Novel benzamide derivative, preparation method thereof and application of novel benzamide derivative as medicine

Abstract

The invention relates to an effective amount of novel benzamide derivative as shown in a general formula (I), a preparation method thereof and application of a pharmaceutical composition containing the derivative as a medicine, compared with the prior art, the compound has better metabolic stability, can be orally taken and has a wider application prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a preparation method and application of a novel class of benzamide derivatives, belonging to the field of medicinal chemistry. The compound structure of the present invention is unique and novel in this field. Background Art

[0002] The prevalence of obesity continues to rise worldwide. The rapid development of modernization and urbanization and the accelerated growth of social economy are conducive to improving the living standards. However, in the past two decades, in most parts of the world, due to lifestyle factors such as high stress, sedentary behavior, and unhealthy eating habits, obesity has become a global epidemic, affecting almost every organ system and threatening people's lives. Currently, obesity is already one of the most common non-communicable diseases and has become a serious global public health problem. The main cause of obesity is the long-term imbalance between calorie intake and consumption. Subcutaneous fat is the main storage depot for storing energy. However, when energy intake is excessive and the storage capacity of subcutaneous fat is exhausted, fat accumulates around abdominal visceral organs such as the liver, forming non-alcoholic fatty liver disease (NAFLD), causing atherosclerotic cardiovascular disease (ASCVD) in the vascular system or leading to insulin resistance in muscles.

[0003] Given these complex connections in the pathogenesis of obesity, current treatment options for managing and treating obesity and type 2 diabetes have some similarities, including lifestyle interventions, drug therapies, various newly developed medical devices, and bariatric surgery. However, lifestyle and surgical interventions still have certain limitations. Therefore, drug control is a relatively less risky option, and anti-obesity drugs have an anti-diabetic effect to a certain extent. Currently, the most popular direction in weight loss drug research is peptide drugs. For example, glucagon-like peptide 1 (GLP-1) is a hot topic in the weight loss research of major pharmaceutical companies. Although existing GLP-1-related weight loss drugs have excellent efficacy, they also cause a large amount of muscle loss during weight loss, resulting in weight rebound and muscle loss-related side effects. Therefore, in recent years, the healthy weight loss concept of reducing fat and increasing muscle has become a craze in the development of weight loss drugs.

[0004] Sarcopenia refers to age-related progressive reduction of total muscle mass and / or decline in muscle strength or deterioration of muscle physiological function. Research shows that the prevalence of sarcopenia is 20% in the elderly aged ≥65 years, and reaches 50% - 60% in those aged ≥80 years. The prevalence of sarcopenia increases with age, and men have a relatively higher risk of the disease than women. The incidence of sarcopenia is very high in the elderly and will be a major future health problem for the elderly. A large number of studies have shown that fractures in the elderly population are closely associated with reduced muscle mass, decreased muscle strength, increased falls, and reduced bone mass. Sarcopenia increases the risk of falls and fractures, reduces the daily living ability of patients, and is associated with heart diseases, respiratory diseases, and cognitive impairment: it can lead to dysfunction of patients' motor functions, decreased quality of life, loss of the ability to live independently, or long-term need for care by others, and increased risk of death. Sarcopenia increases the risk of hospitalization, raises the nursing costs during hospitalization, and increases the hospitalization expenses. However, there is currently no specific drug for sarcopenia, and there is a huge unmet clinical need, urgently requiring the development of safe and effective new drugs.

[0005] Vestibular dysfunction diseases are one of the three major intractable outpatient diseases with extremely high clinical incidence. Research shows that among people over 65 years old, up to 30% of the elderly have a history of dizziness, and even up to 85% of those over 80 years old have vestibular dysfunction. Currently, it mainly improves the autonomic nerve function of patients, eliminates endolymphatic hydrops, and then improves the microcirculation of the inner ear. Although many studies have been conducted on vestibular dysfunction diseases, there is no specific drug to cure the disease. Research shows that activating GPR133 can relieve vestibular dysfunction-related diseases.

[0006] Androgens (such as 5α-DHT) are hormones that control the development of male sexual characteristics and are crucial for bone and muscle function as well as the development of secondary sexual characteristics in adolescent males. As a driving factor for bone and muscle formation, 5α-DHT increases bone mineral density, promotes skeletal muscle growth, and increases muscle strength. A recent study on androgen membrane receptors was published in the journal Cell, which identified the 5α-DHT membrane receptor GPR133 / ADGRD1 and elucidated its regulatory role and molecular mechanism in skeletal muscle (Cell, 2025, https: / / doi.org / 10.1016 / j.cell.2025.01.006). This study identified a novel GPR133 agonist, AP503, which increases muscle strength by activating GPR133 without triggering specific negative effects observed when using androgens. For example, increased and prolonged exposure to androgens promotes the development of prostate cancer, and this side effect has not been observed in the AP503 treatment group. This opens up new possibilities for designing safer androgen replacement drugs in the future.

[0007] Although the GPR133 agonist AP503 has shown great potential in increasing muscle strength, alleviating vestibular dysfunction, and avoiding androgen side effects, this compound is limited to injection administration ([ https: / / doi.org / 10.1016 / https: / / doi.org / 10.1016 / j.cell.2025.01.006 ; CN118146176A), thus reducing patient compliance. The inventors conducted a systematic study on AP503 and found that the compound had poor hepatic microsomal stability, with only 8% remaining after 15 minutes of incubation in mouse liver microsomes. Therefore, it is of great significance to conduct a systematic structural optimization of AP503 to improve its metabolic stability. Through extensive research, the inventors screened out a series of novel GPR133 agonists with both high activity and metabolic stability. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide, for the first time, a preparation method of a metabolically stable novel benzamide derivative, which provides the possibility for the treatment and prevention of related diseases such as muscle atrophy, myasthenia, sarcopenia, erectile dysfunction, vestibular dysfunction, muscle gain and fat loss, obesity, non-alcoholic fatty liver, etc.

[0009] The novel benzamide derivative described in the present invention is a compound containing an effective amount of the compound represented by the general formula (I):

[0010]

[0011] Wherein, R1 and R2 are each independently selected from alkyl, trifluoromethyl, or R1 and R2 are connected to form a C4-C6 ring;

[0012] R3 is optionally selected from alkyl, cycloalkyl, acetyl, benzyl, benzoyl;

[0013] R4 and R5 are each independently selected from hydrogen, alkyl;

[0014] R6, R7, R8, R9, R 10 are each independently selected from hydrogen, alkyl, trifluoromethyl, alkoxy, halogen.

[0015] Preferably, the compound having the general formula (I) defined in the present invention:

[0016] Wherein, R1 and R2 are each independently selected from C1-C3 alkyl, trifluoromethyl, or R1 and R2 are connected to form a C4-C6 ring;

[0017] R3 is optionally selected from C1-C6 alkyl, C3-C6 cycloalkyl, acetyl, benzyl, benzoyl;

[0018] R4 and R5 are each independently selected from hydrogen, C1-C3 alkyl;

[0019] R6, R7, R8, R9, R 10Each independently selected from hydrogen, C1-C6 alkyl, trifluoromethyl, alkoxy, halogen.

[0020] More preferred compounds of the present invention include, but are not limited to:

[0021] 3-(2-(2,4-Dimethylphenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide (1);

[0022] 2-(2,4-Dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(pyrrolidin-1-carbonyl)phenyl)acetamide (2);

[0023] 2-(2,4-Dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(piperidin-1-carbonyl)phenyl)acetamide (3);

[0024] 2-(2,4-Dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(morpholine-4-carbonyl)phenyl)acetamide (4);

[0025] 3-(2-(2-Chlorophenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide (5);

[0026] 3-(2-(4-Chlorophenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide (6);

[0027] 3-(2-(4-(tert-Butyl)phenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide (7);

[0028] 4-(4-Ethylpiperazin-1-yl)-N,N-dimethyl-3-(2-(4-(trifluoromethyl)phenoxy)acetamido)benzamide (8);

[0029] 4-(4-Ethylpiperazin-1-yl)-N,N-dimethyl-3-(2-phenoxypropylamino)benzamide (9);

[0030] 4-(4-Acetylpiperazin-1-yl)-3-(2-(4-fluorophenoxy)acetamido)-N,N-dimethylbenzamide (10);

[0031] 4-(4-Acetylpiperazin-1-yl)-3-(2-(2,4-dichlorophenoxy)acetamido)-N,N-dimethylbenzamide (11);

[0032] 4-(4-Acetylpiperazin-1-yl)-3-(2-(4-(tert-butyl)phenoxy)acetamido)-N,N-dimethylbenzamide (12);

[0033] 4-(4-Benzoylpiperazin-1-yl)-3-(2-(3,5-dimethylphenoxy)acetamido)-N,N-dimethylaniline (13);

[0034] 3-(2-(3,5-Dimethylphenoxy)-2-methylacrylamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide (14);

[0035] 4-(4-Benzylpiperazin-1-yl)-3-(2-(3,5-dimethylphenoxy)acetamido)-N,N-dimethylbenzamide (15);

[0036] 4-(4-Cyclopropylpiperazin-1-yl)-3-(2-(3,5-dimethylphenoxy)acetamido)-N,N-dimethylbenzamide (16).

[0037] Another aspect of the present invention relates to a pharmaceutical composition, which contains an effective dose of the said compound and a suitable carrier, diluent or excipient.

[0038] The present invention also relates to the use of the said compound as a GPR133 / ADGRD1 agonist.

[0039] The present invention also relates to the use of the said compound or its pharmaceutical composition in the preparation of a medicament for preventing and / or treating at least one of the related diseases such as muscle atrophy, myasthenia, sarcopenia, erectile dysfunction, vestibular dysfunction, muscle gain and fat loss, obesity, non-alcoholic fatty liver disease, etc.

[0040] Detailed description of the invention

[0041] Unless otherwise specified, the following terms used in the specification and claims have the following meanings.

[0042] Any general formula or structure shown herein, including the compounds of general formula (I), is also intended to represent the unlabeled form and the isotope-labeled form of the said compound. Examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine. In the compounds of the present invention, any atom not specifically indicated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically marked with "H" or "hydrogen", it should be understood that the position is hydrogen with its isotopic composition. Therefore, any atom specifically marked with deuterium (D) in the compounds of the present invention is intended to represent deuterium.

[0043] "Pharmaceutical composition" refers to a mixture containing one or more compounds of the present invention and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the absorption of the active ingredient by the organism and to facilitate the exertion of biological activity in the organism. Detailed implementation mode

[0044] The present invention will be further described below in conjunction with embodiments. It should be noted that the following embodiments are only for illustration and not for limiting the present invention. All changes made by those skilled in the art according to the teachings of the present invention should be within the protection scope of the claims of this application.

[0045] Synthesis and preparation of the compounds of the present invention:

[0046] General synthetic route:

[0047]

[0048] Reagents and conditions: (a) K2CO3, DMF, 120 °C, 6 h; (b) H2, 5% Pd-C, dichloromethane, 8 h; (c) K2CO3, ethyl chloroacetate, acetonitrile, reflux, 6 h; then LiOH·H2O, THF / MeOH / H2O, room temperature, 4 h; (d) HATU, DIPEA, dichloromethane, room temperature, 10 h; (e) LiOH·H2O, THF / MeOH / H2O, room temperature, 4 h; then starting amine, HATU, DIPEA, dichloromethane, room temperature, 10 h.

[0049] Example 1

[0050] 3-(2-(2,4-Dimethylphenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide (1)

[0051]

[0052] Dissolve starting material A (1.0 equiv.) in 30 mL of DMF, add ethyl piperazine (2.0 equiv.), react at 120 °C for 6 h, monitor the reaction by TLC, after the reaction is completed, add water and ethyl acetate for extraction, and purify by silica gel (200 - 300 mesh) column chromatography to obtain compound B. Take a 25 mL round-bottom flask, add compound B (1.0 equiv.), dissolve it in 15 mL of dichloromethane, add 5% Pd-C, and react at room temperature under the pressure of a hydrogen balloon for 8 h. After the reaction is completed, filter, and rotary evaporate the filtrate to obtain the crude compound C.

[0053] 2,4-Dimethylphenol (1 equiv.), ethyl chloroacetate (1.5 equiv.), and potassium carbonate (2 equiv.) were dissolved in 20 mL of acetonitrile and refluxed for 6 h. The reaction mixture was filtered by suction, and the filtrate was concentrated by rotary evaporation and purified by column chromatography. The product was dissolved in a mixed solvent of THF:MeOH:H2O = 3:3:1, and lithium hydroxide monohydrate (2.5 equiv.) was added dropwise with stirring at room temperature. After the reaction was completed as monitored by TLC, the pH was adjusted to acidic (about 3) with 1 M HCl, and the mixture was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain compound D.

[0054] Compound C (1.0 equiv.) and compound D (1.0 equiv.) were dissolved in 20 mL of dichloromethane, and N,N-diisopropylethylamine (DIPEA, 1.1 equiv.) was added and stirred for 5 min. Then N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 1.1 equiv.) was added and the mixture was stirred for 10 h. After completion, the mixture was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by column chromatography to obtain compound E. Compound E (1.0 equiv.) was dissolved in a mixed solvent of THF:MeOH:H2O = 3:3:1, and lithium hydroxide monohydrate (2.5 equiv.) was added dropwise with stirring at room temperature. After the reaction was completed as monitored by TLC, the pH was adjusted to acidic (about 3) with 1 M HCl, and the mixture was extracted three times with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in 20 mL of dichloromethane, and dimethylamine hydrochloride (1.5 equiv.), base DIPEA (5.0 equiv.), and condensing agent HATU (1.2 equiv.) were added in sequence. The mixture was stirred at room temperature for 10 h. After the reaction was completed as determined by TLC, the mixture was extracted three times with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to obtain compound 1. Yield: 25%. 11H NMR (600 MHz, CDCl3) δ: 9.21 (brs, 1H), 9.04 (d, J = 1.9 Hz, 1H), 7.82 (dd, J = 8.3, 2.0 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 4.67 (s, 2H), 2.96 (s, 3H), 2.91 (s, 3H), 2.88 - 2.84 (m, 4H), 2.51 (q, J = 7.3 Hz, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 2.25 - 2.22 (m, 4H), 1.12 (t, J = 7.3 Hz, 3H).

[0055] 2-(2,4-Dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(pyrrolidine-1-carbonyl)phenyl)acetamide (2)

[0056]

[0057] The synthesis method is the same as that of compound 1. Yield: 38%. 1 1H NMR (600 MHz, CDCl3) δ: 9.21 (brs, 1H), 9.06 (d, J = 1.9 Hz, 1H), 7.82 (dd, J = 8.3, 2.0 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.03 (s, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 4.68 (s, 2H), 3.49 - 3.45 (m, 4H), 2.90 - 2.86 (m, 4H), 2.51 (q, J = 7.3 Hz, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 2.24 - 2.21 (m, 4H), 1.96 - 1.92 (m, 4H), 1.12 (t, J = 7.3 Hz, 3H).

[0058] 2-(2,4-Dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(piperidine-1-carbonyl)phenyl)acetamide (3)

[0059]

[0060] The synthesis method is the same as that of compound 1. Yield: 32%. 11H NMR (600 MHz, CDCl3) δ: 9.21 (brs, 1H), 9.06 (d, J = 1.9 Hz, 1H), 7.82 (dd, J = 8.3, 2.0 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.03 (s, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 4.67 (s, 2H), 3.85 - 3.82 (m, 4H), 2.90 - 2.85 (m, 4H), 2.51 (q, J = 7.3 Hz, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 2.25 - 2.22 (m, 4H), 1.75 - 1.72 (m, 4H), 1.58 - 1.54 (m, 2H), 1.12 (t, J = 7.3 Hz, 3H).

[0061] 2-(2,4-Dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(morpholine-4-carbonyl)phenyl)acetamide (4)

[0062]

[0063] The synthesis method is the same as that of compound 1. Yield: 43%. 1 1H NMR (600 MHz, CDCl3) δ: 9.20 (brs, 1H), 9.06 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.3, 2.1 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.03 (s, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 4.67 (s, 2H), 3.58 - 3.53 (m, 4H), 3.49 - 3.45 (m, 4H), 2.90 - 2.85 (m, 4H), 2.51 (q, J = 7.3 Hz, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 2.26 - 2.22 (m, 4H), 1.12 (t, J = 7.3 Hz, 3H).

[0064] 3-(2-(2-Chlorophenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide (5)

[0065]

[0066] The synthesis method is the same as that of compound 1. Yield: 35%. 11H NMR (600 MHz, CDCl3) δ: 9.35 (s, 1H), 9.02 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.3, 2.0 Hz, 1H), 7.44 (dd, J = 7.9, 1 - 6 Hz, 1H), 7.28 (dd, J = 7.9, 1.3 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.05 (td, J = 7.7, 1.3 Hz, 1H), 6.98 (dd, J = 8.3, 1.2 Hz, 1H), 4.74 (s, 2H), 2.96 (s, 3H), 2.91 (s, 3H), 2.88 - 2.84 (m, 4H), 2.59 - 2.55 (m, 4H), 2.51 (q, J = 7.1 Hz, 2H), 1.12 (t, J = 7.1 Hz, 3H).

[0067] 3-(2-(4-Chlorophenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide (6)

[0068] The synthesis method is the same as that of compound 1. Yield: 35%. 1 1H NMR (600 MHz, CDCl3) δ: 9.42 (s, 1H), 9.06 (d, J = 1.8 Hz, 1H), 7.83 - 7.81 (m, 1H), 7.33 - 7.30 (m, 2H), 7.22 (dd, J = 8.2, 3.6 Hz, 1H), 6.99 - 6.95 (m, 2H), 4.64 (s, 2H), 2.97 (s, 3H), 2.92 (s, 3H), 2.90 - 2.86 (m, 4H), 2.59 - 2.55 (m, 4H), 2.51 (q, J = 7.1 Hz, 2H), 1.11 (t, J = 7.1 Hz, 3H).

[0069] 3-(2-(4-(tert-Butyl)phenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide (7)

[0070]

[0071] The synthesis method is the same as that of compound 1. Yield: 31%. 11H NMR (600 MHz, DMSO-d6) δ: 9.35 (s, 1H), 8.86 (s, 1H), 7.73 (dd, J = 8.3, 1.8 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 8.7 Hz, 2H), 4.64 (s, 2H), 2.99 (s, 3H), 2.93 (s, 3H), 2.85 - 2.82 (m, 4H), 2.45 - 2.42 (m, 4H), 2.37 (q, J = 7.1 Hz, 2H), 1.26 (s, 9H), 1.01 (t, J = 7.1 Hz, 3H).

[0072] 4-(4-Ethylpiperazin-1-yl)-N,N-dimethyl-3-(2-(4-(trifluoromethyl)phenoxy)acetamido)benzamide (8)

[0073]

[0074] The synthesis method is the same as that of compound 1. Yield: 26%. 1 1H NMR (600 MHz, DMSO-d6) δ: 9.33 (s, 1H), 8.78 (s, 1H), 7.75 (d, J = 9.0 Hz, 2H), 7.73 - 7.72 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 4.88 (s, 2H), 2.98 (s, 3H), 2.92 (s, 3H), 2.86 - 2.82 (m, 4H), 2.46 - 2.42 (m, 4H), 2.37 (q, J = 7.1 Hz, 2H), 1.01 (t, J = 7.1 Hz, 3H).

[0075] 4-(4-Ethylpiperazin-1-yl)-N,N-dimethyl-3-(2-phenoxypropylamino)benzamide (9)

[0076]

[0077] The synthesis method is the same as that of compound 1. Yield: 35%. 11H NMR (600 MHz, CDCl3) δ: 9.33 (s, 1H), 9.06 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 8.3, 1.8 Hz, 1H), 7.32 (t, J = 8.0 Hz, 2H), 7.17 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 7.01 (d, J = 8.1 Hz, 2H), 4.81 (q, J = 6.8 Hz, 1H), 2.96 (s, 3H), 2.91 (s, 3H), 2.85 - 2.82 (m, 4H), 2.47 - 2.42 (m, 4H), 2.37 (q, J = 7.1 Hz, 2H), 1.68 (d, J = 6.8 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H).

[0078] 4-(4-Acetylpiperazin-1-yl)-3-(2-(4-fluorophenoxy)acetamido)-N,N-dimethylbenzamide (10)

[0079]

[0080] The synthesis method is the same as that of compound 1. Yield: 29%. 1 1H NMR (600 MHz, CDCl3) δ: 9.42 (s, 1H), 9.04 (d, J = 1.7 Hz, 1H), 7.85 (dd, J = 8.3, 1.6 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.05 (t, J = 8.5 Hz, 2H), 6.94 - 6.91 (m, 2H), 4.64 (s, 2H), 3.69 - 3.62 (m, 2H), 3.48 - 3.45 (m, 2H), 2.96 (s, 3H), 2.91 (s, 3H), 2.86 - 2.82 (m, 4H), 2.13 (s, 3H).

[0081] 4-(4-Acetylpiperazin-1-yl)-3-(2-(2,4-dichlorophenoxy)acetamido)-N,N-dimethylbenzamide (11)

[0082]

[0083] The synthesis method is the same as that of compound 1. Yield: 28%. 11H NMR (600 MHz, CDCl3) δ: 9.35 (s, 1H), 8.99 (d, J = 1.5 Hz, 1H), 7.85 (dd, J = 8.3, 1.7 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.70 (s, 2H), 3.69 - 3.65 (m, 2H), 3.48 - 3.45 (m, 2H), 2.96 (s, 3H), 2.91 (s, 3H), 2.88 - 2.84 (m, 4H), 2.12 (s, 3H).

[0084] 4-(4-Acetylpiperazin-1-yl)-3-(2-(4-(tert-butyl)phenoxy)acetamido)-N,N-dimethylbenzamide (12)

[0085]

[0086] The synthesis method is the same as that of compound 1. Yield: 37%. 1 1H NMR (600 MHz, CDCl3) δ: 9.46 (s, 1H), 9.07 (d, J = 1.9 Hz, 1H), 7.83 (dd, J = 8.3, 2.0 Hz, 1H), 7.37 - 7.35 (m, 2H), 7.15 (d, J = 8.3 Hz, 1H), 6.92 - 6.90 (m, 2H), 4.66 (s, 2H), 3.69 - 3.65 (m, 2H), 3.48 - 3.45 (m, 2H), 2.96 (s, 3H), 2.91 (s, 3H), 2.85 - 2.81 (m, 4H), 2.11 (s, 3H), 1.30 (s, 9H).

[0087] 4-(4-Benzoylpiperazin-1-yl)-3-(2-(3,5-dimethylphenoxy)acetamido)-N,N-dimethylaniline (13)

[0088]

[0089] The synthesis method is the same as that of compound 1. Yield: 44%. 11H NMR (600 MHz, DMSO-d6) δ: 9.35 (s, 1H), 8.78 (d, J = 1.8 Hz, 1H), 7.73 (dd, J = 8.3, 2.0 Hz, 1H), 7.49 - 7.45 (m, 3H), 7.41 - 7.38 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 6.69 (s, 2H), 6.65 (s, 1H), 4.73 (s, 2H), 3.66 - 3.62 (m, 2H), 3.28 - 3.24 (m, 2H), 2.98 (s, 3H), 2.92 (s, 3H), 2.87 - 2.82 (m, 4H), 2.23 (s, 6H).

[0090] 3-(2-(3,5-Dimethylphenoxy)-2-methylacrylamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide (14)

[0091]

[0092] The synthesis method is the same as that of compound 1. Yield: 40%. 1 1H NMR (600 MHz, CDCl3) δ: 9.56 (s, 1H), 9.08 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.3, 2.0 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H), 6.58 (s, 2H), 2.96 (s, 3H), 2.91 (s, 3H), 2.87 - 2.82 (m, 4H), 2.37 (q, J = 7.2 Hz, 2H), 2.28 (s, 6H), 2.25 - 2.20 (m, 4H), 1.62 (s, 6H), 1.04 (t, J = 7.2 Hz, 3H).

[0093] 4-(4-Benzylpiperazin-1-yl) 3-(2-(3,5-dimethylphenoxy)acetamido)-N,N-dimethylbenzamide (15)

[0094]

[0095] The synthesis method is the same as that of compound 1. Yield: 28%. 11H NMR (600 MHz, DMSO-d6) δ: 9.36 (s, 1H), 8.85 (d, J = 1.9 Hz, 1H), 7.72 (dd, J = 8.3, 2.0 Hz, 1H), 7.36 - 7.27 (m, 6H), 6.75 (s, 2H), 6.67 (s, 1H), 4.71 (s, 2H), 3.51 (s, 2H), 2.98 (s, 3H), 2.92 (s, 3H), 2.88 - 2.84 (m, 4H), 2.49 - 2.45 (m, 4H), 2.29 (s, 6H).

[0096] 4-(4-Cyclopropylpiperazin-1-yl)-3-(2-(3,5-dimethylphenoxy)acetamido)-N,N-dimethylbenzamide (16)

[0097]

[0098] The synthesis method is the same as that of compound 1. Yield: 36%. 1 1H NMR (600 MHz, DMSO-d6) δ: 9.37 (s, 1H), 8.86 (d, J = 1.9 Hz, 1H), 7.70 (dd, J = 8.3, 2.1 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.75 (s, 2H), 6.67 (s, 1H), 4.73 (s, 2H), 2.98 (s, 3H), 2.92 (s, 3H), 2.82 - 2.78 (m, 4H), 2.69 - 2.64 (m, 4H), 2.25 (s, 6H), 1.67 - 1.64 (m, 1H), 0.48 - 0.43 (m, 2H), 0.35 - 0.30 (m, 2H).

[0099] Example 2 Study on the in vitro activity and hepatic microsomal stability of the compound

[0100] Determination of GPR133 agonist activity: HEK293 cells overexpressing GPR133 / ADGRD1 and G protein were seeded into 96-well plates and cultured in a cell incubator at 37 °C and 5% CO2. The negative control was HEK293 cells expressing the empty vector pcDNA3.1. Cells in each well were incubated with different concentrations of the test compound. According to the operation manual of the cAMP-Glo TM kit provided by Promega, the fluorescence change of the cAMP signal downstream of GPR133 was detected in real time using a multifunctional microplate reader, and the experimental results were analyzed (Table 1). The results showed that the compounds of the present invention all had good GPR133 agonist activity, and the in vitro activities of some compounds (such as compounds 1, 9, 12) were comparable to that of the positive drug AP503.

[0101] In vitro liver microsome stability study: The test compound at a concentration of 1 μM was incubated with mouse liver microsomes (concentration 0.5 mg / mL) at a constant temperature of 37 °C for 5 min, and the metabolic reaction was initiated by adding reduced coenzyme (NADPH, 5 mM). The incubation system solution was PBS buffer (pH 7.4), and the content of DMSO was less than 1% of the total volume to ensure that it did not affect the activity of microsomal enzymes. An experimental group, a positive control group (testosterone), and a negative control group (without reduced coenzyme) were set up. Incubation samples were immediately taken out at 0 and 15 min after the start of the incubation system and added to 150 μL of ice-cold methanol containing an internal standard to terminate the reaction. After vortexing for 1 min and centrifuging at 10,000 rpm for 5 min, 100 μL of the supernatant was mixed with 300 μL of methanol-aqueous solution (1:1, v / v). After filtration through a filter membrane, 20 μL was taken for LC-MS / MS determination of the response peak areas of the test compound and the internal standard, and the percentage of the remaining original drug after 15 min of liver microsome incubation was calculated. The experimental results are shown in Table 1. The results showed that the previously reported optimal GPR133 agonist AP503 had poor metabolic stability, and only 8% of the original drug remained after 15 min of incubation in the mouse liver microsome stability study; while the liver microsome stability of the compound of the present invention was significantly improved, indicating that the compound of the present invention had better metabolic stability and broader application prospects.

[0102] Table 1: In vitro activity and liver microsome stability of the compound

[0103]

[0104] The experimental results are the average values of three independent experiments; a Percentage of the remaining original drug after 15 min of liver microsome incubation.

[0105] Example 3 Hanging experiment study

[0106] Five-week-old male C57BL / 6 mice weighing 16 - 20 g were purchased from the Guangdong Provincial Medical Experimental Animal Center (license number: SCXK(Y)2022 - 0002) and were housed in an SPF barrier environment. During the entire experimental period, the temperature and relative humidity in the animal room were controlled at 23 ± 2 °C and 50 ± 10%, and the light / dark cycle was kept constant at 12 hours. All mice were adaptively housed for one week before starting the animal experiment. Unless otherwise stated, the mice were housed under specific pathogen-free conditions and had free access to food and water.

[0107] The mice were randomly divided into a negative control group, an AP503 treatment group, and a test compound administration group, with 6 mice in each group. After the adaptation period, the control group was given oral gavage with the vehicle, and the treatment groups were given gavage with AP503 (20 mg / kg) or the test compound (20 mg / kg) respectively for 5 consecutive days. At 1 h after the last gavage on the last day, the mice were placed on a wire platform and then inverted and suspended 750 mm above a landing box filled with cotton to prevent the mice from being injured by the fall. The time for the mice to fall from the inverted platform was recorded (up to 60 s each time). Each mouse was subjected to three consecutive trials with a 5-minute rest period between each trial. The average retention time of the three trials was used for analysis, and the results are shown in Table 2. The results showed that compared with the positive drug AP503, the compound of the present invention had a longer hanging retention time after oral administration, indicating that the compound of the present invention could increase muscle strength and endurance to a greater extent and had the advantage of oral administration.

[0108] Table 2: Hanging retention time

[0109]

[0110] * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001 represents the results of Student's t significance test relative to the positive control AP503 group.

Claims

1. A compound containing an effective amount of the compound represented by the general formula (I): Wherein, R1 and R2 are each independently selected from alkyl, trifluoromethyl, or R1 and R2 are linked to form a C4-C6 ring; R3 is optionally selected from alkyl, cycloalkyl, acetyl, benzyl, benzoyl; R4 and R5 are each independently selected from hydrogen, alkyl; R6, R7, R8, R9, R 10 are each independently selected from hydrogen, alkyl, trifluoromethyl, alkoxy, and halogen.

2. The compound of general formula (I) as defined in claim 1: Wherein, R1 and R2 are each independently selected from C1-C3 alkyl, trifluoromethyl, or R1 and R2 are linked to form a C4-C6 ring; R3 is optionally selected from C1-C6 alkyl, C3-C6 cycloalkyl, acetyl, benzyl, benzoyl; R4 and R5 are each independently selected from hydrogen, C1-C3 alkyl; R6, R7, R8, R9, R 10 Each independently selected from hydrogen, C1-C6 alkyl, trifluoromethyl, alkoxy, halogen.

3. The compound of general formula (I) as defined in any one of claims 1-2 is selected from: 3-(2-(2,4-Dimethylphenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide; 2-(2,4-Dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(pyrrolidin-1-carbonyl)phenyl)acetamide; 2-(2,4-Dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(piperidin-1-carbonyl)phenyl)acetamide; 2-(2,4-Dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(morpholine-4-carbonyl)phenyl)acetamide; 3-(2-(2-Chlorophenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide; 3-(2-(4-Chlorophenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide; 3-(2-(4-(tert-Butyl)phenoxy)acetamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide; 4-(4-ethylpiperazin-1-yl)-N,N-dimethyl-3-(2-(4-(trifluoromethyl)phenoxy)acetamido)benzamide; 4-(4-ethylpiperazin-1-yl)-N,N-dimethyl-3-(2-phenoxypropylamino)benzamide; 4-(4-acetylpiperazin-1-yl)-3-(2-(4-fluorophenoxy)acetamido)-N,N-dimethylbenzamide; 4-(4-acetylpiperazin-1-yl)-3-(2-(2,4-dichlorophenoxy)acetamido)-N,N-dimethylbenzamide: 4-(4-acetylpiperazin-1-yl)-3-(2-(4-(tert-Butyl)phenoxy)acetamido)-N,N-dimethylbenzamide; 4-(4-benzoylpiperazin-1-yl)-3-(2-(3,5-dimethylphenoxy)acetamido)-N,N-dimethylaniline; 3-(2-(3,5-Dimethylphenoxy)-2-methylacrylamido)-4-(4-ethylpiperazin-1-yl)-N,N-dimethylbenzamide; 4-(4-benzylpiperazin-1-yl)-3-(2-(3,5-dimethylphenoxy)acetamido)-N,N-dimethylbenzamide; 4-(4-Cyclopropylpiperazin-1-yl)-3-(2-(3,5-dimethylphenoxy)acetamido)-N,N-dimethylbenzamide.

4. A pharmaceutical composition comprising the compound according to any one of claims 1-3 and a suitable carrier or excipient.

5. Use of the compound defined in any one of claims 1-3 as a GPR133 / ADGRD1 agonist.

6. Use of the compound defined in any one of claims 1-3, or the pharmaceutical composition according to claim 4, in the preparation of a medicament for preventing and / or treating vestibular dysfunction diseases.

7. Use of the compound defined in any one of claims 1-3, or the pharmaceutical composition according to claim 4, in the preparation of a medicament for enhancing muscle strength.

8. Use of the compound defined in any one of claims 1-3, or the pharmaceutical composition according to claim 4, in the preparation of a medicament for preventing or / and treating at least one disease among muscle atrophy, myasthenia, sarcopenia, erectile dysfunction, muscle building and fat loss, obesity, non-alcoholic fatty liver.

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