Analgesic compound, preparation method therefor, and use thereof

Abstract

Provided are an analgesic compound, a preparation method therefor, and the use thereof, which relate to the field of pharmaceutical chemistry. The compound is a compound represented by formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystal form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof. The compound has a uniquely advantageous analgesic effect, is highly safe when used, has only mild toxic side effects, and no dependence develops during use. Therefore, the compound has wide application prospects in the preparation of analgesic pharmaceuticals, and provides a new option when clinically preparing a drug with an analgesic effect.

Description

Analgesic compound and its preparation method and use Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of analgesic compounds and a preparation method and use thereof. Background Art

[0002] The Global Burden of Disease Study reports that pain and pain-related conditions are the leading causes of disability and disease worldwide. The report shows that over 80% of patients undergoing surgery experience acute postoperative pain, while less than half experience adequate pain relief. Nearly 80% of patients experience moderate to severe pain severity, and 10% to 50% experience chronic pain. Therefore, there remains a significant clinical need for analgesics. In the field of pain treatment, traditional opioids remain the most effective and commonly used analgesics for treating moderate to severe pain. Opioids exert their analgesic effects by acting on opioid receptors within the G protein-coupled receptor family, primarily activating the downstream Gi / o protein pathway.

[0003] However, while opioids provide potent analgesia, they are also associated with numerous adverse reactions. These include common respiratory depression, deep sedation, nausea and vomiting, and constipation. Long-term use can lead to tolerance, decreased pain perception, and even drug abuse and addiction, resulting in serious social harm. Opioids that act on μ receptors (e.g., remifentanil) can produce dose-dependent respiratory depression through direct effects on the respiratory center in the human brainstem. Studies have shown that the average addiction rate for opioids is between 8% and 12%. Patients who are physically dependent on or addicted to opioids often abuse opioids to avoid withdrawal symptoms.

[0004] Although researchers have developed many new opioid analgesics and even non-opioid analgesics over the past hundred years, no particularly significant progress has been made. For example, Oliceridine (TRV130), an analgesic targeting the μ receptor designed based on the concept of G protein bias, was approved by the US Food and Drug Administration (FDA) in 2020 for the treatment of moderate to severe pain, but it still emphasizes that it still has opioid-related side effects in the form of a "black box warning." Many known analgesics based on other non-opioid receptor targets have not yet achieved analgesic effects comparable to morphine or remifentanil due to the limitations of analgesic targets or pain models, or have been unable to obtain results consistent with animal experiments in multiple clinical studies.

[0005] In summary, while traditional opioids used clinically are the most effective drugs for treating moderate to severe pain, their associated adverse reactions and drug dependence limit their effectiveness. Furthermore, they reduce safety and can lead to serious social problems such as drug abuse. Therefore, designing novel compounds that retain the analgesic efficacy of opioids while avoiding their severe adverse reactions to create new non-opioid analgesics has significant clinical significance and broad market prospects.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a class of analgesic compounds and their preparation method and use.

[0008] The present invention provides a compound represented by Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystalline form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof:

[0009] in,

[0010] R1 and R3 are independently selected from hydrogen or NR4R5, and one and only one of R1 and R3 is selected from NR4R5;

[0011] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl;

[0012] R4 and R5 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0013] X1, X2 are independently selected from O, S, NR6;

[0014] R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0015] m is an integer selected from 1 to 5; n is an integer selected from 0 to 5;

[0016] M is selected from O, S, NR7;

[0017] R7 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0018] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl;

[0019] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0020] The substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0021] The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is 1 to 5.

[0022] Furthermore, the compound is represented by Formula II:

[0023] in,

[0024] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl;

[0025] X1, X2 are independently selected from O, S, NR6;

[0026] R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0027] m is selected from 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0028] M is selected from O, S, NR7;

[0029] R7 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0030] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl;

[0031] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0032] The substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0033] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0034] Furthermore, the compound is represented by formula III:

[0035] in,

[0036] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl;

[0037] X1, X2 are independently selected from O, S, NR6;

[0038] R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0039] M is selected from O, S, NR7;

[0040] R7 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0041] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl;

[0042] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0043] The substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0044] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0045] Furthermore, the compound is represented by Formula IVa, Formula IVb or Formula IVc:

[0046] in,

[0047] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl;

[0048] X2 is selected from O, S, NR6;

[0049] R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0050] M is selected from O, S, NR7;

[0051] R7 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0052] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl;

[0053] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0054] The substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0055] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0056] Furthermore, the compound is represented by Formula V:

[0057] in,

[0058] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl;

[0059] X1, X2 are independently selected from O, S, NR6;

[0060] R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0061] m is selected from 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0062] M is selected from O, S, NR7;

[0063] R7 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0064] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl;

[0065] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0066] The substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0067] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0068] Furthermore, the compound is represented by Formula VI:

[0069] in,

[0070] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl;

[0071] X1, X2 are independently selected from O, S, NR6;

[0072] R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0073] M is selected from O, S, NR7;

[0074] R7 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0075] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl;

[0076] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0077] The substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0078] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0079] Furthermore, the compound is represented by Formula VIIa, Formula VIIb or Formula VIIc:

[0080] in,

[0081] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl;

[0082] X2 is selected from O, S, NR6;

[0083] R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0084] M is selected from O, S, NR7;

[0085] R7 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0086] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl;

[0087] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto;

[0088] The substituents of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0089] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0090] Furthermore,

[0091] X2 is selected from O, S, NH;

[0092] And / or, M is selected from O, S, NH.

[0093] Furthermore, the A ring is selected from the following substituted or unsubstituted groups:

[0094] ;

[0095] The substituent of the A ring is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0096] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0097] Furthermore,

[0098] The substituent of the A ring is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy;

[0099] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0100] Furthermore, the compound is one of the following compounds:

[0101] The present invention also provides a method for preparing the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, which comprises the following steps:

[0102] Step 1:

[0103] In a solvent, compound 1, an organic base and compound 2 react to obtain compound 3; preferably, the organic base is pyridine;

[0104] Wherein, n, m, X2, A, and M are as described above;

[0105] Step 2:

[0106] (1) Compound 4 reacts with compound 5 in a solvent to obtain compound 6;

[0107] (2) Compound 6 reacts with Pd / C in a solvent under a hydrogen atmosphere to obtain compound 7;

[0108] (3) Compound 7, an organic base and compound 3 react in a solvent to obtain compound 8; preferably, the organic base is DIPEA;

[0109] wherein R2, n, m, X2, A, and M are as described above; At the ortho or meta position of R2;

[0110] or,

[0111] (A) Compound 10 is reacted with formaldehyde solution, acetic acid and NaBH3CN in a solvent;

[0112] (B) Compound 10, an inorganic solid base and compound 3 react in a solvent to obtain compound 11; preferably, the inorganic solid base is Cs2CO3;

[0113] wherein R2, n, m, X2, A, and M are as described above; At the ortho or meta position of R2;

[0114] or,

[0115] (a) Compound 12 reacts with aqueous sodium hydroxide in a solvent to obtain compound 13;

[0116] (b) Compound 13 reacts with formaldehyde and sodium cyanoborohydride in a solvent to obtain compound 14;

[0117] (c) Compound 14, sodium bisulfite formaldehyde and compound 3 are reacted in a solvent to obtain compound 15.

[0118] The present invention also provides the use of the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative in the preparation of a drug with analgesic effect.

[0119] The present invention also provides a drug, which is a preparation prepared with the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative as the active ingredient, and pharmaceutically acceptable excipients.

[0120] The present invention also provides a pharmaceutical composition comprising the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystalline form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof.

[0121] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0122] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0123] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0124] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a ~C b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C1-C6 alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms; and "C1-C6 alkoxy" refers to an alkoxy group containing from 1 to 6 carbon atoms.

[0125] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, among others.

[0126] "Halogen" is fluorine, chlorine, bromine or iodine.

[0127] "Cycloalkyl" refers to a saturated or unsaturated all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) without a conjugated π electron system, including but not limited to: wait.

[0128] "Heterocycloalkyl" refers to a cycloalkyl group in which at least one carbon atom is replaced by a heteroatom, wherein the heteroatom is O, N or S, and is a saturated or unsaturated monocyclic or polycyclic ring (including fused rings, spiro rings or bridged rings) without a conjugated π electron system, including but not limited to: wait.

[0129] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) with a conjugated π electron system, including but not limited to phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N or S. At the same time, the point of attachment to the parent group must be on a carbon atom on the ring with a conjugated π electron system, including but not limited to wait.

[0130] "Heteroaryl" refers to an aromatic group in which at least one carbon atom of the conjugated π-electron system is replaced by a heteroatom, wherein the heteroatom is O, N or S, such as but not limited to thienyl, furyl, isothiazolyl, etc.

[0131] The pharmaceutically acceptable salts of the present invention include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, teasulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthenate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, p-toluenesulfonate, quaternary ammonium salt or succinate, etc.

[0132] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.

[0133] The administration of the compound or pharmaceutical composition of the present invention includes (but is not limited to): intragastric, enteral, parenteral (intravenous, intramuscular or subcutaneous), oral and various topical administrations.

[0134] Compositions for parenteral (intravenous, intramuscular, subcutaneous) injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0135] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0136] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0137] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0138] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0139] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0140] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0141] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0142] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage when administered is a pharmaceutically safe and effective dosage.

[0143] Compared with the prior art, the compounds provided by the present invention have achieved the following beneficial effects:

[0144] The present invention provides a compound having analgesic effects. The compound has excellent analgesic effects, good safety, minimal toxic side effects, and does not cause dependence during use. Therefore, the compound has broad application prospects in the preparation of analgesic drugs and provides a new option for the clinical preparation of analgesic drugs.

[0145] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0146] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0147] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0148] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6The units are given in ppm. NMR measurements were performed using a Bruker Avance III 400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (d6-DMSO), deuterated chloroform (CDCl3), deuterated methanol (d4-MeOH), and deuterated water (D2O). The internal standard was tetramethylsilane (TMS).

[0149] LCMS analysis (Agilent LCMS 1200-6120) (ESI), chromatographic column: Waters Xbridge Prep C 18 OBD 10 μm, 19 x 250 mm. Column temperature: 40°C; flow rate: 2.0 mL / min; mobile phase: gradient from 95% [water + 10 mM ammonium bicarbonate] and 5% [CH3CN] over 1.6 minutes to 5% [water + 10 mM ammonium bicarbonate] and 95% [CH3CN], held for 1.4 minutes, then to 95% [water + 10 mM ammonium bicarbonate] and 5% [CH3CN] over 0.05 minutes, held for 0.7 minutes.

[0150] (1) Medicinal materials and reagents

[0151] The manufacturer of the thin layer chromatography silica gel plate used in thin layer chromatography (TLC) is Qingdao Pu Ke Separation Materials Co., Ltd., with a specification of 50*200mm and a thickness of 0.2-0.25mm.

[0152] Column chromatography silica gel: 200-300 mesh silica gel from Shandong Weihai Rushan Sun Desiccant Co., Ltd.

[0153] (2) Main instruments

[0154] Electronic balance, FA2004, Shanghai Liangping Instrument Co., Ltd.;

[0155] Temperature-controlled and pressure-regulated magnetic stirrer, TY98-1, Shanghai Silu Instrument Co., Ltd.;

[0156] Three-purpose UV analyzer, model ZF-2, Shanghai Anting Scientific Instrument Factory;

[0157] Rotary evaporator, R201, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0158] Liftable water bath, R201D, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0159] Circulating water vacuum pump (desktop), SHB-Ⅲ, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0160] Circulating water vacuum pump (mobile), SHB-B95, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0161] Low-temperature circulation pump, DLSB-5 / 20, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0162] Rotary vane vacuum pump (oil pump), 2XZ-4, Shanghai Vacuum Pump Factory.

[0163] Example 1. Preparation of Compound 1-1-249 of the Present Invention

[0164] 1. Synthesis of Compound SM-7

[0165] AL37-7-1 (1.2 g, 10.62 mmol) was added to a 100 mL single-necked flask and dissolved in tetrahydrofuran (THF) (40 mL). Pyridine (1.68 g, 21.24 mmol) was then added. The system was cooled to 0°C with ice and bromoacetyl bromide (2.4 g, 11.68 mmol) was added dropwise. After addition, the reaction was stirred at room temperature for one hour. After completion of the reaction, the solid was removed by filtration and the solvent was evaporated under reduced pressure to obtain the crude product. Purification on a silica gel column (petroleum ether:ethyl acetate = 100 / 1 to 10 / 1) afforded SM-7 (1.5 g, yield: 61%) as a colorless oil.

[0166] 2. Synthesis of compound 1-1-249

[0167] SM-1 (400 mg, 1.71 mmol) and N,N-diisopropylethylamine (DIPEA) (441 mg, 3.42 mmol) were dissolved in acetonitrile (10 mL), and SM-7 (257 mg, 1.71 mmol) was added, followed by reflux and stirring for 6 hours. After the reaction was complete as monitored by LCMS, saturated brine (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC to obtain compound 1-1-249 (105.64 mg, 20% yield). MS Calcd.: 304.1; MS Found: 305.4 [M+H] + .

[0168] 1H NMR(400MHz, DMSO-d6)δ:7.54(q,J=2.8Hz,1H),7.48(d,J=2.0Hz,1H),7.06(dd,J=1.2,4.8Hz,1H),6.81(d,J=1.6Hz,1H),6.6 7(d,J=8.4Hz,1H),6.32(d,J=8.0Hz,1H),5.24(t,J=1.6Hz,1H),5.13(s,2H),3.97(d,J=6.4Hz,2H),2.56(s,6H),2.17(s,3H).

[0169] Example 2. Preparation of compound 1-1-258 of the present invention

[0170] 1. Synthesis of AL-37-1

[0171] 3-Fluoro-4-nitrotoluene (10.0 g, 64.52 mmol) was dissolved in tetrahydrofuran (50 mL). Dimethylamine (150 mL, 2 mol / L in THF, 60 mmol) was added at 0°C and allowed to react at room temperature for 5 hours. After completion of the reaction as monitored by TLC, saturated brine (100 mL) was added to the reaction system and extracted with ethyl acetate (3 x 100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound AL-37-1 (11.0 g, 95% yield). MS Calcd.: 180.1; MS Found: 181.4 [M+H] + .

[0172] 2. Synthesis of SM-1

[0173] AL-37-1 (10.0 g, 55.56 mmol), ammonium chloride (12.0 g, 222.22 mmol), and iron powder (6.2 g, 111.12 mmol) were dissolved in ethanol (280 mL) and stirred under reflux for 6 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain compound SM-1 (6.5 g, yield 78.3%). MS Calcd.: 150.1; MS Found: 151.4 [M+H] + .

[0174] 3. Synthesis of SM-3

[0175] AL-37-4 (5.0 g, 44.25 mmol) was added to a 250 mL single-necked flask and dissolved in tetrahydrofuran (150 mL). Pyridine (7.0 g, 88.5 mmol) was then added dropwise to the mixture, cooled to 0°C with ice, and bromoacetyl bromide (10.73 g, 53.10 mmol) was added. The mixture was stirred at room temperature for one hour. After completion of the reaction, the solid was removed by filtration, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification on a silica gel column (petroleum ether:ethyl acetate = 100 / 1 to 10 / 1) afforded SM-3 (8.0 g, 80% yield) as a colorless oil.

[0176] 4. Synthesis of 1-1-258

[0177] SM-1 (400 mg, 2.67 mmol) and N,N-diisopropylethylamine (DIPEA) (688 mg, 5.33 mmol) were dissolved in MeCN (10 mL), and SM-3 (622 mg, 2.67 mmol) was added, followed by reflux and stirring for 6 hours. After the reaction was complete as monitored by LCMS, saturated brine (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC to obtain compound 1-1-258 (337.95 mg, yield: 42%). MS Calcd.: 304.1; MS Found: 305.4 [M+H] + .

[0178] 1 H NMR(400MHz, DMSO-d6)δ:7.56(dd,J=1.2,5.2Hz,1H),7.17-7.16(m,1H),7.02(q,J=4.4Hz,1H),6.80(d,J=1.6Hz,1H),6.66( q,J=0.4Hz,1H),6.31(d,J=8.0Hz,1H),5.31(s,2H),5.24(t,J=5.6Hz,1H),3.95(d,J=5.6Hz,2H),2.56(s,6H),2.16(s,3H).

[0179] Example 3. Preparation of compound 1-1-259 of the present invention

[0180] 1. Preparation of compound SM-11

[0181] AL37-10-1 (339 mg, 3 mmol), bromoacetyl bromide (606 mg, 3 mmol), and pyridine (237 mg, 3 mmol) were dissolved in tetrahydrofuran (50 mL) and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, saturated brine (50 mL) was added to the reaction system and extracted with 100 mL (3 x 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain SM-11 (500 mg, 71% yield) as a pale yellow oil.

[0182] 2. Preparation of compound 1-1-259

[0183] SM-11 (232 mg, 1.0 mmol), SM-1 (150 mg, 1.0 mmol), and DIPEA (136 mg, 1.0 mmol) were dissolved in acetonitrile (15 mL) and stirred at 60°C overnight. After the reaction was complete as monitored by TLC, saturated brine (50 mL) was added to the reaction system and extracted with CH2Cl2 (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative purification to obtain compound 1-1-259 (100 mg, 33% yield) as a colorless oil. ESI [M+H] + =289.2.

[0184] 1 H NMR (400MHz, DMSO-d6) δ8.44(t,J=6.4Hz,1H),7.35(dd,J=3.6,2.4Hz,1H),6.92(dd,J=4.8,3.2Hz,2H),6.82(d,J=8.0Hz,1H ), 6.10 (dd, J = 8.0, 2.4Hz, 1H), 5.73 (t, J = 6.0Hz, 1H), 4.44 (d, J = 6.0Hz, 2H), 3.60 (d, J = 6.0Hz, 2H), 2.53 (s, 6H), 2.09 (s, 3H).

[0185] Example 4. Preparation of Compound 1-1-276 of the Present Invention

[0186] 1. Synthesis of compound 1-1-276

[0187] SM-6 (600 mg, 4.0 mmol) and N,N-diisopropylethylamine (DIPEA) (1.03 g, 8.0 mmol) were dissolved in acetonitrile (10 mL). SM-3 (932 mg, 4.0 mmol) was added and the mixture was stirred at reflux at 60°C for 6 hours. After the reaction was complete as monitored by LCMS, saturated brine (20 mL) was added to the reaction system and extracted with dichloromethane (3 × 20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC to obtain compound 1-1-276 (420.02 mg, 36% yield). MS Calcd.: 290.1; MS Found: 291.4 [M+H] + .

[0188] 1 H NMR (400MHz, DMSO-d6) δ: 7.56 (d, J = 4.8Hz, 1H), 7.16 (d, J = 3.2Hz, 1H), 7.03-6.96 (m, 2H), 6.85 (t, J = 7.6Hz, 1H), 6. 60(t,J=7.6Hz,1H), 6.40(d,J=8.0Hz,1H), 5.43(t,J=6.0Hz,1H), 5.32(s,2H), 4.00(d,J=6.0Hz,2H), 2.57(s,6H).

[0189] Example 5. Preparation of Compound 1-1-321 of the Present Invention

[0190] 1. Preparation of compound AL37-6-2

[0191] AL37-6-1 (468 mg, 3 mmol) was dissolved in DMF (15 mL), and 60% sodium hydride (240 mg, 6 mmol) was added. After stirring at room temperature for 2 hours, iodomethane (1.06 g, 7.5 mmol) was added. After the reaction was complete as monitored by TLC, saturated brine (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3×100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain AL37-6-2 (400 mg, yield 72%) as a light yellow oil. ESI [M+H]+=185.2.

[0192] 2. Preparation of compound AL37-6-3

[0193] To a 30 mL methanol solution of AL37-6-2 (368 mg, 2 mmol) was added Pd / C (50 mg), and the reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by TLC, the reaction mixture was filtered and concentrated under reduced pressure to afford the crude product, which was purified by silica gel column chromatography (PE / EA = 5 / 1) to afford AL37-6-3 (155 mg, 50% yield) as a pale yellow oil. ESI [M+H]+ = 155.2.

[0194] 3. Preparation of compound 1-1-321

[0195] AL37-6-3 (154 mg, 1.0 mmol), SM-3 (233 mg, 1.0 mmol), and DIPEA (129 mg, 1.0 mmol) were dissolved in acetonitrile (15 mL) and stirred at 60°C overnight. After the reaction was complete as monitored by TLC, saturated brine (50 mL) was added to the reaction system and extracted with dichloromethane (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative purification to obtain compound 1-1-321 (100 mg, 33% yield) as a colorless oil. ESI [M+H] + =309.2.

[0196] 1 H NMR (400MHz, DMSO-d6) δ7.57(dd,J=5.2,1.2Hz,1H),7.16(d,J=3.0Hz,1H),7.01(dd,J=5.2,2.0Hz,1H),6.83(dd,J=10.4,2.8H z, 1H), 6.69-6.64 (m, 1H), 6.37 (dd, J = 8.8, 6.4Hz, 1H), 5.31 (d, 2H), 5.25 (t, J = 6.0Hz, 1H), 3.98 (d, J = 5.4Hz, 2H), 2.56 (s, 6H).

[0197] Example 6. Preparation of Compound 1-1-312 of the Present Invention

[0198] 1. Synthesis of compound SM-2

[0199] AL37-11-1 (1.23 g, 10 mmol), aqueous formaldehyde solution (7.5 g, 100 mmol), and acetic acid (5 mL) were dissolved in 45 mL of methanol. NaBH3CN (3.1 g, 50 mmol) was added to the reaction system and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, saturated brine (50 mL) was added to the reaction system and extracted with dichloromethane (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound SM-2 (1.5 g, 99% yield) as a light yellow oil. MS Found: 152.2 [M+H] + .

[0200] 2. Synthesis of compound 1-1-312

[0201] SM-2 (302 mg, 2.0 mmol), SM-3 (466 mg, 2.0 mmol) and cesium carbonate (750 mg, 2.0 mmol) were dissolved in acetonitrile (15 mL) and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, saturated brine (50 mL) was added to the reaction system and extracted with dichloromethane (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative purification to obtain compound 1-1-312 (103.06 mg, 17% yield) as a colorless oil. ESI [M+H] + =306.2.

[0202] 1 H NMR (400MHz, DMSO-d6) δ7.58 (dd, J=5.2, 1.2Hz, 1H), 7.20-7.19 (m, 1H), 7.03 (dd, J=5.2, 3.2Hz, 1H),6.67-6.66(m,2H),6.63-6.60(m,1H),5.37(s,2H),4.75(s,2H),2.69(s,6H),2.20(s,3H).

[0203] Example 7. Preparation of Compound 1-1-322 of the Present Invention

[0204] 1. Preparation of compound SM-5

[0205] SM-12 (980 mg, 10 mmol), bromoacetyl bromide (2.01 g, 10 mmol), and pyridine (790 mg, 10 mmol) were dissolved in tetrahydrofuran (50 mL) and stirred at room temperature overnight. After completion of the reaction as monitored by TLC, saturated brine (50 mL) was added to the reaction system and extracted with dichloromethane (3 x 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to afford compound SM-5 (1.2 g, 60% yield).

[0206] 2. Preparation of compound 1-1-322

[0207] SM-5 (200 mg, 1.0 mmol), SM-1 (150 mg, 1.0 mmol), and N,N-diisopropylethylamine (DIPEA) (136 mg, 1.0 mmol) were dissolved in acetonitrile (15 mL) and stirred at 60°C overnight. After the reaction was complete as monitored by TLC, saturated brine (50 mL) was added to the reaction system and extracted with dichloromethane (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative purification to obtain compound 1-1-322 (100 mg, 34% yield) as a colorless oil. ESI [M+H] + =289.2.

[0208] 1 H NMR (400MHz, DMSO-d6) δ7.69(dd,J=2.0,0.8Hz,1H),6.80(d,J=1.6Hz,1H),6.66(dd,J=8.0,1.2Hz,1H),6.52(d,J=3.2Hz,1H),6.46 (dd, J=0.9, 3.2Hz, 1H), 6.30 (d, J=8.0Hz, 1H), 5.22 (t, J=6.4Hz, 1H), 5.10 (s, 2H), 3.95 (d, J=6.4Hz, 2H), 2.56 (s, 6H), 2.16 (s, 3H).

[0209] Example 8. Preparation of Compound 1-2-283 of the Present Invention

[0210] 1. Synthesis of 188-6-2

[0211] 188-6-1 (1.0 g, 6.45 mmol) was dissolved in dimethylamine (30 mL, 2 mol / L in tetrahydrofuran (THF), 60 mmol) in a sealed tube and allowed to react at room temperature for 4 hours. After completion of the reaction as monitored by TLC, saturated brine (30 mL) was added to the reaction system and extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to yield compound 188-6-2 (1.1 g, 95% yield). MS Calcd.: 180.1; MS Found: 181.3 [M+H] + .

[0212] 2. Synthesis of SM-4

[0213] 188-6-2 (1.1 g, 6.11 mmol) was dissolved in MeOH (100 mL), and Pd / C (200 mg) was added. The atmosphere was replaced with hydrogen three times, and the system was stirred under a hydrogen atmosphere for overnight reaction. After completion of the reaction as monitored by LCMS, the reaction solution was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain compound SM-4 (700 mg, 76% yield). MS Calcd.: 150.1; MS Found: 151.4 [M+H] + .

[0214] 3. Synthesis of 1-2-283

[0215] SM-4 (400 mg, 1.71 mmol) and N,N-diisopropylethylamine (DIPEA) (441 mg, 3.42 mmol) were dissolved in MeCN (10 mL), and SM-3 (257 mg, 1.71 mmol) was added and stirred at 60°C for 6 hours. After the reaction was complete as monitored by LCMS, saturated brine (20 mL) was added to the reaction system and extracted with dichloromethane (3 × 20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC to obtain compound 1-2-283 (107.37 mg, 21% yield). MS Calcd.: 304.1; MS Found: 305.4 [M+H] + .

[0216] 1H NMR(400MHz, DMSO-d6)δ:7.56(dd,J=1.2,4.8Hz,1H),7.16(d,J=0.8Hz,1H),7.02(dd,J=3.2,5.2Hz,1H),6.80(d,J=8.0Hz,1H),6.2 2(d,J=2.4Hz,1H),6.08(dd,J=2.4,8.0Hz,1H),5.80(t,J=6.4Hz,1H),5.30(s,2H),3.86(d,J=6.4Hz,2H),2.52(s,6H),2.08(s,3H).

[0217] Example 9. Preparation of Compound 1-7-001 of the Present Invention (P2-0-0-1)

[0218] 1. Synthesis of compound 10-8-2

[0219] 10-8-4 (200 mg, 1.48 mmol) was added to a 100 mL single-necked flask and dissolved in tetrahydrofuran (THF) (8 mL). Pyridine (351 mg, 4.44 mmol) was then added. The system was ice-cooled to 0°C, and bromoacetyl bromide (299 mg, 1.48 mmol) was added dropwise. After addition, the mixture was stirred at room temperature for one hour. After completion of the reaction, the solid was removed by filtration, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification on a silica gel column (petroleum ether:ethyl acetate = 100 / 1-10 / 1) afforded 10-8-2 (180 mg, yield: 55%) as a colorless oil. ESI [M+H] + =219.4[M+H] + .

[0220] 2. Synthesis of compound 1-7-001

[0221] SM-1 (124 mg, 0.826 mmol) and DIPEA (213 mg, 1.65 mmol) were dissolved in acetonitrile (5 mL), and 10-8-2 (180 mg, 0.826 mmol) was added and stirred at 60°C overnight. After the reaction was complete as monitored by LCMS, saturated brine (20 mL) was added to the reaction system and extracted with dichloromethane (3×20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC to obtain compound 1-7-001 (41.26 mg, yield 17%). ESI [M+H] + =289.4[M+H] + .

[0222] 1H NMR(400MHz, DMSO-d6)δ:8.58(t,J=6.0Hz,1H),8.47(d,J=1.6Hz,1H),6.80(d,J=1.6Hz,1H),6.71(t,J=1.2Hz,1H) ,6.29-6.25(m,2H),5.31(t,J=6.0Hz,1H),4.46(d,J=6.0Hz,2H),3.70(d,J=5.6Hz,2H),2.58(s,6H),2.17(s,3H).

[0223] Example 10. Preparation of compound 1-1-313 of the present invention (P2-3-3-5)

[0224] 1. Synthesis of compound 1-1-313

[0225] SM-11 (600 mg, 2.57 mmol) and SM-2 (388 mg, 2.57 mmol) were added to a 100 mL single-necked bottle, dissolved in MeCN (30 mL), and then added with cesium carbonate (837 mg, 2.57 mmol). The mixture was stirred at room temperature for 6 h. After the reaction was completed, water (20 ml) was added to the system and extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 ～ 40 / 1) and reverse phase preparation to obtain a white solid 1-1-313 (188.77 mg, yield 24%). ESI [M+H] + =305.2[M+H] + .

[0226] 1 H NMR(400MHz, DMSO-d6), δ9.02(d,J=5.6Hz,1H),7.4(d,J=3.2Hz,1H),6.95(d,J=3.6Hz,2H),6.87 (d,J=8Hz,1H),6.74~6.70(m,2H),4.52(s,2H),4.49(d,J=5.6Hz,2H),2.62(s,6H),2.21(s,3H).

[0227] Example 11. Preparation of Compound 1-7-002 of the Present Invention (P2-2-3-3)

[0228] 1. Synthesis of compound SM-8

[0229] 2-Furfurylamine SM-10 (500 mg, 5.15 mmol) and pyridine (1.22 g, 15.45 mmol) were dispersed in dry tetrahydrofuran (20 mL) in an ice-water bath at 0°C. Bromoacetyl bromide (1.040 g, 5.15 mmol) was slowly added and stirred at room temperature for 3 hours. After the reaction was complete as monitored by LCMS, n-hexane (20 mL) was added to the reaction system, stirred for 10 minutes, and filtered. The solid was washed with ethyl acetate (3 × 30 mL) and dried to obtain an off-white solid compound SM-8 (400 mg, 36% yield). ESI [M] + =218.0.

[0230] 2. Synthesis of compound 1-7-002

[0231] SM-8 (400 mg, 1.84 mmol) and SM-1 (276 mg, 1.84 mmol) were added to a 100 mL single-necked bottle, MeCN (30 mL) was added to dissolve, and N, N-diisopropylethylamine DIPEA (814 mg, 5.52 mmol) was added. The system was heated to 60 ° C in an oil bath and stirred for 6 hours. After the reaction was completed, water (30 ml) was added to the system and extracted with ethyl acetate (3×30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100 / 1 ～ 30 / 1) to give a white solid 1-7-002 (163.06 mg, yield 31%). ESI [M+H] + =288.2[M+H] + .

[0232] 1 H NMR (400MHz, DMSO-d6), δ8.38(t,J=5.6Hz,1H),7.56(t,J=0.8Hz,1H),6.79(d,J=2Hz,1H),6.69(d,J=8.0Hz,1H),6.37(q,J1=1.6Hz,J2=2.8Hz, 1H),6.27(d,J=8.0Hz,1H),6.20(d,J=3.2Hz,1H),5.27(t,J=5.6Hz,1H) ,4.30(d,J=5.6Hz,2H),3.66(d,J=6.0Hz,2H),2.57(s,6H),2.16(s,3H).

[0233] Example 12. Preparation of Compound 1-7-003 of the Present Invention (P2-3-3-3)

[0234] 1. Synthesis of compound 1-7-003

[0235] SM-8 (450 mg, 2.07 mmol) and SM-2 (312 mg, 2.07 mmol) were added to a 100 mL single-necked bottle, dissolved in acetonitrile (30 mL), and then added with cesium carbonate (672 mg, 2.07 mmol). The mixture was stirred at room temperature for 6 h. After the reaction was completed, water (20 ml) was added to the system and extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100 / 1 ～ 40 / 1) and reverse phase preparation to obtain a white solid 1-7-003 (100.24 mg, yield 34%). ESI [M+H] + =289.1[M+H] + .

[0236] 1 H NMR (400MHz, DMSO-d6), δ8.93 (d, J=5.6Hz, 1H), 7.58 (q, J1=0.8Hz, 1H), 6.88 (d, J=8Hz, 1H), 6.76~6.71 (m, 2H), 6.3 9(q,J1=2Hz,1H),6.21(dd,J1=0.8Hz,J2=3.2Hz,1H),4.52(s,2H),4.32(d,J=5.6Hz,2H),2.64(s,6H),2.22(s,3H).

[0237] Example 13. Preparation of Compound 1-2-301 of the Present Invention (P2-1-2-1)

[0238] 1. Synthesis of compound 1-2-301

[0239] To a reaction flask, add N,N-dimethyl-m-phenylenediamine (300 mg, 2.20 mmol) and dissolve in acetonitrile (10 mL). Then, add N,N-diisopropylethylamine (DIPEA) (569 mg, 4.41 mmol) and SM-3 (518 mg, 2.20 mmol). The atmosphere was purged with nitrogen three times, and the reaction system was heated to 60°C and stirred for six hours while maintaining the temperature. After completion of the reaction, the reaction was cooled to room temperature, the solvent was dried at 40°C, and the mixture was extracted three times with water (15 mL) and dichloromethane (15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. High-performance liquid chromatography (HPLC) yielded 1-2-301 (127 mg, 20% yield) as a white solid. ESI [M+H]+ = 291.1.

[0240] 1H NMR (400MHz, DMSO-d6) δ7.56 (dd, J=4.8, 1.2Hz, 1H), 7.16 (d, J=3.6Hz, 1H), 1.02 (dd, J=1.8, 3.2Hz, 1H), 6.8 5(t,J=8.41H),6.00(m,1H),5.88(m,2H),5.81(t,J=6.4,1H),5.31(s,2H),3.87(d,J=6.4,2H),2.78(s,6H).

[0241] Example 14. Preparation of Compound 1-7-004 of the Present Invention (P2-4-3-5)

[0242] 1. Synthesis of compound 4-4-4

[0243] To a 20 mL ethylene glycol solution containing 4-4-3 (1.63 g, 10 mmol) was added 50% aqueous sodium hydroxide solution (20 mL), and the reaction mixture was stirred at 130°C overnight. After completion of the reaction as monitored by TLC, water (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to afford compound 4-4-4 (1.1 g, 80% yield) as a yellow solid. ESI [M+H] + = 277.2.

[0244] 2. Synthesis of Compound SM-9

[0245] 4-4-4 (1.1 g, 4.0 mmol), aqueous formaldehyde (3.0 g, 40.0 mmol), and acetic acid (5 mL) were dissolved in 45 mL of methanol. NaBH3CN (1.3 g, 20 mmol) was added to the reaction system, and the reaction solution was stirred at room temperature overnight. After the reaction was complete as monitored by TLC, saturated brine (50 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain compound SM-9 (900 mg, 68% yield) as a pale yellow oil. ESI [M+H]+ = 333.2.

[0246] 3. Synthesis of compound 1-7-004

[0247] SM-9 (332 mg, 1.0 mmol), SM-3 (466 mg, 2.0 mmol), sodium bisulfite formaldehyde (1.2 g, 10 mmol), and potassium carbonate (278 mg, 2.0 mmol) were dissolved in DMF (30 mL) and water (3 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was complete as monitored by TLC, water (50 mL) was added to the reaction system and extracted with ethyl acetate (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative purification to obtain compound 1-7-004 (130 mg, 41% yield) as a colorless oil. ESI [M+H] + =322.1[M+H] + .

[0248] 1 H NMR (400MHz, DMSO-d6) δ7.56 (dd, J1=1.2Hz, J=5.2Hz, 1H), 7.12 (d, J=3.6Hz, 1H), 7.04~6..99 (m,2 H),6.92(d,J=1.2Hz,1H),6.78(d,J=8Hz,1H),5.27(s,2H),3.81(s,2H),2.62(s,6H),2.24(s,3H).

[0249] Example 15. Preparation of compound 1-1-267 of the present invention (P2-1-1-1)

[0250] 1. Synthesis of compound 1-1-267

[0251] N,N-dimethyl-o-phenylenediamine SM-6 (440 mg, 1.87 mmol) and N,N-diisopropylethylamine DIPEA (484 mg, 3.74 mmol) were dissolved in acetonitrile (10 mL), and SM-7 (255 mg, 1.87 mmol) was added, followed by reflux and stirring for 6 hours. After the reaction was complete as monitored by LCMS, saturated brine (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / petrol ether (v / v) = 0-60%) to obtain compound 1-1-267 (105.64 mg, yield 20%). ESI [M+H] + =291.2.

[0252] 1H NMR (400MHz, CDCl3) δ: 7.31 (dd, J=5.2, 3.2Hz, 1H), 7.29-7.26 (m, 1H), 7.15-6.91 (m, 3H), 6.74 (dd, J=7.6,7.6Hz,1H),6.50(d,J=7.6Hz,1H),5.61-5.23(m,1H),5.20(s,2H),4.00(s,2H),2.53(s,6H).

[0253] Example 16. Preparation of Compound 1-7-005 of the Present Invention (P2-2-3-2)

[0254] 1. Synthesis of compound AL37-10-5-2

[0255] AL37-10-5-1 (500 mg, 5.15 mmol) was added to a 100 mL single-necked flask and dissolved in tetrahydrofuran (THF) (30 mL). Pyridine (814 mg, 10.3 mmol) was then added. The system was cooled to 0°C in an ice bath. Bromoacetyl bromide (1040 mg, 5.15 mmol) was slowly added dropwise. After addition, the mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LCMS, n-hexane (20 mL) was added to the reaction system, stirred for 10 minutes, and filtered. The solid was washed with ethyl acetate (3 × 30 mL) and dried to give AL37-10-5-2 (400 mg, yield: 35%) as an off-white solid. ESI [M+H] + =219.0[M+H] + .

[0256] 2. Synthesis of compound 1-7-005

[0257] AL37-10-5-2 (400 mg, 1.84 mmol) and SM-1 (276 mg, 1.84 mmol) were added to a 100 mL single-necked bottle, MeCN (30 mL) was added to dissolve, and N, N-diisopropylethylamine DIPEA (814 mg, 5.52 mmol) was added. The system was heated to 60 ° C in an oil bath and stirred for 6 hours. After the reaction was completed, water (30 ml) was added to the system and extracted with ethyl acetate (3×30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100 / 1 ～ 30 / 1) to give a white solid 1-7-005 (204.20 mg, yield 38%). ESI [M+H] + =288.0[M+H] + .

[0258] 1H NMR (400MHz, DMSO-d6), δ8.24(t,J=5.6Hz,1H),7.57(t,J=1.6Hz,1H),7.49(s,1H),6.79(d,J=1.6Hz,1H),6.68(dd,J1=1.2Hz,J2=8Hz ,1H),6.38(s,1H),6.27(d,J=8Hz,1H),5.27(t,J=5.6Hz,1H),4.14(d,J=5.6Hz,2H),3.64(d,J=5.6Hz,2H),2.57(s,6H),2.16(s,3H).

[0259] Example 17. Preparation of Compound 1-7-006 of the Present Invention (P2-2-3-4)

[0260] 1. Synthesis of compound 10-2-2

[0261] 10-2-1 (400 mg, 3.51 mmol) was added to a 100 mL single-necked flask and dissolved in tetrahydrofuran (THF) (20 mL). Pyridine (555 mg, 7.02 mmol) was then added. The system was cooled to 0°C and bromoacetyl bromide (709 mg, 3.51 mmol) was added dropwise. After addition, the mixture was stirred at room temperature for two hours. After completion of the reaction, the solid was removed by filtration and the solvent was evaporated under reduced pressure to obtain the crude product. Purification on a silica gel column (petroleum ether:ethyl acetate = 100 / 1 to 10 / 1) afforded 10-2-2 (340 mg, yield: 41%) as a colorless oil. ESI [M+H] + =234.4[M+H] + .

[0262] 2. Synthesis of compound 1-7-006

[0263] SM-1 (218 mg, 1.45 mmol) and N,N-diisopropylethylamine (DIPEA) (561 mg, 4.35 mmol) were dissolved in acetonitrile (10 mL), and 10-2-2 (340 mg, 1.45 mmol) was added, and the mixture was refluxed and stirred overnight. After the reaction was complete as monitored by LCMS, saturated brine (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (CH2Cl2) (3×20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC to obtain compound 1-7-006 (228.68 mg, yield: 52%). ESI [M+H] + =305.4[M+H] + .

[0264] 1H NMR(400MHz, DMSO-d6)δ:8.69(t,J=7.6Hz,1H),8.42(d,J=1.6Hz,1H),7.23(d,J=1.2Hz,1H),6.80(d,J=1.6Hz,1H),6.69(d,J=8 .0Hz,1H),6.26(d,J=8.0Hz,1H),5.33(t,J=6.0Hz,1H),4.59(d,J=6.0Hz,2H),3.69(d,J=5.6Hz,2H),2.59(s,6H),2.17(s,3H).

[0265] Example 18. Preparation of compound 1-1-324 of the present invention (P2-1-3-2)

[0266] 1. Synthesis of compound 8-1-2

[0267] 8-1-1 (500 mg, 5.10 mmol) was added to a 100 mL single-necked flask and dissolved in tetrahydrofuran (THF) (40 mL). Pyridine (806 mg, 10.20 mmol) was then added. The system was ice-cooled to 0°C and bromoacetyl bromide (1.03 g, 5.10 mmol) was added dropwise. After addition, the mixture was stirred at room temperature overnight. After completion of the reaction, the solid was removed by filtration and the solvent was evaporated under reduced pressure to obtain the crude product. Purification on a silica gel column (petroleum ether:ethyl acetate = 100 / 1-10 / 1) afforded 8-1-2 (600 mg, yield: 55%) as a colorless oil. ESI [M+H] + =218.3[M+H] + .

[0268] 2. Synthesis of compound 1-1-324

[0269] SM-1 (413 mg, 2.75 mmol) and DIPEA (1.06 g, 8.25 mmol) were dissolved in acetonitrile (14 mL), and 8-1-2 (600 mg, 2.75 mmol) was added and refluxed with stirring for 6 hours. After the reaction was complete as monitored by LCMS, saturated brine (20 mL) was added to the reaction system and extracted with dichloromethane (3×20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column (petroleum ether:ethyl acetate = 100 / 1-5 / 1) and prep-HPLC to obtain compound 1-1-324 (227.92 mg, yield: 29%). ESI [M+H] + =288.4[M+H] + .

[0270] 1H NMR(400MHz, DMSO-d6)δ:7.70(s,1H),7.65(t,J=1.6Hz,1H),6.80(d,J=1.6Hz,1H),6.67(dd,J=1.2,8.0Hz,1H),6.4 6(d,J=0.8Hz,1H),6.32(d,J=8.4Hz,1H),5.22(s,1H),5.00(s,2H),3.95(d,J=2.4Hz,2H),2.56(s,6H),2.16(s,3H).

[0271] Example 19. Preparation of Compound 1-7-007 of the Present Invention (P2-1-3-6)

[0272] 1. Synthesis of 10-3-2

[0273] 10-3-1 (1.0 g, 9.09 mmol) was added to a 150 mL reaction flask and dissolved in tetrahydrofuran (THF) (45 mL). The system was cooled to 0°C and lithium aluminum hydride (7.3 mL, 18.18 mmol) was slowly added dropwise to the reaction solution. After addition, the mixture was stirred at room temperature overnight. The reaction was monitored for completion by LCMS. 1 mL of water, 1 mL of 15% sodium hydroxide solution, and 3 mL of water were slowly added to the reaction system to quench the mixture. The mixture was stirred at room temperature for 20 minutes, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain 10-3-2 as a yellow oil (240 mg, yield: 24%). ESI [M+H] + =115.4[M+H] + .

[0274] 2. Synthesis of 10-3-3

[0275] 10-3-2 (240 mg, 2.11 mmol) was added to a 100 mL single-necked flask and dissolved in THF (20 mL). Pyridine (333 mg, 4.22 mmol) was then added. The system was cooled to 0°C in an ice bath and bromoacetyl bromide (426 mg, 2.11 mmol) was added dropwise. After addition, the mixture was stirred at room temperature for two hours. After completion of the reaction, the solid was removed by filtration, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification on a silica gel column (petroleum ether:ethyl acetate = 100 / 1 to 10 / 1) afforded 10-3-3 as a colorless oil (200 mg, yield: 41%). ESI [M+H] + =234.3[M+H] + .

[0276] 3. Synthesis of Compound 1-7-007

[0277] SM-1 (128 mg, 0.855 mmol) and N,N-diisopropylethylamine (DIPEA) (221 mg, 1.71 mmol) were dissolved in acetonitrile (10 mL), and 10-3-3 (200 mg, 0.855 mmol) was added, followed by reflux and stirring for 6 hours. After the reaction was complete as monitored by LCMS, saturated brine (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (CH2Cl2) (3×20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC to obtain compound 1-7-007 (170.57 mg, yield: 66%). ESI [M+H] + =305.4[M+H] + .

[0278] 1 H NMR (400MHz, DMSO-d6) δ: 8.75 (s, 1H), 8.48 (t, J = 6.0Hz, 1H), 8.45 (s, 1H), 6.80 (s, 1H), 6.70 (d, J = 8.0Hz, 1H), 6.2 7(d,J=8.0Hz,1H),5.30(t,J=5.6Hz,1H),4.39(d,J=6.0Hz,2H),3.68(d,J=5.6Hz,2H),2.59(s,6H),2.17(s,3H).

[0279] Example 20. Preparation of Compound 1-7-008 of the Present Invention (P2-4-3-3)

[0280] 1. Synthesis of Compound 1-7-008

[0281] SM-9 (400 mg, 1.20 mmol), SM-5 (528 mg, 2.41 mmol), sodium bisulfite formaldehyde (1.42 g, 12.0 mmol), and K2CO3 (333 mg, 2.41 mmol) were dissolved in DMF (30 mL) and H2O (3 mL). The reaction mixture was stirred at room temperature overnight. After completion of the reaction as monitored by TLC, water (50 mL) was added to the reaction system, and the mixture was extracted with EA (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography to obtain compound 1-7-008 (230.22 mg, yield: 63%) as a colorless oil. ESI [M+H] + =306.1[M+H] + .

[0282] 1H NMR (400MHz, DMSO-d6) δ7.56(dd,J=1.2Hz,2.0Hz,1H),7.04(d,J=8.0Hz,1H),6.92(d,J=1.2Hz,1H),6.79(dd,J=1.2, 7.6Hz,1H),6.49(d,J=3.2Hz,,1H),6.46(dd,J=1.6,3.2Hz,1H),5.07(s,2H),3.82(s,2H),2.63(s,6H),2.24(s,3H).

[0283] Example 21. Preparation of Compound 1-7-009 of the Present Invention (P2-2-4-3)

[0284] 1. Synthesis of compound 4-7-1

[0285] To a solution of compound SM-4 (1 g, 6.66 mmol) in N,N-dimethylformamide (10 mL) were added methyl bromoacetate 10-9-2 (1.16 mL, 7.20 mmol) and potassium carbonate (1.38 g, 9.99 mmol), and the mixture was stirred at 25°C for 14 hours. After completion of the reaction as indicated by LC-MS, the reaction mixture was concentrated under reduced pressure, H2O (40 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ISCO® 12 g SepaFlash® Silica Flash Column, Eluent of 0-5% PE / EA gradient @ 45 mL / min) to afford compound 4-7-1 as a brown oil (0.6 g, 40.55% yield). m / z calculated for [M+H] + 223.3,found 223.1.

[0286] 2. Synthesis of compound 4-7-2

[0287] To a solution of compound 4-7-1 (600 mg, 2.699 mmol) in tetrahydrofuran (12 mL) and water (3 mL) was added lithium hydroxide (193.92 mg, 8.097 mmol) and the mixture was stirred at room temperature for 2 hours. After LC-MS indicated the reaction was complete, the mixture was neutralized with dilute hydrochloric acid and concentrated under reduced pressure to afford compound 4-7-2 (550 mg, 97.84% yield) as a brown oil. m / z calculated for [M+H] + 209.3,found 209.2.

[0288] 3. Synthesis of Compound 1-7-009

[0289] To a solution of compound 4-7-2 (600 mg, 2.881 mmol) in acetonitrile (ACN) (10 mL) were added N-methylimidazole (NMI) (0.5 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH) (3226.74 mg, 11.524 mmol), and 2-furylmethylamine SM-10 (559.61 mg, 5.762 mmol). The mixture was stirred at room temperature for 20 minutes. After completion of the reaction as indicated by LC-MS, water (20 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by pre-HPLC afforded compound 1-7-009 as a colorless oil (244.6 mg, 29.55% yield). m / z calculated for [M+H] + 288.4,found 288.1.

[0290] 1 H NMR (400MHz, DMSO-d6) δ8.30-8.27(m,1H),7.55-7.54(m,1H),6.84-6.82(m,1H),6.37-6.36(m,1H),6.28-6.27(m,1H),6. 17–6.16(m,1H),6.12-6.09(m,1H),5.71-5.68(m,1H),4.28(d,J=4Hz,2H),3.62(d,J=4Hz,2H),2.55(s,6H),2.09(s,3H).

[0291] Example 22. Preparation of Compound 1-7-010 of the Present Invention (P2-2-3-9)

[0292] 1. Synthesis of compound 10-9-3

[0293] To a solution of compound SM-1 (1000 mg, 6.66 mmol) in N,N-dimethylformamide (10 mL) was added compound 10-9-2 (1.17 mL, 7.32 mmol) and potassium carbonate (1839.91 mg, 13.31 mmol) at 0°C, and the mixture was stirred at 60°C for 16 hours. After completion of the reaction as indicated by LC-MS, the reaction mixture was concentrated under reduced pressure, H2O (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 3), washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to afford compound 10-9-3 (1200 mg, 81.10% yield) as a yellow oil. m / z calculated for [M+H] +223.29,found 223.1.

[0294] 2. Synthesis of compound 10-9-4

[0295] To a solution of compound 10-9-3 (1200 mg, 5.40 mmol) in tetrahydrofuran (10 mL) was added lithium hydroxide (0.65 g, 26.99 mmol) and stirred at 0°C for 30 minutes. After the reaction was complete as indicated by LC-MS, the reaction mixture was concentrated under reduced pressure to give compound 10-9-4 (800 mg, 80.09% yield) as a yellow oil. m / z calculated for [M+H] + 209.26,found 209.1.

[0296] 3. Synthesis of Compound 1-7-010

[0297] To a solution of compound 10-9-4 (800 mg, 3.84 mmol) in acetonitrile (10 mL) were added N-methylimidazole (629.98 mg, 7.68 mmol) and tetramethyluronium chloride hexafluorophosphate (1077.80 mg, 3.84 mmol). Compound 10-9-5 (559.61 mg, 5.76 mmol) was stirred at 25°C for 30 minutes. After completion of the reaction as indicated by LC-MS, water was added and the mixture was extracted with ethyl acetate (20 mL x 3), washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by Prep-HPLC to afford compound 1-7-010 as a white solid (155.6 mg, 14.10% yield). m / z calculated for [M+H] + 288.37,found 288.1.

[0298] 1 H NMR(400MHz,DMSO-d6)δ8.43–8.31(m,1H),6.99(s,2H),6.83–6.75(m,1H),6.73–6.60(m,1H),6 .43–6.23(m,1H),5.28(s,1H),4.47–4.25(m,2H),3.89–3.59(m,2H),2.58(s,6H),2.17(s,3H).

[0299] Example 23. Preparation of Compound 1-7-011 of the Present Invention (P2-0-0-2)

[0300] 1. Synthesis of compound 11-1-2

[0301] AL37-8-1 (0.86 mL, 10 mmol, 1.0 equiv.) was dissolved in dichloromethane (5 mL). 11-1-1 (0.88 mL, 11 mmol, 1.1 equiv.) and Et3N (1.67 mL, 12 mmol, 1.2 equiv.) were added at 0°C. After complete addition, the mixture was allowed to react at room temperature for 2 h. After completion of the reaction as monitored by TLC, the reaction was quenched with water, extracted three times with dichloromethane, washed with brine, and the organic phase dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 15:1) to afford compound 11-1-2 (1.45 g, 83% yield) as a yellow oil.

[0302] 2. Synthesis of Compound 1-7-011

[0303] SM-2 (302 mg, 2 mmol, 1.0 equiv.) and 11-1-2 (349 mg, 2 mmol, 1.0 equiv.) were dissolved in MeCN (10 mL), and Cs2CO3 (652 mg, 2 mmol, 1.0 equiv.) was added. The mixture was then allowed to react at room temperature overnight. After completion of the reaction as monitored by TLC, EtOAc and water were added and extracted three times. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography (PE / EtOAc = 15:1) was performed to afford 1-7-011 as a yellow oil: 355 mg 1.23 mmol, 61% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 19 NO4H + 290.1389; Found 290.1389.

[0304] 1 H NMR (400MHz, CDCl3) δ7.45–7.40(m,1H),6.75(s,1H),6.71–6.67(m,1H),6.64(d,J=8.2Hz,1H),6.43(d,J=3.2Hz,1H),6.36(dd,J=3.2,1.8Hz, 1H),5.18(s,2H),4.69(s,2H),2.79(s,6H),2.27(s,3H).

[0305] Example 24. Preparation of Compound 1-2-337 of the Present Invention (P2-0-0-3)

[0306] 1. Synthesis of compound 11-2-2

[0307] To a solution of 11-2-1 (1.23 g, 10 mmol) in methanol (25 mL) were added acetic acid (3 mL, 50 mmol) and paraformaldehyde (3 g, 100 mmol). The mixture was cooled to 0°C, and NaBH3CN (3.15 g, 50 mmol, 5.0 equiv.) was slowly added portionwise. After complete addition, the mixture was allowed to react at room temperature overnight. The reaction was monitored for completion by TLC. The reaction was quenched with saturated NaHCO3(aq), the pH adjusted to approximately 7, and extracted three times with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 10:1) to afford compound 11-2-2 (1.26 g, 83% yield) as a colorless oil.

[0308] 2. Synthesis of compound 11-2-3

[0309] A solution of SM-14 (0.95 mL, 10 mmol, 1.0 equiv.) in dichloromethane (DCM) (5 mL) was cooled to 0°C, followed by the addition of SM-13 (0.88 mL, 11 mmol, 1.1 equiv.) and Et3N (1.67 mL, 12 mmol, 1.2 equiv.). After complete addition, the mixture was allowed to react at room temperature for 2 h. After completion of the reaction as monitored by TLC, the reaction was quenched with water, extracted three times with dichloromethane, and the organic phase was washed with brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 15:1) to afford compound 11-2-3 (1.81 g, 90% yield) as a yellow oil.

[0310] 3. Synthesis of Compound 1-2-337

[0311] To a solution of 11-2-2 (435 mg, 2.6 mmol) and 11-2-3 (611 mg, 2.6 mmol) in acetonitrile (20 mL) was added cesium carbonate (938 mg, 2.88 mmol) and allowed to react at room temperature overnight. After completion of the reaction as monitored by TLC, ethyl acetate and water were added and extracted three times. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography (PE / EtOAc = 15:1) was performed to obtain compound 1-2-337 as a yellow oil: 782 mg, 2.56 mmol, 85% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 19 NO3SH + 306.1158; Found 306.1157.

[0312] 1H NMR (400MHz, CDCl3) δ7.37–7.31(m,1H),7.12(d,J=3.2Hz,1H),7.05–6.96(m,2H),6.63(d,J= 2.6Hz,1H),6.41(dd,J=8.4,2.6Hz,1H),5.39(s,2H),4.61(s,2H),2.65(s,6H),2.23(s,3H).

[0313] Example 25. Preparation of Compound 1-7-012 of the Present Invention (P2-2-3-1)

[0314] 1. Synthesis of Compound 10-6-1

[0315] Chloroacetyl chloride (160 μL, 2 mmol) was placed in a 100 mL round-bottom flask, and 5 mL of tetrahydrofuran was added. The temperature was cooled to -70°C, and a solution of SM-15 (1.13 g, 10 mmol) and Et3N (0.56 mL, 4 mmol) in tetrahydrofuran (5 mL) was added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred. After 5 hours, the mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and purified by silica gel column chromatography to obtain a yellow oily product. After recrystallization, the white solid product 10-6-1 (133 mg, 35% yield) was obtained.

[0316] 2. Synthesis of Compound 1-7-012

[0317] 10-6-1 (133 mg, 0.7 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (5 mL), and potassium iodide (67 mg, 0.4 mmol, 0.5 equiv), potassium carbonate (304 mg, 0.88 mmol, 1.1 equiv), and SM-4 (144 mg, 1 mmol, 1.2 equiv) were added sequentially. The reaction solution was stirred in a 40°C oil bath overnight. The reaction solution was diluted with ethyl acetate and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the white solid product 1-7-012: 160 mg, 0.52 mmol, 75% yield.

[0318] 1H NMR (400MHz, CDCl3) δ8.34(d,J=1.7Hz,1H),7.38(s,1H),7.06(d,J=1.7Hz,1H),6.99(d,J=8.0Hz,1H),6.26(d,J=2.4Hz,1H),6.21(d d,J=8.0,2.5Hz,1H),4.74(d,J=6.3Hz,2H),4.08(s,1H),3.84(d,J=4.2Hz,2H),2.64(s,6H),2.21(s,3H).HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 15 H 21 N4OS + 305.1431; Found 305.1444.

[0319] Example 26. Preparation of compound 1-1-250 of the present invention (P2-0-0-4)

[0320] 1. Synthesis of compound 10-7-2

[0321] Chloroacetyl chloride was placed in a 100 mL round-bottom flask, tetrahydrofuran (10 mL) was added, and the mixture was cooled to -70°C. A solution of 10-7-1 (1.13 g, 10 mmol, 1.0 equiv) and triethylamine (1.39 mL, 10 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred. After 3.5 hours, the mixture was filtered, and the filtrate was rotary evaporated to remove most of the solvent. The mixture was diluted with EtOAc and washed with a saturated aqueous sodium bicarbonate solution and saturated brine in a 1:1 ratio. The organic phase was dried over anhydrous sodium sulfate, concentrated at room temperature, and purified by silica gel column chromatography to obtain a pale yellow solid. Recrystallization afforded the product 10-7-2 as a white solid (800 mg, 42.3% yield).

[0322] 2. Synthesis of compound 1-1-250

[0323] 10-7-2 (378 mg, 2 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (5 mL), and potassium iodide (166 mg, 1.0 mmol, 0.5 equiv) was added, followed by potassium carbonate (304 mg, 2.2 mmol, 1.1 equiv) and SM-1 (300 mg, 2 mmol, 1.0 equiv). The reaction solution was stirred in a 50°C oil bath overnight. The reaction solution was diluted with ethyl acetate and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the white solid product 1-1-250: 160 mg, 1.1 mmol, 54% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 12 N3NaOS + 326.1298; Found 326.1306.

[0324] 1 H NMR (400MHz, CDCl3) δ7.26(q,J=2.9Hz,2H),7.10(s,1H),7.07–7.02(m,1H),6.96(dd,J=4.9,1.4Hz,1H),6.89(d,J=2.0Hz,1H),6.82(dd ,J=8.1,2.0Hz,1H),6.45(d,J=8.1Hz,1H),5.18(t,J=5.6Hz,1H),4.49(d,J=6.0Hz,2H),3.81(d,J=5.6Hz,2H),2.63(s,6H),2.26(s,3H).

[0325] Example 27. Preparation of Compound 1-7-013 of the Present Invention (P2-2-3-0)

[0326] 1. Preparation of compound 10-4-5-2

[0327] 10-4-5-1 (2.7 mL, 20.0 mmol, 1.0 equiv) was placed in a 25 mL flask, and dichloromethane (10 mL) was added. SM-13 (1.75 mL, 22.0 mmol, 1.1 equiv) and triethylamine (3.35 mL, 24.0 mmol, 1.2 equiv) were slowly added dropwise at 0°C. The mixture was warmed to room temperature and stirred for 30 min. The reaction was monitored by TLC. The mixture was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The product was purified by silica gel column chromatography (DCM) to give 10-4-5-2 (3.1 g, 16.8 mmol, 85% yield) as a white solid.

[0328] 2. Preparation of Compound 1-7-013

[0329] SM-1 (300 mg, 2.3 mmol, 1.0 equiv) was placed in a 50 mL flask, and DMSO (3 mL), KI (200 mg, 1.2 mmol, 0.5 equiv), potassium carbonate (345 mg, 2.5 mmol, 1.1 equiv), and 10-4-5-2 (367 mg, 2.3 mmol, 1.0 equiv) were added. The mixture was stirred at 40°C overnight. The reaction was monitored for completion by TLC. After dilution with ethyl acetate, the mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The product 1-7-013 was purified by silica gel column chromatography (PE:EtOAc = 4:1) to obtain 384 mg, 1.3 mmol, and a 56% yield of a white solid. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 24 N3O + 298.1914; Found 298.1947.

[0330] 1 H NMR (400MHz, CDCl3) δ7.37–7.11(m,7H),6.91(d,J=2.0Hz,1H),6.86(d,J=8.1Hz,1H),6.5 0(d,J=8.0Hz,1H),4.52(d,J=6.1Hz,2H),3.85(d,J=4.6Hz,2H),2.64(s,6H),2.29(s,3H).

[0331] Example 28. Preparation of Compound 1-7-014 of the Present Invention (P2-2-3-7)

[0332] 1. Preparation of compound 10-4-6-2

[0333] 10-4-6-1 (810 mg, 6.0 mmol, 1.0 equiv) was weighed into a 25 mL flask, and dichloromethane (3 mL) was added. SM-13 (0.53 mL, 6.6 mmol, 1.1 equiv) and triethylamine (1.0 mL, 1.2 mmol, 1.2 equiv) were slowly added dropwise at 0°C. The mixture was warmed to room temperature and stirred for 30 min. The reaction was monitored by TLC for completion. The mixture was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and spun down to dryness. 10-4-6-2 was purified by silica gel column chromatography to obtain a white solid (732 g, 58% yield).

[0334] 2. Preparation of Compound 1-7-014

[0335] SM-1 (375 mg, 2.0 mmol) was weighed into a 50 mL flask, and DMSO (3 mL) and KI (208 mg, 0.5 mmol) were added. After stirring at room temperature for 10 minutes, potassium carbonate (345 mg, 2.5 mmol) and 10-4-6-2 (530 mg, 2.5 mmol) were added and stirred at 40°C overnight. The reaction was monitored for completion by TLC. After dilution with ethyl acetate, the product was washed twice with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. Purification by silica gel column chromatography (PE:EtOAc = 4:1) afforded 1-7-014 as a white solid (665 mg, 82% yield).

[0336] 1 H NMR(400MHz, CDCl3)δ7.10(s,1H),6.93–6.88(m,2H),6.88–6.81(m,3H),6.51(d,J=8.0Hz,1H),5.21(s,1H ),4.44(d,J=6.0Hz,2H),3.91–3.80(m,2H),2.64(s,6H),2.28(d,J=3.4Hz,9H).HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 20 H 28 N3O + 326.2227; Found 326.2310.

[0337] Example 29. Preparation of Compound 1-2-284 of the Present Invention (P2-2-4-5)

[0338] Preparation of compound 1-2-284

[0339] SM-11 (464 mg, 2.0 mmol), SM-4 (300 mg, 2.0 mmol), and DIPEA (272 mg, 2.0 mmol) were dissolved in acetonitrile (30 mL) and stirred at 60°C overnight. After the reaction was complete as monitored by TLC, saturated brine (50 mL) was added to the reaction system and extracted with CH2Cl2 (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative purification to obtain compound 1-2-284 (228 mg, 38% yield) as an oil. ESI [M+H] + =304.2.

[0340] 1H NMR (400MHz, DMSO-d6) δ8.45(t,J=6.0Hz,1H),7.36(dd,J=3.6,2.4Hz,1H),6.92(dd,J=4.8,3.6Hz,2H),6 .82(d,J=7.6Hz,1H),6.25(d,J=2.4Hz,1H),6.09(dd,J=8.0,2.4Hz,1H),5.74(t,J=6.0Hz,1H),4.43(d,J= 6.0Hz, 2H), 3.60 (d, J = 6.0Hz, 2H), 2.53 (s, 6H), 2.09 (s, 3H).

[0341] Example 30. Preparation of Compound 1-2-350 of the Present Invention (P2-1-4-2)

[0342] 1. Synthesis of Compound 1-2-350

[0343] To a solution of 4-7-2 (3.1 g, 14.89 mmol) in N,N-dimethylformamide (DMF) (50 mL) were slowly added 3-furylmethanol 8-1-1 (1.46 g, 14.89 mmol), HOBt (4.02 g, 29.77 mmol), EDCI (5.71 g, 29.77 mmol), DIEA (7.70 g, 59.54 mmol), and DMAP (1 g, 8.19 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography afforded 1-2-350 as a colorless oil (146.1 mg, 3.40% yield). m / z calculated for [M+H] + 289.2,found 289.2.

[0344] 1 H NMR (400MHz, CD3OD_SPE) δ7.53–7.51(m,1H),7.47–7.45(m,1H),6.90(d,J=8.1Hz,1H),6.43–6.40(m,1H) ,6.38(d,J=2.3Hz,1H),6.23(dd,J=8.1,2.3Hz,1H),5.07(s,2H),3.90(s,2H),2.62(s,6H),2.18(s,3H).

[0345] Example 31. Preparation of Compound 1-7-015 of the Present Invention (P2-2-3-11)

[0346] 1. Synthesis of Compound 1-7-015

[0347] To a dichloromethane solution (10 mL) containing 10-9-4 (500 mg, 2.40 mmol) was added 7-015-1 (300.52 mg, 2.40 mmol), HOBT (648.23 mg, 4.80 mmol), EDCI (917.12 mg, 4.80 mmol), and DIEA (1.58 mL, 9.60 mmol). The mixture was stirred at room temperature overnight. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative chromatography to afford 1-7-015 (135.9 mg, 17.95% yield) as a colorless oil. m / z calculated for [M+H] + 316.42,found 316.1.

[0348] 1 H NMR (400MHz, DMSO-d6) δ8.34-8.31(m,1H),6.80-6.79(m,1H),6.70-6.68(m,1H),6.28(d,J=8.0Hz,1H),5.84(s,1H),5 .27(t,J=12Hz,1H),4.28(d,J=4Hz,2H),3.67(d,J=8Hz,2H),3.62(s,3H),2.57(s,6H),2.16(s,3H),2.07-2.05(m,3H).

[0349] Example 32. Preparation of Compound 1-7-016 of the Present Invention (P2-1-3-11)

[0350] 1. Synthesis of Compound 1-7-016

[0351] To a dichloromethane solution (15 mL) containing 10-9-4 (500 mg, 2.40 mmol) were added 7-016-1 (302.89 mg, 2.40 mmol), HOBT (648.23 mg, 4.80 mmol), EDCI (917.12 mg, 4.80 mmol), and DIEA (1.58 mL, 9.60 mmol). The mixture was stirred at room temperature overnight. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative chromatography to obtain AL37-7-7 (175.1 mg, 23.05% yield) as a colorless oil. m / z calculated for [M+H] + 317.40,found 317.2.

[0352] 1 H NMR (400MHz, DMSO-d6) δ6.81-6.80(m,1H),6.69–6.64(m,1H),6.33-6.31(m,1H),6.04(s,1H),5.25-5. 22(m,1H),5.11(s,2H),3.97(d,J=8Hz,2H),3.62(s,3H),2.57-2.55(m,6H),2.16(s,3H),2.09(s,3H).

[0353] Example 33. Preparation of Compound 1-7-017 of the Present Invention (P2-2-3-10)

[0354] 1. Synthesis of Compound 1-7-017

[0355] To a dichloromethane solution (15 mL) containing 10-9-4 (500 mg, 2.40 mmol) were added 7-017-1 (266.85 mg, 2.40 mmol), HOBT (648.23 mg, 4.80 mmol), EDCI (917.12 mg, 4.80 mmol), and DIEA (2 mL, 9.60 mmol). The mixture was stirred at room temperature overnight. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative chromatography to obtain 1-7-017 (178.8 mg, 24.7% yield) as a colorless oil. m / z calculated for [M+H] + 302.39,found 302.2.

[0356] 1 H NMR (400MHz, DMSO-d6) δ8.58-8.55(m,1H),8.47-8.46(m,1H),6.81-6.80(m,1H),6.72-6.69(m,1H),6. 30–6.25(m,2H),5.32-5.29(m,1H),4.47(d,J=4Hz,2H),3.71(d,J=8Hz,2H),2.58(s,6H),2.17(s,3H).

[0357] Example 34. Preparation of Compound 1-7-018 of the Present Invention (P2-1-3-10)

[0358] 1. Synthesis of Compound 1-7-018

[0359] To a solution of 10-9-4 (700 mg, 3.36 mmol) in dichloromethane (15 mL) were slowly added 7-018-1 (565.34 mg, 5.04 mmol), HOBT (907.52 mg, 6.72 mmol), EDCI (1.28 g, 6.72 mmol), and DIEA (1.3 g, 10.08 mmol). The mixed solution was stirred at room temperature overnight. After the reaction was complete, water was added to quench the reaction and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography gave 1-7-018 (152.52 mg, 15.01% yield) as a white solid. m / z calculated for [M+H] + 303.1,found 303.1.

[0360] 1 H NMR (400MHz, DMSO-d6) δ7.35(d,J=1.8Hz,1H),6.81(d,J=1.6Hz,1H),6.67(d,J=8.0Hz,1H),6.33(d,J=8.0Hz,1H),6. 30(d,J=1.8Hz,1H),5.24(t,J=6.5Hz,1H),5.18(s,2H),3.99(d,J=6.6Hz,2H),3.71(s,3H),2.55(s,6H),2.16(s,3H).

[0361] Example 35. Preparation of Compound 1-7-019 of the Present Invention (P2-1-4-10)

[0362] 1. Synthesis of Compound 1-7-019

[0363] To a solution of 4-7-2 (3.2 g, 15.37 mmol) in DMF (40 mL) were slowly added 7-018-1 (3.45 g, 30.73 mmol), HOBt (4.15 g, 30.73 mmol), EDCI (5.89 g, 30.73 mmol), and DIEA (7.94 g, 61.46 mmol). The mixed solution was stirred at room temperature overnight. After the reaction was complete, 200 mL of water was added to quench the reaction and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography afforded 1-7-019 (183.1 mg, 3.94% yield) as a colorless oil. m / z calculated for [M+H] + 303.1,found 303.1.

[0364] 1H NMR (400MHz, CD3OD_SPE) δ8.07–8.01(m,1H),7.36(d,J=1.9Hz,1H),6.86(d,J=8.1Hz,1H),6.34(d,J=2.4Hz,1 H),6.30(d,J=1.9Hz,1H),6.21–6.15(m,1H),5.20(s,2H),3.92(s,2H),3.70(s,3H),2.58(s,6H),2.15(s,3H).

[0365] Example 36. Preparation of compound 1-1-304 of the present invention (P2-3-3-1)

[0366] 1. Synthesis of Compound 304-1

[0367] To a solution of SM-2 (2 g, 13.23 mmol) in acetonitrile (20 mL) were added cesium carbonate (12.93 g, 39.68 mmol) and ethyl bromoacetate 10-9-2 (2.55 mL, 15.87 mmol), followed by stirring at 85°C for 16 hours. The solvent was removed under reduced pressure to afford the crude product, which was purified by preparative chromatography to afford 304-1 as a brown oil (1.6 g, 57.81% yield). m / z calculated for [M+H] + 210.1,found210.1.

[0368] 2. Synthesis of compound 1-1-304

[0369] To a solution of 304-1 (1 g, 4.78 mmol) in dichloromethane (10 mL) were added DIEA (2.47 g, 19.12 mmol), EDCI (1.29 g, 9.56 mmol), HOBT (1.83 g, 9.56 mmol), and 3-thiophenemethylamine 10-7-1 (0.65 g, 5.73 mmol), and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to give the crude product, which was purified by preparative chromatography to give 1-1-304 as a colorless oil (279.4 g, 19.21% yield). m / z calculated for [M+H] + 305.0,found 305.0.

[0370] 1H NMR (400MHz, DMSO-d6) δ8.83(s,1H),7.52–7.44(m,1H),7.24(s,1H),6.99(d,J=4.8Hz,1H),6.89( d,J=7.8Hz,1H),6.78–6.68(m,2H),4.53(s,2H),4.32(d,J=5.7Hz,2H),2.61(s,6H),2.22(s,3H).

[0371] Example 37. Preparation of Compound 1-7-020 of the Present Invention (P2-1-4-11)

[0372] 1. Synthesis of Compound 1-7-020

[0373] To a solution of 4-7-2 (3.2 g, 15.37 mmol) in DMF (40 mL) were slowly added 7-016-1 (3.88 g, 30.73 mmol), HOBt (4.15 g, 30.73 mmol), EDCI (5.89 g, 30.73 mmol), and DIEA (7.94 g, 61.46 mmol). The mixed solution was stirred at room temperature overnight. After the reaction was complete, 150 mL of water was added to quench the reaction and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography afforded 1-7-020 (110.8 mg, 2.28% yield) as a colorless oil. m / z calculated for [M+H] + 317.1,found 317.1.

[0374] 1 HNMR(400MHz,CD3OD_SPE)δ6.89(d,J=8.1Hz,1H),6.35(d,J=2.3Hz,1H),6.21(dd,J=8.1, 2.3Hz,1H),6.08(s,1H),5.16(s,2H),3.94(s,2H),3.64(s,3H),2.61(s,6H),2.18(s,6H).

[0375] Example 38. Preparation of Compound 1-2-274 of the Present Invention (P2-1-4-1)

[0376] 1. Synthesis of compound 1-2-274

[0377] To a solution of SM-7 (2.03 g, 8.65 mmol) in N,N-dimethylformamide, SM-4 (1.3 g, 8.65 mmol), potassium carbonate (2.39 g, 17.31 mmol), and potassium iodide (1.44 g, 8.65 mmol) were slowly added. The mixed solution was stirred at 80°C for two hours. The reaction was quenched by the addition of 60 mL of water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure, the product was purified by column chromatography to obtain compound 1-2-274 (668.5 mg, 25.4% yield) as an orange oil. m / z calculated for [M+H] + 305.0,found 305.0.

[0378] 1 HNMR (400MHz, CD3OD) δ7.35–7.30(m,1H),7.30–7.25(m,1H),7.03(dd,J=5.0,1.2Hz,1H),6.91(d,J=8.0Hz, 1H), 6.39 (d, J = 2.4Hz, 1H), 6.22 (dd, J = 8.0, 2.4Hz, 1H), 5.16 (s, 2H), 3.89 (s, 2H), 2.60 (s, 6H), 2.20 (s, 3H).

[0379] Example 39. Preparation of Compound 1-7-021 of the Present Invention (P2-1-4-3)

[0380] 1. Synthesis of Compound 1-7-021

[0381] To a solution of 4-7-2 (3.0 g, 14.41 mmol) in DMF (50 mL) were slowly added 2-furylmethanol SM-12 (2.83 g, 28.81 mmol), HOBt (3.89 g, 28.81 mmol), EDCI (5.52 g, 28.81 mmol), DIEA (7.45 g, 57.62 mmol), and DMAP (1 g, 8.19 mmol). The mixed solution was stirred at room temperature overnight. After the reaction was complete, 150 mL of water was added to quench the reaction and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography afforded 1-7-021 (235.5 mg, 5.67% yield) as a colorless oil. m / z calculated for [M+H] + 289.1,found 289.1. 1H NMR(400MHz,CD3OD)δ7.52–7.49(m,1H),6.90(d,J=8.2Hz,1H),6.46–6.43(m,1H),6.41–6.39(m,1H),6 .38(d,J=2.4Hz,1H),6.22(dd,J=8.0,2.4Hz,1H),5.14(s,2H),3.90(s,2H),2.63(s,6H),2.18(s,3H).

[0382] Example 40. Preparation of Compound 1-7-022 of the Present Invention (P2-1-3-8)

[0383] 1. Synthesis of Compound 7-022-3

[0384] To a solution of compound 7-022-1 (500 mg, 5.046 mmol), DCC (911.47 mg, 6.560 mmol), and DMAP (61.65 mg, 0.505 mmol) in DCM (10 mL) was added bromoacetic acid 7-022-2 (6.560 mmol) at 0°C and stirred for 0.5 hours. The mixed solution was allowed to warm to room temperature and stirred for 2 hours. The residue was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to afford compound 7-022-3 (900 mg, 81.07% yield) as a brown oil. m / z calculated for [M+H]+: 220.1, found: 221.9.

[0385] 2. Synthesis of Compound 1-7-022

[0386] To a solution of compound 7-022-3 (400 mg, 1.818 mmol) and SM-1 (2.182 mmol) in DMF (10 mL) was added KCO (502.51 mg, 3.636 mmol) and stirred at 60°C for 1 hour. After completion of the reaction as indicated by LC-MS, water was added and the mixture was extracted with ethyl acetate (10 mL x 3). The mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by pre-HPLC afforded compound 1-7-022 (196.3 mg, 37.32% yield) as a brown oil. m / z calculated for [M+H]+: 290.1, found: 290.2.

[0387] 1H NMR (400MHz, CDCl3) δ8.25 (d, J = 1.6 Hz, 1H), 6.89 (s, 1H), 6.81 (s, 1H), 6.42 (d, J = 8. 0Hz, 1H), 6.29 (d, J = 1.5Hz, 1H), 5.31 (s, 2H), 4.04 (s, 2H), 2.69 (s, 6H), 2.27 (s, 3H).

[0388] The beneficial effects of the present invention are demonstrated below through specific test examples.

[0389] Test Example 1: Study on the potent analgesic effect of the compounds of the present invention

[0390] 1 Test method

[0391] The loss of tail withdrawal reflex (LOTWR) in rats was used as the evaluation index to evaluate the potent analgesic effect of the compounds of the present invention.

[0392] 1.1 Experimental Animals: Adult male Sprague-Dawley rats weighing 220–300 g were selected for the experiment. Rats were housed in sawdust-based cages at 25 ± 1°C, 40%–60% humidity, and a 12-h light / 12-h dark cycle. No more than five rats were housed per cage, with free access to water and food.

[0393] 1.2 Experimental plan:

[0394] (1) The compound of the present invention, the positive control drug remifentanil, and the negative control group (vehicle) were administered in fixed volumes. The lowest effective dose of the compound of the present invention that produced a potent analgesic effect and the lowest dose that caused severe adverse reactions were determined using a dose escalation method.

[0395] (2) The duration of LOTWR for 30 seconds was used as the criterion for the production of a strong analgesic effect. During the experiment, the drug was administered through the rat's tail vein, with a volume of 0.6 mL per rat and an administration rate of 0.02 mL / s. Then, an alligator clip was used to clamp the rat's tail 1 cm away from the base, clamping it once longitudinally and transversely and leaving it in place, while continuously oscillating the distal end of the alligator clip (30 times / min) to continuously produce stimulation. When the rat had an escape reaction (i.e., escape movements, struggles, and squeaking) or the alligator clip stayed on the tail for 30 seconds (to avoid tissue damage), the clip was removed. If the rat had an escape reaction, the time point was recorded as no LOTWR, and the process was repeated every 2 minutes. When all the results were "no LOTWR" at 10 minutes (5 tests), the test was stopped and recorded as "invalid".

[0396] (3) All compounds will be dosed over a range of doses, starting at 1 mg / kg (due to the high potency of remifentanil, the lowest dose is set at 1 μg / kg), followed by 5 mg / kg, 10 mg / kg, 20 mg / kg, and so on (increased by 20 mg / kg each time after 20 mg / kg). Dose escalation will be stopped when the rats die. The lowest effective dose and the lowest dose that causes severe adverse reactions will be recorded throughout the entire process. In this study, severe adverse reactions are defined as: apnea, rigidity, convulsions, opisthotonos, convulsions, etc.

[0397] 1.3 Evaluation indicators: minimum effective dose; minimum dose that causes serious adverse reactions; therapeutic safety index = "minimum dose that causes serious adverse reactions" / "minimum effective dose".

[0398] 2 Test results

[0399] Table 1. Effectiveness and safety window of the compounds of the present invention in rats (single intravenous injection)

[0400] Remark:

[0401] “—” means the test was completed, but it did not work or had no such effect;

[0402] “A” means the lowest effective dose is ≤10.00 mg / kg;

[0403] "B" means 10.00 mg / kg < minimum effective dose ≤ 20.00 mg / kg;

[0404] "C" means 20.00 mg / kg < minimum effective dose ≤ 30.00 mg / kg;

[0405] "D" indicates that the minimum effective dose is greater than 30.00 mg / kg.

[0406] “+” indicates a safe therapeutic index ≤ 2;

[0407] “++” means 2<safe therapeutic index ≤ 4;

[0408] “+++” indicates a therapeutic safety index > 4.

[0409] As shown in Table 1, the compounds of the present invention and the μ-opioid receptor agonist remifentanil can both produce definite systemic potent analgesic effects. At the same time, as shown in the table, compared with the μ-opioid receptor agonist remifentanil, the safety therapeutic index of most of the compounds of the present invention is significantly improved, indicating that the compounds of the present invention have better safety.

[0410] The present invention provides a compound having analgesic effects. The compound has excellent analgesic effects, good safety, minimal toxic side effects, and does not cause dependence during use. Therefore, the compound has broad application prospects in the preparation of analgesic drugs and provides a new option for the clinical preparation of analgesic drugs.

Claims

1. A compound represented by formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystalline form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof: in, R1 and R3 are independently selected from hydrogen or NR4R5, and only one of R1 and R3 is selected from NR4R5; R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl; R4 and R5 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; X1, X2 are independently selected from O, S, NR6; R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; m is an integer selected from 1 to 5; n is an integer selected from 0 to 5; M is selected from O, S, NR7; R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is 1 to 5.

2. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is shown in formula II: in, R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl; X1, X2 are independently selected from O, S, NR6; R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; m is selected from 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5; M is selected from O, S, NR7; R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is 1, 2, 3, 4 or 5.

3. The compound according to claim 2, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is shown in formula III: in, R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl; X1, X2 are independently selected from O, S, NR6; R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; M is selected from O, S, NR7; R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is 1, 2, 3, 4 or 5.

4. The compound according to claim 3, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula Iva, formula IVb or formula IVc: in, R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl; X2 is selected from O, S, NR6; R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; M is selected from O, S, NR7; R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is 1, 2, 3, 4 or 5.

5. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula V: in, R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl; X1, X2 are independently selected from O, S, NR6; R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; m is selected from 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5; M is selected from O, S, NR7; R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is 1, 2, 3, 4 or 5.

6. The compound according to claim 5, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula VI: in, R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl; X1, X2 are independently selected from O, S, NR6; R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; M is selected from O, S, NR7; R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is 1, 2, 3, 4 or 5.

7. The compound according to claim 6, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by Formula VIIa, Formula VIIb or Formula VIIc: in, R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, hydroxyl; X2 is selected from O, S, NR6; R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; M is selected from O, S, NR7; R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is 1, 2, 3, 4 or 5.

8. The compound according to any one of claims 1 to 7, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: X2 is selected from O, S, NH; And / or, M is selected from O, S, NH.

9. The compound according to any one of claims 1 to 7, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: Ring A is selected from the following substituted or unsubstituted groups: The substituent of the A ring is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl and mercapto.

10. The compound according to claim 9, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The substituent of the A ring is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, thiol, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl and mercapto.

11. The compound according to any one of claims 1 to 7, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is one of the following compounds:

12. A method for preparing the compound according to any one of claims 2 to 11, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: It includes the following steps: Step 1: In a solvent, compound 1, an organic base and compound 2 react to obtain compound 3; preferably, the organic base is pyridine; Wherein, n, m, X2, A, and M are as described in any one of claims 2 to 11; Step 2: (1) Compound 4 and Compound 5 react in a solvent to obtain Compound 6; (2) Compound 6 and Pd / C react in a solvent under a hydrogen atmosphere to obtain compound 7; (3) Compound 7, an organic base and compound 3 react in a solvent to obtain compound 8; preferably, the organic base is DIPEA; Wherein, R2, n, m, X2, A, and M are as described in any one of claims 2 to 11; At the ortho or meta position of R2; or, (A) In a solvent, the compound, formaldehyde solution, acetic acid and NaBH3CN react to obtain compound 10; (B) in a solvent, compound 10, an inorganic solid base and compound 3 react to obtain compound 11; preferably, the inorganic solid base is Cs2CO3; Wherein, R2, n, m, X2, A, and M are as described in any one of claims 2 to 11; At the ortho or meta position of R2; or, (a) Compound 12 reacts with aqueous sodium hydroxide solution in a solvent to obtain compound 13; (b) Compound 13 reacts with formaldehyde and sodium cyanoborohydride in a solvent to obtain compound 14; (c) Compound 14, sodium bisulfite formaldehyde and compound 3 are reacted in a solvent to obtain compound 15.

13. Use of the compound according to any one of claims 1 to 11, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative in the preparation of a drug having analgesic effect.

14. A drug, characterized in that: It is a preparation prepared with the compound described in any one of claims 1 to 11, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative as the active ingredient, and pharmaceutically acceptable excipients.

15. A pharmaceutical composition, characterized in that: It includes the compound described in any one of claims 1 to 11, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative.

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