A pyridine-containing compound, and a preparation method and use thereof

Abstract

The application provides a pyridine-containing compound and a preparation method and application thereof, and relates to the field of medicinal chemistry.The pyridine-containing compound is a compound shown in 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 excellent analgesic effect, is safe in use, and does not produce dependence in the use process.Therefore, the compound has wide application prospects in the preparation of analgesic drugs, and provides a new selection for preparing drugs with analgesic effect in the clinic.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a pyridine-containing compound, its preparation method, and its 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 pyridine-containing compound, its preparation method, and its 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] X1, X2, X3, X4, and X5 are each independently selected from N or CR1, and there is exactly one of X1, X2, X3, X4, and X5 selected from N;

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

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

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

[0014] M is selected from O, S, and 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 5-8 aryl groups, substituted or unsubstituted 5-8 heteroaryl groups, substituted or unsubstituted 5-8 cycloalkyl groups, and substituted or unsubstituted 5-8 heterocycloalkyl groups.

[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 groups.

[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 thiophene, R1 is not simultaneously hydrogen;

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

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

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

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

[0025] Furthermore, the compound is of formula Ia or formula Ib:

[0026]

[0027] in,

[0028] X1, X2, X3, X4, and X5 are each independently selected from N or CR1, and there is exactly one of X1, X2, X3, X4, and X5 selected from N;

[0029] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and NR2R3; and there is at most one alkyl and one NR2R3.

[0030] R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups, respectively;

[0031] M is selected from O, S, and NH;

[0032] 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.

[0033] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0034] 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 groups.

[0035] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1 to 5.

[0036] When M is selected from O, m and n are both 1, and ring A is thiophene, R1 is not simultaneously hydrogen;

[0037] When M is selected from O, and m and n are both 0, the A ring is... At that time, R1 is not always hydrogen;

[0038] When M is selected from O, and m and n are both 0, the A ring is... hour, Not for

[0039] When M is selected from NH, ring A is not...

[0040] When M is selected from S, ring A is selected only from substituted or unsubstituted thiophene groups, and ring A is... hour, Not for

[0041] Furthermore, the compound is as shown in Formula II:

[0042]

[0043] in,

[0044] X1, X2, X3, X4, and X5 are each independently selected from N or CR1, and there is exactly one of X1, X2, X3, X4, and X5 selected from N;

[0045] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups, and NR2R3;

[0046] R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups, respectively;

[0047] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0048] 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.

[0049] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0050] 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 groups.

[0051] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0052] When both m and n are 1, and ring A is a thiophene group, R1 is not simultaneously hydrogen;

[0053] When both m and n are 0, ring A is... At that time, R1 is not always hydrogen;

[0054] When both m and n are 0, ring A is... hour, Not for

[0055] Furthermore, the compound is of formula IIa or IIb:

[0056]

[0057] in,

[0058] X1, X2, X3, X4, and X5 are each independently selected from N or CR1, and there is exactly one of X1, X2, X3, X4, and X5 selected from N;

[0059] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and NR2R3; and there is at most one alkyl and one NR2R3.

[0060] R2 and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl groups and substituted or unsubstituted C1-C4 alkoxy groups, respectively;

[0061] 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.

[0062] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0063] 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 groups.

[0064] The heteroatom in the heteroaryl group is O, S or N, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0065] In formula IIa, when ring A is a thiophene group, R1 is not simultaneously hydrogen;

[0066] In equation IIb, ring A is At that time, R1 is not simultaneously hydrogen; ring A is hour, Not for

[0067] Furthermore, the compound is as shown in Formula III:

[0068]

[0069] in,

[0070] X1, X2, X3, X4, and X5 are each independently selected from N or CR1, and there is exactly one of X1, X2, X3, X4, and X5 selected from N;

[0071] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups, and NR2R3;

[0072] R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups, respectively;

[0073] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0074] Ring A is selected from substituted or unsubstituted thiophene groups, and ring A is... hour, Not for

[0075] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0076] The substituents of the thiophene group are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0077] Furthermore, the compound is of formula IIIa or IIIb:

[0078]

[0079] in,

[0080] X1, X2, X3, X4, and X5 are each independently selected from N or CR1, and there is exactly one of X1, X2, X3, X4, and X5 selected from N;

[0081] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, and NR2R3; and there is at most one alkyl and one NR2R3.

[0082] R2 and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl groups and substituted or unsubstituted C1-C4 alkoxy groups, respectively;

[0083] Ring A is selected from substituted or unsubstituted thiophene groups, and ring A is... hour, Not for

[0084] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0085] The substituents of the thiophene group are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0086] Furthermore, the compound is as shown in Formula IV:

[0087]

[0088] in,

[0089] X1, X2, X3, X4, and X5 are each independently selected from N or CR1, and there is exactly one of X1, X2, X3, X4, and X5 selected from N;

[0090] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl groups, and NR2R3;

[0091] R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl groups and substituted or unsubstituted C1-C6 alkoxy groups, respectively;

[0092] m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4 or 5;

[0093] 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, and substituted or unsubstituted 5-8 membered heterocycloalkyl; and ring A is not...

[0094] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0095] 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 groups.

[0096] The heteroaryl group contains O, S, or N heteroatoms, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0097] Furthermore, the compound is of formula IVa or IVb:

[0098]

[0099] in,

[0100] X1, X2, X3, X4, and X5 are each independently selected from N or CR1, and there is exactly one of X1, X2, X3, X4, and X5 selected from N;

[0101] Each R1 is independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, and NR2R3; and there is at most one alkyl and one NR2R3.

[0102] R2 and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl groups and substituted or unsubstituted C1-C4 alkoxy groups, respectively;

[0103] 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, and substituted or unsubstituted 5-8 membered heterocycloalkyl; and ring A is not...

[0104] The substituents of the alkyl and alkoxy groups are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, and hydroxyl groups;

[0105] 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 groups.

[0106] The heteroaryl group contains O, S, or N heteroatoms, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0107] Furthermore,

[0108] Selected from

[0109] X1, X2, X3, X4, and X5 are each 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 to C4 alkyl groups.

[0110] Furthermore,

[0111] Selected from

[0112] Furthermore,

[0113] Ring A is selected from the following groups, whether substituted or unsubstituted:

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120] The substituents of the A ring are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0121] Furthermore,

[0122] The substituents of the A ring are selected from deuterium, halogen, amino, nitro, cyano, carboxyl, hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy.

[0123] Furthermore, the compound is one of the following compounds:

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141] 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:

[0142]

[0143] In a solvent, compound a, an organic base, TCDI or CDI and compound b react to give the compound shown in Formula I;

[0144] The X1, X2, X3, X4, X5, m, n, and A rings are as described above; M is either S or O.

[0145] Furthermore,

[0146] The solvent is dichloromethane;

[0147] And / or, the organic base is Et3N;

[0148] And / or, the reaction temperature is 25–40°C, and the reaction time is 10–12 hours.

[0149] 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:

[0150]

[0151] Step 1: In a solvent, the compound shown in Formula III reacts with CH3I to give compound c;

[0152] Step 2: In a solvent, compound c reacts with ammonia to obtain the compound shown in formula IV;

[0153] The X1, X2, X3, X4, X5, m, n, and A rings are as described above.

[0154] Furthermore,

[0155] In step 1, the solvent is acetonitrile;

[0156] And / or, in step 1, the reaction temperature is 40–60°C and the reaction time is 4–10 hours;

[0157] And / or, in step 2, the solvent is acetonitrile;

[0158] And / or, in step 2, the reaction temperature is 80–100°C and the reaction time is 10–12 hours.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0165] 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.

[0166] "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.

[0167] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0168] "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.

[0169] "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.

[0170] "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.

[0171] "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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0183] 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.

[0184] Compared with the prior art, the compound provided by the present invention has the following beneficial effects:

[0185] This invention provides a compound with analgesic effects. This compound exhibits excellent analgesic efficacy, good safety profile, and does not induce dependence during use. 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.

[0186] 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.

[0187] 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

[0188] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0189] 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 400NMR 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).

[0190] 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.

[0191] (1) Medicinal materials and reagents

[0192] 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.

[0193] Silica gel for column chromatography, 200-300 mesh, from Shandong Weihai Rushan Taiyang Desiccant Co., Ltd.

[0194] (2) Main instruments

[0195] Electronic balance, FA2004, Shanghai Liangping Instruments Co., Ltd.;

[0196] Temperature-controlled and pressure-regulating magnetic stirrer, TY98-1, Shanghai Sile Instruments Co., Ltd.

[0197] Three-in-one ultraviolet analyzer, ZF-2 model, Shanghai Anting Scientific Instrument Factory;

[0198] Rotary evaporator, R201, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0199] Liftable water bath, R201D, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0200] Circulating water vacuum pump (tabletop), SHB-Ⅲ, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0201] Circulating water vacuum pump (portable), SHB-B95, Zhengzhou Huicheng Electronic Technology Co., Ltd.

[0202] Cryogenic circulating pump, DLSB-5 / 20, Zhengzhou Huicheng Electronic Technology Co., Ltd.;

[0203] Rotary vane vacuum pump (oil pump), 2XZ-4, Shanghai Vacuum Pump Factory.

[0204] The general formulas for the synthesis of some compounds in this invention are as follows:

[0205]

[0206]

[0207] Example 1: Preparation of compound 1-1-195 of the present invention (188-4-2)

[0208]

[0209] Synthesis of 1.1-1-195

[0210] 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 system, and the mixture was stirred at room temperature for two hours. Then, thiophene methylamine SM-8 (556 mg, 4.92 mmol) was added, and the mixture was reacted overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by gradient elution using column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and the reaction proceeded in reverse to give a white solid 1-1-195 (940 mg, 69%). MS Calcd.: 277.1; MS Found: 278.2 [M+H]+ .

[0211] 1 H 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).

[0212] Example 2: Preparation of compound 1-1-221 of the present invention (AL37-23-188-4)

[0213]

[0214] 1. Synthesis of 188-4-3

[0215]

[0216] 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, and the tube was sealed and stirred at 40 °C for 4 hours. After the reaction was complete as monitored by LC-MS, the solvent was removed under reduced pressure to obtain the crude product. Gradient elution by column chromatography [petroleum ether: ethyl acetate (100:1-5:1)] yielded a grayish-white solid 188-4-3 (400 mg, 76%). MS Calcd.: 291.1; MS Found: 292.2 [M+H] + .

[0217] 2. Synthesis of 1-1-221

[0218]

[0219] 188-4-3 (400 mg, 2.09 mmol) was added to a sealed tube, dissolved in MeCN (15 mL), and then ammonia (3 mL) was added. The tube was sealed and stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the solvent was removed under reduced pressure to obtain the crude product. The crude product was then subjected to gradient elution by column chromatography [dichloromethane:methanol (100:1-5:1)] and prep-HPLC to obtain a grayish-white solid 1-1-221 (117.97 mg, 33%). MS Calcd.: 260.1; MS Found: 261.1 [M+H] + .

[0220] 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).

[0221] Example 3: Preparation of compound 1-1-195-1 of the present invention (P1-2-2-2)

[0222]

[0223] Synthesis of compound 1-1-195-1

[0224] 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 then added to the system, and the mixture was stirred at room temperature for two hours. SM-2 (345 mg, 2.83 mmol) was then added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared in reverse to give a white solid 1-1-195-1 (178.10 mg, yield: 23%). ESI [M+H] + =227.03[M+H] + .

[0225] 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).

[0226] Example 4: Preparation of compound 1-6-001 of the present invention (P1-1-1-13)

[0227]

[0228] 1. Synthesis of compound SM-3

[0229]

[0230] To a methanol (120 mL) solution containing compound 300-2-1 (12 g, 101.58 mmol), nickel chloride hexahydrate (4.83 g, 20.32 mmol) and sodium borohydride (11.53 g, 304.73 mmol) were added at 0 °C, and the mixture was stirred at 0 °C for 16 hours. After the reaction was indicated by LC-MS to be complete, the reaction mixture was concentrated under reduced pressure. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 3), 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 SM-3 (3.9 g, yield 31.43%). m / z calculated for [M+H] + 123.17, found 123.1.

[0231] 2. Synthesis of compound 300-2-3

[0232]

[0233] N,N-diisopropylethylamine (DIEA) (1586.92 mg, 12.28 mmol) and N,N'-carbonyldiimidazole (CDI) (796.34 mg, 4.91 mmol) were added to a solution of compound SM-3 (500 mg, 4.09 mmol) in 5 mL of tetrahydrofuran (THF), and the mixture was stirred at 0 °C for 30 min. After the reaction was indicated by LC-MS to be complete, the mixture was concentrated under reduced pressure to give a yellow oily compound 300-2-3 (600 mg, yield 98.95%). (m / z calculated for [M+H)) + 149.17, found 149.2.

[0234] 3. Synthesis of Compound 1-6-001

[0235]

[0236] N,N-diisopropylethylamine (DIEA) (1570.21 mg, 12.15 mmol) and compound SM-5 (471.95 mg, 4.86 mmol) were added to a 10 mL solution of tetrahydrofuran containing compound 300-2-3 (600 mg, 4.05 mmol), 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 1-6-001 (163.9 mg, yield 16.50%). (m / z calculated for [M+H)) + 246.29, found 246.2.

[0237] 1 HNMR(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).

[0238] Example 5: Preparation of compound 1-1-195-3 of the present invention (P1-2-1-2)

[0239]

[0240] 1. Synthesis of compound SM-4

[0241]

[0242] At 0°C, sulfur phosgene (0.8 mL) was slowly added over 5 minutes to a solution of N,N-diisopropylethylamine (DIEA) (2 mL) and dichloromethane (DCM) containing compound SM-3 (600 mg, 4.911 mmol). The mixture was heated to room temperature and stirred for 2 hours. After the reaction was indicated by LC-MS to be complete, the mixture was concentrated under reduced pressure to give a brown oily compound SM-4 (800 mg, yield 99.19%).

[0243] 2. Synthesis of compound 1-1-195-3

[0244]

[0245] SM-1 (826.99 mg, 7.307 mmol) and N,N-diisopropylethylamine (DIEA) (2 mL) were added to a tetrahydrofuran (10 mL) solution containing compound SM-4 (600 mg, 3.653 mmol), and the mixture was stirred at 80 °C for 3 hours. 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 Na₂SO₄, concentrated under vacuum, and purified by Prep-HPLC to give a brown oily compound 1-1-195-3 (286.9 mg, yield 28.31%). (m / z calculated for [M+H]) + 278.4, found 278.1.

[0246] 1 H 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).

[0247] Example 6: Preparation of compound 1-6-002 of the present invention (P1-2-3-6)

[0248]

[0249] 1. Synthesis of compound 342-4-2

[0250] Add 342-4-1 (2.0 g, 10 mmol) to a reaction flask, dissolve in methanol (30 mL), then add oxalyl chloride (6.4 g, 50 mmol) to the reaction system. Stir the reaction mixture overnight at room temperature. After the reaction is complete as monitored by LCMS, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain crude product 342-4-2 (~700 mg, yield: 52%), a pale yellow oil.

[0251] 2. Synthesis of compound 1-6-002

[0252] Add 342-4-2 (700 mg, 5.2 mmol) to a reaction flask, dissolve in dichloromethane (DCM) (40 mL), then add pyridine (2.05 g, 26 mmol) and N,N'-thiocarbonyldiimidazole (TCDI) (926 mg, 5.2 mmol) to the reaction system and stir at room temperature for 2 hours; then add SM-6 (562 mg, 5.2 mmol) and stir overnight at room temperature. After the reaction is complete as monitored by LCMS, remove the solvent under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–3%) and prep-HPLC to obtain a white solid 1-6-002 (400 mg, yield: 31%). ESI[M+H] + =250.2.

[0253] 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).

[0254] Example 7: Preparation of compound 1-6-003 of the present invention (P1-2-1-1)

[0255]

[0256] 1. Preparation of compound 4-10-2

[0257]

[0258] Pyridine (1 mL), BoC₂O (5 g, 22.936 mmol), and ammonium bicarbonate (1.47 g, 18.586 mmol) were added to a solution of compound 4-10-1 (2 g, 15.488 mmol) in dioxane (20 mL), and the mixture was stirred at room temperature for 14 hours. After the reaction was indicated by LC-MS, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3), washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give a brown oily compound 4-10-2 (1.5 g, 75.57% yield). m / z calculated for [M+H] + 129.1, found 129.0.

[0259] 2. Preparation of compound 4-10-3

[0260]

[0261] At 0 °C, BH3·THF (30 mL) was added to a tetrahydrofuran (THF) solution containing 1.4 g (10.925 mmol) of compound 4-10-2 with stirring over 10 minutes. The mixture was heated to 80 °C and stirred for 14 hours. After the reaction was complete, MeOH was 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 the reaction was indicated by LC-MS, H2O (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was washed with concentrated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give a brown oily compound 4-10-3 (850 mg, yield 36.31%). (m / z calculated for [M+H]) + 215.2, found 215.2.

[0262] 3. Preparation of compound SM-7

[0263]

[0264] Trifluoroacetic acid (TFA) (3 mL) was added to a solution of compound 4-10-3 (850 mg, 3.967 mmol) in dichloromethane (DCM) (9 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was indicated by LC-MS to be complete, the reaction mixture was concentrated under reduced pressure to give a brown oily compound SM-7 (450 mg, 99.36% yield). (m / z calculated for [M+H)) + 115.1, found 115.2

[0265] 4. Preparation of compound 1-6-003

[0266]

[0267] Compound SM-4 (1438.47 mg, 8.759 mmol) and N,N-diisopropylethylamine (DIEA) (2 mL) were added to a tetrahydrofuran (15 mL) solution containing compound SM-7 (450 mg, 4.379 mmol). The mixture was stirred at 80 °C for 3 hours. 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 brown oily compound 1-6-003 (223.4 mg, yield 18.32%). (m / z calculated for [M+H]) + 279.3, found 279.0.

[0268] 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).

[0269] Example 8: Preparation of compound 1-6-004 of the present invention

[0270]

[0271] 1. Synthesis of compound 1-6-004

[0272] Add 4-5-1 (300 mg, 3.09 mmol) to a reaction flask, dissolve in dichloromethane (DCM) (20 mL), then add pyridine (Py) (732 mg, 9.27 mmol) and N,N'-thiocarbonyldiimidazole (TCDI) (550 mg, 3.09 mmol) to the system and stir at room temperature for two hours; then add SM-2 (377 mg, 3.09 mmol) to the system and react overnight at room temperature. After the reaction is complete, remove the solvent under reduced pressure to obtain the crude product, which is purified by column chromatography [eluent: dichloromethane-methanol (100:1-95:5)] and reverse-phase chromatography to obtain a white solid 1-6-004 (310.22 mg, 38%). ESI [M+H] + =278.2[M+H] + .

[0273] 1H 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)

[0274] Example 9: Preparation of compound 1-1-337 of the present invention (P1-3-3-6)

[0275]

[0276] 1. Synthesis of compound AL37-11-342-4-B

[0277] Add 1-6-002 (249 mg, 1.0 mmol) to a reaction tube, dissolve in acetonitrile (10 mL), then add iodomethane (426 mg, 3.0 mmol), seal the tube, and stir overnight at 40 °C. After the reaction is complete as monitored by LCMS, remove the solvent under reduced pressure to obtain the crude product. Column chromatography [petroleum ether:ethyl acetate (100:1–2:1)] yields a pale yellow solid, AL37-11-342-4-B (200 mg, yield: 76%). ESI [M+H] + =264.1.

[0278] 2. Synthesis of compound 1-1-337

[0279] AL37-11-342-4-B (200 mg, 0.76 mmol) was added to a sealed tube, dissolved in acetonitrile (10 mL), and then ammonia (5 mL). The mixture was stirred overnight at 80 °C. After the reaction was complete as monitored by LCMS, the solvent was removed under reduced pressure to obtain the crude product. Column chromatography [dichloromethane:methanol (100:1-5:1)] and prep-HPLC yielded a grayish-white solid 1-1-337 (72.32 mg, 41%). ESI [M+H] + =233.2.

[0280] 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).

[0281] Example 10: Preparation of compound 1-6-005 of the present invention

[0282]

[0283] Synthesis of compound 1-6-005

[0284] 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 then added to the reaction system, and the mixture was stirred at room temperature for two hours. SM-3 (253.8 mg, 2.08 mmol) was then added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete as monitored by LCMS, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–3%) and prep-HPLC to obtain a white solid 1-6-005 (154.15 mg, yield: 28%). ESI [M+H] + =263.1.

[0285] 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).

[0286] Example 11: Preparation of compound 1-6-006 of the present invention

[0287]

[0288] Synthesis of Compound 1-6-006

[0289] 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 then added to the system, and the mixture was stirred at room temperature for two hours. SM-2 (377 mg, 3.09 mmol) was then added to the system, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-95:5)], and further purified by prep-HPLC to obtain a white solid 1-6-006 (215.09 mg, yield 25%). ESI [M+H] +=279.3[M+H] + .

[0290] 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).

[0291] Example 12: Preparation of compound 1-1-342-1 of the present invention

[0292]

[0293] Synthesis of compound 1-1-342-1

[0294] Add 342-3-1 (408 mg, 3.0 mmol) to a reaction flask, dissolve in dichloromethane (20 mL), then add pyridine (1.2 g, 15.0 mmol) and N,N'-carbonyldiimidazole CDI (486 mg, 3.0 mmol) to the reaction system and stir at room temperature for 2 hours; then add SM-6 (324 mg, 3.0 mmol) and stir overnight at room temperature. After the reaction is complete as monitored by LCMS, remove the solvent under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–3%) and prep-HPLC to obtain a white solid 1-1-342-1 (104.30 mg, yield: 15%). ESI[M+H] + =234.2.

[0295] 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),9.35(s,1H),8.09(d,J=1.6Hz,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).

[0296] Example 13: Preparation of compound 1-1-196 of the present invention

[0297]

[0298] Synthesis of compound 1-1-196

[0299] 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 the mixture was stirred at room temperature for two hours. Then, 4-7-1 (286 mg, 2.65 mmol) was added to the system, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-95:5)], and further purified by prep-HPLC to obtain a white solid 1-1-196 (123.09 mg, 17%). ESI [M+H] + =264[M+H] + .

[0300] 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).

[0301] Example 14: Preparation of compound 1-6-007 of the present invention

[0302]

[0303] The synthesis of compound 1-6-007: 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 the mixture was stirred at room temperature for 2 hours. Then, 17-A-2 (162 mg, 1.5 mmol) was added to the system, and the mixture was stirred overnight at room temperature. The reaction solution was directly evaporated to dryness, and the residue was dissolved in chloroform (10 mL) and pyridine (592 mg, 7.5 mmol), and the mixture was stirred overnight at 70 °C. After the reaction was monitored by LCMS to be complete, the solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–3%) and prep-HPLC to obtain a pale yellow oily 1-6-007 (78.03 mg, yield: 21%). ESI[M+]

[0304] H]+ =251.2.

[0305] 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).

[0306] Example 15: Preparation of compound 1-1-164 of the present invention

[0307]

[0308] Synthesis of compound 1-1-164

[0309] 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 then added to the system, and the mixture was stirred at room temperature for two hours. SM-2 (345 mg, 2.83 mmol) was then added to the system, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. This crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared in reverse to give a white solid 1-1-164 (185.44 mg, yield: 25%). ESI [M+H] + =261.03[M+H] + .

[0310] 1 H 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).

[0311] Example 16: Preparation of compound 1-6-008 of the present invention (P1-2-1-13)

[0312]

[0313] Synthesis of compound 1-6-008

[0314] To a solution of compound SM-4 (650 mg, 4.05 mmol) in tetrahydrofuran (10 mL), N,N-diisopropylethylamine (DIEA) (1570.21 mg, 12.15 mmol) and compound SM-5 (471.95 mg, 4.86 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 (163.8 mg, yield 17.15%). (m / z calculated for [M+H]) + 262.35, found 262.1.

[0315] 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).

[0316] Example 17: Preparation of compound 1-6-009 of the present invention

[0317]

[0318] Synthesis of compound 1-6-009

[0319] SM-7 (450 mg, 3.95 mmol) was dissolved in dichloromethane (10 mL) in a reaction flask. Et3N (1.06 g, 10.53 mmol) and N,N'-carbazyldiimidazole CDI (639 mg, 3.95 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, 300-1-A (426 mg, 3.95 mmol) was added, and the mixture was reacted overnight at room temperature. After the reaction was complete as monitored by LCMS, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] and prepared in reverse to give a white solid 1-6-009 (124.37 mg, 12%) ESI [M+H]. + =249.1[M+H] + .

[0320] 1H 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).

[0321] Example 18: Preparation of compound 1-6-010 of the present invention

[0322]

[0323] 1. Preparation of compound 0-2-2

[0324]

[0325] Triethanolamine (TEA) (1.488 mL, 10.706 mmol) and diphenyl azide phosphate (DPPA) (2.70 g, 9.814 mmol) were slowly added to a 40 mL solution of tetrahydrofuran (THF) containing compound 0-2-1 (1 g, 8.922 mmol) at 0 °C. The mixture was stirred at 60 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give 1.3 g of a white crude product of compound 0-2-2.

[0326] 2. Preparation of compound 1-6-010

[0327]

[0328] Compound SM-6 (1.03 g, 9.482 mmol) was added to a 20 mL solution of dioxane containing compound O-2-2 (1.3 g, 9.482 mmol), and the mixture was stirred at 100 °C for 16 hours. After stirring, 10 mL of H₂O 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 give a yellow solid 1-6-010 (67.8 mg, yield 3.29%). (m / z calculated for [M+H)) + 218.1, found 218.0.

[0329] 1H 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).

[0330] Example 19: Preparation of compound 1-6-011 of the present invention

[0331]

[0332] 1. Synthesis of compound 16-2

[0333] Add 16-1 (1 g, 5 mmol) to a 100 mL single-necked flask, dissolve in DOX (15 mL), then add HCl / DOX (4 M) (15 mL), and stir overnight at room temperature. After the reaction is complete, remove the solvent by vacuum distillation, slurry with acetonitrile (30 mL * 5), filter, collect the filtrate and evaporate to dryness to obtain 16-2 (584 mg, yield 85%). ESI [M + H + =133.2[M+H] + .

[0334] 2. Synthesis of compound 1-6-011

[0335] 16-2 (584 mg, 4.3 mmol) was added to a reaction flask and dissolved in dichloromethane (20 mL). Pyridine (Py) (1.01 g, 12.9 mmol) and N,N'-carbazyldiimidazole (CDI) (697 mg, 4.3 mmol) were added to the system, and the mixture was stirred at room temperature for two hours. Then, 17-A-2 (464 mg, 4.3 mmol) was added to the system, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation to obtain a crude product. This crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-95:5)] to obtain a white crude product of approximately 380 mg. Reverse purification yielded an off-white solid, 1-6-011 (340 mg, 34%). ESI [M+H] + =235.3

[0336] 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).

[0337] Example 20: Preparation of compound 1-6-012 of the present invention

[0338]

[0339] Synthesis of compound 1-6-012

[0340] 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'-carbazyldiimidazole CDI (337 mg, 2.08 mmol) were then added to the reaction system, and the mixture was stirred at room temperature for two hours. SM-2 (253.8 mg, 2.08 mmol) was then added to the system, and the mixture was stirred overnight at room temperature. After the reaction was complete as monitored by LCMS, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–3%) and prep-HPLC to obtain a white solid 1-6-012 (137.67 mg, yield: 25%). ESI [M+H] + =263.1.

[0341] 1 H 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).

[0342] Example 21: Preparation of compound 1-6-013 of the present invention

[0343]

[0344] 1. Preparation of compound 202-1-2

[0345] 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. Diisopropyl azodicarbonate (DIAD) (2 mL, 10.0 mmol) was added dropwise at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to give a white solid 202-1-2 (4.3 g, 74% yield).

[0346] 2. Preparation of compound 202-1-3

[0347] 202-1-2 (2.09 g, 9.0 mmol) was dissolved in anhydrous ethanol (70 mL), and hydrazine hydrate solution (1.4 mL) was added. The mixture was heated 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 sonicated for 5 min. The mixture was filtered through diatomaceous earth, and 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, and the mixture was evaporated to dryness to obtain the crude product. Recrystallization from PE / EtOAc gave a pale yellow solid product 202-1-3 (452 ​​mg, 3.0 mmol, overall yield of the two-step reaction 40%).

[0348] 3. Preparation of compound 202-1-6

[0349] 202-1-4 (2.53 g, 10 mmol) was dissolved in dichloromethane (3 mL), and potassium carbonate (1.39 g, 10.05 mmol) was added. After stirring at room temperature for 2 hours, 202-1-5 and tetramethylguanidine (2.85 g, 16.7 mmol) were added. The mixture was stirred overnight at room temperature. The reaction solution was diluted with dichloromethane (20 mL) and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a yellow oily product 202-1-6 (950 mg, 50% yield).

[0350] 4. Preparation of compound 202-1-7

[0351] 202-1-6 (141 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL), and I2 (12 mg, 0.05 mmol) and peroxytert-butanol (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 overnight at room temperature. The reaction mixture was diluted with dichloromethane, washed once with saturated aqueous Na2S2O3 solution, and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and column filtered to give a pale yellow oily product 202-1-7 (160 mg, 24% yield).

[0352] 5. Preparation of compound 1-6-013

[0353] Add 5 mL of ethyl acetate solution (2.0 M) of hydrochloric acid to 202-1-7 (160 mg, 0.48 mmol). Stir at room temperature for 10 hours, then adjust the pH to approximately 10 with sodium hydroxide aqueous solution. Extract with dichloromethane. Dry and concentrate the organic phase, then purify by silica gel column chromatography to give a yellow oily product 1-6-013:100 mg, 48% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 12 H1N4OS + 231.1240; Found 231.1248.

[0354] 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).

[0355] Example 22: Preparation of compound 1-6-014 of the present invention

[0356]

[0357] 1. Synthesis of compound 188-4-9-2

[0358] 188-4-9-1 (3.94 g, 30 mmol) was dissolved in ether (60 mL), and lithium aluminum hydride (2.85 g, 75 mmol) was slowly added in portions at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours. After the reaction was monitored by TLC until it was complete, 3 mL of 15% sodium hydroxide solution was added to quench the reaction, followed by the addition of 3 mL of water, and then another 3 mL of 15% sodium hydroxide solution. The mixture was filtered through diatomaceous earth and anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily compound 188-4-9-2 (3.74 g, 92% yield).

[0359] 2. Synthesis of compound 188-4-9-3

[0360] 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. After the addition was complete, the mixture was reacted at room temperature for 1 hour. Then, 4-dimethylaminopyridine (DMAP) (37 mg, 0.3 mmol) and Boc2O (2.3 mL, 10 mmol) were added at 0 °C, and the mixture was then reacted at room temperature overnight. After the reaction was monitored by TLC until complete, the mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 50:1) to give a colorless oily compound 188-4-9-3 (1.16 g, 66% yield).

[0361] 3. Synthesis of compound 1-6-014

[0362] 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 the reaction was carried out at room temperature for 2 hours. After the reaction was completed as monitored by TLC, column chromatography (PE / EtOAc = 2:1) gave a yellow oily compound 1-6-014:361 mg, 80% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 17 H 22 N3S + 300.1529; Found 300.1532.

[0363] 1 H 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).

[0364] Example 23: Preparation of compound 1-6-015 of the present invention

[0365]

[0366] 1. Preparation of compound 188-4-8-3

[0367] Dissolve 188-4-8-1 (268 mg, 2 mmol) in dichloromethane (DCM) (2 mL). While in an ice bath, add N,N-diisopropylethylamine (DIPEA) (416 μL, 2.4 mmol) dropwise. 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 a colorless oily product 188-4-8-3 (170 mg, 60% yield).

[0368] 2. Preparation of compound 1-6-015

[0369] 188-4-8-3 (170 mg, 1.2 mmol) and SM-2 (161 mg, 1.32 mmol) were dissolved in toluene (2 mL). After stirring at room temperature for 15 hours, a white solid precipitated. The reaction was monitored by TLC until complete. The mixture was filtered and washed with PE:EA at a ratio of 10:1 to give a 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.

[0370] 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).

[0371] Example 24: Preparation of compound 1-6-016 of the present invention

[0372]

[0373] 1. Preparation of compound 188-4-0-2

[0374] 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. After the addition was complete, the mixture was reacted at room temperature for 1 h. Then, 4-dimethylaminopyridine (DMAP) (73 mg, 0.6 mmol) and Boc2O (4.6 mL, 20 mmol) were added at 0 °C, and the mixture was then reacted at room temperature overnight. After the reaction was monitored by TLC until complete, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (EA / EtOAc = 40:1) to give a yellow oily compound 188-4-0-2 (2.61 g, 88% yield).

[0375] 2. Synthesis of compound 1-6-016

[0376] 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 the reaction was carried out at room temperature for 2 hours. After the reaction was completed as monitored by TLC, column chromatography (PE / EtOAc = 2:1) gave a blue solid compound 1-6-016:220 mg, 81% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 15 H 18 N3S + 272.1216; Found 272.1218.

[0377] 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.

[0378] Example 25: Preparation of compound 1-6-017 of the present invention

[0379]

[0380] 1. Synthesis of compound 188-4-14-1

[0381] 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. After the addition was complete, the mixture was reacted at room temperature for 1 hour. Then, DMAP (9.6 mg, 0.078 mmol) and Boc2O (0.6 mL, 2.6 mmol) were added at 0 °C, and the mixture was then reacted at room temperature overnight. After the reaction was monitored by TLC until complete, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE / EtOAc = 40:1) to give a yellow oily compound 188-4-14-1 (300 mg, 83% yield).

[0382] 2. Synthesis of compound 1-6-017

[0383] 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 the reaction was completed as monitored by TLC, column chromatography (PE / EtOAc = 2:1) gave a green oily compound 1-6-017: 344 mg, 66% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 13 H 16 N3OS + 262.1009; Found 262.1007.

[0384] 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).

[0385] Example 26: Preparation of compound 1-6-018 of the present invention

[0386]

[0387] Synthesis of compound 1-6-018

[0388] 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 the reaction was completed as monitored by TLC, column chromatography (DCM / MeOH = 10:1) gave a yellow solid compound 1-6-018:509 mg, 78% yield. HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 12 H 15 N4OS + 263.0962; Found 263.0957.

[0389] 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).

[0390] Example 27: Preparation of compound 1-6-019 of the present invention

[0391]

[0392] 1. Synthesis of compound 6-019-3

[0393] 6-019-1 (863 μL, 10 mmol) and 6-019-2 (2.9 g, 10 mmol) were dissolved in tetrahydrofuran (40 mL), followed by the addition of PPh3 (2.62 g, 10 mmol), and DIAD (2 mL, 10 mmol) was slowly added dropwise at 0 °C. The reaction mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and subjected to column chromatography (PE / EtOAc = 20:1) to give a yellow oily compound 6-019-3 (1.8 g, 49% yield).

[0394] 2. Synthesis of compound 6-019-4

[0395] 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 subjected to column chromatography (PE / EtOAc = 5:1) to give a colorless oily compound 6-019-4 (1.4 g, 62% yield).

[0396] 3. Synthesis of compound 1-6-019

[0397] Dissolve 6-019-4 (1.4 g, 3 mmol, 1.0 equiv.) in ethyl acetate (20 mL), then add HCl solution (2 mL, in DOX 4.0 M). After the addition is complete, react at room temperature for 16 hours. A white solid precipitates and adheres to the flask wall. Discard the reaction solution, dissolve the remaining solid in DCM, and adjust the pH to 8 with saturated sodium bicarbonate solution. Separate the layers. Add sodium sulfate to the aqueous phase to saturate, and extract three times with dichloromethane. Combine the organic phases, dry with sodium sulfate, filter, concentrate under reduced pressure, and perform column chromatography (DCM / MeOH = 5:1) to give a yellow oily product 1-6-019 (235 mg, 32% yield). HRMS (ESI-TOF) m / z: [M+H] + Calcd forC 14 H 17 N4O + 245.1397Found 245.1392.

[0398] 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).

[0399] Example 28: Preparation of compound 1-6-020 of the present invention

[0400]

[0401] 1. Synthesis of compound 6-020-1

[0402] At 0 °C, sulfur phosgene (637.76 mg, 5.55 mmol) was added over 5 minutes to a solution of dichloromethane (10 mL) containing compound 342-4-2 (500 mg, 5.04 mmol) and DIEA (1.66 mL, 10.09 mmol). The mixture was heated to room temperature and stirred at room temperature for 2 hours. The reaction was confirmed to be complete by LC-MS. The mixture was concentrated under reduced pressure to give a brown oily compound 6-020-1 (700 mg, 98.30% yield).

[0403] 2. Synthesis of compound 1-6-020

[0404] Compound SM-2 (826.99 mg, 7.307 mmol) and DIEA (2 mL) were added to a tetrahydrofuran (10 mL) solution containing compound 6-020-1 (500 mg, 3.653 mmol). The reaction was stirred at 80 °C for 3 hours. The reaction was indicated by LC-MS to be complete. 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 brown oily compound 1-6-020 (251.1 mg, 26.0% yield). m / z calculated for [M+H] + 264.38, found 264.0.

[0405] 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).

[0406] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0407] Experimental Example 1: Study on the potent analgesic effect of the compound of the present invention

[0408] 1. Experimental Methods

[0409] 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.

[0410] 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.

[0411] 1.2 Experimental Design:

[0412] (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.

[0413] (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."

[0414] (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.

[0415] 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".

[0416] 2. Experimental Results

[0417] Table 1. Efficacy and safety window of the compounds of this invention in rats (single intravenous injection)

[0418]

[0419] Remark:

[0420] "—" indicates that the test was completed, and the test was ineffective or had no effect.

[0421] “A” indicates that the minimum effective dose is ≤10.00mg / kg;

[0422] "B" indicates that 10.00 mg / kg < minimum effective dose ≤ 20.00 mg / kg;

[0423] "C" indicates that 20.00 mg / kg < minimum effective dose ≤ 30.00 mg / kg;

[0424] “D” indicates that the minimum effective dose is >30.00 mg / kg.

[0425] "+" indicates that the safety treatment index is ≤2;

[0426] “++” indicates that 2 < safety treatment index ≤ 4;

[0427] "+++" indicates a safety treatment index > 4.

[0428] 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.

[0429] This invention provides a compound with analgesic effects. This compound exhibits excellent analgesic efficacy, good safety profile, and does not induce dependence during use. 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, or a crystal form thereof, or a deuterated derivative thereof, characterized in that: The compound is shown as formula IIa or formula IIb: wherein, X1, X2, X3, X4, X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, X5 is selected from N; each R1 is independently selected from hydrogen, methyl, and one methyl; A ring is selected from 2.The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a deuterated derivative thereof, characterized in that: selected from 3. A compound, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a deuterated derivative thereof, characterized in that: The compound is one of the following compounds:

4. A compound, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a deuterated derivative thereof, characterized in that: The compound is shown as formula IIIa or formula IIIb: wherein, X1, X2, X3, X4, X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, X5 is selected from N; each R1 is independently selected from hydrogen, methyl, and one methyl; A ring is selected from 5.The compound of claim 4, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a deuterated derivative thereof, characterized in that: selected from 6. A compound, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a deuterated derivative thereof, characterized in that: ###0002### The compound is one of the following compounds:

7. A compound, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a deuterated derivative thereof, according to any one of claims 1-6. The compound is shown as formula IVa or formula IVb: wherein, X1, X2, X3, X4, X5 are independently selected from N or CR1, and only one of X1, X2, X3, X4, X5 is selected from N; each R1 is independently selected from hydrogen, methyl, and one methyl; A ring is selected from 8.The compound of claim 7, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a deuterated derivative thereof, characterized in that: selected from 9. A compound, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a deuterated derivative thereof, according to any one of claims 1-8. The compound is one of the following compounds:

10. A method of preparing a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a deuterated derivative thereof, characterized in that: It comprises the following steps: In a solvent, compound a, organic base, TCDI or CDI and compound b are reacted to obtain a compound shown as formula I; the compound shown as formula I is the compound of any one of claims 1-6. 11.The preparation method of claim 10, characterized in that: The solvent is dichloromethane; And / or, the organic base is Et3N; And / or, the reaction temperature is 25-40℃, and the reaction time is 10-12 hours.

12. A method of preparing a compound according to any one of claims 7 to 9, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a deuterated derivative thereof, characterized in that: It comprises the following steps: Step 1: in a solvent, a compound shown as formula III and CH3I are reacted to obtain compound c; Step 2: in a solvent, compound c and ammonia are reacted to obtain a compound shown as formula IV; the compound shown as formula IV is the compound of any one of claims 7-9. 13.The preparation method of claim 12, characterized in that: In step 1, the solvent is acetonitrile; And / or, in step 1, the reaction temperature is 40-60℃, and the reaction time is 4-10 hours; And / or, in step 2, the solvent is acetonitrile; And / or, in step 2, the reaction temperature is 80-100℃, and the reaction time is 10-12 hours. 14.Use of the compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a deuterated derivative thereof in the preparation of a drug with analgesic effect.

15. A medicament, characterized by comprising: It is a preparation prepared from the compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a crystal form thereof, or a deuterated derivative thereof as an active ingredient, plus a pharmaceutically acceptable adjuvant.

16. A pharmaceutical composition, characterized by: It includes the compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a deuterated derivative thereof.

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