Azaspiro compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention relates to an azaspiro compound as well as a preparation method, a pharmaceutical composition and application thereof. The azaspiro compound has the structural characteristics as shown in the following formula (I). The azaspiro compound has an analgesic mechanism different from that of a traditional compound, and is good in analgesic effect and higher in safety. # imgabs0 #

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical chemistry, and in particular to an azaspirocyclic compound and a preparation method, a pharmaceutical composition and application thereof. Background Art

[0002] Pain is a physical and even mental burden for many people in the world. At present, drug therapy is still the main method of pain treatment. Commonly used analgesics in clinical practice include opioid receptor drugs (such as morphine, pethidine, etc.), non-steroidal anti-inflammatory drugs (such as aspirin, ibuprofen, etc.), antidepressants and anti-epileptic drugs (such as gabapentin, pregabalin, etc.). In 2021, The Lancet showed that the first-line treatment for neuropathic pain is antidepressants and anti-epileptic drugs, and the first-line treatment for non-neuropathic pain is non-steroidal anti-inflammatory drugs.

[0003] Opioid receptor (MOR) drugs are the first choice for moderate to severe acute pain. Among the drugs that have been applied for marketing and are under clinical development for the treatment of pain, drugs targeting opioid receptors dominate. Although opioid receptor drugs have good analgesic effects, the serious adverse reactions of this type of drug, such as drug resistance, respiratory depression and addiction, have always been a problem that cannot be ignored in pain treatment. Since 1999, the number of deaths due to opioid abuse has increased sharply, and an "opioid receptor epidemic" has emerged. Although some improvements have been made in recent years on how to reduce the adverse reactions of opioid receptor drugs, only the MOR subtype-biased agonist Oliceridine has been approved for marketing among new mechanism drugs. The development of analgesics with good analgesic effects and greater safety has always been a hot topic in drug research and development. Summary of the invention

[0004] Based on this, the present application provides an azaspiro compound and a preparation method, a pharmaceutical composition and application thereof. The azaspiro compound has an analgesic mechanism different from that of traditional compounds, has good analgesic effect and higher safety.

[0005] In the first aspect of the present application, there is provided an azaspiro compound or a pharmaceutically acceptable salt or stereoisomer thereof having the following formula (I):

[0006]

[0007] in,

[0008] R 1 is 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 20Aryl or substituted or unsubstituted 5- to 20-membered heteroaryl, wherein the heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur;

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

[0010] R 3 and R 4 Each independently represents H, C1-C6 alkyl, or R 3 and R 4 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group;

[0011] R 5 and R 6 Each independently represents H, C1-C6 alkyl, C1-C6 alkoxy, or R 5 and R 6 Together with the attached carbon atom, it forms a carbonyl group;

[0012] n is 1, 2 or 3;

[0013] The substituted 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 embodiments, R 1 is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted heterocyclic group containing 3 to 10 ring atoms, a substituted or unsubstituted C6-C 20 Aryl or substituted or unsubstituted 5- to 20-membered heteroaryl, wherein the heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur;

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

[0016] In some embodiments, R 1It is a substituted or unsubstituted C2-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted heterocyclyl 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 heterocycloalkyl group each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur.

[0017] In some embodiments, R 2 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 embodiments, R 3 and R 4 Each independently represents H, C1-C2 alkyl, or R 3 and R 4 Together with the carbon atom to which it is attached, it forms a C3-C4 cycloalkyl group;

[0019] In some 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] The second aspect of the present application provides a method for preparing the azaspirocyclic compound described in the first aspect, comprising the following steps:

[0022]

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

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

[0025] (c) intermediate m4 is subjected to acylation reaction with ethyl chloroformyl acetate under alkaline conditions to obtain intermediate m5;

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

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

[0028] (f) Intermediate m7 is deprotected under the action of trifluoroacetic acid and then reacted with a halide R 2 -(CR 5R 6 ) n -X1 or intermediate m2 undergoes nucleophilic substitution reaction under alkaline conditions to obtain intermediate m8, where X1 is a halogen;

[0029] (g) intermediate m8 is deprotected under the action of trifluoroacetic acid and anisole to obtain intermediate m9;

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

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

[0032] The fourth aspect of the present 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 drug for treating diseases related to 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 related to pain, neuroprotection, learning and memory, and immunity, while σ2R is related to tumors. Studies have found that σ1R antagonists have a sensitizing effect on MOR agonists (morphine). This can not only enhance the analgesic effect of MOR by inhibiting σ1R, but also reduce the serious adverse reactions of MOR agonists by reducing the agonist activity of MOR or the dosage of agonists. The combination of σ1R antagonists and MOR agonists has the potential problem of drug interactions, such as affecting the efficacy and metabolism of the two. σ1R / MOR dual-target compounds can avoid this problem while maintaining the sensitization effect of σ1R.

[0034] Based on this, the present application provides an azaspirocyclic compound, which is a σ1R / MOR dual-target compound having sigma-1 receptor inhibitory activity and / or MOR agonist activity, thereby being able to utilize the sensitizing effect of σ1R on MOR to enhance the analgesic effect, while achieving a similar analgesic effect, reducing dependence on MOR agonist activity, thereby reducing the adverse reactions of MOR agonists and improving the safety of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1The results of mechanical allodynia test of compound 20 of the present application, wherein, N=6, ***P<0.001, ###P<0.001 (One-way ANOVA);

[0036] Figure 2 Comparison of the mechanical pain test results of compound 20 of the present application and other drugs, wherein N=6, ***P<0.001 (One-way ANOVA);

[0037] Figure 3 The thermal pain test results of compound 20 of the present application, wherein N=6, ** P < 0.01 (One-way ANOVA);

[0038] Figure 4 Comparison of the thermal pain test results of compound 20 of the present application and other drugs, wherein N=6, **P<0.01, *P<0.05 (One-way ANOVA);

[0039] Figure 5 Comparison of respiratory function test results between compound 20 of the present application and other drugs, wherein N=6, **P<0.01, *P<0.05 (Two-way ANOVA). DETAILED DESCRIPTION

[0040] The following is a further detailed description of the azaspiro compounds and preparation methods, pharmaceutical compositions and applications of the present application in conjunction with specific examples. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thoroughly understood.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0042] The optional scope of the terms "and / or", "or / and", and "and / or" used in this article includes any one of two or more related listed items, and also includes any and all combinations of the related listed items, said any and all combinations include any combination of any two related listed items, any more related listed items, or all related listed items.

[0043] As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

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

[0045] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0046] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0047] The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

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

[0049] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range of instrument control.

[0050] The room temperature in the present application generally refers to 4°C to 30°C, preferably 20±5°C.

[0051] Herein, 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, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing this term, for example, "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, and each occurrence can be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, 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( 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 ring carbon atoms, which can be a monocyclic alkyl, a spirocyclic alkyl, or a bridged cycloalkyl. Phrases containing this term, for example, "C3-C8 cycloalkyl" refers to a cycloalkyl containing 3 to 8 carbon atoms, each occurrence of which can be independently C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, C8 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In addition, "cycloalkyl" may also contain one or more double bonds, and representative examples of cycloalkyl containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl.

[0053] "Heterocyclyl" means that at least one carbon atom is replaced by a non-carbon atom on the basis of a cycloalkyl group, and the non-carbon atom can be an N atom, an O atom, an S atom, etc., and can be a saturated ring or a partially unsaturated ring. Phrases containing this term, for example, "heterocyclyl of 3-10 ring atoms", each time it appears, can be independently 3-membered heteroalkyl, 4-membered heteroalkyl, 5-membered heteroalkyl, 6-membered heteroalkyl, 7-membered heteroalkyl, 8-membered heteroalkyl, 9-membered heteroalkyl, 10-membered heteroalkyl. Suitable examples include, but are not limited to, dihydropyridyl, tetrahydropyridyl (piperidyl), tetrahydrothienyl, sulfur-oxidized tetrahydrothienyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydroindole.

[0054] Herein, the term "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing a hydrogen atom. It can be a monocyclic aromatic group, a condensed aromatic group, or a polycyclic aromatic group. For polycyclic rings, at least one is an aromatic ring system. For example, "C6-C 20 "Aryl" refers to an aromatic group containing 6 to 20 carbon atoms, each occurrence of which can be independently C5 aromatic group, C6 aromatic group, C7 aromatic group, C8 aromatic group, C9 aromatic group, C 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 Suitable examples include, but are not limited to, benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene, and derivatives thereof.

[0055] Herein, the term "heteroaryl" refers to an aromatic group in which at least one carbon atom is replaced by a non-carbon atom, and the non-carbon atom may 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, and each occurrence may be independently a 5-membered heteroaryl, a 6-membered heteroaryl, a 7-membered heteroaryl, an 8-membered heteroaryl, a 9-membered heteroaryl, a 10-membered heteroaryl, an 11-membered heteroaryl, a 12-membered heteroaryl, a 13-membered heteroaryl, a 14-membered heteroaryl, a 15-membered heteroaryl, a 16-membered heteroaryl, a 17-membered heteroaryl, an 18-membered heteroaryl, a 19-membered heteroaryl, or a 20-membered heteroaryl. Suitable examples include, but are not limited to, furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furanopyrrole, furanofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, o-naphthylidene, quinoxaline, phenanthridine, primidine, quinazoline, and quinazolinone.

[0056] The term "alkoxy" refers to a group having the structure -O-alkyl, i.e., an alkyl group as defined above is connected to an adjacent group via an oxygen atom. Phrases containing the term, for example, "C1-C6 alkoxy" means that the alkyl portion contains 1 to 6 carbon atoms, and each occurrence can be independently C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, 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 "halo" refers to F, Cl, Br or I.

[0058] "Pharmaceutically acceptable" refers to those ligands, materials, compositions, and / or dosage forms that are suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0059] "Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are compatible with drug administration. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful 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 carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragacanth; (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 starch, etc. 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 buffered saline; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0060] "Pharmaceutically acceptable salt" refers to a salt suitable for use as a drug formed by any compound in the structure shown and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. Among them, one type of salt is a salt formed by the compound of the present invention and an acid. Acids suitable for forming salts 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 a salt formed by a compound of the present invention and a base. Suitable bases for forming salts include but are not limited to alkali metal salts (e.g., sodium salts or potassium salts), alkaline earth metal salts (e.g., magnesium salts or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), for example, 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] In some examples of the present application, an azaspirocyclic compound or a pharmaceutically acceptable salt or stereoisomer thereof having the following formula (I) is provided:

[0062]

[0063] in,

[0064] R 1 is 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 Aryl or substituted or unsubstituted 5- to 20-membered heteroaryl, wherein the heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur;

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

[0066] R 3 and R 4 Each independently represents H, C1-C6 alkyl, or R 3 and R 4 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group;

[0067] R 5 and R 6 Each independently represents H, C1-C6 alkyl, C1-C6 alkoxy, or R 5 and R 6 Together with the attached carbon atom, it forms a carbonyl group;

[0068] n is 1, 2 or 3;

[0069] The substituted 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 is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted heterocyclic group containing 3 to 10 ring atoms, a substituted or unsubstituted C6-C 20Aryl or substituted or unsubstituted 5- to 20-membered heteroaryl, wherein the heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur;

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

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

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

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

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

[0076]

[0077] In some of these examples, R 2 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 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted group Substituted or unsubstituted thiophene, substituted or unsubstituted group Substituted or unsubstituted pyridyl. 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 limitation, R 2is H or one of the following groups:

[0080]

[0081] In some of these examples, R 3 and R 4 Each independently represents H, C1-C2 alkyl, or R 3 and R 4 Together with the attached carbon atom, it forms a C3-C4 cycloalkyl group.

[0082] Without limitation, R 3 and R 4 Each independently is methyl, H, isopropyl, ethyl, R 3 and R 4 Together with the attached carbon atom, it forms 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 limitation, R 5 and R 6 are independently 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] In addition, without limitation, the azaspirocyclic compound has a structure shown in any one of formulas (II-1) to (II-3):

[0087]

[0088] Among them, R 5’ , R 5” Same definition as R 5 , R 6’ , R 6” Same definition as R 6 .

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

[0090]

[0091]

[0092]

[0093] Some other examples of the present application also provide a method for preparing the above-mentioned azaspirocyclic compound, comprising the following steps:

[0094]

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

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

[0097] (c) intermediate m4 is subjected to acylation reaction with ethyl chloroformyl acetate under alkaline conditions to obtain intermediate m5;

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

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

[0100] (f) Intermediate m7 is deprotected under the action of trifluoroacetic acid and then reacted with a halide R 2 -(CR 5 R 6 ) n -X1 or intermediate m2 undergoes nucleophilic substitution reaction under alkaline conditions to obtain intermediate m8, where X1 is a halogen;

[0101] (g) intermediate m8 is deprotected under the action of trifluoroacetic acid and anisole to obtain intermediate m9;

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

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

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

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

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

[0107] Some other examples of the present application also provide a pharmaceutical composition, including the azaspirocyclic compound as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.

[0108] Some other examples of the present application also provide the use of the azaspirocyclic compounds as described above, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or the pharmaceutical compositions as described above in the preparation of drugs for treating diseases related to or mediated by Sigma receptor and / or opioid receptor activity.

[0109] Furthermore, the diseases associated with or mediated by the activity of Sigma receptors and / or opioid receptors 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 a σ1R subtype.

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

[0112] The following are specific examples. Unless otherwise specified, the reagents used in the examples are all 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. Sodium triacetoxyborohydride (2.94 g, 13.88 mmol) was slowly added in batches, and the mixture was reacted at room temperature overnight. After the reaction was completed, cold water was added to quench the mixture, and the mixture was extracted twice with ethyl acetate (100 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM:MeOH=15:1, volume ratio) to obtain 3.75 g of a yellow-brown oil, i.e., 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) m2 (3.75 g, 8.04 mmol) was weighed and dissolved in 32 mL of anhydrous DCM, pyridine (1.91 g, 24.11 mmol) and 4-dimethylaminopyridine (99 mg, 0.8 mmol) were added in sequence, the reaction solution was cooled to 0°C, ethyl chloroformyl acetate (1.33 g, 8.84 mmol) was weighed and dissolved in 8 mL of DCM and slowly added dropwise to the above reaction solution, and reacted at room temperature overnight. After the reaction was completed, cold water was added to quench, and ethyl acetate (100 mL × 2) was used to extract twice, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (petroleum ether: ethyl acetate = 1:1, volume ratio) to obtain 3.56 g of a yellow oil, i.e., compound m3, with a yield of 76.3%.

[0118] (c) m3 (3.56 g, 6.13 mmol) was weighed and dissolved in 61 mL of anhydrous methanol, sodium methoxide (1.66 g, 30.65 mmol) was added, and refluxed at 60°C for 15 h. After the reaction was completed, cold water was added to quench, dilute hydrochloric acid was added to adjust the pH to neutral, and ethyl acetate (100 mL×2) was used for extraction twice. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, namely compound m4, which was directly used in the next step.

[0119] (d) The crude product m4 was dissolved in 120 mL of a mixed solvent of acetonitrile-water (1:1, volume ratio) and refluxed at 80°C for 4 h. After the reaction was completed, cold water was added to quench the mixture, and the mixture was 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 a crude product. The crude product was purified by column chromatography (DCM:MeOH=50:1, volume ratio) to obtain 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) m5 (1.3 g, 2.81 mmol) was weighed and dissolved in 14 mL of anhydrous acetone, potassium carbonate (1.17 g, 8.43 mmol) was added, methyl iodide (1.2 g, 8.43 mmol) was added dropwise, and the temperature was raised to 50°C for reaction for 16 h. After the reaction was completed, the excess methyl iodide was removed under reduced pressure, and the mixture was extracted twice with ethyl acetate and water (100 mL×2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (DCM:MeOH=50:1, volume ratio) to obtain 1.18 g of a bright yellow solid, namely compound m6, with a yield of 85.5%.

[0122] (f) m6 (1.5 g, 3.07 mmol) was weighed and dissolved in 4.3 mL DCM, and trifluoroacetic acid (10.5 g, 91.71 mmol) was added and reacted at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, TFA salt, i.e., compound m7, which was directly used in the next step.

[0123] (g) The crude product m7 (1.19 mg, 3.04 mmol) was dissolved in 16 mL of acetonitrile, potassium carbonate (2.11 g, 15.29 mmol) and 3-fluorophenethyl bromide (1.06 g, 4.86 mmol) were added in sequence, and the temperature was raised to 80°C for 16 h. After the reaction was completed, cold water was added to quench, and ethyl acetate (30 mL×2) was used for extraction twice. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM: MeOH = 50: 1, volume ratio) to obtain 1.357 g of a light yellow oil, namely compound 1A, with a yield of 86.86%.

[0124] (h) 1A (1.357 g, 2.65 mmol) was weighed and dissolved in anisole (20.61 mg, 190.83 mmol), and 40 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 48 h under nitrogen protection. After the reaction was completed, the excess trifluoroacetic acid was removed by concentration under reduced pressure, and the mixture was extracted twice with ethyl acetate and water (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 a crude product, which was purified by column chromatography (DCM:MeOH=10:1, volume ratio) to obtain 635 mg of a 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, and cesium carbonate (20 mg, 0.084 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21 mg, 0.009 mmol) and 3-bromo-2-trifluoromethylpyridine (13 mg, 0.06 mmol) were added in sequence. After nitrogen substitution, tris(dibenzylideneacetone)dipalladium (2.7 mg, 0.003 mmol) was added, and nitrogen substitution was performed again. The temperature was raised to 100°C and the mixture was reacted overnight. After the reaction was completed, 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 a crude product, which was purified by column chromatography (DCM:MeOH=50:1, volume ratio) to obtain 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 by the same procedure 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 temperature was lowered to 0°C for reaction for 0.5 h. 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, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, 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 a crude product, which was purified by column chromatography (DCM: MeOH = 50: 1, volume ratio) to obtain 48 mg of a white solid, namely 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 by the same procedure 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 by the same procedure 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, and 4-dimethylaminopyridine (22 mg, 0.18 mmol), copper acetate (2 mg, 0.012 mmol), sodium bis(trimethylsilyl)amide (11 mg, 0.06 mmol) and cyclopropylboric acid (10.5 mg, 0.12 mmol) were added in sequence, and the temperature was raised to 95°C under air conditions for overnight reaction. After the reaction was completed, ethyl acetate and water (20 mL×2) were extracted twice, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (DCM:MeOH=35:1, volume ratio) to obtain 7 mg of a yellow solid, namely 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 by the same procedure 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 by the same procedure 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] Compound 9 was prepared by the same procedure as in Example 2, except that β-bromophenethyl bromide was used instead of 2-fluorophenethyl bromide in step (g) of Example 9.

[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 DCM. Triethylamine (505 mg, 4.99 mmol), 4-dimethylaminopyridine (20 mg, 0.17 mmol) and p-toluenesulfonyl chloride (381 mg, 2 mmol) were added in turn under ice bath conditions and reacted at room temperature for 7 h. After the reaction was completed, cold water was added to quench the reaction, and the mixture was 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 a crude product. After column chromatography (eluted with DCM), 460 mg of a light yellow oil was obtained, namely compound 10B, with a yield of 90.8%.

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

[0163] (m) m7 (91.5 mg, 0.218 mmol) was weighed and dissolved in 1.1 mL of acetonitrile, potassium carbonate (162 mg, 1.09 mmol) and 10B (89 mg, 0.283 mmol) were added in sequence, and the temperature was raised to 80°C for 16 h. After the reaction was completed, cold water was added to quench, and ethyl acetate (30 mL×2) was used for extraction twice. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM: MeOH = 50: 1, volume ratio) to obtain 82 mg of a light yellow oil with a yield of 81.8%.

[0164] (i) The preparation conditions of this step are the same as those of 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] Embodiment 11

[0167]

[0168] Compound 11 was prepared by the same procedure as in Example 10, except that 3-fluorophenethyl alcohol was used instead of 2-(2,5-difluorophenyl)ethane-1-ol in step (1) 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 by the same procedure as in Example 10, except that 4-methoxyphenethanol was used instead of 2-(2,5-difluorophenyl)ethane-1-ol in step (1) 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] Embodiment 13

[0175]

[0176] Compound 13 was prepared by the same procedure as in Example 10, except that 4-chlorophenethyl alcohol was used instead of 2-(2,5-difluorophenyl)ethane-1-ol in step (1) 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] Embodiment 14

[0179]

[0180] Compound 14 was prepared by the same procedure as in Example 10, except that 3-trifluoromethylphenethanol was used instead of 2-(2,5-difluorophenyl)ethane-1-ol in step (1) 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] Embodiment 15

[0183]

[0184] Compound 15 was prepared by the same procedure as in Example 2, except that benzyl bromide was used instead of 2-fluorophenethyl bromide in step (g) of Example 15.

[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 by the same procedure as in Example 2, except that 1-bromo-3-phenylpropane was used instead of 2-fluorophenethyl 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] Embodiment 17

[0191]

[0192] Compound 17 was prepared by the same procedure as in Example 2, except that 5-(2-bromoethyl)-2,3-dihydrobenzofuran was used instead of 2-fluorophenethyl bromide in step (g) of Example 17.

[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] Embodiment 18

[0195]

[0196] Compound 18 was prepared by the same procedure as in Example 10, except that 2-thiopheneethanol was used instead of 2-(2,5-difluorophenyl)ethane-1-ol in step (1) 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] Embodiment 19

[0199]

[0200] Compound 19 was prepared by the same procedure as in Example 2, except that iodopropane was used instead of 2-fluorophenethyl 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] Embodiment 20

[0203]

[0204] Compound 20 was prepared by the same procedure as in Example 3, except that β-bromophenethyl bromide was used instead of 2-fluorophenethyl 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) calculation for C 23 H 32 N2O2 m / z[M+H] + :369.25,found:369.6.

[0206] Embodiment 21

[0207]

[0208] Compound 21 was prepared by the same procedure 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] Embodiment 22

[0211]

[0212] Compound 22 was prepared by the same procedure 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] Embodiment 23

[0215]

[0216] Compound 23 was prepared by the same procedure 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] Embodiment 24

[0219]

[0220] Compound 24 was prepared by the same procedure 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] Embodiment 25

[0223]

[0224] Compound 25 was prepared by the same procedure as in Example 3, except that bromomethylcyclopropane was used instead of 2-(2,5-difluorophenyl)ethan-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] Embodiment 26

[0227]

[0228] Compound 26 was prepared by the same procedure 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] Embodiment 27

[0231]

[0232] Compound 27 was prepared by the same procedure 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) calculation for C 26 H 28 F3N2O2 m / z[M+H] + :458.53,found:459.5.

[0234] Embodiment 28

[0235]

[0236] Compound 28 was prepared by the same procedure 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] Embodiment 29

[0239]

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

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

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

[0243] (j) The preparation conditions of this step are the same as those of 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] Embodiment 30

[0246]

[0247] Compound 30 was prepared by the same procedure as in Example 29, except that 4-methoxyphenethanol was used instead of 1-phenylpropan-2-ol in step (1) 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] Embodiment 31

[0250]

[0251] Compound 31 was prepared by the same procedure as in Example 29, except that 4-chlorophenethyl alcohol was used instead of 1-phenylpropan-2-ol in step (1) 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] Embodiment 32

[0254]

[0255] Compound 32 was prepared by the same procedure as in Example 29, except that 3-chlorophenethyl alcohol was used instead of 1-phenylpropan-2-ol in step (1) 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] Embodiment 33

[0258]

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

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

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

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

[0263] (j) The preparation conditions of this step are the same as those of 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] Embodiment 34

[0266]

[0267] Compound 34 was prepared by the same procedure as in Example 33, except that ethyl iodide was used instead of methyl iodide 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] Embodiment 35

[0270]

[0271] Compound 35 was prepared by the same procedure as in Example 33, except that iodoethane was used instead of iodomethyl 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] Embodiment 36

[0274]

[0275] Compound 36 was prepared by the same procedure 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] Embodiment 37

[0278]

[0279] Compound 37 was prepared by the same procedure as in Example 20, except that 2,3-difluorophenethyl bromide was used instead of 2-fluorophenethyl 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] Embodiment 38

[0282]

[0283] Compound 38 was prepared by the same procedure as in Example 20, except that 2-trifluoromethylphenethyl bromide was used instead of 2-fluorophenethyl 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] Embodiment 39

[0286]

[0287] Compound 39 was prepared by the same procedure as in Example 20, except that 4-trifluoromethylphenethyl bromide was used instead of 2-fluorophenethyl 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] Embodiment 40

[0291]

[0292] Compound 40 was prepared by the same procedure as in Example 20, except that 2,3-fluorophenethyl bromide was used instead of 2-fluorophenethyl 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) calculation for C 23 H 30 F2N2O2 m / z[M+H] + :405.47,found:404.5.

[0294] Embodiment 41

[0295]

[0296] Compound 41 was prepared by the same procedure as in Example 29, except that thiophene-3-ethanol was used instead of 1-phenylpropan-2-ol in step (1) 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] Embodiment 42

[0299]

[0300] Compound 42 was prepared by the same procedure as in Example 29, except that 4-methyl-5-thiazoleethanol was used instead of 1-phenylpropan-2-ol in step (1) 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] Embodiment 43

[0303]

[0304] Compound 43 was prepared by the same procedure as in Example 20, except that (2-bromo-1-methoxyethyl)benzene was used instead of 2-fluorophenethyl bromide 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] Embodiment 44

[0307]

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

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

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

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

[0312] (n) 44E (45 mg, 0.11 mmol) was weighed and dissolved in 2.0 mL MeOH / H2O (1:1), and iron powder (45 mg, 0.81 mmol) and ammonium chloride (58 mg, 1.08 mmol) were added in sequence, and the mixture was reacted at 40°C for 2 h. After the reaction was completed, the iron powder was filtered out, the mixture was quenched with cold water, and the mixture was 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 a crude product, which was purified by column chromatography (eluted with DCM) to obtain 19 mg of compound 44F.

[0313] (o) 44F (19 mg, 0.05 mmol) was weighed and dissolved in 2.0 mL DCM, and formaldehyde (1.49 mg, 0.05 mmol) and acetic acid (10 mg, 0.17 mmol) were added in sequence, and sodium cyanoborohydride (10 mg, 0.17 mmol) was added under stirring, and the mixture was reacted at room temperature for 12 h. After the reaction was completed, cold water was added to quench the mixture, and the mixture was 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 a crude product, which was purified by column chromatography (eluted with DCM) to obtain 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] Embodiment 45

[0316]

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

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

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

[0320] (i) The preparation conditions of this step are the same as those of 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) calculation for C 21 H 31 N3O2S m / z[M+H]+:403.43,found:402.51.

[0322] Embodiment 46

[0323]

[0324] Compound 46 was prepared by the same procedure as in Example 20, except that 2-fluorobenzyl bromide was used instead of 2-fluorophenethyl 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] Embodiment 47

[0327]

[0328] Compound 47 was prepared by the same procedure as in Example 20, except that p-fluorobenzyl bromide was used instead of 2-fluorophenethyl 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] Embodiment 48

[0331]

[0332] Compound 48 was prepared by the same procedure as in Example 20, except that 3-fluorobenzyl bromide was used instead of 2-fluorophenethyl 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] Embodiment 49

[0335]

[0336] Compound 49 was prepared by the same procedure as in Example 20, except that 3-methoxybenzyl bromide was used instead of 2-fluorophenethyl 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] Embodiment 50

[0339]

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

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

[0342] Embodiment 51

[0343]

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

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

[0346] Embodiment 52

[0347]

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

[0349] LCMS (ESI) calculation 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 assay

[0353] Take the whole brain of the guinea pig, add an appropriate amount of sucrose-Tris (320mM sucrose, 50mM Tris, pH 7.4) solution, break it, balance it and centrifuge it at 700g for 10min, transfer the upper liquid suspension to a weighed 50mL centrifuge tube after centrifugation, add 20mL sucrose-Tris solution to the remaining precipitate to break it, repeat the centrifugation at 700g for 10min. Combine the membrane protein suspensions collected twice and discard the precipitate, centrifuge the suspensions collected twice at 48,000g for 25min, discard the supernatant and take the precipitate, add 20mL sucrose-Tris solution to the precipitate to break it and repeat the centrifugation at 48,000g for 25min, discard the supernatant and take the precipitate, obtain σ1R enriched membrane protein, weigh it to calculate the weight, and store it at -80℃ for later use.

[0354] Add the compounds to be tested to the test tubes in groups and add [ 3 H]-Pentazocin (final concentration 4 nM), add σ1R protein suspension (final concentration 300 mg / mL) on ice, and place 250 μL of the reaction system in a 25°C water bath for incubation for 135 min. Immediately after the incubation, add pre-cooled Tris-HCl (50 mM, pH 7.4) and filter onto filter paper (GF / C, Whatman). When there is no obvious water mark on the filter paper, transfer the filter paper to a scintillation bottle cup, place it in a 60°C oven to dry for 30 min, then add scintillation liquid, let it stand at room temperature for 2 h, and use a liquid scintillation spectrometer (MicroBeta 2 Microplate Counters, PerkinElmer, USA) were used to detect the DPM value of each dosing group. 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, 0.4mg / mL G418), use 10cm culture dishes to culture human MOR overexpressing CHO cells in a 37℃ incubator (5% CO2). Collect cells into 15mL centrifuge tubes and add appropriate amount of Standard-Buffer (50mM Tris buffer, 10mM MgCl2, 0.1mM EDTA, pH 7.4) solution, centrifuge at 2000g for 10min after balancing, take the precipitate (cells) and transfer it to a weighed 15mL centrifuge tube. Add 3mL Standard-Buffer, break and centrifuge at 48,000g for 25min, pour out the supernatant and take the precipitate (containing membrane protein), add 3mL Standard-Buffer to the precipitate, repeat breaking and centrifuging at 48,000g for 25min, pour out the supernatant and take the precipitate, obtain MOR enriched membrane protein, weigh and calculate the weight, and store at -80℃ for use. Add the test compounds in groups to a 96-well deep-well plate and add [ 3 H]-DAMGO (final concentration 4nM), add MOR membrane protein suspension (final concentration 2mg / ml) on ice, and incubate 250μL of the reaction system in a 25℃ constant temperature shaker for 90min. Immediately after the incubation, add pre-cooled Tris-HCl (50mM, pH 7.4), and use a well plate filter (Filtermate-harvester, PerkinElmer) to filter the suspension onto a 96-well filter plate (UniFilter-96 GF / C, PerkinElmer). After the filtration is completed, place the filter plate in a 60℃ oven to dry for 30min, then add scintillation liquid, let it stand at room temperature for 2h, and use a liquid scintillation spectrometer (MicroBeta 2 Microplate Counters, PerkinElmer, USA) were used to detect the DPM value of each dosing group. 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 Binding rate of compounds to σ1R and MOR at 1 μM

[0359]

[0360]

[0361] +++: represents that the binding rate of the compound is 70-100%; ++: represents that the binding rate of the compound is 30-70%; +: represents that the binding rate of the compound is greater than 0 and less than 30%.

[0362] 2. Mechanical pain measurement

[0363] The plantar inflammation model was established by injecting 0.1 mL of λ-carrageenan (1% w / v dissolved in saline) into the subcutaneous tissue of the plantar surface of the right hind paw of rats. After the plantar injection, the animals were placed in the laboratory for 3 hours to adapt, and the rats with right hind paw pain model were placed in a separate opaque metal mesh floor evaluation room for 1 hour to adapt. After the adaptation, the animals were intraperitoneally administered (the animals were divided into 8 groups, 6 animals in each group, and the doses of compound 20 were 0 mg / kg (equivalent saline replacement), 1 mg / kg, 3 mg / kg, 5 mg / kg, 7 mg / kg, and compound 20 5 mg / kg + PRE084 40 mg / kg, compound 20 5 mg / kg + naloxone 2 mg / kg, morphine 5 mg / kg). After 30 minutes, the left and right hind paws of the rats were subjected to increasing mechanical stimulation using a mechanical pain meter (model 38450, Ugo-Basile, Varese, Italy), and the stimulation threshold when the rats lifted their feet was recorded. The limit of the stimulation was 60 g. If the rats did not lift their feet after the mechanical stimulation reached 60 g, the stimulation was stopped and no more stimulation was added. The left and right hind paws of each rat were stimulated three times cumulatively, with an interval of more than 1 minute between stimulations. The average of the three times was taken, and the threshold of the right hind paw lifting and the difference between the left and right paw lifting thresholds were calculated to evaluate the analgesic effect of the drug on mechanical pain stimulation.

[0364] The test results are as follows Figure 1-2 As shown. Figure 1 It can be seen that when the dose reaches 5 mg / kg, compound 20 can effectively alleviate mechanical pain sensitivity under inflammatory conditions. Figure 2 It can be seen that at the same dose (5 mg / kg), the analgesic effect of compound 20 on mechanical stimulation is better than that of morphine. After combined use with the σ1R selective agonist PRE084, the analgesic effect of compound 20 on mechanical stimulation is inhibited. After combined use with naloxone to selectively block MOR, the analgesic effect of compound 20 on mechanical stimulation disappears. This proves that compound 20 is a dual-target analgesic with high selectivity for σ1R and MOR.

[0365] 3. Thermal pain sensitivity measurement

[0366] The plantar inflammation model was established by injecting 0.1 ml of λ-carrageenan (1% w / v dissolved in saline) into the subcutaneous tissue of the plantar surface of the right hind paw of rats. After the plantar injection, the animals were placed in the laboratory for 3 hours to adapt, and the rats with right hind paw pain model were placed in a separate opaque glass floor evaluation room for 1 hour to adapt. After the adaptation, the animals were intraperitoneally administered (the animals were divided into 8 groups, 6 in each group, and the doses of compound 20 were 0 mg / kg (equivalent saline replacement), 1 mg / kg, 3 mg / kg, 5 mg / kg, 7 mg / kg, and compound 20 5 mg / kg + PRE084 40 mg / kg, compound 20 5 mg / kg + naloxone 2 mg / kg, morphine 5 mg / kg), and 30 minutes later, the thermal pain test was performed using the Hargreaves pain meter (Hargreaves Apparatus, Ugo-Basile, Varese, Italy). At the beginning of the test, an infrared heat flux laser (model 37300, Ugo-Basile) was used at 85 mW / cm 2 A laser beam was focused on the left or right hind paw of the rat with a thermal radiation intensity of 100 nm. The latency of the rat to lift its foot was detected. The maximum stimulation time was 15 seconds. If the rat did not lift its foot after 15 seconds of thermal stimulation, the stimulation was stopped and no longer extended. The left and right hind paws of each rat were stimulated three times cumulatively, with an interval of more than 1 minute. The average of the three times was taken to calculate the latency of the right hind paw and the difference in the latency of the left and right paws to evaluate the analgesic effect of the drug on thermal pain stimulation.

[0367] The test results are as follows Figure 3-4 As shown. Figure 3 It can be seen that when the dose reaches 5 mg / kg, compound 20 can effectively alleviate thermal pain sensitivity under inflammatory conditions. Figure 4 It can be seen that at the same dose (5 mg / kg), the analgesic effect of compound 20 on heat stimulation is better than that of morphine. After combined use with the σ1R selective agonist PRE084, the analgesic effect of compound 20 on heat stimulation is inhibited. After combined use with naloxone to selectively block MOR, the analgesic effect of compound 20 on heat stimulation disappears. This proves that compound 20 is a dual-target analgesic with high selectivity for σ1R and MOR.

[0368] (IV) Respiratory function testing

[0369] The respiratory function of rats was tested using the EMKA animal lung function test system (EMKA TECHNOLOGIES, Paris, France). After the rats were adapted to the laboratory for more than 1 hour, they were placed in a sealed air pressure test chamber for 30 minutes, and intraperitoneally injected with drugs (the animals were divided into 3 groups, 6 in each group, and the doses of compound 20 were 0 mg / kg (equivalent saline replacement), 10 mg / kg, and 10 mg / kg of morphine), and returned to the sealed air pressure test chamber, and the air pressure change values ​​in each test chamber were recorded every minute. The respiratory rate, tidal volume and minute ventilation of the animals were analyzed by EMKA IOX software to evaluate the effect of the drugs on respiratory function.

[0370] The test results are as follows Figure 5 As shown. Figure 5 It can be seen that at the same dose (10 mg / kg), the inhibitory effect of compound 20 on respiration is weaker than that of morphine, and the inhibition of respiratory rate and minute ventilation is weaker than that of morphine, and it is safer than morphine in terms of respiratory depression.

[0371] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described 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 above-described embodiments only express several implementation methods of the present application, which is convenient for understanding the technical solution of the present application in detail, but it cannot be understood as limiting the scope of protection of the patent application. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present application, several modifications and improvements can be made, which all belong to the scope of protection of the present application. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the scope of protection of the claims attached to the present application. Therefore, the scope of protection of the patent of this application shall be based on the contents of the attached claims, and the description and drawings may be used to interpret the contents of the claims.

Claims

1. An azaspirocyclic compound represented by the following formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: in, R 1 is 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 Aryl or substituted or unsubstituted 5- to 20-membered heteroaryl, wherein the heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur; R 2 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted heterocyclic group containing 3-10 ring atoms, substituted or unsubstituted C6-C 20 Aryl or substituted or unsubstituted 5- to 20-membered heteroaryl, wherein the heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur; R 3 and R 4 Each independently represents H, C1-C6 alkyl, or R 3 and R 4 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group; R 5 and R 6 Each independently represents H, C1-C6 alkyl, C1-C6 alkoxy, or R 5 and R 6 Together with the attached carbon atom, it forms a carbonyl group; n is 1, 2 or 3; The substituted 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.

2. The azaspiro compound according to claim 1, characterized in that R 1 is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted heterocyclic group containing 3 to 10 ring atoms, a substituted or unsubstituted C6-C 20 Aryl or substituted or unsubstituted 5- to 20-membered heteroaryl, wherein the heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur; R 2 is H, substituted or unsubstituted C6-C 20 Aryl or substituted or unsubstituted 5- to 20-membered heteroaryl, said heteroaryl and heterocycloalkyl each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur.

3. The azaspiro compound according to claim 1, characterized in that R 1 It is a substituted or unsubstituted C2-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted heterocyclyl 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 heterocycloalkyl group each independently contain at least one heteroatom selected from nitrogen, oxygen and sulfur.

4. The azaspiro compound according to claim 1, characterized in that R 2 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.

5. The azaspiro compound according to claim 1, characterized in that: R 3 and R 4 Each independently represents H, C1-C2 alkyl, or R 3 and R 4 Together with the attached carbon atom, it forms a C3-C4 cycloalkyl group.

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

7. The azaspiro compound according to any one of claims 1 to 6, characterized in that: n is 2.

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

9. A pharmaceutical composition, characterized in that The invention comprises the azaspiro compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.

10. Use of the azaspiro compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to 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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