Novel aminoketone compounds, their preparation methods, and applications

Abstract

The present invention relates to novel aminoketone compounds and their preparation methods and uses.Specifically, the compound of the present invention has the structure represented by formula (I), wherein each group and substituent is as defined herein, and the present invention further discloses the preparation method of said compound and its use in antidepressant. [Formula 1] TIFF2025508010000262.tif35167

Description

Detailed description of the invention

[0001] [Technical field] This invention relates to the field of medicine, and more specifically to novel aminoketone compounds, as well as methods for preparing them and their uses.

[0002] [Background technology] Depression is a mood disorder characterized by low mood, sadness, despair, and feelings of melancholy, usually accompanied by symptoms such as sleep disturbances, anxiety, and physical discomfort. As a common and serious mental illness, it can have a profound impact on patients' ability to work and quality of life, and can be life-threatening. With the increasing number of various stressors, depression has become a common illness with a high prevalence in modern society, and its prevalence is increasing rapidly year by year. According to World Health Organization statistics, there are approximately 350 million people with depression worldwide, and it is currently the fourth largest disease burden globally. It is one of the main causes of functional impairment in patients, and it is projected that by 2030, the disease burden due to depression will become the largest globally.

[0003] Currently, the primary treatment for depression remains pharmacotherapy. More than 60 years have passed since antidepressants were first introduced to the market, and they have evolved from tricyclic antidepressants (TCAs, imipramine, clomipramine, amitriptyline, etc.) and monoamine oxidase inhibitors (MAOIs, moclobemide, etc.) to more advanced selective 5-serotonin (5-HT) reuptake inhibitors (SSRIs, fluoxetine, paroxetine, citalopram, sertraline, fluvoxamine, etc.), selective norepinephrine (NE) reuptake inhibitors (NaRIs, reboxetine), 5-HT and NE double reuptake inhibitors (SNRIs, venlafaxine, duloxetine, etc.), and NE and specific 5-HT double reuptake inhibitors (NaSSAs, mirtazapine), playing a crucial role in the prevention and treatment of depression. However, these drugs also have significant drawbacks. 1. The onset of action is slow, and it usually takes 2-4 weeks or more for a more significant therapeutic effect to be observed. 2. The treatment response rate is low, with only about one-third of patients responding to the first medication, and about two-thirds responding only after trying multiple antidepressants. In particular, for patients with major depressive disorder (MDD) who have suicidal tendencies, all existing antidepressants have the drawback of a slow onset of action (significant therapeutic effects appearing 2-4 weeks after taking the medication), making them extremely harmful to patients at high risk of suicide.

[0004] Ketamine has been used clinically as a traditional anesthetic for over 50 years. However, subsequent research (Arch Gen Psychiatry, 2006;63(8):856-864) has shown that subanesthetically low doses of ketamine are ineffective in treating treatment-resistant depression. It was found to produce a rapid (within a few hours), significant, and relatively sustained (about a week) antidepressant effect in patients with treatment-resistant depression (TRD), and gradually began to attract clinical attention. Currently, the FDA has approved esketamine nasal spray (spravato), developed by Johnson & Johnson, for the treatment of treatment-resistant depression (TRD) and major depression associated with suicidal ideation / suicidal behavior, ushering in a new era of rapid treatment for depression.

[0005] Ketamine exhibits rapid and sustained antidepressant effects, but it also has several unique issues that may affect its clinical use. 1. Side effects: These include psychotic symptoms, dissociative side effects, elevated blood pressure, respiratory depression, and other side effects, and long-term use may cause urinary tract dysfunction or renal failure. 2. It has low oral bioavailability and is difficult to administer orally. Currently administered as a nasal spray, 3. Ketamine causes euphoria, hallucinations, and is addictive. These side effects of ketamine require use under the supervision of a qualified medical institution, as it causes significant inconvenience to the patient's daily life.

[0006] In May 2016, Zanos et al. published research findings (Nature, 2016, 533, 481-486) ​​showing that the rapid and sustained antidepressant effect of ketamine is not due to ketamine itself, but primarily to its metabolite, (2R,6R)-HNK. Currently, (2R,6R)-HNK is in Phase I clinical trials.

[0007] (2R,6R)-HNK has the highly desirable characteristic of being able to rapidly treat depression, but it still has many drawbacks. For example, its antidepressant activity is weak, exposure to brain tissue is not high, the brain / plasma ratio is not high, and due to its chemical structure, (2R,6R)-HNK has low chemical stability and decomposes easily, generating impurities, thus requiring higher storage conditions. Currently, in clinical studies, it is administered by intravenous injection, resulting in insufficient patient compliance.

[0008] Therefore, there is an urgent clinical need for a novel antidepressant that has immediate efficacy, excellent therapeutic effects, a high brain exposure level, a high brain / plasma ratio, high safety, excellent chemical stability, and is orally ingestible.

[0009] [Summary of the Invention] [Problems to be Solved by the Invention] An object of the present invention is to provide a compound having a novel structure, rapid and sustained antidepressant activity, a high brain / plasma ratio, high safety, and excellent chemical stability.

[0010] [Means for Solving the Problems] A first aspect of the present invention provides a compound represented by formula (I), or a tautomer, enantiomer, diastereomer, solvate or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0011] [Chemical Formula]

[0012] Here, R 1 is selected from the group consisting of deuterium and C1-C6 alkyl groups, R 2 , R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl groups, deuterated C1-C6 alkyl groups, and -(C=O)-C1-C6 alkyl groups, R 5 , R 6 , R 7 , R 8 , R 9 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, C1-C6 alkoxy groups, halogenated C1-C6 alkoxy groups, halogens, nitro groups, and cyano groups, and R 5 , R 6 I , R 7 , R 8 , R 9At least two of them are hydrogen, The stereochemistry of the α- or β-position carbon atom is independently selected from the group consisting of R, S, and (R,S).

[0013] In another preferred example, the additional condition is R 6 , R 7 , R 8 If R is hydrogen, 5 and / or R 9 It is not Cl. In another preferred example, the compound is a compound represented by formula (IA), (IB), (IC), (ID), (IE), (IF), or (IG),

[0014] [ka]

[0015] In equations (IA) and (IB), R 1 , R 5 , R 6 , R 7 , R 8 , R 9 This is as defined above,

[0016] [ka]

[0017] In equations (IC) and (ID), R 1 , R 5 , R 6 , R 7 , R 8 , R 9 As defined above, R 3 , R 4 Each of these is independently hydrogen, a C1-C6 alkyl group, or a deuterated C1-C6 alkyl group, and R 3 , R 4 At the same time, it is not hydrogen,

[0018] [ka]

[0019] In expressions (IE) and (IF), R 1 , R 5 , R 6 , R 7 , R 8 , R 9 As defined above, R 3 It is a -(C=O)-C1-C6 alkyl group,

[0020] [ka]

[0021] In equation (IG), R 1 , R 5 , R 6 , R 7 , R 8 , R 9 As defined above, R 2 R is selected from the group consisting of C1-C6 alkyl groups, deuterated C1-C6 alkyl groups, and -(C=O)-C1-C6 alkyl groups. 3 This is selected from the group consisting of hydrogen, C1-C6 alkyl groups, and deuterated C1-C6 alkyl groups.

[0022] In another preferred example, R 5 , R 6 , R 7 , R 8 , R 9 Two, three, or four of them are hydrogen atoms. In another preferred example, R 1 It is either a deuterium or a methyl group.

[0023] In another preferred example, R 2 , R 3 , R 4 These are, independently, hydrogen, a methyl group, a deuterated methyl group, an ethyl group, an isopropyl group, an acetyl group, or a propionyl group.

[0024] In another preferred example, R 2 is hydrogen, and R 3 It is hydrogen, R 4 These are a methyl group, a deuterated methyl group, an ethyl group, an isopropyl group, an acetyl group, or a propionyl group.

[0025] In another preferred example, R 5 , R 6 , R 7 , R 8 , R 9 These are, independently, hydrogen, fluorine, chlorine, methoxy group, trifluoromethyl group, trifluoromethoxy group, or cyano group.

[0026] In another preferred example, the compound is a compound represented by formula (IC) or (ID),

[0027] [ka]

[0028] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 This is as defined above, R 3 It is hydrogen, R 4 The group is selected from the group consisting of C1-C6 alkyl groups, deuterated C1-C6 alkyl groups, and -(C=O)-C1-C6 alkyl groups.

[0029] In another preferred example, the compound is selected from the group consisting of the following:

[0030] [ka] TIFF0007888184000008.tif234167TIFF0007888184000009.tif232167TIFF0007888184000010.tif246167TIFF0007888184000011.tif24016 7TIFF0007888184000012.tif239167TIFF0007888184000013.tif244167TIFF0007888184000014.tif244167TIFF0007888184000015.tif45167

[0031] A second aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition is 1) One or more safe and effective amounts of the compounds described in the first aspect of the present invention, or their tautomers, enantiomers, diastereomers, ceramides or mixtures thereof, or pharmaceutically acceptable salts thereof, and 2) Contains pharmaceutically acceptable carriers or excipients.

[0032] In another preferred example, the pharmaceutical composition is an oral formulation. A third aspect of the present invention provides a method for preparing the compound described in the first aspect of the present invention, or its tautomer, enantiomer, diastereomer, ceramide or mixture thereof, or a pharmaceutically acceptable salt thereof. (1) The above method includes steps a to e,

[0033] [ka]

[0034] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 This is as defined in the first aspect of the present invention, a. In an aprotic solvent, compound I-1 is reacted with a deuterating reagent or an alkylating reagent to form compound I-2. b. In an aprotic solvent, compound I-2 is reacted with trimethylchlorosilane to form compound I-3. c. In an aprotic solvent, compound I-3 and the oxidizing agent are oxidized to form compound I-4. d. In an aprotic solvent, remove the trimethylsilyl protecting group from compound I-4 to form compound I-5. e. In polar aprotic solvents, the t-butoxycarbonyl protecting group from compound I-5 Remove to form compound IA, or (2) The method comprising steps a to h,

[0035] [ka]

[0036] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 This is as defined in the first aspect of the present invention, a. In a polar aprotic solvent, the t-butoxycarbonyl protecting group is removed from compound I-2 to form compound II-1. b. In an aprotic solvent, compound II-1 is reacted with p-methoxybenzyl chloride to form compound II-2. c. In an aprotic solvent, compound II-2 is reacted with trifluoroacetic anhydride to form compound II-3. d. Compound II-3 is reacted with trimethylchlorosilane in an aprotic solvent to form compound II-4. e. In an aprotic solvent, compound II-4 and the oxidizing agent are oxidized to form compound II-5. f. In an aprotic solvent, remove the trimethylsilyl protecting group from compound II-5 to form compound II-6. g. In a protic solvent, the trifluoroacetyl group is removed from Compound II-6 to form Compound II-7, h. Under acidic conditions, the p-methoxybenzyl group is removed from Compound II-7 to form Compound I-B, or (3) The method includes steps a to d,

[0037]

Chemical formula

[0038] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 is as defined in the first aspect of the present invention, and R 3 is a C1-C6 alkyl group or a deuterated C1-Cz alkyl group, and R 10 is a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkoxy group, or a benzyloxy group, a. In an aprotic solvent, Compound III-1 is reacted with trimethylchlorosilane to form Compound III-2, <000071Z>b. In an aprotic solvent, Compound III-2 is oxidized with an oxidizing agent to form Compound III-3, c. In an aprotic solvent, the trimethylsilyl protecting group is removed from Compound III-3 to form Compound III-4, d. In a protic solvent or an aprotic solvent, the R 10 carbonyl protecting group is removed from Compound III-4 to form Compound I-D, or (4) The method includes step a,

[0039]

Chemical formula

[0040] Here, R 1 , R5 , R 6 , R 7 , R 8 , R 9 R is as defined in the first aspect of the present invention, 3 , R 4 Each of these is independently hydrogen, a C1-C6 alkyl group, and a deuterated C1-C6 alkyl group, and R 3 , R 4 At the same time, it is not hydrogen, a. In a protic or aprotic solvent, compound IA or IB is reacted with the corresponding aldehyde or ketone to form the corresponding compound IC or ID. or (5) the method comprising step a,

[0041] [ka]

[0042] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 R is as defined in the first aspect of the present invention, 3 It is a -(C=O)-C1-C6 alkyl group, a. In an aprotic solvent, compound IA or IB is reacted with the corresponding acyl chloride or acid anhydride to form the corresponding compound IE or IF. or (6) the method comprising steps a to b,

[0043] [ka]

[0044] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9R is as defined in the first aspect of the present invention, 2 These are C1-C6 alkyl groups, deuterated C1-C6 alkyl groups, and -(C=O)-C1-C6 alkyl groups, and R 3 These are hydrogen, a C1-C6 alkyl group, and a deuterated C1-C6 alkyl group. a. In an aprotic solvent, compound VI-1 is reacted with the corresponding alkylating reagent, deuterated alkylating reagent, acyl chloride, or acid anhydride to form the corresponding compound VI-2. b. In a polar aprotic solvent, the t-butoxycarbonyl protecting group is removed from compound VI-2 to form compound IG.

[0045] In another preferred example, The method for preparing compound III-1 includes steps a to b,

[0046] [ka]

[0047] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 R is as defined in the first aspect of the present invention, 3 is a C1-C6 alkyl group or a deuterated C1-C6 alkyl group, R 10 These are C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, C1-C6 alkoxy groups, and benzyloxy groups. a. In a protic or aprotic solvent, compound II-1 is reacted with the corresponding aldehyde or ketone to form compound VII-1. b. In an aprotic solvent, compound VII-1 is reacted with an acid anhydride or acyl chloride to form compound III-1. Alternatively, the method for preparing compound III-1 includes steps a to b,

[0048] [ka]

[0049] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 R is as defined in the first aspect of the present invention, 3 is a C1-C6 alkyl group or a deuterated C1-C6 alkyl group, R 10 These are C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, C1-C6 alkoxy groups, and benzyloxy groups. a. In an aprotic solvent, compound II-1 is reacted with an acid anhydride or acyl chloride to form compound VIII-1. b. Compound VIII-1 is reacted with the corresponding alkylating reagent or deuterated alkylating reagent in a protic or aprotic solvent to form compound III-1.

[0050] A fourth aspect of the present invention provides uses for the compounds described in the first aspect of the present invention, or their tautomers, enantiomers, diastereomers, ceramides or mixtures thereof, or pharmaceutically acceptable salts thereof, for use in the preparation of drugs for treating diseases related to the nervous system.

[0051] In another preferred example, the neurological disorder is selected from the group consisting of depression, post-traumatic stress disorder, obsessive-compulsive disorder, anxiety, and pain.

[0052] [Effects of the invention] It should be understood that, within the scope of the present invention, new or preferred technical solutions can be constructed by combining the above-described technical features of the present invention with the technical features specifically described below (e.g., in the examples). Due to space limitations, this will not be repeated here. [Modes for carrying out the invention]

[0053] After conducting extensive experimental studies including drug design, chemical synthesis, and structural testing, the inventors synthesized a series of compounds represented by a novel structure and general structural formula (I). Through the most classical antidepressant efficacy experiments—forced swimming experiments in mice, metabolic studies, and other scientific experiments—the inventors discovered for the first time that the compound represented by the following general formula (I) possesses excellent drug potential, including rapid oral onset, potent and sustained antidepressant activity, high brain exposure, a high brain / plasma ratio, and excellent chemical stability, making it particularly suitable as an antidepressant for the treatment of depression and neurological disorders. Based on this, the inventors completed the present invention.

[0054] term In this invention, unless otherwise specified, terms used have the general meanings known to those skilled in the art.

[0055] In this invention, the term "halogen" refers to F, Cl, Br, or I. In the present invention, "C1-C6 alkyl group" or "C1-C6 alkyl group" refers to a linear or branched alkyl group containing 1 to 6 carbon atoms, such as a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, neopentyl group, t-pentyl group, or similar groups.

[0056] In the present invention, the term "C1-C6 alkoxy group" or "C1-C6 alkoxy group" non-limitingly refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. Preferably, it is a C1-C4 alkoxy group.

[0057] In this invention, the term "halogenation" refers to substitution with a halogen. In this invention, the term "deuterated" refers to substitution with deuterium.

[0058] In the present invention, the term “substitution” refers to the substitution of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is one of the substituents described correspondingly in this specification or in each example. Unless otherwise specified, the particular substituent may have substituents selected from the particular group at any substitutable site of the group, and such substituents may be identical or different at each position. Those skilled in the art will understand that the substituent combinations intended by the present invention are either stable combinations or scientifically achievable combinations.

[0059] It should be understood that when a particular group is present simultaneously at multiple different positions in a compound, its definition at each position is independent of each other and may be the same or different. In other words, the phrase "selected from the group consisting of..." has the same meaning as the phrase "selected independently from the group consisting of...".

[0060] compound The present invention provides a compound represented by formula (I), or its tautomers, enantiomers, diastereomers, ceramides or mixtures thereof, or pharmaceutically acceptable salts thereof. ,

[0061] [ka]

[0062] Here, each group is as defined above. In another preferred example, in the compound, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 Any one of these is independently the corresponding group in the specific compound described in the present invention.

[0063] In another preferred example, the compound is preferably the compound prepared in the example. As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is suitable as a drug when formed with an acid or base of the compound of the present invention. pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is one formed with an acid of the compound of the present invention. 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.

[0064] Preparation method The following describes in more detail the methods for preparing compounds of the formula (I) structure of the present invention, but these specific methods do not limit the present invention in any way. Compounds of the present invention can also be conveniently prepared by arbitrarily combining various synthesis methods described herein or known in the art, and such combinations can be easily performed by those skilled in the art.

[0065] Typically, the preparation process for the compounds of the present invention is as follows, and all raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0066] The compounds of the present invention can be prepared by the following methods, but the conditions of such methods, such as reactants, solvents, acids, bases, amounts of compounds used, reaction temperature, and reaction time, are not limited to those described below. The compounds of the present invention can also be conveniently prepared by arbitrarily combining various synthesis methods described herein or known to those skilled in the art.

[0067] The compound of formula (I) of the present invention can be prepared according to the preferred methods of reaction formula (1), reaction formula (2), reaction formula (3), reaction formula (4), reaction formula (5), and reaction formula (6).

[0068] Reaction equation (1):

[0069] [ka]

[0070] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 This is as defined above, a. Compound I-1 is reacted with heavy water or an alkylating reagent in an aprotic solvent under inert gas protection in the presence of an inorganic or organic base at -80°C to room temperature to obtain compound I-2. The alkylating reagent may be C1-C6 alkyl iodide, C1-C6 alkyl bromide, or C1-C6 alkyl sulfate; the inorganic or organic base may be sodium hydrogen, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), potassium hexamethyldisilazide (KHMDS), or butyllithium; the aprotic solvent may be toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or N,N-dimethylformamide; and the inert gas may be nitrogen gas or argon gas.

[0071] b. Compound I-2 and trimethylchlorosilane are reacted under inert gas protection in an aprotic solvent at -80°C to room temperature and under organic base conditions to obtain compound I-3. The aprotic solvent may be tetrahydrofuran or 2-methyltetrahydrofuran, the organic base may be lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilamide, or butyllithium, and the inert gas may be nitrogen gas or argon gas.

[0072] c. Compound I-3 is oxidized with an oxidizing agent in an aprotic solvent under conditions of -40°C to room temperature to obtain compound I-4. The aprotic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or chloroform, and the oxidizing agent may be m-chloroperoxybenzoic acid or hydrogen peroxide.

[0073] d. Compound I-4 is subjected to the removal of the trimethylsilyl protecting group with a fluorine-containing reagent in an aprotic solvent under conditions of 0°C to room temperature to produce compound I-5. The aprotic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or chloroform, and the fluorine-containing reagent may be tetrabutylammonium fluoride.

[0074] e. Under the action of an organic or inorganic acid, in a polar aprotic solvent under conditions of 0°C to room temperature, the t-butoxycarbonyl protecting group is removed from compound I-5 to obtain compound IA. The organic or inorganic acid may be hydrochloric acid, sulfuric acid, hydrobromic acid, or trifluoroacetic acid, and the polar aprotic solvent may be tetrahydrofuran, dimethyltetrahydrofuran, or dichloro It could be methane or chloroform.

[0075] Reaction equation (2):

[0076] [ka]

[0077] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 This is as defined above, a. Under the action of an organic acid or an inorganic acid, in an aprotic polar solvent, at 0 °C to room temperature, the tert-butoxycarbonyl protecting group is removed from Compound I-2 to obtain Compound II-1. The organic acid or inorganic acid may be hydrochloric acid, sulfuric acid, hydrobromic acid, or trifluoroacetic acid, and the aprotic polar solvent may be tetrahydrofuran, dimethyltetrahydrofuran, dichloromethane, or chloroform.

[0078] b. Compound II-1 and p-methoxybenzaldehyde are reacted in a protic or aprotic solvent or a mixed solvent thereof, at 0 °C to room temperature, in the presence of a reducing agent to obtain Compound II-2. The protic or aprotic solvent may be methanol, ethanol, tetrahydrofuran, ethyl acetate, dichloromethane, or 1,4-dioxane, and the reducing agent may be sodium cyanoborohydride or sodium borohydride acetate.

[0079] c. Compound II-2 and trifluoroacetic anhydride are reacted in an aprotic solvent, at 0 °C to room temperature and in the presence of an organic base to obtain Compound II-3. The aprotic solvent may be tetrahydrofuran, 1,4-dioxane, or dichloromethane, and the organic base may be triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, or imidazole.

[0080] d. Compound II-3 and trimethylchlorosilane are reacted under the protection of an inert gas, in an aprotic solvent, at -80 °C to room temperature and in the presence of an organic base to obtain Compound II-4. The aprotic solvent may be tetrahydrofuran or 2-methyltetrahydrofuran, the organic base may be lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, or butyllithium, and the inert gas may be nitrogen gas or argon gas.

[0081] e. Compound II-4 is oxidized with an oxidizing agent in an aprotic solvent under conditions of -40°C to room temperature to obtain compound II-5. The aprotic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or chloroform, and the oxidizing agent may be m-chloroperoxybenzoic acid or hydrogen peroxide.

[0082] f. In an aprotic solvent, under conditions of 0°C to room temperature, the trimethylsilyl protecting group is removed from compound II-5 with a fluorine-containing reagent to produce compound II-6. The aprotic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or chloroform, and the fluorine-containing reagent may be tetrabutylammonium fluoride.

[0083] g. Under the action of an inorganic base, in a protic solvent, under conditions of 0°C to room temperature, the trifluoromethanesulfonyl protecting group is removed from compound II-6 to obtain compound II-7. The inorganic base may be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or cesium carbonate, and the protic solvent may be methanol, ethanol, water, or a mixture thereof.

[0084] h. Under the action of an organic or inorganic acid, at room temperature to 100°C, the p-methoxybenzyl protecting group is removed from compound II-7 to obtain compound IB. The organic or inorganic acid may be hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, or trifluoroacetic acid. Reaction equation (3):

[0085] [ka]

[0086] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 As defined above, R 3is a C1-C6 alkyl group or a deuterated C1-C6 alkyl group, R 10 These are C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, C1-C6 alkoxy groups, and benzyloxy groups. a. Compound III-1 and trimethylchlorosilane are reacted under inert gas protection in an aprotic solvent at -80°C to room temperature and under organic base conditions to obtain compound III-2. The aprotic solvent may be tetrahydrofuran or 2-methyltetrahydrofuran, the organic base may be lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilamide, or butyllithium, and the inert gas may be nitrogen gas or argon gas.

[0087] b. Compound III-2 is oxidized with an oxidizing agent in an aprotic solvent under conditions of -40°C to room temperature to obtain compound III-3. The aprotic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or chloroform, and the oxidizing agent may be m-chloroperoxybenzoic acid or hydrogen peroxide.

[0088] c. In an aprotic solvent, under conditions of 0°C to room temperature, the trimethylsilyl protecting group is removed from compound III-3 with a fluorine-containing reagent to produce compound III-4. The aprotic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or chloroform, and the fluorine-containing reagent may be tetrabutylammonium fluoride.

[0089] d. Compounds III-4 to R in a protic or aprotic solvent under the action of an inorganic base, inorganic acid, or organic acid, under conditions of 0°C to room temperature. 10The carbonyl protecting group is removed to obtain compound ID. The inorganic base may be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or cesium carbonate; the inorganic or organic acid may be hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, or trifluoroacetic acid; the protic solvent may be methanol, ethanol, water, or a mixture thereof; and the aprotic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or chloroform.

[0090] Reaction equation (4):

[0091] [ka]

[0092] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 As defined above, R 3 , R 4 Each of these is independently hydrogen, a C1-C6 alkyl group, and a deuterated C1-C6 alkyl group, and R 3 , R 4 At the same time, it is not hydrogen, a. Compound IA or IB is reacted with an aldehyde or ketone in a protic or aprotic solvent or a mixed solvent in the presence or absence of a catalyst and in the presence of a hydrogen source to obtain a compound IC or ID having a substituent on the amino group. The aldehyde or ketone may be a deuterated or non-deuterated C1-C6 alkyl aldehyde or a deuterated or non-deuterated C1-C6 alkyl ketone; the protic or aprotic solvent may be methanol, ethanol, water, tetrahydrofuran, ethyl acetate, dichloromethane, or 1,4-dioxane; the catalyst may be Pd / C or Pd(OH)2 / C; and the hydrogen source may be hydrogen gas, formic acid, sodium borohydride acetate, or sodium borohydride cyanohydride.

[0093] Reaction formula (5):

[0094]

Chem.

[0095] Here, R 1 、R 5 、R 6 、R 7 、R 8 、R 9 are as defined above, and R 3 is a -(C=O)-C1-C6 alkyl group, a. React compound I-A or I-B with an acyl chloride or acid anhydride in an aprotic solvent at 0 °C to room temperature and under organic base conditions to obtain compound I-E or I-F. The aprotic solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, ethyl acetate, and the organic base can be triethylamine, imidazole, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine. The acyl chloride can be a C2-C6 alkyl acyl chloride, and the acid anhydride can be a C4-C 12 alkyl acid anhydride.

[0096] Reaction formula (6):

[0097]

Chem.

[0098] Here, R 1 、R 5 、R 6 、R 7 、R 8 、R 9 are as defined above, and R 2 is a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a -(C=O)-C1-C6 alkyl group, and R 3 is hydrogen, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group. a. Compound VI-1 is reacted with an alkylating reagent, a deuterated alkylating reagent, an asyl chloride, or an acid anhydride in an aprotic solvent at 0°C to room temperature and under conditions of an organic base to obtain compound VI-2. The aprotic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or dichloromethane; the organic base may be triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, or imidazole; the alkylating reagent or deuterated alkylating reagent may be a deuterated or non-deuterated C1-C6 iodide alkane, a deuterated or non-deuterated C1-C6 bromide alkane, or a deuterated or non-deuterated C1-C6 alkyl sulfate; the asyl chloride may be a C2-C6 alkylasyl chloride; and the acid anhydride may be a C4-C 12 It may be an alkyl anhydride.

[0099] b. Under the action of an organic or inorganic acid, in a polar aprotic solvent under conditions of 0°C to room temperature, the t-butoxycarbonyl protecting group is removed from compound VI-2 to obtain compound IG. The organic or inorganic acid may be hydrochloric acid, sulfuric acid, hydrobromic acid, or trifluoroacetic acid, and the polar aprotic solvent may be tetrahydrofuran, dimethyltetrahydrofuran, dichloromethane, or chloroform.

[0100] Intermediate III-1 can be prepared according to the method of reaction formula (7) or reaction formula (8). Reaction equation (7)

[0101] [ka]

[0102] Here, R 1 , R 5 , R 6 , R 7 , R 8 , R 9 As defined above, R 3is a C1-C6 alkyl group or a deuterated C1-C6 alkyl group, R 10 These are C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, C1-C6 alkoxy groups, and benzyloxy groups. a. Compound II-1 is reacted with an aldehyde or ketone in a protic or aprotic solvent or a mixed solvent in the presence or absence of a catalyst and in the presence of a hydrogen source to obtain compound VII-1. The aldehyde or ketone may be a deuterated or non-deuterated C1-C6 alkyl aldehyde or a deuterated or non-deuterated C1-C6 alkyl ketone; the protic or aprotic solvent may be methanol, ethanol, water, tetrahydrofuran, ethyl acetate, dichloromethane, or 1,4-dioxane; the catalyst may be Pd / C or Pd(OH)2 / C; and the hydrogen source may be hydrogen gas, formic acid, sodium borohydride acetate, or sodium borohydride cyanohydride.

[0103] b. Compound VII-1 is reacted with an asyl chloride or acid anhydride in an aprotic solvent at 0°C to room temperature and under organic base conditions to obtain compound III-1. The aprotic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, or ethyl acetate; the organic base may be triethylamine, imidazole, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, or pyridine; the asyl chloride may be C2-C6 alkyl asyl chloride or benzyl chloroformate; and the acid anhydride may be C4-C 12 Alkyl anhydrides It may be di-t-butyl dicarbonate or trifluoroacetic anhydride.

[0104] Reaction equation (8)

[0105] [ka]

[0106] Here, R 1 , R5 , R 6 , R 7 , R 8 , R 9 As defined above, R 3 is a C1-C6 alkyl group or a deuterated C1-C6 alkyl group, R 10 These are C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, C1-C6 alkoxy groups, and benzyloxy groups. a. Compound II-1 is reacted with an asyl chloride or acid anhydride in an aprotic solvent at 0°C to room temperature and under organic base conditions to obtain compound VIII-1. The aprotic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, or ethyl acetate; the organic base may be triethylamine, imidazole, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, or pyridine; the asyl chloride may be C2-C6 alkyl asyl chloride or benzyl chloroformate; and the acid anhydride may be C4-C6 12 These may be alkyl anhydrides, di-t-butyl dicarbonate, or trifluoroacetic anhydride.

[0107] b. Compound III-1 is obtained by reacting compound VIII-1 with an alkylating reagent or deuterated alkylating reagent in an aprotic solvent under inert gas protection in the presence of an inorganic or organic base at -80°C to room temperature. The alkylating reagent or deuterated alkylating reagent may be a deuterated or non-deuterated C1-C6 alkyl iodide, a deuterated or non-deuterated C1-C6 alkyl bromide, or a deuterated or non-deuterated C1-C6 alkyl sulfate; the inorganic or organic base may be sodium hydrogen, lithium diisopropylamide, lithium hexamethyldisylamide, potassium hexamethyldisylamide, or butyllithium; the aprotic solvent may be toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or N,N-dimethylformamide; and the inert gas may be nitrogen gas or argon gas.

[0108] The pharmaceutically acceptable salts are those formed by a compound of general formula (I) (for example, a compound of general formula (IA), a compound of general formula (IB), a compound of general formula (IC), a compound of general formula (ID), or a compound of general formula (IG)) with an inorganic acid or an organic acid, and preferably, suitable inorganic acids for salt formation are hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, trifluoroacetic acid, nitric acid, or phosphoric acid, and suitable organic acids for salt formation are formic acid, acetic acid, propionic acid, oxalic acid, benzoic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, proline, phenylalanine, glutamic acid, and aspartic acid.

[0109] A pharmaceutically acceptable salt of compound I can be prepared by the following method: The compound of formula I (e.g., compounds IA, IB, IC, ID, or IG) or general formula I-5, general formula II-7, or general formula VI-2 is used in an aprotic solvent or a protic solvent. The compound I is reacted with various organic or inorganic acids in a rotonic solvent or a mixed solvent to obtain the corresponding organic or inorganic salt of compound I.

[0110] The aprotic or protic solvent may be methanol, ethanol, water, dichloromethane, tetrahydrofuran, ethyl acetate, or dioxane, and the organic or inorganic acid may be hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, trifluoroacetic acid, nitric acid, or phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, benzoic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, proline, phenylalanine, aspartic acid, or glutamic acid.

[0111] Pharmaceutical composition and administration method The present invention further provides a pharmaceutical composition, the pharmaceutical composition is 1) One or more safe and effective amounts of the compound, or its tautomers, enantiomers, diastereomers, ceramides or mixtures thereof, or pharmaceutically acceptable salts thereof, and 2) Contains pharmaceutically acceptable carriers or excipients.

[0112] In another preferred example, the pharmaceutical composition is an oral formulation. The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or vector in a safe and effective amount. Here, “safe and effective amount” means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000 mg of the compound / agent of the present invention, more preferably 10 to 1000 mg of the compound / agent of the present invention. Preferably, “one agent” is one capsule or tablet.

[0113] "Pharmacochemically acceptable carrier" means one or more compatible solid or liquid fillers or gels that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" means that each component of the composition can be blended with each other in relation to the compounds of the present invention and among them without significantly reducing the potency of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0114] The aforementioned pharmaceutical composition is in the form of an injection, capsule, tablet, pill, powder, or granule. The method of administering the compound or pharmaceutical composition of the present invention is not particularly limited, and typical methods of administration include (but are not limited to) oral, parenteral (intravenous, intramuscular, nasal spray, or subcutaneous), and topical administration.

[0115] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inactive excipient (or vector), such as sodium citrate or dicalcium phosphate, or (a) fillers or compatibilizers such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic, (c) glycerides (d) Humectants such as (agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and disintegrants such as sodium carbonate, (e) retarders such as paraffin, (f) absorption enhancers such as quaternary amine compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include a buffer.

[0116] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coating and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compound from such compositions can be delayed in specific parts of the digestive tract. Examples of usable embedding components are polymers and waxes. If necessary, the active compound can form microcapsules with one or more of the above excipients.

[0117] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, sesame oil, and sesame oil, or mixtures thereof.

[0118] In addition to these inert diluents, the composition may also include auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances. In addition to the active compound, the suspension may include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures thereof.

[0119] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous vectors, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0120] Dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable vector and any preservatives, buffers, or propellants as needed.

[0121] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable drugs (e.g., antidepressants). The therapeutic method of the present invention can be used alone or in combination with other therapeutic means or therapeutic agents.

[0122] When the pharmaceutical composition is used, the compound of the present invention is applied to mammals (e.g., humans) in need of treatment, where the dose at the time of administration is the effective dose to be considered, and for a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 20 to 1000 mg. Of course, the specific dose will depend on the route of administration, the patient's health condition, and other factors. The contributing factors must also be taken into consideration, and these are all within the scope of a skilled physician's abilities.

[0123] Compared to the prior art, the present invention has the following main advantages. (1) The present invention provides a compound having a novel structure, rapid and sustained antidepressant activity, and good drug discovery potential.

[0124] (2) The compounds of the present invention are expected to have superior antidepressant activity and chemical stability, and to lead to the development of new antidepressants with rapid and sustained therapeutic effects.

[0125] (3) Compared to (2R,6R)-HNK, the compounds of the present invention have higher exposure to brain tissue and a higher brain / plasma ratio, which means that the compounds of the present invention have a lower risk of peripheral side effects.

[0126] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are used solely for illustrative purposes and do not limit the scope of the invention. In the following embodiments, experimental methods that do not specify conditions generally follow conventional conditions or conditions proposed by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0127] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those well known to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can all be applied to the methods of the present invention. Preferred methods and materials described herein are for demonstration purposes only.

[0128] In all embodiments, 1 ¹H-NMR was recorded using a VarianMercury 300 or VarianMercury 400 nuclear magnetic resonance spectrometer, chemical shifts were expressed in δ (ppm), silica gel was used for separation, all were 200-300 mesh unless otherwise specified, and eluent ratios were all expressed by volume.

[0129] Preparation Examples Example 1: Preparation of 2-amino-2-(2-fluoro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methylcyclohexane-1-one (Compound 1)

[0130] [ka]

[0131] Step a: Preparation of 1-a

[0132] [ka]

[0133] (1-(2-fluoro-3-(trifluoromethoxy)phenyl)-2-oxocyclohexyl)carbamate t-butyl ester (5 g, 12.78 mmol) is dissolved in anhydrous THF (70 mL), cooled to -78 °C, and LDA (9.6 mL, 19.2 mmol) is added dropwise under Ar gas protection. After the dropwise addition is complete, the mixture is stirred at -78 °C for 1 hour, MeI (2.36 g, 16.63 mmol) is added, the temperature is slowly raised to 0 °C, and the mixture is stirred at 0 °C for 3 hours. The completion of the reaction of the starting materials was detected by TLC (PE / EA = 10 / 1), the reaction was quenched by adding saturated NH4Cl aqueous solution (10 mL), diluted with water (150 mL), extracted with ethyl acetate (60 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, column chromatography (PE / EA = 20 / 1-10 / 1) was performed, and the low-boiling point solvent was removed using a rotary evaporator to obtain 2.57 g of a colorless oily substance, with a yield of 49.6%. 1 H NMR(400MHz,CDCl3)δ 7.71(s,1H),7.25-7.18(m,2H), 6.62(s,1H),3.79(m,1H),2.46(m,1H),2.01(m,1H),1.85-1.63(m,3H),1.43(m,1H),1.31(s,9H) ),1.06(d,J=6.2Hz,3H). MS[M+H] + :406.

[0134] Step b: Preparation of 1-b

[0135] [ka]

[0136] Step 1: Dissolve compound 1-a (3.54 g, 8.73 mmol) in dry THF (60 mL), cool to -78 °C, and under Ar gas protection, add LDA (17.5 mL, 35.0 mmol) dropwise. After the dropwise addition is complete, stir at -78 °C for 1 hour, add TMSCl (3.79 g, 34.88 mmol), continue stirring for 10 minutes, then allow to rise naturally to room temperature and react for 1 hour. Detect completion of the reaction of the starting materials by TLC (PE / EA = 10 / 1), add saturated NH4Cl solution (10 mL) to quench the reaction, dilute with water (100 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, wash with saturated NaCl aqueous solution, dry over anhydrous sodium sulfate, filter, and remove the low-boiling point solvent from the filtrate using a rotary evaporator to obtain the crude product.

[0137] Step 2: Dissolve the obtained crude product in DCM (50 mL), cool to -20°C, add m-CPBA (3.54 g, 17.44 mmol) under Ar protection, stir at -20°C for 10 minutes, then raise to room temperature and stir for 1 hour.Detect completion of the reaction of the starting materials by TLC (PE / EA = 10 / 1), add saturated Na2SO3 aqueous solution (50 mL) and saturated NaHCO3 aqueous solution (50 mL) to quench the reaction, extract with DCM (60 mL x 3), combine the organic phases, and spin-dry the solvent to obtain the crude product.

[0138] Step 3: The obtained crude product is dissolved in THF (50 mL), cooled in an ice bath, and a solution of TBAF·3H2O (4.13 g, 13.09 mmol) dissolved in THF (10 mL) is added dropwise. After stirring for 30 minutes, the completion of the reaction of the starting materials is detected by TLC (PE / EA = 3 / 1). The reaction is quenched by adding saturated NaHCO3 aqueous solution (100 mL), extracted with ethyl acetate (60 mL x 3), the organic phases are combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and subjected to column chromatography (PE / EA = 10 / 1-5 / 1) to obtain 2.58 g of pale yellow solid. The yield is 70.1%. 1 H NMR(400MHz,CDCl3)δ 7.65(s,1H),7 .33-7.28(m,1H),7.23(m,1H),6.71(s,1H),3.8 2(s,1H),2.13(d,J=9.2Hz,1H),1.90-1.68(m,4 H),1.29(s,9H),0.88(s,3H). MS[M+H] + :422.

[0139] Step c: Preparation of Compound 1

[0140] [ka]

[0141] Compound 1-b (140 mg, 0.33 mmol) was dissolved in DCM (2.5 mL), and HCl / dioxane solution (0.7 mL, 4 M) was added under an ice bath. The mixture was stirred for 1 hour at room temperature, and the completion of the reaction of the starting materials was detected by TLC (PE / EA = 3 / 1). Saturated NaHCO3 aqueous solution was added to adjust the pH to approximately 10, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Column chromatography (DCM / MeOH = 100 / 1 to 50 / 1) was performed to obtain 95 mg of a white solid, with a yield of 88.8%. 1 H NMR(400MHz,CDCl3)δ 7.41(t,J=6.9Hz,1H),7.31(t,J=7.5Hz,1H),7.23(t,J=8.1Hz,1H),2.72-2.61(m ,1H),2.06-1.95(m,2H),1.94-1.81(m,2H),1.80-1.70(m,1H),1.08(s,3H). MS[M+H] + :322.

[0142] Example 2: Preparation of 2-amino-6-hydroxy-6-methyl-2-(2,4,6-trifluorotolyl)cyclohexane-1-one (Compound 2)

[0143] [ka]

[0144] Step a: Preparation of 2-a

[0145] [ka]

[0146] (2-oxo-1-(2,4,6-trifluorophenyl)cyclohexyl)carbamate t-butyl ester (2.9 g, 8.45 mmol) was used as a starting material and prepared according to the method described in step a of Example 1 to obtain 2.4 g of a colorless oily liquid with a yield of 79.5%. 1 H NMR(400MHz,CDCl3)δ 6.67(t,J=9.1Hz,2H),6.55(s,1H),3.82(d,J=7.8Hz,1H),2.57(m,1H),2.04(m,1H),1.89-1.64(m,3H),1.49- 1.41(m,1H),1.34(s,9H),1.06(d,J=6.1Hz,3H). MS[M+H] + :358.

[0147] Step b: Preparation of 2-b

[0148] [ka]

[0149] Compound 2-a (2.4 g, 6.72 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 1.71 g of a yellow oily substance, with a yield of 68.2%. MS(M+Na) + :396.

[0150] Step c: Preparation of Compound 2

[0151] [ka]

[0152] Compound 2-b (1.5 g, 4.02 mmol) was used as a raw material and prepared according to the method described in step c of Example 1 to obtain 0.93 g of a pale yellow oily substance, with a yield of 84.7%. 1 H NMR(400MHz,CDCl3)δ 6.67(t,J=9.5Hz,2H),2.83-2.72(m,1H),2.12(m,1H),1.92(m,3 H),1.71(m,1H),1.19(s,3H). MS(M+H) + :274.

[0153] Example 3: Preparation of 2-amino-2-(4-chloro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methylcyclohexane-1-one (Compound 3)

[0154] [ka]

[0155] Step a: Preparation of 3-a

[0156] [ka]

[0157] (1-(4-chloro-3-(trifluoromethoxy)phenyl)-2-oxocyclohexyl)carbamate t-butyl ester (1.5 g, 3.68 mmol) was used as a starting material and prepared according to the method described in step a of Example 1 to obtain 0.9 g of a pale yellow solid, with a yield of 58.0%. 1 H NMR(400MHz,CDCl3)δ 7.82(d,J=7.4Hz,1H),7.40(t,J=8.2Hz,1H),7.32(d,J=8.3Hz,1H),6.67(s,1H),3.82(d,J=11.9Hz,1H),2.47- 2.35(m,1H),2.02(m,1H),1.82-1.59(m,3H),1.45(dt,J=15.7,11.5Hz,1H),1.31(s,9H),1.06(d,J=6.4Hz,3H). MS(M+H) +:422.

[0158] Step b: Preparation of 3-b

[0159] [ka]

[0160] Compound 3-a (888 mg, 2.10 mmol) was used as a raw material and prepared according to the method described in step b of Example 1 to obtain 297 mg of a yellow oily substance, with a yield of 32.2%. 1 H NMR(400MHz,CDCl3)δ 7.77(d,J=7.1Hz,1H),7.41(t,J=8.1Hz,1H),7.34(d,J=9.1Hz,1H),6.85(s,1H),3.87(d,J =11.6Hz,1H),2.14(d,J=12.9Hz,1H),1.80(m,2H),1.71(m,2H),1.29(s,9H),0.87(s,3H). MS(M+H) + :438.

[0161] Step c: Preparation of Compound 3

[0162] [ka]

[0163] Compound 3-b (290 mg, 0.66 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 170 mg of a white solid, with a yield of 75.9%. 1 H NMR(400MHz,CDCl3)δ 7.55(d,J=7.6Hz,1H),7.39(t,J=8.0Hz,1H),7.34(d,J=8.3Hz,1H),2.68(dd,J=11.7,7.0Hz,1H),2.02(m,2H),1. 92-1.73(m,3H),1.14(s,3H). MS(M+H) + :338. Example 4: Preparation of 2-amino-2-(3-fluoro-2-(trifluoromethyl)phenyl)-6-hydroxy-6-methylcyclohexane-1-one (Compound 4)

[0164] [ka]

[0165] Step a: Preparation of 4-a

[0166] [ka]

[0167] (1-(3-fluoro-2-(trifluoromethyl)phenyl)-2-oxocyclohexyl)carbamate t-butyl ester (4.0 g, 10.66 mmol) was used as a starting material and prepared according to the method described in step a of Example 1 to obtain 2.0 g of a white solid, with a yield of 48.2%. 1 H NMR(400MHz,CDCl3)δ 7.88(d,J=7.1Hz,1H),7.62(q,J=7.7Hz,1H),7.24-7 .17(m,1H),6.48(s,1H),3.89(d,J=12.7Hz,1H),2.42(m,1H),2.03(m,1H),1.73(m,3H),1.48(m,1H),1.32(s,9H),1.02(d,J=6.3Hz,3H). MS(M+Na)+:412.

[0168] Step b: Preparation of 4-b

[0169] [ka]

[0170] Compound 4-a (2.0 g, 5.14 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 1.0 g of a white solid, with a yield of 48.1%. 1H NMR(400MHz,CDCl3)δ 7.56(m,2H),7.19(t,J=7.5Hz,1H),3.13(m,1H),2.37(m,1H),2.04(m,1H),1.95(m,2H),1.85(m,1H),1.29(s,9H),1.13(s,3H). MS(M+H) + :406.

[0171] Step c: Preparation of Compound 4

[0172] [ka]

[0173] Compound 4-b (200 mg, 0.49 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 100 mg of a white solid, with a yield of 66.2%. 1 H NMR(400MHz,CDCl3)δ 7.58-7.49(m,2H) ,7.18(t,J=9.2Hz,1H),2.38-2.17(m,2H),2.09 (dd,J=22.9,13.5Hz,2H),1.85(t,J=14.1Hz,1H),1.74(d,J=13.4Hz,1H),1.36(s,3H). MS(M+H) + :306.

[0174] Example 5: Preparation of 3-(1-amino-3-hydroxy-3-methyl-2-oxocyclohexyl)benzonitrile (Compound 5)

[0175] [ka]

[0176] Step a: Preparation of 5-a

[0177] [ka]

[0178] (1-(3-cyanophenyl)-2-oxocyclohexyl)carbamate t-butyl ester (3.6 g, 11.45 mmol) was used as a starting material and prepared according to the method described in step a of Example 1 to obtain 1.2 g of a white solid with a yield of 31.9%. 1 H NMR(400MHz,CDCl3)δ 7.61(m,3H),7.47(t,J=7.5Hz,1H),6.59(s,1H),3.74(m,1H),2.30(m,1H),2.03(d,J=12.4Hz,1H),1.86(m,3H),1.51- 1.41(m,1H),1.30(s,9H),1.02(d,J=6.1Hz,3H). MS[M+H] + :329.

[0179] Step b: Preparation of 5-b

[0180] [ka]

[0181] Compound 5-a (1.0 g, 3.04 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 208 mg of a white solid, with a yield of 19.8%. 1 H NMR(400MHz,CDCl3)δ 7.68(m,1H),7.60(m,2H),7.49(t,J=7.7Hz,1H),6.47(s,1H),3.66(m,1H),2.11 (d,J=8.9Hz,1H),1.99(m,2H),1.83(q,J=13.9Hz,2H),1.30(s,9H),0.73(s,3H). MS[M+H] + :345.

[0182] Step c: Preparation of compound 5

[0183] [ka]

[0184] Compound 5-b (300 mg, 0.87 mmol) was used as a raw material and prepared according to the method described in step c of Example 1 to obtain 200 mg of a colorless oily substance, with a yield of 93.9%. 1 H NMR(400MHz,CDCl3)δ 7.63(m,2H),7.51(d,J=3.5Hz,2H),2.80(d,J=14.0Hz,1H),2.06(d,J=11.3Hz,1H),1.9 8(d,J=14.3Hz,1H),1.88(t,J=13.3Hz,2H),1.75(dd,J=24.6,12.0Hz,1H),0.85(s,3H). MS[M+H] + :245.

[0185] Example 6: Preparation of 2-amino-2-(2,3-difluorophenyl)-6-hydroxy-6-methylcyclohexane-1-one (compound 6)

[0186] [ka]

[0187] Step a: Preparation of 6-a

[0188] [ka]

[0189] (1-(2,3-difluorophenyl)-2-oxocyclohexyl)carbamate t-butyl ester (4.2 g, 12.91 mmol) was used as a starting material and prepared according to the method described in step a of Example 1 to obtain 2.98 g of a white solid, with a yield of 68.0%. 1 H NMR(400MHz,CDCl3)δ 7.50(s,1H),7.14(m,2H),6.61(s,1H),3.81(d,J=12.3Hz,1H),2.49(m,1H),2.02(m,1H),1.80-1.72(m,2H),1.6 5(m,1H),1.49-1.38(m,1H),1.32(s,9H),1.06( d,J=6.3Hz,3H). MS[M+H] + :340.

[0190] Step b: Preparation of 6-b

[0191] [ka]

[0192] Compound 6-a (2.91 g, 8.57 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 1.8 g of a white solid, with a yield of 59.1%. 1 H NMR(400MHz,CDCl3)δ 7.42(s,1H),7.15(t,J=6.1Hz,2H),6.69(s,1H),3.83(s,1H),2.13(d,J=11.8Hz,1H),1.86-1.67(m,4H),1.31(s,9 H), 0.91(s,3H). MS[M+H] + :356.

[0193] Step c: Preparation of compound 6

[0194] [ka]

[0195] Compound 6-b (600 mg, 1.69 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 405 mg of a white solid, with a yield of 94.0%. 1 H NMR(400MHz,CDCl3)δ 7.22-7.12(m,3H) ,2.72-2.61(m,1H),2.00(m,2H),1.94-1.73(m,3H),1.10(s,3H). MS[M+H] + :256.

[0196] Example 7: Preparation of 2-amino-6-hydroxy-6-methyl-2-(3-(trifluoromethoxy)phenyl)cyclohexane-1-one (Compound 7)

[0197] [ka]

[0198] Step a: Preparation of 7-a

[0199] [ka]

[0200] (2-oxo-1-(3-(trifluoromethoxy)phenyl)cyclohexyl)carbamate t-butyl ester (2 g, 5.36 mmol) was used as a starting material and prepared according to the method described in step a of Example 1 to obtain 0.79 g of a colorless oily substance with a yield of 38.1%. 1 H NMR(400MHz,CDCl3)δ 7.39(t,J=8.1Hz,1H),7.29(m,1H),7.14(m,2H),6.56(s,1H),3.71(s,1H),2.34(s,1H),2.04-1.98(m,1H),1 .88(m,3H),1.48-1.41(m,1H),1.30(s,9H),1.0 1 (d, J=6.4Hz, 3H). MS[M+H] + :388.

[0201] Step b: Preparation of 7-b

[0202] [ka]

[0203] Compound 7-a (790 mg, 2.04 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 145 mg of a white solid, with a yield of 17.6%. 1H NMR(400MHz,CDCl3)δ 7.46-7.33(m,2H) ,7.19(m,2H),6.35(s,1H),3.57(s,1H),2.09(m,2H),1.86(m,3H),1.31(s,9H),0.74(s,3H). MS[M+Na] + :426.

[0204] Step c: Preparation of compound 7

[0205] [ka]

[0206] Compound 7-b (140 mg, 0.35 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 50 mg of a white solid, with a yield of 47.6%. 1 H NMR(400MHz,CDCl3)δ 7.42(t,J=8.0Hz,1H),7.23(d,J=7.8Hz,1H),7.18(d,J=8.2Hz,1H),7.14(s ,1H),2.83(d,J=12.2Hz,1H),2.07(m,1H),1.94-1.74(m,4H),0.82(s,3H). MS[M+H] + :3 04.

[0207] Example 8: Preparation of 2-amino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (Compound 8)

[0208] [ka]

[0209] Step a: Preparation of 8-a

[0210] [ka]

[0211] (2-oxo-1-(4-(trifluoromethyl)phenyl)cyclohexyl)carbamate t-butyl ester (1.0 g, 2.80 mmol) was used as a raw material and prepared according to the method described in step a of Example 1 to obtain 488 mg of a colorless oily substance, with a yield of 46.9%. 1 H NMR(400MHz,CDCl3)δ 7.62(d,J=8.2Hz,2H),7.43(d,J=8.2Hz,2H),6.60(s,1H),3.77(m,1H),2.32(m, 1H),2.01(m,1H),1.86(m,3H),1.46(m,1H),1.30(s,9H),1.01(d,J=6.3Hz,3H). MS(M+Na)+:394.

[0212] Step b: Preparation of 8-b

[0213] [ka]

[0214] Compound 8-a (488 mg, 1.31 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 282 mg of a white solid, with a yield of 55.4%. be. 1 H NMR(400MHz,CDCl3)δ 7.63(d,J=8.0Hz,2H),7.50(d,J=8.0Hz,2H),6.42(s,1H),3.67(m,1H),2.16-1.96(m,2H),1.88(m,3H),1.30(s,9 H), 0.72 (s, 3H). MS (M+H) + :388.

[0215] Step c: Preparation of compound 8

[0216] [ka]

[0217] Compound 8-b (100 mg, 0.26 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 58 mg of a white solid, with a yield of 78.4%. 1 H NMR(400MHz,CDCl3)δ 7.65(d,J=8.0Hz,2H),7.42(d,J=8.0Hz,2H),2.87(m,1H),2.11-2. 03(m,1H),1.97-1.75(m,4H),0.83(s,3H). MS(M +H) + :288.

[0218] Example 9: Preparation of (2R,6R)-2-amino-6-hydroxy-6-deuterium-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (Compound 9)

[0219] [ka]

[0220] Step a: Preparation of 9-a

[0221] [ka]

[0222] (R)-(2-oxo-1-(4-(trifluoromethyl)phenyl)cyclohexyl)carbamate t-butyl ester (0.6 g, 1.68 mmol) was dissolved in anhydrous THF (6 mL), NaOD (1.8 mL) and D2O (1.2 mL) were added, and the mixture was reacted at 120 °C for 2 hours under microwave conditions. The completion of the reaction of the starting materials was monitored by TLC (DCM / MeOH = 15 / 1), the solvent was concentrated to dryness, and column chromatography (PE / EA = 5 / 1 to 1 / 1) was performed to obtain 0.56 g of a colorless oily substance, with a yield of 92.9%. 1 H NMR(400MHz,CDCl3)δ 7.62(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,2H),6.41(s,1H),3.65( d,J=11.1Hz,1H),2.01(d,J=10.8Hz,1H),1.96- 1.71(m,4H),1.32(s,9H). MS[M+H] + :360.

[0223] Step b: Preparation of 9-b

[0224] [ka]

[0225] Compound 9-a (300 mg, 0.83 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 130 mg of a white solid, with a yield of 41.7%. MS[M+Na] + :397.

[0226] Step c: Preparation of compound 9

[0227] [ka]

[0228] Compound 9-b (130 mg, 0.35 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 70 mg of a white solid, with a yield of 73.7%. 1 H NMR(400MHz,CDCl3)δ 7.66(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),2.90(d,J=13.9Hz,1H),2.37(d,J=12.0Hz,1H),1.79(m,2H),1.71-1. 61(m,1H),1.62-1.50(m,1H). MS[M+Na] + :297.

[0229] Example 10: Preparation of (2R,6R)-2-amino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (Compound 10)

[0230] [ka]

[0231] Step a: Preparation of 10-a

[0232] [ka]

[0233] Using (R)-(2-oxo-1-(4-(trifluoromethyl)phenyl)cyclohexyl)carbamate t-butyl ester (2.0 g, 5.60 mmol) as a starting material, the mixture was prepared according to the method described in step a of Example 1 to obtain 1.05 g of a colorless oily substance with a yield of 50.5%. 1 H NMR(400MHz,CDCl3)δ 7.62(d,J=8.3Hz,2H),7.43(d,J=8.3Hz,2H),6.60(s,1H),3.77(m,1H),2.32(m, 1H),2.01(m,1H),1.86(m,3H),1.45(m,1H),1.30(s,9H),1.01(d,J=6.4Hz,3H). MS(M+Na)+:394.

[0234] Step b: Preparation of 10-b

[0235] [ka]

[0236] Compound 10-a (500 mg, 1.35 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 310 mg of a white solid, with a yield of 59.4%. 1 H NMR(400MHz,CDCl3)δ 7.63(d,J=7.9Hz,2H),7.50(d,J=7.9Hz,2H),6.42(s,1H),3.67(m,1H),2.16-1.97(m,2H),1.88(m,3H),1.30(s, 9H),0.72(s,3H). MS(M+Na)+:410.

[0237] Step c: Preparation of compound 10

[0238] [ka]

[0239] Compound 10-b (100 mg, 0.26 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 62 mg of a white solid, with a yield of 83.8%. 1 H NMR(400MHz, CDCl3)δ 7.65(d,J=8.0Hz,2H),7.42(d,J=8.0Hz,2H),2.87(d,J=13.7Hz,1H),2.11-2.02(m,1H),1.97-1.74(m,4H),0.83(s,3H). MS(M+H) + :288.

[0240] Example 11: Preparation of (2S,6S)-2-amino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (Compound 11)

[0241] [ka]

[0242] Step a: Preparation of 11-a

[0243] [ka]

[0244] (S)-(2-oxo-1-(4-(trifluoromethyl)phenyl)cyclohexyl)carbamate t-butyl ester (3.0 g, 8.39 mmol) was used as a starting material and prepared according to the method described in step a of Example 1 to obtain 1.64 g of a colorless oily substance with a yield of 52.6%.

[0245] 1 H NMR(400MHz,CDCl3)δ 7.62(d,J=8.2Hz,2H),7.43(d,J=8.1Hz,2H),6.61(s,1H),3.77(m,1H),2.32(s,1H),2.01(d,J=14.3Hz,1H),1.94-1 .79(m,3H),1.47(dd,J=14.7,10.1Hz,1H),1.30(s,9H),1.01(d,J=6.3Hz,3H). MS(M+Na)+ :394.

[0246] Step b: Preparation of 11-b

[0247] [ka]

[0248] Compound 11-a (1.0 g, 2.69 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 690 mg of a white solid, with a yield of 66.1%. 1 H NMR(400MHz,CDCl3)δ 7.63(d,J=8.2Hz,2H),7.50(d,J=8.2Hz,2H),6.42(s,1H),3.68(d,J=14. 6Hz, 1H), 2.17-2.01 (m, 2H), 1.95-1.75 (m, 3H), 1.29 (s, 9H), 0.72 (s, 3H). MS(M+Na)+:410.

[0249] Step c: Preparation of compound 11

[0250] [ka]

[0251] Compound 11-b (300 mg, 0.77 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 202 mg of a white solid, with a yield of 91.0%. 1H NMR(400MHz, CDCl3)δ 7.65(d,J=8.0Hz,2H),7.42(d,J=8.0Hz,2H),2.87(d,J=13.6Hz,1H),2.11-2.03(m,1H),1.97-1.73(m,4H),0.83(s,3H). MS(M+H) + :288.

[0252] Example 12: Preparation of (2R,6S)-2-amino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (Compound 12)

[0253] [ka]

[0254] Step a: Preparation of 12-a

[0255] [ka]

[0256] ((1R)-3-methyl-2-oxo-1-(4-(trifluoromethyl)phenyl)cyclohexyl)carbamate t-butyl ester (1.52 g, 4.09 mmol) is dissolved in dichloromethane (20 mL), cooled to 0°C, TFA (5 mL) is added, and after the addition is complete, the temperature is raised to room temperature and the reaction is stirred for 1 hour. The completion of the reaction of the starting materials is detected by TLC (PE / EA = 10 / 1), the solvent is spin-dried, and it is dissolved again in dichloromethane (50 mL), the pH is adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution, liquid-liquid is separated, and the aqueous phase is dichloromethane Extraction was performed with lomethane (50 mL x 2), the organic phase was combined, washed with saturated NaCl aqueous solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 1.13 g of a pale yellow oily substance. The crude yield was 101.8%. MS[M+H] + :272.

[0257] Step b: Preparation of 12-b

[0258] [ka]

[0259] 1.13 g of the crude product of compound 12-a is dissolved in DCE (12 mL), glacial acetic acid (51 mg, 0.84 mmol) and p-methoxybenzaldehyde (744 mL, 5.46 mmol) are added, and the mixture is reacted at room temperature for 16 hours. After cooling to 0°C, sodium triacetoxyborohydride (1.34 g, 6.32 mmol) is added in batches, and the mixture is reacted at room temperature for 1 hour. The completion of the reaction of the starting materials is detected by TLC (PE / EA = 3 / 1), the pH is adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution, diluted with water (100 mL), extracted with dichloromethane (30 mL x 3), the organic phases are combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Column chromatography (PE / EA = 5 / 1) yields 1.4 g of pale yellow solid, with a yield of 87.4% (combining the two steps). 1 H NMR(400MHz,CDCl3)δ 7.66(d,J=8.1Hz,2H),7.40(d,J=8.1Hz,2H),7.12(d,J=8.2Hz,2H),6.78(d,J=8.3Hz,2H),3.75(s,3H),3.31(d,J=12.0Hz,1H ),3.20(d,J=12.1Hz,1H),3.01(d,J=12.1Hz,1H),2.39(dt,J=12.6,6.3Hz,1H),2.04-1.91(m,2H),1.80(m,2H),1.48(m,1H), 1.05 (d, J=6.4Hz, 3H). MS[M+H] + :392.

[0260] Step c: Preparation of 12-c

[0261] [ka]

[0262] Compound 12-b (600 mg, 1.53 mmol) was dissolved in THF (10 mL), triethylamine (465 mg, 4.59 mmol) and DMAP (94 mg, 0.77 mmol) were added, and anhydrous trifluoroacetic acid (644 mg, 3.06 mmol) was added dropwise under an ice bath. The mixture was reacted at room temperature for 1 hour. The completion of the reaction of the starting materials was detected by TLC (PE / EA = 5 / 1), the reaction was quenched by adding saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and subjected to column chromatography (PE / EA = 20 / 1) to obtain 740 mg of a colorless viscous substance. The yield was 99.1%. 1 H NMR(400MHz,CDCl3)δ 7.46(d,J=8.3Hz,2H),7.3 2(d,J=8.0Hz,2H),6.65(d,J=8.5Hz,2H),6.50(d,J=8.4Hz,2H),4.59(d,J=16.9Hz,1H),4.04(d ,J=17.1Hz,1H),3.77(s,3H),2.80(m,1H),2.43(d,J=14.2Hz,1H),2.01-1.89(m,1H),1.83(m,3 H),1.55(m,1H),1.12(d,J=6.4Hz,3H). MS[M+H] + :488.

[0263] Step d: Preparation of 12-d

[0264] [ka]

[0265] Compound 12-c (430 mg, 0.88 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 165 mg of a white solid, with a yield of 37.2%. 1H NMR(400MHz,DMSO-d6)δ 7.53(d,J=8.1Hz,2H),7.45(d,J=8.4Hz,2H),6.69(d,J=8.3Hz,2H),6.52(d,J=8.3Hz,2H),4.89(s,1H) ,4.47(d,J=17.7Hz,1H),4.12(d,J=17.4Hz,1H),3.69(s,3H),2.40(m,2H),1.84-1.65(m,3H),1.54(m, 1H), 1.20(s,3H). MS[M+H] + :504.

[0266] Step e: Preparation of 12-e

[0267] [ka]

[0268] Compound 12-d (160 mg, 0.32 mmol) was dissolved in methanol (5 mL), and 0.5 M sodium hydroxide aqueous solution (3 mL) was added dropwise under ice bath. The mixture was reacted at room temperature for 0.5 hours. The completion of the reaction of the starting materials was detected by TLC (PE / EA = 3 / 1), diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and subjected to concentrated acid dry column chromatography (PE / EA = 10 / 1 to 3 / 1) to obtain 110 mg of a colorless, viscous oily substance. The yield was 85.3%. 1 H NMR(400MHz,DMSO-d6)δ 7.69(d,J=8.2Hz,2H),7.53(d,J=8.2Hz,2H),7.19(d,J=8.4Hz,2H),6.86(d,J=8.4Hz,2H),5.02(s,1H),3.72(s,3H),3. 28(d,J=5.8Hz,1H),3.00(s,1H),2.98(s,1H),2.27(t,J=10.3Hz,1H),1.97-1.88(m,2H),1.84(d,J=5.5Hz,2H),1.71(m, 1H), 1.39(s,3H). MS[M+H] + :408.

[0269] Step f: Preparation of compound 12

[0270] [ka]

[0271] Compound 12-e (110 mg, 0.27 mmol) was dissolved in trifluoroacetic acid (2 mL), stirred at 100°C for 16 hours, and the completion of the reaction of the starting materials was detected by TLC (PE / EA = 3 / 1). Trifluoroacetic acid was removed using a rotary evaporator, saturated sodium carbonate aqueous solution (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography (DCM / MeOH = 150 / 1 to 80 / 1) to obtain 40 mg of a pale yellow oily substance. The yield was 89.7%. 1 H NMR(400MHz,CD3OD)δ 7.63(d,J=8.3Hz,2H),7.54(d,J=8.2Hz,2H),2.86-2.76(m,1H),2.08(qd,J=13.5,7 .0Hz,1H),2.00-1.91(m,1H),1.84(ddd,J=14.3 ,12.1,3.6Hz,1H),1.74(ddt,J=15.6,8.0,4.1Hz,2H),1.33(s,3H). MS[M+H] + :288.

[0272] Example 13: Preparation of (2S,6R)-2-amino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (Compound 13)

[0273] [ka]

[0274] Step a: Preparation of 13-a

[0275] [ka]

[0276] Compound 11-a (2.1 g, 5.65 mmol) was used as a starting material and prepared according to the method described in step a of Example 12 to obtain 1.51 g of a crude pale yellow oily product, with a yield of 98.4%. MS[M+H] + :272.

[0277] Step b: Preparation of 13-b

[0278] [ka]

[0279] Using the crude product of compound 13-a (1.51 g) from the previous step as a starting material, the mixture was prepared according to the method described in step b of Example 12 to obtain 1.88 g of a white solid, with a yield of 85.0% (combining the two steps). 1 H NMR(400MHz,CDCl3)δ 7.66(d,J=8.1Hz,2H),7.40(d,J=8.1Hz,2H),7.12(d,J=8.2Hz,2H),6.78(d,J=8.2Hz,2H),3.75(s,3H),3.31(d,J=12.0 Hz,1H),3.20(d,J=12.1Hz,1H),3.01(d,J=12.1Hz,1H),2.38(m,1H),2.03-1.90(m,2H),1.80(m,2H),1.48(m,1H),1.05 (d,J=6.3Hz,3H). MS[M+H] + :392.

[0280] Step c: Preparation of 13-c

[0281] [ka]

[0282] Using compound 13-b (500 mg, 1.28 mmol) from the previous step as a raw material, a colorless oily substance of 610 mg was prepared according to the method described in step c of Example 12, with a yield of 97.9%. 1 H NMR(400MHz,CDCl3)δ 7.46(d,J=8.3Hz,2H),7.32(d,J=8.0Hz,2H),6.65(d,J=8.5Hz,2H),6.50(d,J=8.4Hz,2H),4.59(d,J =16.9Hz,1H),4.04(d,J=17.1Hz,1H),3.77(s,3H),2.80(m,1H),2.43(d,J=14.2Hz,1H),2.01-1.89( m,1H),1.83(m,3H),1.55(m,1H),1.12(d,J=6.3Hz,3H). MS[M+H] + :488.

[0283] Step d: Preparation of 13-d

[0284] [ka]

[0285] Compound 13-c (400 mg, 0.82 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 178 mg of a white solid, with a yield of 43.1%. 1 H NMR(400MHz,DMSO-d6)δ 7.53(d,J=8.1Hz,2H),7.45(d,J=8.4Hz,2H),6.69(d,J=8.3Hz,2H),6.52(d,J=8.3Hz,2H),4.90(s,1H) ,4.47(d,J=17.7Hz,1H),4.12(d,J=17.4Hz,1H),3.69(s,3H),2.40(m,2H),1.83-1.63(m,3H),1.53(m, 1H), 1.20(s,3H). MS[M+H] + :504.

[0286] Step e: Preparation of 13-e

[0287] [ka]

[0288] Compound 13-d (100 mg, 0.20 mmol) was used as a starting material and prepared according to the method described in step e of Example 12 to obtain 65 mg of a colorless oily substance, with a yield of 80.2%. 1 H NMR(400MHz,DMSO-d6)δ 7.69(d,J=8.2Hz,2H),7.53(d,J=8.2Hz,2H),7.19(d,J=8.4Hz,2H),6.86(d,J=8.4Hz,2H),5.02(s,1H) ),3.72(s,3H),3.28(d,J=5.8Hz,1H),3.00(s,1H),2.98(s,1H),2.27(t,J=10.3Hz,1H),1.98-1.87(m, 2H), 1.84 (d, J=5.5Hz, 2H), 1.70 (m, 1H), 1.39 (s, 3H). MS[M+H] + :408.

[0289] Step f: Preparation of compound 13

[0290] [ka]

[0291] Compound 13-e (50 mg, 0.12 mmol) was used as a starting material and prepared according to the method described in step f of Example 12 to obtain 18 mg of a colorless oily substance, with a yield of 51.4%. That is the case. 1 H NMR(400MHz,CD3OD)δ 7.62(d,J=8.4Hz,2H),7.54(d,J=8.2Hz,2H),2.80(dd,J=14.5,3.1Hz,1H),2.14 -2.01(m,1H),1.99-1.90(m,1H),1.85(dd,J=15.0,3.0Hz,1H),1.83-1.69(m,2H) ,1.32(s,3H). MS[M+H] + :288.

[0292] Example 14: Preparation of 2-(2-fluoro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methyl-2-(methylamino)cyclohexane-1-one (Compound 14)

[0293] [ka]

[0294] Compound 1 (230 mg, 0.72 mmol) and 37% formaldehyde aqueous solution (58 mg, 0.72 mmol) are dissolved in formic acid (3 mL), and the mixture is heated to 100°C and stirred for 3 hours. The reaction mixture is cooled to room temperature, saturated sodium carbonate aqueous solution is added to adjust the pH to approximately 10, and the mixture is extracted with ethyl acetate (15 mL x 3). The organic phases are combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is spin-dried. Column chromatography (PE / EA = 10 / 1) is performed to obtain 110 mg of a pale yellow oily substance. The yield is 45.8%. 1 H NMR(400MHz,CDCl3)δ 7.31(t,J=7.5Hz,1H),7.25-7.16(m,2H),2.46-2.36(m,1H),2.16(s,3H),2.15-2.05(m,2H),1.98(m,1 H),1.94-1.86(m,1H),1.72(m,1H),1.16(s,3H) MS[M+H] + :336.

[0295] Example 15: Preparation of (2R,6S)-2-(2-fluoro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methyl-2-(methylamino)cyclohexane-1-one (Compound 15)

[0296] [ka]

[0297] Step a: Preparation of 15-a

[0298] [ka]

[0299] (R)(1-(2-fluoro-3-(trifluoromethoxy)phenyl)-2-oxo Using cyclohexyl)carbamate t-butyl ester (1.7 g, 4.34 mmol) as a raw material, a colorless oily substance of 1.05 g was obtained by preparing it according to the method described in step a of Example 1, with a yield of 59.6%. 1 1H NMR (400MHz, CDCl3)δ 7.71(s,1H),7.25-7.17(m,2H),6.62(s,1H),3 .79(m,1H),2.46(m,1H),2.01(m,1H),1.85-1.6 2(m,3H),1.42(m,1H),1.31(s,9H),1.06(d,J=6.2Hz,3H). MS[M+H] + :406.

[0300] Step b: Preparation of 15-b

[0301] [ka]

[0302] ((1R)-1-(2-fluoro-3-(trifluoromethoxy)phenyl)-3-methyl-2-oxocyclohexyl)carbamate t-butyl ester (1.1 g, 2.71 mmol) is dissolved in anhydrous THF (15 mL), cooled to -78 °C, and LDA (2.62 mL, 5.24 mmol) is slowly added dropwise under N2 gas protection. After the addition is complete, the mixture is stirred at -78 °C for 1 hour. Then, iodomethane (0.25 mL, 3.93 mmol) is dissolved in THF (1 mL) and slowly added dropwise to the reaction mixture at -78 °C. After the addition is complete, the mixture is allowed to rise naturally to room temperature and reacted for 3 hours. A small amount of raw material was detected by TLC (PE / EA = 10 / 1), the reaction was quenched by adding saturated NH4Cl aqueous solution (10 mL), diluted with water (40 mL), extracted with ethyl acetate (15 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and subjected to column chromatography (PE / EA = 20 / 1) to obtain 850 mg of white solid, with a yield of 74.7%. 1 H NMR(400MHz,CDCl3)δ 7.26(s,1H),7.09(t,J=8.0Hz,1H),6.76(s,1H),3.05(s,3H),2.79(m,1H),2 .58(m,1H),2.31(m,1H),2.08(m,1H),1.75(m,3H),1.49(s,9H),1.11(s,3H). MS[M+Na] + :442.27.

[0303] Step c: Preparation of 15-c

[0304] [ka]

[0305] Compound 15-b (350 mg, 0.83 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 162 mg of a white solid, with a yield of 44.6%. MS[M+H] + :436.

[0306] Step d: Preparation of compound 15

[0307] [ka]

[0308] Compound 15-c (150 mg, 0.34 mmol) was used as a raw material and prepared according to the method described in step c of Example 1 to obtain 91 mg of a colorless oily liquid, with a yield of 78.4%. 1 H NMR(400MHz,CDCl3)δ 7.32(t,J=7.0Hz,1H),7.24(m,1H),7.16(t,J=8.1Hz,1H),2.25-2.18(m,4H),2.17-2.08(m,1H),2.05-1.94(m,4 H), 1.60 (s, 3H). MS[M+H] + :336.

[0309] Example 16: Preparation of 2-hydroxy-2-methyl-6-methylamino-6-(2,4,6-trifluorotolyl)cyclohexane-1-one (Compound 16)

[0310] [ka]

[0311] Compound 2 (75 mg, 0.27 mmol) was used as a raw material and prepared according to the method described in Example 14 to obtain 30 mg of a pale yellow oily substance, with a yield of 38.0%. 1 H NMR(400MHz,CDCl3)δ 6.67(t,J=9.6Hz,2H),2.51-2.42(m,1H),2.30(m,1H),2.26(s,3H),2.13 (m,1H),1.99(m,1H),1.90-1.80(m,1H),1.64(m ,1H),1.23(s,3H). MS[M+H] + :288.

[0312] Example 17: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(2,4,6-trifluorophenyl)cyclohexane-1-one (Compound 17)

[0313] [ka]

[0314] Step a: Preparation of 17-a

[0315] [ka]

[0316] Using (R)(2-oxo-1-(2,4,6-trifluorophenyl)cyclohexyl)carbamate t-butyl ester (3.1 g, 9.03 mmol) as a starting material, the mixture was prepared according to the method described in step a of Example 1 to obtain 2.8 g of a colorless oily liquid, with a yield of 86.8%. 1 H NMR(400MHz,CDCl3)δ 6.67(t,J=9.0Hz,2H),6.55(s,1H),3.82(d,J=8.0Hz,1H),2.56(m,1H),2.03(m,1H),1.88-1.65(m,3H),1 .49-1.43(m,1H),1.34(s,9H),1.06(d,J=6.1Hz ,3H). MS[M+H] + :358.

[0317] Step b: Preparation of 17-b

[0318] [ka]

[0319] Compound 17-a (2.0 g, 5.60 mmol) was used as a starting material and prepared according to the method described in step b of Example 15 to obtain 1.68 g of a white solid, with a yield of 80.8%. MS(M+H) + :372.

[0320] Step c: Preparation of 17-c

[0321] [ka]

[0322] Compound 17-b (1.2 g, 3.23 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 600 mg of a white foamy substance, with a yield of 47.9%. MS(M+H) + :388.

[0323] Step d: Preparation of compound 17

[0324] [ka]

[0325] Compound 17-c (400 mg, 1.03 mmol) was used as a raw material and prepared according to the method described in step c of Example 1 to obtain 265 mg of a colorless oily substance, with a yield of 89.2%. 1 H NMR(400MHz,CDCl3)6.68(t,J=9.5Hz,1H),2.21(m,1H),2.12(s,3H),2.08-2.01(m,2H ),1.93(m,2H),1.82(m,1H),1.56(s,3H). MS(M+H) + :288.

[0326] Example 18: Preparation of 2-(4-chloro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methyl-2-methylaminocyclohexane-1-one (Compound 18)

[0327] [ka]

[0328] Compound 3 (145 mg, 0.43 mmol) was used as a raw material and prepared according to the method described in Example 14 to obtain 35 mg of a white solid, with a yield of 23.2%. 1 H NMR(400MHz,CDCl3)δ 7.35(m,3H),2.37(t,J=11.1Hz,1H),2.26-2.19(m,1H),2.17-2.06(m,4H),2.01(m,1H),1.93-1.84(m,1H),1.76-1.68(m,1H),1.22(s,3H). MS(M+H) + :352.

[0329] Example 19: Preparation of (2R,6S)-2-(4-chloro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methyl-2-methylamino-cyclohexane-1-one (Compound 19)

[0330] [ka]

[0331] Step a: Preparation of 19-a

[0332] [ka]

[0333] (R)-(1-(4-chloro-3-(trifluoromethoxy)phenyl)-2-oxocyclohexyl)carbamate t-butyl ester (3.0 g, 7.36 mmol) was used as a starting material and prepared according to the method described in step a of Example 1 to obtain 2.5 g of a colorless oily liquid with a yield of 80.6%. 1 1H NMR (400MHz, CDCl3)δ 7.82(d,J=7.4Hz,1H),7.40(t,J=8.2Hz,1H),7.32(d,J=8.2Hz,1H),6.66(s,1H),3.82(d,J=11.9Hz,1H ),2.46-2.36(m,1H),2.02(m,1H),1.83-1.58(m,3H),1.45(m,1H),1.31(s,9H),1.06(d,J=6.3Hz,3H). MS(M+H) + :422.

[0334] Step b: Preparation of 19-b

[0335] [ka]

[0336] Compound 19-a (2.0 g, 4.74 mmol) was used as a starting material and prepared according to the method described in step b of Example 15 to obtain 1.52 g of a white solid, with a yield of 73.5%. MS(M+H) + :436.

[0337] Step c: Preparation of 19-c

[0338] [ka]

[0339] Compound 19-b (1.4 g, 3.21 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 570 mg of a colorless oily liquid, with a yield of 39.3%. MS(M+H) + :452.

[0340] Step d: Preparation of compound 19

[0341] [ka]

[0342] Compound 19-c (200 mg, 0.44 mmol) was used as a raw material and prepared according to the method described in step c of Example 1 to obtain 120 mg of a colorless oily substance, with a yield of 76.9%. 1 H NMR(400MHz,CDCl3)δ 7.43(m,1H),7.20-6.98(m,2H),2.20(m,4H),2.13(m,1H),2.01 (m,1H),1.95(m,2H),1.85-1.78(m,1H),1.54(s ,3H). MS(M+H) + :352.

[0343] Example 20: Preparation of 2-(3-fluoro-2-(trifluoromethyl)phenyl)-6-hydroxy-6-methyl-2-methylamino-cyclohexane-1-one (Compound 20)

[0344] [ka]

[0345] Compound 4 (300 mg, 0.98 mmol) was used as a raw material and prepared according to the method described in Example 14 to obtain 70 mg of a white solid, with a yield of 22.3%. 1 H NMR(400MHz,CDCl3)δ 7.52(dd,J=14.1,7.1Hz,1H),7.33(m,1H),7.16(t,J=9.1Hz,1H),2.26-2.0 0(m,6H),1.81(m,1H),1.67(m,2H),1.36(s,3H). MS(M+H) + :320.

[0346] Example 21: Preparation of 3-(3-hydroxy-3-methyl-1-methylamino-2-oxocyclohexyl)benzonitrile (Compound 21)

[0347] [ka]

[0348] Compound 5 (200 mg, 0.82 mmol) was used as a raw material and prepared according to the method described in Example 14 to obtain 50 mg of a white solid, with a yield of 23.7%. 1 H NMR(400MHz,CDCl3)δ 7.65-7.55(m,2H),7.54-7.45(m,2H),2.67(d,J=14.2Hz,1H),2.09-1.92(m, 7H), 1.79-1.66(m, 1H), 0.90(s, 3H). MS(M+H) + : 259.

[0349] Example 22: Preparation of 3-((1R,3S)-3-hydroxy-3-methyl-1-methylamino-2-oxocyclohexyl)benzonitrile (Compound 22)

[0350] [ka]

[0351] Step a: Preparation of 22-a

[0352] [ka]

[0353] Using (R)(1-(3-cyanophenyl)-2-oxocyclohexyl)carbamate t-butyl ester (3.0 g, 9.54 mmol) as a starting material, the mixture was prepared according to the method described in step a of Example 1 to obtain 2.2 g of a white solid, with a yield of 70.2%. 1 H NMR(400MHz,CDCl3)δ 7.61(m,3H),7.47(t,J=7.4Hz,1H),6.59(s,1H),3.73(m,1H),2.30(m,1H),2.03(m,1H),1.85(m,3H),1.50-1.42(m, 1H),1.30(s,9H),1.02(d,J=6.2Hz,3H). MS[M+H] + :329.

[0354] Step b: Preparation of 22-b

[0355] [ka]

[0356] Compound 22-a (2.0 g, 6.09 mmol) was used as a starting material and prepared according to the method described in step b of Example 15 to obtain 1.22 g of a white solid, with a yield of 58.5%. 1 H NMR(400MHz,CDCl3)δ 7.57(d,J=6.7Hz,1H),7.51-7.41(m,3H),3.05(s,1H),2.89(s,3 H),2.41(m,1H),2.10-2.01(m,2H),1.80(m,3H) ,1.50(s,9H),1.09(d,J=6.4Hz,3H). MS(M+H) + :343.

[0357] Step c: Preparation of 22-c

[0358] [ka]

[0359] Compound 22-b (800 mg, 2.34 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 390 mg of a colorless oily liquid, with a yield of 46.6%. MS(M+H) + :359.

[0360] Step d: Preparation of compound 22

[0361] [ka]

[0362] Compound 22-c (200 mg, 0.56 mmol) was used as a raw material and prepared according to the method described in step c of Example 1 to obtain 90 mg of a colorless oily substance, with a yield of 62.5%. 1 H NMR(400MHz,CDCl3)δ 7.62(s,1H),7.56(d,J=7.1Hz,1H),7.46(dq,J=15.6,7.9Hz,2H),2.18-2.08(m,5H),2.03(m,1H),1.92(m,2H),1 .85-1.78(m,1H),1.56(s,3H). MS(M+H) + :259.

[0363] Example 23: Preparation of 2-(2,3-difluorophenyl)-6-hydroxy-6-methyl-2-methylaminocyclohexane-1-one (Compound 23)

[0364] [ka]

[0365] Compound 6 (300 mg, 1.18 mmol) was used as a raw material and prepared according to the method described in Example 14 to obtain 73 mg of a white solid, with a yield of 23.1%. 1 H NMR(400MHz,CDCl3)δ 7.20-7.07(m,2H),7.03(t, J=6.8Hz,1H),2.43-2.34(m,1H),2.16(m,4H),2 .13-2.04(m,1H),2.00(m,1H),1.86(m,1H),1.7 7-1.66(m,1H),1.17(s,3H). MS(M+H) + :270.

[0366] Example 24: Preparation of (2R,6S)-2-(2,3-difluorophenyl)-6-hydroxy-6-methyl-2-methylaminocyclohexane-1-one (Compound 24)

[0367] [ka]

[0368] Step a: Preparation of 24-a

[0369] [ka]

[0370] ((1R)-1-(2,3-difluorophenyl)-3-methyl-2-oxocyclohexyl)carbamate t-butyl ester (1.3 g, 4.0 mmol) was used as a starting material and prepared according to the method described in step a of Example 1 to obtain 1.2 g of a white solid with a yield of 88.5%. 1 H NMR(400MHz,CDCl3)δ 7.50(s,1H),7.14(m,2H),6.61(s,1H),3.81(m,1H),2.49(m,1H),2.02(m,1H),1.80-1.71(m,2H),1.65 (m,1H),1.48-1.37(m,1H),1.32(s,9H),1.06(d (J=6.2Hz,3H). MS[M+H] + :340.

[0371] Step b: Preparation of 24-b

[0372] [ka]

[0373] Compound 24-a (1.2 g, 3.54 mmol) was used as a starting material and prepared according to the method described in step b of Example 15 to obtain 350 mg of a colorless oily liquid, with a yield of 28%. MS[M+H] + :354.36.

[0374] Step c: Preparation of 24-c

[0375] [ka]

[0376] Compound 24-b (350 mg, 0.99 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 150 mg of a white solid, with a yield of 41%. MS[M+H] + :370.37.

[0377] Step d: Preparation of compound 24

[0378] [ka]

[0379] Compound 24-c (150 mg, 0.41 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 85 mg of a white solid, with a yield of 79.0%. 1 H NMR (400MHz, CDCl3) δ 7.10 (m, 3H), 2.21 (m, 4H), 2.13 (m, 1H), 1.99 (m, 3H), 1.77 (m, 1H), 1.60 (s, 3H). MS[M+H] + :270.

[0380] Example 25: Preparation of 2-hydroxy-2-methyl-6-methylamino-6-(3-(trifluoromethoxy)phenyl)cyclohexane-1-one (Compound 25)

[0381] [ka]

[0382] Compound 7 (200 mg, 0.66 mmol) was used as a starting material and prepared according to the method described in Example 14 to obtain 75 mg of a white solid, with a yield of 35.9%. 1H NMR(400MHz,CDCl3)δ 7.41(t,J=8.0Hz,1H),7.18(t,J=7.3Hz,2H),7.10(s,1H),2.77(d,J=15. 8Hz, 1H), 2.02 (s, 3H), 2.00-1.84 (m, 4H), 1.80-1.69 (m, 1H), 0.84 (s, 3H). MS[M+H] + :318.

[0383] Example 26: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(3-(trifluoromethoxy)phenyl)cyclohexane-1-one (Compound 26)

[0384] [ka]

[0385] Step a: Preparation of 26-a

[0386] [ka]

[0387] (R)-(2-oxo-1-(3-(trifluoromethoxy)phenyl)cyclohexyl)carbamate t-butyl ester (2.5 g, 6.70 mmol) was used as a starting material and prepared according to the method described in step a of Example 1 to obtain 1.4 g of a white solid with a yield of 53.9%. 1 H NMR(400MHz,CDCl3)δ 7.39(t,J=8.1Hz,1H),7.29(m,1H),7.14(m,2H),6.56(s,1H),3.71(s,1H),2.34(s,1H),2.03-1.97(m,1 H),1.88(m,3H),1.47-1.40(m,1H),1.30(s,9H) ,1.01(d,J=6.3Hz,3H). MS[M+H] + :388.

[0388] Step b: Preparation of 26-b

[0389] [ka]

[0390] Compound 26-a (1.47 g, 3.79 mmol) was used as a starting material and prepared according to the method described in step b of Example 15 to obtain 685 mg of a colorless oily substance, which is a diastereomer mixture in a ratio of approximately 1:1.8, with a yield of 44.9%. 1 H NMR(400MHz,CDCl3)δ 7.35(t,J=7.6Hz,3H),7.19-7.0 2(m,7.2H),6.95(s,1H),3.04(s,4H),2.88(s,7.2H),2.38(m,2.8H),2.03(m,5.6H),1.91-1.70 (m, 5.6H), 1.49 (s, 16.2H), 1.41 (m, 1.8H), 1.30 (s, 9H), 1.25 (s, 1H), 1.10 (m, 8.4H). MS[M+Na] + :424.

[0391] Step c: Preparation of 26-c

[0392] [ka]

[0393] Compound 26-b (685 mg, 1.71 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 145 mg of a colorless oily substance, with a yield of 20.4%. 1 H NMR(400MHz,CDCl3)δ 7.38(t,J=8.4Hz,1H),7.16(d,J=8.3Hz,2H),7.00(s,1H),4.30(s,1H),2.94(s ,3H),2.41(d,J=14.8Hz,1H),2.23(m,1H),2.11(m,1H),1.76(s,2H),1.49(s,9H) ), 1.26(s,3H). MS[M+Na] + :440.

[0394] Step d: Preparation of compound 26

[0395] [ka]

[0396] Compound 26-c (140 mg, 0.34 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 80 mg of a white solid, with a yield of 75.5%. 1 H NMR(400MHz,CDCl3)δ 7.37(t,J=8.2Hz,1H),7.18-7.09(m,3H),2.22(m,1H),2.12(s,3H) ),2.03(m,2H),1.92(m,2H),1.81(m,1H),1.55(s,3H). MS[M+H] + :318.

[0397] Example 27: Preparation of (2R,6S)-2-(2-chlorophenyl)-6-hydroxy-6-methyl-2-methylaminocyclohexane-1-one (compound 27) and (2R,6R)-2-(2-chlorophenyl)-6-hydroxy-6-methyl-2-methylaminocyclohexane-1-one (compound 28)

[0398] [ka]

[0399] Step a: Preparation of 27-a

[0400] [ka]

[0401] (R)-(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate t-butyl ester (2.1 g, 6.48 mmol) was used as a starting material and prepared according to the method described in step a of Example 1 to obtain 410 mg of a white solid, with a yield of 18.7%. 1 H NMR(400MHz,CDCl3)δ 7.85(s,1H),7.33(m,2H),7.24(m,1H),6.66(s,1H),3.84(m,1H),2.48(m,1H),1.99(m,1H),1.71(m,3H),1.43(d d,J=12.4,4.3Hz,1H),1.06(d,J=6.3Hz,3H). MS[M+H] + :338.

[0402] Step b: Preparation of 27-b

[0403] [ka]

[0404] Compound 27-a (410 mg, 1.21 mmol) was dissolved in dichloromethane (5 mL), cooled to 0°C, and TFA (2.5 mL) was added. After the addition was complete, the temperature was raised to room temperature and the reaction was allowed to proceed for 1 hour. The completion of the reaction of the starting materials was detected by TLC (PE / EA = 10 / 1), the solvent was spin-dried, and the compound was dissolved again in dichloromethane (20 mL). The pH was adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution, and the solution was separated. The aqueous phase was extracted again with didichloromethane (10 mL x 2), the organic phase was combined, washed with saturated NaCl aqueous solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 288 mg of a colorless oily substance. The yield was 99.8%. MS[M+H] + :238.

[0405] Step c: Preparation of 27-c

[0406] [ka]

[0407] Compound 27-b (288 mg, 1.21 mmol) is dissolved in methanol (4 mL), glacial acetic acid (15 mg, 0.24 mmol) and 38% formaldehyde aqueous solution (95.6 mg, 1.21 mmol) are added, and the mixture is reacted at room temperature for 2 hours. After cooling to 0°C, sodium borohydride cyanohydride (114 mg, 1.82 mmol) is added in batches, and the mixture is reacted at room temperature for 1 hour. The completion of the reaction of the starting materials is detected by TLC (PE / EA = 1 / 1), the pH is adjusted to approximately 8 with saturated sodium bicarbonate solution, diluted with water (30 mL), extracted with dichloromethane (15 mL x 3), the organic phases are combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Column chromatography (EA / PE = 0~3 / 2) is performed to obtain 260 mg of a colorless oily substance, with a yield of 85.0% (combining the two steps). MS[M+H] + :252.

[0408] Step d: Preparation of compound 27-d

[0409] [ka]

[0410] Compound 27-c (260 mg, 1.03 mmol) was dissolved in THF (4 mL), triethylamine (313 mg, 3.09 mmol) and DMAP (63 mg, 0.52 mmol) were added, and anhydrous trifluoroacetic acid (433 mg, 2.06 mmol) was added dropwise under an ice bath. The mixture was reacted at room temperature for 2 hours. The completion of the reaction of the starting materials was detected by TLC (PE / EA = 5 / 1), and the reaction was quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (15 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The filtrate was then subjected to column chromatography (PE / EA = 10 / 1) to obtain 243 mg of a white solid, with a yield of 67.7%. 1H NMR(400MHz,CDCl3)δ 7.47-7.43(m,1H),7.39-7.34(m,1H),7.31(dd,J=5.9,3.5Hz,2H),3.25(dd,J=14.1,2.9Hz,1H),2.95(s,3H),2.77-2.65(m,2 H),2.02-1.92(m,1H),1.83-1.74(m,1H),1.66(dt,J=25.0,7.9Hz,1H),1.51-1.41(m,1H),1.19( d,J=6.5Hz,3H). MS[M+H] + :348.

[0411] Step e: Preparation of compound 27-e-1 and compound 27-e-2

[0412] [ka]

[0413] Using compound 27-d (330 mg, 0.95 mmol) as a starting material, a white solid compound 27-e-1 (75 mg, yield 21.7%) is obtained by preparing it according to the method described in step b of Example 1. 1 H NMR(400MHz,CDCl3)δ 7.49(d,J=7.2Hz,1H),7.31(dd,J=13.8,7.2Hz,2H),7.21(d,J=7.2Hz,1H),3.10(dt,J=14.3,7.0Hz,1H) ,2.99(s,3H),2.80-2.72(m,1H),2.07-1.98(m,1H),1.95-1.85(m,1H),1.82-1.73(m,2H),1.54(s,3H). MS[M+H] + :364.

[0414] A white solid compound 27-e-2 (50 mg, yield 14.5%) is obtained. MS[M+H] + :364. Step f: Preparation of compounds 27 and 28

[0415] [ka]

[0416] Compound 27-e-1 (25 mg, 0.069 mmol) is dissolved in methanol (1.5 mL), and 1 M sodium hydroxide aqueous solution (0.5 mL) is added dropwise under ice bath conditions. At room temperature, 0.5 The mixture was allowed to react for a set time. The completion of the reaction of the starting materials was detected by TLC (PE / EA = 3 / 1), diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), combined the organic phases, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 11 mg of a colorless, viscous oily substance. The yield was 61.1%. 1 H NMR(400MHz,CDCl3)δ 7.51(d,J=7.7Hz,1H),7.36(d,J=7.7Hz,1H),7.30(t,J=7.5Hz,1H),7.22(t,J=7.5Hz,1H ),2.55-2.44(m,1H),2.24-2.14(m,4H),2.08(m,1H),1.93(d,J=13.0Hz,1H),1.88-1.80 (m,2H), 1.56(s,3H). MS[M+H] + :268.

[0417] Using compound 27-e-2 (25 mg, 0.069 mmol) as a starting material, the mixture was prepared according to the method described above to obtain 12 mg of a white solid (compound 28), with a yield of 66.7%. 1 H NMR(400MHz,CDCl3)δ 7.38(t,J=8.2Hz,2H),7.29(dd,J=16.9,8.4Hz,2H),2.46-2.35( m,1H),2.22(m,1H),2.09(m,4H),2.02-1.94(m, 1H), 1.87(m, 1H), 1.75(m, 1H), 1.20(s, 3H). MS[M+H] + :268.

[0418] Example 28: Preparation of (2R,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (Compound 29)

[0419] [ka]

[0420] Compound 10 (200 mg, 0.70 mmol) was used as a raw material and prepared according to the method described in Example 14 to obtain 35 mg of a white solid, with a yield of 16.7%. 1 H NMR(400MHz,CDCl3)δ 7.64(d,J=8.1Hz,2H),7.38(d,J=8.1Hz,2H),2.78(d,J=14.2Hz,1H),2.05-1.96(m,6H),1.89(dd,J=18.8,9.6Hz,1H),1.7 5(dd,J=26.7,12.5Hz,1H),0.86(s,3H). MS[M+H] + :302.

[0421] Example 29: Preparation of (2R,6R)-2-dimethylamino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (Compound 30)

[0422] [ka]

[0423] Compound 10 (100 mg, 0.35 mmol) and a 38% formaldehyde aqueous solution (5 ml) were used as raw materials, and the mixture was prepared according to the method described in Example 14 to obtain 70 mg of a white solid, with a yield of 63.6%. 1 H NMR(400MHz,CDCl3)δ 7.63(d,J=8.2Hz,2H),7.48(d,J=8.2Hz,2H),2.72-2.64(m,1H),2.22-2.07(m,8H),2.05-1.96(m,1 H),1.86-1.71(m,2H),1.08(s,3H). MS[M+H] + :3 16.

[0424] Example 30: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (compound 31)

[0425] [ka]

[0426] Step a: Preparation of 31-a (R)-(2-oxo-1-(4-(trifluoromethyl)phenyl)cyclohexyl)carbamate t-butyl ester (5.5 g, 15.39 mmol) was dissolved in dry THF (60 mL), cooled in an ice bath under Ar gas protection, CH3I (5.5 g, 38.75 mmol) was added dropwise, and NaH (1.85 g, 46.2 mmol) was added in batches. After the addition was complete, the temperature was raised to room temperature and the mixture was allowed to react for 1 hour. The completion of the reaction of the starting materials was detected by TLC. The mixture was diluted with water (100 mL), extracted with ethyl acetate (40 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, the low-boiling point solvent was removed using a rotary evaporator, and the mixture was subjected to column chromatography (PE / EA = 15 / 1) to obtain 1.32 g of a white solid, which was a diastereomer mixture in a ratio of approximately 1:1.7. The yield is 22.2%. 1 H NMR(400MHz,CDCl3)δ 7.59(d,J=6.5Hz,5.4H),7.33(d,J=7.7Hz,3.4H),7.22(d,J=7.2Hz,2H),3.06(s,4H),2.89(s ,6.8H),2.42(d,J=14.4Hz,1.7H),2.33(d,J=15.3Hz,1H),2.17-2.03(m,5.4H),1.83(m,5.4H) ),1.50(s,15.3H),1.46-1.39(m,2.7H),1.30(s ,9H),1.10(m,8.1H). MS(M+Na)+:408.

[0427] Step b: Preparation of 31-b

[0428] [ka]

[0429] Compound 31-a (1.32 g, 3.42 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 500 mg of a yellow oily substance, with a yield of 36.4%. MS(M+Na)+: 424.

[0430] Step c: Preparation of compound 31

[0431] [ka]

[0432] Compound 31-b (580 mg, 1.44 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 158 mg of a white solid, with a yield of 36.3%. 1 H NMR(400MHz,CDCl3)δ 7.60(d,J=7.8Hz,2H),7.38(d,J=8.0Hz,2H),2.21(m,1H),2.12(s,3H),2.07(m,1H),2.01(m,1H),1.97-1.90(m, 2H), 1.82(m, 1H), 1.56(s, 3H). MS(M+H) + :302.

[0433] Example 31: Preparation of (2S,6S)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (compound 32)

[0434] [ka]

[0435] Compound 11 (200 mg, 0.70 mmol) was used as a raw material and prepared according to the method described in Example 14 to obtain 130 mg of a white solid, with a yield of 61.9%. 1H NMR(400MHz,CDCl3)δ 7.64(d,J=8.0Hz,2H),7.38(d,J=8.1Hz,2H),2.78(d,J=11.7Hz,1H),2.07-1.95(m,6H),1.89(m,1H),1.75(m,1H),0.86( s,3H). MS(M+H) + :302.

[0436] Example 32: Preparation of (2R,6S)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (compound 33)

[0437] [ka]

[0438] Step a: Preparation of 33-a

[0439] [ka]

[0440] (S)-(2-oxo-1-(4-(trifluoromethyl)phenyl)cyclohexyl)carbamate t-butyl ester (2.0 g, 5.60 mmol) was used as a starting material and prepared according to the method described in step a of Example 30 to obtain 923 mg of a white solid, which is a diastereomer mixture in a ratio of approximately 1:1.7. The yield was 42.8%. 1 H NMR(400MHz,CDCl3)δ 7.60(t,J=7.3Hz,5.4H),7.32(d,J=8.0Hz,3.4H),7.21(d,J=8.2Hz,2H),3.06(s,4H) ),2.89(s,6.8H),2.40(t,J=11.1Hz,1.7H),2.33(d,J=16.2Hz,1H),2.18-2.03(m,5. 4H), 1.90-1.75(m, 5.4H), 1.50(s, 15.3H), 1.48-1.39(m, 2.7H), 1.30(s, 9H), 1.10(m, 8.1H). MS(M+H)+ :386.

[0441] Step b: Preparation of 33-b

[0442] [ka]

[0443] Compound 33-a (915 mg, 2.37 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 253 mg of a yellow oily substance, with a yield of 26.5%. MS(M+Na)+: 424.

[0444] Step c: Preparation of compound 33

[0445] [ka]

[0446] Compound 33-b (250 mg, 0.62 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 100 mg of a white solid, with a yield of 53.2%. 1 H NMR(400MHz,CDCl3)δ 7.60(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),2.26-2.18(m,1H), 2.12(s,3H),2.07(m,1H),2.01(m,1H),1.93(dd,J=21.1,10.8Hz,2H),1.84-1.79(m,1H),1.56( s,3H). MS(M+H) + :302.

[0447] Example 33: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-triduteriomethylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (compound 34)

[0448] [ka]

[0449] Step a: Preparation of 34-a (R)-(2-oxo-1-(4-(trifluoromethyl)phenyl)cyclohexyl)carbamate t-butyl ester (2.5 g, 7.00 mmol) was dissolved in dry THF (40 mL), cooled in an ice bath under Ar gas protection, CD3I (1.49 g, 10.50 mmol) was added dropwise, and NaH (420 mg, 10.50 mmol) was added in batches. After the addition was complete, the temperature was raised to room temperature and the mixture was reacted for 30 minutes. The completion of the reaction of the starting materials was detected by TLC. The reaction was quenched with water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, the low-boiling point solvent was removed using a rotary evaporator, and the mixture was subjected to column chromatography (PE / EA = 10 / 1-5 / 1) to obtain 1.55 g of a white solid. The yield was 59.2%. 1 H NMR(400MHz, CDCl3)δ 7.61(d,J=8.2Hz,2H),7.32(d,J=8.2Hz,2H),2.80(m,1H),2.47(m,2H),2.14(m,2H),1.80(m,3H),1.43(s,9H). MS(M+Na)+:397.

[0450] Step b: Preparation of 34-b

[0451] [ka]

[0452] Compound 34-a (1.52 g, 4.06 mmol) was dissolved in dry THF (25 mL), cooled to -78 °C under Ar gas protection, LDA (4.06 mL, 8.12 mmol) was added dropwise, and the mixture was stirred for 1 hour. Then CH3I (0.86 g, 6.06 mmol) was added dropwise, and after the addition was complete, the mixture was slowly raised to room temperature and allowed to react overnight. The completion of the reaction of the starting materials was detected by TLC. The reaction was quenched by adding saturated NH4Cl aqueous solution (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, the low-boiling solvent was removed using a rotary evaporator, and the mixture was subjected to column chromatography (PE / EA = 30 / 1 to 20 / 1) to obtain 770 mg of a white solid, which was a diastereomer mixture in a ratio of approximately 1:1.4, with a yield of 48.8%. 1 H NMR(400MHz,CDCl3)δ 7.60(t,J=7.5Hz,4.8H),7.32(d,J=8.1Hz,2.8H),7.21(d,J=8.3Hz,2H),3.07(m,1H),2.93-2.83(m,1.4H),2.41( m,1.4H),2.31(m,1H),2.18-2.02(m,4.8H),1.9 2-1.74(m, 4.8H), 1.50(s, 12.6H), 1.47-1.43(m, 2.4H), 1.29(s, 9H), 1.10(m, 7.2H). MS(M+Na)+:411.

[0453] Step c: Preparation of 34-c

[0454] [ka]

[0455] Compound 34-b (760 mg, 1.96 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 193 mg of a white solid, with a yield of 24.4%. MS(M+Na)+: 427.

[0456] Step d: Preparation of compound 34

[0457] [ka]

[0458] Compound 34-c (190 mg, 0.47 mmol) was used as a raw material, and the same process as in Example 1 was used. Prepared according to the method described in step c, 87 mg of a white solid was obtained, with a yield of 60.8%. 1 H NMR(400MHz,CDCl3)δ 7.60(d,J=8.0Hz,2H),7.39(d,J=8.0Hz,2H),2.21(m,1H),2.08(m,1H),2.00(m,1H),1.96-1.87(m,2H),1.84-1.80(m,1H),1.56(s,3H). MS(M+H) + :305.

[0459] Example 34: Preparation of (2R,6S)-2-ethylamine-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (compound 35)

[0460] [ka]

[0461] Step a: Preparation of 35-a

[0462] [ka]

[0463] (2R)-2-amino-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexanone (1.13 g, 4.16 mmol) is dissolved in DCE (20 mL), glacial acetic acid (50 mg, 0.83 mmol) and a solution of 5 M acetaldehyde in tetrahydrofuran (0.91 mL, 4.58 mmol) are added, and the mixture is reacted at room temperature for 1 hour. The mixture is then cooled to 0°C, and sodium triacetoxyborohydride (1.32 g, 6.23 mmol) is added in batches. The mixture is reacted at 0°C for 1 hour. The completion of the reaction of the starting materials was detected by TLC (PE / EA = 1 / 1), the pH was adjusted to approximately 8 with saturated NaHCO3 aqueous solution, diluted with water (100 mL), extracted with dichloromethane (30 mL x 3), the organic phase was combined, washed with saturated NaCl aqueous solution, dried with anhydrous sodium sulfate, filtered, concentrated to dryness using the filtrate, and subjected to column chromatography (MeOH / DCM = 1 / 50) to obtain 0.99 g of pale yellow solid, with a yield of 79.4%. 1 H NMR(400MHz,CDCl3)δ 7.62(d,J=8.2Hz,2H),7.33(d,J=8.2Hz,2H),2.97(dd,J=13.9,2.8Hz,1H),2.38-2.22(m,2H),2.04-1.95(m,2H),1.9 1-1.79(m,2H),1.78-1.71(m,1H),1.46(ddd,J=25.1,12.7,3.9Hz,1H),1.03(d,J=6.4Hz,3H),0.99(t,J=7.1Hz,3H). MS[M+H] + :300.

[0464] Step b: Preparation of 35-b

[0465] [ka]

[0466] Compound 35-a (990 mg, 3.31 mmol) was dissolved in toluene (10 mL), potassium carbonate (1.37 g, 9.90 mmol) and (Boc)2O (1.08 g, 4.95 mmol) were added, and the mixture was stirred at 85°C for 16 hours. The completion of the reaction of the starting materials was detected by TLC (PE / EA = 2 / 1), filtered, and the filtrate was concentrated to dryness. Column chromatography (PE / EA = 50 / 1 to 20 / 1) yielded 0.66 g of a colorless, viscous oily substance, with a yield of 50.0%. MS[M+Na] + :422.

[0467] Step c: Preparation of 35-c

[0468] [ka]

[0469] Compound 35-b (320 mg, 0.80 mmol) was used as a starting material and prepared according to the method described in step b of Example 1 to obtain 72 mg of a colorless oily substance, with a yield of 21.6%. MS(M+Na)+: 438.

[0470] Step d: Preparation of compound 35

[0471] [ka]

[0472] Compound 35-c (70 mg, 0.17 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 27 mg of a white solid, with a yield of 50.9%. 1 H NMR(400MHz,CDCl3)δ 7.59(d,J=8.1Hz,2H),7.38(d,J=8.0Hz,2H),2.42(dq,J=14.4,7.3Hz,1H),2.25-2.15(m,1H),2.06(m,3H),1.95(m ,2H),1.86-1.77(m,1H),1.56(s,3H),1.09(t,J =7.1Hz, 3H). MS[M+H] + :316.

[0473] Example 35: Preparation of (2S,6R)-2-hydroxy-6-isopropylamine-2-methyl-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (Compound 36)

[0474] [ka]

[0475] Step a: Preparation of 36-a

[0476] [ka]

[0477] (2R)-2-amino-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (950 mg, 3.50 mmol) was dissolved in acetone (10 mL), acetic acid (0.042 mL, 0.70 mmol) was added, the tube was sealed, and the mixture was stirred overnight at 56 °C. After cooling to room temperature, sodium borohydride acetate (1.11 g, 5.24 mmol) was added under an ice bath, and the mixture was continued at room temperature for 1 hour. The completion of the reaction of the starting materials was detected by TLC (PE / EA = 3 / 1), the reaction was quenched by adding saturated NaHCO3 aqueous solution (50 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and subjected to column chromatography (PE / EA = 10 / 1) to obtain 800 mg of a colorless oily substance. The yield was 72.9%. 1H NMR(400MHz,CDCl3)δ 7.63(d,J=8.2Hz,2H),7.35(d,J=8.2Hz,2H),3.01(dd,J=14.3,2.5Hz,1H),2.42(dt,J=12.6,6.3Hz,1H),2.30(dq,J=19.1,6.3Hz,1H ),1.94(m,2H),1.80(m,2H),1.45(ddd,J=25.4,12.8,4.9Hz,1H),1.01(d,J=6.4Hz,3H),0.90(d,J=6.2Hz,3H),0.75(d,J=6.4Hz,3H). MS[M+H] + :314.25.

[0478] Step b: Preparation of 36-b

[0479] [ka]

[0480] Compound 36-a (740 mg, 2.36 mmol) is dissolved in anhydrous THF (10 mL), TEA (1 mL) and DMAP (148 mg, 1.21 mmol) are added, and anhydrous trifluoroacetic acid (990 mg, 4.72 mmol) is added under stirring conditions at 0°C. The mixture is then gradually heated to room temperature and stirred for 1 hour. The completion of the reaction of the starting materials is detected by TLC (PE / EA = 3 / 1) Add saturated NH4Cl aqueous solution (60 mL) to quench the reaction, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated NaCl aqueous solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, and perform column chromatography (PE / EA = 10 / 1) to obtain 250 mg of pale yellow solid, with a yield of 25.8%. 1 H NMR(400MHz,CDCl3)δ 7.83(d,J=8.1Hz,2H),7.66(d,J=8.1Hz,2H),3.82-3.66(m,1H),2.96(d, J=13.6Hz,1H),2.67(td,J=13.9,4.3Hz,1H),2.00-1.74(m,5H),1.11(d,J=6.6Hz,6H),1.02(d, J=7.0Hz, 3H). MS[M+H] + :410.20.

[0481] Step c: Preparation of 36-c

[0482] [ka]

[0483] Compound 36-b (500 mg, 1.22 mmol) was used as a raw material and prepared according to the method described in step b of Example 1 to obtain 134 mg of a pale yellow oily substance, with a yield of 25.8%. 1 H NMR(400MHz,CDCl3)δ 7.93(d,J=8.3Hz,2H),7.65(d,J=8.3Hz,2H),3.77-3.61(m,1H ),2.93(d,J=14.5Hz,1H),2.49(td,J=13.8,4.0Hz,1H),2.04(dd,J=24.1,8.4Hz,2H),1.88-1.7 7(m,2H),1.45(s,3H),1.15(d,J=7.0Hz,3H),1.11(d,J=7.0Hz,3H). MS[M+H] + :426.23.

[0484] Step d: Preparation of compound 36

[0485] [ka]

[0486] Compound 36-c (134 mg, 0.32 mmol) was used as a starting material and prepared according to the method described in step f of Example 27 to obtain 22 mg of a white solid, with a yield of 21.2%. 1 H NMR(400MHz,CDCl3)δ 7.59(d,J=8.1Hz,2H),7.46(d,J=8.1Hz,2H),2.56(d,J=15.5Hz,1H),2.47(dt,J=12.5,6.1Hz,1H),2.12-1.86(m ,5H),1.45(s,3H),0.95(d,J=6.2Hz,3H),0.82(d,J=6.3Hz,3H). MS[M+H] + :330.29.

[0487] Example 36: Preparation of N-((1R,3S)-3-hydroxy-3-methyl-2-oxo-1-(4-(trifluoromethyl)phenyl)cyclohexyl)acetamide (Compound 37)

[0488] [ka]

[0489] Compound 12 (300 mg, 1.04 mmol) was dissolved in THF (5 mL), and triethylamine (210 mg, 2.08 mmol), DMAP (26 mg, 0.21 mmol), and anhydride acetate (155 mg, 1.52 mmol) were added sequentially. The mixture was allowed to react at room temperature for 1 hour, and the completion of the reaction of the starting materials was monitored by TLC. The reaction was quenched with saturated aqueous NH4Cl, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, the low-boiling solvent was removed using a rotary evaporator, and the mixture was subjected to column chromatography (DCM / MeOH = 150 / 1 to 50 / 1) to obtain 142 mg of a white solid. The yield was 41.3%. 1 H NMR(400MHz,DMSO-d6)δ 8.49(s,1H),7.68(d,J=8.4Hz,2H),7.53(d,J=8.3Hz,2H),4.95(s,1H),2.42(m,1H),2.28-2.18(m,1H),1.90(s,3H),1. 88-1.74(m,4H),1.28(s,3H). MS[M+H] + :330.

[0490] Example 37: Preparation of N-((1R,3S)-3-hydroxy-3-methyl-2-oxo-1-(4-(trifluoromethyl)phenyl)cyclohexyl)propionamide (Compound 38)

[0491] [ka]

[0492] Compound 12 (130 mg, 0.45 mmol) and propionic anhydride (88 mg, 0.68 mmol) were used as raw materials, and the mixture was prepared according to the method described in Example 36 to obtain 95 mg of a white solid, with a yield of 61.3%. 1 H NMR(400MHz,DMSO-d6)δ 8.40(s,1H),7.69(d,J=8.3Hz,2H),7.54(d,J=8.2Hz,2H),4.94(s,1H),2.43(m ,1H),2.29-2.16(m,3H),1.91-1.73(m,4H),1.28(s,3H),0.98(t,J=7.6Hz,3H). MS(M+H) + :344.

[0493] Example 38: Preparation of (2R,6R)-2-methoxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (compound 39)

[0494] [ka]

[0495] Step a: Preparation of 39-a

[0496] [ka]

[0497] Compound 10-b (150 mg, 0.39 mmol) was dissolved in anhydrous THF (5 mL), CH3I (220 mg, 1.55 mmol) was added under an ice bath, and the mixture was stirred for 10 minutes under N2 protection. Then, NaH (62 mg, 1.55 mmol) was added under an ice bath, and the mixture was reacted at room temperature for approximately 2 hours after the addition was complete. The completion of the reaction of the starting materials was monitored by TLC (PE / EA = 10 / 1), and the reaction was quenched by adding saturated NH4Cl aqueous solution (20 mL). Extraction was performed with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Column chromatography (PE / EA = 100 / 1) was performed to obtain 84 mg of a colorless oily substance, with a yield of 52.2%. MS[M+H] + :416.

[0498] Step b: Preparation of compound 39

[0499] [ka]

[0500] Compound 39-a (84 mg, 0.20 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 60 mg of a white solid, with a yield of 93.8%. 1 H NMR(400MHz,CDCl3)δ 7.60(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),3.31(s,3H),2.51-2. 38(m,1H),2.14(m,2H),2.02(s,3H),1.97(m,1H),1.76-1.65(m,2H),1.04(s,3H). MS[M+H] + :31 6.29.

[0501] Example 39: Preparation of (2S,6R)-2-methoxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one (compound 40)

[0502] [ka]

[0503] Step a: Preparation of 40-a

[0504] [ka]

[0505] Compound 31-b (100 mg, 0.25 mmol) was dissolved in anhydrous THF (5 mL), and under N2 protection and ice bath cooling conditions, NaH (40 mg, 1.0 mmol) was added and the mixture was reacted at 0°C for 20 minutes. Then CH3I (227 mg, 1.60 mmol) was slowly added dropwise to the reaction mixture and allowed to react at room temperature for 2 hours. The completion of the reaction of the starting materials was detected by TLC (PE / EA = 3 / 1), and the reaction was quenched by adding saturated NH4Cl aqueous solution (50 mL). Extraction was performed with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Column chromatography (PE / EA = 10 / 1) was performed to obtain 45 mg of a yellow oily substance, with a yield of 43.7%. 1 H NMR(400MHz,CDCl3)δ 7.66(d,J=8.2Hz,2H),7.59(d,J=8.2Hz,2H),2.68(d,J=13.8Hz,1H),2.47(s,3H),2.45 (s,3H),2.38(m,1H),2.13(m,2H),1.98(m,1H),1.73(m,1H),1.46(s,9H),1.29(s,3H). MS[M+H] + :416. Step b: Preparation of compound 40

[0506] [ka]

[0507] Compound 40-a (45 mg, 0.11 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 26 mg of a white solid, with a yield of 76.5%.1 H NMR(400MHz,CDCl3)δ 7.60(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),2.88(d,J=14.3Hz,1H),2.41 (s,3H),2.14(m,2H),1.96(s,3H),1.89(m,1H),1.69(m,2H),1.22(s,3H). MS[M+H] + :316.17.

[0508] Example 40: (1S,3R)-1-methyl-3-methylamino-2-oxo-3-(4 Preparation of (trifluoromethyl)phenyl)cyclohexanolpropionate (compound 41)

[0509] [ka]

[0510] Step a: Preparation of 41-a

[0511] [ka]

[0512] Compound 31-b (50 mg, 0.12 mmol) was dissolved in anhydrous THF (5 mL), and under N2 protection, anhydrous acetic acid (14 mg, 0.14 mmol) and DMAP (29 mg, 0.24 mmol) were slowly added, and the mixture was stirred overnight at 40°C. The completion of the reaction of the starting materials was monitored by TLC (PE / EA = 5 / 1), and the reaction was quenched by adding saturated NaHCO3 aqueous solution (20 mL). Extraction was performed with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Column chromatography (PE / EA = 10 / 1) yielded 40 mg of gray solid, with a yield of 72.7%. MS[M+Na] + :466.27.

[0513] Step b: Preparation of compound 41

[0514] [ka]

[0515] Compound 41-a (40 mg, 0.09 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 18 mg of a white solid, with a yield of 58.1%. 1 H NMR(400MHz,CDCl3)δ 7.59(d,J=7.9Hz,2H),7.49(d,J=8.0Hz,2H),2.55(t,J=11.2Hz,1H),2.40(t,J=10.9Hz,1H),2.10(s,3H),1.99-1. 82 (m, 7H), 1.62 (s, 3H). MS[M+H] + :344.24.

[0516] Example 41: Preparation of (1S,3R)-1-methyl-3-methylamino-2-oxo-3-(4-(trifluoromethyl)phenyl)cyclohexanolpropionate (Compound 42)

[0517] [ka]

[0518] Step a: Preparation of 42-a

[0519] [ka]

[0520] Compound 31-b (50 mg, 0.12 mmol) and propionic anhydride (18 mg, 0.14 mmol) were used as raw materials, and the preparation was carried out according to the method described in step a of Example 40 to obtain 40 mg of a grayish-white solid, with a yield of 70.2%. MS[M+Na] + :480.26.

[0521] Step b: Preparation of compound 42

[0522] [ka]

[0523] Compound 42-a (40 mg, 0.09 mmol) was used as a starting material and prepared according to the method described in step c of Example 1 to obtain 14 mg of a white solid, with a yield of 45.2%. 1 H NMR(400MHz,CDCl3)δ 7.59(d,J=8.0Hz,2H),7.49(d,J=8.0Hz,2H),2.54(t,J=11.4Hz,1H),2.43(t,J=11.1Hz,1H),2.25-2.12(m,1H),2. 09(s,3H),2.07-1.98(m,1H),1.88(m,4H),1.62 (s,3H),1.03(t,J=7.4Hz,3H). MS[M+H] + :358.25.

[0524] Example 42: Preparation of 2-amino-2-(2-fluoro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methylcyclohexane-1-one hydrochloride (compound 43)

[0525] [ka]

[0526] Compound 1 (90 mg, 0.28 mmol) was dissolved in DCM (2 mL), and under an ice bath, HCl / dioxane (0.5 mL, 4 M) was added and stirred at room temperature for 30 minutes until a solid precipitated. The mixture was filtered, and the filter cake was washed with a 1 / 1 mixture of ethyl acetate / petroleum ether and dried to obtain 91 mg of a white solid. The yield was 91.0%. 1 H NMR(400MHz,CD3OD)δ 7.84(t,J=7.4Hz,1H),7.71(t,J=7.6Hz,1H),7.55(t,J=8.2Hz,1H),3.17(d,J=14.2Hz,1H),2.11-1.96(m,3H),1.92-1.78(m,2H),0.97(s,3H). MS[M+H]+ :322.

[0527] Example 43: Preparation of 2-amino-6-hydroxy-6-methyl-2-(2,4,6-trifluorotolyl)cyclohexane-1-one hydrochloride (compound 44)

[0528] [ka]

[0529] Compound 2 (400 mg, 1.46 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 423 mg of a white solid, with a yield of 93.4%. 1 H NMR(400MHz,CD3OD)δ 7.20-7.11(m,2H),3.31(m ,1H),2.08(m,1H),2.03(m,1H),1.96-1.80(m,3 H), 1.14(s,3H). MS[M+H] + :274.

[0530] Example 44: Preparation of 2-amino-2-(4-chloro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methylcyclohexane-1-one hydrochloride (compound 45)

[0531] [ka]

[0532] Compound 3 (150 mg, 0.44 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 145 mg of a white solid, with a yield of 87.3%. 1 H NMR(400MHz,CD3OD)δ 7.96(t,J=4.7Hz,1H),7.73(d,J=5.0Hz,2H),3.21(d,J=15.1Hz,1H),2.04(m,3H),1.95-1.79(m,2H),0.98(s,3H). MS(M+H ) + :338.

[0533] Example 45: Preparation of 2-amino-2-(3-fluoro-2-(trifluoromethyl)phenyl)-6-hydroxy-6-methylcyclohexane-1-one hydrochloride (compound 46)

[0534] [ka]

[0535] Compound 4 (80 mg, 0.26 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 82 mg of a white solid, with a yield of 91.1%. 1 H NMR(400MHz,CD3OD)δ 7.81(dd,J=14.3,7.8Hz,1H),7.51(dd,J=23.7,9.3Hz,2H),2.80(m,1H),2.45-2.25(m,2H),2.20(m,1H),1.90(m,2H),1.37( s,3H). MS(M+H) + :306.

[0536] Example 46: Preparation of 3-(1-amino-3-hydroxy-3-methyl-2-oxocyclohexyl)benzonitrile hydrochloride (compound 47)

[0537] [ka]

[0538] Compound 5 (150 mg, 0.61 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 145 mg of a white solid, with a yield of 84.3%. 1 H NMR(400MHz,CD3OD)δ 7.97-7.89(m,2H),7.86-7.72(m,2H),3.16(d,J=14.3Hz,1H),2.14(t,J=13.1Hz,1H),2.04(m,2H),1.91(q,J=12.1Hz,2H),0.82(s,3H). MS[M+H] + :245.

[0539] Example 47: Preparation of 2-amino-2-(2,3-difluorophenyl)-6-hydroxy-6-methylcyclohexane-1-one hydrochloride (compound 48)

[0540] [ka]

[0541] Compound 6 (150 mg, 0.59 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 132 mg of a white solid, with a yield of 77.2%. 1 H NMR(400MHz,CD3OD)δ 7.62-7.50(m,2H),7.45(d d,J=13.6,8.1Hz,1H),3.16(d,J=13.6Hz,1H),2.03(m,3H),1.87(m,2H),1.00(s,3H). MS[M+H] + :256.

[0542] Example 48: Preparation of 2-amino-6-hydroxy-6-methyl-2-(3-(trifluoromethoxy)phenyl)cyclohexane-1-one hydrochloride (compound 49)

[0543] [ka]

[0544] Compound 7 (30 mg, 0.099 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 28 mg of a white solid, with a yield of 82.4%. 1 H NMR(400MHz,CD3OD)δ 7.71(t,J=8.1Hz,1H),7.57(d,J=8.0Hz,1H),7.51(d,J=8.2Hz,1H),7.40(s,1H),3.12(t,J=13.6Hz,1H),2.19-2.00(m,3H) ,1.95-1.86(m,2H),0.81(s,3H). MS[M+H] + :304 .

[0545] Example 49: Preparation of 2-amino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (compound 50)

[0546] [ka]

[0547] Compound 8 (30 mg, 0.10 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 30 mg of a white solid, with a yield of 88.2%. 1 H NMR(400MHz,CD3OD)δ 7.89(d,J=8.2Hz,2H),7.74(d,J=8.2Hz,2H),3.18(d,J=12.2Hz,1H),2.14(dd,J=17.8,7.8Hz,1H),2.04(m,2H),1.92(m,2H),0.81(s,3H). MS(M+H) + :288.

[0548] Example 50: Preparation of (2R,6R)-2-amino-6-hydroxy-6-deuterium-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (Compound 51)

[0549] [ka]

[0550] Compound 9 (40 mg, 0.14 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 39 mg of a white solid, with a yield of 86.7%. 1 H NMR(400MHz,CD3OD)δ 7.90(d,J=8.1Hz,2H),7.67(d,J=8.0Hz,2H),3.17(d,J=13.5Hz,1H),2.32(d,J=10 .6Hz,1H),2.09(dd,J=18.9,8.5Hz,1H),1.99(d,J=14.8Hz,1H),1.88-1.65(m,2H). MS[M+ H] + :275.

[0551] Example 51: Preparation of (2R,6R)-2-amino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (compound 52)

[0552] [ka]

[0553] Compound 10 (40 mg, 0.14 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 35 mg of a white solid, with a yield of 77.8%. 1 H NMR(400MHz,CD3OD)δ 7.89(d,J=8.2Hz,2H),7.74(d,J=8.2Hz,2H),3.18(d,J=12.2Hz,1H),2.14(dd, J=17.8,7.8Hz,1H),2.04(d,J=8.4Hz,2H),1.92(t,J=8.7Hz,2H),0.81(s,3H). MS(M+H) + :288.

[0554] Example 52: Preparation of (2S,6S)-2-amino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (compound 53)

[0555] [ka]

[0556] Compound 11 (40 mg, 0.14 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 40 mg of a white solid, with a yield of 88.9%. 1H NMR(400MHz,CD3OD)δ 7.89(d,J=8.3Hz,2H),7.74(d,J=8.3Hz,2H),3.17(d,J=13.8Hz,1H),2.14(t d,J=13.2,4.1Hz,1H),2.04(dd,J=7.0,4.2Hz,2H),1.93(m,2H),0.81(s,3H). MS(M+H) + :288.

[0557] Example 53: Preparation of (2R,6S)-2-amino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (compound 54)

[0558] [ka]

[0559] Compound 12 (20 mg, 0.70 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 18 mg of a white solid, with a yield of 81.8%. 1 H NMR(400MHz,DMSO-d6)δ 8.73(s,3H),7.82(d,J=8.2Hz,2H),7.63(d,J=8.2Hz,2H),5.15(s,1H),3.01(d,J=12.1Hz,1H),2.07(d d,J=23.6,12.2Hz,1H),1.98(d,J=13.2Hz,1H),1.90(d,J=14.8Hz,1H),1.72-1.53(m,2H),1.21(s,3H). MS[M+H] + :288.

[0560] Example 54: Preparation of (2S,6R)-2-amino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (compound 55)

[0561] [ka]

[0562] Compound 13 (20 mg, 0.70 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 15 mg of a white solid, with a yield of 68.2%. 1 H NMR(400MHz,DMSO-d6)δ 8.72(s,3H),7.82(d,J=8.2Hz,2H),7.63(d,J=8.2Hz,2H),5.15(s,1H),3.01(d,J=12.0Hz,1H),2.07(d d,J=23.6,12.2Hz,1H),1.98(d,J=13.1Hz,1H),1.90(d,J=14.6Hz,1H),1.73-1.52(m,2H),1.21(s,3H). MS[M+H] + :288.

[0563] Example 55: Preparation of 2-(2-fluoro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methyl-2-(methylamino)cyclohexane-1-one hydrochloride (compound 56)

[0564] [ka]

[0565] Compound 14 (100 mg, 0.30 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 92 mg of a white solid, with a yield of 82.9%. 1 H NMR(400MHz,CD3OD)δ 7.85(s,1H),7.77(s,1H),7.59(s,1H),3.29-3.22(m,1H),2.37(s,3H),2. 04(m,2H),1.98-1.77(m,3H),0.96(s,3H). MS[M +H] + :336.

[0566] Example 56: Preparation of (2R,6S)-2-(2-fluoro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methyl-2-(methylamino)cyclohexane-1-one hydrochloride (Compound 57)

[0567] [ka]

[0568] Compound 15 (40 mg, 0.12 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 37 mg of a white solid, with a yield of 84.1%. 1 H NMR(400MHz,CD3OD)δ 7.75(t,J=7.3Hz,1H),7.60(t,J=7.6Hz,1H),7.45(t,J=8.1Hz,1H),3.29 (m,1H),2.35(s,3H),2.11-1.98(m,2H),1.90-1.64(m,3H),1.35(s,3H). MS[M+H] + :336.34.

[0569] Example 57: Preparation of 2-hydroxy-2-methyl-6-methylamino-6-(2,4,6-trifluorotolyl)cyclohexane-1-one hydrochloride (compound 58)

[0570] [ka]

[0571] Compound 16 (20 mg, 0.070 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 17 mg of a white solid, with a yield of 77.3%. 1 H NMR(400MHz,CD3OD)δ 7.26-7.17(m,2H),3.46(d ,J=11.2Hz,1H),2.53(s,3H),2.07(m,2H),1.79(m,3H),1.12(s,3H). MS[M+H] + :288.

[0572] Example 58: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(2,4,6-trifluorophenyl)cyclohexane-1-one hydrochloride (Compound 59)

[0573] [ka]

[0574] Compound 17 (20 mg, 0.070 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 15 mg of a white solid, with a yield of 68.2%. 1 H NMR(400MHz,CD3OD)δ 7.14-7.05(m,2H),3.29(m ,1H),2.33(s,3H),2.09-1.97(m,2H),1.88-1.61(m,3H),1.32(s,3H). MS[M+H] + :288.MS[M+H] + :288.

[0575] Example 59: Preparation of 2-(4-chloro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methyl-2-methylaminocyclohexane-1-one hydrochloride (compound 60)

[0576] [ka]

[0577] Compound 18 (20 mg, 0.057 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 17 mg of a white solid, with a yield of 77.3%. 1 H NMR(400MHz,CD3OD)δ 7.97(m,1H),7.77(m,2H),3.41(d,J=12.7Hz,1H),2.33(s,3H),2.09(d, J=10.4Hz,1H),2.00(m,1H),1.89(dt,J=21.0,11.1Hz,3H),0.95(s,3H). MS(M+H) + :352.

[0578] Example 60: Preparation of (2R,6S)-2-(4-chloro-3-(trifluoromethoxy)phenyl)-6-hydroxy-6-methyl-2-methylamino-cyclohexane-1-one hydrochloride (Compound 61)

[0579] [ka]

[0580] Compound 19 (20 mg, 0.057 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 15 mg of a white solid, with a yield of 68.2%. 1 H NMR(400MHz,CD3OD)δ 7.65(m,1H),7.42-7.18(m ,2H),3.22(d,J=13.5Hz,1H),2.25(s,3H),2.14(m,1H),2.05(m,1H),1.93(m,1H),1.82(m,1H), 1.70(m,1H),1.35(s,3H). MS[M+H] + :352.

[0581] Example 61: Preparation of 2-(3-fluoro-2-(trifluoromethyl)phenyl)-6-hydroxy-6-methyl-2-methylamino-cyclohexane-1-one hydrochloride (compound 62)

[0582] [ka]

[0583] Compound 20 (40 mg, 0.12 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 32 mg of a white solid, with a yield of 72.7%. 1 H NMR(400MHz,CD3OD)δ 7.87(dd,J=14.4,7.4Hz,1H),7.58(t,J=8.5Hz,2H),2.53(s,4H),2.27(d,J=10.7Hz,1H),2.11(s,1H),1.90(d,J=10.9Hz,2H),1.31(s,4H). MS(M+H) + :320.

[0584] Example 62: Preparation of 3-(3-hydroxy-3-methyl-1-methylamino-2-oxocyclohexyl)benzonitrile hydrochloride (compound 63)

[0585] [ka]

[0586] Compound 21 (25 mg, 0.097 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 18 mg of a white solid, with a yield of 64.3%. 1 H NMR(400MHz,CD3OD)δ 7.98(m,1H),7.91(m,1H),7.80(m,2H),3.26(d,J=13.9Hz,1H),2.31(s,3H),2.04(m,3H),1.89(q,J=14.0Hz,2H),0.80(s,3H). MS[M+H] + :259.

[0587] Example 63: Preparation of 3-((1R,3S)-3-hydroxy-3-methyl-1-methylamino-2-oxocyclohexyl)benzonitrile hydrochloride (compound 64)

[0588] [ka]

[0589] Compound 22 (25 mg, 0.097 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 22 mg of a white solid, with a yield of 78.6%. 1 HN MR(400MHz,CD3OD)δ 7.87(d,J=7.6Hz,1H),7.78(m,2H),7.70(t,J=7.9Hz,1H),3.23(d,J=13.7Hz,1H),2. 27(s,3H),2.13(dd,J=26.8,13.6Hz,1H),2.03(d,J=13.9Hz,1H),1.99-1.89(m,1H), 1.84(d,J=14.3Hz,1H),1.78-1.68(m,1H),1.33 (s,3H). MS[M+H] + :259.

[0590] Example 64: Preparation of 2-(2,3-difluorophenyl)-6-hydroxy-6-methyl-2-methylaminocyclohexane-1-one hydrochloride (compound 65)

[0591] [ka]

[0592] Compound 23 (30 mg, 0.11 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 25 mg of a white solid, with a yield of 73.5%. 1 H NMR(400MHz,CD3OD)δ 7.59(t,J=7.8Hz,2H),7.49(dd,J=13.6,8.0Hz,1H),3.29(s,1H),2.37(s,3H),2.05(m,2H),1.96-1.79(m,3H),0.98(s,3H) MS[M+H] + :270.

[0593] Example 65: Preparation of (2R,6S)-2-(2,3-difluorophenyl)-6-hydroxy-6-methyl-2-methylaminocyclohexane-1-one hydrochloride (compound 66)

[0594] [ka]

[0595] Compound 24 (40 mg, 0.15 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 32 mg of a white solid, with a yield of 71.1%. 1 H NMR(400MHz,CD3OD)δ 7.53(s,1H),7.45(d,J=7.4Hz,1H),7.37(s,1H),3.25(m,1H),2.34(s,3H),2.14-1.97(m,2H),1.76(m,3H),1.35(s,3H). M.S. [M+H] + :270.36.

[0596] Example 66: Preparation of 2-hydroxy-2-methyl-6-methylamino-6-(3-(trifluoromethoxy)phenyl)cyclohexane-1-one hydrochloride (compound 67)

[0597] [ka]

[0598] Compound 25 (40 mg, 0.13 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 30 mg of a white solid, with a yield of 68.2%. 1 H NMR(400MHz,CD3OD)δ 7.74(t,J=8.1Hz,1H),7.57(t,J=7.8Hz,2H),7.39(s,1H),3.25(d,J=11.6Hz,1 H),2.31(s,3H),2.04(dd,J=23.5,12.6Hz,3H),1.94-1.81(m,2H),0.79(s,3H). MS[M+H] + :3 18.

[0599] Example 67: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(3-(trifluoromethoxy)phenyl)cyclohexane-1-one hydrochloride (Compound 68)

[0600] [ka]

[0601] Compound 26 (40 mg, 0.13 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 34 mg of a white solid, with a yield of 77.3%. 1H NMR(400MHz,CD3OD)δ 7.62(t,J=8.1Hz,1H),7.43(d,J=8.2Hz,2H),7.39(s,1H),3.20(d,J=13.8Hz,1H),2.27(s,3H),2.23-2.10(m,1H),2.03(d, J=13.5Hz,1H),1.93(td,J=13.6,3.5Hz,1H),1.83(d,J=13.9Hz,1H),1.73(td,J=13.7,3.7Hz,1H),1.32(s,3H). MS[M+H] + :318.34.

[0602] Example 68: (2R,6S)-2-(2-chlorophenyl)-6-hydroxy-6-methyl-2-methylaminocyclohexane-1-one hydrochloride (Compound 69)

[0603] [ka]

[0604] Compound 27 (25 mg, 0.093 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 19 mg of a white solid, with a yield of 67.8%. 1 H NMR(400MHz,CD3OD)δ 7.81(d,J=7.1Hz,1H),7.55-7.47(m,3H),3.36(m,1H),2.27(s,3H),2.21-2.06(m,1H),2.03(d,J=13.0Hz,1H),1.83-1.63( m,3H), 1.37(s,3H). MS[M+H] + :268.

[0605] Example 69: (2R,6R)-2-(2-chlorophenyl)-6-hydroxy-6-methyl-2-methylaminocyclohexane-1-one hydrochloride (Compound 70)

[0606] [ka]

[0607] Compound 28 (25 mg, 0.093 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 22 mg of a white solid, with a yield of 78.6%. 1 H NMR(400MHz,CD3OD)δ 7.95-7.88(m,1H),7.67-7.58(m,3H),3.40(d,J=11.0Hz,1H),2.30(s,3H),2.13-2.05(m,1H),2.03-1.93(m,1H),1.83(m,3H),0.97(s,3H). MS[M+H] + :268.

[0608] Example 70: Preparation of (2R,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (Compound 71)

[0609] [ka]

[0610] Compound 29 (20 mg, 0.066 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 18 mg of a white solid, with a yield of 81.8%. 1 H NMR(400MHz,CD3OD)δ 7.93(d,J=8.1Hz,2H),7.73(d,J=8.1Hz,2H),3.26(m,1H),2.30(s,3H),2.12-1.98(m,3H),1.92(m,2H),0.79(s,3H). MS(M +H) + :302.

[0611] Example 71: Preparation of (2R,6R)-2-dimethylamino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (Compound 72)

[0612] [ka]

[0613] Compound 30 (40 mg, 0.13 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 38 mg of a white solid, with a yield of 84.4%. 1 H NMR(400MHz,CD3OD)δ 7.95(d,J=8.4Hz,2H),7.79(d,J=8.4Hz,2H),3.11(d,J=14.1Hz,1H),2.93( s, 3H), 2.44 (m, 1H), 2.36 (s, 3H), 2.15 (d, J=13.5Hz, 1H), 1.94 (m, 3H), 0.76 (s, 3H). MS(M+H) + :316.

[0614] Example 72: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (Compound 73)

[0615] [ka]

[0616] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 45 mg of a white solid, with a yield of 80.4%. 1 H NMR(400MHz,CD3OD)δ 7.82(d,J=8.2Hz,2H),7.66(d,J=8.2Hz,2H),3.24(dd,J=13.8,2.4Hz,1H),2.26(s,3H),2.24-2.11(m,1H),2.04(dd,J=14. 0,2.2Hz,1H),1.95(td,J=13.6,3.7Hz,1H),1.84(d,J=13.8Hz,1H),1.74(td,J=13.8,3.8Hz,1H),1.32(s,3H). MS(M+H) + :302.

[0617] Example 73: Preparation of (2S,6S)-2-dimethylamino-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (Compound 74)

[0618] [ka]

[0619] Compound 32 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 50 mg of a white solid, with a yield of 89.3%. 1 H NMR(400MHz,CD3OD)δ 7.93(d,J=8.2Hz,2H),7.73(d,J=8.2Hz,2H),3.26(s,1H),2.30(s,3H),2.12-1.98(m,3H),1.92(m,2H),0.78(s,3H). MS(M+ H) + :302.

[0620] Example 74: Preparation of (2R,6S)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (Compound 75)

[0621] [ka]

[0622] Compound 33 (50 mg, 0.16 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 47 mg of a white solid, with a yield of 83.9%. 1 H NMR(400MHz,CD3OD)δ 7.82(d,J=8.3Hz,2H),7.66(d,J=8.3Hz,2H),3.24(dd,J=13.7,2.8Hz,1H),2.26(s,3H),2.24-2.12(m,1H),2.04(dd,J=14. 7,2.8Hz,1H),1.94(td,J=13.6,3.9Hz,1H),1.88-1.80(m,1H),1.74(td,J=13.7,4.0Hz,1H),1. 32(s,3H). MS(M+H) + :302.

[0623] Example 75: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-triduteriomethylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (Compound 76)

[0624] [ka]

[0625] Compound 34 (50 mg, 0.16 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 50 mg of a white solid, with a yield of 89.3%. 1 H NMR(400MHz,CD3OD)δ 7.82(d,J=8.3Hz,2H),7.66(d,J=8.2Hz,2H),3.24(dd,J=13.8,2.9Hz,1H),2.25-2.11 (m,1H),2.08-2.00(m,1H),1.94(td,J=13.6,3.9Hz,1H),1.88-1.80(m,1H),1.74(td, J=13.7,4.0Hz,1H),1.32(s,3H). MS(M+H) + :305.

[0626] Example 76: Preparation of (2R,6S)-2-ethylamine-6-hydroxy-6-methyl-2-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (Compound 77)

[0627] [ka]

[0628] Compound 35 (20 mg, 0.063 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 15 mg of a white solid, with a yield of 68.2%. 1 H NMR(400MHz,CD3OD)δ 7.81(d,J=8.2Hz,2H),7.68(d,J=8.2Hz,2H),3.27(dd,J=13.9,2.5Hz,1H),2.88(dq,J=14.4,7.3Hz,1H),2.2 9(dq,J=14.5,7.2Hz,1H),2.16(qt,J=12.6,2.8Hz,1H),2.00(qd,J=13.8,3.3Hz,2H),1.87-1.80(m,1H),1.7 3(td,J=13.6,3.9Hz,1H),1.33(s,3H),1.21(t,J=7.2Hz,3H). MS[M+H] + :316.

[0629] Example 77: Preparation of (2S,6R)-2-hydroxy-6-isopropylamine-2-methyl-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (Compound 78)

[0630] [ka]

[0631] Compound 36 (20 mg, 0.061 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 18 mg of a white solid, with a yield of 81.8%. 1 H NMR(400MHz,CD3OD)δ 7.81(d,J=8.3Hz,2H),7.75(d,J=8.3Hz,2H),3.40(dd,J=13.0,6.5Hz,1H),2.27-1.96(m,4H),1.84(d,J=13.3Hz,1H),1.7 5(td,J=13.5,3.6Hz,1H),1.32(s,3H),1.22(d,J=6.5Hz,3H),0.76(d,J=6.4Hz,3H). MS[M+H] + :330.29.

[0632] Example 78: Preparation of (2R,6R)-2-methoxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (Compound 79)

[0633] [ka]

[0634] Compound 39 (30 mg, 0.095 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 26 mg of a white solid, with a yield of 78.8%. 1 H NMR(400MHz,CD3OD)δ 7.93(d,J=8.2Hz,2H),7.74(d,J=8.2Hz,2H),3.38(s,3H),3.24(dd,J=13.7,2.7Hz,1H),2.30(s,3H),2.17-2.01(m,3H),1 .96-1.83(m,2H),0.85(s,3H). MS[M+H] + :316.2 9.

[0635] Example 79: Preparation of (2S,6R)-2-methoxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrochloride (Compound 80)

[0636] [ka]

[0637] Compound 40 (30 mg, 0.095 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 25 mg of a white solid, with a yield of 75.8%. 1 H NMR(400MHz,CD3OD)δ 7.87(d,J=8.6Hz,2H),7.70(d,J=8.3Hz,2H),3.22(dd,J=14.0,2.8Hz,1H),2.49(s,3H),2.27(s,3H),2.26-2.15(m,2H),2 .05-1.94(m,1H),1.86(dt,J=7.0,3.0Hz,1H),1 .74(td,J=13.9,3.8Hz,1H),1.29(s,3H). MS[M+H] + :316.17.

[0638] Example 80: Preparation of (1S,3R)-1-methyl-3-methylamino-2-oxo-3-(4-(trifluoromethyl)phenyl)cyclohexanolpropionate (Compound 81)

[0639] [ka]

[0640] Compound 41 (20 mg, 0.058 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 14 mg of a white solid, with a yield of 63.6%. 1 H NMR(400MHz,CD3OD)δ 7.89(d,J=8.3Hz,2H),7.69(d,J=8.3Hz,2H),3.26(m,1H),2.47(dd,J=14.3,2.4Hz,1H), 2.31(d,J=13.1Hz,1H),2.23(s,3H),2.01(m,2H),1.83(m,1H),1.56(s,3H),1.13(s,3H). MS[M+H] + :344.24.

[0641] Example 81: Preparation of (1S,3R)-1-methyl-3-methylamino-2-oxo-3-(4-(trifluoromethyl)phenyl)cyclohexanolpropionate (Compound 82)

[0642] [ka]

[0643] Compound 42 (20 mg, 0.056 mmol) was used as a starting material and prepared according to the method described in Example 42 to obtain 16 mg of a white solid, with a yield of 72.7%. 1H NMR(400MHz,CD3OD)δ 7.87(d,J=8.3Hz,2H),7.68(d,J=8.3Hz,2H),3.28(m,1H),2.45(d,J=14.6Hz,1H),2.30(m,1H),2.21(s,3H),2.07-1.94(m ,2H),1.85(m,1H),1.72-1.61(m,1H),1.56(s,3 H),1.10-0.99(m,1H),0.61(t,J=7.4Hz,3H). M.S. [M+H] + :358.25.

[0644] Example 82: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one hydrobromide (compound 83)

[0645] [ka]

[0646] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 55 mg of a white solid, with a yield of 87.3%. 1 H NMR(400MHz,CD3OD)δ 7.82(d,J=8.2Hz,2H),7.66(d,J=8.3Hz,2H),3.25(dd,J=13.7,2.4Hz,1H),2.26(s,3H),2.17(t,J=13.5Hz,1H),2.0 3(d,J=14.2Hz,1H),1.95(dt,J=17.3,8.5Hz,1H),1.84(d,J=14.1Hz,1H),1.74(td,J=13.6,3.8Hz,1H),1.32(s,3H). MS(M+H) + :302.

[0647] Example 83: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one sulfate (compound 84)

[0648] [ka]

[0649] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 50 mg of a white solid, with a yield of 75.8%. 1 H NMR(400MHz,CD3OD)δ 7.82(d,J=8.2Hz,2H),7.66(d,J=8.3Hz,2H),3.24(dd,J=13.8,2.5Hz,1H),2.26(s,3H),2.18(q,J=13.2Hz,1H),2.03(d d,J=14.2,2.5Hz,1H),1.93(td,J=13.5,3.8Hz,1H),1.84(d,J=14.0Hz,1H),1.73(td,J=13.8,4.0Hz,1H),1.32(s,3H). MS(M+H) + :302.

[0650] Example 84: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-ion phosphate (Compound 85)

[0651] [ka]

[0652] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 53 mg of a white solid, with a yield of 80.3%. 1 H NMR(400MHz,CD3OD)δ 7.82(d,J=8.2Hz,2H),7.66(d,J=8.2Hz,2H),3.23-3.17(m,1H),2.24(s,3H) ),2.16(t,J=13.3Hz,1H),2.09-1.93(m,2H),1. 90-1.72(m,2H),1.34(s,3H). MS(M+H) + :302.

[0653] Example 85: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one acetate (compound 86)

[0654] [ka]

[0655] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 53 mg of a white solid, with a yield of 80.3%. 1 H NMR(400MHz,CD3OD)δ 7.71(d,J=8.2Hz,2H),7.56(d,J=8.2Hz,2H),2.92(d,J=14.6Hz,1H),2.08(s,4H),1.97(d,J=16.9Hz,4H),1.92-1.72(m,3H) ), 1.34(s,3H). MS(M+H) + :302.

[0656] Example 86: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-on fumarate (Compound 87)

[0657] [ka]

[0658] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 53 mg of a white solid, with a yield of 80.3%. 1 H NMR(400MHz,CD3OD)δ 7.79(d,J=8.3Hz,2H),7.63(d,J=8.3Hz,2H),6.69(s,2H),3.16(dd,J=13.9,2.6Hz,1H),2.21(s,3H),2.20-2.09(m,1H),2. 02(dd,J=14.1,2.7Hz,1H),1.93(td,J=13.4,3.7Hz,1H),1.87-1.79(m,1H),1.75(td,J=13.6,3 0.9Hz, 1H), 1.33(s, 3H). MS(M+H) + :302.

[0659] Example 87: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-oncitrate (Compound 88)

[0660] [ka]

[0661] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 53 mg of a white solid, with a yield of 80.3%. 1 H NMR(400MHz,CD3OD)δ 7.80(d,J=8.1Hz,2H),7.64(d,J=8.2Hz,2H),3.17(d,J=12.5Hz,1H),2.78(q,J=15.4Hz,4H),2 .21(s,3H),2.15(dd,J=25.6,12.1Hz,1H),2.06-1.96(m,2H),1.97-1.69(m,2H),1.33(s,3H). MS(M+H) + :302.

[0662] Example 88: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one maleate (Compound 89)

[0663] [ka]

[0664] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 53 mg of a white solid, with a yield of 80.3%. 1 H NMR(400MHz,CD3OD)δ 7.82(d,J=8.2Hz,2H),7.65(d,J=8.1Hz,2H),6.26(s,2H),3.23(dd,J=14.0,2.5Hz,1H),2.26(s,3H),2.16(m ,1H),2.03(dd,J=14.5,2.5Hz,1H),1.93(td,J=13.5,3.8Hz,1H),1.87-1.80(m,1H),1.73(td,J=13.7,3.8Hz, 1H), 1.32(s,3H). MS(M+H) + :302.

[0665] Example 89: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-onemethanesulfonate (Compound 90)

[0666] [ka]

[0667] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 53 mg of a white solid, with a yield of 80.3%. 1 H NMR(400MHz,CD3OD)δ 7.82(d,J=8.2Hz,2H),7.66(d,J=8.3Hz,2H),3.24(dd,J=13.6,2.8Hz,1H),2.70(s,3H),2.26(s,3H),2.23-2.11(m,1H),2. 03(dd,J=14.2,2.4Hz,1H),1.93(td,J=13.8,3.5Hz,1H),1.88-1.80(m,1H),1.73(td,J=13.7,3 0.9Hz, 1H), 1.32(s, 3H). MS(M+H) + :302.

[0668] Example 90: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one L-(+)-tartrate (compound 91)

[0669] [ka]

[0670] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 53 mg of a white solid, with a yield of 80.3%. 1 H NMR(400MHz,CD3OD)δ 7.80(d,J=8.2Hz,2H),7.64(d,J=8.2Hz,2H),4.40(s,2H),3.17(dd,J=14.0,2.4Hz,1H ),2.23(s,3H),2.15(dd,J=26.7,13.4Hz,1H),1.98(m,2H),1.77(m,2H),1.33(s,3H). MS(M+H) + :302.

[0671] Example 91: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one benzoate (Compound 92)

[0672] [ka]

[0673] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 53 mg of a white solid, with a yield of 80.3%. 1H NMR(400MHz,CD3OD)δ 7.98(d,J=8.1Hz,2H),7.72(d,J=8.2Hz,2H),7.58(d,J=8.3Hz,2H),7.49(t,J=7.3Hz ,1H),7.40(t,J=7.6Hz,2H),2.97(d,J=13.4Hz,1H),2.14-2.03(m,4H),1.99(m,1H),1 .91(dd,J=14.2,2.2Hz,1H),1.87-1.71(m,2H), 1.34 (s, 3H). MS (M+H) + :302.

[0674] Example 92: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-one L-lactate (Compound 93)

[0675] [ka]

[0676] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 53 mg of a white solid, with a yield of 80.3%. 1 H NMR(400MHz,CD3OD)δ 7.76(d,J=8.2Hz,2H),7.61(d,J=8.2Hz,2H),4.06(q,J=6.8Hz,1H),3.06(d,J=13.9Hz,1H),2.16(s,3H),2.14-2.06(m,1H) ,2.00(dd,J=14.0,2.3Hz,1H),1.93(dd,J=13.4,3.2Hz,1H),1.89-1.80(m,1H),1.80-1.71(m,1H),1.34(d,J=5.2Hz,3H),1.33(s,3H). MS(M+H) + :302.

[0677] Example 93: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-onebenzenesulfonate (Compound 94)

[0678] [ka]

[0679] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 53 mg of a white solid, with a yield of 80.3%. 1 H NMR(400MHz,CD3OD)δ 7.82(t,J=6.7Hz,4H),7.65(d,J=8.2Hz,2H),7.43(d,J=5.4Hz,3H),3.24(dd,J=13.8,2.4Hz,1H),2.26(s,3H) ),2.17(q,J=13.5Hz,1H),2.03(dd,J=14.4,2.6Hz,1H),1.93(td,J=13.6,3.4Hz,1H),1.88-1.80(m,1H),1.73 (td,J=13.6,3.8Hz,1H),1.32(s,3H). MS(M+H) + :302.

[0680] Example 94: Preparation of (2S,6R)-2-hydroxy-2-methyl-6-methylamino-6-(4-(trifluoromethyl)phenyl)cyclohexane-1-onxalate (Compound 95)

[0681] [ka]

[0682] Compound 31 (50 mg, 0.16 mmol) was used as a raw material and prepared according to the method described in Example 42 to obtain 53 mg of a white solid, with a yield of 80.3%. 1H NMR(400MHz,CD3OD)δ 7.81(d,J=8.2Hz,2H),7.65(d,J=8.3Hz,2H),3.22(dd,J=13.8,2.4Hz,1H),2.25(s,3H),2.18(dd,J=29.8,16.4H z,1H),2.07-2.00(m,1H),2.00-1.90(m,1H),1.84(d,J=13.4Hz,1H),1.74(td,J=13.9,4.1Hz,1H),1.32(s,3H). MS(M+H) + :302.

[0683] Biological and chemical performance evaluation The effects of the present invention will be further explained below in combination with test examples, but these examples do not limit the scope of the present invention.

[0684] Test Example 1. Evaluation of the antidepressant activity of the compound of the present invention in a forced swimming experiment after oral administration to mice. 2.1. Experimental Objectives Forced swimming experiments were conducted 1 hour and 24 hours after a single oral administration of 20 mg / kg, respectively, to observe the effects of different compounds on the depressive-like behavior of C57 mice.

[0685] 2.2. Experimental Plan 1)Animals The experimental animals were 6-week-old male C57 mice, purchased from Shanghai Slack Laboratory Animal Co., Ltd., weighing 20.45 ± 0.19 g. Prior to the experiment, the animals arrived at the Animal Husbandry Center of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (Animal Production License: SCXK9[Shanghai]2004-0002, Use License: SYXK[Shanghai]2003-0029) and were allowed to adapt to the animal facility for at least 3 days, with 6 animals per cage. The rearing environment was maintained at a room temperature of 23 ± 0.2°C, with light and dark alternating every 12 / 12 hours. Before the behavioral tests, the animals were moved to the behavioral testing room 2 hours prior to the tests to allow them to adapt to the environment and reduce their stress.

[0686] 2) Grouping of animals The animal grouping information and related dosage information are shown in Table 1.

[0687] [Table 1]

[0688] 3) Experimental Steps Preparation of test samples: Each test compound is accurately weighed and dissolved in a 0.9% NaCl solution. The mixture is thoroughly and uniformly prepared into 1 mg / ml and 2 mg / ml solutions, which are then stored.

[0689] 24 hours prior to administration, mice are placed in a cylindrical cylinder and adapted to an aquatic environment for 10 minutes. On the day of the behavioral test, the animals are administered a single intragastric / intraperitoneal injection 1 hour and 24 hours prior to the behavioral test, respectively (as shown in Table 1). Mice are placed individually in a cylindrical glass cylinder 30 cm high and 20 cm in diameter, with a water depth of 15 cm so that the animals cannot escape from the glass cylinder, their feet and tails do not touch the bottom of the cylinder, and the water temperature is 23°C to 25°C. A 6-minute video is taken of the mice after they enter the water, and since most animals are very active in the first 2 minutes, the immobility time of the following 4 minutes is calculated (criterion for determining immobility: the mouse stops struggling in the water; immobility is a balanced or floating state with small limb movements).

[0690] 4) Test results The antidepressant effect of the compound will be evaluated by its ability to reduce the immobility time of animals in forced swimming experiments compared to a blank group.

[0691] Inhibition rate 1h (%) = [Idle time] (空白、1h) -Immobile time (投与、1h) ] / Immobile time (空白、1h) ×100% Inhibition rate 24h (%) = [Idle time] (空白、24h) -Immobile time (投与、24h) ] / Immobile time (空白、24h) ×100%

[0692] [Table 2] TIFF0007888184000228.tif196166

[0693] Ketamine has poor oral absorption and low oral therapeutic efficacy, and when used clinically as an anesthetic, it is administered by injection. However, currently, when used clinically for rapid antidepressant treatment, intranasal administration is employed, which makes clinical use inconvenient.

[0694] As can be seen from Table 2, oral administration of the conventional antidepressant fluoxetine did not show an antidepressant effect at 1 hour and 24 hours in the forced swimming experiment. This indicates that fluoxetine does not possess the rapid onset characteristics of an antidepressant, which is consistent with clinical results. When the compound of the present invention is orally administered to mice, the immobility time during forced swimming in mice can be significantly reduced at both 1 hour and 24 hours, and it exhibits a rapid and long-lasting potent antidepressant effect.

[0695] The compounds of the present invention exhibit significantly improved antidepressant activity compared to the positive control drugs S-ketamine and (2R,6R)-HNK, as well as each comparative compound, and have clear advantages.

[0696] The compounds of the present invention are orally effective and can be formulated into oral dosage forms in the future, which offers another significant advantage over ketamine.

[0697] Test Example 2. Study on the distribution of the compound of the present invention in rat brain tissue. Healthy male SD rats were randomly divided into groups of three, and the test compound was administered intragastricly. The specific arrangements are shown in Table 3 below.

[0698] [Table 3]

[0699] Each test compound is dissolved in physiological saline to prepare a solution of a certain concentration, which is then administered.

[0700] For 12-14 hours the day before administration, fast and provide water, then feed 4 hours after administration. Brain tissue was collected from animals after hemorrhage, washed, and homogenized with 50% ice-cold methanol in a ratio of 1:4 (m / v). Collection points were 5 minutes, 10 minutes, 30 minutes, and 2 hours after administration of the test substance. 30.0 μL of tissue sample (removed from a -80°C refrigerator, allowed to thaw naturally at room temperature, and vortexed for 30 seconds) was placed in a 1.5 mL centrifuge tube, 300.0 μL of internal standard solution (30 ng / mL buspiroflavone acetonitrile solution) was added, and after vortexing for 60 seconds, the tube was centrifuged for 3 minutes (centrifugal force 12000 rpm). 75 μL of the supernatant was taken and transferred to a 96-well injection plate filled with an equal volume of water. After shaking and mixing, the sample was injected for LC-MS / MS analysis, with an injection volume of 10 μL.

[0701] [Table 4]

[0702] For the treatment of depression, a central nervous system disorder, the drug needs to be distributed to the CNS system, such as brain tissue, and the amount of drug that enters the brain tissue directly affects its therapeutic effect. As can be seen from Table 4, the maximum drug concentration (Cmax) of the compound of the present invention in the brain is more than three times higher than the maximum drug concentration of 2R,6R-HNK, and the brain drug exposure (AUC) is also high. 0-t ) is more than twice as much.

[0703] At the same time, while the brain drug exposure of the compound of the present invention is high, its plasma drug exposure is low compared to 2R,6R-HNK; that is, the brain / plasma ratio of the compound of the present invention is significantly increased compared to 2R,6R-HNK. However, this significant increase in the brain / plasma ratio also indicates a reduced risk of peripheral side effects and improved safety.

[0704] Test Example 3. In vivo pharmacokinetic experiment of the compound of the present invention in beagle dogs. Healthy male beagle dogs will be randomly divided into groups of three, and the test compound will be administered either intragastricly or intravenously. Specific arrangements are shown in Table 5.

[0705] [Table 5]

[0706] Each test compound is dissolved in physiological saline to prepare a solution of a certain concentration, which is then administered.

[0707] For 12-14 hours the day before administration, the subjects should be fasted and given water, and then fed 4 hours after administration. Fasting is not required for intravenous experiments. For each animal, 0.6 mL of blood was collected from the jugular vein and treated with EDTAK2 anticoagulation. Collection times were as follows: PO group: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours after administration of the test substance; IV group: 2 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours after administration of the test substance. After blood sample collection, the samples were placed on ice and the plasma was centrifuged within 30 minutes (centrifugation conditions: 5000 rpm, 10 minutes, 4°C). The samples were stored at -80°C until analysis.

[0708] [Table 6]

[0709] As can be seen from the results of the pharmacokinetic experiments in dogs shown in Table 6, the compounds of the present invention are rapidly absorbed orally, have good exposure levels and bioavailability, and exhibit good metabolic properties.

[0710] Test Example 4. Evaluation of the Solid State Chemical Stability of the Compound of the Present Invention Chemical stability, along with in vivo and in vitro activity and metabolic properties, is a key factor in determining the success of drug candidate development (Di L, Kerns EH. Stability challenges in drug discovery. Chem). Biodivers. 2009, Nov;6(11):1875-1886.). The stability of chemical drugs is fundamental to quality control and is closely related to the safety and therapeutic efficacy of drugs. Compounds with stable chemical properties not only ensure patient administration safety and provide superior therapeutic effects, but also simplify subsequent formulation development and storage conditions, extend the effective life of the drug after launch, and facilitate daily administration to patients. Therefore, improving and enhancing the stability of candidate compounds is of particular importance. Due to the importance of chemical stability in drug research and development, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) specially develops corresponding technical guidelines to standardize corresponding research.

[0711] Each sample was sealed in a low-density polyethylene bag as inner packaging and an aluminum foil bag as outer packaging for storage. After being stored for a certain period under different temperature / humidity conditions (40°C, 75% relative humidity; 25°C, 60% relative humidity), analysis was performed by liquid chromatography. The solid chemical stability of the compound of the present invention was compared with that of a comparative compound, and the superior solid chemical stability of the compound of the present invention was observed.

[0712] The conditions for high-performance liquid chromatography are as follows: Method 1: Preparation of the test solution: Take an appropriate amount of sample, dissolve it in a diluent (0.03 mol / L phosphate buffer - acetonitrile (80:20)), and dilute it to a 1 mg / mL solution.

[0713] Chromatography conditions: According to high-performance liquid chromatography (Chinese Pharmacopoeia 2020 version, Part 4, General Chapter 0512), octadecyl-bonded silica gel (Agilent) An Eclipse Plus C18 (4.6 mm × 250 mm, 5.0 μm, P / N 959990-902 or equivalent chromatography column) is used as the packing material, 0.03 mol / L phosphate buffer (4.08 g of potassium dihydrogen phosphate dissolved in 1000 ml of water and shaken uniformly) is mobile phase A, acetonitrile is mobile phase B, the flow rate is 1 ml / min, the column temperature is 30°C, the detection wavelength is 220 nm, the injection volume is 10 ul, the sample tray temperature is controlled to 8°C, and the process is run for 65 minutes. Gradient elution is performed according to the following table.

[0714] [Table 7]

[0715] Method 2: Preparation of the test solution: Take an appropriate amount of the product, dissolve it in the diluent (0.1% phosphate-acetonitrile (80:20)), and dilute it to a 1 mg / mL solution.

[0716] Chromatography conditions: According to high-performance liquid chromatography (Chinese Pharmacopoeia 2020 version, Part 4, General Chapter 0512), octadecyl-bonded silica gel (Agilent) An Eclipse Plus C18 (4.6 mm × 250 mm, 5.0 μm, P / N 959990-902 or equivalent chromatography column) is used as the packing material, 0.1% phosphate buffer (take 1 ml of phosphoric acid, add 1000 ml of water and shake uniformly) is mobile phase A, acetonitrile is mobile phase B, the flow rate is 1 ml / min, the column temperature is 30°C, the detection wavelength is 220 nm, the injection volume is 10 ul, and the run is 48 minutes. Gradient elution is performed according to the following table.

[0717] [Table 8]

[0718] [Table 9] TIFF0007888184000236.tif247166TIFF0007888184000237.tif250166TIFF00078881840 00238.tif227166TIFF0007888184000239.tif248166TIFF0007888184000240.tif191167

[0719] As can be seen from Table 7, the solid-state chemical stability of the compound of the present invention (in which a methyl group is added to the α-position of the carbonyl group) is significantly improved compared to each comparative compound (where only a hydroxyl group is located at the α-position of the carbonyl group), which clearly has advantages and indicates superior development and drug discovery potential.

[0720] All documents referenced in this invention are cited as references in this application, as if each document were cited individually. Furthermore, after reading the above teachings of this invention, persons skilled in the art can make various changes or modifications to the invention, and these equivalent forms are also included within the scope defined by the claims appended to this application.

Claims

1. A compound represented by formula (I), or its tautomers, enantiomers, diastereomers, racemates or mixtures thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Here, R １ C １ -C ６ It is an alkyl group, R ２ 、 R ３ 、 R ４ are each independently selected from the group consisting of hydrogen, C １ -C ６ -alkyl group, deuterated C １ -C ６ -alkyl group, -(C=O)-C １ -C ６ -alkyl group, R ５ , R ６ , R ７ , R ８ , R ９ These are, independently, hydrogen and C １ -C ６ Alkyl alkyl groups, halogenated C １ -C ６ Alkyl alkyl group, C １ -C ６ Alkoxy group, halogenated C １ -C ６ Selected from the group consisting of alkoxy groups, halogens, nitro groups, and cyano groups, and also R ５ , R ６ , R ７ , R ８ , R ９ At least two of them are hydrogen, A compound represented by formula (I), or a tautomer, enantiomer, diastereomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the stereochemistry of the α- or β- carbon atom is independently selected from the group consisting of R and S.

2. The aforementioned compound is a compound represented by formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), or (I-G), 【Chemistry 2】 In equations (I-A) and (I-B), R １ , R ５ , R ６ , R ７ , R ８ , R ９ This is as defined in claim 1, 【Transformation 3】 In equations (I-C) and (I-D), R １ , R ５ , R ６ , R ７ , R ８ , R ９ R is as defined in claim 1, ３ , R ４ These are, independently, hydrogen and C １ -C ６ Alkyl or deuterated C １ -C ６ It is an alkyl group and R ３ , R ４ At the same time, it is not hydrogen, 【Chemistry 4】 In equations (I-E) and (I-F), R １ , R ５ , R ６ , R ７ , R ８ , R ９ R is as defined in claim 1, ３ is -(C=O)-C １ -C ６ It is an alkyl group, 【Transformation 5】 In equation (I-G), R １ , R ５ , R ６ , R ７ , R ８ , R ９ R is as defined in claim 1, ２ C １ -C ６ Alkyl alkyl groups, deuterated C １ -C ６ Alkyl alkyl group, -(C=O)-C １ -C ６ Selected from the group consisting of alkyl groups, R ３ is hydrogen, C １ -C ６ Alkyl alkyl groups, deuterated C １ -C ６ Characterized by being selected from the group consisting of alkyl groups. The compound described in claim 1, or its tautomer, enantiomer, diastereomer, racemic mixture or mixture thereof, or a pharmaceutically acceptable salt thereof.

3. R １ It is characterized by being a methyl group. The compound described in claim 1, or its tautomer, enantiomer, diastereomer, racemic mixture or mixture thereof, or a pharmaceutically acceptable salt thereof.

4. R ２ , R ３ , R ４ Each of these is independently characterized by being hydrogen, a methyl group, a deuterated methyl group, an ethyl group, an isopropyl group, an acetyl group, or a propionyl group. The compound described in claim 1, or its tautomer, enantiomer, diastereomer, racemic mixture or mixture thereof, or a pharmaceutically acceptable salt thereof.

5. R ２ is hydrogen, and R ３ It is hydrogen, R ４ This is characterized by being a methyl group, a deuterated methyl group, an ethyl group, an isopropyl group, an acetyl group, or a propionyl group. The compound described in claim 1, or its tautomer, enantiomer, diastereomer, racemic mixture or mixture thereof, or a pharmaceutically acceptable salt thereof.

6. Characterized by being selected from the following group The compound described in claim 1, or its tautomer, enantiomer, diastereomer, racemic mixture or mixture thereof, or a pharmaceutically acceptable salt thereof. 【Transformation 6】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

7. A pharmaceutical composition, The aforementioned pharmaceutical composition, 1) One or more safe effective amounts of the compound described in claim 1, or its tautomers, enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts thereof, and 2) The pharmaceutical composition, characterized by comprising a pharmaceutically acceptable carrier or excipient.

8. A method for preparing the compound described in claim 1, or its tautomer, enantiomer, diastereomer, racemate or mixture thereof, or a pharmaceutically acceptable salt thereof, (1) The above method includes the following steps: 【Transformation 7】 Here, R １ 、 R ５ 、 R ６ 、 R ７ 、 R ８ 、 R ９ are as defined in claim 1, a. Compound I-1 is reacted with a deuterating agent or alkylating agent in an aprotic solvent to form compound I-2. b. Compound I-2 is reacted with trimethylchlorosilane in an aprotic solvent to form compound I-3. c. In an aprotic solvent, compound I-3 and an oxidizing agent are oxidized to form compound I-4. d. In an aprotic solvent, remove the trimethylsilyl protecting group from compound I-4 to form compound I-5. e. In a polar aprotic solvent, remove the t-butoxycarbonyl protecting group from compound I-5 to form compound I-A. or (2) The method includes steps a to h, 【Transformation 8】 Here, R １ , R ５ , R ６ , R ７ , R ８ , R ９ This is as defined in claim 1, a. In a polar aprotic solvent, the t-butoxycarbonyl protecting group is removed from compound I-2 to form compound II-1. b. Compound II-1 is reacted with p-methoxybenzyl chloride in an aprotic solvent to form compound II-2. c. Compound II-2 is reacted with trifluoroacetic anhydride in an aprotic solvent to form compound II-3. d. Compound II-3 is reacted with trimethylchlorosilane in an aprotic solvent to form compound II-4. e. In an aprotic solvent, compound II-4 and an oxidizing agent are oxidized to form compound II-5. f. In an aprotic solvent, remove the trimethylsilyl protecting group from compound II-5 to form compound II-6. g. In a protic solvent, remove the trifluoroacetyl group from compound II-6 to form compound II-7. h. Under acidic conditions, the p-methoxybenzyl group is removed from compound II-7 to form compound I-B. or (3) The method includes steps a to d, 【Chemistry 9】 Here, R １ R ５ R ６ R ７ R ８ R ９ is as defined in claim 1, and R[[ID=[13]] ３ is a C １ -C ６ alkyl group or a deuterated C １ -C ６ alkyl group, and R １０ is a C １ -C ６ alkyl group, a halogenated C １ -C ６ alkyl group, a C １ -C ６ alkoxy group, or a benzyloxy group. a. Compound III-1 is reacted with trimethylchlorosilane in an aprotic solvent to form compound III-2. b. In an aprotic solvent, compound III-2 and an oxidizing agent are oxidized to form compound III-3. c. In an aprotic solvent, remove the trimethylsilyl protecting group from compound III-3 to form compound III-4. d. In a protic or aprotic solvent, compounds III-4 to R １０ The carbonyl protecting group is removed to form compound I-D. or (4) The method includes step a, 【Chemistry 10】 Here, R １ , R ５ , R ６ , R ７ , R ８ , R ９ R is as defined in claim 1, ３ , R ４ These are, independently, hydrogen and C １ -C ６ Alkyl alkyl groups, deuterated C １ -C ６ It is an alkyl group and R ３ , R ４ At the same time, it is not hydrogen, a. In a protic or aprotic solvent, compound I-A or I-B is reacted with the corresponding aldehyde or ketone to form the corresponding compound I-C or I-D. or (5) the method comprising step a, 【Chemistry 11】 Here, R １ , R ５ , R ６ , R ７ , R ８ , R ９ R is as defined in claim 1, ３ is -(C=O)-C １ -C ６ It is an alkyl group, a. In an aprotic solvent, compound I-A or I-B is reacted with the corresponding acyl chloride or acid anhydride to form the corresponding compound I-E or I-F. or (6) The method comprising steps a to b, 【Chemistry 12】 Here, R １ , R ５ , R ６ , R ７ , R ８ , R ９ R is as defined in claim 1, ２ C １ -C ６ Alkyl alkyl groups, deuterated C １ -C ６ Alkyl alkyl group, -(C=O)-C １ -C ６ It is an alkyl group, R ３ is hydrogen, C １ -C ６ Alkyl alkyl groups, deuterated C １ -C ６ It is an alkyl group, a. In an aprotic solvent, compound VI-1 is reacted with the corresponding alkylating reagent, deuterated alkylating reagent, acyl chloride, or acid anhydride to form the corresponding compound VI-2. b. A method for preparing the compound according to claim 1, or a tautomer, enantiomer, diastereomer, racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized by removing the t-butoxycarbonyl protecting group from compound VI-2 in a polar aprotic solvent to form compound I-G.

9. The use of the compound described in claim 1, or its tautomer, enantiomer, diastereomer, racemate or mixture thereof, or a pharmaceutically acceptable salt thereof, The use is characterized by being used in the preparation of drugs for treating diseases related to the nervous system.

10. The aforementioned neurological disorders are characterized by being selected from the group consisting of depression, post-traumatic stress disorder, obsessive-compulsive disorder, anxiety, and pain. The use described in claim 9.

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