Pyridine-containing compound, preparation method therefor, and use thereof

Abstract

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

Description

A pyridine-containing compound and its preparation method and use Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a pyridine-containing compound, a preparation method thereof, and an application thereof. Background Art

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

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

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

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

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a pyridine-containing compound and a preparation method and use thereof.

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

[0009] in,

[0010] X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N;

[0011] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3;

[0012] R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0013] m is an integer selected from 0 to 5; n is an integer selected from 0 to 5;

[0014] M is selected from O, S, NR4;

[0015] R4 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy;

[0016] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl;

[0017] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0018] The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy;

[0019] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1 to 5;

[0020] When M is selected from O, m and n are both 1, and ring A is thienyl, R1 is not hydrogen at the same time;

[0021] When M is selected from O, m and n are both 0, and ring A is When R1 is not hydrogen at the same time;

[0022] When M is selected from O, m and n are both 0, and ring A is hour, Not for

[0023] When M is selected from NH, the A ring is not

[0024] When M is selected from S, Ring A is selected only from substituted or unsubstituted thienyl groups, and Ring A is hour, Not for

[0025] Furthermore, the compound is represented by Formula Ia or Formula Ib:

[0026] in,

[0027] X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N;

[0028] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3; and there is at most one alkyl and NR2R3;

[0029] R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0030] M is selected from O, S, and NH;

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

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

[0033] The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy;

[0034] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1 to 5;

[0035] When M is selected from O, m and n are both 1, and ring A is thienyl, R1 is not hydrogen at the same time;

[0036] When M is selected from O, m and n are both 0, and ring A is When R1 is not hydrogen at the same time;

[0037] When M is selected from O, m and n are both 0, and ring A is hour, Not for

[0038] When M is selected from NH, the A ring is not

[0039] When M is selected from S, Ring A is selected only from substituted or unsubstituted thienyl groups, and Ring A is hour, Not for

[0040] Furthermore, the compound is represented by Formula II:

[0041] in,

[0042] X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N;

[0043] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3;

[0044] R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0045] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0046] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl;

[0047] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0048] The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy;

[0049] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0050] When m and n are both 1, and ring A is a thienyl group, R1 is not hydrogen at the same time;

[0051] When m and n are both 0, the A ring is When R1 is not hydrogen at the same time;

[0052] When m and n are both 0, the A ring is hour, Not for

[0053] Furthermore, the compound is represented by Formula IIa or Formula IIb:

[0054] in,

[0055] X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N;

[0056] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3; and there is at most one alkyl and NR2R3;

[0057] R2 and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy;

[0058] Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl;

[0059] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0060] The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy;

[0061] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0062] In formula IIa, when ring A is thienyl, R1 is not hydrogen at the same time;

[0063] In formula IIb, ring A is When R1 is not hydrogen at the same time; Ring A is hour, Not for

[0064] Furthermore, the compound is represented by formula III:

[0065] in,

[0066] X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N;

[0067] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3;

[0068] R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0069] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0070] Ring A is selected from substituted or unsubstituted thienyl, and Ring A is hour, Not for

[0071] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0072] The substituent of the thienyl group is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0073] Furthermore, the compound is represented by Formula IIIa or Formula IIIb:

[0074] in,

[0075] X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N;

[0076] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, NR2R3; and there is at most one alkyl and NR2R3;

[0077] R2 and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy;

[0078] Ring A is selected from substituted or unsubstituted thienyl, and Ring A is hour, Not for

[0079] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0080] The substituent of the thienyl group is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0081] Furthermore, the compound is represented by Formula IV:

[0082] in,

[0083] X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N;

[0084] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3;

[0085] R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0086] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0087] Ring A is selected from substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 5-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered heterocycloalkyl; and Ring A is not

[0088] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0089] The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy;

[0090] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0091] Furthermore, the compound is represented by Formula IVa or Formula IVb:

[0092] in,

[0093] X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N;

[0094] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, NR2R3; and there is at most one alkyl and NR2R3;

[0095] R2 and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy;

[0096] Ring A is selected from substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 5-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered heterocycloalkyl; and Ring A is not

[0097] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0098] The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy;

[0099] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0100] Further,

[0101] Selected from

[0102] X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N; R1 is selected from hydrogen and C1-C4 alkyl.

[0103] Further,

[0104] Selected from

[0105] Further,

[0106] Ring A is selected from the following substituted or unsubstituted groups:

[0107] The substituent of the A ring is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0108] Further,

[0109] The substituent of the A ring is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy.

[0110] Furthermore, the compound is one of the following compounds:

[0111] The present invention also provides a method for preparing the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, which comprises the following steps:

[0112] In a solvent, compound a, an organic base, TCDI or CDI and compound b react to obtain a compound represented by formula I;

[0113] X1, X2, X3, X4, X5, m, n, and A ring are as described above; M is S or O.

[0114] Further,

[0115] The solvent is dichloromethane;

[0116] And / or, the organic base is Et3N;

[0117] And / or, the reaction temperature is 25-40° C., and the reaction time is 10-12 hours.

[0118] The present invention also provides a method for preparing the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, which comprises the following steps:

[0119] Step 1: In a solvent, the compound represented by formula III reacts with CH3I to obtain compound c;

[0120] Step 2: Compound C reacts with aqueous ammonia in a solvent to obtain a compound represented by Formula IV;

[0121] X1, X2, X3, X4, X5, m, n, and A ring are as described above.

[0122] Further,

[0123] In step 1, the solvent is acetonitrile;

[0124] And / or, in step 1, the reaction temperature is 40-60° C., and the reaction time is 4-10 hours;

[0125] And / or, in step 2, the solvent is acetonitrile;

[0126] And / or, in step 2, the reaction temperature is 80-100° C., and the reaction time is 10-12 hours.

[0127] The present invention also provides the use of the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative in the preparation of a drug with analgesic effect.

[0128] The present invention also provides a drug, which is a preparation prepared with the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative as the active ingredient, and pharmaceutically acceptable excipients.

[0129] The present invention also provides a pharmaceutical composition comprising the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystalline form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof.

[0130] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0131] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0132] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0133] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a ~C bAlkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C1-C6 alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms; and "C1-C6 alkoxy" refers to an alkoxy group containing from 1 to 6 carbon atoms.

[0134] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, among others.

[0135] "Halogen" is fluorine, chlorine, bromine or iodine.

[0136] "Cycloalkyl" refers to a saturated or unsaturated all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) without a conjugated π electron system, including but not limited to: wait.

[0137] "Heterocycloalkyl" refers to a cycloalkyl group in which at least one carbon atom is replaced by a heteroatom, wherein the heteroatom is O, N or S, and is a saturated or unsaturated monocyclic or polycyclic ring (including fused rings, spiro rings or bridged rings) without a conjugated π electron system, including but not limited to: wait.

[0138] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) with a conjugated π electron system, including but not limited to phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N or S. At the same time, the point of attachment to the parent group must be on a carbon atom on the ring with a conjugated π electron system, including but not limited to wait.

[0139] "Heteroaryl" refers to an aromatic group in which at least one carbon atom of the conjugated π-electron system is replaced by a heteroatom, wherein the heteroatom is O, N or S, such as but not limited to thienyl, furyl, isothiazolyl, etc.

[0140] The pharmaceutically acceptable salts of the present invention include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, teasulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthenate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, p-toluenesulfonate, quaternary ammonium salt or succinate, etc.

[0141] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.

[0142] The administration of the compound or pharmaceutical composition of the present invention includes (but is not limited to): intragastric, enteral, parenteral (intravenous, intramuscular or subcutaneous), oral and various topical administrations.

[0143] Compositions for parenteral (intravenous, intramuscular, subcutaneous) injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0144] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0145] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0146] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0147] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0148] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0149] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0150] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0151] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage when administered is a pharmaceutically safe and effective dosage.

[0152] Compared with the prior art, the compounds provided by the present invention have achieved the following beneficial effects:

[0153] The present invention provides a compound having analgesic effects. The compound of the present invention has excellent analgesic effects, is safe for use, and does not cause dependence during use. Therefore, the compound of the present invention has broad application prospects in the preparation of analgesic drugs and provides a new option for the clinical preparation of analgesic drugs.

[0154] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0155] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0156] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0157] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The units are given in ppm. NMR measurements were performed using a Bruker Avance III 400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (d6-DMSO), deuterated chloroform (CDCl3), deuterated methanol (d4-MeOH), and deuterated water (D2O). The internal standard was tetramethylsilane (TMS).

[0158] LCMS analysis (Agilent LCMS 1200-6120) (ESI), chromatographic column: Waters Xbridge Prep C 18 OBD 10 μm 19 x 250 mm. Column temperature: 40°C; flow rate: 2.0 mL / min; mobile phase: gradient from 95% [water + 10 mM ammonium bicarbonate] and 5% [CH3CN] over 1.6 minutes to 5% [water + 10 mM ammonium bicarbonate] and 95% [CH3CN], held for 1.4 minutes, then to 95% [water + 10 mM ammonium bicarbonate] and 5% [CH3CN] over 0.05 minutes, held for 0.7 minutes.

[0159] (1) Medicinal materials and reagents

[0160] The manufacturer of the thin layer chromatography silica gel plate used in thin layer chromatography (TLC) is Qingdao Pu Ke Separation Materials Co., Ltd., with a specification of 50*200mm and a thickness of 0.2-0.25mm.

[0161] Column chromatography silica gel: 200-300 mesh silica gel from Shandong Weihai Rushan Sun Desiccant Co., Ltd.

[0162] (2) Main instruments

[0163] Electronic balance, FA2004, Shanghai Liangping Instrument Co., Ltd.;

[0164] Temperature-controlled and pressure-regulated magnetic stirrer, TY98-1, Shanghai Silu Instrument Co., Ltd.;

[0165] Three-purpose UV analyzer, model ZF-2, Shanghai Anting Scientific Instrument Factory;

[0166] Rotary evaporator, R201, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0167] Liftable water bath, R201D, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0168] Circulating water vacuum pump (desktop), SHB-Ⅲ, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0169] Circulating water vacuum pump (mobile), SHB-B95, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0170] Low-temperature circulation pump, DLSB-5 / 20, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0171] Rotary vane vacuum pump (oil pump), 2XZ-4, Shanghai Vacuum Pump Factory.

[0172] The general synthetic formula of some compounds of the present invention is as follows:

[0173] Example 1. Preparation of Compound 1-1-195 of the Present Invention (188-4-2)

[0174] 1. Synthesis of 1-1-195

[0175] SM-2 (600 mg, 4.92 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Et3N (1.98 g, 19.67 mmol) and N,N'-thiocarbonyldiimidazole (TCDI) (1.20 g, 7.38 mmol) were added to the mixture and stirred at room temperature for two hours. Thiophenemethylamine SM-8 (556 mg, 4.92 mmol) was then added to the mixture and allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography using a gradient elution solvent (dichloromethane-methanol (100:1-20:1)) and reverse synthesis to afford 1-1-195 (940 mg, 69%) as a white solid. MS Calcd.: 277.1; MS Found: 278.2 [M+H] + .

[0176] 1H NMR(400MHz, DMSO-d6)δ:8.34(s,1H),8.14(s,1H),8.01(s,1H),7.57(d,J=7.6Hz,1H),7.50(q,J=1 .6Hz,1H),7.33(s,1H),7.19(s,1H),7.09(d,J=4.0Hz,4H),4.70(s,2H),6.65(s,2H),2.28(s,6H).

[0177] Example 2. Preparation of Compound 1-1-221 of the Present Invention (AL37-23-188-4)

[0178] 1. Synthesis of 188-4-3

[0179] 1-1-195 (500 mg, 1.81 mmol) was added to a sealed tube and dissolved in MeCN (20 mL). Iodomethane (771 mg, 5.43 mmol) was then added. The mixture was sealed and stirred at 40°C for 4 hours. After completion of the reaction, as monitored by LCMS, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography with a gradient elution method (petroleum ether:ethyl acetate (100:1-5:1)) afforded the off-white solid 188-4-3 (400 mg, 76%). MS Calcd.: 291.1; MS Found: 292.2 [M+H] + .

[0180] 2. Synthesis of 1-1-221

[0181] 188-4-3 (400 mg, 2.09 mmol) was added to a sealed tube and dissolved in MeCN (15 mL). Ammonia (3 mL) was then added, and the tube was sealed and stirred at 80°C overnight. After completion of the reaction, as monitored by LCMS, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography with a gradient elution of dichloromethane:methanol (100:1-5:1) and prep-HPLC afforded 1-1-221 (117.97 mg, 33%) as an off-white solid. MS Calcd.: 260.1; MS Found: 261.1 [M+H] + .

[0182] 1H NMR(400MHz, DMSO-d6)δ:8.38(s,1H),7.66(dd,J=1.6,8.0Hz,1H),7.45(q,J=2.8Hz,1H),7.34(q,J=1 .2Hz,1H),7.27(t,J=8.4Hz,1H),7.09(dd,J=1.2,5.2Hz,1H),4.48(s,2H),4.45(s,2H),2.37(s,3H).

[0183] Example 3. Preparation of Compound 1-1-195-1 of the Present Invention (P1-2-2-2)

[0184] Synthesis of compound 1-1-195-1

[0185] SM-1 (320 mg, 2.83 mmol) was added to a reaction flask and dissolved in dichloromethane (DCM) (20 mL). Triethylamine (857 mg, 8.49 mmol) and N,N'-thiocarbonyldiimidazole (TCDI) (504 mg, 2.83 mmol) were added to the system and stirred at room temperature for two hours. SM-2 (345 mg, 2.83 mmol) was then added to the system and allowed to react at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed phase to obtain 1-1-195-1 (178.10 mg, yield: 23%) as a white solid. ESI [M+H] + =227.03[M+H] + .

[0186] 1H NMR(400MHz, DMSO-d6)δ:8.34(s,1H),8.21(s,1H),8.03(s,1H),7.56(dd,J=1.6,8.0Hz,2H),7.39(dd,J=0.8,4.8Hz,1H), 7.19(d,J=8.0Hz,1H),7.02(d,J=2.8Hz,1H),6.96(dd,J=3.6,5.2Hz,1H),4.85(d,J=4.8Hz,2H),4.71(s,2H),2.27(s,3H).

[0187] Example 4. Preparation of Compound 1-6-001 of the Present Invention (P1-1-1-13)

[0188] 1. Synthesis of Compound SM-3

[0189] To a solution of compound 300-2-1 (12 g, 101.58 mmol) in methanol (120 mL) was added nickel chloride hexahydrate (4.83 g, 20.32 mmol) and sodium borohydride (11.53 g, 304.73 mmol) at 0°C and stirred at 0°C for 16 hours. After the reaction was complete as indicated by LC-MS, the reaction mixture was concentrated under reduced pressure. Water (200 mL) was added and extracted with ethyl acetate (200 mL x 3), washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound SM-3 (3.9 g, yield 31.43%) as a yellow oil. m / z calculated for [M+H] + 123.17,found 123.1.

[0190] 2. Synthesis of Compound 300-2-3

[0191] To a solution of compound SM-3 (500 mg, 4.09 mmol) in tetrahydrofuran (THF) (5 mL) were added N,N-diisopropylethylamine (DIEA) (1586.92 mg, 12.28 mmol) and N,N'-carbonyldiimidazole (CDI) (796.34 mg, 4.91 mmol), and the mixture was stirred at 0°C for 30 minutes. After LC-MS indicated the reaction was complete, the mixture was concentrated under reduced pressure to afford compound 300-2-3 as a yellow oil (600 mg, 98.95% yield). m / z calculated for [M+H] + 149.17,found 149.2.

[0192] 3. Synthesis of Compound 1-6-001

[0193] To a solution of compound 300-2-3 (600 mg, 4.05 mmol) in tetrahydrofuran (10 mL) were added N,N-diisopropylethylamine (DIEA) (1570.21 mg, 12.15 mmol) and compound SM-5 (471.95 mg, 4.86 mmol), and the mixture was stirred at 25°C for 30 minutes. After the reaction was complete as indicated by LC-MS, water was added and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by Prep-HPLC afforded compound 1-6-001 (163.9 mg, 16.50% yield) as a white solid. m / z calculated for [M+H] + 246.29,found 246.2.

[0194] 1HNMR(400MHz,DMSO-d6)δ11.73(s,1H),8.39–8.25(m,1H),7.59–7.49(m,1H),7.23–7.15(m,1H),7. 03–6.96(m,1H),6.80(s,1H),6.59–6.53(m,1H),6.42–6.34(m,1H),4.26–4.17(m,4H),2.42(s,3H).

[0195] Example 5. Preparation of Compound 1-1-195-3 of the Present Invention (P1-2-1-2)

[0196] 1. Synthesis of Compound SM-4

[0197] To a solution of compound SM-3 (600 mg, 4.911 mmol) in N,N-diisopropylethylamine (DIEA) (2 mL) and dichloromethane (DCM) (10 mL) was slowly added thiophosgene (0.8 mL) over 5 minutes at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction as indicated by LC-MS, the mixture was concentrated under reduced pressure to afford compound SM-4 (800 mg, 99.19% yield) as a brown oil.

[0198] 2. Synthesis of compound 1-1-195-3

[0199] To a solution of compound SM-4 (600 mg, 3.653 mmol) in tetrahydrofuran (10 mL) were added SM-1 (826.99 mg, 7.307 mmol) and N,N-diisopropylethylamine (DIEA) (2 mL), and the mixture was stirred at 80°C for 3 hours. After completion of the reaction as indicated by LC-MS, water was added and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by Prep-HPLC afforded compound 1-1-195-3 as a brown oil (286.9 mg, 28.31% yield). m / z calculated for [M+H] + 278.4,found 278.1.

[0200] 1H NMR(400MHz,DMSO-d6)δ8.36-8.35(m,1H),8.01(s,2H),7.57-7.54(m,1H),7.39-7.37(m ,1H),7.19-7.17(m,1H),7.03–6.93(m,2H),4.84-4.83(m,2H),4.64(s,2H),2.42(s,3H).

[0201] Example 6. Preparation of Compound 1-6-002 of the Present Invention (P1-2-3-6)

[0202] 1. Synthesis of compound 342-4-2

[0203] 342-4-1 (2.0 g, 10 mmol) was added to a reaction flask and dissolved in methanol (30 mL). Oxalyl chloride (6.4 g, 50 mmol) was then added to the reaction system and stirred overnight at room temperature. After completion of the reaction as monitored by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to afford the crude product 342-4-2 as a pale yellow oil (~700 mg, yield: 52%).

[0204] 2. Synthesis of compound 1-6-002

[0205] 342-4-2 (700 mg, 5.2 mmol) was added to a reaction flask and dissolved in dichloromethane (DCM) (40 mL). Pyridine (2.05 g, 26 mmol) and N,N'-thiocarbonyldiimidazole (TCDI) (926 mg, 5.2 mmol) were added to the reaction system and stirred at room temperature for 2 hours. SM-6 (562 mg, 5.2 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete as monitored by LCMS, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-3%) and prep-HPLC afforded 1-6-002 (400 mg, yield: 31%) as an off-white solid. ESI [M+H] + =250.2.

[0206] 1 H NMR (400MHz, DMSO-d6) δ14.87(s,1H),11.00(s,1H),8.20(d,J=2.0Hz,1H),7.70(dd,J=2.0,8.8Hz,1H),7.15(d,J =8.4,Hz,1H),7.07(dd,J=1.2,5.2Hz,1H),7.01(dd,J=2.0,3.6Hz,1H),6.94(dd,J=4.0,5.6Hz,1H),2.27(s,3H).

[0207] Example 7. Preparation of Compound 1-6-003 of the Present Invention (P1-2-1-1)

[0208] 1. Preparation of compound 4-10-2

[0209] To a solution of compound 4-10-1 (2 g, 15.488 mmol) in dioxane (20 mL) were added pyridine (1 mL), BoC2O (5 g, 22.936 mmol), and ammonium bicarbonate (1.47 g, 18.586 mmol), and the mixture was stirred at room temperature for 14 hours. After completion of the reaction as indicated by LC-MS, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 3), washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to afford compound 4-10-2 (1.5 g, 75.57% yield) as a brown oil. m / z calculated for [M+H] + 129.1,found 129.0.

[0210] 2. Preparation of compound 4-10-3

[0211] To a solution of compound 4-10-2 (1.4 g, 10.925 mmol) in tetrahydrofuran (THF) (15 mL) was added BH₃·THF (30 mL) with stirring over 10 minutes at 0°C. The mixture was heated to 80°C and stirred for 14 hours. MeOH was then added to the reaction mixture at 0°C, followed by BoC₂O (4.76 g, 21.849 mmol) and 2-[ethyl(2-hydroxyethyl)amino]ethanol-1-ol (4.3 mL, 43.255 mmol). The mixture was heated to room temperature and stirred for 2 hours. After completion of the reaction as indicated by LC-MS, H₂O (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (20 mL x 3). The mixture was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography to afford compound 4-10-3 (850 mg, 36.31% yield) as a brown oil. m / z calculated for [M+H] + 215.2,found 215.2.

[0212] 3. Preparation of Compound SM-7

[0213] To a solution of compound 4-10-3 (850 mg, 3.967 mmol) in dichloromethane (DCM) (9 mL) was added trifluoroacetic acid (TFA) (3 mL). The reaction was stirred at room temperature for 2 hours. After LC-MS indicated the reaction was complete, the reaction mixture was concentrated under reduced pressure to afford compound SM-7 (450 mg, 99.36% yield) as a brown oil. m / z calculated for [M+H] + 115.1,found 115.2

[0214] 4. Preparation of Compound 1-6-003

[0215] To a solution of compound SM-7 (450 mg, 4.379 mmol) in tetrahydrofuran (15 mL) were added compound SM-4 (1438.47 mg, 8.759 mmol) and N,N-diisopropylethylamine (DIEA) (2 mL), and the mixture was stirred at 80°C for 3 hours. After completion of the reaction as indicated by LC-MS, water was added and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by Prep-HPLC afforded compound 1-6-003 as a brown oil (223.4 mg, 18.32% yield). m / z calculated for [M+H] + 279.3,found 279.0.

[0216] 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.35(s,1H),8.18(s,2H),7.57-7.55(m,1H ),7.27(s,1H),7.21-7.19(m,1H),4.97-4.96(m,2H),4.63(s,2H),2.43(s,3H).

[0217] Example 8. Preparation of Compound 1-6-004 of the Present Invention

[0218] 1. Synthesis of Compound 1-6-004

[0219] 4-5-1 (300 mg, 3.09 mmol) was added to a reaction flask and dissolved in dichloromethane (DCM) (20 mL). Pyridine (732 mg, 9.27 mmol) and N,N'-thiocarbonyldiimidazole (TCDI) (550 mg, 3.09 mmol) were added to the system and stirred at room temperature for two hours. SM-2 (377 mg, 3.09 mmol) was then added to the system and allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-95:5)] and reverse phase preparative chromatography to afford 1-6-004 (310.22 mg, 38%) as an off-white solid. ESI [M+H] + =278.2[M+H] + .

[0220] 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.10(br,1H),8.01(br,1H),7.59(s,1H)7.57(d,J=9.6 ,2H),7.19(d,J=8.0Hz,1H),6.41~6.39(m,1H),6.29(s,1H),4.69~4.65(m,4H),2.27(s,3H)

[0221] Example 9. Preparation of compound 1-1-337 of the present invention (P1-3-3-6)

[0222] 1. Synthesis of compound AL37-11-342-4-B

[0223] 1-6-002 (249 mg, 1.0 mmol) was added to a sealed reaction tube and dissolved in acetonitrile (10 mL). Methyl iodide (426 mg, 3.0 mmol) was then added. The tube was sealed and stirred at 40°C overnight. After completion of the reaction, as monitored by LCMS, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1 to 2:1)] afforded a light yellow solid, AL37-11-342-4-B (200 mg, yield: 76%). ESI [M+H] + =264.1.

[0224] 2. Synthesis of compound 1-1-337

[0225] AL37-11-342-4-B (200 mg, 0.76 mmol) was added to a sealed tube and dissolved in acetonitrile (10 mL). Ammonia (5 mL) was then added and stirred at 80°C overnight. After completion of the reaction, as monitored by LCMS, the solvent was evaporated under reduced pressure to obtain the crude product. Column chromatography (dichloromethane:methanol (100:1-5:1)) and prep-HPLC yielded 1-1-337 (72.32 mg, 41%) as an off-white solid. ESI [M+H] + =233.2.

[0226] 1 H NMR (400MHz, CD3OD) δ: 8.01 (dd, J = 0.8, 1.6 Hz, 1H), 7.50 (dd, J = 2.0, 5.6 Hz, 1H), 6.90-6.84 (m, 3H), 6.48 (dd, J = 1.6, 4.0 Hz, 1H), 2.25 (s, 3H).

[0227] Example 10. Preparation of Compound 1-6-005 of the Present Invention

[0228] Synthesis of compound 1-6-005

[0229] SM-7 (237.1 mg, 2.08 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Pyridine (822 mg, 10.4 mmol) and N,N'-carbonyldiimidazole (CDI) (337 mg, 2.08 mmol) were added to the reaction system and stirred at room temperature for two hours. SM-3 (253.8 mg, 2.08 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete as monitored by LCMS, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-3%) and prep-HPLC afforded 1-6-005 (154.15 mg, yield: 28%) as an off-white solid. ESI [M+H] + =263.1.

[0230] 1 H NMR (400MHz, DMSO-d6) δ8.41(d,J=1.2Hz,1H),8.33(d,J=2.0Hz,1H),7.53(dd,J=2.4,8.0Hz,1H),7.21-7.18( m,2H),6.78(t,J=6.0Hz,1H),6.68(t,J=6.0Hz,1H),4.51(d,J=6.0Hz,2H),4.20(d,J=6.0Hz,2H),2.43(s,3H).

[0231] Example 11. Preparation of Compound 1-6-006 of the Present Invention

[0232] Synthesis of compound 1-6-006

[0233] SM-7 (352 mg, 3.09 mmol) was added to a reaction flask and dissolved in dichloromethane (DCM) (20 mL). Pyridine (732 mg, 9.27 mmol) and N,N'-thiocarbonyldiimidazole (TCDI) (550 mg, 3.09 mmol) were added to the system and stirred at room temperature for two hours. SM-2 (377 mg, 3.09 mmol) was then added to the system and allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-95:5)]. The crude product was then purified by prep-HPLC to afford 1-6-006 (215.09 mg, 25% yield) as an off-white solid. ESI [M+H] + =279.3[M+H] + .

[0234] 1 H NMR (400MHz, DMSO-d6), δ8.42 (d, J=1.6Hz, 1H), 8.35~8.34 (m, 2H), 8.21 (br, 1H), 7.58 (dd, J1=2Hz, J2=8Hz,1H),7.29(s,1H),7.18(d,J=8.0Hz,1H),4.98(d,J=4.4Hz,2H),4.70(br,2H),2.27(s,3H).

[0235] Example 12. Preparation of Compound 1-1-342-1 of the Present Invention

[0236] Synthesis of compound 1-1-342-1

[0237] 342-3-1 (408 mg, 3.0 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Pyridine (1.2 g, 15.0 mmol) and N,N'-carbonyldiimidazole (CDI) (486 mg, 3.0 mmol) were added to the reaction system and stirred at room temperature for 2 hours. SM-6 (324 mg, 3.0 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete as monitored by LCMS, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-3%) and prep-HPLC afforded 1-1-342-1 (104.30 mg, yield: 15%) as a white solid. ESI [M+H] + =234.2.

[0238] 1 H NMR (400MHz, DMSO-d6) δ10.71 (s, 1H), 9.35 (s, 1H), 8.09 (d, J = 1.6 Hz,1H),7.58(dd,J=2.4,8.4Hz,1H),7.47(dd,J=2.4,8.8Hz,1H),7.36(dd,J=2.4,7.6Hz,1H),7.10(dd,J=1.2,5.2Hz,1H),2.27(s,3H).

[0239] Example 13. Preparation of Compound 1-1-196 of the Present Invention

[0240] Synthesis of compound 1-1-196

[0241] SM-1 (300 mg, 2.65 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Pyridine (732 mg, 5.3 mmol) and N,N'-thiocarbonyldiimidazole (TCDI) (471 mg, 2.65 mmol) were added to the system and stirred at room temperature for two hours. 4-7-1 (286 mg, 2.65 mmol) was then added to the system and allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-95:5)] and purified by prep-HPLC to obtain 1-1-196 (123.09 mg, 17%) as an off-white solid. ESI [M+H] + =264[M+H] + .

[0242] 1 H NMR (400MHz, DMSO-d6), δ8.5 (dd, J1=3.2Hz, J2=4Hz, 1H), 8.23 ​​(s, 1H), 8.06 (s, 1H), 7.75 (td, J1=8Hz, J2=1.6Hz, 1H), 7.39 (dd , J1=1.2Hz, J2=5.2Hz, 1H), 7.29~7.25(m,2H), 7.02(d,J=2.8Hz,1H), 6.96(q,J=2Hz,1H), 4.86(d,J=4.8Hz,2H), 4.57(s,1H).

[0243] Example 14. Preparation of Compound 1-6-007 of the Present Invention

[0244] Synthesis of compound 1-6-007

[0245] 17-A-1 (200 mg, 1.5 mmol) was added to a reaction flask and dissolved in dichloromethane (DCM) (10 mL). Pyridine (592 mg, 7.5 mmol) and N,N'-thiocarbonyldiimidazole (TCDI) (267 mg, 1.5 mmol) were added to the reaction system and stirred at room temperature for 2 hours. 17-A-2 (162 mg, 1.5 mmol) was then added to the system and stirred at room temperature overnight. The reaction solution was directly spin-dried to dryness, and the residue was dissolved in chloroform (10 mL) and pyridine (592 mg, 7.5 mmol). The reaction was stirred at 70°C overnight. After the reaction was complete as monitored by LCMS, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-3%) and prep-HPLC afforded 1-6-007 (78.03 mg, yield: 21%) as a pale yellow oil. ESI [M+H] + =251.2.

[0246] 1 H NMR(400MHz,DMSO-d6)δ11.77(s,1H),10.16(s,1H),8.47(s,1H),8.25(s,1 H),7.82(d,J=6.8Hz,1H),7.27(d,J=8.4Hz,1H),7.06(s,1H),2.47(s,3H).

[0247] Example 15. Preparation of Compound 1-1-164 of the Present Invention

[0248] Synthesis of compound 1-1-164

[0249] SM-8 (320 mg, 2.83 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Et3N (857 mg, 8.49 mmol) and N,N'-carbonyldiimidazole (CDI) (458 mg, 2.83 mmol) were added to the system and stirred at room temperature for two hours. SM-2 (345 mg, 2.83 mmol) was then added to the system and allowed to react at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and reversed phase to obtain 1-1-164 (185.44 mg, yield: 25%) as a white solid. ESI [M+H] + =261.03[M+H] + .

[0250] 1H NMR(400MHz, DMSO-d6)δ:8.32(dd,J=0.8,1.2Hz,1H),7.56(dd,J=1.6,8.0Hz,1H),7.47(dd,J=2.8,4.8Hz,1H),7.25-7.24(m,1H),7.17(d,J=8 .0Hz,1H),7.02(dd,J=1.2,5.2Hz,1H),6.53(t,J=5.6Hz,1H),6.49(t,J=5.6Hz,1H),4.27(d,J=6.0Hz,2H),4.21(d,J=5.6Hz,2H),2.27(s,3H).

[0251] Example 16. Preparation of Compound 1-6-008 of the Present Invention (P1-2-1-13)

[0252] Synthesis of compound 1-6-008

[0253] To a solution of compound SM-4 (650 mg, 4.05 mmol) in tetrahydrofuran (10 mL) were added N,N-diisopropylethylamine (DIEA) (1570.21 mg, 12.15 mmol) and compound SM-5 (471.95 mg, 4.86 mmol), and the mixture was stirred at 25°C for 30 minutes. After completion of the reaction as indicated by LC-MS, water was added and the mixture was extracted with ethyl acetate (20 mL x 3), washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by Prep-HPLC afforded the compound as a white solid (163.8 mg, 17.15% yield). m / z calculated for [M+H] + 262.35,found 262.1.

[0254] 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.45–8.33(m,1H),8.15(s,1H),7.96–7.84(m,1H), 7.61–7.55(m,1H),7.22–7.18(m,1H),7.03–6.85(m,2H),4.71–4.52(m,4H),2.43(s,3H).

[0255] Example 17. Preparation of Compound 1-6-009 of the Present Invention

[0256] Synthesis of compound 1-6-009

[0257] SM-7 (450 mg, 3.95 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Et3N (1.06 g, 10.53 mmol) and N,N'-carbonyldiimidazole (CDI) (639 mg, 3.95 mmol) were added to the mixture and stirred at room temperature for two hours. 300-1-A (426 mg, 3.95 mmol) was then added to the mixture and allowed to react overnight at room temperature. After completion of the reaction as monitored by LCMS, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by column chromatography (eluent: dichloromethane-methanol (100:1-20:1)) and reverse chromatographic analysis afforded 1-6-009 (124.37 mg, 12%) as a white solid. ESI [M+H] + =249.1[M+H] + .

[0258] 1 H NMR (400MHz, DMSO-d6), δ8.47(d,J=2.0Hz,1H),8.43(dd,J1=1.6Hz,J1=4.8Hz,1H),8.41(d,J=1.6Hz,1H),7.66~7.63(m,1H) ,7.35~7.32(m,1H),7.21(t,J=0.4Hz,1H),6.80(t,J=6Hz,1H),6.73(t,J=6Hz,1H),4.51(d,J=6Hz,2H),4.25(d,J=6Hz,2H).

[0259] Example 18. Preparation of Compound 1-6-010 of the Present Invention

[0260] 1. Preparation of Compound 0-2-2

[0261] To a solution of compound 0-2-1 (1 g, 8.922 mmol) in tetrahydrofuran (THF) (40 mL) was slowly added triethanolamine (TEA) (1.488 mL, 10.706 mmol) and diphenylphosphoryl azide (DPPA) (2.70 g, 9.814 mmol) at 0°C. The mixture was stirred at 60°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain 1.3 g of a white crude product of compound 0-2-2.

[0262] 2. Preparation of Compound 1-6-010

[0263] Compound SM-6 (1.03 g, 9.482 mmol) was added to a solution of compound 0-2-2 (1.3 g, 9.482 mmol) in dioxane (20 mL) and stirred at 100°C for 16 hours. H2O (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride (50 mL x 2), dried over sodium sulfate, and concentrated. The residue was purified by Prep-HPLC to afford 1-6-010 (67.8 mg, 3.29% yield) as a yellow solid. m / z calculated for [M+H] + 218.1,found 218.0.

[0264] 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.41(s,1H),8.08(s,1H),7.84(s,1H), 7.61–7.51(m,2H),7.34(d,J=8.4Hz,1H),6.54(d,J=0.9Hz,1H),2.22(s,3H).

[0265] Example 19. Preparation of Compound 1-6-011 of the Invention

[0266] 1. Synthesis of Compound 16-2

[0267] 16-1 (1 g, 5 mmol) was added to a 100 mL single-necked flask, dissolved in DOX (15 mL), and then HCl / DOX (4 M) (15 mL) was added. The reaction was stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure, the mixture was slurried with acetonitrile (30 mL x 5), filtered, and the filtrate was collected and dried to obtain 16-2 (584 mg, 85% yield). ESI [M+H] + =133.2[M+H] + .

[0268] 2. Synthesis of Compound 1-6-011

[0269] 16-2 (584 mg, 4.3 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Pyridine (1.01 g, 12.9 mmol) and N,N'-carbonyldiimidazole (CDI) (697 mg, 4.3 mmol) were added to the system and stirred at room temperature for two hours. 17-A-2 (464 mg, 4.3 mmol) was then added to the system and allowed to react overnight at room temperature. After the reaction, the solvent was evaporated under reduced pressure to obtain a crude product. Purification by column chromatography [eluent: dichloromethane-methanol (100:1-95:5)] afforded a white crude product (approximately 380 mg). Purification by reverse preparative purification afforded 1-6-011 (340 mg, 34%) as an off-white solid. ESI [M+H] + =235.3

[0270] 1 H NMR(400MHz, CD3OD), δ9.63(br,1H)8.94(d,J=2.4Hz,1H),8.92(s,1H),8.47(d,J=2.4Hz,1H ),7.82(dd,J1=2.8Hz,J2=8.4Hz,1H),7.32(d,J=2Hz,1H),7.17(d,J=8.4Hz,1H),2.4(s,3H).

[0271] Example 20. Preparation of Compound 1-6-012 of the Present Invention

[0272] Synthesis of compound 1-6-012

[0273] SM-7 (237.1 mg, 2.08 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Pyridine (822 mg, 10.4 mmol) and N,N'-carbonyldiimidazole (CDI) (337 mg, 2.08 mmol) were added to the reaction system and stirred at room temperature for two hours. SM-2 (253.8 mg, 2.08 mmol) was then added to the system and stirred at room temperature overnight. After the reaction was complete as monitored by LCMS, the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-3%) and prep-HPLC afforded 1-6-012 (137.67 mg, yield: 25%) as an off-white solid. ESI [M+H] + =263.1.

[0274] 1H NMR (400MHz, DMSO-d6) δ8.42(d,J=1.6Hz,1H),8.33(t,J=0.8Hz,1H),7.57(dd,J=2.0,8.0Hz,1H),7.23-7.17( m,2H),6.89(t,J=6.0Hz,1H),6.72(t,J=6.0Hz,1H),4.52(d,J=5.6Hz,2H),4.28(d,J=6.0Hz,2H),2.27(s,3H).

[0275] Example 21. Preparation of Compound 1-6-013 of the Present Invention

[0276] 1. Preparation of compound 202-1-2

[0277] 202-1-1 (4.2 g, 25.6 mmol) was dissolved in tetrahydrofuran (20 mL), and phthalimide (809 mg, 5.5 mmol) and triphenylphosphine (2.62 g, 10.0 mmol) were added dropwise at 0°C. The mixture was then heated to room temperature and stirred. After the reaction was complete, the mixture was filtered through Celite, and the filtrate was dried. The residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to afford 202-1-2 (4.3 g, 74% yield) as a white solid.

[0278] 2. Preparation of compound 202-1-3

[0279] 202-1-2 (2.09 g, 9.0 mmol) was dissolved in anhydrous ethanol (70 mL), and hydrated hydrazine solution (1.4 mL) was added. The temperature was raised to 80°C and stirred for 4 h. After the reaction was complete, the mixture was cooled to room temperature, ethyl acetate was added, and the mixture was ultrasonically treated for 5 min. The mixture was filtered through celite. The filtrate was diluted with water and extracted with ethyl acetate (50 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and half of the solvent was evaporated. HCl was added to ethyl acetate (2.0 M) to adjust the pH to 4.0. The crude product was evaporated to dryness to obtain a light yellow solid product 202-1-3 (452 ​​mg, 3.0 mmol, 40% overall yield for the two-step reaction).

[0280] 3. Preparation of compound 202-1-6

[0281] Dissolve 202-1-4 (2.53 g, 10 mmol) in dichloromethane (3 mL), add potassium carbonate (1.39 g, 10.05 mmol), and stir at room temperature for 2 hours before adding 202-1-5 and tetramethylguanidine (2.85 g, 16.7 mmol). Stir overnight at room temperature. The reaction mixture is diluted with dichloromethane (20 mL) and washed twice with saturated brine. The organic phase is dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the yellow oily product 202-1-6 (950 mg, 50% yield).

[0282] 4. Preparation of compound 202-1-7

[0283] 202-1-6 (141 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL), and I2 (12 mg, 0.05 mmol) and tert-butyl peroxide (70% in water) (128 μL, 1.0 mmol) were added. 202-1-3 (133 mg, 1 mmol) and 1,8-diazabicyclo(5,4,0)-7-undecene (DBU) (746 μL, 5.0 mmol) were added with stirring. The reaction mixture was stirred at room temperature overnight. After dilution with dichloromethane, the reaction mixture was washed once with a saturated aqueous solution of Na2S2O3 and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford 202-1-7 (160 mg, 24% yield) as a light yellow oil.

[0284] 5. Preparation of Compound 1-6-013

[0285] To 202-1-7 (160 mg, 0.48 mmol) was added 5 mL of a 2.0 M solution of hydrochloric acid in ethyl acetate. After stirring at room temperature for 10 hours, an aqueous sodium hydroxide solution was added to adjust the pH to approximately 10, and the mixture was extracted with dichloromethane. The organic phase was dried, concentrated, and purified on a silica gel column to afford the yellow oily product 1-6-013 (100 mg, 48% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 12 H1N4OS + 231.1240; Found 231.1248.

[0286] 1 H NMR (400MHz, CDCl3) δ8.42(s,1H),7.72(s,1H),7.50(s,1H),7.37(s,2H),7.27(s,2H),6.36(s,1H),4.39(d,J=37.9Hz,4H),1.26(d,J=12.3Hz,2H).

[0287] Example 22. Preparation of Compound 1-6-014 of the Present Invention

[0288] 1. Synthesis of compound 188-4-9-2

[0289] 188-4-9-1 (3.94 g, 30 mmol) was dissolved in diethyl ether (60 mL), and lithium aluminum hydride (2.85 g, 75 mmol) was slowly added portionwise at 0°C. After completion of the addition, the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction as monitored by TLC, 3 mL of 15% sodium hydroxide solution was added to quench the reaction, followed by the dropwise addition of 3 mL of water, and then 3 mL of 15% sodium hydroxide solution. The mixture was filtered through celite and anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound 188-4-9-2 (3.74 g, 92% yield) as a yellow oil.

[0290] 2. Synthesis of compound 188-4-9-3

[0291] 188-4-9-2 (1.35 g, 10 mmol) was dissolved in ethanol (20 mL), and carbon disulfide (1.8 mL, 30 mmol) and triethylamine (1.39 mL, 10 mmol) were added at room temperature. The mixture was allowed to react at room temperature for 1 hour. 4-Dimethylaminopyridine (DMAP) (37 mg, 0.3 mmol) and Boc2O (2.3 mL, 10 mmol) were then added at 0°C, and the mixture was allowed to react at room temperature overnight. After completion of the reaction as monitored by TLC, the solution was diluted with water (25 mL) and extracted with ethyl acetate (25 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 50:1) to afford compound 188-4-9-3 (1.16 g, 66% yield) as a colorless oil.

[0292] 3. Synthesis of Compound 1-6-014

[0293] SM-2 (183 mg, 1.5 mmol) and 188-4-9-3 (266 mg, 1.5 mmol) were dissolved in toluene (4.5 mL) and allowed to react at room temperature for 2 hours. After completion of the reaction, as monitored by TLC, column chromatography (PE / EtOAc = 2:1) afforded 1-6-014 as a yellow oil (361 mg, 80% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 17 H 22 N3S + 300.1529; Found 300.1532.

[0294] 1H NMR (400MHz, CDCl3): δ8.20(s,1H),7.48–7.40(m,2H),7.16(d,J=7.8Hz,1H),6.91(d,J=7.2Hz,3H),4.79–4.52(m,4H),2.30(s,3H),2.28(s,6H).

[0295] Example 23. Preparation of Compound 1-6-015 of the Present Invention

[0296] 1. Preparation of compound 188-4-8-3

[0297] Dissolve 188-4-8-1 (268 mg, 2 mmol) in dichloromethane (DCM) (2 mL). Add N,N-diisopropylethylamine (DIPEA) (416 μL, 2.4 mmol) dropwise under an ice bath. Add 188-4-8-2 (465 mg, 2 mmol) in portions. Stir at room temperature for 30 minutes, then concentrate under reduced pressure. Purify by silica gel column chromatography (PE:EtOAc = 20:1) to obtain 188-4-8-3 as a colorless oil (170 mg, 60% yield).

[0298] 2. Preparation of Compound 1-6-015

[0299] 188-4-8-3 (170 mg, 1.2 mmol) and SM-2 (161 mg, 1.32 mmol) were dissolved in toluene (2 mL) and stirred at room temperature for 15 hours to precipitate a white solid. After completion of the reaction, the mixture was filtered and washed with PE:EA (10:1) to obtain the white solid product 1-6-015 (300 mg, 99.7% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 12 H 15 N4OS + 263.0961; Found 263.0953.

[0300] 1 H NMR (400MHz, CDCl3) δ9.38(s,1H),8.29(d,J=2.2Hz,1H),8.19(d,J=1.8Hz,1H),7.51(dd,J=7.8,2.2H z,1H),7.17(d,J=7.9Hz,1H),6.27(d,J=1.8Hz,1H),4.98(d,J=5.5Hz,2H),4.60(s,2H),2.33(s,3H).

[0301] Example 24. Preparation of Compound 1-6-016 of the Present Invention

[0302] 1. Preparation of compound 188-4-0-2

[0303] 188-4-0-1 (2.18 mL, 20 mmol) was dissolved in ethanol (40 mL), and carbon disulfide (3.61 mL, 60 mmol) and triethylamine (2.78 mL, 20 mmol, 1.0 equiv.) were added at room temperature. The mixture was allowed to react at room temperature for 1 h. 4-Dimethylaminopyridine (DMAP) (73 mg, 0.6 mmol) and Boc2O (4.6 mL, 20 mmol) were then added at 0°C, and the mixture was allowed to react at room temperature overnight. After completion of the reaction, as monitored by TLC, the solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (EA / EtOAc = 40:1) to afford compound 188-4-0-2 (2.61 g, 88% yield) as a yellow oil.

[0304] 2. Synthesis of Compound 1-6-016

[0305] SM-2 (122 mg, 1.0 mmol) and 188-4-0-2 (149 mg, 1.0 mmol) were dissolved in toluene (3.0 mL) and allowed to react at room temperature for 2 hours. After completion of the reaction, TLC was used to monitor the reaction. Column chromatography (PE / EtOAc = 2:1) afforded 220 mg of the blue solid 1-6-016 in 81% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 15 H 18 N3S + 272.1216; Found 272.1218.

[0306] 1 H NMR (400MHz, CDCl3): δ8.18 (s, 1H), 7.50–7.44 (m, 2H), 7.36–7.23 (m, 4H), 7.15 (d, J = 8.0Hz, 1H), 4.68 (s, 4H), 2.29 (s, 3H). 13 C NMR (100MHz, CDCl3): δ182.18,153.04,148.76,137.84,132.29,128.69,127.84,127.64,122.07,49.29,18.13.

[0307] Example 25. Preparation of Compound 1-6-017 of the Present Invention

[0308] 1. Synthesis of compound 188-4-14-1

[0309] 202-1-3 (250 mg, 2.6 mmol) was dissolved in ethanol (5 mL), and carbon disulfide (0.47 mL, 7.8 mmol) and triethylamine (0.36 mL, 2.6 mmol) were added at room temperature. The mixture was allowed to react at room temperature for 1 hour. DMAP (9.6 mg, 0.078 mmol) and Boc2O (0.6 mL, 2.6 mmol) were then added at 0°C, and the mixture was allowed to react at room temperature overnight. After completion of the reaction as monitored by TLC, the solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 40:1) to afford compound 188-4-14-1 (300 mg, 83% yield) as a yellow oil.

[0310] 2. Synthesis of Compound 1-6-017

[0311] SM-2 (244 mg, 1.0 mmol) and 188-4-14-1 (278 mg, 1.0 mmol) were added to toluene (2 mL) and reacted at room temperature for 1 hour. After completion of the reaction as monitored by TLC, column chromatography (PE / EtOAc = 2:1) afforded compound 1-6-017 as a green oil: 344 mg, 66% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 13 H 16 N3OS + 262.1009; Found 262.1007.

[0312] 1 H NMR (400MHz, CDCl3): δ8.25 (s, 1H), 7.50 (dd, J = 8.0, 2.0Hz, 1H), 7.45 (s, 1H), 7 .39(s,1H),7.17(d,J=8.0Hz,1H),6.42(s,1H),4.76–4.37(m,4H),2.32(s,3H).

[0313] Example 26. Preparation of Compound 1-6-018 of the Present Invention

[0314] Synthesis of compound 1-6-018

[0315] SM-3 (244 mg, 2 mmol) and 188-4-8-3 (280 mg, 2 mmol) were added to toluene (4 mL) and reacted at room temperature for 1 hour. After completion of the reaction, as monitored by TLC, column chromatography (DCM / MeOH = 10:1) afforded 509 mg of the yellow solid compound 1-6-018 in 78% yield. HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 12 H 15 N4OS + 263.0962; Found 263.0957.

[0316] 1 H NMR (400MHz, CDCl3): δ8.26 (s, 1H), 8.17–8.12 (m, 1H), 7.60 (d, J = 7.8Hz, 1H), 7.49–7.43 (m, 2H), 7.37–7. 31(m,2H),7.10(d,J=7.8Hz,1H),6.26(s,1H),4.94(d,J=5.4Hz,2H),4.72(d,J=5.1Hz,2H),2.45(s,3H).

[0317] Example 27. Preparation of Compound 1-6-019 of the Present Invention

[0318] 1. Synthesis of Compound 6-019-3

[0319] Dissolve 6-019-1 (863 μL, 10 mmol) and 6-019-2 (2.9 g, 10 mmol) in tetrahydrofuran (40 mL). Add PPh3 (2.62 g, 10 mmol). Then slowly add DIAD (2 mL, 10 mmol) dropwise at 0°C. Allow to react at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (PE / EtOAc = 20:1) to afford compound 6-019-3 (1.8 g, 49% yield) as a yellow oil.

[0320] 2. Synthesis of Compound 6-019-4

[0321] 6-019-3 (1.8 g, 4.9 mmol) and SM-2 (598 mg, 4.9 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at 50°C for 36 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (PE / EtOAc = 5:1) to afford compound 6-019-4 (1.4 g, 62% yield) as a colorless oil.

[0322] 3. Synthesis of Compound 1-6-019

[0323] 6-019-4 (1.4 g, 3 mmol, 1.0 equiv.) was dissolved in ethyl acetate (20 mL) and HCl solution (2 mL, inDOX 4.0 M) was added. The mixture was allowed to react at room temperature for 16 hours, resulting in the precipitation of a white solid adhering to the wall of the flask. The reaction solution was discarded, and the remaining solid was dissolved in DCM. The pH was adjusted to 8 with a saturated aqueous sodium bicarbonate solution, and the layers were separated. Sodium sulfate was added to the aqueous phase to saturate the mixture, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product 1-6-019 (235 mg, 32% yield) was obtained by column chromatography (DCM / MeOH = 5:1) as a yellow oil. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 14 H 17 N4O + 245.1397 Found 245.1392.

[0324] 1 H NMR (400MHz, CDCl3) δ8.67(s,1H),8.23(d,J=2.3Hz,1H),7.85(s,2H),7.47(dd,J=7.8,2.5Hz,1H),7.25(d,J =7.9Hz,1H),6.40(d,J=3.2Hz,1H),6.24(s,1H),4.46(d,J=45.3Hz,4H),2.65(s,1H),2.30(d,J=2.3Hz,3H).

[0325] Example 28. Preparation of Compound 1-6-020 of the Present Invention

[0326] 1. Synthesis of Compound 6-020-1

[0327] To a solution of compound 342-4-2 (500 mg, 5.04 mmol) and DIEA (1.66 mL, 10.09 mmol) in dichloromethane (10 mL) was added thiophosgene (637.76 mg, 5.55 mmol) over 5 minutes at 0°C. The mixture was then allowed to warm to room temperature and stirred for 2 hours. LC-MS indicated the reaction was complete. The mixture was concentrated under reduced pressure to afford compound 6-020-1 (700 mg, 98.30% yield) as a brown oil.

[0328] 2. Synthesis of Compound 1-6-020

[0329] Compound SM-2 (826.99 mg, 7.307 mmol) and DIEA (2 mL) were added to a solution of compound 6-020-1 (500 mg, 3.653 mmol) in tetrahydrofuran (10 mL). The reaction was stirred at 80°C for 3 hours. LC-MS indicated the reaction was complete. Water was added, the mixture was extracted with ethyl acetate (20 mL x 3), washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by Prep-HPLC to obtain compound 1-6-020 (251.1 mg, 26.0% yield) as a brown oil. m / z calculated for [M+H] + 264.38,found 264.0.

[0330] 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.37(s,1H),8.22(s,1H),7.61-7.59(m,1H),7.26-7.2 4(m,1H),6.98-6.97(m,1H),6.88-6.85(m,1H),6.73-6.72(m,1H),4.74(s,2H),2.29(s,3H).

[0331] The beneficial effects of the present invention are demonstrated below through specific test examples.

[0332] Test Example 1: Study on the potent analgesic effect of the compounds of the present invention

[0333] 1 Test method

[0334] The loss of tail withdrawal reflex (LOTWR) in rats was used as the evaluation index to evaluate the potent analgesic effect of the compounds of the present invention.

[0335] 1.1 Experimental Animals: Adult male Sprague-Dawley rats weighing 220–300 g were selected for the experiment. Rats were housed in sawdust-based cages at 25 ± 1°C, 40%–60% humidity, and a 12-h light / 12-h dark cycle. No more than five rats were housed per cage, with free access to water and food.

[0336] 1.2 Experimental plan:

[0337] (1) The compound of the present invention, the positive control drug remifentanil, and the negative control group (vehicle) were administered in fixed volumes. The lowest effective dose of the compound of the present invention that produced a potent analgesic effect and the lowest dose that caused severe adverse reactions were determined using a dose escalation method.

[0338] (2) The duration of LOTWR for 30 seconds was used as the criterion for the production of a strong analgesic effect. During the experiment, the drug was administered through the rat's tail vein, with a volume of 0.6 mL per rat and an administration rate of 0.02 mL / s. Then, an alligator clip was used to clamp the rat's tail 1 cm away from the base, clamping it once longitudinally and transversely and leaving it in place, while continuously oscillating the distal end of the alligator clip (30 times / min) to continuously produce stimulation. When the rat had an escape reaction (i.e., escape movements, struggles, and squeaking) or the alligator clip stayed on the tail for 30 seconds (to avoid tissue damage), the clip was removed. If the rat had an escape reaction, the time point was recorded as no LOTWR, and the process was repeated every 2 minutes. When all the results were "no LOTWR" at 10 minutes (5 tests), the test was stopped and recorded as "invalid".

[0339] (3) All compounds will be dosed over a range of doses, starting at 1 mg / kg (due to the high potency of remifentanil, the lowest dose is set at 1 μg / kg), followed by 5 mg / kg, 10 mg / kg, 20 mg / kg, and so on (increased by 20 mg / kg each time after 20 mg / kg). Dose escalation will be stopped when the rats die. The lowest effective dose and the lowest dose that causes severe adverse reactions will be recorded throughout the entire process. In this study, severe adverse reactions are defined as: apnea, rigidity, convulsions, opisthotonos, convulsions, etc.

[0340] 1.3 Evaluation indicators: minimum effective dose; minimum dose that causes serious adverse reactions; therapeutic safety index = "minimum dose that causes serious adverse reactions" / "minimum effective dose".

[0341] 2 Test results

[0342] Table 1. Effectiveness and safety window of the compounds of the present invention in rats (single intravenous injection)

[0343] Remark:

[0344] “—” means the test was completed, but it did not work or had no such effect;

[0345] “A” means the lowest effective dose is ≤10.00 mg / kg;

[0346] "B" means 10.00 mg / kg < minimum effective dose ≤ 20.00 mg / kg;

[0347] "C" means 20.00 mg / kg < minimum effective dose ≤ 30.00 mg / kg;

[0348] "D" indicates that the minimum effective dose is greater than 30.00 mg / kg.

[0349] “+” indicates a safe therapeutic index ≤ 2;

[0350] “++” means 2<safe therapeutic index ≤ 4;

[0351] “+++” indicates a therapeutic safety index > 4.

[0352] As shown in Table 1, the compounds of the present invention and the μ-opioid receptor agonist remifentanil can both produce definite systemic potent analgesic effects. At the same time, as shown in the table, compared with the μ-opioid receptor agonist remifentanil, the safety therapeutic index of most of the compounds of the present invention is significantly improved, indicating that the compounds of the present invention have better safety.

[0353] The present invention provides a compound having analgesic effects. The compound of the present invention has excellent analgesic effects, is safe for use, and does not cause dependence during use. Therefore, the compound of the present invention has broad application prospects in the preparation of analgesic drugs and provides a new option for the clinical preparation of analgesic drugs.

Claims

1. A compound represented by formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystalline form thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof: in, X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N; Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3; R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; m is an integer selected from 0 to 5; n is an integer selected from 0 to 5; M is selected from O, S, NR4; R4 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1 to 5; When M is selected from O, m and n are both 1, and the A ring is thienyl, R1 is not hydrogen at the same time; When M is selected from O, m and n are both 0, the A ring is When R1 is not hydrogen at the same time; When M is selected from O, m and n are both 0, the A ring is hour, Not for When M is selected from NH, the A ring is not When M is selected from S, the A ring is selected only from substituted or unsubstituted thienyl, and the A ring is hour, Not for 2. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by Formula Ia or Formula Ib: in, X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N; Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3; and there is at most one alkyl and NR2R3 respectively; R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; M is selected from O, S, NH; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1 to 5; When M is selected from O, m and n are both 1, and the A ring is thienyl, R1 is not hydrogen at the same time; When M is selected from O, m and n are both 0, the A ring is When R1 is not hydrogen at the same time; When M is selected from O, m and n are both 0, the A ring is hour, Not for When M is selected from NH, the A ring is not When M is selected from S, the A ring is selected only from substituted or unsubstituted thienyl, and the A ring is hour, Not for 3. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is shown in formula II: in, X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N; Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3; R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5; When m and n are both 1, and ring A is a thienyl group, R1 is not hydrogen at the same time; When m and n are both 0, the A ring is When R1 is not hydrogen at the same time; When m and n are both 0, the A ring is hour, Not for 4. The compound according to claim 3, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula IIa or formula IIb: in, X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N; Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3; and there is at most one alkyl and NR2R3 respectively; R2 and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; Ring A is selected from substituted or unsubstituted 5- to 8-membered aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered cycloalkyl, and substituted or unsubstituted 5- to 8-membered heterocycloalkyl; The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5; In formula IIa, when ring A is thienyl, R1 is not hydrogen at the same time; In Formula IIb, Ring A is When R1 is not hydrogen at the same time; Ring A is hour, Not for 5. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is shown in formula III: in, X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N; Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3; R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5; Ring A is selected from substituted or unsubstituted thienyl, and Ring A is hour, Not for The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups; The substituent of the thienyl group is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

6. The compound according to claim 5, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula IIIa or IIIb: in, X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N; Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, NR2R3; and there is at most one alkyl and NR2R3 respectively; R2 and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; Ring A is selected from substituted or unsubstituted thienyl, and Ring A is hour, Not for The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups; The substituent of the thienyl group is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

7. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is shown in formula IV: in, X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N; Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, NR2R3; R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5; Ring A is selected from substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 5-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered heterocycloalkyl; and Ring A is not The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is 1, 2, 3, 4 or 5.

8. The compound according to claim 7, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is represented by formula IVa or IVb: in, X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N; Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, NR2R3; and there is at most one alkyl and NR2R3 respectively; R2 and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; Ring A is selected from substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 5-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered heterocycloalkyl; and Ring A is not The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups; The substituents of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy; The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is 1, 2, 3, 4 or 5.

9. The compound according to any one of claims 1 to 8, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: Selected from X1, X2, X3, X4, and X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, and X5 is selected from N; R1 is selected from hydrogen, C1-C4 alkyl.

10. The compound according to claim 9, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: Selected from 11. The compound according to any one of claims 1 to 8, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: Ring A is selected from the following substituted or unsubstituted groups: The substituent of the A ring is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

12. The compound according to claim 11, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The substituent of the A ring is selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy.

13. The compound according to any one of claims 1 to 8, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystalline form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The compound is one of the following compounds:

14. A method for preparing the compound according to any one of claims 1 to 13, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: It includes the following steps: In a solvent, compound a, an organic base, TCDI or CDI and compound b react to obtain a compound of formula I; X1, X2, X3, X4, X5, m, n, and A ring are as described in any one of claims 1 to 13; M is S or O.

15. The preparation method according to claim 14, characterized in that: The solvent is dichloromethane; And / or, the organic base is Et3N; And / or, the reaction temperature is 25-40° C., and the reaction time is 10-12 hours.

16. A method for preparing the compound according to any one of claims 1 to 13, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: It includes the following steps: Step 1: In a solvent, the compound represented by formula III reacts with CH3I to obtain compound c; Step 2: Compound c reacts with aqueous ammonia in a solvent to obtain a compound represented by formula IV; X1, X2, X3, X4, X5, m, n, and A ring are as described in any one of claims 1 to 13.

17. The preparation method according to claim 16, characterized in that: In step 1, the solvent is acetonitrile; And / or, in step 1, the reaction temperature is 40 to 60° C., and the reaction time is 4 to 10 hours; And / or, in step 2, the solvent is acetonitrile; And / or, in step 2, the reaction temperature is 80-100° C., and the reaction time is 10-12 hours.

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

19. A drug, characterized in that: It is a preparation prepared with the compound described in any one of claims 1 to 13, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative as the active ingredient, and pharmaceutically acceptable excipients.

20. A pharmaceutical composition, characterized in that: It includes the compound described in any one of claims 1 to 13, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative.

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