Pain-relieving compounds, methods for their preparation and use

Abstract

The application provides a kind of analgesic compound and its preparation method and use, it is related to the field of medicinal chemistry.The compound of the application is the compound shown in formula I, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterium derivative.The analgesic effect of the compound of the application is excellent, safe to use, with little side effects, and no dependence during use.Therefore, the compound of the application has a broad application prospect in the preparation of analgesic drugs, and provides a new choice for preparing drugs with analgesic effect in clinic.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a class of analgesic compounds, their preparation methods, and uses. Background Technology

[0002] The Global Burden of Disease Study reports that pain and pain-related disorders are a leading cause of disability and disease burden globally. The report shows that over 80% of patients undergoing surgery experience acute postoperative pain, less than half achieve adequate pain relief, and nearly 80% of these patients have moderate to severe pain scores. Furthermore, 10% to 50% of patients experience chronic postoperative pain. Therefore, there remains a significant clinical need for analgesics. In the field of pain management, traditional opioids remain the most effective and commonly used analgesics for moderate to severe pain. Opioids exert their analgesic effect by acting on opioid receptors in the G protein-coupled receptor family, primarily activating the downstream Gi / o protein pathway.

[0003] However, while opioids provide potent analgesia, they also come with numerous adverse reactions. These include common respiratory depression, deep sedation, nausea, vomiting, and constipation. Long-term use can lead to tolerance, decreased pain perception, and even drug abuse and addiction, causing serious social harm. Opioids that act on μ-receptors (such as remifentanil) can produce dose-dependent respiratory depression through direct action on the brainstem respiratory center. Studies have shown that the addiction rate of opioids averages between 8% and 12%. Patients with physical dependence or addiction to opioids often abuse them to avoid withdrawal symptoms.

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

[0005] In conclusion, while traditional opioids are the most effective drugs for treating moderate to severe pain, their adverse reactions and drug dependence limit their effectiveness. Furthermore, they reduce safety and lead to serious social problems such as drug abuse. Therefore, designing a novel non-opioid analgesic that retains the analgesic efficacy of opioids while avoiding their serious adverse reactions is of great clinical significance and has broad market prospects. Summary of the Invention

[0006] The purpose of this invention is to provide a class of analgesic compounds, their preparation methods, and uses.

[0007] This invention provides compounds of Formula I, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their crystal forms, or their prodrugs, or their metabolites, or their deuterated derivatives:

[0008]

[0009] in,

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

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

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

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

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

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

[0016] M is selected from O, S, and 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 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, and substituted or unsubstituted 5-8 heterocycloalkyl groups.

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

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

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

[0022] Furthermore, the compound is as shown in Formula II:

[0023]

[0024] in,

[0025] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, and hydroxyl;

[0026] X1 and X2 are independently selected from O, S, and NR6, respectively;

[0027] R6 is selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0028] m is selected from 1, 2, 3, 4, or 5; n is selected from 0, 1, 2, 3, 4, or 5;

[0029] M is selected from O, S, and NR7;

[0030] R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0031] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, and substituted or unsubstituted 5-8 heterocycloalkyl groups.

[0032] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0033] The aryl, heteroaryl, cycloalkyl, and heterocycloalkyl substituents are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy.

[0034] The heteroaryl group contains O, S, or N heteroatoms, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0035] Furthermore, the compound is as shown in Formula III:

[0036]

[0037] in,

[0038] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, and hydroxyl;

[0039] X1 and X2 are independently selected from O, S, and NR6, respectively;

[0040] R6 is selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0041] M is selected from O, S, and NR7;

[0042] R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0043] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, and substituted or unsubstituted 5-8 heterocycloalkyl groups.

[0044] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0045] The aryl, heteroaryl, cycloalkyl, and heterocycloalkyl substituents are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy.

[0046] The heteroaryl group contains O, S, or N heteroatoms, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0047] Furthermore, the compound is of formula IVa, IVb, or IVc:

[0048]

[0049]

[0050] in,

[0051] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, and hydroxyl;

[0052] X2 is selected from O, S, and NR6;

[0053] R6 is selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0054] M is selected from O, S, and NR7;

[0055] R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0056] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, and substituted or unsubstituted 5-8 heterocycloalkyl groups.

[0057] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0058] The aryl, heteroaryl, cycloalkyl, and heterocycloalkyl substituents are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy.

[0059] The heteroaryl group contains O, S, or N heteroatoms, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0060] Furthermore, the compound is as shown in formula V:

[0061]

[0062] in,

[0063] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, and hydroxyl;

[0064] X1 and X2 are independently selected from O, S, and NR6, respectively;

[0065] R6 is selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0066] m is selected from 1, 2, 3, 4, or 5; n is selected from 0, 1, 2, 3, 4, or 5;

[0067] M is selected from O, S, and NR7;

[0068] R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0069] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, and substituted or unsubstituted 5-8 heterocycloalkyl groups.

[0070] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0071] The aryl, heteroaryl, cycloalkyl, and heterocycloalkyl substituents are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy.

[0072] The heteroaryl group contains O, S, or N heteroatoms, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0073] Furthermore, the compound is as shown in Formula VI:

[0074]

[0075] in,

[0076] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, and hydroxyl;

[0077] X1 and X2 are independently selected from O, S, and NR6, respectively;

[0078] R6 is selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0079] M is selected from O, S, and NR7;

[0080] R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0081] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, and substituted or unsubstituted 5-8 heterocycloalkyl groups.

[0082] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0083] The aryl, heteroaryl, cycloalkyl, and heterocycloalkyl substituents are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy.

[0084] The heteroaryl group contains O, S, or N heteroatoms, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0085] Furthermore, the compound is of formula VIIa, VIIb, or VIIc:

[0086]

[0087]

[0088] in,

[0089] R2 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen, and hydroxyl;

[0090] X2 is selected from O, S, and NR6;

[0091] R6 is selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups;

[0092] M is selected from O, S, and NR7;

[0093] R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0094] Ring A is selected from substituted or unsubstituted 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, and substituted or unsubstituted 5-8 heterocycloalkyl groups.

[0095] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0096] The aryl, heteroaryl, cycloalkyl, and heterocycloalkyl substituents are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy.

[0097] The heteroaryl group contains O, S, or N heteroatoms, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0098] Furthermore,

[0099] X2 is selected from O, S, and NH;

[0100] And / or, M is selected from O, S, NH.

[0101] Furthermore, ring A is selected from the following groups, whether substituted or unsubstituted:

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108] The substituents of the A ring are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy.

[0109] The alkyl and alkoxy substituents are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0110] Furthermore,

[0111] The substituents of the A ring are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, mercapto, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy.

[0112] The alkyl and alkoxy substituents are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, and mercapto.

[0113] Furthermore, the compound is one of the following compounds:

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126] 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 crystal form, or its prodrug, or its metabolite, or its deuterated derivative, comprising the following steps:

[0127] Step 1:

[0128]

[0129] In a solvent, compound 1, an organic base, and compound 2 react to yield compound 3; preferably, the organic base is pyridine.

[0130] Wherein, n, m, X2, A, and M are as described above;

[0131] Step 2:

[0132]

[0133] (1) In the solvent, compound 4 and compound 5 react to give compound 6;

[0134] (2) In a solvent, compound 6 and Pd / C react in a hydrogen atmosphere to give compound 7;

[0135] (3) In a solvent, compound 7, an organic base and compound 3 react to give compound 8; preferably, the organic base is DIPEA;

[0136] Among them, R2, n, m, X2, A, and M are as described above; In the adjacent or intermediate position of R2;

[0137] or,

[0138]

[0139] (A) In a solvent, the compound, an aqueous formaldehyde solution, acetic acid and NaBH3CN react to give compound 10;

[0140] (B) In a solvent, compound 10, an inorganic solid base, and compound 3 react to yield compound 11; preferably, the inorganic solid base is Cs2CO3;

[0141] Among them, R2, n, m, X2, A, and M are as described above; In the adjacent or intermediate position of R2;

[0142] or,

[0143]

[0144] (a) In a solvent, compound 12 reacts with an aqueous sodium hydroxide solution to give compound 13;

[0145] (b) In a solvent, compound 13 reacts with formaldehyde and sodium cyanoborohydride to give compound 14;

[0146] (c) In a solvent, compound 14, sodium formaldehyde sulfoxylate and compound 3 react to give compound 15.

[0147] The present invention also provides the use of the aforementioned compounds, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or crystal forms thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof, in the preparation of medicaments having analgesic effects.

[0148] The present invention also provides a drug preparation which is a formulation made 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 as the active ingredient, plus pharmaceutically acceptable excipients.

[0149] 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 crystal form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof.

[0150] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0151] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0152] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0153] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a ~C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C1 to C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms; "C1 to C6 alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms.

[0154] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group with 1 to 6 carbon atoms, that is, alkyl groups with 1, 2, 3, 4, 5, or 6 carbon atoms. Alkyl groups can be straight-chain 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, etc.

[0155] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0156] "Cycloalkyl" refers to saturated or unsaturated all-carbon monocyclic or polycyclic (including fused, spiro, or bridged rings) that do not possess a conjugated π-electron system, such as, but not limited to: wait.

[0157] "Heterocyclic alkyl" refers to a cycloalkyl group in which at least one carbon atom on the ring is replaced by a heteroatom, which is O, N, or S, and is a saturated or unsaturated monocyclic or polycyclic (including fused, spiro, or bridged rings) that does not have a conjugated π-electron system, such as including but not limited to: wait.

[0158] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused rings, spiro rings, or bridged rings) with a conjugated π-electron system, such as, but not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indeneyl. The aromatic ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N, or S. Furthermore, the point of attachment to the parent group must be on a carbon atom of a ring with a conjugated π-electron system, such as, but not limited to, [other types of rings]. wait.

[0159] "Heteroaryl" refers to an aryl group in which at least one carbon atom on the ring of a conjugated π-electron system is replaced by a heteroatom, which is O, N, or S, such as including but not limited to thienyl, furanyl, isothiazolyl, etc.

[0160] The pharmaceutically acceptable salts described in this invention include acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates, carbonates, bisulfates, sulfates, borates, camphor sulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, hexafluorophosphates, hydrochlorides, hydrobromide, hydroiodates, hydroxyethyl sulfonates, lactates, malates, maleic acid esters, malonates, methyl sulfates, naphthates, theosulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxyacetate, phosphates, hydrogen phosphates, dihydrogen phosphates, pyroglutamates, glycosides, stearates, succinates, tannins, tartrates, toluenesulfonates, trifluoroacetates, sine sulfonates, methanesulfonates, p-toluenesulfonates, quaternary ammonium salts, or succinates, etc.

[0161] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.

[0162] The compounds or pharmaceutical compositions of the present invention may be used in the following ways (but are not limited to): intragastric, enteric, parenteral (intravenous, intramuscular or subcutaneous), oral and various local administration methods.

[0163] Compositions intended for parenteral (intravenous, intramuscular, subcutaneous) injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0164] 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 components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0165] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0166] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0167] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0168] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0169] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0170] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0171] 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 dose administered is a pharmaceutically considered safe and effective dose.

[0172] Compared with the prior art, the compound provided by the present invention has the following beneficial effects:

[0173] This invention provides a compound with analgesic effects. This compound exhibits excellent analgesic efficacy, good safety profile, low toxicity and side effects, and does not induce dependence. Therefore, this compound has broad application prospects in the preparation of analgesic drugs, providing a new option for the clinical preparation of drugs with analgesic effects.

[0174] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0175] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0176] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0177] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR 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); deuterated water (D2O); and the internal standard was tetramethylsilane (TMS).

[0178] LCMS determination was performed using an Agilent LCMS1200-6120 (ESI) column: Waters Xbridge PrepC. 18 OBD 10μm 19*250mm. Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Gradient from 95% [water + 10mM ammonium bicarbonate] and 5% [CH3CN] to 5% [water + 10mM ammonium bicarbonate] and 95% [CH3CN] over 1.6 minutes, held at this condition for 1.4 minutes, then gradient to 95% [water + 10mM ammonium bicarbonate] and 5% [CH3CN] over 0.05 minutes, and held at this condition for 0.7 minutes.

[0179] (1) Medicinal materials and reagents

[0180] The thin-layer chromatography (TLC) silica gel plates used are manufactured by Qingdao Spectrum Separation Materials Co., Ltd., with specifications of 50*200mm and a thickness of 0.2~0.25mm.

[0181] Silica gel for column chromatography, 200-300 mesh, from Shandong Weihai Rushan Taiyang Desiccant Co., Ltd.

[0182] (2) Main instruments

[0183] Electronic balance, FA2004, Shanghai Liangping Instruments Co., Ltd.;

[0184] Temperature-controlled and pressure-regulating magnetic stirrer, TY98-1, Shanghai Sile Instruments Co., Ltd.

[0185] Three-in-one ultraviolet analyzer, ZF-2 model, Shanghai Anting Scientific Instrument Factory;

[0186] Rotary evaporator, R201, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0187] Liftable water bath, R201D, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0188] Circulating water vacuum pump (tabletop), SHB-Ⅲ, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0189] Circulating water vacuum pump (portable), SHB-B95, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0190] Cryogenic circulating pump, DLSB-5 / 20, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0191] Rotary vane vacuum pump (oil pump), 2XZ-4, Shanghai Vacuum Pump Factory.

[0192] Example 1: Preparation of compound 1-1-249 of the present invention

[0193]

[0194] 1. Synthesis of compound SM-7

[0195] AL37-7-1 (1.2 g, 10.62 mmol) was added to a 100 mL single-necked flask, dissolved in 40 mL of tetrahydrofuran (THF), and then pyridine (1.68 g, 21.24 mmol) was added. The system was cooled to 0 °C, and bromoacetyl bromide (2.4 g, 11.68 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for one hour. After the reaction was completed as monitored by TLC, the solid was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 10 / 1) to give a colorless oily substance SM-7 (1.5 g, yield: 61%).

[0196] 2. Synthesis of compound 1-1-249

[0197] SM-1 (400 mg, 1.71 mmol) and N,N-diisopropylethylamine (DIPEA) (441 mg, 3.42 mmol) were dissolved in acetonitrile (10 mL), and then SM-7 (257 mg, 1.71 mmol) was added and the mixture was refluxed and stirred for 6 hours. After the reaction was monitored by LCMS to be complete, 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, concentrated under reduced pressure, and the crude product was purified by prep-HPLC to give compound 1-1-249 (105.64 mg, yield 20%). MS Calcd.: 304.1; MS Found: 305.4 [M+H] + .

[0198] 1 H 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).

[0199] Example 2: Preparation of compound 1-1-258 of the present invention

[0200]

[0201] 1. Synthesis of AL-37-1

[0202]

[0203] 3-Fluoro-4-nitrotoluene (10.0 g, 64.52 mmol) was dissolved in tetrahydrofuran (50 mL), and dimethylamine (150 mL, 2 mol / LinTHF, 60 mmol) was added at 0 °C. The reaction was carried out at room temperature for 5 hours. After the reaction was completed as monitored by TLC, saturated brine (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound AL-37-1 (11.0 g, 95% yield). MS Calcd.: 180.1; MS Found: 181.4 [M+H] + .

[0204] 2. Synthesis of SM-1

[0205]

[0206] 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 give compound SM-1 (6.5 g, yield 78.3%). MS Calcd.: 150.1; MS Found: 151.4 [M+H] + .

[0207] 3. Synthesis of SM-3

[0208]

[0209] AL-37-4 (5.0 g, 44.25 mmol) was added to a 250 mL single-necked flask, dissolved in tetrahydrofuran (150 mL), and then pyridine (7.0 g, 88.5 mmol) was added. The system was cooled to 0 °C, and bromoacetyl bromide (10.73 g, 53.10 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for one hour. After the reaction was complete, the solid was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 10 / 1) to give a colorless oily substance SM-3 (8.0 g, yield: 80%).

[0210] 4. Synthesis of 1-1-258

[0211]

[0212] SM-1 (400 mg, 2.67 mmol) and N,N-diisopropylethylamine (DIPEA) (688 mg, 5.33 mmol) were dissolved in MeCN (10 mL), and then SM-3 (622 mg, 2.67 mmol) was added. The mixture was refluxed and stirred 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, concentrated under reduced pressure, and the crude product was purified by prep-HPLC to give compound 1-1-258 (337.95 mg, yield: 42%). MS Calcd.: 304.1; MS Found: 305.4 [M+H] + .

[0213] 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).

[0214] Example 3: Preparation of compound 1-1-259 of the present invention

[0215]

[0216] 1. Preparation of compound SM-11

[0217] 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 overnight at room temperature. 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 (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give a pale yellow oily compound SM-11 (500 mg, yield 71%).

[0218] 2. Preparation of compound 1-1-259

[0219] 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 overnight at 60 °C. 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 CH2Cl2 (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography to give a colorless oily compound 1-1-259 (100 mg, yield 33%). ESI[M+H] + =289.2.

[0220] 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).

[0221] Example 4: Preparation of compound 1-1-276 of the present invention

[0222]

[0223] 1. Synthesis of compound 1-1-276

[0224] SM-6 (600 mg, 4.0 mmol) and N,N-diisopropylethylamine (DIPEA) (1.03 g, 8.0 mmol) were dissolved in acetonitrile (10 mL), and then SM-3 (932 mg, 4.0 mmol) was added. The mixture was refluxed at 60 °C and stirred 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, concentrated under reduced pressure, and the crude product was purified by prep-HPLC to give compound 1-1-276 (420.02 mg, yield 36%). MS Calcd.: 290.1; MS Found: 291.4 [M+H] + .

[0225] 1H 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).

[0226] Example 5: Preparation of compound 1-1-321 of the present invention

[0227]

[0228] 1. Preparation of compound AL37-6-2

[0229] AL37-6-1 (468 mg, 3 mmol) was dissolved in N,N-dimethylformamide 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, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give a pale yellow oily compound AL37-6-2 (400 mg, yield 72%). ESI [M+H]+ = 185.2.

[0230] 2. Preparation of compound AL37-6-3

[0231] Pd / C (50 mg) was added to 30 mL of methanol solution containing AL37-6-2 (368 mg, 2 mmol), and the reaction mixture was stirred overnight at room temperature. After the reaction was completed as monitored by TLC, the reaction mixture was filtered, concentrated under reduced pressure to obtain a crude product, and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain a pale yellow oily compound AL37-6-3 (155 mg, yield 50%). ESI [M+H]+ = 155.2.

[0232] 3. Preparation of compound 1-1-321

[0233] 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 overnight at 60 °C. 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, concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography to give a colorless oily compound 1-1-321 (100 mg, yield 33%). ESI[M+H] + =309.2.

[0234] 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).

[0235] Example 6: Preparation of compound 1-1-312 of the present invention

[0236]

[0237] 1. Synthesis of compound SM-2

[0238]

[0239] AL37-11-1 (1.23 g, 10 mmol), formaldehyde aqueous 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 then added to the reaction system, and the mixture was stirred overnight at room temperature. 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, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to give a pale yellow oily compound SM-2 (1.5 g, 99% yield). MS Found: 152.2 [M+H] + .

[0240] 2. Synthesis of compound 1-1-312

[0241]

[0242] 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 overnight at room temperature. 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, concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography to give a colorless oily compound 1-1-312 (103.06 mg, yield 17%). ESI [M+H] + =306.2.

[0243] 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).

[0244] Example 7: Preparation of compound 1-1-322 of the present invention

[0245]

[0246] 1. Preparation of compound SM-5

[0247] 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 overnight at room temperature. 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, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give compound SM-5 (1.2 g, 60% yield).

[0248] 2. Preparation of compound 1-1-322

[0249] 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 overnight at 60 °C. 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, concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography to give a colorless oily compound 1-1-322 (100 mg, yield 34%). ESI[M+H] + =289.2.

[0250] 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).

[0251] Example 8: Preparation of compound 1-2-283 of the present invention

[0252]

[0253] 1. Synthesis of 188-6-2

[0254]

[0255] 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 reacted at room temperature for 4 hours. After the reaction was complete as monitored by TLC, saturated brine (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 188-6-2 (1.1 g, 95% yield). MS Calcd.: 180.1; MS Found: 181.3 [M+H] + .

[0256] 2. Synthesis of SM-4

[0257]

[0258] 188-6-2 (1.1 g, 6.11 mmol) was dissolved in MeOH (100 mL), and Pd / C (200 mg) was added. The mixture was purged three times with hydrogen, and the reaction mixture was stirred and passed through a hydrogen atmosphere. After the reaction was monitored by LCMS until complete, the reaction solution was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound SM-4 (700 mg, yield 76%). MS Calcd.: 150.1; MS Found: 151.4 [M+H] + .

[0259] 3. Synthesis of 1-2-283

[0260]

[0261] SM-4 (400 mg, 1.71 mmol) and N,N-diisopropylethylamine (DIPEA) (441 mg, 3.42 mmol) were dissolved in MeCN (10 mL), and then SM-3 (257 mg, 1.71 mmol) was added. The mixture was 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 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, concentrated under reduced pressure, and the crude product was purified by prep-HPLC to give compound 1-2-283 (107.37 mg, yield 21%). MS Calcd.: 304.1; MS Found: 305.4 [M+H] + .

[0262] 1 H 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).

[0263] Example 9: Preparation of compound 1-7-001 of the present invention (P2-0-0-1)

[0264]

[0265] 1. Synthesis of compound 10⁻⁸⁻²

[0266] 10⁻⁸⁻⁴ (200 mg, 1.48 mmol) was added to a 100 mL single-necked flask, dissolved in 8 mL of tetrahydrofuran (THF), followed by the addition of pyridine (351 mg, 4.44 mmol). The system was cooled to 0 °C, and 299 mg, 1.48 mmol of bromoacetyl bromide was added dropwise. After the addition was complete, the mixture was stirred at room temperature for one hour. After the reaction was complete, the solid was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1-10 / 1) to give a colorless oily substance 10⁻⁸⁻⁴ (180 mg, yield: 55%). ESI [M+H] + =219.4[M+H] + .

[0267] 2. Synthesis of Compound 1-7-001

[0268] SM-1 (124 mg, 0.826 mmol) and DIPEA (213 mg, 1.65 mmol) were dissolved in acetonitrile (5 mL), and then 10⁻⁸⁻² (180 mg, 0.826 mmol) was added and stirred overnight at 60 °C. 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 (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by prep-HPLC to give compound 1-7-001 (41.26 mg, yield 17%). ESI [M+H] + =289.4[M+H] + .

[0269] 1 H 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).

[0270] Example 10: Preparation of compound 1-1-313 of the present invention (P2-3-3-5)

[0271]

[0272] 1. Synthesis of compound 1-1-313

[0273] SM-11 (600 mg, 2.57 mmol) and SM-2 (388 mg, 2.57 mmol) were added to a 100 mL single-necked flask, dissolved in MeCN (30 mL), and then cesium carbonate (837 mg, 2.57 mmol) was added. The mixture was stirred at room temperature for 6 h. After the reaction was complete, water (20 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1). ～ Prepared by 40 / 1) and reverse phase reaction, yielding a white solid 1-1-313 (188.77 mg, yield 24%). ESI [M+H] + =305.2[M+H] + .

[0274] 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).

[0275] Example 11: Preparation of compound 1-7-002 of the present invention (P2-2-3-3)

[0276]

[0277] 1. Synthesis of compound SM-8

[0278] 2-Furfuralamine SM-10 (500 mg, 5.15 mmol) and pyridine (1.22 g, 15.45 mmol) were dispersed in a dry tetrahydrofuran (20 mL) solution at 0 °C in an ice-water bath. Bromoacetyl bromide (1.040 g, 5.15 mmol) was slowly added, and the mixture was 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, and the mixture was stirred for 10 minutes. The mixture was filtered, and the solid was washed with ethyl acetate (3 × 30 mL). After drying, a white solid compound SM-8 (400 mg, 36% yield) was obtained. (ESI [M]) + =218.0.

[0279] 2. Synthesis of Compound 1-7-002

[0280] SM-8 (400 mg, 1.84 mmol) and SM-1 (276 mg, 1.84 mmol) were added to a 100 mL single-necked flask, dissolved in MeCN (30 mL), and then N,N-diisopropylethylamine (DIPEA) (814 mg, 5.52 mmol) were added. The system was heated to 60 °C in an oil bath and stirred for 6 hours. After the reaction was complete, water (30 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1). ～ 30 / 1), yielding a white solid 1-7-002 (163.06 mg, yield 31%). ESI [M+H] + =288.2[M+H] + .

[0281] 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).

[0282] Example 12: Preparation of compound 1-7-003 of the present invention (P2-3-3-3)

[0283]

[0284] 1. Synthesis of compound 1-7-003

[0285] SM-8 (450 mg, 2.07 mmol) and SM-2 (312 mg, 2.07 mmol) were added to a 100 mL single-necked flask, dissolved in acetonitrile (30 mL), and then cesium carbonate (672 mg, 2.07 mmol) was added. The mixture was stirred at room temperature for 6 h. After the reaction was complete, water (20 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1). ～ Prepared by 40 / 1) and reverse phase reaction, yielding a white solid 1-7-003 (100.24 mg, yield 34%). ESI [M+H] +=289.1[M+H] + .

[0286] 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).

[0287] Example 13: Preparation of compound 1-2-301 of the present invention (P2-1-2-1)

[0288]

[0289] 1. Synthesis of compound 1-2-301

[0290] N,N-dimethyl-m-phenylenediamine (300 mg, 2.20 mmol) was added to the reaction flask and dissolved in acetonitrile (10 mL). Then, N,N-diisopropylethylamine (DIPEA) (569 mg, 4.41 mmol) and SM-3 (518 mg, 2.20 mmol) were added to the system. The mixture was purged with nitrogen three times, and the reaction system was heated to 60 °C and stirred for six hours after the temperature stabilized. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was evaporated to dryness at 40 °C. 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 removed under reduced pressure. The resulting product was then subjected to high-performance liquid chromatography (HPLC) to obtain a white solid 1-2-301 (127 mg, yield: 20%). ESI [M+H]+ = 291.1.

[0291] 1 H 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).

[0292] Example 14: Preparation of compound 1-7-004 of the present invention (P2-4-3-5)

[0293]

[0294] 1. Synthesis of compound 4-4-4

[0295] To 20 mL of ethylene glycol solution containing 4-4-3 (1.63 g, 10 mmol), 20 mL of 50% sodium hydroxide aqueous solution was added, and the reaction mixture was stirred overnight at 130 °C. After the reaction was complete as monitored by TLC, 100 mL of water 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 the crude product concentrated under reduced pressure was purified by silica gel column chromatography (PE / EA = 5 / 1) to give a yellow solid compound 4-4-4 (1.1 g, 80% yield). ESI [M+H]+ = 277.2.

[0296] 2. Synthesis of compound SM-9

[0297] 4-4-4 (1.1 g, 4.0 mmol), formaldehyde aqueous solution (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 then added to the reaction system, and the mixture was stirred overnight at room temperature. 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, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to give a pale yellow oily compound SM-9 (900 mg, yield 68%). ESI [M+H]+ = 333.2.

[0298] 3. Synthesis of compound 1-7-004

[0299] 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 N,N-dimethylformamide (DMF) (30 mL) and water (3 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was completed as monitored by TLC, water (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, concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography to give a colorless oily compound 1-7-004 (130 mg, yield 41%). ESI [M+H] + =322.1[M+H] + .

[0300] 1H 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).

[0301] Example 15: Preparation of compound 1-1-267 of the present invention (P2-1-1-1)

[0302]

[0303] 1. Synthesis of compound 1-1-267

[0304] 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 then SM-7 (255 mg, 1.87 mmol) was added. The mixture was refluxed and stirred for 6 hours. After the reaction was monitored by LCMS until complete, 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, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EtOAc / petrol ether (v / v) = 0–60%) to give compound 1-1-267 (105.64 mg, yield 20%). ESI [M+H] + =291.2.

[0305] 1 H 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).

[0306] Example 16: Preparation of compound 1-7-005 of the present invention (P2-2-3-2)

[0307]

[0308] 1. Synthesis of compound AL37-10-5-2

[0309] AL37-10-5-1 (500 mg, 5.15 mmol) was added to a 100 mL single-necked flask, dissolved in 30 mL of tetrahydrofuran (THF), followed by pyridine (814 mg, 10.3 mmol). The system was cooled to 0 °C in an ice bath, and 1040 mg, 5.15 mmol of bromoacetyl bromide was slowly added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was complete as monitored by LCMS, 20 mL of n-hexane was added to the reaction system, and the mixture was stirred for 10 minutes. The mixture was filtered, and the solid was washed with ethyl acetate (3 × 30 mL). After drying, a white solid compound AL37-10-5-2 (400 mg, yield: 35%) was obtained. (ESI [M+H]) + =219.0[M+H] + .

[0310] 2. Synthesis of compound 1-7-005

[0311] 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 flask, dissolved in MeCN (30 mL), and then N,N-diisopropylethylamine (DIPEA) (814 mg, 5.52 mmol) were added. The system was heated to 60 °C in an oil bath and stirred for 6 h. After the reaction was complete, water (30 mL) was added to the system, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1). ～ 30 / 1), yielding a white solid 1-7-005 (204.20 mg, yield 38%). ESI [M+H] + =288.0[M+H] + .

[0312] 1 H 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).

[0313] Example 17: Preparation of compound 1-7-006 of the present invention (P2-2-3-4)

[0314]

[0315] 1. Synthesis of compound 10-2-2

[0316] 10⁻²⁻¹ (400 mg, 3.51 mmol) was added to a 100 mL single-necked flask, dissolved in 20 mL of tetrahydrofuran (THF), followed by the addition of pyridine (555 mg, 7.02 mmol). The system was then cooled to 0 °C, and bromoacetyl bromide (709 mg, 3.51 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for two hours. After the reaction was complete, the solid was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100 / 1 to 10 / 1) to give a colorless oily substance 10⁻²⁻² (340 mg, yield: 41%). ESI [M+H] + =234.4[M+H] + .

[0317] 2. Synthesis of compound 1-7-006

[0318] SM-1 (218 mg, 1.45 mmol) and N,N-diisopropylethylamine (DIPEA) (561 mg, 4.35 mmol) were dissolved in acetonitrile (10 mL), and then 10⁻²⁻ (340 mg, 1.45 mmol) was added and refluxed with stirring overnight. After the reaction was monitored by LCMS to be complete, 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, concentrated under reduced pressure, and the crude product was purified by prep-HPLC to give compound 1-7-006 (228.68 mg, yield: 52%). ESI [M+H] + =305.4[M+H] + .

[0319] 1 H 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).

[0320] Example 18: Preparation of compound 1-1-324 of the present invention (P2-1-3-2)

[0321]

[0322] 1. Synthesis of compound 8-1-2

[0323] Add 500 mg (5.10 mmol) of 8-1-1 to a 100 mL single-necked flask, dissolve in 40 mL of tetrahydrofuran (THF), then add pyridine (806 mg, 10.20 mmol). Cool the system to 0 °C, then add 1.03 g (5.10 mmol) of bromoacetyl bromide dropwise. After the addition is complete, stir the mixture overnight at room temperature. After the reaction is complete as monitored by TLC, filter to remove the solid, evaporate the solvent under reduced pressure to obtain the crude product, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1-10 / 1) to give a colorless oily substance 8-1-2 (600 mg, yield: 55%). ESI [M+H] + =218.3[M+H] + .

[0324] 2. Synthesis of compound 1-1-324

[0325] SM-1 (413 mg, 2.75 mmol) and DIPEA (1.06 g, 8.25 mmol) were dissolved in acetonitrile (14 mL), and then 8-1-2 (600 mg, 2.75 mmol) was added and the mixture was refluxed and stirred 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, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1-5 / 1) and prep-HPLC to give compound 1-1-324 (227.92 mg, yield: 29%). ESI [M+H] + =288.4[M+H] + .

[0326] 1 H 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).

[0327] Example 19: Preparation of compound 1-7-007 of the present invention (P2-1-3-6)

[0328]

[0329] 1. Synthesis of 10⁻³⁻²

[0330] 10⁻³⁻¹ (1.0 g, 9.09 mmol) was added to a 150 mL reaction flask and dissolved in 45 mL of tetrahydrofuran (THF). 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 the addition was complete, the mixture was stirred overnight at room temperature. The reaction was monitored for completeness by LCMS. 1 mL of water, 1 mL of 15% sodium hydroxide solution, and 3 mL of water were slowly added sequentially to the reaction system to quench the mixture. The mixture was stirred for 20 minutes at room temperature, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain a yellow oily substance 10⁻³⁻² (240 mg, yield: 24%). ESI [M+H] + =115.4[M+H] + .

[0331] 2. Synthesis of 10⁻³⁻³

[0332] Add 10⁻³⁻² (240 mg, 2.11 mmol) to a 100 mL single-necked flask, dissolve in THF (20 mL), then add pyridine (333 mg, 4.22 mmol). Cool the system to 0 °C in an ice bath and add bromoacetyl bromide (426 mg, 2.11 mmol) dropwise. After the addition is complete, stir the mixture at room temperature for two hours. After the reaction is complete, filter to remove the solid, evaporate the solvent under reduced pressure to obtain the crude product, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1). ～ 10 / 1), yielding a colorless oily substance 10⁻³⁻³ (200 mg, yield: 41%). ESI [M+H] + =234.3[M+H] + .

[0333] 3. Synthesis of compound 1-7-007

[0334] SM-1 (128 mg, 0.855 mmol) and N,N-diisopropylethylamine (DIPEA) (221 mg, 1.71 mmol) were dissolved in acetonitrile (10 mL), and then 10⁻³⁻³ (200 mg, 0.855 mmol) was added and the mixture was refluxed and stirred for 6 hours. After the reaction was monitored by LCMS to be complete, 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, concentrated under reduced pressure, and the crude product was purified by prep-HPLC to give compound 1-7-007 (170.57 mg, yield: 66%). ESI [M+H] +=305.4[M+H] + .

[0335] 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).

[0336] Example 20: Preparation of compound 1-7-008 of the present invention (P2-4-3-3)

[0337]

[0338] 1. Synthesis of compound 1-7-008

[0339] SM-9 (400 mg, 1.20 mmol), SM-5 (528 mg, 2.41 mmol), sodium formaldehyde sulfoxylate (1.42 g, 12.0 mmol), and K₂CO₃ (333 mg, 2.41 mmol) were dissolved in N,N-dimethylformamide (DMF) (30 mL) and H₂O (3 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was completed 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, concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography to obtain a colorless oily compound 1-7-008 (230.22 mg, yield: 63%). ESI[M+H] + =306.1[M+H] + .

[0340] 1 H 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).

[0341] Example 21: Preparation of compound 1-7-009 of the present invention (P2-2-4-3)

[0342]

[0343] 1. Synthesis of compound 4-7-1

[0344] To a solution of N,N-dimethylformamide (10 mL) containing compound SM-4 (1 g, 6.66 mmol), methyl bromoacetate 10-9-2 (1.16 mL, 7.20 mmol) and potassium carbonate (1.38 g, 9.99 mmol) were added, and the mixture was stirred at 25 °C for 14 hours. After the reaction was indicated by LC-MS to be complete, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate (20 mL x 3), washed with concentrated 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 give a brown oily compound 4-7-1 (0.6 g, yield 40.55%). m / z calculated for [M+H] + 223.3, found 223.1.

[0345] 2. Synthesis of compound 4-7-2

[0346] Lithium hydroxide (193.92 mg, 8.097 mmol) was added to a solution of compound 4-7-1 (600 mg, 2.699 mmol) in tetrahydrofuran (12 mL) and water (3 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was indicated by LC-MS, the mixture was neutralized with dilute hydrochloric acid and concentrated under reduced pressure to give a brown oily compound 4-7-2 (550 mg, yield 97.84%). (m / z calculated for [M+H]) + 209.3, found 209.2.

[0347] 3. Synthesis of compound 1-7-009

[0348] To a solution of compound 4-7-2 (600 mg, 2.881 mmol) in acetonitrile ACN (10 mL), N-methylimidazolium (NMI) (0.5 mL), N,N,N',N'-tetramethylchloromethanemidane hexafluorophosphate (TCFH) (3226.74 mg, 11.524 mmol), and 2-furanylamine (SM-10) (559.61 mg, 5.762 mmol) were added, and the mixture was stirred at room temperature for 20 min. After the reaction was indicated by LC-MS to be complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3), washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by pre-HPLC to give a colorless oily compound 1-7-009 (244.6 mg, yield 29.55%). (m / z calculated for [M+H]) + 288.4, found 288.1.

[0349] 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).

[0350] Example 22: Preparation of compound 1-7-010 of the present invention (P2-2-3-9)

[0351]

[0352] 1. Synthesis of compound 10⁻⁹⁻³

[0353] Compound 10⁻⁹⁻² (1.17 mL, 7.32 mmol) and potassium carbonate (1839.91 mg, 13.31 mmol) were added to a solution of N,N-dimethylformamide (10 mL) containing compound SM-1 (1000 mg, 6.66 mmol) at 0 °C, and the mixture was stirred at 60 °C for 16 hours. After the reaction was indicated by LC-MS to be complete, 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). The mixture was washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give a yellow oily compound 10⁻⁹⁻³ (1200 mg, 81.10% yield). m / z calculated for [M+H] +223.29, found 223.1.

[0354] 2. Synthesis of compound 10⁻⁹⁻⁴

[0355] Lithium hydroxide (0.65 g, 26.99 mmol) was added to a 10 mL solution of tetrahydrofuran containing compound 10⁻⁹⁻³ (1200 mg, 5.40 mmol), and the mixture was stirred at 0 °C for 30 min. After the reaction was indicated by LC-MS to be complete, the reaction mixture was concentrated under reduced pressure to give a yellow oily compound 10⁻⁹⁻⁴ (800 mg, yield 80.09%). (m / z calculated for [M+H)) + 209.26, found 209.1.

[0356] 3. Synthesis of compound 1-7-010

[0357] To a solution of compound 10-9-4 (800 mg, 3.84 mmol) in acetonitrile (10 mL), N-methylimidazole (629.98 mg, 7.68 mmol) and tetramethylchlorourea hexafluorophosphate (1077.80 mg, 3.84 mmol) and compound 10-9-5 (559.61 mg, 5.76 mmol) were added, and the mixture was stirred at 25 °C for 30 min. After the reaction was indicated by LC-MS, water was added and the mixture was extracted with ethyl acetate (20 mL x 3), washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by Prep-HPLC to give a white solid compound 1-7-010 (155.6 mg, yield 14.10%). m / z calculated for [M+H] + 288.37, found 288.1.

[0358] 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).

[0359] Example 23: Preparation of compound 1-7-011 of the present invention (P2-0-0-2)

[0360]

[0361] 1. Synthesis of compound 11-1-2

[0362] AL37-8-1 (0.86 mL, 10 mmol, 1.0 equiv.) was dissolved in dichloromethane (5 mL), and 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 the addition was complete, the mixture was allowed to react at room temperature for 2 h. After the reaction was monitored by TLC until complete, the reaction was quenched with water, then extracted three times with dichloromethane, washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 15:1) to give a yellow oily compound 11-1-2 (1.45 g, 83% yield).

[0363] 2. Synthesis of compound 1-7-011

[0364] 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), followed by the addition of Cs₂CO₃ (652 mg, 2 mmol, 1.0 equiv.), and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed as monitored by TLC, EtOAc and water were added for extraction three times. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 15:1) to give a yellow oily compound 1-7-011: 355 mg 1.23 mmol, 61% yield. HRMS (ESI-TO F) m / z: [M+H] + Calcd for C 16 H 19 NO4H + 290.1389; Found 290.1389.

[0365] 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),6.4 3(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).

[0366] Example 24: Preparation of compound 1-2-337 of the present invention (P2-0-0-3)

[0367]

[0368] 1. Synthesis of compound 11-2-2

[0369] To a methanol solution (25 mL) of 11-2-1 (1.23 g, 10 mmol), acetic acid (3 mL, 50 mmol) and paraformaldehyde (3 g, 100 mmol) were added. The mixture was cooled to 0 °C, and then NaBH3CN (3.15 g, 50 mmol, 5.0 equiv.) was slowly added in portions. After the addition was complete, the mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched with saturated NaHCO3(aq), the pH was adjusted to approximately 7, and the mixture was extracted three times with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 10:1) to give a colorless oily compound 11-2-2 (1.26 g, 83% yield).

[0370] 2. Synthesis of compound 11-2-3

[0371] A solution of SM-14 (0.95 mL, 10 mmol, 1.0 equiv.) in dichloromethane DCM (5 mL) was cooled to 0 °C, and then SM-13 (0.88 mL, 11 mmol, 1.1 equiv.) and Et3N (1.67 mL, 12 mmol, 1.2 equiv.) were added. After the addition was complete, the mixture was allowed to react at room temperature for 2 h. After the reaction was monitored by TLC until complete, the reaction was quenched with water, followed by extraction three times with dichloromethane and washing of the organic phase with concentrated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 15:1) to give a yellow oily compound 11-2-3 (1.81 g, 90% yield).

[0372] 3. Synthesis of compound 1-2-337

[0373] Cesium carbonate (938 mg, 2.88 mmol) was added to 20 mL solutions of acetonitrile (435 mg, 2.6 mmol) of 11-2-2 and 11-2-3 (611 mg, 2.6 mmol), and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed as monitored by TLC, the mixture was extracted three times with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 15:1) to give a yellow oily compound 1-2-3 (37: 782 mg, 2.56 mmol, 85% yield). HRMS (ESI-TO F) m / z: [M+H] + Calcd forC 16 H 19 NO3SH + 306.1158; Found 306.1157.

[0374] 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).

[0375] Example 25: Preparation of compound 1-7-012 of the present invention (P2-2-3-1)

[0376]

[0377] 1. Synthesis of compound 10-6-1

[0378] Chloroacetyl chloride (160 μL, 2 mmol) was placed in a 100 mL round-bottom flask, and 5 mL of tetrahydrofuran was added. The mixture was cooled to -70 °C, and a tetrahydrofuran solution of SM-15 (1.13 g, 10 mmol) and Et3N (0.56 mL, 4 mmol) was added dropwise (5 mL). After the addition was complete, the reaction mixture was brought to room temperature and stirred. After 5 hours, the mixture was filtered, washed with ethyl acetate, and the filtrate was concentrated and purified by silica gel column chromatography to give a yellow oily product. After recrystallization, a white solid product 10⁻⁶⁻¹ (133 mg, 35% yield) was obtained.

[0379] 2. Synthesis of compound 1-7-012

[0380] 10-6-1 (133 mg, 0.7 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 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). The reaction mixture was stirred overnight in an oil bath at 40 °C. After diluting the reaction mixture with ethyl acetate, it was washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and column chromatography to give a white solid product 1-7-012: 160 mg, 0.52 mmol, 75% yield.

[0381] 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.

[0382] Example 26: Preparation of compound 1-1-250 of the present invention (P2-0-0-4)

[0383]

[0384] 1. Synthesis of compound 10-7-2

[0385] Chloroacetyl chloride was placed in a 100 mL round-bottom flask, and tetrahydrofuran (10 mL) was added. The mixture was cooled to -70 °C, and a tetrahydrofuran solution (5 mL) of 10⁻⁷⁻¹ (1.13 g, 10 mmol, 1.0 equiv) and triethylamine (1.39 mL, 10 mmol, 1.0 equiv) was added dropwise. After the addition was complete, the reaction mixture was brought to room temperature and stirred. After 3.5 h, the mixture was filtered, and most of the solvent was removed by rotary evaporation. The filtrate was diluted with EtOAc and washed with a 1:1 mixture of saturated sodium bicarbonate solution and saturated saline solution. 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. After recrystallization, a white solid product 10⁻⁷⁻² (800 mg, 42.3% yield) was obtained.

[0386] 2. Synthesis of compound 1-1-250

[0387] 10⁻⁷⁻² (378 mg, 2 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (5 mL), followed by potassium iodide (166 mg, 1.0 mmol, 0.5 equiv), then potassium carbonate (304 mg, 2.2 mmol, 1.1 equiv) and SM-1 (300 mg, 2 mmol, 1.0 equiv). The reaction mixture was stirred overnight in an oil bath at 50 °C. The reaction mixture was diluted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column-secred to give a white solid product 1⁻¹⁵⁰: 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.

[0388] 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).

[0389] Example 27: Preparation of compound 1-7-013 of the present invention (P2-2-3-0)

[0390]

[0391] 1. Preparation of compound 10-4-5-2

[0392] Measure 2.7 mL (20.0 mmol, 1.0 equiv) of 10⁻⁴⁻⁵⁻¹ into a 25 mL flask, add 10 mL of dichloromethane, and slowly add 1.75 mL (22.0 mmol, 1.1 equiv) and 3.35 mL (24.0 mmol, 1.2 equiv) dropwise at 0 °C. Heat to room temperature and stir for 30 min. Monitor the reaction by TLC until complete. Quench with water, extract with dichloromethane, wash with saturated brine, dry to dryness with anhydrous sodium sulfate, evaporate to dryness, and purify by silica gel column chromatography (DCM) to obtain a white solid 10⁻⁴⁻⁵⁻² (3.1 g, 16.8 mmol, 85% yield).

[0393] 2. Preparation of compound 1-7-013

[0394] SM-1 (300 mg, 2.3 mmol, 1.0 equiv) was weighed into 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 10⁻⁴⁵⁻² (367 mg, 2.3 mmol, 1.0 equiv) were added. The mixture was stirred overnight at 40 °C. The reaction was monitored by TLC until complete. After dilution with ethyl acetate, the product was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. Purification was achieved by silica gel column chromatography (PE:EtOAc = 4:1) to give a white solid product 1-7-013: 384 mg, 1.3 mmol, 56% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 18 H 24 N3O + 298.1914; Found 298.1947.

[0395] 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).

[0396] Example 28: Preparation of compound 1-7-014 of the present invention (P2-2-3-7)

[0397]

[0398] 1. Preparation of compound 10-4-6-2

[0399] Weigh 10⁻⁴⁻⁶⁻¹ (810 mg, 6.0 mmol, 1.0 equiv) into a 25 mL flask, add dichloromethane (3 mL), and slowly add SM-13 (0.53 mL, 6.6 mmol, 1.1 equiv) and triethylamine (1.0 mL, 1.2 mmol, 1.2 equiv) dropwise at 0 °C. Heat to room temperature and stir for 30 min. Monitor the reaction by TLC until complete. Quench with water, extract with dichloromethane, wash with saturated brine, dry to anhydrous sodium sulfate, evaporate to dryness, and purify by silica gel column chromatography to obtain a white solid 10⁻⁴⁻⁶⁻² (732 g, 58% yield).

[0400] 2. Preparation of compound 1-7-014

[0401] 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. The mixture was stirred at room temperature for 10 min, followed by the addition of potassium carbonate (345 mg, 2.5 mmol) and 10⁻⁴⁶⁻² (530 mg, 2.5 mmol). The mixture was stirred overnight at 40 °C. The reaction was monitored by TLC until complete. After dilution with ethyl acetate, the mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The resulting product was purified by silica gel column chromatography (PE:EtOAc = 4:1) to give a white solid 1-7-014:665 mg, 82% yield.

[0402] 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.

[0403] Example 29: Preparation of compound 1-2-284 of the present invention (P2-2-4-5)

[0404]

[0405] Preparation of compound 1-2-284

[0406] 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 overnight at 60 °C. 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 CH2Cl2 (3 × 100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography to give an oily compound 1-2-284 (228 mg, yield 38%). ESI[M+H] + =304.2.

[0407] 1 H 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).

[0408] Example 30: Preparation of compound 1-2-350 of the present invention (P2-1-4-2)

[0409]

[0410] 1. Synthesis of compound 1-2-350

[0411] To a 50 mL solution of N,N-dimethylformamide (DMF) containing 4-7-2 (3.1 g, 14.89 mmol), 3-furanethanol 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) were slowly added. The mixture was stirred overnight at room temperature. After the reaction was complete, it 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 yielded a colorless oil, 1-2-350 (146.1 mg, yield 3.40%). (m / z calculated for [M+H]) + 289.2, found289.2.

[0412] 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).

[0413] Example 31: Preparation of compound 1-7-015 of the present invention (P2-2-3-11)

[0414]

[0415] 1. Synthesis of compound 1-7-015

[0416] To a 10 mL solution of dichloromethane containing 10⁻⁹⁻⁴ (500 mg, 2.40 mmol), 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) were added. The mixture was stirred overnight at room temperature. 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 give a colorless oily substance 1-7-015 (135.9 mg, yield 17.95%). (m / z calculated for [M+H)) + 316.42, found 316.1.

[0417] 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).

[0418] Example 32: Preparation of compound 1-7-016 of the present invention (P2-1-3-11)

[0419]

[0420] 1. Synthesis of compound 1-7-016

[0421] To a 15 mL solution of dichloromethane containing 10⁻⁹⁻⁴ (500 mg, 2.40 mmol), 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) were added. The mixture was stirred overnight at room temperature. 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 give a colorless oil, AL37-7-7 (175.1 mg, yield 23.05%). m / z calculated for [M+H] + 317.40, found 317.2.

[0422] 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).

[0423] Example 33: Preparation of compound 1-7-017 of the present invention (P2-2-3-10)

[0424]

[0425] 1. Synthesis of compound 1-7-017

[0426] To a 15 mL solution of dichloromethane containing 10⁻⁹⁻⁴ (500 mg, 2.40 mmol), 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) were added. The mixture was stirred overnight at room temperature. 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 give a colorless oil, 1-7-017 (178.8 mg, yield 24.7%). m / z calculated for [M+H] + 302.39, found 302.2.

[0427] 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).

[0428] Example 34: Preparation of compound 1-7-018 of the present invention (P2-1-3-10)

[0429]

[0430] 1. Synthesis of compound 1-7-018

[0431] To a solution of 15 mL of dichloromethane containing 10⁻⁹⁻⁴ (700 mg, 3.36 mmol), 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) were slowly added. The mixture was stirred overnight at room temperature. 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. The solution was purified by column chromatography to give a white solid 1-7-018 (152.52 mg, yield 15.01%). (m / z calculated for [M+H)) + 303.1, found 303.1.

[0432] 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).

[0433] Example 35: Preparation of compound 1-7-019 of the present invention (P2-1-4-10)

[0434]

[0435] 1. Synthesis of compound 1-7-019

[0436] To a DMF (40 mL) solution containing 4-7-2 (3.2 g, 15.37 mmol), 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) were slowly added. The mixture was stirred overnight at room temperature. 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. The solution was purified by column chromatography to give a colorless oily substance 1-7-019 (183.1 mg, yield 3.94%). (m / z calculated for [M+H)) + 303.1, found 303.1.

[0437] 1 H 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).

[0438] Example 36: Preparation of compound 1-1-304 of the present invention (P2-3-3-1)

[0439]

[0440] 1. Synthesis of compound 304-1

[0441] Cesium carbonate (12.93 g, 39.68 mmol) and ethyl bromoacetate 10⁻⁹⁻² (2.55 mL, 15.87 mmol) were added to a 20 mL solution of acetonitrile containing SM⁻² (2 g, 13.23 mmol), and the mixture was stirred at 85 °C for 16 hours. The solvent was removed under reduced pressure to obtain the crude product, which was purified by preparative chromatography to give a brown oily substance 304⁻¹ (1.6 g, yield 57.81%). (m / z calculated for [M + H⁺]) + 210.1, found210.1.

[0442] 2. Synthesis of compound 1-1-304

[0443] To a solution of 304-1 (1 g, 4.78 mmol) in dichloromethane (10 mL), DIEA (2.47 g, 19.12 mmol), EDCI (1.29 g, 9.56 mmol), HOBT (1.83 g, 9.56 mmol), and 3-thiophene methylamine 10-7-1 (0.65 g, 5.73 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to obtain the crude product, which was then purified by preparative chromatography to give a colorless oily substance 1-1-304 (279.4 g, yield 19.21%). (m / z calculated for [M+H)) + 305.0, found 305.0.

[0444] 1 H 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).

[0445] Example 37: Preparation of compound 1-7-020 of the present invention (P2-1-4-11)

[0446]

[0447] 1. Synthesis of compound 1-7-020

[0448] To a DMF (40 mL) solution containing 4-7-2 (3.2 g, 15.37 mmol), 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) were slowly added. The mixture was stirred overnight at room temperature. 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. The solution was purified by column chromatography to give a colorless oily substance 1-7-020 (110.8 mg, yield 2.28%). (m / z calculated for [M+H)) + 317.1, found 317.1.

[0449] 1HNMR(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).

[0450] Example 38: Preparation of compound 1-2-274 of the present invention (P2-1-4-1)

[0451]

[0452] 1. Synthesis of compound 1-2-274

[0453] 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 to a solution of N,N-dimethylformamide containing SM-7 (2.03 g, 8.65 mmol). The mixture was stirred at 80 °C for two hours. The reaction was quenched with 60 mL of water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the solution was purified by column chromatography to give an orange oily compound 1-2-274 (668.5 mg, yield 25.4%). (m / z calculated for [M+H]) + 305.0, found 305.0.

[0454] 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).

[0455] Example 39: Preparation of compound 1-7-021 of the present invention (P2-1-4-3)

[0456]

[0457] 1. Synthesis of compound 1-7-021

[0458] To a DMF (50 mL) solution containing 4-7-2 (3.0 g, 14.41 mmol), 2-furanethanol 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) were slowly added. The mixture was stirred overnight at room temperature. 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. The solution was purified by column chromatography to give a colorless oily substance 1-7-021 (235.5 mg, yield 5.67%). (m / z calculated for [M+H)) + 289.1, found 289.1. 1 HNMR(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).

[0459] Example 40: Preparation of compound 1-7-022 of the present invention (P2-1-3-8)

[0460]

[0461] 1. Synthesis of compound 7-022-3

[0462] To a DCM (10 mL) solution containing compound 7-022-1 (500 mg, 5.046 mmol), DCC (911.47 mg, 6.560 mmol), and DMAP (61.65 mg, 0.505 mmol), bromoacetic acid 7-022-2 (6.560 mmol) was added at 0 °C and stirred for 0.5 h. The mixture was then heated to room temperature and stirred for 2 h. The residue was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give a brown oily compound 7-022-3 (900 mg, yield 81.07%). m / z calculated for [M+H]+220.1, found 221.9.

[0463] 2. Synthesis of compound 1-7-022

[0464] K₂CO₃ (502.51 mg, 3.636 mmol) was added to a DMF (10 mL) solution containing compound 7-022-3 (400 mg, 1.818 mmol) and SM-1 (2.182 mmol), and the mixture was stirred at 60 °C for 1 hour. After the reaction was indicated by LC-MS, water was added, and the mixture was extracted with ethyl acetate (10 mL x 3), washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The resulting product was purified by pre-HPLC to give a brown oily compound 1-7-022 (196.3 mg, yield 37.32%). m / z calculated for [M+H]+290.1, found 290.2.

[0465] 1 H 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).

[0466] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0467] Experimental Example 1: Study on the potent analgesic effect of the compound of the present invention

[0468] 1. Experimental Methods

[0469] The potent analgesic effect of the compounds of this invention was evaluated using the loss of tail withdrawal reflex (LOTWR) in rats as a criterion.

[0470] 1.1 Experimental Animals: Adult male SD rats weighing between 220 and 300 grams were selected for the experiment. The rats were housed in sawdust bedding cages at 25 ± 1 degrees Celsius, with humidity between 40% and 60%, and 12 hours of light / 12 hours of darkness. No more than 5 rats were housed per cage, and they had free access to water and food.

[0471] 1.2 Experimental Design:

[0472] (1) The compound of the present invention, the positive control drug remifentanil, and the negative control group (solvent) were administered in fixed volumes. The minimum effective dose at which the compound of the present invention produced a strong analgesic effect and the minimum dose at which serious adverse reactions occurred were determined by dose escalation.

[0473] (2) The duration of LOTWR for 30 seconds was used as the indicator of potent analgesia. During the experiment, the drug was administered via the tail vein of rats, with a volume of 0.6 mL per rat and an administration rate of 0.02 mL / s. Then, an alligator clip was placed 1 cm from the base of the rat's tail, clamping once longitudinally and once laterally, and left in place while continuously pulsating the distal end of the clip (30 times / min) to continuously generate stimulation. The clip was removed when the rat exhibited an escape response (i.e., exhibiting evasive movements, struggling, and squeaking) or when the clip remained on the tail for 30 seconds (to avoid tissue damage). If the rat exhibited an escape response, this time point was recorded as "no LOTWR," and the process was repeated after 2 minutes. When all results were "no LOTWR" after 10 minutes (5 tests), the test was stopped and recorded as "invalid."

[0474] (3) All compounds will be escalated over a dose range, starting at 1 mg / kg (the minimum dose is set at 1 μg / kg due to the high potency of remifentanil), then 5 mg / kg, 10 mg / kg, 20 mg / kg, and so on (increasing by 20 mg / kg each time after 20 mg / kg). The dose escalation will be stopped when the rats reach the lethal dose. The lowest effective dose and the lowest dose at which a serious adverse reaction occurs will be recorded throughout the process. In this study, serious adverse reactions are defined as: respiratory arrest, generalized rigidity, convulsions, opisthotonus, seizures, etc.

[0475] 1.3 Evaluation indicators: lowest effective dose; lowest dose at which serious adverse reactions occur; safe treatment index = "lowest dose at which serious adverse reactions occur" / "lowest effective dose".

[0476] 2. Experimental Results

[0477] Table 1. Efficacy and safety window of the compounds of this invention in rats (single intravenous injection)

[0478]

[0479]

[0480] Remark:

[0481] "—" indicates that the test was completed, and the test was ineffective or had no effect.

[0482] “A” indicates that the minimum effective dose is ≤10.00mg / kg;

[0483] "B" indicates that 10.00 mg / kg < minimum effective dose ≤ 20.00 mg / kg;

[0484] "C" indicates that 20.00 mg / kg < minimum effective dose ≤ 30.00 mg / kg;

[0485] “D” indicates that the minimum effective dose is >30.00 mg / kg.

[0486] "+" indicates that the safety treatment index is ≤2;

[0487] “++” indicates that 2 < safety treatment index ≤ 4;

[0488] "+++" indicates a safety treatment index > 4.

[0489] As shown in Table 1, both the compounds of this invention and the μ-opioid receptor agonist remifentanil can produce definite and potent systemic analgesic effects. At the same time, as shown in the table, the safety and therapeutic index of most of the compounds of this invention are significantly improved compared with the μ-opioid receptor agonist remifentanil, indicating that the compounds of this invention have better safety.

[0490] This invention provides a compound with analgesic effects. This compound exhibits excellent analgesic efficacy, good safety profile, low toxicity and side effects, and does not induce dependence. Therefore, this compound has broad application prospects in the preparation of analgesic drugs, providing a new option for the clinical preparation of drugs with analgesic effects.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in Formula III: Formula I II in, R2 is selected from hydrogen, C1-C6 alkyl groups, and halogens; X1 is selected from O, S, and NR6; R6 is selected from hydrogen. X2 is selected from O and NR6; R6 is selected from hydrogen and C1~C6 alkyl groups; M is selected from O; Ring A is selected from substituted or unsubstituted phenyl groups or substituted or unsubstituted 5-membered heteroaryl groups; The substituents of the phenyl and heteroaryl groups are selected from C1 to C6 alkyl groups; The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1 or 2; The compound is not selected from .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula IVa: Formula I Va in, R2 is selected from hydrogen, C1-C6 alkyl groups, and halogens; X2 is selected from O and NR6; R6 is selected from hydrogen and C1~C6 alkyl groups; M is selected from O; Ring A is selected from the following groups, whether substituted or unsubstituted: , , , , , , , ; The substituents of ring A are selected from C1 to C6 alkyl groups.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula IVb: Formula IVb in, R2 is selected from hydrogen, C1-C6 alkyl groups, and halogens; X2 is selected from O and NR6; R6 is selected from hydrogen and C1~C6 alkyl groups; M is selected from O; Ring A is selected from the following groups, whether substituted or unsubstituted: , , ; The substituents of ring A are selected from C1 to C6 alkyl groups.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula IVc: Formula IVc in, R2 is selected from hydrogen, C1-C6 alkyl groups, and halogens; X2 is selected from O and NR6; R6 is selected from hydrogen and C1~C6 alkyl groups; M is selected from O; Ring A is selected from the following groups, whether substituted or unsubstituted: , , ; The substituents of ring A are selected from C1 to C6 alkyl groups.

5. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in Formula VI: Style VI in, R2 is selected from hydrogen and C1~C6 alkyl groups; X1 is selected from O and NR6; R6 is selected from hydrogen. X2 is selected from O and NR6; R6 is selected from hydrogen and C1~C6 alkyl groups; M is selected from O; Ring A is selected from substituted or unsubstituted 5-membered heteroaryl groups; The substituents of the heteroaryl group are selected from C1-C6 alkyl groups; The heteroaryl group has a heteroatom that is either O or S, and the number of heteroatoms is 1.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula VIIa: Formula VIIa in, R2 is selected from hydrogen and C1~C6 alkyl groups; X2 is selected from O and NR6; R6 is selected from hydrogen and C1~C6 alkyl groups; M is selected from O; Ring A is selected from the following groups, whether substituted or unsubstituted: , , , , , ; The substituents of ring A are selected from C1 to C6 alkyl groups.

7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula VIIb: Equation VIIb in, R2 is selected from hydrogen and C1~C6 alkyl groups; X2 is selected from O; M is selected from O; Ring A is selected from the following groups, whether substituted or unsubstituted: , ; The substituents of ring A are selected from C1 to C6 alkyl groups.

8. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is one of the following compounds: 。 9. A method for preparing the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, characterized in that: It includes the following steps: Step 1: In a solvent, compound 1, an organic base, and compound 2 react to yield compound 3; Wherein, n, m, X2, A, and M are as described in any one of claims 1 to 8; Step 2: (1) In the solvent, compound 4 and compound 5 react to give compound 6; (2) In a solvent, compound 6 and Pd / C react in a hydrogen atmosphere to give compound 7; (3) In a solvent, compound 7, an organic base and compound 3 react to give compound 8; Wherein, R2, n, m, X2, A, and M are as described in any one of claims 1 to 8; In the adjacent or intermediate position of R2; or, (A) In a solvent, the compound, an aqueous formaldehyde solution, acetic acid and NaBH3CN react to give compound 10; (B) In a solvent, compound 10, an inorganic solid base and compound 3 react to give compound 11; Wherein, R2, n, m, X2, A, and M are as described in any one of claims 1 to 8; In the adjacent or intermediate position of R2; or, (a) In a solvent, compound 12 reacts with an aqueous sodium hydroxide solution to give compound 13; (b) In a solvent, compound 13 reacts with formaldehyde and sodium cyanoborohydride to give compound 14; (c) In a solvent, compound 14, sodium formaldehyde sulfoxylate and compound 3 react to give compound 15.

10. The preparation method according to claim 9, characterized in that: In step 1, the organic base is pyridine.

11. The preparation method according to claim 9, characterized in that: In step 2, the organic base in step (3) is DIPEA; Alternatively, in step 2, the inorganic solid base in step (B) is Cs2CO3.

12. Use of the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament having analgesic effects.

13. A drug, characterized in that: It is a formulation prepared by using the compound of any one of claims 1 to 8 or its pharmaceutically acceptable salt as the active ingredient, plus pharmaceutically acceptable excipients.

14. A pharmaceutical composition, characterized in that: It includes the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

Images