), 1.97 - 1.78 (m, 6H), 1.66 - 1.52 (m, 1H), 0.94 (s, 9H), 0.91 - 0.83 (m, 1H), 0.56 - 0.47 (m, 1H), 0.47 - 0.34 (m, 1H), -0.02 - -0.17 (m, 1H).

[0608] Compound M-92: 87 mg, colorless oil, ESI [M+H] + = 307.2.

[0609] 1H NMR (400 MHz, d6-DMSO) δ 8.21 (d, J = 0.7 Hz, 1H), 7.69 (d, J = 0.8 Hz, 1H), 4.48 - 4.41 (m, 2H), 4.36 - 4.24 (m, 4H), 4.21 (d, J = 10.7 Hz, 1H), 1.65 - 1.50 (m, 1H), 1.31 (s, 3H), 0.94 (s, 9H), 0.91 - 0.80 (m, 1H), 0.60 - 0.48 (m, 1H), 0.45 - 0.33 (m, 1H), 0.05 - -0.19 (m, 1H).

[0610] Compound M-93: 91 mg, white solid, ESI [M+H] + = 293.2.

[0611] 1 H NMR (400 MHz, d6-DMSO) δ 8.21 (s, 1H), 7.69 (s, 1H), 4.70 (dd, J = 11.4, 7.2 Hz, 2H), 4.50 (d, J = 7.5 Hz, 2H), 4.14 (d, J = 10.7 Hz, 1H), 1.69 (s, 3H), 1.62 - 1.48 (m,

[0612] 1H), 0.92 (s, 9H), 0.89 - 0.77 (m, 1H), 0.59 - 0.45 (m, 1H), 0.45 - 0.31 (m, 1H), -0.04 - -0.15 (m, 1H).

[0613] Compound M-95: 64 mg, colorless oil, ESI [M+H] + = 293.3.

[0614] 1 H NMR (400 MHz, d6-DMSO) δ 8.18 (d, J = 0.8 Hz, 1H), 7.62 (d, J = 0.9 Hz, 1H), 4.94 - 4.77 (m, 1H), 4.24 (d, J = 10.7 Hz, 1H), 1.77 - 1.44 (m, 5H), 1.02 - 0.80 (m, 16H), 0.56 - 0.47 (m, 1H), 0.46 - 0.37 (m, 1H), -0.04 - -0.15 (m, 1H).

[0615] Compound M-97: 110 mg, colorless oil, ESI [M+H] + = 317.2.

[0616] 1H NMR (400 MHz, d6-DMSO) δ 8.26 (s, 1H), 7.76 (s, 1H), 5.85 (t, J = 6.7 Hz, 1H), 5.20 - 5.07 (m, 2H), 4.83 (dd, J = 15.5, 7.4 Hz, 2H), 4.69 (dd, J = 7.2, 3.5 Hz, 2H), 4.15 (d, J = 10.8 Hz, 1H), 1.68 - 1.53 (m, 1H), 0.95 (s, 9H), 0.93 - 0.81 (m, 1H), 0.59 - 0.49 (m, 1H), 0.47 - 0.36 (m, 1H), 0.00 - -0.11 (m, 1H).

[0617] Compound M-98: 73 mg, colorless oil, ESI [M+H] + = 333.1.

[0618] 1 H NMR (400 MHz, d6-DMSO) δ 8.21 (s, 1H), 7.67 (s, 1H), 5.90 (t, J = 6.6 Hz, 1H), 5.18 (d, J = 6.6 Hz, 2H), 4.13 (d, J = 10.7 Hz, 1H), 3.83 (d, J = 10.6 Hz, 1H), 3.78 (d, J = 10.7 Hz, 1H), 3.36 (d, J = 10.8 Hz, 2H), 1.62 - 1.52 (m, 1H), 0.93 (s, 9H), 0.90 - 0.81 (m, 1H), 0.58 - 0.49 (m, 1H), 0.45 - 0.35 (m, 1H), -0.02 - -0.12 (m, 1H).

[0619] Compound M-100: 278 mg, colorless oil, ESI [M+H] + = 307.2.

[0620] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.68 (s, 1H), 4.21 (s, 2H), 4.17 - 4.08 (m, 1H), 3.38 (s, 2H), 3.29 (s, 3H), 2.04 - 1.77 (m, 8H), 1.53 - 1.36 (m, 1H), 0.78 (t, J = 7.4 Hz, 3H), 0.75 - 0.65 (m, 1H), 0.49 - 0.34 (m, 2H), 0.23 - 0.08 (m, 1H).

[0621] Compound M-102: 161 mg, colorless oil, ESI [M+H] + = 279.2.

[0622] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.70 (d, J = 0.9 Hz, 1H), 4.45 (dd, J = 5.9, 1.8 Hz, 2H), 4.33 - 4.24 (m, 4H), 4.19 - 4.07 (m, 1H), 2.04 - 1.83 (m, 2H), 1.53 - 1.38 (m, 1H), 1.32 (s, 3H), 0.78 (t, J = 7.4 Hz, 3H), 0.74 - 0.65 (m, 1H), 0.49 - 0.35 (m, 2H), 0.23 - 0.11 (m, 1H).

[0623] Compound M-103: 204 mg, white solid, ESI [M+H] + = 265.2.

[0624] 1H NMR (400 MHz, d6-DMSO) δ 8.26 (s, 1H), 7.72 (d, J = 0.9 Hz, 1H), 4.74 (d, J = 6.4 Hz, 2H), 4.51 (d, J = 7.7 Hz, 2H), 4.15 - 3.96 (m, 1H), 2.00 - 1.81 (m, 2H), 1.72 (s, 3H), 1.52 - 1.31 (m, 1H), 0.79 (t, J = 7.4 Hz, 3H), 0.76 - 0.64 (m, 1H), 0.49 - 0.34 (m, 2H), 0.24 - 0.10 (m, 1H).

[0625] Compound M-105: 188 mg, colorless oil, ESI [M+H] + = 265.2.

[0626] 1 H NMR (400 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.64 (d, J = 0.9 Hz, 1H), 4.94 - 4.80 (m, 1H), 4.22 - 4.03 (m, 1H), 2.03 - 1.87 (m, 2H), 1.74 - 1.52 (m, 4H), 1.49 - 1.34 (m, 1H), 0.94 - 0.83 (m, 6H), 0.78 (t, J = 7.4 Hz, 3H), 0.75 - 0.64 (m, 1H), 0.49 - 0.32 (m, 2H), 0.21 - 0.10 (m, 1H).

[0627] Compound M-107: 200 mg, colorless oil, ESI [M+H] + = 289.2.

[0628] 1H NMR (400 MHz, d6-DMSO) δ 8.28 (s, 1H), 7.76 (d, J = 0.7 Hz, 1H), 5.86 (t, J = 6.7 Hz, 1H), 5.15 (d, J = 6.7 Hz, 2H), 4.84 (dd, J = 7.5, 3.0 Hz, 2H), 4.69 (d, J = 7.7 Hz, 2H), 4.14 - 3.94 (m, 1H), 2.02 - 1.80 (m, 2H), 1.52 - 1.30 (m, 1H), 0.79 (t, J = 7.4 Hz, 3H), 0.75 - 0.64 (m, 1H), 0.50 - 0.35 (m, 2H), 0.24 - 0.13 (m, 1H).

[0629] Compound M-108: 110 mg, colorless oil, ESI [M+H] + = 305.2.

[0630] 1 H NMR (400 MHz, d6-DMSO) δ 8.25 (s, 1H), 7.69 (s, 1H), 5.91 (t, J = 6.6 Hz, 1H), 5.19 (d, J = 6.6 Hz, 2H), 4.05 (dd, J = 16.7, 7.4 Hz, 1H), 3.84 (dd, J = 10.8, 2.7 Hz, 2H), 3.42 - 3.27 (m, 2H), 1.98 - 1.84 (m, 2H), 1.50 - 1.36 (m, 1H), 0.78 (t, J = 7.4 Hz, 3H), 0.73 - 0.64 (m, 1H), 0.48 - 0.35 (m, 2H), 0.23 - 0.12 (m, 1H).

[0631] Compound M-110: 243 mg, colorless oil, ESI [M+H] + = 321.2.

[0632] 1 H NMR (400 MHz, d6-DMSO) δ 8.09 (s, 1H), 7.67 (s, 1H), 5.01 - 4.83 (m, 1H), 4.24 (s, 2H), 3.40 (s, 2H), 3.30 (s, 3H), 2.94 - 2.78 (m, 1H), 2.15 - 2.04 (m, 1H), 1.96 - 1.65 (m, 12H), 1.61 - 1.48 (m, 1H), 0.68 (t, J = 7.4 Hz, 3H).

[0633] Compound M-112: 137 mg, colorless oil, ESI [M+H] + = 293.2.

[0634] 1 H NMR (400 MHz, d6-DMSO) δ 8.10 (d, J = 0.5 Hz, 1H), 7.70 (d, J = 0.9 Hz, 1H), 5.03 - 4.80 (m, 1H), 4.48 (dd, J = 5.9, 1.0 Hz, 2H), 4.35 (s, 2H), 4.32 (d, J = 5.9 Hz, 2H), 2.97 - 2.75 (m, 1H), 2.18 - 2.04 (m, 1H), 1.94 - 1.66 (m, 6H), 1.62 - 1.48 (m, 1H), 1.34 (s, 3H), 0.68 (t, J = 7.4 Hz, 3H).

[0635] Compound M-113: 181 mg, colorless oil, ESI [M+H] + = 279.2.

[0636] 1 H NMR (400 MHz, d6-DMSO) δ 8.11 (s, 1H), 7.72 (d, J = 0.9 Hz, 1H), 4.95 - 4.81 (m, 1H), 4.76 (d, J = 7.2 Hz, 2H), 4.53 (d, J = 7.7 Hz, 2H), 2.95 - 2.76 (m, 1H), 2.16 - 2.00 (m, 1H), 1.92 - 1.62 (m, 9H), 1.61 - 1.47 (m, 1H), 0.68 (t, J = 7.4 Hz, 3H).

[0637] Compound M-115: 160 mg, colorless oil, ESI [M+H] + = 279.2.

[0638] 1 H NMR (400 MHz, d6-DMSO) δ 8.07 (d, J = 0.7 Hz, 1H), 7.63 (d, J = 0.9 Hz, 1H), 5.04 - 4.75 (m, 2H), 2.94 - 2.72 (m, 1H), 2.19 - 2.01 (m, 1H), 1.93 - 1.42 (m, 11H), 0.90 (t, J = 7.4 Hz, 6H), 0.67 (d, J = 7.4 Hz, 3H).

[0639] Compound M-117: 215 mg, colorless oil, ESI [M+H] + = 303.2.

[0640] 1H NMR (400 MHz, d6-DMSO) δ 8.12 (s, 1H), 7.75 (d, J = 0.5 Hz, 1H), 5.88 (t, J = 6.7 Hz, H), 5.15 (d, J = 6.7 Hz, 2H), 4.86 (d, J = 7.5 Hz, 3H), 4.70 (d, J = 7.8 Hz, 2H), 2.91 - 2.76 (m, 1H), 2.14 - 2.01 (m, 1H), 1.89 - 1.62 (m, 6H), 1.61 - 1.46 (m, 1H), 0.67 (t, J = 7.4 Hz, 3H).

[0641] Compound M-118: 143 mg, colorless oil, ESI [M+H] + = 303.2.

[0642] 1 H NMR (400 MHz, d6-DMSO) δ 8.12 (s, 1H), 7.75 (d, J = 0.5 Hz, 1H), 5.88 (t, J = 6.7 Hz, H), 5.15 (d, J = 6.7 Hz, 2H), 4.86 (d, J = 7.5 Hz, 3H), 4.70 (d, J = 7.8 Hz, 2H), 2.91 - 2.76 (m, 1H), 2.14 - 2.01 (m, 1H), 1.89 - 1.62 (m, 6H), 1.61 - 1.46 (m, 1H), 0.67 (t, J = 7.4 Hz, 3H).

[0643] Compound M-128: 53 mg, light yellow oil, ESI [M+H] + = 163.1.

[0644] 1 H NMR (400 MHz, d6-DMSO) δ 8.12 (s, 1H), 7.75 (d, J = 0.5 Hz, 1H), 5.88 (t, J = 6.7 Hz, H), 5.15 (d, J = 6.7 Hz, 2H), 4.86 (d, J = 7.5 Hz, 3H), 4.70 (d, J = 7.8 Hz, 2H), 2.91 - 2.76 (m, 1H), 2.14 - 2.01 (m, 1H), 1.89 - 1.62 (m, 6H), 1.61 - 1.46 (m, 1H), 0.67 (t, J = 7.4 Hz, 3H).

[0645] Compound M-236: 147 mg, white solid, ESI [M+H] + = 296.9.

[0646] 1H NMR (400 MHz, d6-DMSO) δ 8.11 (s, 1H), 5.71 (p, J = 7.9 Hz, 1H), 3.67 (t, J = 8.6 Hz, 1H), 3.57 - 3.48 (m, 2H), 3.37 - 3.33 (m, 2H), 1.56 - 1.41 (m, 2H), 0.72 - 0.58 (m, 2H), 0.53 - 0.37 (m, 4H), 0.30 - 0.17 (m, 2H).

[0647] Compound M-238: 108 mg, colorless oil, ESI [M+H] + = 296.9.

[0648] 1 H NMR (400 MHz, d6-DMSO) δ 8.12 (d, J = 1.7 Hz, 1H), 5.68 (p, J = 7.9 Hz, 1H), 4.89 (s, 1H), 4.55 (s, 1H), 4.43 (d, J = 10.3 Hz, 1H), 3.57 - 3.45 (m, 2H), 3.40 - 3.34 (m, 2H), 1.73 (s, 3H), 1.59 - 1.42 (m, 1H), 0.94 - 0.78 (m, 1H), 0.68 - 0.49 (m, 2H), 0.37 - 0.19 (m, 1H).

[0649] Compound M-243: 147 mg, colorless oil, ESI [M+H] + = 291.0.

[0650] 1 H NMR (400 MHz, d6-DMSO) δ 8.08 (d, J = 1.3 Hz, 1H), 5.56 - 5.40 (m, 2H), 5.11 - 4.91 (m, 2H), 3.71 (t, J = 8.8 Hz, 1H), 1.58 - 1.43 (m, 2H), 1.38 (d, J = 6.2 Hz, 3H), 0.71 - 0.61 (m, 2H), 0.52 - 0.39 (m, 4H), 0.29 - 0.19 (m, 2H).

[0651] Compound M-245: 106 mg, colorless oil, ESI [M+H] + = 291.0.

[0652] 1H NMR (400 MHz, d6-DMSO) δ 8.08 (s, 1H), 5.54 - 5.39 (m, 2H), 5.08 - 4.94 (m, 2H), 4.90 (s, 1H), 4.58 (d, J = 5.3 Hz, 1H), 4.48 (d, J = 10.1 Hz, 1H), 1.73 (s, 3H), 1.59 - 1.42 (m, 1H), 1.36 (d, J = 6.2 Hz, 3H), 0.92 - 0.78 (m, 1H), 0.68 - 0.49 (m, 2H), 0.37 - 0.22 (m, 1H).

[0653] Compound M-250: 46 mg, colorless oil, ESI [M+H] + = 305.0.

[0654] 1 H NMR (400 MHz, d6-DMSO) δ 8.04 (d, J = 1.4 Hz, 1H), 5.73 (t, J = 6.7 Hz, 1H), 5.03 (d, J = 6.7 Hz, 2H), 3.68 (t, J = 8.9 Hz, 1H), 1.58 (s, 6H), 1.54 - 1.43 (m, 2H), 0.72 - 0.61 (m, 2H), 0.53 - 0.37 (m, 4H), 0.28 - 0.18 (m, 2H).

[0655] Compound M-257: 140 mg, colorless oil, ESI [M+H] + = 303.0.

[0656] 1 H NMR (400 MHz, d6-DMSO) δ 8.12 (d, J = 1.4 Hz, 1H), 6.02 - 5.89 (m, 1H), 5.74 - 5.60 (m, 3H), 3.69 (t, J = 9.1 Hz, 1H), 1.54 (d, J = 6.7 Hz, 3H), 1.53 - 1.44 (m, 2H), 0.73 - 0.62 (m, 2H), 0.54 - 0.38 (m, 4H), 0.31 - 0.19 (m, 2H).

[0657] Compound M-259: 113 mg, colorless oil, ESI [M+H] + = 303.0.

[0658] 1H NMR (400 MHz, d6-DMSO) δ 8.13 (dd, J = 2.7, 2.1 Hz, 1H), 6.01 - 5.89 (m, 1H), 5.78 - 5.58 (m, 3H), 4.90 (d, J = 4.3 Hz, 1H), 4.58 (d, J = 13.9 Hz, 1H), 4.47 (d, J = 10.3 Hz, 1H), 1.75 (s, 3H), 1.60 - 1.39 (m, 4H), 1.02 - 0.78 (m, 1H), 0.67 - 0.45 (m, 2H), 0.39 - 0.23 (m, 1H).

[0659] Compound M-264: 119 mg, white solid, ESI [M+H] + = 267.0.

[0660] 1 H NMR (400 MHz, d6-DMSO) δ 8.06 (d, J = 1.6 Hz, 1H), 5.18 - 4.99 (m, 1H), 3.71 (t, J = 9.1 Hz, 1H), 1.58 - 1.39 (m, 2H), 1.28 (d, J = 6.2 Hz, 6H), 0.74 - 0.57 (m, 2H), 0.54 - 0.36 (m, 4H), 0.33 - 0.11 (m, 2H).

[0661] Compound M-266: 63 mg, colorless oil, ESI [M+H] + = 267.0.

[0662] 1 H NMR (400 MHz, d6-DMSO) δ 8.06 (d, J = 1.8 Hz, 1H), 5.14 - 4.99 (m, 1H), 4.89 (s, 1H), 4.58 (s, 1H), 4.49 (d, J = 10.3 Hz, 1H), 1.73 (s, 3H), 1.26 (d, J = 6.3 Hz, 7H), 0.91 - 0.79 (m, 1H), 0.67 - 0.50 (m, 2H), 0.35 - 0.21 (m, 1H).

[0663] Compound M-271: 142 mg, white solid, ESI [M+H] + = 295.0.

[0664] 1H NMR (400 MHz, d6-DMSO) d 8.09 (d, J = 1.1 Hz, 1H), 3.93 (s, 2H), 3.73 (t, J = 8.6 Hz, 1H), 1.58 - 1.42 (m, 2H), 0.97 (s, 9H), 0.73 - 0.59 (m, 2H), 0.52 - 0.35 (m, 4H), 0.30 - 0.18 (m, 2H).

[0665] Compound M-273: 121 mg, white solid, ESI [M+H] + = 295.0.

[0666] 1 H NMR (400 MHz, d6-DMSO) d 4.89 (s, 1H), 4.59 (s, 1H), 4.52 (d, J = 10.4 Hz, 1H), 3.98 - 3.83 (m, 2H), 1.74 (s, 3H), 1.59 - 1.44 (m, 1H), 0.95 (s, 9H), 0.90 - 0.77 (m, 1H), 0.67 - 0.49 (m, 2H), 0.38 - 0.20 (m, 1H).

[0667] Compound M-278: 133 mg, white semi-solid, ESI [M+H] + = 318.9.

[0668] 1 H NMR (400 MHz, d6-DMSO) d 8.13 (s, 1H), 5.86 (t, J = 6.7 Hz, 1H), 5.16 (d, J = 6.7 Hz, 2H), 4.82 (d, J = 7.7 Hz, 2H), 4.68 (d, J = 7.9 Hz, 2H), 3.66 (t, J = 8.6 Hz, 1H), 1.56 - 1.41 (m, 2H), 0.74 - 0.60 (m, 2H), 0.56 - 0.36 (m, 4H), 0.32 - 0.15 (m, 2H).

[0669] Compound M-280: 140 mg, colorless oil, ESI [M+H] + = 319.0.

[0670] 1H NMR (400 MHz, d6-DMSO) δ 8.13 (d, J = 1.7 Hz, 1H), 5.81 (t, J = 6.7 Hz, 1H), 5.14 (dd, J = 6.7, 2.1 Hz, 2H), 4.91 (s, 1H), 4.82 (d, J = 7.4 Hz, 1H), 4.75 (d, J = 7.4 Hz, 1H), 4.67 (d, J = 8.1 Hz, 2H), 4.59 (s, 1H), 4.42 (d, J = 10.3 Hz, 1H), 1.72 (s, 3H), 1.58 - 1.44 (m, 1H), 0.91 - 0.78 (m, 1H), 0.67 - 0.51 (m, 2H), 0.38 - 0.25 (m, 1H).

[0671] Compound M-292: 140 mg, colorless oil, ESI [M+H] + = 334.9.

[0672] 1 H NMR (400 MHz, d6-DMSO) δ 8.10 (s, 1H), 5.90 (t, J = 6.6 Hz, 1H), 5.20 (d, J = 6.6 Hz, 2H), 3.81 (d, J = 10.7 Hz, 2H), 3.69 - 3.58 (m, 1H), 3.38 - 3.33 (m, 2H), 1.56 - 1.40 (m, 2H), 0.74 - 0.58 (m, 2H), 0.54 - 0.37 (m, 4H), 0.31 - 0.16 (m, 2H).

[0673] Compound M-294: 42 mg, colorless oil, ESI [M+H] + = 334.9.

[0674] 1 H NMR (400 MHz, d6-DMSO) δ 8.10 (d, J = 1.8 Hz, 1H), 5.86 (t, J = 6.6 Hz, 1H), 5.19 (d, J = 6.6 Hz, 2H), 4.91 (s, 1H), 4.58 (s, 1H), 4.42 (d, J = 10.4 Hz, 1H), 3.82 (d, J = 10.2 Hz, 1H), 3.74 (d, J = 10.2 Hz, 1H), 3.35 (t, J = 6.3 Hz, 2H), 1.72 (s, 3H), 1.58 - 1.44 (m, 1H), 0.91 - 0.78 (m, 1H), 0.67 - 0.50 (m, 2H), 0.36 - 0.23 (m, 1H).

[0675] Compound M-365: 19 mg, light yellow solid, ESI [M+H] + = 276.2.

[0676] 1 H NMR (400 MHz, d6-DMSO) d 7.85 (d, J = 1.3 Hz, 1H), 7.77 (d, J = 1.3 Hz, 1H), 7.03 (s, 1H), 1.41 (s, 6H), 1.38 - 1.29 (m, 1H), 1.28 (s, 6H), 1.27 - 1.23 (m, 1H), 0.53 - 0.47 (m, 2H), 0.47 - 0.41 (m, 2H), 0.41 - 0.33 (m, 4H).

[0677] Compound M-501: 229 mg, white solid, ESI [M+H] + = 307.2.

[0678] 1 H NMR (400 MHz, d6-DMSO) d 8.16 (s, 1H), 6.34 (dd, J = 17.4, 10.9 Hz, 1H), 5.36 (dd, J = 14.1, 11.7 Hz, 2H), 4.81 (d, J = 7.8 Hz, 2H), 4.70 (d, J = 7.9 Hz, 2H), 3.73 - 3.55 (m, 1H), 1.56 - 1.42 (m, 2H), 0.71 - 0.59 (m, 2H), 0.53 - 0.37 (m, 4H), 0.29 - 0.18 (m, 2H).

[0679] Compound M-503: 47 mg, colorless oil, ESI [M+H] + = 333.1.

[0680] 1 H NMR (400 MHz, CDC13) d 7.97 (s, 1H), 7.91 (s, 1H), 7.45 (d, J = 5.0 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.07 (d, J = 4.6 Hz, 1H), 6.65 - 6.52 (m, 1H), 6.24 (dd, J = 17.1, 10.8 Hz, 1H), 5.28 (dd, J = 17.9, 14.2 Hz, 2H), 4.96 (d, J = 7.5 Hz, 1H), 4.85 (d, J = 7.6 Hz, 1H), 4.77 (d, J = 8.1 Hz, 2H), 1.93 (d, J = 6.8 Hz, 3H).

[0681] Compound M-504: 58 mg, white solid, ESI [M+H] + = 351.1.

[0682] 1H NMR (400 MHz, CDC13) δ 7.49 - 7.40 (m, 1H), 7.32 (dd, J = 4.5, 2.0 Hz, 2H), 7.30 (s, 1H), 7.01 - 6.93 (m, 1H), 6.43 (d, J = 7.0 Hz, 1H), 6.21 (dd, J = 17.4, 10.9 Hz, 1H), 5.23 (dd, J = 15.8, 14.2 Hz, 2H), 4.95 (d, J = 7.4 Hz, 1H), 4.82 (d, J = 7.5 Hz, 1H), 4.74 (dd, J = 7.4, 3.9 Hz, 2H), 1.88 (d, J = 7.0 Hz, 3H).

[0683] Compound M-505: 93 mg, colorless oil, ESI [M+H] + = 289.0.

[0684] 1 H NMR (400 MHz, d6-DMSO) δ 8.29 (s, 1H), 7.82 (s, 1H), 6.32 (dd, J = 17.4, 10.9 Hz, 1H), 5.33 (dd, J = 14.1, 10.1 Hz, 2H), 4.88 (s, 1H), 4.83 (d, J = 7.5 Hz, 1H), 4.78 (d, J = 7.4 Hz, 1H), 4.73 - 4.65 (m, 2H), 4.56 (s, 1H), 4.50 (d, J = 10.3 Hz, 1H), 1.69 (s, 3H), 1.62 - 1.47 (m, 1H), 0.89 - 0.77 (m, 1H), 0.65 - 0.48 (m, 2H), 0.27 (td, J = 9.3, 4.8 Hz, 1H).

[0685] Compound M-550: 35 mg, colorless oil, ESI [M+H] + = 335.1.

[0686] 1 H NMR (400 MHz, d6-DMSO) δ 8.20 (s, 1H), 7.80 (s, 1H), 7.32 (d, J = 7.0 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 6.60 (d, J = 7.1 Hz, 1H), 6.35 (q, J = 7.0 Hz, 1H), 4.69 (d, J = 7.1 Hz, 1H), 4.52 (d, J = 7.2 Hz, 1H), 4.43 (dd, J = 6.9, 3.6 Hz, 2H), 2.37 (s, 3H), 1.83 (d, J = 7.1 Hz, 3H), 1.50 (s, 3H).

[0687] Compound M-551: 34 mg, colorless oil, ESI [M+H] + = 347.1.

[0688] 1 H NMR (400 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.86 (s, 1H), 7.32 (d, J = 7.0 Hz, 1H), 7.23 (s, 1H), 6.60 (d, J = 7.2 Hz, 1H), 6.36 (q, J = 6.9 Hz, 1H), 6.14 (dd, J = 17.4, 10.9 Hz, 1H), 5.14 (d, J = 10.9 Hz, 1H), 5.03 (d, J = 17.4 Hz, 1H), 4.80 (d, J = 7.2 Hz, 1H), 4.62 (d, J = 4.5 Hz, 3H), 2.35 (s, 3H), 1.83 (d, J = 7.0 Hz, 3H).

[0689] Compound M-552: 78 mg, colorless oil, ESI [M+H] + = 359.1.

[0690] 1 H NMR (400 MHz, d6-DMSO) δ 8.20 (s, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.33 (d, J = 6.8 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 6.63 (d, J = 7.0 Hz, 1H), 6.37 (d, J = 7.0 Hz, 1H), 5.62 (t, J = 6.7 Hz, 1H), 5.03 (dd, J = 11.9, 6.7 Hz, 1H), 4.90 (dd, J = 11.9, 6.6 Hz, 1H), 4.79 (d, J = 7.3 Hz, 1H), 4.63 (d, J = 6.8 Hz, 3H), 2.37 (s, 3H), 1.82 (t, J = 5.2 Hz, 3H).

[0691] Compound M-553: 276 mg, colorless syrup, ESI [M+H] + = 318.9.

[0692] 1H NMR (400 MHz, d6-DMSO) δ 8.26 (s, 1H), 7.78 (d, J = 0.9 Hz, 1H), 7.24 (t, J = 7.1 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.75 - 6.68 (m, 1H), 6.34 (q, J = 7.1 Hz, 1H), 4.69 (d, J = 7.2 Hz, 1H), 4.57 (d, J = 7.2 Hz, 1H), 4.48 - 4.42 (m, 2H), 2.25 (d, J = 1.9 Hz, 3H), 1.84 (d, J = 7.1 Hz, 3H), 1.57 (s, 3H).

[0693] Compound M-554: 54 mg, colorless oil, ESI [M+H] + = 330.9.

[0694] 1 H NMR (400 MHz, d6-DMSO) δ 8.28 (s, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.70 (t, J = 7.5 Hz, 1H), 6.34 (q, J = 7.1 Hz, 1H), 6.19 (dd, J = 17.4, 10.9 Hz, 1H), 5.16 (dd, J = 27.7, 14.2 Hz, 2H), 4.79 (d, J = 7.3 Hz, 1H), 4.69 - 4.60 (m, 3H), 2.23 (d, J = 1.7 Hz, 3H), 1.84 (d, J = 7.1 Hz, 3H).

[0695] Compound M-555: 221 mg, colorless oil, ESI [M+H] + = 342.9.

[0696] 1 H NMR (400 MHz, d6-DMSO) δ 8.27 (s, 1H), 7.81 (d, J = 0.9 Hz, 1H), 7.24 (t, J = 7.1 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.71 (t, J = 6.9 Hz, 1H), 6.35 (q, J = 7.1 Hz, 1H), 5.69 (t, J = 6.7 Hz, 1H), 5.05 (dd, J = 11.9, 6.7 Hz, 1H), 4.93 (dd, J = 11.9, 6.7 Hz, 1H), 4.79 (d, J = 7.4 Hz, 1H), 4.69 - 4.61 (m, 3H), 2.24 (d, J = 1.7 Hz, 3H), 1.84 (d, J = 7.1 Hz, 3H).

[0697] Compound M-572: 108 mg, white solid, ESI [M+H] + = 329.1.

[0698] 1 H NMR (400 MHz, d6-DMSO) δ 8.17 (s, 1H), 7.39 (d, J = 8.9 Hz, 1H), 7.20 (d, J = 5.1 Hz, 1H), 6.72 (s, 1H), 6.33 (d, J = 7.2 Hz, 1H), 4.36 - 4.16 (m, 2H), 3.52 (t, J = 4.7 Hz, 2H), 3.23 (s, 3H), 1.85 (d, J = 7.1 Hz, 3H).

[0699] Compound M-573: 112 mg, colorless oil, ESI [M+H] + = 311.1.

[0700] 1 H NMR (400 MHz, d6-DMSO) δ 8.35 (s, 1H), 7.74 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.24 - 7.13 (m, 1H), 6.68 (t, J = 7.2 Hz, 1H), 6.43 (d, J = 7.2 Hz, 1H), 4.34 - 4.16 (m, 2H), 3.55 (t, J = 4.6 Hz, 2H), 3.25 (s, 3H), 1.87 (d, J = 7.2 Hz, 3H).

[0701] Compound M-574: 177 mg, colorless oil, ESI [M+H] + = 325.1.

[0702] 1 H NMR (400 MHz, d6-DMSO) δ 8.07 (d, J = 1.6 Hz, 1H), 7.24 (s, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.75 (s, 1H), 6.33 (d, J = 7.1 Hz, 1H), 4.26 (dd, J = 10.0, 5.5 Hz, 2H), 3.59 - 3.48 (m, 2H), 3.24 (s, 3H), 2.25 (d, J = 1.6 Hz, 3H), 1.82 (d, J = 7.1 Hz, 3H).

[0703] Compound M-575: 172 mg, colorless oil, ESI [M+H] + = 307.1.

[0704] 1H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H), 7.71 (s, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.72 (t, J = 7.4 Hz, 1H), 6.42 (q, J = 7.1 Hz, 1H), 4.38 - 4.16 (m, 2H), 3.55 (dd, J = 6.4, 2.8 Hz, 2H), 3.25 (s, 3H), 2.24 (s, 3H), 1.83 (d, J = 7.1 Hz, 3H).

[0705] Compound M-577: 176 mg, white solid, ESI [M+H] + = 323.1.

[0706] 1 H NMR (400 MHz, d6-DMSO) δ 8.19 (s, 1H), 7.74 (s, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 6.46 (q, J = 7.0 Hz, 1H), 4.37 - 4.11 (m, 2H), 3.54 (td, J = 5.6, 3.6 Hz, 2H), 3.33 (s, 2H), 3.24 (s, 3H), 2.38 (s, 3H), 1.83 (d, J = 7.1 Hz, 3H).

[0707] Compound M-579: 141 mg, white solid, ESI [M+H] + = 337.1.

[0708] 1 H NMR (400 MHz, d6-DMSO) δ 8.10 (d, J = 1.6 Hz, 1H), 7.25 (s, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.74 (s, 1H), 6.25 (d, J = 7.1 Hz, 1H), 4.66 (d, J = 7.2 Hz, 1H), 4.53 (d, J = 7.2 Hz, 1H), 4.44 (d, J = 7.4 Hz, 2H), 2.25 (d, J = 1.5 Hz, 3H), 1.83 (d, J = 7.1 Hz, 3H), 1.53 (s, 3H).

[0709] Compound M-644: 21 mg, colorless oil, ESI [M+H] + = 283.1.

[0710] 1H NMR (400 MHz, CDC13) δ 7.31 (s, 1H), 5.00 (dd, J = 9.7, 6.7 Hz, 1H), 4.93 (d, J = 7.2 Hz, 2H), 4.61 (d, J = 7.6 Hz, 2H), 2.73 (dd, J = 16.6, 7.4 Hz, 1H), 2.19 (d, J = 7.4 Hz, 1H), 2.03 - 1.89 (m, 2H), 1.86 (s, 3H), 1.86 - 1.79 (m, 2H), 1.75 (dd, J = 17.2, 9.2 Hz, 1H), 1.39 (d, J = 6.7 Hz, 3H).

[0711] Compound M-645: 17 mg, white solid, ESI [M+H] + = 295.1.

[0712] 1 H NMR (400 MHz, CDC13) δ 7.34 (s, 1H), 6.37 (dd, J = 17.4, 10.9 Hz, 1H), 5.44 (dd, J = 24.9, 14.2 Hz, 2H), 5.09 - 4.93 (m, 3H), 4.81 (d, J = 7.4 Hz, 2H), 2.73 (dd, J = 16.6, 7.9 Hz, 1H), 2.17 (dt, J = 11.7, 8.2 Hz, 1H), 2.03 - 1.91 (m, 2H), 1.90 - 1.79 (m, 2H), 1.74 (dd, J = 17.0, 8.9 Hz, 1H), 1.39 (t, J = 7.2 Hz, 3H).

[0713] Compound M-646: 34 mg, colorless oil, ESI [M+H] + = 307.

[0714] 1 H NMR (400 MHz, CDC13) δ 7.32 (s, 1H), 5.76 (t, J = 6.7 Hz, 1H), 5.10 (d, J = 6.6 Hz, 2H), 5.05 - 4.93 (m, 3H), 4.85 (d, J = 7.5 Hz, 2H), 2.81 - 2.66 (m, 1H), 2.19 (d, J = 7.8 Hz, 1H), 2.08 - 1.91 (m, 2H), 1.91 - 1.80 (m, 2H), 1.75 (dd, J = 17.2, 8.9 Hz, 1H), 1.39 (d, J = 6.7 Hz, 3H).

[0715] Compound M-650: 27 mg, colorless oil, ESI [M+H] + = 365.1.

[0716] 1 H NMR (400 MHz, CDC13) δ 7.79 (s, 1H), 7.31 (d, J = 0.9 Hz, 2H), 7.16 (s, 1H), 7.02 (d, J = 3.9 Hz, 1H), 5.30 (d, J = 9.5 Hz, 1H), 4.83 (d, J = 7.1 Hz, 1H), 4.72 (d, J = 7.2 Hz, 1H), 4.52 (dd, J = 8.9, 7.7 Hz, 2H), 1.70 (s, 3H), 1.50 (ddd, J = 12.6, 8.1, 4.7 Hz, 1H), 0.97 - 0.83 (m, 2H), 0.66 (td, J = 9.5, 4.7 Hz, 1H), 0.56 (dt, J = 9.7, 4.9 Hz, 1H).

[0717] Compound M-651 : 28 mg, white solid, ESI [M+H] + = 377.1.

[0718] 1 H NMR (400 MHz, CDC13) δ 7.82 (s, 1H), 7.31 (d, J = 5.3 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.05 - 6.95 (m, 1H), 6.21 (dd, J = 17.4, 10.9 Hz, 1H), 5.32 - 5.19 (m, 3H), 4.90 (d, J = 7.6 Hz, 1H), 4.76 (d, J = 7.7 Hz, 1H), 4.71 (d, J = 7.7 Hz, 2H), 1.56 - 1.43 (m, 1H), 0.89 (ddd, J = 12.3, 8.5, 4.6 Hz, 2H), 0.69 - 0.60 (m, 1H), 0.55 (dt, J = 10.0, 4.9 Hz, 1H).

[0719] Compound M-652: 38 mg, white solid, ESI [M+H] + = 389.1.

[0720] 1H NMR (400 MHz, CDC13) δ 7.80 (d, J = 1.1 Hz, 1H), 7.31 (d, J = 1.0 Hz, 2H), 7.14 (s, 1H), 7.02 (dd, J = 5.7, 1.6 Hz, 1H), 5.58 (t, J = 6.6 Hz, 1H), 5.30 (d, J = 9.6 Hz, 1H), 5.00 (dd, J = 11.6, 6.7 Hz, 1H), 4.95 - 4.84 (m, 2H), 4.75 (dd, J = 12.5, 7.2 Hz, 3H), 1.50 (ddd, J = 12.7, 8.0, 4.6 Hz, 1H), 0.97 - 0.79 (m, 2H), 0.71 - 0.61 (m, 1H), 0.56 (dt, J = 9.9, 5.0 Hz, 1H).

[0721] Compound M-654: 23 mg, white solid, ESI [M+H] + = 345.2.

[0722] 1 H NMR (400 MHz, CDC13) δ 7.78 (s, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 7.1 Hz, 2H), 5.31 (d, J = 9.4 Hz, 1H), 4.81 (d, J = 7.0 Hz, 1H), 4.71 (d, J = 7.1 Hz, 1H), 4.51 (t, J = 7.5 Hz, 2H), 2.36 (s, 3H), 1.69 (s, 3H), 1.51 (dd, J = 8.1, 4.1 Hz, 1H), 0.92 - 0.77 (m, 2H), 0.63 (td, J = 9.3, 4.6 Hz, 1H), 0.54 (dt, J = 9.7, 4.8 Hz, 1H).

[0723] Compound M-655: 73 mg, colorless oil, ESI [M+H] + = 357.2.

[0724] 1H NMR (400 MHz, CDC13) δ 7.80 (s, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 7.4 Hz, 2H), 6.21 (dd, J = 17.3, 11.0 Hz, 1H), 5.33 - 5.15 (m, 3H), 4.89 (d, J = 7.4 Hz, 1H), 4.76 (d, J = 7.5 Hz, 1H), 4.70 (d, J = 9.0 Hz, 2H), 2.35 (s, 3H), 1.51 (s, 1H), 0.89 - 0.77 (m, 2H), 0.61 (dd, J = 9.1, 4.5 Hz, 1H), 0.57 - 0.48 (m, 1H).

[0725] Compound M-656: 47 mg, colorless oil, ESI [M+H] + = 369.2.

[0726] 1 H NMR (400 MHz, CDC13) δ 7.79 (s, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 5.57 (t, J = 6.6 Hz, 1H), 5.32 (d, J = 9.1 Hz, 1H), 4.96 (d, J = 6.7 Hz, 1H), 4.88 (dd, J = 11.0, 6.9 Hz, 2H), 4.82 - 4.71 (m, 3H), 2.36 (s, 3H), 1.49 (s, 1H), 0.84 (d, J = 24.2 Hz, 2H), 0.62 (s, 1H), 0.53 (s, 1H).

[0727] Compound M-872: 32 mg, colorless oil, ESI [M+H] + = 320.9.

[0728] 1 H NMR (400 MHz, d6-DMSO) δ 8.26 (s, 1H), 7.74 (d, J = 0.8 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.69 (t, J = 7.0 Hz, 1H), 6.42 (q, J = 7.1 Hz, 1H), 4.27 - 4.10 (m, 2H), 3.39 - 3.31 (m, 2H), 3.21 (s, 3H), 2.25 (d, J = 1.8 Hz, 3H), 1.88 - 1.77 (m, 5H).

[0729] Compound M-874: 53 mg, colorless oil, ESI [M+H]+ = 320.9.

[0730] 1 H NMR (400 MHz, d6-DMSO) δ 8.25 (s, 1H), 7.72 (d, J = 0.6 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.73 (t, J = 7.1 Hz, 1H), 6.43 (q, J = 7.1 Hz, 1H), 4.33 - 4.19 (m, 2H), 3.68 - 3.53 (m, 2H), 3.45 (q, J = 7.0 Hz, 2H), 2.24 (d, J = 1.7 Hz, 3H), 1.84 (d, J = 7.2 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H).

[0731] Compound M-877: 136 mg, colorless oil, ESI [M+H] + = 338.9.

[0732] 1 H NMR (400 MHz, d6-DMSO) δ 8.09 (d, J = 1.7 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.72 (t, J = 7.1 Hz, 1H), 6.33 (q, J = 7.1 Hz, 1H), 4.26 - 4.10 (m, 2H), 3.33 (t, J = 6.3 Hz, 2H), 3.20 (s, 3H), 2.25 (d, J = 1.8 Hz, 3H), 1.87 - 1.75 (m, 5H).

[0733] Compound M-879: 92 mg, colorless oil, ESI [M+H] + = 338.9.

[0734] 1 H NMR (400 MHz, d6-DMSO) δ 8.08 (d, J = 1.6 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.75 (t, J = 7.3 Hz, 1H), 6.34 (q, J = 7.1 Hz, 1H), 4.32 - 4.18 (m, 2H), 3.63 - 3.50 (m, 2H), 3.43 (q, J = 7.0 Hz, 2H), 2.25 (d, J = 1.7 Hz, 3H), 1.82 (d, J = 7.1 Hz, 3H), 1.06 (t, J = 7.0 Hz, 3H).

[0735] Compound M-1250: 409 mg, white semisolid, ESI [M+H]+ = 359.1.

[0736] 1 H NMR (400 MHz, d6-DMSO) δ 8.16 (d, J = 1.6 Hz, 1H), 7.61 - 7.50 (m, 1H), 6.81 - 6.70 (m, 1H), 6.28 (q, J = 7.0 Hz, 1H), 4.69 (d, J = 7.2 Hz, 1H), 4.56 (d, J = 7.2 Hz, 1H), 4.47 (d, J = 3.2 Hz, 1H), 4.45 (d, J = 3.3 Hz, 1H), 1.85 (d, J = 7.1 Hz, 3H), 1.59 (s, 3H).

[0737] Compound M-1251: 275 mg, white solid, ESI [M+H] + = 373.1.

[0738] 1 H NMR (400 MHz, d6-DMSO) δ 8.16 (d, J = 1.5 Hz, 1H), 7.61 - 7.45 (m, 1H), 6.79 - 6.64 (m, 1H), 6.27 (q, J = 7.1 Hz, 1H), 4.67 (d, J = 7.3 Hz, 1H), 4.58 - 4.45 (m, 3H), 2.08 - 1.92 (m, 2H), 1.85 (d, J = 7.1 Hz, 3H), 0.75 (t, J = 7.4 Hz, 3H).

[0739] Compound M-1252: 473 mg, colorless syrup, ESI [M+H] + = 371.1.

[0740] 1 H NMR (400 MHz, d6-DMSO) δ 8.18 (d, J = 1.6 Hz, 1H), 7.61 - 7.45 (m, 1H), 6.80 - 6.63 (m, 1H), 6.32 - 6.14 (m, 2H), 5.21 (d, J = 10.9 Hz, 1H), 5.13 (d, J = 17.4 Hz, 1H), 4.79 (d, J = 7.3 Hz, 1H), 4.66 (d, J = 7.1 Hz, 3H), 1.85 (d, J = 7.1 Hz, 3H).

[0741] Compound M-1253: 238 mg, colorless syrup, ESI [M+H] + = 383.1.

[0742] 1H NMR (400 MHz, d6-DMSO) δ 8.17 (s, 1H), 7.63 - 7.46 (m, 1H), 6.84 - 6.61 (m, 1H), 6.27 (q, J = 7.0 Hz, 1H), 5.72 (t, J = 6.6 Hz, 1H), 5.13 - 5.02 (m, 1H), 5.00 - 4.92 (m, 1H), 4.80 (d, J = 7.3 Hz, 1H), 4.65 (q, J = 7.8 Hz, 3H), 1.85 (d, J = 7.1 Hz, 3H).

[0743] Compound M-1254: 46 mg, white solid, ESI [M+H] + = 359.1.

[0744] 1 H NMR (400 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.58 - 7.39 (m, 1H), 7.22 - 7.07 (m, 1H), 6.18 (q, J = 7.1 Hz, 1H), 4.68 (d, J = 7.1 Hz, 1H), 4.52 - 4.37 (m, 3H), 1.93 (d, J = 7.2 Hz, 3H), 1.52 (s, 3H).

[0745] Compound M-1255: 74 mg, colorless syrup, ESI [M+H] + = 373.1.

[0746] 1 H NMR (400 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.56 - 7.39 (m, 1H), 7.22 - 7.00 (m, 1H), 6.17 (q, J = 7.1 Hz, 1H), 4.64 (d, J = 7.3 Hz, 1H), 4.53 - 4.32 (m, 3H), 2.12 - 1.67 (m, 5H), 0.71 (t, J = 7.4 Hz, 3H).

[0747] Compound M-1256: 71 mg, colorless syrup, ESI [M+H] + = 371.1.

[0748] 1H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.55 - 7.41 (m, 1H), 7.19 - 7.07 (m, 1H), 6.23 - 6.09 (m, 2H), 5.15 (d, J = 11.0 Hz, 1H), 5.04 (d, J = 17.4 Hz, 1H), 4.78 (d, J = 7.3 Hz, 1H), 4.67 - 4.53 (m, 3H), 1.93 (d, J = 7.2 Hz, 3H).

[0749] Compound M-1257: 127 mg, white solid, ESI [M+H] + = 383.1.

[0750] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.55 - 7.41 (m, 1H), 7.19 - 7.07 (m, 1H), 6.23 - 6.09 (m, 2H), 5.15 (d, J = 11.0 Hz, 1H), 5.04 (d, J = 17.4 Hz, 1H), 4.78 (d, J = 7.3 Hz, 1H), 4.67 - 4.53 (m, 3H), 1.93 (d, J = 7.2 Hz, 3H).

[0751] Compound M-1258: 132 mg, light yellow syrup, ESI [M+H] + = 343.1.

[0752] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.55 - 7.41 (m, 1H), 7.19 - 7.07 (m, 1H), 6.23 - 6.09 (m, 2H), 5.15 (d, J = 11.0 Hz, 1H), 5.04 (d, J = 17.4 Hz, 1H), 4.78 (d, J = 7.3 Hz, 1H), 4.67 - 4.53 (m, 3H), 1.93 (d, J = 7.2 Hz, 3H).

[0753] Compound M-1339: 82 mg, colorless syrup, ESI [M+H] + = 336.9.

[0754] 1H NMR (400 MHz, d6-DMSO) δ 8.08 (d, J = 1.6 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.74 (t, J = 7.3 Hz, 1H), 6.34 (q, J = 7.1 Hz, 1H), 4.32 - 4.15 (m, 2H), 2.95 - 2.88 (m, 1H), 2.71 - 2.62 (m, 1H), 2.48 - 2.41 (m, 1H), 2.25 (d, J = 1.7 Hz, 3H), 1.86 - 1.73 (m, 5H).

[0755] Compound M-1344: 54 mg, colorless syrup, ESI [M+H] + = 340.9.

[0756] 1 H NMR (400 MHz, d6-DMSO) δ 8.17 (d, J = 1.7 Hz, 1H), 7.44 - 7.34 (m, 1H), 7.27 - 7.15 (m, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.35 (q, J = 7.1 Hz, 1H), 4.36 - 4.15 (m, 2H), 2.96 - 2.89 (m, 1H), 2.72 - 2.63 (m, 1H), 2.47 - 2.40 (m, 1H), 1.85 (d, J = 7.2 Hz, 3H), 1.83 - 1.74 (m, 2H).

[0757] Compound M-1347: 149 mg, colorless syrup, ESI [M+H] + = 340.9.

[0758] 1 H NMR (400 MHz, d6-DMSO) δ 8.16 (s, 1H), 7.47 - 7.35 (m, 1H), 7.13 - 7.03 (m, 2H), 6.24 (q, J = 7.2 Hz, 1H), 4.28 - 4.13 (m, 2H), 2.96 - 2.84 (m, 1H), 2.71 - 2.60 (m, 1H), 2.47 - 2.37 (m, 1H), 1.91 (d, J = 7.2 Hz, 3H), 1.82 - 1.72 (m, 2H).

[0759] Compound M-1354: 98 mg, colorless syrup, ESI [M+H] + = 358.9.

[0760] 1H NMR (400 MHz, d6-DMSO) δ 8.20 (s, 1H), 7.77 (s, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.45 (qd, J = 7.0, 2.4 Hz, 1H), 4.32 - 4.14 (m, 2H), 2.96 - 2.88 (m, 1H), 2.71 - 2.60 (m, 1H), 2.48 - 2.40 (m, 1H), 2.37 (s, 3H), 1.82 (d, J = 7.1 Hz, 3H), 1.80 - 1.70 (m, 2H).

[0761] Compound M-1439: 76 mg, colorless syrup, ESI [M+H] + = 334.9.

[0762] 1 H NMR (400 MHz, d6-DMSO) δ 8.20 (s, 1H), 7.77 (s, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.45 (qd, J = 7.0, 2.4 Hz, 1H), 4.32 - 4.14 (m, 2H), 2.96 - 2.88 (m, 1H), 2.71 - 2.60 (m, 1H), 2.48 - 2.40 (m, 1H), 2.37 (s, 3H), 1.82 (d, J = 7.1 Hz, 3H), 1.80 - 1.70 (m, 2H).

[0763] Compound M-1446: 95 mg, colorless syrup, ESI [M+H] + = 323.0.

[0764] 1 H NMR (400 MHz, d6-DMSO) δ 8.20 (s, 1H), 7.77 (s, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.45 (qd, J = 7.0, 2.4 Hz, 1H), 4.32 - 4.14 (m, 2H), 2.96 - 2.88 (m, 1H), 2.71 - 2.60 (m, 1H), 2.48 - 2.40 (m, 1H), 2.37 (s, 3H), 1.82 (d, J = 7.1 Hz, 3H), 1.80 - 1.70 (m, 2H).

[0765] Compound M-1469: 225 mg, colorless syrup, ESI [M+H] + = 311.0.

[0766] 1H NMR (400 MHz, d6-DMSO) δ 8.30 (s, 1H), 7.67 (s, 1H), 7.46 - 7.34 (m, 1H), 7.12 - 7.01 (m, 2H), 6.31 (q, J = 7.2 Hz, 1H), 4.31 - 4.16 (m, 2H), 3.58 - 3.42 (m, 2H), 3.23 (s, 3H), 1.92 (d, J = 7.3 Hz, 3H).

[0767] Compound M-1613: 184 mg, colorless syrup, ESI [M+H] + = 367.1.

[0768] 1 H NMR (400 MHz, d6-DMSO) δ 8.18 (dd, J = 5.6, 1.5 Hz, 1H), 7.63 - 7.48 (m, 1H), 6.78 - 6.59 (m, 1H), 6.28 (p, J = 6.9 Hz, 1H), 5.64 - 5.53 (m, 1H), 3.61 - 3.49 (m, 2H), 3.27 (s, 1.6H), 3.24 (s, 1.4H), 1.86 (d, J = 7.1 Hz, 3H), 1.82 (d, J = 2.2 Hz, 1.4H), 1.80 (d, J = 2.2 Hz, 1.6H).

[0769] Compound M-1614: 159 mg, colorless syrup, ESI [M+H] + = 367.1.

[0770] 1 H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H), 7.57 - 7.42 (m, 1H), 7.21 - 7.05 (m, 1H), 6.27 - 6.13 (m, 1H), 5.62 - 5.47 (m, 1H), 3.61 - 3.46 (m, 2H), 3.27 (s, 1.7H), 3.19 (s, 1.3H), 1.94 (d, J = 7.2 Hz, 3H), 1.81 (d, J = 2.2 Hz, 1.3H), 1.76 (d, J = 2.2 Hz, 1.7H).

[0771] Compound M-1615: 144 mg, colorless syrup, ESI [M+H] + = 348.9.

[0772] 1H NMR (400 MHz, d6-DMSO) d 8.16 (d, J = 1.6 Hz, 0.47H), 8.14 (d, J = 1.6 Hz, 0.52H), 7.43 - 7.33 (m, 1H), 7.29 - 7.14 (m, 2H), 7.00 - 6.86 (m, 1H), 6.31 (q, J = 7.0 Hz, 1H), 5.64 - 5.56 (m, 0.55H), 5.56 - 5.49 (m, 0.45H), 3.61 - 3.48 (m, 2H), 3.26 (s, 1.6H), 3.22 (s, 1.4H), 1.84 (d, J = 7.1 Hz, 3H), 1.81 (d, J = 2.2 Hz, 1.4H), 1.79 (d, J = 2.2 Hz, 1.6H).

[0773] Compound M-1618: 146 mg, colorless syrup, ESI [M+H] + = 364.9.

[0774] 1 H NMR (400 MHz, d6-DMSO) d 8.16 (d, J = 1.6 Hz, 0.47H), 8.14 (d, J = 1.6 Hz, 0.52H), 7.43 - 7.33 (m, 1H), 7.29 - 7.14 (m, 2H), 7.00 - 6.86 (m, 1H), 6.31 (q, J = 7.0 Hz, 1H), 5.64 - 5.56 (m, 0.55H), 5.56 - 5.49 (m, 0.45H), 3.61 - 3.48 (m, 2H), 3.26 (s, 1.6H), 3.22 (s, 1.4H), 1.84 (d, J = 7.1 Hz, 3H), 1.81 (d, J = 2.2 Hz, 1.4H), 1.79 (d, J = 2.2 Hz, 1.6H).

[0775] Compound M-1624: 114 mg, colorless syrup, ESI [M+H] + = 362.9.

[0776] 1H NMR (400 MHz, d6-DMSO) d 8.13 (d, J = 1.6 Hz, 0.48H), 8.12 (d, J = 1.6 Hz, 0.51H), 7.25 (dd, J = 13.4, 6.6 Hz, 1H), 7.08 (dd, J = 14.5, 7.4 Hz, 1H), 6.78 - 6.68 (m, 1H), 6.38 - 6.19 (m, 1H), 5.68 - 5.57 (m, 0.53H), 5.57 - 5.47 (m, 0.47H), 3.63 - 3.46 (m, 2H), 3.27 (s, 1.6H), 3.23 (s, 1.4H), 2.26 (s, 3H), 1.89 - 1.73 (m, 6H).

[0777] Compound M-1625: 119 mg, colorless syrup, ESI [M+H] + = 378.9.

[0778] 1 H NMR (400 MHz, d6-DMSO) d 8.13 (d, J = 1.6 Hz, 0.48H), 8.12 (d, J = 1.6 Hz, 0.51H), 7.25 (dd, J = 13.4, 6.6 Hz, 1H), 7.08 (dd, J = 14.5, 7.4 Hz, 1H), 6.78 - 6.68 (m, 1H), 6.38 - 6.19 (m, 1H), 5.68 - 5.57 (m, 0.53H), 5.57 - 5.47 (m, 0.47H), 3.63 - 3.46 (m, 2H), 3.27 (s, 1.6H), 3.23 (s, 1.4H), 2.26 (s, 3H), 1.89 - 1.73 (m, 6H).

[0779] Compound M-1629: 84 mg, colorless syrup, ESI [M+H] + = 366.9.

[0780] 1H NMR (400 MHz, d6-DMSO) d 8.21 (d, J = 1.6 Hz, 0.47H), 8.20 (d, J = 1.6 Hz, 0.52H), 7.46 - 7.33 (m, 1H), 7.24 - 7.12 (m, 1H), 6.75 - 6.62 (m, 1H), 6.36 - 6.23 (m, 1H), 5.62 - 5.56 (m, 0.55H), 5.56 - 5.51 (m, 0.44H), 3.59 - 3.48 (m, 2H), 3.25 (s, 1.7H), 3.21 (s, 1.3H), 1.85 (d, J = 7.1 Hz, 3H), 1.80 (d, J = 2.2 Hz, 1.3H), 1.78 (d, J = 2.2 Hz, 1.7H).

[0781] Compound M-1632: 145 mg, colorless syrup, ESI [M+H] + = 366.9.

[0782] 1 H NMR (400 MHz, d6-DMSO) d 8.20 (s, 1H), 7.51 - 7.33 (m, 1H), 7.17 - 7.00 (m, 2H), 6.21 (q, J = 7.1 Hz, 1H), 5.60 - 5.54 (m, 0.54H), 5.54 - 5.48 (m, 0.44H), 3.60 - 3.44 (m, 2H), 3.27 (s, 1.7H), 3.19 (s, 1.3H), 1.92 (d, J = 7.2 Hz, 3H), 1.82 (d, J = 2.1 Hz, 1.3H), 1.76 (d, J = 2.1 Hz, 1.7H).

[0783] Compound M-1642: 11 mg, white semisolid, ESI [M+H] + = 346.9.

[0784] 1H NMR (400 MHz, d6-DMSO) d 8.28 (s, 0.6H), 8.26 (s, 0.4H), 7.78 (d, J = 0.7 Hz, 0.6H), 7.77 (d, J = 0.7 Hz, 0.4H), 7.54 - 7.46 (m, 1H), 7.38 - 7.28 (m, 2H), 6.84 - 6.78 (m, 0.4H), 6.77 - 6.71 (m, 0.6H), 6.45 - 6.36 (m, 1H), 5.64 - 5.57 (m, 0.4H), 5.56 - 5.50 (m, 0.6H), 3.64 - 3.49 (m, 2H), 3.26 (s, 1.3H), 3.22 (s, 1.7H), 1.87 - 1.83 (m, 3H), 1.82 (d, J = 2.2 Hz, 1.7H), 1.79 (d, J = 2.2 Hz, 1.3H).

[0785] Compound M-1648: 180 mg, colorless syrup, ESI [M+H] + = 345.0.

[0786] 1 H NMR (400 MHz, d6-DMSO) d 8.30 (s, 0.5H), 8.28 (s, 0.5H), 7.77 - 7.71 (m, 1H), 7.23 (q, J = 6.4 Hz, 1H), 7.06 (q, J = 7.5 Hz, 1H), 6.76 - 6.65 (m, 1H), 6.40 (q, J = 7.1 Hz, 1H), 5.65 - 5.58 (m, 0.5H), 5.58 - 5.50 (m, 0.5H), 3.64 - 3.51 (m, 2H), 3.28 (s, 1.5H), 3.24 (s, 1.5H), 2.28 - 2.20 (m, 3H), 1.89 - 1.73 (m, 6H).

[0787] Compound M-1656: 180 mg, colorless syrup, ESI [M+H] + = 349.0.

[0788] 1H NMR (400 MHz, d6-DMSO) d 8.34 (s, 0.5H), 8.33 (s, 0.5H), 7.71 (d, J = 0.6 Hz, 0.5H), 7.70 (d, J = 0.6 Hz, 0.5H), 7.46 - 7.34 (m, 1H), 7.13 - 7.00 (m, 2H), 6.29 (q, J = 7.2 Hz, 1H), 5.62 - 5.55 (m, 0.5H), 5.55 - 5.48 (m, 0.5H), 3.63 - 3.46 (m, 2H), 3.28 (s, 0.5H), 3.19 (s, 1.5H), 1.82 (d, J = 2.2 Hz, 1.5H), 1.77 (d, J = 2.2 Hz, 1.5H).

[0789] Compound M-1664: 12 mg, colorless syrup, ESI [M+H] + = 366.9.

[0790] 1 H NMR (400 MHz, d6-DMSO) d 8.39 (s, 1H), 7.75 - 7.71 (m, 1H), 7.57 - 7.43 (m, 1H), 7.19 - 7.05 (m, 1H), 6.27 (q, J = 7.1 Hz, 1H), 5.64 - 5.50 (m, 1H), 3.65 - 3.49 (m, 2H), 3.28 (s, 1.4H), 3.21 (s, 1.6H), 1.96 (d, J = 7.2 Hz, 3H), 1.82 (d, J = 2.2 Hz, 1.6H), 1.78 (d, J = 2.2 Hz, 1.4H).

[0791] Compound M-1713: 69 mg, white solid, ESI [M+H] + = 284.9.

[0792] 1 H NMR (400 MHz, d6-DMSO) d 8.36 (s, 1H), 7.72 (s, 1H), 7.54 - 7.41 (m, 1H), 7.21 - 7.06 (m, 1H), 6.30 (q, J = 7.2 Hz, 1H), 3.69 (s, 3H), 1.95 (d, J = 7.3 Hz, 3H).

[0793] Compound M-1714: 176 mg, colorless syrup, ESI [M+H] + = 398.0.

[0794] 1H NMR (400 MHz, d6-DMSO) δ 8.30 (d, J = 4.4 Hz, 1H), 7.68 (d, J = 3.5 Hz, 1H), 7.48 - 7.32 (m, 1H), 7.14 - 7.01 (m, 2H), 6.32 (q, J = 7.3 Hz, 1H), 5.22 - 5.00 (m, 1H), 3.48 - 3.36 (m, 6H), 3.25 (s, 1.5H), 3.15 (s, 1.5H), 2.47 (s, 1.5H), 2.45 - 2.39 (m, 1H), 2.37 (s, 1.5H), 1.94 (d, J = 7.2 Hz, 3H), 1.84 - 1.60 (m, 2H).

[0795] Example 17, Preparation of compounds M-535, M-537, M-539 and M-559 ~ M-561 of the application

[0796] To a solution of M-521 (4.5 g, 14.51 mmol) in dry THF (100 mL) was added lithium aluminum hydride (1.66 g, 43.55 mmol, 3 eq) portionwise at 0 °C under ice water bath, stirred for 4 h. After the reaction was completed by TLC monitoring, excess sodium sulfate decahydrate was added to the reaction mixture portionwise, stirred for 1 h, suction 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 / 10 ~ 1 / 2), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) monitoring, the fraction with Rf= 0.5 ~ 0.6 was collected to give compound M-561.1 (3.2 g, yield 82.7%). ESI [M+H] + = 269.1.

[0797] To a solution of M-561.1 (3.2 g, 11.94 mmol) in CH2Cl2(100 mL) was added activated manganese dioxide (20.78 g, 238.8 mmol) portionwise at room temperature, stirred overnight under reflux. After the reaction was completed by TLC monitoring, suction 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 / 20 ~ 1 / 2), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) monitoring, the fraction with Rf= 0.5 ~ 0.6 was collected to give compound M-561.2 (2.54 g, yield 80.1%). ESI [M+H] + = 267.1.

[0798] M-561.2 (2.54 g, 9.55 mmol) and ethoxycarbonylmethylene triphenylphosphonium bromide (15.5 g, 14.33 mmol) were dissolved in dry dioxane (50 mL) and stirred at reflux for 4 h. After the reaction was completed by TLC, the reaction mixture was poured into ice water, extracted with EtOAc (3 x 50 mL), the 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 / 20 ~ 1 / 2), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2), and the fraction with Rf= 0.4 ~ 0.5 was collected to give compound M-561 (2.54 g, yield 80.1%) as colorless oil. ESI [M+H] + = 337.1

[0799] 1 H NMR (400 MHz, d6-DMSO) δ 8.16 (s, 1H), 7.72 (s, 1H), 7.36 - 7.14 (m, 2H), 6.87 (d, J = 6.0 Hz, 1H), 6.34 (d, J = 15.8 Hz, 1H), 5.94 (d, J = 6.9 Hz, 1H), 4.12 (dd, J = 7.1, 2.4 Hz, 2H), 2.32 (d, J = 2.3 Hz, 3H), 1.82 (d, J = 6.9 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H).

[0800] The preparation of compounds M-559 ~ M-560 of the application is similar to that of compound M-561 of the application.

[0801] Compounds M-559, M-560 and M-561 were reduced by palladium-carbon to give compounds M-535, M-539 and M-537 of the application, respectively.

[0802] Compound M-559 hydrochloride: 99 mg, white solid, ESI [M+H] + = 288.9.

[0803] 1 H NMR (400 MHz, d6-DMSO) δ 9.28 (s, 1H), 8.25 (s, 1H), 7.50 - 7.38 (m, 2H), 7.35 - 7.22 (m, 3H), 6.62 (d, J = 15.9 Hz, 1H), 6.19 (q, J = 6.9 Hz, 1H), 4.22 - 4.03 (m, 3H), 1.93 (d, J = 6.9 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H).

[0804] Compound M-560: 187 mg, colorless syrup, ESI [M+H] + = 302.9.

[0805] 1 H NMR (400 MHz, d6-DMSO) δ 8.13 (s, 1H), 7.68 (s, 1H), 7.43 (d, J = 15.8 Hz, 1H), 7.26 (t, J = 7.2 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.95 - 6.87 (m, 1H), 6.35 (d, J = 15.8 Hz, 1H), 5.90 (q, J = 7.0 Hz, 1H), 4.22 - 4.04 (m, 2H), 2.25 (d, J = 1.9 Hz, 3H), 1.85 (d, J = 7.0 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H).

[0806] Compound M-535: 147 mg, colorless oil, ESI [M+H] + = 290.9.

[0807] 1 H NMR (400 MHz, d6-DMSO) δ 7.86 (s, 1H), 7.42 - 7.34 (m, 1H), 7.29 - 7.18 (m, 2H), 7.05 - 6.96 (m, 1H), 6.68 (s, 1H), 5.65 (q, J = 7.0 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 2.85 - 2.40 (m, 4H), 1.82 (d, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H).

[0808] Compound M-539: 180 mg, colorless oil, ESI [M+H] + = 304.9.

[0809] 1 H NMR (400 MHz, d6-DMSO) δ 7.83 (s, 1H), 7.25 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.81 (t, J = 7.5 Hz, 1H), 6.67 (s, 1H), 5.63 (q, J = 7.0 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 2.26 (d, J = 1.9 Hz, 3H), 1.81 (d, J = 7.0 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H).

[0810] The following demonstrates the advantageous effects of the present application by way of Test Examples.

[0811] Test Example 1, Determination of pharmacological data of compounds of the present application

[0812] 1. Test method

[0813] 1.1 Test of the anesthetic effect of compounds of the present application after intravenous injection in the tail of rats (determination of the minimum anesthetic effective dose): The experimental animals are 7-9 week old male SD rats, which are administered intravenously in the tail (administration rate 0.02 mL / s, administration volume 0.6 mL per rat). The initial dose of each test compound is 1 mg / kg, and the actual administration amount is calculated based on the body weight of each rat measured before the test. The subsequent dose is increased or decreased depending on whether the experimental rat shows loss of righting reflex, and the lowest dose at which loss of righting reflex occurs is determined as the minimum anesthetic effective dose.

[0814] While testing the anesthetic effect of compounds of the present application after intravenous injection in the tail of rats, it is also determined whether the compounds have analgesic effect. Once it is determined that the compound has anesthetic effect (loss of righting reflex ≥ 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 shows no reaction within 30 s, it is determined that the compound has analgesic effect, otherwise it has no analgesic effect. If the compound has no anesthetic effect (loss of righting reflex < 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 shows no reaction within 30 s, it is determined that the compound has analgesic effect, otherwise it has no analgesic effect. 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.

[0815] 1.2 Determination of the main pharmacological effects of compounds of the present application

[0816] 1.2.1 ED of compounds of the present application for general anesthetic effect with loss of righting reflex as the determination index 50

[0817] Male SD rats of 7-9 weeks of age are selected for the test. The median effective dose (ED 50 ) of compounds of the present application for general anesthetic effect with loss of righting reflex as the determination index is determined by the Up-and-down method. The rats are administered intravenously in the tail during the test, with an administration volume of 0.6 mL and an administration rate of 0.02 mL / s per rat. Loss of righting reflex (LORR) ≥ 30 s is used as the determination criterion for anesthetic effect.

[0818] 1.2.2 The ED50 of the compound of the present application in the rat 50 Dose comparison of the pharmacological effects of the compound of the present application

[0819] The ED50 of the compound of the present application was determined 50 Afterwards, the 2ED50 of the compound of the present application in the rat 50 was determined. The test was performed by intravenous administration to the tail vein of the rat, with a volume of 0.6 mL per rat and a speed of 0.02 mL / s. The time of loss of righting reflex (LORR) was taken 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 times were recorded and observed.

[0820] 2ED50 50 Pharmacological characteristics of the equivalent dose of the compound of the present application:

[0821] In the above test, in addition to recording the dose at which loss of righting reflex occurs, the time of onset and recovery of anesthetic effect, the duration of righting reflex and the duration of sedative effect can also be recorded. In the dose of the compound of the present application that causes loss of righting reflex, the effect of the compound on the respiration of the experimental animal can also be observed.

[0822] 2. Experimental results

[0823] Table 1. Pharmacological data of single intravenous injection of the compound of the present application with anesthetic effect

[0824] Table 2. Minimum analgesic effective dose of single intravenous injection of the compound of the present application

[0825] Table 3. ED50 and 2ED50 of some compounds of the present application in the rat 50 and the pharmacological characteristics of the equivalent dose of the compound of the present application: 50

[0826] The experimental results show that the compound of the present application has high anesthetic, sedative, and hypnotic effects, can control status epilepticus, and also has analgesic effect.​

Claims

1. 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: ###0001### Formula I R B selected from substituted or unsubstituted C 1-8 alkyl, phenyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocycloalkyl, 5-6 membered heteroaromatic ring; each of said substituents is independently selected from halo or unhalo C 1-8 alkyl, C 1-8 alkoxy, =O, halo, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclyl, amino protecting group; R2, R3are each independently selected from the group consisting of hydrogen, cyano, C 2-6 alkynyl, halogen, C 1-6 alkyl, which is unsubstituted or substituted by one or more R', C 2-6 alkenyl, 3- to 6-membered saturated cycloalkyl, halogenated or unhalogenated C 1-6 alkoxy, hydroxy, or R2, R3are joined to form a 3- to 6-membered saturated cycloalkyl or a 3- to 6-membered saturated heterocyclyl, or R2, R3together with the C atom between them form a C(=CR h R j ), CO; R' is selected from the group consisting of halogen, C 1-6 alkyl, C 2-6 alkenyl; R h , R j are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl; L3is selected from the group consisting of none, C 1-6 alkylene, OL5, L5is selected from the group consisting of C 1-6 alkylene; A ring is selected from each of y, z is independently selected from 0, 1, 2, 3; X' is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-5 alkyl; R k each independently selected from L4(W) d R9R'9、 W is selected from C or N; d is selected from 0, 1, 2; G is selected from O, NH; When the A ring is R k For Time, For When the A ring is R k For Time, For When For A ring is at the time, R k is L4is selected from the group consisting of none, CO, C 2-6 alkenylene, unsubstituted or substituted by one or two or more C 1-6 alkyl; and R4is selected from the group consisting of H, C 1-6 alkylene; R c selected from hydrogen, C 1-8 alkyl, R d selected from hydrogen, C 1-8 alkyl, or R c , R d to form a 3-8 membered saturated oxacycle; Y is selected from the group consisting of nothing, NR9, CR 10 R 11 ; R 10 is selected from the group consisting of hydrogen, C 1-8 alkyl, hydroxy, C 1-8 alkoxy, R 11 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, or R 10 , R 11 together form a 3-8 membered saturated heterocyclic ring, unsubstituted or substituted with one or more R 12 , a 3-8 membered saturated cycloalkyl ring, unsubstituted or substituted with one or more R 12 ; R 12 is each independently selected from the group consisting of C 1-8 alkyl; L, L' are each independently selected from the group consisting of none, NR9R'9, C 1-6 alkylene, CR9R'9; R0, R0', R e each independently selected from the group consisting of hydrogen, hydroxyl, COOR 10 , NR9R'9, the following groups, which are unsubstituted or substituted by one or more than one R8: C 1-8 alkyl, C 1-8 alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated cycloalkyl, 3-8 membered saturated heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, R8is each independently selected from the group consisting of halogen, NR9R'9, hydroxyl, thiol, C 1-8 alkyl, C 1-8 alkoxy, C 2- 8alkenyl, C 2-8 alkynyl, COR' 10 , COOR' 10 , C=CR9R'9, 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated cycloalkyl, 3-8 membered saturated heterocyclyl, R0" is selected from hydrogen, hydroxyl, C 1-8 alkyl; R9, R'9, R' 10 each independently selected from none, hydrogen, halogen, hydroxyl, C 2-6 alkenyl, halo- or unhalo-genated C 1- 8alkyl, cyano, or R9, R'9together form a 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated heterocyclyl, The compound is not 2. The compound, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or deuterated derivative thereof of claim 1, wherein, The compound is shown as formula II: wherein, X is selected from CH2, O, NR G ; R G is selected from hydrogen or an amino protecting group; each of a, b is independently selected from 1, 2, 3; m is selected from 0, 1, 2, 3, 4; R a each independently selected from C 1-5 alkyl, C 1-5 alkoxy, =0, halogen, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, an amino protecting group; R2, R3are each independently selected from the group consisting of hydrogen, cyano, C 2-4 alkynyl, halogen, C 1-5 alkyl, which is unsubstituted or substituted by one or more R'; C 2-4 alkenyl, 3- to 6-membered saturated cycloalkyl, halogenated or unhalogenated C 1-5 alkoxy, hydroxy, or R2, R3are joined to form a 3- to 6-membered saturated cycloalkyl or a 3- to 6-membered saturated heterocyclyl, or R2, R3together with the C atom between them form a C(=CR h R j ); CO; R' is selected from the group consisting of halogen, C 1-5 alkyl, C 2-4 alkenyl; R h , R j are each independently selected from the group consisting of hydrogen, halogen, C 1-5 alkyl; L3is selected from the group consisting of none, C 1-5 alkylene, OL5, L5is selected from the group consisting of C 1-5 alkylene; L is selected from the group consisting of none, NR9R'9, C 1-4 alkylene, CR9R'9; R0 is selected from the following groups that are unsubstituted or substituted by one or more R8 groups: C 1-5 Alkyl, C 1-5 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated cycloalkyl, 3-6 membered saturated heterocyclic group, C 2-4 alkenyl, C 2-4 acetylinyl R8is each independently selected from the group consisting of halogen, NR9R'9, hydroxyl, thiol, C 1-5 alkyl, C 1-5 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, COR' 10 , COOR' 10 , C=CR9R'9, 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated cycloalkyl, 3-6 membered saturated heterocyclyl, R0" is selected from hydrogen, hydroxyl, C 1-5 alkyl; R9, R'9are each independently selected from the group consisting of nothing, hydrogen, halogen, hydroxyl, C 2-4 alkenyl, halo- or unhalo- genated C 1-5 alkyl, cyano, or R9, R'9together form a 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated heterocyclyl; X' is selected from hydrogen, halogen, halo- or unhalo- genated C 1-5 alkyl; The compound is not 3. The compound, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or deuterated derivative thereof of claim 1, wherein, The compound is shown as formula III: wherein, t is selected from 0, 1, 2, 3, 4; R b each independently selected from C 1-5 alkyl, C 1-5 alkoxy, =0, halogen, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, an amino protecting group; R2, R3are each independently selected from the group consisting of hydrogen, cyano, C 2-4 alkynyl, halogen, C 1-5 alkyl, which is unsubstituted or substituted by one or more R'; 2-4 alkenyl, 3- to 6-membered saturated cycloalkyl, halogenated or unhalogenated C 1-5 alkoxy, hydroxy, or R2, R3are linked to form a 3- to 6-membered saturated cycloalkyl or a 3- to 6-membered saturated heterocyclyl, or R2, R3together with the C atom between them form a C(=CR h R j ); CO; R' is selected from the group consisting of halogen, C 1-5 alkyl, C 2-4 alkenyl; R h , R j are each independently selected from the group consisting of hydrogen, halogen, C 1-5 alkyl; L3is selected from the group consisting of none, C 1-5 alkylene, OL5, L5is selected from the group consisting of C 1-5 alkylene; A ring is selected from each of y, z is independently selected from 0, 1, 2, 3; X' is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-5 alkyl; R k each independently selected from L4(W) d R9R'9、 W is selected from C or N; d is selected from 0, 1, 2; G is selected from O, NH; When the A ring is R k For Time, For When the A ring is R k For Time, For When For A ring is at the time, R k is L4is selected from the group consisting of none, CO, C 2-4 alkenylene, unsubstituted or substituted by one or two or more C 1-4 alkyl; C 1-4 alkylene; R c selected from hydrogen, C 1-5 alkyl, R d selected from hydrogen, C 1-5 alkyl, or R c , R d to form a 3-6 membered saturated oxacyclic ring; Y is selected from the group consisting of nothing, NR9, CR 10 R 11 ; R 10 is selected from the group consisting of hydrogen, C 1-5 alkyl, hydroxy, C 1-5 alkoxy, R 11 is selected from the group consisting of hydrogen, C 1-5 alkyl, C 1-5 alkoxy, or R 10 , R 11 together form a 3-6 membered saturated heterocyclic ring which is unsubstituted or substituted by one or more R 12 , a 3-6 membered saturated cycloalkyl which is unsubstituted or substituted by one or more R 12 ; R 12 is each independently selected from the group consisting of C 1-5 alkyl; L, L' are each independently selected from the group consisting of none, NR9R'9, C 1-4 alkylene, CR9R'9; R0, R0', R e each independently selected from the group consisting of hydrogen, hydroxyl, COOR 10 , NR9R'9, the following groups, which are unsubstituted or substituted by one or more than one R8: C 1-5 alkyl, C 1-5 alkoxy, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered unsaturated cycloalkyl, 3- to 6-membered saturated heterocyclyl, C 2-4 alkenyl, C 2-4 alkynyl, R8is each independently selected from the group consisting of halogen, NR9R'9, hydroxyl, thiol, C 1-5 alkyl, C 1-5 alkoxy, C 2- 4alkenyl, C 2-4 alkynyl, COR' 10 , COOR' 10 , C=CR9R'9, 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated cycloalkyl, 3-6 membered saturated heterocyclyl, R0" is selected from hydrogen, hydroxyl, C 1-5 alkyl; R9, R'9, R' 10 each independently selected from none, hydrogen, halogen, hydroxyl, C 2-4 alkenyl, halo- or unhalo-genated C 1- 5alkyl, cyano, or R9, R'9 together form a 3-6 membered saturated cycloalkyl, 3-6 membered unsaturated heterocyclyl, The compound is not 4. The compound, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or deuterated derivative thereof of claim 3, wherein, The compound is shown as formula IV: t, R b , R2, R3, y, z, X', R k As in claim 3.

5. The compound, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or deuterated derivative thereof of claim 4, wherein, The compounds are as shown in formula IV-a, IV-b: t, R b , R2, R3, y, z, X', R k As in claim 4.

6. The compound, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or deuterated derivative thereof of claim 5, wherein, The compound is as shown in formula V-a, V-b: t, R b R2, R3, y, X', L4, L, R0are as defined in claim 5.

7. The compound of claim 3, 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 compounds are as shown in formulae VI-a, VI-b: t, R b , R2, R3, z, R k As in claim 3.

8. A compound of the following formula, 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 compound is selected from one of the following compounds:

9. The compound, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or deuterated derivative thereof of any one of claims 1-8, 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, monohydrogenphosphate, dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, xinafoate, or p-toluenesulfonate.

10. A pharmaceutical composition, characterized by, The pharmaceutical composition is a preparation prepared by adding a pharmaceutically acceptable adjuvant to the compound, stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof, prodrug thereof, metabolite thereof, or deuterated derivative thereof of any one of claims 1-9 as an active ingredient.

11. Use of the compound, stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof, prodrug thereof, metabolite thereof, or deuterated derivative thereof of any one of claims 1-9 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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