Aza-spiro compounds, methods of making, pharmaceutical compositions, and uses thereof

Abstract

The application relates to a kind of azaspiro compounds and preparation method, pharmaceutical composition and application thereof.The azaspiro compound has the structural characteristics shown in the following formula (I).The azaspiro compound has analgesic mechanism different from traditional compounds, and is safer while having good analgesic effect.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry, and in particular to an azaspirocyclic compound, its preparation method, pharmaceutical composition, and application. Background Technology

[0002] Pain is a physical and even psychological burden for many people around the world. Currently, medication remains the primary method for pain management. Commonly used analgesics include opioid receptor agonists (such as morphine and pethidine), nonsteroidal anti-inflammatory drugs (NSAIDs) (such as aspirin and ibuprofen), antidepressants, and antiepileptic drugs (such as gabapentin and pregabalin). In 2021, *The Lancet* reported that antidepressants and antiepileptic drugs are the first-line treatments for neuropathic pain, while NSAIDs are the first-line treatment for non-neuropathic pain.

[0003] Opioid receptor (MOR) drugs are the first-line treatment for moderate to severe acute pain, and drugs targeting opioid receptors dominate the market for pain management applications and those under clinical investigation. Although opioid receptor drugs have good analgesic effects, their serious adverse reactions, such as drug tolerance, respiratory depression, and addiction, remain a significant concern in pain management. Since 1999, the number of deaths due to opioid abuse has surged, leading to an "opioid receptor epidemic." While some improvements have been made in recent years to reduce the adverse reactions of opioid receptor drugs, only the MOR subtype-biased agonist Oliceeridine has been approved for marketing as a new mechanism of action. Developing analgesics with good analgesic efficacy and greater safety remains a hot topic in drug development. Summary of the Invention

[0004] Based on this, this application provides an azaspirocyclic compound, its preparation method, pharmaceutical composition, and application. The azaspirocyclic compound has an analgesic mechanism different from that of traditional compounds, and has better analgesic effect and higher safety.

[0005] A first aspect of this application provides a spirocyclic compound having the following formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:

[0006]

[0007] in,

[0008] R 1 H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted heterocyclic group containing 3-10 ring atoms, substituted or unsubstituted C6-C 20A 5- to 20-membered heteroaryl group, either aryl or substituted or unsubstituted, wherein the heteroaryl group and the heterocycloalkyl group each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur;

[0009] R 2 H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted heterocyclic group containing 3-10 ring atoms, substituted or unsubstituted C6-C 20 A 5- to 20-membered heteroaryl group, either aryl or substituted or unsubstituted, wherein the heteroaryl group and the heterocycloalkyl group each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur;

[0010] R 3 and R 4 Each is independently H, C1-C6 alkyl, or R 3 and R 4 Together with the connected carbon atoms, they form C3-C6 cycloalkyl groups;

[0011] R 5 and R 6 Each of the following is independently H, C1-C6 alkyl, C1-C6 alkoxy, or R 5 and R 6 Together with the bonded carbon atom, they form a carbonyl group;

[0012] n is 1, 2, or 3;

[0013] The substituent is one or more of the following groups: halogen, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, -N(C1-C6 alkyl)2 or cyano.

[0014] In some of these embodiments, R 1 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted heterocyclic groups containing 3-10 ring atoms, substituted or unsubstituted C6-C 20 A 5- to 20-membered heteroaryl group, either aryl or substituted or unsubstituted, wherein the heteroaryl group and the heterocycloalkyl group each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur;

[0015] R 2 H, substituted or unsubstituted C6-C 20 The aryl or substituted or unsubstituted 5 to 20-membered heteroaryl groups, wherein the heteroaryl and heterocycloalkyl groups each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur.

[0016] In some of these embodiments, R 1The heteroaryl group is a substituted or unsubstituted C2-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted heterocyclic group containing 3-4 ring atoms, a substituted or unsubstituted C6-C8 aryl group, or a substituted or unsubstituted 6- to 8-membered heteroaryl group, wherein the heteroaryl group and the heterocyclic alkyl group each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur.

[0017] In some of these embodiments, R 2 The heteroaryl group is a substituted or unsubstituted C6-C8 aryl group or a substituted or unsubstituted 5- to 10-membered heteroaryl group, wherein the heteroaryl group and the heterocycloalkyl group each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur.

[0018] In some of these embodiments, R 3 and R 4 Each is independently H, C1-C2 alkyl, or R 3 and R 4 Together with the connected carbon atoms, they form C3-C4 cycloalkyl groups;

[0019] In some of these embodiments, R 5 and R 6 Each is independently H, C1-C3 alkyl, or C1-C3 alkoxy.

[0020] In some of these embodiments, n is 2.

[0021] A second aspect of this application provides a method for preparing the azaspirocyclic compounds described in the first aspect, comprising the following steps:

[0022]

[0023] (a) Compound m1 reacts with p-toluenesulfonyl chloride under alkaline conditions to give intermediate m2;

[0024] (b) The original compound m3 and 2,4,6-trimethoxybenzaldehyde undergo a reductive amination reaction in the presence of sodium triacetoxyborohydride to give intermediate m4;

[0025] (c) Intermediate m4 was acylated with ethyl chloroformyl under alkaline conditions to obtain intermediate m5;

[0026] (d) Intermediate m5 undergoes a condensation reaction under alkaline conditions, followed by a decarboxylation reaction under heating to obtain intermediate m6;

[0027] (e) Intermediate m6 undergoes a nucleophilic substitution reaction with the halide under basic conditions to give intermediate m7;

[0028] (f) Intermediate m7 is deprotected by trifluoroacetic acid, and then reacts with halogenated product R. 2 -(CR 5R 6 ) n - X1 or intermediate m2 undergoes a nucleophilic substitution reaction under basic conditions to give intermediate m8, where X1 is a halogen;

[0029] (g) Intermediate m8 was deprotected by trifluoroacetic acid and anisole to obtain intermediate m9;

[0030] (h) Intermediate m9 and halogenated product R 1 -X2 is obtained by nucleophilic substitution under basic conditions to obtain the azaspirocyclic compound, where X2 is a halogen.

[0031] A third aspect of this application provides a pharmaceutical composition comprising the azaspirocyclic compound described in the first aspect, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0032] A fourth aspect of this application provides the use of the azaspirocyclic compound described in the first aspect, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition described in the third aspect, in the preparation of a medicament for treating diseases associated with or mediated by Sigma receptor and / or opioid receptor activity.

[0033] Sigma receptors include two subtypes: σ1R (Sigma-1 Receptor) and σ2R (Sigma-2 Receptor). σ1R is associated with pain, neuroprotection, learning and memory, and immunity, while σ2R is associated with tumors. Studies have found that σ1R antagonists have a sensitizing effect on MOR agonists (morphine). This not only enhances the analgesic effect of MOR by inhibiting σ1R, but also reduces the serious adverse reactions of MOR agonists by decreasing their agonistic activity or dosage. The combined use of σ1R antagonists and MOR agonists carries the potential problem of drug interactions, such as affecting the efficacy and metabolism of both. σ1R / MOR dual-target compounds can avoid this problem while maintaining the sensitizing effect of σ1R.

[0034] Based on this, this application provides an azaspirocyclic compound that is a σ1R / MOR dual-target compound with sigma-1 receptor inhibitory activity and / or MOR agonist activity. This allows the sensitization effect of σ1R on MOR to enhance the analgesic effect. While achieving a similar analgesic effect, it reduces the dependence on MOR agonist activity, thereby reducing the adverse reactions of MOR agonists and improving the safety of the drug. Attached Figure Description

[0035] Figure 1The results of the mechanoreparesis assay for compound 20 of this application are shown, where N = 6, ***P < 0.001, ###P < 0.001 (One-way ANOVA);

[0036] Figure 2 The results of mechanical pain sensitivity assays of compound 20 of this application with other drugs were compared, where N=6, ***P<0.001 (One-way ANOVA);

[0037] Figure 3 The results of the thermal pain sensitivity assay for compound 20 of this application are shown, where N = 6. ** P < 0.01 (One-way ANOVA);

[0038] Figure 4 The results of thermal pain sensitivity assays for compound 20 of this application were compared with those of other drugs, where N = 6, **P < 0.01, *P < 0.05 (One-way ANOVA);

[0039] Figure 5 The results of respiratory function tests of compound 20 of this application were compared with those of other drugs, where N = 6, **P < 0.01, *P < 0.05 (Two-way ANOVA). Detailed Implementation

[0040] The following detailed description, in conjunction with specific embodiments, illustrates the azaspirocyclic compounds, their preparation methods, pharmaceutical compositions, and applications of this application. This application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of this application.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0042] As used herein, the terms “and / or,” “or / and,” and “and / or” may include any one of two or more of the related listed items, as well as any and all combinations of the related listed items, including any two related listed items, any more related listed items, or a combination of all the related listed items.

[0043] In this article, "one or more" refers to any one, two or more of the listed items.

[0044] In this application, terms such as "first aspect," "second aspect," "third aspect," and "fourth aspect" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, terms such as "first," "second," "third," and "fourth" serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on quantity.

[0045] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0046] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0047] Unless otherwise specified, the percentage content mentioned in this application refers to mass percentage for solid-liquid mixtures and solid-phase-solid mixtures, and volume percentage for liquid-phase-liquid mixtures.

[0048] Unless otherwise specified, all percentage concentrations mentioned in this application refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of that component.

[0049] Unless otherwise specified, the temperature parameters in this application may be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows for temperature fluctuations within the precision range controlled by the instrument.

[0050] In this application, room temperature generally refers to 4℃~30℃, and preferably 20±5℃.

[0051] In this document, the term "alkyl" refers to a monovalent residue formed by the loss of a hydrogen atom from a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Phrases containing this term, such as "C1-C6 alkyl," refer to alkyl groups containing 1 to 6 carbon atoms, and each occurrence can be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(C H3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH( CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3).

[0052] The term "cycloalkyl" refers to a non-aromatic hydrocarbon containing a ring of carbon atoms, which can be monocycloalkyl, spirocycloalkyl, or bridged cycloalkyl. Phrases containing this term, such as "C3-C8 cycloalkyl," refer to cycloalkyl compounds containing 3 to 8 carbon atoms, and each occurrence can independently be C3-cycloalkyl, C4-cycloalkyl, C5-cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, or C8-cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Additionally, "cycloalkyl" may contain one or more double bonds; representative examples of cycloalkyl compounds containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl.

[0053] "Heterocyclic group" refers to a cycloalkyl group in which at least one carbon atom is replaced by a non-carbon atom. The non-carbon atom can be an N atom, O atom, S atom, etc., and can be a saturated ring or a partially unsaturated ring. Phrases containing this term, such as "heterocyclic group with 3-10 ring atoms," can independently be 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered heteroalkyl groups. Suitable examples include, but are not limited to: dihydropyridyl, tetrahydropyridyl (piperidinyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and dihydroindolyl.

[0054] In this article, the term "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom. It can be a monocyclic aryl, a fused-ring aryl, or a polycyclic aryl; for polycyclic compounds, at least one must be an aromatic ring system. For example, "C6~C 20 "Aryl" refers to an aryl group containing 6 to 20 carbon atoms. Each time it appears, it can independently be C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 ... 10 Aryl, C 11 Aryl, C 12 Aryl, C 13 Aryl, C 14 Aryl, C 15 Aryl, C 16 Aryl, C17 aryl, C18 aryl, C19 aryl, C 20 Aryl groups. Suitable examples include, but are not limited to: benzene, biphenyl, naphthalene, anthracene, phenanthrene, dinaphthalene, triphenylene and their derivatives.

[0055] In this article, the term "heteroaryl" refers to an aryl group in which at least one carbon atom is replaced by a non-carbon atom, which can be an N atom, an O atom, an S atom, etc. For example, "5 to 20-membered heteroaryl" refers to a heteroaryl group containing 5 to 20 ring atoms. Each occurrence can be independently of 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 11-membered heteroaryl, 12-membered heteroaryl, 13-membered heteroaryl, 14-membered heteroaryl, 15-membered heteroaryl, 16-membered heteroaryl, 17-membered heteroaryl, 18-membered heteroaryl, 19-membered heteroaryl, and 20-membered heteroaryl. Suitable examples include, but are not limited to: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazolium, indole, carbazole, pyrrole-imidazolium, pyrrole-pyrrole, thiophene-pyrrole, thiophene-thiophene, furan-pyrrole, furan-furan, thiophene-furan, benzoisoxazole, benzoisothiazolium, pyridine, pyrazine, pyrimidine, triazine, quinoline, isoquinoline, o-diazonine, quinoxaline, phenanthridine, primidine, quinazoline, and quinazolineone.

[0056] The term "alkoxy" refers to a group with the structure -O-alkyl, i.e., an alkyl group as defined above connected to an adjacent group via an oxygen atom. Phrases containing this term, such as "C1-C6 alkoxy," refer to alkyl moieties containing 1 to 6 carbon atoms, and each occurrence can be independently C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, or C6 alkoxy. Suitable examples include, but are not limited to: methoxy (-O-CH3 or -OMe), ethoxy (-O-CH2CH3 or -OEt), and tert-butoxy (-OC(CH3)3 or -OtBu).

[0057] "Halogen" or "halogen group" refers to F, Cl, Br or I.

[0058] "Pharmaceutical acceptable" means those ligands, materials, compositions, and / or dosage forms that are appropriate for administration to patients within the bounds of reasonable medical judgment and that are commensurate with a reasonable benefit / risk ratio.

[0059] "Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. As used herein, the term "pharmaceutically acceptable carrier" includes buffers compatible with drug administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of compatibility with other components in the formulation and harmlessness to the patient. Suitable examples include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch and substituted or unsubstituted β-cyclodextrins; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn... Rice oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0060] "Pharmaceutically acceptable salt" refers to a salt formed by any compound in the indicated structure with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. One class of salts is the salt formed by the compounds of this invention with an acid. Acids suitable for salt formation include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another type of salt is the salt formed by the compounds of the present invention with a base. Suitable bases for forming salts include, but are not limited to: alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0061] Some examples of this application provide an azaspirocyclic compound having the following formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:

[0062]

[0063] in,

[0064] R 1 H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted heterocyclic group containing 3-10 ring atoms, substituted or unsubstituted C6-C 20 A 5- to 20-membered heteroaryl group, either aryl or substituted or unsubstituted, wherein the heteroaryl group and the heterocycloalkyl group each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur;

[0065] R 2 H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted heterocyclic group containing 3-10 ring atoms, substituted or unsubstituted C6-C 20 A 5- to 20-membered heteroaryl group, either aryl or substituted or unsubstituted, wherein the heteroaryl group and the heterocycloalkyl group each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur;

[0066] R 3 and R 4 Each is independently H, C1-C6 alkyl, or R 3 and R 4 Together with the connected carbon atoms, they form C3-C6 cycloalkyl groups;

[0067] R 5 and R 6 Each of the following is independently H, C1-C6 alkyl, C1-C6 alkoxy, or R 5 and R 6 Together with the bonded carbon atom, they form a carbonyl group;

[0068] n is 1, 2, or 3;

[0069] The substituent is one or more of the following groups: halogen, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, -N(C1-C6 alkyl)2 or cyano.

[0070] In some of these examples, R 1 Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted heterocyclic groups containing 3-10 ring atoms, substituted or unsubstituted C6-C 20A 5- to 20-membered heteroaryl group, either aryl or substituted or unsubstituted, wherein the heteroaryl group and the heterocycloalkyl group each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur;

[0071] R 2 H, substituted or unsubstituted C6-C 20 The aryl or substituted or unsubstituted 5 to 20-membered heteroaryl groups, wherein the heteroaryl and heterocycloalkyl groups each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur.

[0072] In some of these examples, R 1 The heteroaryl group can be a substituted or unsubstituted C2-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted heterocyclic group containing 3-4 ring atoms, a substituted or unsubstituted C6-C8 aryl group, or a substituted or unsubstituted 6- to 8-membered heteroaryl group, wherein each heteroaryl group and heterocyclic alkyl group independently contains at least one heteroatom selected from nitrogen, oxygen, and sulfur. This allows for a better σ1R / MOR dual-targeting effect.

[0073] Furthermore, R 1 The substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl group. Furthermore, the substituted substituent is halogen or a halogen-substituted C1-C3 alkyl group.

[0074] Furthermore, R 1 It is a C2-C4 alkyl, C3-C6 cycloalkyl, or a heterocyclic group containing 3-4 ring atoms. Furthermore, the heteroatom in the heterocyclic group is oxygen.

[0075] Without restriction, R 1 It is one of the following groups:

[0076]

[0077] In some of these examples, R 2 The heteroaryl group is a substituted or unsubstituted C6-C8 aryl group or a substituted or unsubstituted 5- to 10-membered heteroaryl group, wherein the heteroaryl group and the heterocycloalkyl group each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur.

[0078] Furthermore, R 2 substituted or unsubstituted phenyl groups Substituted or unsubstituted thiophene, substituted or unsubstituted groups Substituted or unsubstituted pyridinyl group. Furthermore, the substituted substituent is one or more of the following groups: halogen, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl or -N(C1-C3 alkyl)2.

[0079] Without restriction, R 2It is H or one of the following groups:

[0080]

[0081] In some of these examples, R 3 and R 4 Each is independently H, C1-C2 alkyl, or R 3 and R 4 Together with the connected carbon atoms, they form C3-C4 cycloalkyl groups.

[0082] Without restriction, R 3 and R 4 Each of the following is independent: methyl, H, isopropyl, ethyl, R 3 and R 4 Together with the connected carbon atom, they form a C3 cycloalkyl group.

[0083] In some of these examples, R 5 and R 6 Each is independently H, C1-C3 alkyl, or C1-C3 alkoxy.

[0084] Without restriction, R 5 and R 6 Each of the following is independent: H, methyl, methoxy, R 5 and R 6 Together with the attached carbon atom, it forms a carbonyl group.

[0085] In some of these examples, n is 2.

[0086] Furthermore, without limitation, the aforementioned azaspirocyclic compounds have any of the structures shown in formulas (II-1) to (II-3):

[0087]

[0088] Among them, R 5’ R 5” The definition is the same as R 5 R 6’ R 6” The definition is the same as R 6 .

[0089] Without limitation, the azaspirocyclic compound is one of the following compounds:

[0090]

[0091]

[0092]

[0093] Other examples of this application also provide methods for preparing azaspirocyclic compounds as described above, comprising the following steps:

[0094]

[0095] (a) Compound m1 reacts with p-toluenesulfonyl chloride under alkaline conditions to give intermediate m2;

[0096] (b) The original compound m3 and 2,4,6-trimethoxybenzaldehyde undergo a reductive amination reaction in the presence of sodium triacetoxyborohydride to give intermediate m4;

[0097] (c) Intermediate m4 was acylated with ethyl chloroformyl under alkaline conditions to obtain intermediate m5;

[0098] (d) Intermediate m5 undergoes a condensation reaction under alkaline conditions, followed by a decarboxylation reaction under heating to obtain intermediate m6;

[0099] (e) Intermediate m6 undergoes a nucleophilic substitution reaction with the halide under basic conditions to give intermediate m7;

[0100] (f) Intermediate m7 is deprotected by trifluoroacetic acid, and then reacts with halogenated product R. 2 -(CR 5 R 6 ) n - X1 or intermediate m2 undergoes a nucleophilic substitution reaction under basic conditions to give intermediate m8, where X1 is a halogen;

[0101] (g) Intermediate m8 was deprotected by trifluoroacetic acid and anisole to obtain intermediate m9;

[0102] (h) Intermediate m9 and halogenated product R 1 -X2 is obtained by nucleophilic substitution under basic conditions to obtain the azaspirocyclic compound, where X2 is a halogen.

[0103] Without limitation, in step (a), the base providing the alkaline conditions is one or more of triethylamine and diisopropylethylamine.

[0104] Without limitation, in step (c), the base providing the alkaline conditions is one or more of pyridine and 4-dimethylaminopyridine.

[0105] Without limitation, in step (d), the base providing the alkaline conditions is sodium methoxide.

[0106] Without limitation, in steps (e) and / or (f), the base providing the alkaline conditions is one or more of potassium carbonate, sodium hydride, and cesium carbonate.

[0107] Other examples of this application also provide a pharmaceutical composition comprising, as described above, a azeotropic compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.

[0108] Other examples of this application also provide the use of the azaspirocyclic compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, as described above, or pharmaceutical compositions as described above, in the preparation of medicaments for treating diseases associated with or mediated by Sigma receptor and / or opioid receptor activity.

[0109] Furthermore, diseases associated with or mediated by Sigma receptor and / or opioid receptor activity include, but are not limited to, pain (e.g., moderate to severe acute pain), Alzheimer's disease, Huntington's disease, ischemic stroke, tumors, etc.

[0110] Furthermore, the Sigma receptor is the σ1R subtype.

[0111] Furthermore, the drug is a σ1R antagonist and / or a MOR agonist.

[0112] The following are specific examples. Unless otherwise stated, all reagents used in the examples are commercially available products.

[0113] Example 1

[0114]

[0115] (a) Compound m1 (2.65 g, 9.25 mmol) was weighed and dissolved in 28 mL of anhydrous ethanol. 2,4,6-Trimethoxybenzaldehyde (1.82 g, 9.25 mmol) was added, and the mixture was reacted at room temperature for 2 h. Then, sodium triacetoxyborohydride (2.94 g, 13.88 mmol) was slowly added in portions, and the mixture was reacted overnight at room temperature. After the reaction was completed, the mixture was quenched with cold water, extracted twice with ethyl acetate (100 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography (DCM:MeOH = 15:1, v / v) to give 3.75 g of a yellowish-brown oil, which was compound m2, with a yield of 86.8%.

[0116] 1H NMR (400MHz, CDCl3) δ6.10 (s, 2H), 4.10 (q, J = 7.1Hz, 2H), 3.92 (s, 2H), 3.80 (s, 3H), 3.79 (s, 6H), 3.76-3.69 (m,2H),3.02(s,2H),2.67(s,2H),2.02(d,J=13.5Hz,2H),1.41(s,9H),1.23(s,2H),1.19(t,J=7.1Hz,3H). LCMS(ESI)calcd for C 24 H 38 N2O7 m / z[M+H]+:467.28,found:467.1.

[0117] (b) Weigh m2 (3.75 g, 8.04 mmol) and dissolve it in 32 mL of anhydrous DCM. Add pyridine (1.91 g, 24.11 mmol) and 4-dimethylaminopyridine (99 mg, 0.8 mmol) sequentially. Cool the reaction solution to 0 °C. Weigh ethyl chloroformyl (1.33 g, 8.84 mmol) and dissolve it in 8 mL of DCM. Slowly add the ethyl chloroformyl to the above reaction solution and let it react overnight at room temperature. After the reaction is complete, quench with cold water and extract twice with ethyl acetate (100 mL × 2). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product. Column chromatography (petroleum ether:ethyl acetate = 1:1, v / v) yields 3.56 g of a yellow oil, namely compound m3, with a yield of 76.3%.

[0118] (c) Weigh m3 (3.56 g, 6.13 mmol) and dissolve it in 61 mL of anhydrous methanol. Add sodium methoxide (1.66 g, 30.65 mmol) and reflux at 60 °C for 15 h. After the reaction is complete, quench with cold water, adjust the pH to neutral with dilute hydrochloric acid, extract twice with ethyl acetate (100 mL × 2), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product, i.e., compound m4, which is directly added to the next reaction.

[0119] (d) The crude product m4 was dissolved in 120 mL of acetonitrile-water (1:1, volume ratio) mixed solvent and refluxed at 80 °C for 4 h. After the reaction was completed, the mixture was quenched with cold water, extracted twice with ethyl acetate (150 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. Column chromatography (DCM:MeOH = 50:1, volume ratio) yielded 2.2 g of a yellow oil, namely compound m5, with a yield of 77.5%.

[0120] 1H NMR (400MHz, CDCl3) δ6.13(s,2H),4.69(s,2H),3.82(s,3H),3.79(s,6H),3.52-3.44(m,2H),3.33(s, 2H), 3.20 (s, 2H), 2.81 (ddd, J=13.5, 9.5, 3.4Hz, 2H), 1.69 (ddd, J=13.6, 9.2, 4.2Hz, 4H), 1.42 (s, 9H). LCMS(ESI)calcd for C 24 H 34 N2O7 m / z[M+H]+:463.24,found:463.3.

[0121] (e) Weigh m5 (1.3 g, 2.81 mmol) and dissolve it in 14 mL of anhydrous acetone. Add potassium carbonate (1.17 g, 8.43 mmol) and dropwise add iodomethane (1.2 g, 8.43 mmol). Heat to 50 °C and react for 16 h. After the reaction is complete, remove excess iodomethane under reduced pressure. Extract twice with ethyl acetate and water (100 mL × 2). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Column chromatography (DCM:MeOH = 50:1, v / v) yields 1.18 g of a bright yellow solid, namely compound m6, with a yield of 85.5%.

[0122] (f) Weigh m6 (1.5 g, 3.07 mmol), dissolve it in 4.3 mL of DCM, add trifluoroacetic acid (10.5 g, 91.71 mmol), and react at room temperature for 1 h. After the reaction is complete, concentrate under reduced pressure to obtain the crude product TFA salt, i.e., compound m7, which is directly added to the next reaction step.

[0123] (g) The crude product m7 (1.19 mg, 3.04 mmol) was dissolved in 16 mL of acetonitrile, and potassium carbonate (2.11 g, 15.29 mmol) and 3-fluorophenylethyl bromide (1.06 g, 4.86 mmol) were added sequentially. The mixture was heated to 80 °C and reacted for 16 h. After the reaction was completed, the mixture was quenched with cold water, extracted twice with ethyl acetate (30 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography (DCM:MeOH = 50:1, v / v) to give 1.357 g of a pale yellow oil, namely compound 1A, with a yield of 86.86%.

[0124] (h) Weigh 1A (1.357 g, 2.65 mmol) and dissolve it in anisole (20.61 mg, 190.83 mmol). Add 40 mL of trifluoroacetic acid and react at room temperature for 48 h under nitrogen protection. After the reaction is complete, concentrate under reduced pressure to remove excess trifluoroacetic acid. Extract twice with ethyl acetate and water (30 mL × 2). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product. Column chromatography (DCM:MeOH = 10:1, v / v) gives 635 mg of white solid, namely compound 1B, with a yield of 72.16%.

[0125] (i) Compound 1B (15 mg, 0.06 mmol) was weighed and dissolved in 0.4 mL of anhydrous dioxane. Cesium carbonate (20 mg, 0.084 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (21 mg, 0.009 mmol), and 3-bromo-2-trifluoromethylpyridine (13 mg, 0.06 mmol) were added sequentially. After nitrogen purging, tris(dibenzylacetone)dipalladium (2.7 mg, 0.003 mmol) was added, followed by another nitrogen purging. The mixture was then heated to 100 °C and reacted overnight. After the reaction was complete, the mixture was extracted twice with ethyl acetate and water (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography (DCM:MeOH = 50:1, v / v) to give 7 mg of a yellow solid, with a yield of 32.42%.

[0126] 1 H NMR (400MHz, CDCl3) δ8.74(t,J=3.1Hz,1H),7.66(d,J=3.1Hz,2H),7.19(q,J=6.8,6.1Hz,2H),7.03(dt,J=22.6,8.3Hz ,2H),2.86(d,J=10.2Hz,2H),2.67(s,4H),2.21(d,J=7.8Hz,2H),2.09(s,2H),1.99(s,2H),1.44(s,3H),1.41(s,3H). LCMS(ESI)calcd for C 25 H 27 F4N3O2 m / z[M+H]+:478.21,found:478.5.

[0127] Example 2

[0128]

[0129] Compound 2 was prepared using the same method as in Example 1, except that bromobenzene was used instead of 3-bromo-2-trifluoromethylpyridine in step (i) of Example 2.

[0130] 1 H NMR(400MHz, CDCl3)δ7.43(t,J=7.8Hz,2H),7.32-7.27(m,1H),7.26(s,1H),7.24-7.15(m,3H),7.08-6.9 7(m,2H),3.75(s,2H),2.88(s,2H),2.70(s,6H),2.12(dt,J=11.7,5.2Hz,2H),1.77(s,2H),1.43(s,6H). LCMS(ESI)calcd for C 25 H 29 FN2O2 m / z[M+H] + :409.23,found:409.4.

[0131] Example 3

[0132]

[0133] (j) Compound 1B (68 mg, 0.216 mmol) was weighed and dissolved in 1 mL of anhydrous DMF. 60% sodium hydroxide (27 mg, 0.649 mmol) was added, and the mixture was cooled to 0 °C and reacted for 0.5 h. Separately, cyclopropylmethyl bromide (44 mg, 0.324 mmol) was weighed and dissolved in 0.2 mL of DMF, and slowly added dropwise to the above reaction solution. The mixture was allowed to react overnight at room temperature. After the reaction was complete, the mixture was extracted twice with ethyl acetate and water (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (DCM:MeOH = 50:1, v / v) yielded 48 mg of a white solid, compound 3, with a yield of 60.2%.

[0134] 1 H NMR (400MHz, CDCl3) δ7.25-7.16(m,2H),7.09-6.97(m,2H),4.89(p,J=6.8Hz,1H),3.20(s,2H),3.03-2.88(m,4 H), 2.84-2.72 (m, 4H), 1.98 (dt, J = 14.8, 4.0Hz, 2H), 1.85 (d, J = 12.3Hz, 2H), 1.30 (s, 6H), 1.14 (d, J = 6.9Hz, 6H). LCMS(ESI)calcd forC22H31FN2O2 m / z[M+H]+:375.24,found:375.4.

[0135] Example 4

[0136]

[0137] Compound 4 was prepared using the same method as in Example 1, except that 2-bromopyridine was used instead of 3-bromo-2-trifluoromethylpyridine in step (i) of Example 4.

[0138] 1 H NMR (400MHz, CDCl3) δ8.44(d,J=5.0Hz,1H),7.92(d,J=8.3Hz,1H),7.76-7.69(m,1H),7.16(dq,J=23.0,6.6,5. 7Hz,3H),7.08-6.95(m,2H),4.20(s,2H),2.89-2.78(m,2H),2.70-2.54(m,6H),2.08-1.95(m,4H),1.44(s,6H). LCMS(ESI)calcd for C 24 H 28 FN3O2m / z[M+H] + :410.22,found:410.4.

[0139] Example 5

[0140]

[0141] Compound 5 was prepared using the same method as in Example 1, except that 3-bromopyridine was used instead of 3-bromo-2-trifluoromethylpyridine in step (i) of Example 5.

[0142] 1 H NMR (400MHz, CDCl3) δ8.55(d,J=10.6Hz,2H),7.67(s,1H),7.17(d,J=7.8Hz,2H),7.09-6.92(m, 3H),3.77(s,2H),2.81(s,2H),2.63(s,4H),2.55(s,2H),2.11(s,2H),2.01(s,2H),1.44(s,6H). LCMS(ESI)calcd for C 24 H 28 FN3O2 m / z[M+H] + :410.22,found:410.5.

[0143] Example 6

[0144]

[0145] (k) Compound 1B (20 mg, 0.06 mmol) was weighed and dissolved in 0.4 mL of anhydrous toluene. 4-Dimethylaminopyridine (22 mg, 0.18 mmol), copper acetate (2 mg, 0.012 mmol), sodium bis(trimethylsilyl)aminoacetate (11 mg, 0.06 mmol), and cyclopropylboronic acid (10.5 mg, 0.12 mmol) were added sequentially. The mixture was heated to 95 °C overnight under air. After the reaction was complete, the mixture was extracted twice with ethyl acetate and water (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography (DCM:MeOH = 35:1, v / v) yielded 7 mg of a yellow solid, compound 6, with a yield of 31.2%.

[0146] 1 H NMR (400MHz, CDCl3) δ7.23-7.14(m,2H),7.08-6.96(m,2H),3.33(s,2H),2.86-2.80(m,2H),2.78(dt,J=7.3,3.8Hz,1H),2.61 (dd,J=15.3,8.1Hz,5H),1.97(dt,J=11.6,5.2Hz,2H),1.55-1.47(m,2H),1.29(s,6H),0.91-0.87(m,2H),0.68-0.61(m,2H). LCMS(ESI)calcd for C22H29FN2O2 m / z[M+H]+:373.23,found:373.4.

[0147] Example 7

[0148]

[0149] Compound 7 was prepared using the same method as in Example 3, except that iodomethane was used instead of 2-iodopropane in step (j) of Example 7.

[0150] 1 H NMR (400MHz, CDCl3) δ7.24-7.16(m,2H),7.09-6.98(m,2H),3.36(s,2H),3.09(s,3H),2.9 5-2.88(m,2H),2.72(q,J=5.8Hz,6H),2.04-1.99(m,2H),1.77-1.66(m,2H),1.32(s,6H). LCMS(ESI)calcd for C 20 H 27 FN2O2 m / z[M+H] + :347.21,found:347.3.

[0151] Example 8

[0152]

[0153] Compound 8 was prepared using the same method as in Example 3, except that iodoethane was used instead of 2-iodopropane in step (j) of Example 8.

[0154] 1 H NMR (400MHz, CDCl3) δ7.20(t,J=6.6Hz,2H),7.04(dt,J=23.1,8.2Hz,2H),3.51(q,J=7.1Hz,2H),3.33(s,2H ), 2.94 (s, 2H), 2.81-2.68 (m, 6H), 2.00 (d, J = 12.9Hz, 2H), 1.76 (s, 2H), 1.31 (s, 6H), 1.16 (t, J = 7.2Hz, 3H). LCMS(ESI)calcd for C 21 H 29 FN2O2 m / z[M+H] + :361.23,found:361.4.

[0155] Example 9

[0156]

[0157] Except that β-bromophenylethane was used instead of 2-fluorophenylethyl bromide in step (g) of Example 9, compound 9 was prepared using the same method as in Example 2.

[0158] 1 H NMR (400MHz, CDCl3) δ7.43(t,J=7.8Hz,2H),7.33-7.27(m,3H),7.22(ddd,J=10.8,7.8,6.4Hz,5H),3.76(s,2H) ,2.92(s,2H),2.79(s,4H),2.14(dt,J=14.0,4.6Hz,2H),2.04-1.78(m,2H),1.44(s,6H),0.88(t,J=6.0Hz,2H). LCMS(ESI)calcd forC 25 H 30 N₂O₂ m / z[M+H] + :391.24,found:391.4.

[0159] Example 10

[0160]

[0161] (l) 10A (250 mg, 1.66 mmol) was weighed and dissolved in 2.5 mL of DCM. Triethylamine (505 mg, 4.99 mmol), 4-dimethylaminopyridine (20 mg, 0.17 mmol), and p-toluenesulfonyl chloride (381 mg, 2 mmol) were added sequentially under ice bath conditions, and the reaction was carried out at room temperature for 7 h. After the reaction was completed, the mixture was quenched with cold water, extracted twice with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography (eluted with DCM) to give 460 mg of a pale yellow oil, namely compound 10B, with a yield of 90.8%.

[0162] (g) The preparation conditions for this step are the same as those for compound 1.

[0163] (m) Weigh out m7 (91.5 mg, 0.218 mmol) and dissolve it in 1.1 mL of acetonitrile. Add potassium carbonate (162 mg, 1.09 mmol) and 10B (89 mg, 0.283 mmol) sequentially. Heat to 80 °C and react for 16 h. After the reaction is complete, quench with cold water and extract twice with ethyl acetate (30 mL × 2). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain crude product. Column chromatography (DCM:MeOH = 50:1, v / v) yields 82 mg of a pale yellow oil, with a yield of 81.8%.

[0164] (i) The preparation conditions for this step are the same as those for compound 1.

[0165] 1 H NMR (400MHz, CDCl3) δ7.43(t,J=7.8Hz,2H),7.30(t,J=7.3Hz,1H),7.25(d,J=7.5Hz,2H),7.00-6.81(m,3H),3.73 (s, 2H), 2.80 (t, J = 7.8Hz, 2H), 2.62 (q, J = 8.7, 7.5Hz, 6H), 2.16-2.06 (m, 2H), 1.68 (d, J = 13.2Hz, 2H), 1.43 (s, 6H). LCMS(ESI)calcd forC 25 H 28 F2N2O2 m / z[M+H] + :427.22,found:427.4.

[0166] Example 11

[0167]

[0168] Compound 11 was prepared using the same method as in Example 10, except that 3-fluorophenylethanol was used instead of 2-(2,5-difluorophenyl)ethane-1-ol in step (l) of Example 11.

[0169] 1 H NMR (400MHz, CDCl3) δ7.43(t,J=7.8Hz,2H),7.30(td,J=7.2,1.3Hz,1H),7.26-7.18(m,3H),6.97-6.93(m,1H),6.92-6.84(m,2H),3.73(s ,2H),2.78(dd,J=9.8,6.1Hz,2H),2.68-2.49(m,6H),2.12(ddd,J=13.6,7.2,3.7Hz,2H),1.67(ddd,J=12.8,7.9,3.7Hz,2H),1.43(s,6H). LCMS(ESI)calcd for C 25 H 29 FN2O2 m / z[M+H] + :409.23,found:409.6.

[0170] Example 12

[0171]

[0172] Compound 12 was prepared using the same method as in Example 10, except that 4-methoxyphenylethanol was used instead of 2-(2,5-difluorophenyl)ethane-1-ol in step (l) of Example 12.

[0173] 1 H NMR (400MHz, CDCl3) δ7.45 (t, J = 7.7Hz, 2H), 7.39-7.29 (m, 2H), 7.27-7.24 (m, 1H), 7.15-7.09 (m, 2H), 6.87-6.82 (m, 2H), 3.8 0(s,3H),3.76(s,2H),2.79(t,J=8.1Hz,2H),2.67(s,6H),2.14(dt,J=10.8,4.9Hz,2H),1.76(s,2H),1.45(d,J=2.2Hz,6H). LCMS(ESI)calcd for C 26 H 32 N₂O₃ m / z[M+H] + :421.25,found:421.5.

[0174] Example 13

[0175]

[0176] Compound 13 was prepared using the same method as in Example 10, except that 4-chlorophenylethanol was used instead of 2-(2,5-difluorophenyl)ethane-1-ol in step (l) of Example 13.

[0177] 1 H NMR (400MHz, CDCl3) δ7.43(t,J=7.8Hz,2H),7.30(td,J=7.2,1.3Hz,1H),7.26-7.21(m,4H),7.13-7.08(m,2H),3.73(s,2H),2.78(dd,J =9.9, 6.0Hz, 2H), 2.65 (dq, J = 11.2, 6.9, 5.4Hz, 6H), 2.12 (dt, J = 13.8, 5.0Hz, 2H), 1.73 (dt, J = 13.2, 6.1Hz, 2H), 1.43 (d, J = 1.9Hz, 6H). LCMS(ESI)calcd for C 25 H 29 ClN2O2m / z[M+H] + :425.20,found:425.6.

[0178] Example 14

[0179]

[0180] Compound 14 was prepared using the same method as in Example 10, except that 3-trifluoromethylphenylethanol was used instead of 2-(2,5-difluorophenyl)ethane-1-ol in step (l) of Example 14.

[0181] 1 H NMR (400MHz, CDCl3) δ7.50-7.33(m,7H),7.33-7.27(m,1H),7.24(s,1H),3.74(s,2H),2.85(dd,J=9. 7,6.2Hz,2H),2.72-2.50(m,6H),2.12(ddd,J=13.9,6.9,3.7Hz,2H),1.76-1.63(m,2H),1.43(s,6H). LCMS(ESI)calcd for C 26 H 29 F3N2O2 m / z[M+H] + :459.23,found:459.5.

[0182] Example 15

[0183]

[0184] Except that benzyl bromide was used instead of 2-fluorophenylethyl bromide in step (g) of Example 15, compound 15 was prepared using the same method as in Example 2.

[0185] 1 H NMR (400MHz, CDCl3) δ7.42(t,J=7.8Hz,2H),7.30(d,J=4.4Hz,5H),7.26-7.21(m,3H),3.74( s,2H),3.51(s,2H),2.57(s,2H),2.47(s,2H),2.14-2.04(m,2H),1.66(s,2H),1.42(s,6H). LCMS(ESI)calcd for C 24 H 28 N₂O₂ m / z[M+H] + :377.22,found:377.3.

[0186] Example 16

[0187]

[0188] Compound 16 was prepared using the same method as in Example 2, except that 1-bromo-3-phenylpropane was used instead of 2-fluorophenylethyl bromide in step (g) of Example 16.

[0189] 1 H NMR (400MHz, CDCl3) δ7.41 (t, J = 7.7Hz, 2H), 7.31-7.26 (m, 3H), 7.23-7.19 (m, 3H), 7.18-7.14 (m, 2H), 3.75 (s,2H),3.04(s,2H),2.89(d,J=13.5Hz,2H),2.69(dt,J=14.9,7.7Hz,4H),2.16-1.99(m,6H),1.41(s,6H). LCMS(ESI)calcd for C 26 H 32 N₂O₂ m / z[M+H] + :405.25,found:405.5.

[0190] Example 17

[0191]

[0192] Except that in step (g) of Example 17, 2-fluorophenylethyl bromide was replaced with 5-(2-bromoethyl)-2,3-dihydrobenzofuran, compound 17 was prepared using the same method as in Example 2.

[0193] 1 H NMR (400MHz, CDCl3) δ7.43 (t, J=7.8Hz, 2H), 7.30 (td, J=7.2, 1.2Hz, 1H), 7.26-7.22 (m, 2H), 7.02 (s, 1H), 6.90 (dd, J=8.1, 1.9Hz, 1H), 6.69 (d, J= 8.0Hz,1H),4.54(t,J=8.7Hz,2H),3.74(s,2H),3.17(t,J=8.7Hz,2H),2. 85-2.68(m,8H),2.13(d,J=14.1Hz,2H),1.88-1.77(m,2H),1.43(s,6H). LCMS(ESI)calcd for C 27 H 32 N₂O₃ m / z[M+H] + :433.25,found:433.3.

[0194] Example 18

[0195]

[0196] Compound 18 was prepared using the same method as in Example 10, except that 2-thiopheneethanol was used instead of 2-(2,5-difluorophenyl)ethane-1-ol in step (l) of Example 18.

[0197] 1 H NMR (400MHz, CDCl3) δ7.43 (t, J = 7.8Hz, 2H), 7.33-7.26 (m, 2H), 7.26-7.23 (m, 1H), 7.1 2(dd,J=5.1,1.2Hz,1H),6.91(dd,J=5.1,3.4Hz,1H),6.80(dd,J=3.4,1.1Hz,1H),3.7 4(s,2H),3.00(t,J=7.6Hz,2H),2.70-2.60(m,4H),2.53(ddd,J=11.7,7.5,3.7Hz,2H) ,2.12(ddd,J=13.6,7.4,3.7Hz,2H), 1.67(ddd,J=13.0,7.9,3.7Hz,2H), 1.43(s,6H). LCMS(ESI)calcd for C 23 H 28 N₂O₂S m / z[M+H]+ :397.19,found:397.4.

[0198] Example 19

[0199]

[0200] Compound 19 was prepared using the same method as in Example 2, except that iodopropane was used instead of 2-fluorophenylethyl bromide in step (g) of Example 19.

[0201] 1 H NMR (400MHz, CDCl3) δ7.41 (t, J = 7.8Hz, 2H), 7.31-7.26 (m, 1H), 7.25-7.21 (m ,2H),3.71(s,2H),2.55(ddd,J=11.8,8.1,3.7Hz,2H),2.49-2.40(m,2H),2. 32-2.27(m,2H),2.08(ddd,J=13.7,7.4,3.7Hz,2H),1.65(ddd,J=12.8,7.9, 3.8Hz, 2H), 1.47 (dt, J = 15.0, 7.5Hz, 2H), 1.41 (s, 6H), 0.87 (t, J = 7.4Hz, 3H). LCMS(ESI)calcd for C 20 H 28 N₂O₂ m / z[M+H] + :329.22,found:329.4.

[0202] Example 20

[0203]

[0204] Compound 20 was prepared using the same method as in Example 3, except that β-bromophenylethane was used instead of 2-fluorophenylethyl bromide in step (g) of Example 20 and bromomethylcyclopropane was used instead of 2-iodopropane in step (j).

[0205] 1H NMR (400MHz, CDCl3) δ7.32-7.26(m,2H),7.25-7.17(m,3H),3.42(s,2H),3.36(d ,J=7.1Hz,2H),2.84(dd,J=10.3,6.0Hz,2H),2.66(td,J=8.7,7.4,4.0Hz,4H),2 .02(dt,J=14.5,4.8Hz,2H),1.67(t,J=7.5Hz,2H),1.32(s,6H),1.24(s,2H),0. 99(ddt,J=10.2,7.4,3.7Hz,1H),0.58-0.49(m,2H),0.29(dt,J=6.3,4.6Hz,2H). LCMS(ESI)calcdfor C 23 H 32 N₂O₂ m / z[M+H] + :369.25,found:369.6.

[0206] Example 21

[0207]

[0208] Compound 21 was prepared using the same method as in Example 20, except that bromomethylcyclopentane was used instead of 2-iodopropane in step (j) of Example 21.

[0209] 1 H NMR (400MHz, CDCl3) δ7.31-7.26(m,2H),7.22-7.16(m,3H),3.43(d,J=7.8 Hz,2H),3.32(s,2H),2.79(dd,J=10.2,6.0Hz,2H),2.65-2.61(m,2H),2.58 (dd,J=8.3,4.4Hz,4H),2.20(p,J=7.4Hz,1H),2.00(dt,J=13.9,5.2Hz,2H) ,1.74-1.62(m,4H),1.60-1.49(m,4H),1.31(s,6H),1.25(d,J=6.1Hz,2H). LCMS(ESI)calcd for C 25 H 36 N₂O₂ m / z[M+H] + :397.29,found:397.3.

[0210] Example 22

[0211]

[0212] Compound 22 was prepared using the same method as in Example 20, except that benzyl bromide was used instead of 2-iodopropane in step (j) of Example 22.

[0213] 1 H NMR (400MHz, CDCl3) δ7.37-7.27(m,6H),7.26-7.13(m,4H),4.66(s,2H),3.24(s,2H),2.72(dd,J=10.3,6 .1Hz,2H),2.59-2.39(m,4H),2.23(q,J=7.9,7.4Hz,2H),1.88(ddd,J=11.6,8.1,3.6Hz,4H),1.37(s,6H). LCMS(ESI)calcd for C 26 H 32 N₂O₂ m / z[M+H] + :405.25,found:405.5.

[0214] Example 23

[0215]

[0216] Compound 23 was prepared using the same method as in Example 3, except that bromomethylcyclopentane was used instead of 2-iodopropane in step (j) of Example 23.

[0217] 1 H NMR (400MHz, CDCl3) δ7.25-7.20(m,1H),6.97(d,J=7.6Hz,1H),6.91(dd,J=10.6,3.8Hz,2H),3.44(d,J=7.8Hz,2H),3.34(s,2H),2.88(s,2H),2.7 1(s,6H),2.20(dt,J=15.7,7.8Hz,2H),2.03-1.97(m,2H),1.54(d,J=4.5 Hz, 6H), 1.42 (d, J = 2.7Hz, 1H), 1.32 (s, 6H), 0.87 (dd, J = 13.2, 6.2Hz, 4H). LCMS(ESI)calcd for C 25 H 35 FN2O2 m / z[M+H] + :415.28,found:415.5.

[0218] Example 24

[0219]

[0220] Compound 24 was prepared using the same method as in Example 3, except that bromomethylcyclobutane was used instead of 2-iodopropane in step (j) of Example 24.

[0221] 1 H NMR (400MHz, CDCl3) δ7.25-7.19 (m, 1H), 6.95 (dt, J=7.6, 1.3Hz, 1H), 6.88 (ddd, J=8.1, 7.2,1.1Hz,2H),3.52(d,J=7.6Hz,2H),3.27(s,2H),2.77(dd,J=9.9,6.1Hz,2H),2.63- 2.59(m,2H),2.57(d,J=1.9Hz,1H),2.54(p,J=3.6Hz,4H),2.06-1.93(m,4H),1.89(dt, J=8.0,5.9Hz,2H),1.82-1.73(m,2H),1.50(ddd,J=13.6,9.8,5.4Hz,2H),1.29(s,6H). LCMS(ESI)calcd for C 24 H 33 FN2O2 m / z[M+H] + :401.26,found:401.4.

[0222] Example 25

[0223]

[0224] Compound 25 was prepared using the same method as in Example 3, except that bromomethylcyclopropane was used instead of 2-(2,5-difluorophenyl)ethane-1-ol in step (j) of Example 25.

[0225] 1H NMR (400MHz, CDCl3) δ7.22 (tdd, J=7.5, 6.1, 1.6Hz, 1H), 6.95 (dt, J=7.6, 1.3Hz, 1H), 6.88 (dd d,J=8.2,7.2,1.1Hz,2H),3.41(s,2H),3.35(d,J=7.1Hz,2H),2.78(dd,J=10.0,6.0Hz,2H),2. 64-2.59(m,2H),2.57(t,J=5.9Hz,4H),2.01(dt,J=13.9,5.2Hz,2H),1.57(dt,J=13.1,6.1Hz, 2H), 1.31 (s, 6H), 0.99 (tt, J = 7.6, 4.7Hz, 1H), 0.57-0.51 (m, 2H), 0.29 (dt, J = 6.0, 4.6Hz, 2H). LCMS(ESI)calcd for C 23 H 31 FN2O2 m / z[M+H] + :387.24,found:387.4.

[0226] Example 26

[0227]

[0228] Compound 26 was prepared using the same method as in Example 1, except that 4-trifluoromethylbromobenzene was used instead of 3-bromo-2-trifluoromethylpyridine in step (i) of Example 26.

[0229] 1 H NMR (400MHz, CDCl3) δ7.69(d,J=8.4Hz,2H),7.42(d,J=8.4Hz,2H),7.25-7.18(m,1H),6.95(d,J=7.6Hz,1H),6. 92-6.86(m,2H),3.77(s,2H),2.81(s,2H),2.66(s,6H),2.16-2.07(m,2H),2.01(d,J=6.3Hz,2H),1.44(s,6H). LCMS(ESI)calcd for C 26 H 28 F4N2O2m / z[M+H] + :477.22,found:477.4.

[0230] Example 27

[0231]

[0232] Compound 27 was prepared using the same method as in Example 1, except that 2-trifluoromethylbromobenzene was used instead of 3-bromo-2-trifluoromethylpyridine in step (i) of Example 27.

[0233] 1 H NMR (400MHz, CDCl3) δ7.67(d,J=7.7Hz,1H),7.59(t,J=7.7Hz,1H),7.47(t,J=7. 7Hz,1H),7.22(dd,J=16.5,8.0Hz,2H),7.00-6.83(m,2H),6.82-6.49(m,1H),3.8 3-3.51(m,2H),2.87-2.77(m,2H),2.66(d,J=8.3Hz,2H),2.22(t,J=7.7Hz,1H),2 .13(s,2H),2.00(d,J=6.3Hz,2H),1.43(d,J=14.3Hz,4H),1.25(d,J=4.1Hz,6H). LCMS(ESI)calcd for C 26 H 28 F3N2O2 m / z[M+H] + :458.53,found:459.5.

[0234] Example 28

[0235]

[0236] Compound 28 was prepared using the same method as in Example 1, except that 3-chlorobromobenzene was used instead of 3-bromo-2-trifluoromethylpyridine in step (i) of Example 28.

[0237] 1 H NMR (400MHz, CDCl3) δ7.36(td,J=8.3,2.1Hz,1H),7.29(t,J=2.0Hz,2H),7.22(s,1H),7.16(d,J=7.9Hz,1H),6.96(d,J=7.7Hz,1H),6. 93-6.86(m,2H),3.72(d,J=2.1Hz,2H),2.82(d,J=8.4Hz,2H),2.68(s,6H),2.11(d,J=13.6Hz,2H),2.00(d,J=5.9Hz,2H),1.42(s,6H). LCMS(ESI)calcd for C 25 H 28 ClFN2O2 m / z[M+H] + :443.19,found:443.4.

[0238] Example 29

[0239]

[0240] (l) The preparation conditions for this step are the same as those for compound 10.

[0241] (g) The preparation conditions for this step are the same as those for compound 10.

[0242] (m) The preparation conditions for this step are the same as those for compound 10.

[0243] (j) The preparation conditions for this step are the same as those for compound 3.

[0244] 1 H NMR (400MHz, CDCl3) δ7.28 (d, J = 7.6Hz, 1H), 7.25 (s, 1H), 7.21-7.13 (m, 3H), 3.41(s,2H),3.36(d,J=7.1Hz,2H),2.77-2.64(m,4H),2.42(dd,J=12.9,9.7H z,1H),2.00(q,J=5.3Hz,4H),1.62(s,2H),1.32(s,6H),0.97(d,J=6.6Hz,3H) ,0.86(q,J=10.4,8.3Hz,1H),0.59-0.51(m,2H),0.30(dd,J=7.1,3.4Hz,2H). .LCMS(ESI)calcd forC 24 H 34 N₂O₂ m / z[M+H] + :383.27,found:383.3.

[0245] Example 30

[0246]

[0247] Compound 30 was prepared using the same method as in Example 29, except that 4-methoxyphenylethanol was used instead of 1-phenylpropane-2-ol in step (l) of Example 30.

[0248] 1H NMR (400MHz, CDCl3) δ7.13-7.07(m,2H),6.85-6.79(m,2H),3.78(s,3H),3.41(s,2H),3.36(d,J=7.1Hz,2H),2.74(dd,J=10.3,6.0Hz,2H),2.62 -2.54(m,6H),2.02(dt,J=13.8,5.1Hz,2H),1.59(dt,J=12.9,6.0Hz,2H ),1.32(s,6H),1.05-0.95(m,1H),0.57-0.51(m,2H),0.33-0.27(m,2H). LCMS(ESI)calcd for C 24 H 34 N₂O₃ m / z[M+H] + :399.26,found:399.3.

[0249] Example 31

[0250]

[0251] Compound 31 was prepared using the same method as in Example 29, except that 4-chlorophenylethanol was used instead of 1-phenylpropane-2-ol in step (l) of Example 31.

[0252] 1 H NMR (400MHz, CDCl3) δ7.25-7.21(m,2H),7.13-7.09(m,2H),3.41(s,2H),3.35(d,J=7.1Hz,2H),2.75(dd,J=9.9,6.0Hz,2H),2.57(q,J=6.8,5.2Hz ,6H),2.01(dt,J=14.0,5.1Hz,2H),1.56(dt,J=13.0,6.0Hz,2H),1.31(s ,6H),0.99(tt,J=7.8,4.9Hz,1H),0.57-0.51(m,2H),0.32-0.26(m,2H). LCMS(ESI)calcd for C 23 H 31 ClN2O2 m / z[M+H] + :403.22,found:403.3.

[0253] Example 32

[0254]

[0255] Compound 32 was prepared using the same method as in Example 29, except that 3-chlorophenylethanol was used instead of 1-phenylpropane-2-ol in step (l) of Example 32.

[0256] 1 H NMR (400MHz, CDCl3) δ7.23-7.15(m,3H),7.09-7.04(m,1H),3.41(s,2H),3.36(d,J=7.1Hz,2H),2.77(dd,J=10.0,6.1Hz,2H),2.59(dt,J=16.6,5.4 Hz,6H),2.02(dt,J=11.6,5.1Hz,2H),1.57(dt,J=13.0,6.1Hz,2H),1.32( s, 6H), 1.04-0.95 (m, 1H), 0.58-0.51 (m, 2H), 0.30 (dt, J = 6.1, 4.6Hz, 2H). LCMS(ESI)calcd for C 23 H 31 ClN2O2 m / z[M+H] + :403.22,found:403.3.

[0257] Example 33

[0258]

[0259] (e) The preparation conditions for this step are the same as those for compound 1.

[0260] (f) The preparation conditions for this step are the same as those for compound 1.

[0261] (g) The preparation conditions for this step are the same as those for compound 1.

[0262] (h) The preparation conditions for this step are the same as those for compound 1.

[0263] (j) The preparation conditions for this step are the same as those for compound 3.

[0264] 1H NMR (400MHz, CDCl3) δ7.31-7.25(m,2H),7.19(ddt,J=7.3,3.4,2.0Hz,3H),4.99(s,1H),4.34( hept,J=6.1Hz,1H),3.38(s,2H),3.27(d,J=7.0Hz,2H),2.83(tt,J=11.1,4.5Hz,4H),2.65-2.5 6(m,2H),2.26(td,J=11.8,2.8Hz,2H),2.08(ddd,J=13.8,11.3,4.2Hz,2H),1.56(d,J=14.0Hz ,2H),1.26(d,J=6.0Hz,6H),1.00-0.90(m,1H),0.55-0.46(m,2H),0.25(dt,J=6.1,4.5Hz,2H). LCMS(ESI)calcd for C 24 H 34 N₂O₂ m / z[M+H] + :383.27,found:383.5.

[0265] Example 34

[0266]

[0267] Compound 34 was prepared using the same method as in Example 33, except that iodoethane was used instead of iodomethane in step (e) of Example 34.

[0268] 1 H NMR (400MHz, CDCl3) δ7.32-7.26(m,2H),7.20(t,J=2.0Hz,2H),7.19-7.17(m,1H),3.43(s,2H),3.39(d,J= 7.1Hz,2H),2.83-2.76(m,2H),2.69(ddd,J=11.4,7.4,3.7Hz,2H),2.65-2.59(m,2H),2.48(ddd,J=11.8,8 .1,3.5Hz,2H),2.03(ddd,J=12.4,8.0,3.7Hz,2H),1.90-1.74(m,4H),1.55(ddd,J=13.7,7.4,3.5Hz,2H), 1.00(ddd,J=12.6,6.1,3.8Hz,1H),0.77(t,J=7.4Hz,6H),0.56-0.50(m,2H),0.30(dt,J=6.4,4.6Hz,2H). LCMS(ESI)calcd for C 26 H 36N₂O₂ m / z[M+H] + :397.29,found:397.4.

[0269] Example 35

[0270]

[0271] Compound 35 was prepared using the same method as in Example 33, except that iodoethane was used instead of iodomethane in step (e) of Example 35.

[0272] 1 H NMR (400MHz, CDCl3) δ7.32-7.26(m,2H),7.19(dq,J=7.4,2.3Hz,3H),5.01(s,1H),3.83(q,J=7.0Hz ,2H),3.39(s,2H),3.28(d,J=7.0Hz,2H),2.84(tt,J=11.3,4.5Hz,4H),2.67-2.55(m,2H),2.25(dd, J=11.6,2.7Hz,2H),2.11(ddd,J=15.3,11.3,4.1Hz,2H),1.63-1.54(m,2H),1.34(t,J=7.0Hz,3H), 0.95(ddt,J=10.2,7.4,3.7Hz,1H),0.53-0.47(m,2H),0.25(dt,J=6.3,4.5Hz,2H).LCMS(ESI)calcd for C 23 H 32 N₂O₂m / z[M+H] + :369.25,found:369.4.

[0273] Example 36

[0274]

[0275] Compound 36 was prepared using the same method as in Example 33, except that 1,2-dibromoethane was used instead of iodomethane in step (e) of Example 36.

[0276] 1H NMR (400MHz, CDCl3) δ7.28(s,2H),7.19(d,J=7.8Hz,3H),3.47(s,2H),3.36(d,J=7.0Hz,2H),2.82-2.76(m,4H),2.64-2.58(m,4H),2 .54(d,J=9.6Hz,2H),1.68-1.61(m,4H),1.55-1.51(m,2H),0.88(t,J=6.6Hz,1H),0.55(dd,J=8.2,1.6Hz,2H),0.29(d,J=5.2Hz,2H). LCMS(ESI)calcd for C 23 H 30 N₂O₂m / z[M+H] + :367.24,found:367.4.

[0277] Example 37

[0278]

[0279] Compound 37 was prepared using the same method as in Example 20, except that 2,3-difluorophenylethyl bromide was used instead of 2-fluorophenylethyl bromide in step (g) of Example 37.

[0280] 1 H NMR(400MHz,Chloroform-d)δ7.14-6.96(m,2H),6.95-6.84(m,1H),3.42(s,2H),3.36(d,J=7.1Hz,2H),2.82(t,J=8.0Hz,2H),2.69(s,2H), 2.66(s,4H),2.02(dt,J=14.0,4.7Hz,2H),1.65(d,J=16.8Hz,2H),1.32(s,6H),0.87(t,J=6.5Hz,1H),0.60-0.47(m,2H),0.35-0.23(m,2H). LCMS(ESI)calcd for C 23 H 30 F2N2O2 m / z[M+H] + :405.44,found:404.5.

[0281] Example 38

[0282]

[0283] Compound 38 was prepared using the same method as in Example 20, except that 2-trifluoromethylphenylethyl bromide was used instead of 2-fluorophenylethyl bromide in step (g) of Example 38.

[0284] 1 H NMR(400MHz,Chloroform-d)δ7.61(d,J=7.9Hz,1H),7.46(t,J=7.5Hz,1H),7.36-7. 27(m,2H),3.42(s,2H),3.36(d,J=7.1Hz,2H),2.97(dd,J=10.3,6.2Hz,2H),2.71-2 .54(m,6H),2.02(dt,J=13.9,5.2Hz,2H),1.59(dt,J=13.0,6.1Hz,2H),1.32(s,6H) ,1.00(ddt,J=9.6,7.6,3.8Hz,1H),0.59-0.50(m,2H),0.29(dt,J=6.1,4.6Hz,2H). LCMS(ESI)calcd for C 24 H 31 F3N2O2 m / z[M+H] + :437.46,found:436.5.

[0285] Example 39

[0286]

[0287] Compound 39 was prepared using the same method as in Example 20, except that 4-trifluoromethylphenylethyl bromide was used instead of 2-fluorophenylethyl bromide in step (g) of Example 39.

[0288] 1 H NMR(400MHz,Chloroform-d)δ7.53(d,J=8.0Hz,2H),7.30(d,J=7.9Hz,2H),3.42(s,2H),3.36(d,J= 7.1Hz,2H),2.91-2.78(m,2H),2.71-2.52(m,6H),2.02(dt,J=13.9,5.1Hz,2H),1.32(s,6H),1.02-

[0289] 0.92(m,1H),0.60-0.50(m,2H),0.29(dt,J=6.2,4.6Hz,2H). LCMS(ESI)calcdfor C 24 H 31 F3N2O2 m / z[M+H] + :437.43,found:436.5.

[0290] Example 40

[0291]

[0292] Compound 40 was prepared using the same method as in Example 20, except that 2,3-fluorophenylethyl bromide was used instead of 2-fluorophenylethyl bromide in step (g) of Example 40.

[0293] 1 H NMR(400MHz,Chloroform-d)δ6.70(h,J=4.3Hz,2H),6.63(tt,J=9.1,2.4Hz,1H ),3.40(s,2H),3.35(d,J=7.1Hz,2H),2.76(dd,J=9.6,6.1Hz,2H),2.64-2.48( m,6H),2.00(dt,J=13.8,5.1Hz,2H),1.56(dt,J=13.2,6.1Hz,2H),1.31(s,6H) ,0.98(ddt,J=15.0,12.3,6.2Hz,1H),0.59-0.45(m,2H),0.29(t,J=5.0Hz,2H). LCMS(ESI)calcd forC 23 H 30 F2N2O2 m / z[M+H] + :405.47,found:404.5.

[0294] Example 41

[0295]

[0296] Compound 41 was prepared using the same method as in Example 29, except that thiophene-3-ethanol was used instead of 1-phenylpropane-2-ol in step (l) of Example 41.

[0297] 1H NMR(400MHz,Chloroform-d)δ7.25-7.19(m,1H),6.99(dd,J=2.8,1.3Hz,1H),6.95(dd, J=4.9,1.3Hz,1H),3.55(t,J=7.1Hz,2H),3.31(s,2H),2.84(dd,J=10.0,5.9Hz,2H),2. 66(dd,J=9.6,6.3Hz,2H),2.61-2.55(m,4H),2.34(q,J=7.0Hz,2H),2.00(q,J=4.1,3.0 Hz, 2H), 1.56 (dt, J = 13.0, 5.9 Hz, 2H), 1.32 (s, 2H), 1.30 (s, 6H), 0.87 (t, J = 6.8 Hz, 1H). LCMS(ESI)calcd for C 21 H 30 N₂O₂S m / z[M+H] + :375.31,found:374.5.

[0298] Example 42

[0299]

[0300] Compound 42 was prepared using the same method as in Example 29, except that 4-methyl-5-thiazolylethanol was used instead of 1-phenylpropane-2-ol in step (l) of Example 42.

[0301] 1 H NMR(400MHz,Chloroform-d)δ8.55(s,1H),3.56(t,J=7.1Hz,1H),3.42(s,1H),3.36(d,J=7.1Hz,1H),3.32(s,1H),2.92-2.87(m,2H),2 .61-2.54(m,6H),2.38(s,3H),2.00(d,J=6.3Hz,2H),1.59-1.48(m,2H),1.32(s,2H),1.30(s,6H),1.24(s,2H),0.87(t,J=6.7Hz,1H). LCMS(ESI)calcd for C21H31N3O2S m / z[M+H] + :390.37,found:389.6.

[0302] Example 43

[0303]

[0304] Compound 43 was prepared using the same method as in Example 20, except that (2-bromo-1-methoxyethyl)benzene was used instead of 2-fluorophenylethylbromide in step (g) of Example 43.

[0305] 1 H NMR (400MHz, CDCl3) δ7.31(s,1H),7.29(s,1H),7.24(s,1H),7.23(s,1H),4.33(dd,J=9.0,3.2Hz,1H),3.37(s,2H),3.31(d,J=7.1Hz,3H),3.18(s ,3H),2.86-2.53(m,6H),2.00-1.93(m,2H),1.60-1.53(m,2H),1.27(s,6 H), 0.95 (td, J = 7.7, 4.0Hz, 1H), 0.52-0.49 (m, 2H), 0.25 (d, J = 5.1Hz, 2H). LCMS(ESI)calcd for C 21 H 31 N3O2S m / z[M+H]+:399.41,found:398.55.

[0306] Example 44

[0307]

[0308] (l) The preparation conditions for this step are the same as those for compound 10.

[0309] (g) The preparation conditions for this step are the same as those for compound 29.

[0310] (m) The preparation conditions for this step are the same as those for compound 29.

[0311] (i) The preparation conditions for this step are the same as those for compound 29.

[0312] (n) Weigh 44E (45 mg, 0.11 mmol) and dissolve it in 2.0 mL MeOH / H2O (1:1). Add iron powder (45 mg, 0.81 mmol) and ammonium chloride (58 mg, 1.08 mmol) sequentially. React at 40 °C for 2 h. After the reaction is complete, filter to remove iron powder, quench with cold water, extract twice with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain crude product. Column chromatography (DCM elution) yields 19 mg of compound 44F.

[0313] (o) Weigh 44F (19 mg, 0.05 mmol) and dissolve it in 2.0 mL of DCM. Add formaldehyde (1.49 mg, 0.05 mmol) and acetic acid (10 mg, 0.17 mmol) sequentially. Add sodium cyanoborohydride (10 mg, 0.17 mmol) while stirring. React at room temperature for 12 h. After the reaction is complete, quench with cold water and extract twice with ethyl acetate (20 mL × 2). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product. Column chromatography (eluting with DCM) yields 460 mg of compound 44.

[0314] 1 H NMR (400MHz, CDCl3) δ7.16(t,J=7.8Hz,1H),6.66-6.48(m,3H),3.44(s,2H),3.36(d,J=7.1Hz,2H),2.93(s,6H),2.24-2.16(m, 1H), 2.02(q,J=5.0Hz,2H),1.32(s,6H),1.27-1.24(m,6H),0.92-0.77(m,2H),0.62-0.49(m,2H),0.30(dt,J=6.1,4.6Hz,2H). LCMS(ESI)calcd for C 21 H 31 N3O2S m / z[M+H]+:412.41,found:411.59.

[0315] Example 45

[0316]

[0317] (l) The preparation conditions for this step are the same as those for compound 10.

[0318] (g) The preparation conditions for this step are the same as those for compound 1.

[0319] (m) The preparation conditions for this step are the same as those for compound 1.

[0320] (i) The preparation conditions for this step are the same as those for compound 29.

[0321] 1H NMR (400MHz, CDCl3) δ7.25-7.16(m,1H),6.96(d,J=7.7Hz,1H),6.94-6.81(m,2 H),4.78(dd,J=7.9,6.2Hz,2H),4.52(t,J=6.2Hz,2H),3.80(d,J=7.2Hz,2H),3. 31(s,2H),2.80(dd,J=9.9,6.1Hz,2H),2.61(ddd,J=16.3,8.5,4.3Hz,6H),2.00 -1.95(m,2H),1.52(dt,J=13.5,6.3Hz,2H),1.30(s,6H),0.87(t,J=6.3Hz,1H). LCMS(ESI)calcd forC 21 H 31 N3O2S m / z[M+H]+:403.43,found:402.51.

[0322] Example 46

[0323]

[0324] Compound 46 was prepared using the same method as in Example 20, except that 2-fluorobenzyl bromide was used instead of 2-fluorophenylethyl bromide in step (g) of Example 46.

[0325] 1 H NMR (400MHz, CDCl3) δ7.44-7.32(m,1H),7.23(td,J=5.4,2.6Hz,1H),7.10(td,J=7 .4,1.2Hz,1H),7.02(ddd,J=9.7,8.1,1.2Hz,1H),3.60(s,2H),3.48(s,4H),3.41( s,2H),3.34(d,J=7.1Hz,2H),2.59-2.51(m,2H),1.99(ddd,J=11.8,7.2,3.9Hz,2H ), 1.31 (s, 6H), 0.98-0.94 (m, 1H), 0.57-0.41 (m, 2H), 0.28 (dt, J = 6.1, 4.6Hz, 2H). LCMS(ESI)calcd for C 21 H 31 N3O2S m / z[M+H]+:373.0,found:372.48.

[0326] Example 47

[0327]

[0328] Compound 47 was prepared using the same method as in Example 20, except that p-fluorobenzyl bromide was used instead of 2-fluorophenylethyl bromide in step (g) of Example 47.

[0329] 1 H NMR (400MHz, CDCl3) δ7.61-7.47(m,1H),7.35(s,1H),6.99(s,1H),5.30(s,2H),2.2 2(t,J=7.6Hz,6H),2.01(d,J=5.8Hz,4H),0.99-0.94(m,2H),0.71(t,J=7.5Hz,1H). LCMS(ESI)calcd for C 21 H 31 N3O2S m / z[M+H]+:374.0,found:372.48.

[0330] Example 48

[0331]

[0332] Compound 48 was prepared using the same method as in Example 20, except that 3-fluorobenzyl bromide was used instead of 2-fluorophenylethyl bromide in step (g) of Example 48.

[0333] 1 H NMR (400MHz, CDCl3) δ8.54(s,1H),7.54(s,1H),7.35(d,J=2.6Hz,1H),7.08(dd,J=8.5,2.7Hz,1H),6.99(s,1H),3.49(d,J=25.7H z,2H),3.44-3.35(m,2H),2.35-2.09(m,2H),2.01(s,2H),1.25(s,6H),0.89(d,J=5.9Hz,2H),0.54(d,J=8.0Hz,2H),0.07(s,1H). LCMS(ESI)calcd for C 21 H 31 N3O2S m / z[M+H]+:373.0,found:372.48.

[0334] Example 49

[0335]

[0336] Compound 49 was prepared using the same method as in Example 20, except that 3-methoxybenzyl bromide was used instead of 2-fluorophenylethyl bromide in step (g) of Example 49.

[0337] 1H NMR (400MHz, CDCl3) δ7.23(t,J=7.9Hz,1H),6.97-6.89(m,1H),6.88-6.76(m,1H),4.12(q,J=7.1Hz,2H),3.81(s,2H),3.53-3.32(m,3H) ,2.04(s,6H),1.78-1.68(m,2H),1.63(t,J=7.3Hz,2H),1.31(s,6H),0.97(dt,J=9.9,6.0Hz,2H),0.89-0.84(m,2H),0.55-0.50(m,1H). LCMS(ESI)calcd for C 21 H 31 N3O2S m / z[M+H]+:385.1,found:384.52.

[0338] Example 50

[0339]

[0340] Compound 50 was prepared using the same method as in Example 20, except that 4-(bromomethyl)pyridine hydrobromide was used instead of 2-fluorophenylethyl bromide in step (g) of Example 50.

[0341] LCMS(ESI)calcd for C 21 H 31 N3O2S m / z[M+H]+:356.0,found:355.48.

[0342] Example 51

[0343]

[0344] Compound 51 was prepared using the same method as in Example 20, except that 2-bromoacetophenone was used instead of 2-fluorophenylethyl bromide in step (g) of Example 51.

[0345] LCMS(ESI)calcd for C 21 H 31 N3O2S m / z[M+H]+:382.44,found:382.23.

[0346] Example 52

[0347]

[0348] Compound 52 was prepared using the same method as in Example 29, except that (S)-1-phenyl-2-propanol was used instead of 2-fluorophenylethyl bromide in step (l) of Example 52.

[0349] LCMS(ESI)calcd for C 21 H 31 N3O2S m / z[M+H]+:383.39,found:382.55.

[0350] Test case

[0351] (I) Radioligand-receptor binding assay (affinity determination)

[0352] 1) σ1R receptor binding experiment

[0353] Whole guinea pig brains were collected and an appropriate amount of sucrose-Tris solution (320 mM sucrose, 50 mM Tris, pH 7.4) was added for disruption. After balancing, the mixture was centrifuged at 700 g for 10 min. The supernatant was transferred to a pre-weighed 50 mL centrifuge tube. 20 mL of sucrose-Tris solution was added to the remaining precipitate, and the mixture was disrupted. The centrifugation at 700 g for 10 min was repeated. The membrane protein suspensions collected from both centrifugations were combined and the precipitate was discarded. The two suspensions were centrifuged at 48,000 g for 25 min, the supernatant was discarded, and the precipitate was collected. 20 mL of sucrose-Tris solution was added to the precipitate, and the mixture was disrupted. The mixture was centrifuged at 48,000 g for 25 min was repeated, and the supernatant was discarded, and the precipitate was collected to obtain σ1R-enriched membrane proteins. The weight was calculated, and the precipitate was stored at -80℃ for later use.

[0354] Add the test compound to the test tubes in groups, and add [ 3 H]-Pentazocin (final concentration 4 nM) was added to σ1R protein suspension (final concentration 300 mg / mL) on ice, and the 250 μL reaction system was incubated in a 25°C water bath for 135 min. Immediately after incubation, pre-chilled Tris-HCl (50 mM, pH 7.4) was added, and the mixture was filtered onto filter paper (GF / C, Whatman). Once the filter paper showed no obvious watermarks, it was transferred to a scintillation flask, dried in a 60°C oven for 30 min, and then scintillation solution was added. After standing at room temperature for 2 h, the mixture was analyzed using a liquid scintillation number spectrometer (MicroBeta). 2 The DPM values ​​of each administration group were measured using Microplate Counters (PerkinElmer, USA). The DPM value of 10 μM haloperidol was recorded as NB (0%), and the DPM value of the blank control was recorded as TB (100%). The binding rate of the test compound (1 μM) = (TB - DPM value of the test compound) / (TB - NB) * 100%.

[0355] 2) MOR receptor binding assay

[0356] Prepare F12 medium (containing 10% fetal bovine serum, 0.4 mg / mL G418) and culture human MOR-overexpressing CHO cells in 10 cm culture dishes at 37°C (5% CO2). Collect cells into 15 mL centrifuge tubes and add an appropriate amount of Standard-Buffer (50 mM Tris buffer, 10 mM MgCl2, 0.1 mM EDTA, pH 7.4). Balance the solution and centrifuge at 2000 g for 10 min. Collect the pellet (cells) and transfer it to a pre-weighed 15 mL centrifuge tube. Add 3 mL of Standard-Buffer, homogenize, and centrifuge at 48,000 g for 25 min. Discard the supernatant and collect the pellet (containing membrane proteins). Add 3 mL of Standard-Buffer to the pellet, repeat homogenization and centrifugation at 48,000 g for 25 min, discard the supernatant and collect the pellet to obtain MOR-enriched membrane proteins. Weigh the pellet, calculate its weight, and store at -80°C for later use. The test compound was added in groups to a 96-well deep-well plate, and [[] was added. 3 H]-DAMGO (final concentration 4 nM) was added to MOR membrane protein suspension (final concentration 2 mg / ml) on ice, and the 250 μL reaction system was incubated in a 25°C shaker for 90 min. Immediately after incubation, pre-chilled Tris-HCl (50 mM, pH 7.4) was added, and the suspension was filtered through a Filtermate-Harvester (PerkinElmer) onto a 96-well plate (UniFilter-96 GF / C, PerkinElmer). After filtration, the plate was dried in a 60°C oven for 30 min, then scintillation fluid was added, and the mixture was allowed to stand at room temperature for 2 h before being analyzed using a liquid scintillation number spectrometer (MicroBeta). 2 The DPM values ​​of each administration group were measured using Microplate Counters (PerkinElmer, USA). The DPM value of 10 μM naloxone was recorded as NB (0%), and the DPM value of the blank control was recorded as TB (100%). The binding rate of the test compound (1 μM) = (TB - DPM value of the test compound) / (TB - NB) * 100%.

[0357] The test results are shown in Table 1 below.

[0358] Table 1 shows the binding rates of the compounds to σ1R and MOR at 1 μM.

[0359]

[0360]

[0361] +++: indicates a compound binding rate of 70-100%; ++: indicates a compound binding rate of 30-70%; +: indicates a compound binding rate greater than 0 and less than 30%.

[0362] (II) Mechanical pain sensitivity test

[0363] A plantar inflammatory model was established by injecting 0.1 mL of λ-carrageenan (1% w / v dissolved in physiological saline) into the subcutaneous tissue of the right hind paw of rats. After the plantar injection, the animals were placed in the laboratory for 3 hours to acclimatize, and then the rats with right hind paw pain model were placed in a separate opaque metal mesh floor assessment room for 1 hour to acclimatize. After adaptation, animals were intraperitoneally administered compound 20 at doses of 0 mg / kg (replaced by an equal volume of saline), 1 mg / kg, 3 mg / kg, 5 mg / kg, and 7 mg / kg, respectively; and at doses of 5 mg / kg of compound 20 + 40 mg / kg of PRE084, 5 mg / kg of compound 20 + 2 mg / kg of naloxone, and 5 mg / kg of morphine. Thirty minutes later, the left and right hind paws of rats were subjected to incremental mechanical stimulation using a mechanical pain meter (model 38450, Ugo-Basile, Varese, Italy). The stimulation threshold at which the rats lifted their paws was recorded. The limit of stimulation was 60 g; if the rats did not lift their paws after reaching 60 g, stimulation was stopped and no further increases were made. Each rat's left and right hind paws were stimulated three times cumulatively, with an interval of more than one minute between stimulations. The average of the three stimulations was taken to calculate the right hind paw lifting threshold and the difference in lifting thresholds between the left and right paws, evaluating the analgesic effect of the drug on mechanical pain stimulation.

[0364] Test results are as follows Figure 1-2 As shown. By Figure 1 It is known that at a dose of 5 mg / kg, compound 20 can effectively relieve mechanical pain sensitivity in an inflammatory state. Figure 2 It was found that, at the same dose (5 mg / kg), compound 20 exhibited superior analgesic effects on mechanical stimulation compared to morphine. When combined with the σ1R selective agonist PRE084, the analgesic effect of compound 20 on mechanical stimulation was inhibited. Furthermore, when combined with naloxone to selectively block MOR, the analgesic effect of compound 20 on mechanical stimulation disappeared. This demonstrates that compound 20 is a highly selective dual-target analgesic for both σ1R and MOR.

[0365] (III) Thermal pain sensitivity test

[0366] A plantar inflammatory model was established by injecting 0.1 ml of λ-carrageenan (1% w / v dissolved in physiological saline) into the subcutaneous tissue of the right hind paw of rats. After the plantar injection, the animals were placed in the laboratory for 3 hours to acclimatize, and then placed in a separate opaque glass-floored assessment room for 1 hour to acclimatize. After acclimatization, the animals were intraperitoneally administered the following drugs: (the animals were divided into 8 groups of 6 animals each, and were given compound 20 at doses of 0 mg / kg (replaced with an equal volume of physiological saline), 1 mg / kg, 3 mg / kg, 5 mg / kg, and 7 mg / kg, respectively; and compound 20 at 5 mg / kg + PRE084 at 40 mg / kg, compound 20 at 5 mg / kg + naloxone at 2 mg / kg, and morphine at 5 mg / kg). Thirty minutes later, a thermal pain sensitivity test was performed using a Hargreaves Apparatus (Hargreaves Apparatus, Ugo-Basile, Varese, Italy). At the start of the detection, an infrared thermal flux laser (model 37300, Ugo-Basile) was used at 85 mW / cm². 2 A laser beam was focused on the left or right hind paw of a rat to measure the thermal radiation intensity. The latency of the rat lifting its paw was measured, with a maximum stimulation time of 15 seconds. If the rat did not lift its paw after 15 seconds of thermal stimulation, the stimulation was stopped and not prolonged. Each rat's left and right hind paws were stimulated three times cumulatively, with an interval of more than 1 minute between stimulations. The average of the three stimulations was taken, and the latency of the right hind paw lifting and the difference in latency between the left and right paws were calculated to evaluate the analgesic effect of the drug on thermal pain stimulation.

[0367] Test results are as follows Figure 3-4 As shown. By Figure 3 It is known that at a dose of 5 mg / kg, compound 20 can effectively relieve thermal pain sensitivity in an inflammatory state. Figure 4 It was found that, at the same dose (5 mg / kg), compound 20 exhibited superior analgesic effects on thermal stimulation compared to morphine. When combined with the σ1R selective agonist PRE084, the analgesic effect of compound 20 on thermal stimulation was inhibited. Furthermore, when combined with naloxone to selectively block MOR, the analgesic effect of compound 20 on thermal stimulation disappeared. This demonstrates that compound 20 is a highly selective dual-target analgesic for both σ1R and MOR.

[0368] (iv) Respiratory function testing

[0369] Respiratory function in rats was assessed using the EMKA Animal Lung Function Testing System (EMKA TECHNOLOGIES, Paris, France). After acclimatizing in the laboratory for more than one hour, rats were placed in a sealed barometric pressure chamber for 30 minutes. They were then injected intraperitoneally with drugs (animals were divided into three groups of six each, receiving compound 20 at doses of 0 mg / kg (replaced with an equal volume of saline), 10 mg / kg, and morphine at 10 mg / kg, respectively). The rats were then returned to the sealed barometric pressure chamber, and the minute pressure changes in each chamber were recorded. The respiratory rate, tidal volume, and minute ventilation were analyzed using EMKA IOX software to assess the effects of the drugs on respiratory function.

[0370] Test results are as follows Figure 5 As shown. By Figure 5 It is known that at the same dose (10 mg / kg), compound 20 has a weaker inhibitory effect on respiration than morphine, and its inhibitory effect on respiratory rate and minute ventilation is weaker than that of morphine, making it safer than morphine in terms of respiratory depression.

[0371] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0372] The embodiments described above are merely illustrative of several implementation methods of this application, intended to facilitate a detailed understanding of the technical solutions of this application, but should not be construed as limiting the scope of protection of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. It should be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent application should be determined by the content of the appended claims, and the specification and drawings can be used to interpret the content of the claims.

Claims

1. A spirocyclic compound having the following formula (I) or a pharmaceutically acceptable salt thereof: （I） in, R 1 It is a C1-C4 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted C6-C8 aryl or substituted or unsubstituted 5 to 8-membered heteroaryl, wherein the heteroaryl contains at least one heteroatom selected from nitrogen, oxygen and sulfur; the substituted substituent is one or more of the following groups: halogen or halogen-substituted C1-C3 alkyl. Or, R 1 for ; R 2 The substituted group is H, a substituted or unsubstituted C6-C8 aryl group, or a substituted or unsubstituted 5- to 10-membered heteroaryl group, wherein the heteroaryl group contains at least one heteroatom selected from nitrogen, oxygen, and sulfur; the substituted group is one or more of the following groups: halogen, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl, or -N(C1-C3 alkyl)2; R 3 H, C1-C4 alkyl, R 4 It is a C1-C4 alkyl group, or R 3 and R 4 Together with the connected carbon atoms, they form C3-C6 cycloalkyl groups; R 5 and R 6 Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, or R 5 and R 6 Together with the bonded carbon atom, they form a carbonyl group; n is 1, 2, or 3.

2. The azaspirocyclic compound according to claim 1, characterized in that, R 1 It is a C2-C4 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted C6-C8 aryl or substituted or unsubstituted 5 to 8-membered heteroaryl, wherein the heteroaryl contains at least one heteroatom selected from nitrogen, oxygen and sulfur; the substituted substituent is one or more of the following groups: halogen or halogen-substituted C1-C3 alkyl. Or, R 1 for .

3. The azaspirocyclic compound according to claim 1, characterized in that, R 2 The substituted or unsubstituted C6-C8 aryl group or the substituted or unsubstituted 5- to 10-membered heteroaryl group contains at least one heteroatom selected from nitrogen, oxygen and sulfur; the substituted substituent is one or more of the following groups: halogen, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl or -N(C1-C3 alkyl)2.

4. The azaspirocyclic compound according to claim 1, characterized in that, R 3 H, C1-C2 alkyl, R 4 It is a C1-C2 alkyl group, or R 3 and R 4 Together with the connected carbon atoms, they form C3-C4 cycloalkyl groups.

5. The azaspirocyclic compound according to claim 1, characterized in that, R 5 and R 6 Each is independently H, C1-C3 alkyl, or C1-C3 alkoxy.

6. The azaspirocyclic compound according to any one of claims 1 to 5, characterized in that, n is 2.

7. The azaspirocyclic compound according to claim 1, characterized in that, The azaspirocyclic compound is one of the following compounds: 。 8. The method for preparing the azaspirocyclic compound according to any one of claims 1 to 6, characterized in that, Includes the following steps: (a) Compound m1 reacts with p-toluenesulfonyl chloride under alkaline conditions to give intermediate m2; (b) The original compound m3 and 2,4,6-trimethoxybenzaldehyde undergo a reductive amination reaction in the presence of sodium triacetoxyborohydride to give intermediate m4; (c) Intermediate m4 was acylated with ethyl chloroformyl under alkaline conditions to obtain intermediate m5; (d) Intermediate m5 undergoes a condensation reaction under alkaline conditions, followed by a decarboxylation reaction under heating to obtain intermediate m6; (e) Intermediate m6 undergoes a nucleophilic substitution reaction with the halide under basic conditions to give intermediate m7; (f) Intermediate m7 is deprotected by trifluoroacetic acid, and then reacts with halogenated product R. 2 -(CR 5 R 6 ) n - X1 or intermediate m2 undergoes a nucleophilic substitution reaction under basic conditions to give intermediate m8, where X1 is a halogen; (g) Intermediate m8 is deprotected by trifluoroacetic acid and anisole to obtain intermediate m9; (h) Intermediate m9 and halogenated product R 1 -X2 is obtained by nucleophilic substitution under basic conditions to obtain the azaspirocyclic compound, where X2 is a halogen.

9. A pharmaceutical composition, characterized in that, Includes the azaspirocyclic compound as described in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

10. The use of the azaspirocyclic compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for treating diseases associated with or mediated by Sigma receptor and / or opioid receptor activity.

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