isoindole derivatives

Abstract

Isoindole derivatives, the compounds of general formula (I), their stereoisomers are disclosed: #imgabs0# wherein R1, R2, R3 and R4 are as defined in the present disclosure.

Description

[0001] Citation of Related Applications

[0002] This disclosure claims the entire benefit of the patent application for "Isoindole derivatives with anti-inflammatory effects, their preparation and applications" with application number 201810341153.0, filed with the State Intellectual Property Office of the People's Republic of China on April 17, 2018, and incorporates the entire content of the above-mentioned patent application into this disclosure by reference.

[0003] Field

[0004] This disclosure generally relates to the fields of organic chemistry and medicinal chemistry. Background

[0005] Immunoglobulin E (IgE) is a secreted immunoglobulin composed of two light chains and two heavy chains. It is produced by plasma cells in the lamina propria of the nasopharynx, tonsils, bronchi, gastric mucosa, etc., and is the main antibody causing type I allergic reactions. Although this antibody is present in the least amount in human serum, it plays an important role in allergic diseases and can cause inflammatory immune responses in different tissues and organs. The clinical manifestations of IgE-related diseases range from mild symptoms to life-threatening events, which can significantly affect the physical and mental health of patients, leading to a decline in quality of life and have received increasing attention.

[0006] Eczema is a chronic, recurrent, inflammatory skin disease that is common in infants and children, but can also occur in adults. According to research, the prevalence of eczema in Western countries is as high as over 10%, and in the United States it is 10.7%. In recent years, epidemiological studies have shown that the prevalence of eczema in the general population in my country is close to that in Western countries, and the incidence in industrialized countries has been increasing in the past 20 years. As my country continues to advance its industrialization process, the living standards of the people have significantly improved, infectious skin diseases have gradually decreased, while allergic skin diseases have gradually increased. Its pathogenesis is complex and is mainly related to genetic background, environmental stimulation, epidermal barrier defects, immune disorders and other factors. The destruction of the epidermal barrier stimulates inflammatory response, and B cells produce IgE in the acute phase, leading to degranulation of mast cells and basophils. In the acute phase, the epidermis thickens, nerve fibers proliferate, and the expression of chemokines increases. The disease is often accompanied by severe itching, repeated attacks, sometimes mild and sometimes severe, and a prolonged course of disease that is difficult to cure. It is a chronic, recurrent, inflammatory skin disease in clinical practice that can last for months, years or even decades. The most significant symptom is severe itching, which can significantly affect the patient's study, work and life, and in severe cases, it can also affect sleep. The impact of this type of allergic skin disease on the quality of life of patients and their families and the gradual increase in the economic burden on society urgently require the exploration of the disease's pathogenic factors and pathogenesis, as well as the establishment of appropriate response measures at the social level to alleviate or eliminate clinical symptoms, eliminate inducing and / or aggravating factors, reduce and prevent recurrence, improve the patient's quality of life, and eliminate or improve symptoms so that patients can enjoy a normal life.

[0007] More than 80% of patients with atopic dermatitis have serum total IgE significantly higher than that of normal people (Zhang Jintao et al., Guangdong Medical Journal, 2007, 28(10), 1688-1690). The serum total IgE concentration of patients with atopic dermatitis is positively correlated with the severity of the disease, indicating that serum IgE is an indicator of the activity of atopic dermatitis. In the pathogenesis of atopic dermatitis, IgE plays a very important role. After the external antigen binds to IgE, it promotes the increase of blood eosinophils through two pathways: ① Binding to the IgE receptor on mast cells to stimulate mast cells to release eosinophil chemotactic factor. ② Being phagocytosed by Langerhans cells in the epidermis, the antigen is presented to T cells, which activate them to produce a variety of cytokines including eosinophil chemotactic factor. The basic protein released by the degranulation of a large number of eosinophils causes tissue damage.

[0008] Asthma, also known as bronchial asthma, is a chronic tracheal disease with tracheal spasm as the main pathological feature. It is a chronic airway inflammation involving multiple cells and cell components. Airway inflammation is almost a common feature of all types of asthma and is also the basis for clinical symptoms and airway hyperresponsiveness. IgE plays a very important role in the inflammatory response of asthma (Zhao Xinyu et al., Journal of Clinical Pulmonary Medicine, 2018, 23(7), pp. 1325-1328). When an allergen first enters the body, it triggers a series of inflammatory cascade reactions through the presentation of dendritic cells, causing B cells to produce a large amount of IgE. IgE binds to the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils to form the FcεRI-IgE complex. When the allergen enters the body again, it can quickly bind to this complex, resulting in the massive release of inflammatory mediators such as histamine, leukotrienes, and prostaglandins, causing mucus secretion, airway smooth muscle contraction, and increased vascular permeability. Under the action of these inflammatory mediators, inflammatory cells can cascade to expand the production of IgE, resulting in a late-phase allergic reaction and accelerating the progression of asthma. Another study pointed out that specific IgE molecules can also bind to dendritic cells, enhancing their antigen presentation function and upregulating the expression of FcεRI receptors on the surface of mast cells and basophils. Research results showed that IgE can cause airway remodeling by increasing the extracellular matrix (ECM) and also participates in the process of virus-induced acute asthma attacks.

[0009] Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is an obstructive airway disease that includes both asthma and COPD (He Zhong et al., International Journal of Respiration, 2017, 37(16), pp. 1207-1210). There are usually three common pathophysiological changes, namely: airway inflammation, airway obstruction (AO), and airway hyperresponsiveness (AHR). The Spanish expert consensus believes that COPD patients with a strongly positive bronchodilation test, eosinophils detected in sputum, increased total IgE content, asthma before the age of 40, and a personal history of allergy can be considered for the diagnosis of ACOS.

[0010] Urticaria (Xu Yawei et al., Acta Universitatis Medicinalis Secondae Shanghai, Vol.14, Suppl.1994, pp. 118-120), commonly known as "wind bumps", is a localized edema reaction caused by the dilation and increased permeability of small blood vessels in the skin and mucous membranes. Clinically, it is manifested as wheals of varying sizes accompanied by itching. It usually subsides within 2 to 24 hours, but new rashes occur repeatedly. Chronic urticaria refers to the occurrence of the above-mentioned wheals accompanied by itching almost every day for more than 6 weeks. Although the pathogenesis of urticaria is relatively complex, it is related to mast cell activation. Mast cell activation has two types of pathways, immune and non-immune. The former, skin edema wheals occur either in an IgE-dependent or complement system-mediated immune response process.

[0011] Allergic rhinitis, also known as allergic rhinitis, refers to a non-infectious inflammatory disease of the nasal mucosa mainly mediated by IgE (mainly histamine) release after a specific individual contacts an allergen, and involves a variety of immune active cells and cytokines. Allergic rhinitis can be perennial or seasonal and occurs at any age, with the highest incidence in adolescents. The symptoms of patients include sneezing, tearing, runny nose, nasal itching, and olfactory loss. The type I allergic reaction mediated by IgE is the basis for the occurrence of allergic reactions. Li Zhaohui et al. (Li Zhaohui et al., Journal of Preventive Medicine of Chinese People's Liberation Army, 2018, 36(10), 13-15) found that the IgE level in patients with allergic rhinitis was significantly higher than that in normal people. IgE plays an important role in the pathogenesis of allergic rhinitis. IgE is involved in the immune pathogenesis of allergic rhinitis and can be used as an effective monitoring index for allergic rhinitis, with important clinical significance.

[0012] Common diseases associated with elevated IgE also include: seasonal allergic rhinitis (Holgate S T, World Allergy Organization Journal, 2014, 7, 17 and Wang Hanmei, Sun Renshan, Clinical Journal of Medical Officers, 2017(8), 872-874), drug-induced interstitial pneumonia (Yin Wenjie et al., Chinese Pharmaceutical Congress and Chinese Pharmacist Week, 2010), bronchopulmonary aspergillosis (Holgate S T, World Allergy Organization Journal, 2014, 7, 17), leprosy (He Haoming et al., Chinese Journal of Leprosy and Skin Diseases, 1989(4), 210-211), pemphigoid (Yin Yue, Li Li, Chinese Journal of Laboratory Medicine, 2018, 41(3), 242-245), and certain parasitic infections, etc.

[0013] In - depth understanding of the mechanism of action of IgE molecules has promoted the development of drugs targeting the IgE inflammatory pathway. Anti - IgE therapy exerts its efficacy by reducing the free IgE level, resulting in a decrease in the high - affinity IgE receptor (FcεRI) expressed on mast cells, basophils, and dendritic cells, and reducing inflammatory markers. Omalizumab is the first humanized IgE monoclonal antibody targeting IgE. Omalizumab is used for the treatment of patients with severe persistent allergic asthma aged 6 years or 12 years and above, children, adolescents, and adults. It can reduce the frequency of asthma acute attacks, reduce the use of inhaled corticosteroids, improve the quality of life related to asthma, reduce the number of hospitalizations and emergency visits, and has good safety. The most common adverse event is transient injection - site reaction. However, as protein antibody drugs, they not only have high production difficulty and complex processes, but also have extremely demanding requirements for storage and transportation. More importantly, as therapeutic proteins, they inevitably have potential immunogenicity. Small - molecule IgE inhibitors are a direction for the development of drugs for allergic diseases. Small - molecule compounds have good pharmacological properties, better safety, low price, and good patient compliance, etc.

[0014] Overview

[0015] On the one hand, the present disclosure relates to compounds of general formula (I), their stereoisomers:

[0016]

[0017] Wherein,

[0018] R1 is selected from one or more substituents selected from hydrogen, halogen, hydroxyl, C1 - C8 hydrocarbyl, amino, C1 - C8 hydrocarbylcarbonylamino, C1 - C8 hydrocarbyloxycarbonylamino, amino substituted with one or more C1 - C4 hydrocarbyls, substituted aminocarbonyl C1 - C8 hydrocarbyl;

[0019] R2 is selected from carboxyl or ester group;

[0020] R3 is selected from hydrogen, hydroxyl, halogen, C1 - C8 hydrocarbyloxy, C5 - C 12 aryloxy or C5 - C 12 cycloaryloxy;

[0021] R4 is selected from hydrogen, halogen, hydroxyl, C1 - C8 hydrocarbyloxy or C5 - C 12 aryloxy.

[0022] On the other hand, the present disclosure relates to a pharmaceutical composition comprising a compound of general formula (I) or its stereoisomer and a pharmaceutically acceptable carrier:

[0023]

[0024] Among them,

[0025] R1 is selected from one or more substituents selected from hydrogen, halogen, hydroxyl, C1-C8 hydrocarbyl, amino, C1-C8 hydrocarbylcarbonylamino, C1-C8 hydrocarbyloxycarbonylamino, amino substituted with one or more C1-C4 hydrocarbyls, substituted aminocarbonyl C1-C8 hydrocarbyl;

[0026] R2 is selected from carboxyl or ester group;

[0027] R3 is selected from hydrogen, hydroxyl, halogen, C1-C8 hydrocarbyloxy, C5-C 12 aryloxy or C5-C 12 cycloaryloxy;

[0028] R4 is selected from hydrogen, halogen, hydroxyl, C1-C8 hydrocarbyloxy or C5-C 12 aryloxy.

[0029] On the other hand, the present disclosure relates to the use of a compound of general formula (I) or its stereoisomer or a pharmaceutical composition comprising a compound of general formula (I) or its stereoisomer and a pharmaceutically acceptable carrier in the preparation of a medicament for treating skin diseases, psoriasis, eczema and atopic dermatitis:

[0030]

[0031] Among them,

[0032] R1 is selected from one or more substituents selected from hydrogen, halogen, hydroxyl, C1-C8 hydrocarbyl, amino, C1-C8 hydrocarbylcarbonylamino, C1-C8 hydrocarbyloxycarbonylamino, amino substituted with one or more C1-C4 hydrocarbyls, substituted aminocarbonyl C1-C8 hydrocarbyl;

[0033] R2 is selected from carboxyl or ester group;

[0034] R3 is selected from hydrogen, hydroxyl, halogen, C1-C8 hydrocarbyloxy, C5-C 12 aryloxy or C5-C 12 cycloaryloxy;

[0035] R4 is selected from hydrogen, halogen, hydroxyl, C1-C8 hydrocarbyloxy or C5-C 12 aryloxy.

[0036] On another aspect, the present disclosure relates to a method for preparing a compound of general formula (I) or its stereoisomer:

[0037]

[0038] Among them,

[0039] R1 is selected from one or more substituents selected from hydrogen, halogen, hydroxyl, C1-C8 hydrocarbon group, amino, C1-C8 hydrocarbon group carbonyl amino, C1-C8 hydrocarbon group oxycarbonyl amino, amino substituted by one or more C1-C4 hydrocarbon groups, substituted amino carbonyl C1-C8 hydrocarbon group;

[0040] R2 is selected from carboxyl or ester group;

[0041] R3 is selected from hydrogen, hydroxyl, halogen, C1-C8 hydrocarbon oxy, C5-C 12 aryloxy or C5-C 12 cycloaryloxy;

[0042] R4 is selected from hydrogen, halogen, hydroxyl, C1-C8 hydrocarbon oxy or C5-C 12 aryloxy;

[0043] Wherein the preparation method includes:

[0044] (1) Reacting the compound of general formula (A-I) with malonic acid and ammonium acetate to obtain the compound of general formula (A-II),

[0045]

[0046] Wherein the groups represented by R 3’ 、R 4’ in the general formula (A-I) and the general formula (A-II) are the same as the definitions of R3 and R4 in the general formula (I),

[0047] (2) Esterifying the compound of general formula (A-II) with an alcohol to obtain the compound of general formula (A-III),

[0048]

[0049] Wherein the groups represented by R 3’ 、R 4’ in the general formula (A-II) and the general formula (A-III) are the same as the definitions of R3 and R4 in the general formula (I), and R 2’ is selected from hydrogen, C1-C4 alkyl;

[0050] (3) Reacting the compound of general formula (A-IV) with the compound of general formula (A-III) to obtain the compound of general formula (I),

[0051]

[0052] Wherein the R 1’ 、R 3’ 、R 4’The group represented has the same definition as R1, R3, and R4 in general formula (I), and R 2’ is selected from hydrogen or C1-C4 alkyl.

[0053] On the other hand, the present disclosure relates to a compound of general formula (II), its stereoisomers, or its pharmaceutically acceptable salts:

[0054]

[0055] wherein,

[0056] R1 is selected from one or more of the following same or different substituents: halogen, hydroxyl, optionally substituted hydrocarbon group, optionally substituted amino group, optionally substituted hydrocarbon carbonyl amino group, optionally substituted hydrocarbon carbonyl oxy group, optionally substituted hydrocarbon oxy carbonyl amino group, optionally substituted hydrocarbon carbonyl amino group;

[0057] R2 is selected from optionally substituted hydrocarbon oxy carbonyl or carboxyl;

[0058] R3 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group, or optionally substituted cycloalkyl oxy group; and

[0059] R4 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group, or optionally substituted cycloalkyl oxy group;

[0060] X is -CR5R6-, where n is 0, 1, 2, 3, or 4 when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group, or optionally substituted heteroaryl group; and R6 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group, or optionally substituted heteroaryl group; n is 1 when R5, R6, and the carbon atom to which they are attached together form an optionally substituted cycloalkyl group.

[0061] On yet another aspect, the present disclosure relates to the following compounds, their stereoisomers, or their pharmaceutically acceptable salts:

[0062] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0063] Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0064] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3,4-dimethoxyphenyl)propionate;

[0065] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3,4-diethoxyphenyl)propionate;

[0066] 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid;

[0067] Ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0068] (R)-Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0069] (S)-Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0070] (R)-Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0071] (S)-Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0072] Propyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0073] Isopropyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0074] Butyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0075] Methyl 3-(4-(2-chloroacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0076] Methyl 3-(4-(2-(dimethylamino)acetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0077] Methyl 3-(4-(dimethylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0078] Methyl 3-(4-(2-hydroxyacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0079] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-isopropoxyphenyl)propionate;

[0080] Methyl 3-(4-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0081] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-cyclopentyloxyphenyl)propionate;

[0082] Methyl 3-(4-methyl-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0083] Methyl 3-(5-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0084] Methyl 3-(4,7-dichloro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0085] Methyl 3-(4-(N-methylacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0086] Methyl 3-(5-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0087] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-(benzyloxy)-4-methoxyphenyl)propionate;

[0088] Methyl 3-(4-(N-methyltert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0089] Methyl 3-(4-(methylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0090] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionate;

[0091] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionate;

[0092] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-propoxyphenyl)propionate;

[0093] Methyl 3-(4-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0094] Methyl 3-(4-acetoxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0095] Methyl 3-(4-amino-7-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0096] Methyl 3-(4-amino-5-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0097] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-hydroxy-4-methoxyphenyl)propionate;

[0098] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-(benzyloxy)phenyl)propionate;

[0099] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-hydroxyphenyl)propionate;

[0100] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-methoxy-4-(benzyloxy)phenyl)propionate;

[0101] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-methoxy-4-hydroxyphenyl)propionate;

[0102] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-phenylpropionate;

[0103] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-chlorophenyl)propionate;

[0104] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-ethoxyphenyl)propionate;

[0105] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-chlorophenyl)propionate;

[0106] Methyl 3-(4-(tert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0107] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)propionate;

[0108] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-(difluoromethoxy)-3-ethoxyphenyl)propionate;

[0109] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-(trifluoromethoxy)phenyl)propionate;

[0110] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-(difluoromethoxy)-4-methoxyphenyl)propionate;

[0111] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-methoxy-3-(trifluoromethoxy)phenyl)propionate;

[0112] (R)-Ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0113] (S)-Ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0114] (R)-Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)propionate;

[0115] (S)-Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)propionate;

[0116] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(benzo[d][1,3]dioxol-5-yl)propionate; and

[0117] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propionate.

[0118] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient:

[0119]

[0120] Wherein,

[0121] R1 is selected from one or more of the following same or different substituents: halogen, hydroxy, optionally substituted hydrocarbon group, optionally substituted amino group, optionally substituted hydrocarbon carbonyl amino group, optionally substituted hydrocarbon carbonyloxy group, optionally substituted hydrocarbon oxycarbonyl amino group, optionally substituted hydrocarbon carbonyl amino group;

[0122] R2 is selected from optionally substituted hydrocarbon oxycarbonyl or carboxyl;

[0123] R3 is selected from hydrogen, halogen, hydroxy, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group;

[0124] R4 is selected from hydrogen, halogen, hydroxy, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group; and

[0125] X is -CR5R6-, where n is 0, 1, 2, 3 or 4 when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group; and R6 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group; n is 1 when R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl group.

[0126] On the other hand, the present disclosure relates to a method for treating or preventing an immunoglobulin E (IgE)-related, preferably IgE-mediated disease, which comprises administering to an individual in need of said method a therapeutically effective amount of a compound of general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient:

[0127]

[0128] Wherein,

[0129] R1 is selected from one or more of the following same or different substituents: halogen, hydroxyl, optionally substituted hydrocarbon group, optionally substituted amino group, optionally substituted hydrocarbon carbonyl amino group, optionally substituted hydrocarbon carbonyloxy group, optionally substituted hydrocarbon oxycarbonyl amino group, optionally substituted hydrocarbon carbonyl amino group;

[0130] R2 is selected from optionally substituted hydrocarbon oxycarbonyl or carboxyl;

[0131] R3 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group;

[0132] R4 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group; and

[0133] X is -CR5R6-, where n is 0, 1, 2, 3 or 4 when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group; and R6 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group; n is 1 when R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl group.

[0134] In another aspect, the present disclosure relates to a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for treating or preventing an immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE)-mediated disease:

[0135]

[0136] Wherein,

[0137] R1 is selected from one or more of the following same or different substituents: halogen, hydroxyl, optionally substituted hydrocarbon group, optionally substituted amino group, optionally substituted hydrocarbon carbonyl amino group, optionally substituted hydrocarbon carbonyloxy group, optionally substituted hydrocarbon oxycarbonyl amino group, optionally substituted hydrocarbon carbonyl amino group;

[0138] R2 is selected from optionally substituted hydrocarbon oxycarbonyl or carboxyl;

[0139] R3 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group;

[0140] R4 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group; and

[0141] X is -CR5R6-, where n is 0, 1, 2, 3 or 4 when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R6 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; n is 1 when R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl.

[0142] In another aspect, the present disclosure relates to a pharmaceutical composition for treating or preventing an immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE)-mediated disease, comprising a therapeutically effective amount of a compound of general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient:

[0143]

[0144] wherein,

[0145] R1 is selected from one or more of the following same or different substituents: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxycarbonylamino, optionally substituted hydrocarbylcarbonylamino;

[0146] R2 is selected from optionally substituted hydrocarbyloxycarbonyl or carboxy;

[0147] R3 is selected from hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted arylhydrocarbyloxy or optionally substituted cycloalkyloxy;

[0148] R4 is selected from hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted arylhydrocarbyloxy or optionally substituted cycloalkyloxy; and

[0149] X is -CR5R6-, where n is 0, 1, 2, 3 or 4 when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R6 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; n is 1 when R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl.

[0150] On the other hand, the present disclosure relates to a compound of general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for treating or preventing skin diseases, psoriasis, eczema, atopic dermatitis, urticaria, asthma, asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), allergic rhinitis, seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, pemphigoid and parasitic infections.

[0151]

[0152] Wherein,

[0153] R1 is selected from one or more of the following same or different substituents: halogen, hydroxyl, optionally substituted hydrocarbon group, optionally substituted amino group, optionally substituted hydrocarbon carbonylamino group, optionally substituted hydrocarbon carbonyloxy group, optionally substituted hydrocarbon oxycarbonylamino group, optionally substituted hydrocarbon carbonylamino group;

[0154] R2 is selected from optionally substituted hydrocarbon oxycarbonyl or carboxyl;

[0155] R3 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group;

[0156] R4 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group; and

[0157] X is -CR5R6-, wherein when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group; when R6 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group, n is 0, 1, 2, 3 or 4; when R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl group, n is 1.

[0158] In another aspect, the present disclosure relates to a compound of general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for treating or preventing immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE)-mediated skin diseases, psoriasis, eczema, atopic dermatitis, urticaria, asthma, asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), allergic rhinitis, seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, pemphigoid and parasitic infections:

[0159]

[0160] Wherein,

[0161] R1 is selected from one or more of the following same or different substituents: halogen, hydroxyl, optionally substituted hydrocarbon group, optionally substituted amino group, optionally substituted hydrocarbon carbonylamino group, optionally substituted hydrocarbon carbonyloxy group, optionally substituted hydrocarbon oxycarbonylamino group, optionally substituted hydrocarbon carbonylamino group;

[0162] R2 is selected from optionally substituted hydrocarbon oxycarbonyl or carboxyl;

[0163] R3 is selected from hydrogen, halogen, hydroxyl, optionally substituted alkyloxy, optionally substituted arylalkyloxy or optionally substituted cycloalkyloxy;

[0164] R4 is selected from hydrogen, halogen, hydroxyl, optionally substituted alkyloxy, optionally substituted arylalkyloxy or optionally substituted cycloalkyloxy; and

[0165] X is -CR5R6-, where n is 0, 1, 2, 3 or 4 when R5 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R6 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and n is 1 when R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl.

[0166] In another aspect, the present disclosure relates to a method for preparing a compound of general formula (II), its stereoisomers or its pharmaceutically acceptable salts, which comprises:

[0167] (1) Reacting a compound of general formula (B-I) with malonic acid and ammonium acetate to obtain a compound of general formula (B-II),

[0168]

[0169] wherein the groups represented by R 3’ and R 4’ in general formula (B-I) and general formula (B-II) have the same definitions as R3 and R4 in general formula (II),

[0170] (2) Esterifying the compound of general formula (B-II) with an alcohol to obtain a compound of general formula (B-III),

[0171]

[0172] wherein the groups represented by R 3’ and R 4’ in general formula (B-II) and general formula (B-III) have the same definitions as R3 and R4 in general formula (II), and R 2’ is selected from hydrogen or alkyl;

[0173] (3) Reacting a compound of general formula (B-IV) with a compound of general formula (B-III) to obtain a compound of general formula (II)

[0174]

[0175] wherein the groups represented by R 1’ and R 3’, R 4’ The group represented has the same definition as R1, R3, and R4 in general formula (II), and R 2’ is selected from hydrogen or a hydrocarbon group;

[0176] wherein X is -CR5R6-, R5 is hydrogen, R6 is hydrogen, and n is 1. Brief Description of the Drawings

[0177] Figure 1 Shows the method for inducing and administering drugs to the model animals in Biological Example 1 of the present disclosure.

[0178] Figure 2 Shows the method for inducing and administering drugs to the model animals in Biological Example 2 of the present disclosure.

[0179] Figure 3 Shows the method for inducing and administering drugs to the model animals in Biological Example 3 of the present disclosure.

[0180] Figure 4 Shows the change trend of the body weights of male animals in each test group of Biological Example 7 of the present disclosure.

[0181] Figure 5 Shows the change trend of the body weights of female animals in each test group of Biological Example 7 of the present disclosure.

[0182] Figure 6 Shows the change trend of the body weights of male animals in each test group of Biological Example 8 of the present disclosure.

[0183] Figure 7 Shows the change trend of the body weights of female animals in each test group of Biological Example 8 of the present disclosure.

[0184] Figure 8 Shows the change trend of the body weights of male animals in each test group of Biological Example 9 of the present disclosure.

[0185] Figure 9 Shows the change trend of the body weights of female animals in each test group of Biological Example 9 of the present disclosure.

[0186] Detailed Description

[0187] In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, those skilled in the relevant art will recognize that the embodiments can be implemented without one or more of these specific details and by using other methods, components, materials, etc.

[0188] Unless otherwise required in the present disclosure, throughout the specification and the claims that follow, the words "comprising" and "including" shall be construed in an open, inclusive sense, i.e., "including but not limited to".

[0189] As used throughout this specification, the phrases "one embodiment", "another embodiment", "an embodiment", or "certain embodiments" mean that a particular reference element, structure, or feature associated therewith is included in at least one embodiment. Thus, the phrases "one embodiment", "an embodiment", or "another embodiment" that appear in various places throughout the specification do not necessarily all refer to the same embodiment. In addition, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0190] It should be understood that the singular forms of the articles "a" (corresponding to "a", "an", and "the" in English) used in the specification and appended claims of the present disclosure include plural objects, unless otherwise expressly specified herein. Thus, for example, a pharmaceutical composition comprising "a compound of formula (II), its stereoisomers, or a pharmaceutically acceptable salt thereof" includes one compound of formula (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, or two or more compounds of formula (II), its stereoisomers, or a pharmaceutically acceptable salt thereof.

[0191] Definitions

[0192] Thus, unless otherwise indicated to the contrary, the following terms used in the specification and appended claims have the following meanings:

[0193] The shorthand symbols placed in front of certain chemical groups named in the present disclosure represent the total number of carbon atoms present in the indicated chemical group. For example, C1-C4 alkyl describes an alkyl group having a total of 1 to 4 carbon atoms as defined hereinafter, and C3-C 10 Cycloalkyl describes a cycloalkyl group having a total of 3 to 10 carbon atoms as defined hereinafter. The total number of carbons in the shorthand symbol does not include the carbons that may be present in the substituents of the group.

[0194] In the present disclosure, the term "halogen" means fluorine, chlorine, bromine, or iodine.

[0195] In the present disclosure, the term "hydroxy" means the -OH group.

[0196] In the present disclosure, the term "amino" means the -NH2 group.

[0197] In the present disclosure, the term "carboxy" means the -COOH group.

[0198] In the present disclosure, the term "hydrocarbyl group" refers to an aliphatic hydrocarbon group. The hydrocarbyl moiety can be a "saturated hydrocarbyl" group, meaning that it does not contain any olefinic or acetylenic moieties. The hydrocarbyl moiety can also be an "unsaturated hydrocarbyl" moiety, meaning that it contains at least one olefinic or acetylenic moiety. An "olefin" moiety refers to a group consisting of two to eight carbon atoms and at least one carbon-carbon double bond, and a straight-chain or branched-chain hydrocarbon chain group connected to the rest of the molecule by a single bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc., and an "acetylene" moiety refers to a group consisting of two to eight carbon atoms and at least one carbon-carbon triple bond, and a straight-chain or branched-chain hydrocarbon chain group connected to the rest of the molecule by a single bond. The hydrocarbyl moiety, whether saturated or unsaturated, can be branched or straight-chain.

[0199] The hydrocarbyl group can have 1 to 8 carbon atoms (each time the numerical range such as "1 to 8" appears in the present disclosure, it means each integer in the given range; for example, "1 to 8" means that the hydrocarbyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc. up to and including 8 carbon atoms, although this definition also covers the occurrence of the term "hydrocarbyl" without a specified numerical range).

[0200] The hydrocarbyl group can be optionally substituted, that is, substituted or unsubstituted. When substituted, the substituents are independently selected from one or more of the following groups: cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfinylamino, N-sulfinylamino, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR’R” (where R’ and R” are hydrocarbyl groups as defined in the present disclosure) or amino groups including mono- and di-substituted amino groups, and their protected derivatives. Generally, the hydrocarbyl group includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, ethynyl, propynyl, and butynyl. Whenever a substituent is described as being "optionally substituted", the substituent can be substituted by one of the above substituents.

[0201] In certain embodiments, "C1-C4 hydrocarbyl" refers to a hydrocarbyl group as defined above containing one to four carbon atoms. The C1-C4 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.

[0202] In certain embodiments, "C1-C6 hydrocarbyl" refers to a hydrocarbyl group as defined above having from one to six carbon atoms. The C1-C6 hydrocarbyl group may be optionally substituted as defined for hydrocarbyl groups.

[0203] In certain embodiments, "C1-C 12 hydrocarbyl" refers to a hydrocarbyl group as defined above having from one to twelve carbon atoms. The C1-C 12 hydrocarbyl group may be optionally substituted as defined for hydrocarbyl groups.

[0204] In certain embodiments, "C2-C6 hydrocarbyl" refers to a hydrocarbyl group as defined above having from two to six carbon atoms. The C2-C6 hydrocarbyl group may be optionally substituted as defined for hydrocarbyl groups.

[0205] In certain embodiments, "C3-C6 hydrocarbyl" refers to a hydrocarbyl as defined above having from three to six carbon atoms. The C3-C6 hydrocarbyl group may be optionally substituted as defined for hydrocarbyl groups.

[0206] In certain embodiments, "C3-C 12 hydrocarbyl" refers to a hydrocarbyl as defined above having from three to twelve carbon atoms. The C3-C 12 hydrocarbyl group may be optionally substituted as defined for hydrocarbyl groups.

[0207] In certain embodiments, "C6-C 12 hydrocarbyl" refers to a hydrocarbyl as defined above having from six to twelve carbon atoms. The C6-C 12 hydrocarbyl group may be optionally substituted as defined for hydrocarbyl groups.

[0208] In certain embodiments, "C7-C 12 hydrocarbyl" refers to a hydrocarbyl as defined above having from seven to twelve carbon atoms. The C7-C 12 hydrocarbyl group may be optionally substituted as defined for hydrocarbyl groups.

[0209] In the present disclosure, the term "hydrocarbyloxy" refers to the general formula -O-hydrocarbyl, where hydrocarbyl is as defined in the present disclosure. Exemplary examples of hydrocarbyloxy include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and tert-pentyloxy.

[0210] In the present disclosure, the term "aryl" refers to a carbocyclic (all-carbon) or two or more fused rings (rings sharing two adjacent carbon atoms) having a fully delocalized pi-electron system. Aryl groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. An aryl group may have, for example, five to twelve carbon atoms. The aryl groups of the present disclosure may be substituted or unsubstituted. When substituted, a hydrogen atom is substituted by one or more groups independently selected from the following substituents: hydrocarbyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, protected hydroxy, hydrocarbyloxy, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfinylamino, N-sulfinylamino, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR’R” (wherein R’ and R” are hydrocarbyl groups as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted by one of the above substituents.

[0211] In the present disclosure, the term "arylhydrocarbyloxy" refers to the general formula -O-hydrocarbylaryl, wherein the hydrocarbyl and aryl are as defined in the present disclosure, respectively. Exemplary examples of arylhydrocarbyloxy include, but are not limited to, benzyloxy, phenethyloxy, and phenylpropyloxy.

[0212] In certain embodiments, "C6-C 16 arylhydrocarbyloxy" refers to an arylhydrocarbyloxy as defined above containing six to sixteen carbon atoms. The C6-C 16 arylhydrocarbyloxy group may be optionally substituted, respectively, as defined for the hydrocarbyl group and the aryl group.

[0213] In certain embodiments, "C6-C 18 arylhydrocarbyloxy" refers to an arylhydrocarbyloxy as defined above containing six to eighteen carbon atoms. The C6-C 18 arylhydrocarbyloxy group may be optionally substituted, respectively, as defined for the hydrocarbyl group and the aryl group.

[0214] In certain embodiments, "C7-C 18 arylhydrocarbyloxy" refers to an arylhydrocarbyloxy as defined above containing seven to eighteen carbon atoms. The C7-C 18 arylhydrocarbyloxy group may be optionally substituted, respectively, as defined for the hydrocarbyl group and the aryl group.

[0215] In certain embodiments, "C8-C 18 arylhydrocarbyloxy" refers to an arylhydrocarbyloxy as defined above containing eight to eighteen carbon atoms. The C8-C18 The arylalkyloxy group can be optionally substituted respectively as defined for the alkyl group and the aryl group.

[0216] In certain embodiments, "C8-C 24 aryalkyloxy" refers to the arylalkyloxy as defined above containing from eight to twenty-four carbon atoms. C8-C 24 The arylalkyloxy group can be optionally substituted respectively as defined for the alkyl group and the aryl group.

[0217] In certain embodiments, "C 11 -C 24 aryalkyloxy" refers to the arylalkyloxy as defined above containing from eleven to twenty-four carbon atoms. C 11 -C 24 The arylalkyloxy group can be optionally substituted respectively as defined for the alkyl group and the aryl group.

[0218] In certain embodiments, "C 12 -C 24 aryalkyloxy" refers to the arylalkyloxy as defined above containing from twelve to twenty-four carbon atoms. C 12 -C 24 The arylalkyloxy group can be optionally substituted respectively as defined for the alkyl group and the aryl group.

[0219] In certain embodiments, "C6-C 24 aryalkyloxy" refers to the arylalkyloxy as defined above containing from six to twenty-four carbon atoms. C6-C 24 The arylalkyloxy group can be optionally substituted respectively as defined for the alkyl group and the aryl group.

[0220] In the present disclosure, the term "heteroaryl" refers to an aromatic ring group having from 5 to 18 ring atoms composed of one to seventeen carbon atoms and one to ten heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include a fused or bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atoms can be optionally quaternized. Exemplary examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, chromenyl, chromenone, benzofuranyl, benzofuranone, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanone, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl. The heteroaryl groups of the present disclosure can be substituted or unsubstituted. When substituted, the hydrogen atoms are substituted by one or more groups independently selected from the following substituents: hydrocarbyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfinylamino, N-sulfinylamino, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, cyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR’R” (wherein R’ and R” are hydrocarbyls as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted", the substituent can be substituted by one of the above substituents.

[0221] In the present disclosure, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon group consisting of only carbon and hydrogen atoms, having three to fifteen carbon atoms, having three to twelve carbon atoms in certain embodiments, being saturated or unsaturated, and being linked to the rest of the molecule by a single bond, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl, etc. Unless otherwise explicitly stated in the present disclosure, the term "cycloalkyl" is intended to include cycloalkyl groups as defined above that are optionally substituted with one or more groups selected from the following substituents: cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfinylamino, N-sulfinamino, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR’R” (where R’ and R” are alkyl groups as defined in the present disclosure) or amino groups including mono- and di-substituted amino groups, and their protected derivatives.

[0222] In certain embodiments, "C3-C6 cycloalkyl" refers to a cycloalkyl group as defined above having three to six carbon atoms. The C3-C6 cycloalkyl group can be optionally substituted as defined for the cycloalkyl above.

[0223] In certain embodiments, "C3-C 10 cycloalkyl" refers to a cycloalkyl group as defined above having three to ten carbon atoms. The C3-C 10 cycloalkyl group can be optionally substituted as defined for the cycloalkyl above.

[0224] In certain embodiments, "C3-C 12 cycloalkyl" refers to a cycloalkyl group as defined above having three to twelve carbon atoms. The C3-C 12 cycloalkyl group can be optionally substituted as defined for the cycloalkyl above.

[0225] In the present disclosure, the term "cycloalkyloxy" refers to -O-cycloalkyl, where cycloalkyl is as defined in the present disclosure. Exemplary examples of cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and cyclodecyloxy.

[0226] In the present disclosure, the term "alkylcarbonylamino" refers to -NHC(=O)-alkyl, where alkyl is as defined in the present disclosure. Exemplary examples of alkylcarbonylamino include, but are not limited to, acetamido, propionamido, butyramido, and valeramido.

[0227] In the present disclosure, the term "hydrocarbylcarbonyloxy" means -OC(=O)-hydrocarbyl, wherein the hydrocarbyl is as defined in the present disclosure. Exemplary examples of hydrocarbylcarbonyloxy include, but are not limited to, acetoxy, propionyloxy, butyryloxy, and pentyryloxy.

[0228] In the present disclosure, the term "hydrocarbyloxycarbonylamino" means -NHC(=O)O-hydrocarbyl, wherein the hydrocarbyl is as defined in the present disclosure. Exemplary examples of hydrocarbyloxycarbonylamino include, but are not limited to, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, and tert-butoxycarbonylamino.

[0229] In the present disclosure, the term "hydrocarbyloxycarbonyl" means -C(=O)O-hydrocarbyl, wherein the hydrocarbyl is as defined in the present disclosure. Exemplary examples of hydrocarbyloxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, and butoxycarbonyl.

[0230] In the present disclosure, the term "the compounds of the present disclosure, their stereoisomers or their pharmaceutically acceptable salts" means the compounds of general formula (I) of the present disclosure, their stereoisomers and their pharmaceutically acceptable salts, the compounds of general formula (II), their stereoisomers and their pharmaceutically acceptable salts, and any specific compounds falling within general formula (I) and general formula (II), their stereoisomers and their pharmaceutically acceptable salts.

[0231] In the present disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans. In certain embodiments, the mammal includes humans.

[0232] In the present disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cows, pigs, and sheep). In certain embodiments, the patient is a mammal including both males and females. In certain embodiments, the patient is a human.

[0233] In the present disclosure, the term "pharmaceutically acceptable" means a carrier, vehicle, diluent, excipient, and / or salt that must be compatible with the other ingredients of the formulation and not harmful to its recipient.

[0234] In the present disclosure, the term "optional" or "optionally" means that the subsequent described event or condition may or may not occur, and the specification includes the cases where the event or condition occurs and the cases where it does not occur.

[0235] In the present disclosure, the term "pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier, etc. that have been approved by the US Food and Drug Administration and are used in humans or animals, and are various forms of carriers that have no side effects on the composition of the pharmaceutical composition.

[0236] In the present disclosure, the term "carrier" is defined as a compound that facilitates the introduction of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it easily introduces certain organic compounds into the cells or tissues of an organism.

[0237] In the present disclosure, the term "pharmaceutically acceptable salt" includes "acceptable acid addition salts" and "acceptable base addition salts".

[0238] In the present disclosure, the term "acceptable acid addition salt" refers to those salts that maintain the biological effectiveness and properties of the free base, and the acid addition salts are biologically or otherwise suitable and are formed using inorganic acids or organic acids. The inorganic acids include, for example, but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. The organic acids include, for example, but are not limited to acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexylaminosulfonic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0239] In the present disclosure, the term "acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acid and are biologically or otherwise suitable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzylamine, phenethylenediamine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0240] In the present disclosure, the term "solvent or solvent mixture" refers to any and all solvents. In certain embodiments, the solvent or solvent mixture is an organic solvent and water, including but not limited to methanol, ethanol, 2-propanol, n-butanol, isobutanol, acetone, methyl ethyl ketone, ethyl acetate, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, N,N-dimethylformamide, cyclohexane, cyclopentane, n-hexane, n-heptane, n-pentane, toluene, o-xylene, p-xylene, dimethyl sulfoxide (DMSO), pyridine, acetic acid, anisole, butyl acetate, cumene, ethyl formate, formic acid, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone, 2-methyl-1-propanol, 1-pentanol, propyl acetate, ethylene glycol, and 1-methyl-2-pyrrolidone, and any and all mixtures of two or more such solvents. In certain embodiments, the solvent or solvent mixture is a single solvent and a binary mixture. In certain embodiments, the solvent or solvent mixture is a single solvent of water and an organic solvent and a binary mixture of water and an organic solvent.

[0241] In the present disclosure, the term "pharmaceutical composition" refers to a preparation formed by the compounds described in the present disclosure and a medium that is generally acceptable in the art for delivering a bioactive compound to a mammal such as a human. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0242] In the present disclosure, the term "therapeutically effective amount" refers to the amount of a compound or combination of compounds that improves, attenuates, or eliminates a particular disease or condition and the symptoms of a particular disease or condition, or prevents or delays the onset of a particular disease or condition or the symptoms of a particular disease or condition. Depending on the compound, the disease state and its severity, and the age, body weight, etc. of the mammal to be treated, the amount of the compound described in the present disclosure that constitutes a "therapeutically effective amount" will vary, but a person skilled in the art can, based on their own knowledge and the present disclosure, conventionally determine the amount of the compound described in the present disclosure.

[0243] As used in the present disclosure, "treating" or "treatment" encompasses treating a relevant disease or disease state in a mammal, such as a human, suffering from the relevant disease or disorder, and includes:

[0244] (i) preventing the occurrence of a disease or disease state in a mammal, especially when the mammal is susceptible to the disease state but has not been diagnosed with the disease state;

[0245] (ii) inhibiting a disease or disease state, i.e., preventing its occurrence; or

[0246] (iii) alleviating a disease or disease state, i.e., causing the disease or disease state to regress or not progress.

[0247] As used in the present disclosure, the terms "disease" and "disease state" may be used interchangeably or may be different, since a particular disease or disease state may not have a known causative agent (and thus cannot be explained etiologically), and thus is not recognized as a disease but is considered an undesirable disease state or disorder, in which a clinician has identified more or less a particular series of symptoms.

[0248] In the present disclosure, the term "physiologically acceptable" refers to a carrier or diluent that does not eliminate the biological activity and properties of the compound.

[0249] The compounds or their pharmaceutically acceptable salts described in the present disclosure may contain one or more asymmetric centers and, therefore, can give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined as (R)- or (S)- according to absolute stereochemistry, or (D)- or (L)- for amino acids. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as HPLC on a chiral column. When the compounds described in the present disclosure contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise stated, it means that the compounds include E and Z geometric isomers. Similarly, it also means that all tautomeric forms are included.

[0250] In the present disclosure, the term "stereoisomer" refers to compounds composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers and their mixtures. Specific embodiments

[0251] In one aspect, the present disclosure relates to compounds of general formula (I), their stereoisomers:

[0252]

[0253] wherein,

[0254] R1 is selected from one or more substituents selected from hydrogen, halogen, hydroxy, C1-C8 hydrocarbyl, amino, C1-C8 hydrocarbylcarbonylamino, C1-C8 hydrocarbyloxycarbonylamino, one or more C1-C4 hydrocarbyl-substituted amino, substituted aminocarbonyl C1-C8 hydrocarbyl;

[0255] R2 is selected from carboxyl or ester group;

[0256] R3 is selected from hydrogen, hydroxy, halogen, C1-C8 hydrocarbyloxy, C5-C 12 aryloxy or C5-C 12 cycloaryloxy;

[0257] R4 is selected from hydrogen, halogen, hydroxy, C1-C8 hydrocarbyloxy or C5-C 12 aryloxy.

[0258] In certain embodiments, R1 is selected from one or more substituents selected from hydrogen, halogen, hydroxy, C1-C8 alkyl, amino, C1-C8 alkylcarbonylamino, C1-C8 alkyloxycarbonylamino, one or more C1-C4 alkyl-substituted amino, substituted aminocarbonyl C1-C8 alkyl.

[0259] In certain embodiments, R3 is selected from hydrogen, hydroxy, halogen, C1-C8 alkoxy, C5-C 12 aryloxy or C5-C 12 cycloaryloxy.

[0260] In certain embodiments, R4 is selected from hydrogen, hydroxy, halogen, C1-C8 alkoxy, C5-C 12 aryloxy or C5-C 12 cycloaryloxy.

[0261] In certain embodiments, R1 is selected from hydrogen, -OH, -F, -Cl, -CH3, -CH2CH3, -CH2CH2CH3, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -NHCOOCH3, -NHCOCH2OH, -NHCOCH2Cl, -NHCOCH2F or -NCH3COCH3.

[0262] In certain embodiments, R2 is selected from -COOH, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3 or -COOCH(CH3)2.

[0263] In certain embodiments, R3 is selected from hydrogen, hydroxy, halogen, benzyloxy, C1-C4 alkoxy, C5-C 12 aryloxy or C5-C 12 cycloaryloxy.

[0264] In certain embodiments, R3 is selected from -H, -OH, -Cl, -F, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2 or benzyloxy.

[0265] In certain embodiments, R4 is selected from hydrogen, halogen, hydroxy, C1-C4 hydrocarbyloxy, benzyloxy or C5-C 12 aryloxy.

[0266] In certain embodiments, R4 is selected from -H, -Cl, -F, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2 or benzyloxy.

[0267] On the other hand, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof and a pharmaceutically acceptable carrier:

[0268]

[0269] wherein,

[0270] R1 is selected from one or more substituents selected from hydrogen, halogen, hydroxy, C1-C8 hydrocarbon group, amino, C1-C8 hydrocarbon carbonyl amino, C1-C8 hydrocarbon oxycarbonyl amino, one or more C1-C4 hydrocarbon group-substituted amino, substituted amino carbonyl C1-C8 hydrocarbon group;

[0271] R2 is selected from -COOH, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3 or -COOCH(CH3)2;

[0272] R3 is selected from hydrogen, hydroxy, halogen, benzyloxy, C1-C4 alkoxy, C5-C 12 aryloxy or C5-C 12 cycloaryloxy;

[0273] R4 is selected from hydrogen, halogen, hydroxy, C1-C4 hydrocarbon oxy, benzyloxy or C5-C 12 aryloxy.

[0274] In another aspect, the present disclosure relates to the use of a compound of general formula (I) or its stereoisomer or a pharmaceutical composition comprising a compound of general formula (I) or its stereoisomer and a pharmaceutically acceptable carrier in the preparation of a medicament for treating skin diseases, psoriasis, eczema and atopic dermatitis:

[0275]

[0276] wherein,

[0277] R1 is selected from one or more substituents selected from hydrogen, halogen, hydroxy, C1-C8 hydrocarbon group, amino, C1-C8 hydrocarbon carbonyl amino, C1-C8 hydrocarbon oxycarbonyl amino, one or more C1-C4 hydrocarbon group-substituted amino, substituted amino carbonyl C1-C8 hydrocarbon group;

[0278] R2 is selected from -COOH, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3 or -COOCH(CH3)2;

[0279] R3 is selected from hydrogen, hydroxy, halogen, benzyloxy, C1-C4 alkoxy, C5-C 12 aryloxy or C5-C 12 cycloaryloxy;

[0280] R4 is selected from hydrogen, halogen, hydroxy, C1-C4 hydrocarbon oxy, benzyloxy or C5-C 12 aryloxy.

[0281] In yet another aspect, the present disclosure relates to a method for preparing a compound of general formula (I) or its stereoisomer:

[0282]

[0283] Among them,

[0284] R1 is selected from one or more substituents selected from hydrogen, halogen, hydroxyl, C1-C8 hydrocarbon group, amino group, C1-C8 hydrocarbon group carbonyl amino group, C1-C8 hydrocarbon group oxycarbonyl amino group, amino group substituted by one or more C1-C4 hydrocarbon groups, substituted amino carbonyl C1-C8 hydrocarbon group;

[0285] R2 is selected from -COOH, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3 or -COOCH(CH3)2;

[0286] R3 is selected from hydrogen, hydroxyl, halogen, benzyloxy, C1-C4 alkoxy, C5-C 12 aryloxy or C5-C 12 cycloaryloxy;

[0287] R4 is selected from hydrogen, halogen, hydroxyl, C1-C4 hydrocarbon oxy, benzyloxy or C5-C 12 aryloxy;

[0288] Among them, the preparation method includes:

[0289] (1) Reacting the compound of general formula (A-I) with malonic acid and ammonium acetate to obtain the compound of general formula (A-II),

[0290]

[0291] Among them, the groups represented by R 3’ , R 4’ in the general formula (A-I) and the general formula (A-II) are the same as the definitions of R3 and R4 in the general formula (I),

[0292] (2) Esterifying the compound of general formula (A-II) with an alcohol to obtain the compound of general formula (A-III),

[0293]

[0294] Among them, the groups represented by R 3’ , R 4’ in the general formula (A-II) and the general formula (A-III) are the same as the definitions of R3 and R4 in the general formula (I), and R 2’ is selected from hydrogen, C1-C4 alkyl;

[0295] (3) Reacting the compound of general formula (A-IV) with the compound of general formula (A-III) to obtain the compound of general formula (I)

[0296]

[0297] Among them, R in general formula (A-III) and general formula (A-IV) 1’ , R 3’ , R 4’ represent groups having the same definitions as R1, R3, and R4 in general formula (I), and R 2’ is selected from hydrogen or C1-C4 alkyl.

[0298] In certain embodiments, the method of reacting a compound of general formula (A-I) with malonic acid and ammonium acetate to obtain a compound of general formula (A-II) is carried out in an organic solvent.

[0299] In certain embodiments, exemplary examples of suitable organic solvents that can be used in the present disclosure for reacting a compound of general formula (A-I) with malonic acid and ammonium acetate to obtain a compound of general formula (A-II) include but are not limited to methanol, ethanol, isopropanol, and water.

[0300] In certain embodiments, the compound of general formula (A-I) is reacted with malonic acid and ammonium acetate at about 50 °C to about 130 °C to obtain a compound of general formula (A-II).

[0301] In certain embodiments, exemplary examples of suitable esterifying agents that can be used to prepare a compound of general formula (A-III) from a compound of general formula (A-II) include but are not limited to thionyl chloride, oxalyl chloride, HCl gas, and acetyl chloride.

[0302] In certain embodiments, the method of reacting a compound of general formula (A-II) with an alcohol compound to obtain a compound of general formula (A-III) is carried out in an organic solvent.

[0303] In certain embodiments, exemplary examples of suitable organic solvents that can be used in the present disclosure for reacting a compound of general formula (A-II) with an alcohol compound to obtain a compound of general formula (A-III) include but are not limited to alcohols, tetrahydrofuran, dichloromethane, ethyl acetate, and methyl tert-butyl ether.

[0304] In certain embodiments, exemplary examples of suitable alcohols that can be used in the present disclosure for reacting a compound of general formula (A-II) with an alcohol compound to obtain a compound of general formula (A-III) include but are not limited to methanol, ethanol, and isopropanol, etc.

[0305] In certain embodiments, the compound of general formula (A-II) is reacted with an alcohol compound at about -20 °C to about 30 °C to obtain a compound of general formula (A-III).

[0306] In certain embodiments, a catalyst is added in the method of reacting a compound of general formula (A-IV) with a compound of general formula (A-III) to obtain a compound of general formula (I).

[0307] In certain embodiments, exemplary instances of suitable catalysts that can be used in the present disclosure for reacting a compound of general formula (A-IV) with a compound of general formula (A-III) to obtain a compound of general formula (I) include, but are not limited to, sodium acetate, potassium acetate, sodium carbonate, and potassium carbonate.

[0308] In certain embodiments, the method of reacting a compound of general formula (A-IV) with a compound of general formula (A-III) to obtain a compound of general formula (I) is carried out in an organic solvent.

[0309] In certain embodiments, exemplary instances of suitable organic solvents that can be used in the present disclosure for reacting a compound of general formula (A-IV) with a compound of general formula (A-III) to obtain a compound of general formula (I) include, but are not limited to, acetic acid, formic acid, dimethylformamide, and dimethylacetamide.

[0310] In certain embodiments, the compound of general formula (A-IV) is reacted with the compound of general formula (A-III) at about 50 °C to about 180 °C to obtain a compound of general formula (I).

[0311] On the other hand, the present disclosure relates to a compound of general formula (II), its stereoisomers, or its pharmaceutically acceptable salts:

[0312]

[0313] wherein,

[0314] R1 is selected from one or more of the following same or different substituents: halogen, hydroxyl, optionally substituted hydrocarbon group, optionally substituted amino group, optionally substituted hydrocarbon carbonyl amino group, optionally substituted hydrocarbon carbonyl oxy group, optionally substituted hydrocarbon oxy carbonyl amino group, optionally substituted hydrocarbon carbonyl amino group;

[0315] R2 is selected from optionally substituted hydrocarbon oxy carbonyl or carboxyl;

[0316] R3 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group, or optionally substituted cyclo hydrocarbon oxy group;

[0317] R4 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group, or optionally substituted cyclo hydrocarbon oxy group; and

[0318] X is -CR5R6-, where n is 0, 1, 2, 3 or 4 when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R6 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and n is 1 when R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl.

[0319] In certain embodiments, R1 is selected from one or more of the following same or different substituents: halogen, hydroxy, optionally substituted C1-C6 hydrocarbyl, optionally substituted amino, optionally substituted C1-C6 hydrocarbylcarbonylamino, optionally substituted C1-C6 hydrocarbylcarbonyloxy, optionally substituted C1-C6 hydrocarbyloxycarbonylamino, optionally substituted C1-C6 hydrocarbylcarbonylamino.

[0320] In certain embodiments, R1 is selected from one or more of the following same or different substituents: halogen, hydroxy, optionally substituted alkyl, optionally substituted amino, optionally substituted alkylcarbonylamino, optionally substituted alkylcarbonyloxy, optionally substituted alkyloxycarbonylamino, optionally substituted alkylcarbonylamino.

[0321] In certain embodiments, R1 is selected from one or more of the following same or different substituents: halogen, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkylcarbonylamino, optionally substituted C1-C6 alkylcarbonyloxy, optionally substituted C1-C6 alkyloxycarbonylamino, optionally substituted C1-C6 alkylcarbonylamino.

[0322] In certain embodiments, R1 is selected from one or more of the following same or different substituents: halogen, hydroxy, optionally substituted methyl, optionally substituted amino, optionally substituted acetylamino, optionally substituted acetyloxy, optionally substituted tert-butoxycarbonylamino.

[0323] In certain embodiments, R1 is selected from one or more of the following same or different substituents: fluorine, chlorine, hydroxy, methyl, amino, C1-C6 alkyl-substituted amino, acetylamino, haloacetylamino, C1-C6 alkyl-substituted acetylamino, hydroxy-substituted acetylamino, C1-C6 alkyl-substituted amino-substituted acetylamino, N-C1-C6 alkyl-substituted acetylamino, acetyloxy, tert-butoxycarbonylamino, C1-C6 alkyl-substituted tert-butoxycarbonylamino.

[0324] In certain embodiments, R1 is selected from one or more of the following same or different substituents: fluorine, chlorine, hydroxy, methyl, amino, methylamino, dimethylamino, acetylamino, 2-chloroacetylamino, 2-hydroxyacetylamino, N-methylacetylamino, 2-(dimethylamino)acetylamino, acetoxy, tert-butoxycarbonylamino, N-methyltert-butoxycarbonylamino.

[0325] In certain embodiments, R1 is selected from acetylamino.

[0326] In certain embodiments, R2 is selected from optionally substituted C1-C6 hydrocarbyloxycarbonyl or carboxy.

[0327] In certain embodiments, R2 is selected from optionally substituted alkyloxycarbonyl or carboxy.

[0328] In certain embodiments, R2 is selected from optionally substituted C1-C6 alkyloxycarbonyl or carboxy.

[0329] In certain embodiments, R2 is selected from optionally substituted methoxycarbonyl, optionally substituted ethoxycarbonyl, optionally substituted propoxycarbonyl, optionally substituted butoxycarbonyl, optionally substituted isopropoxycarbonyl or carboxy.

[0330] In certain embodiments, R2 is selected from methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isopropoxycarbonyl or carboxy.

[0331] In certain embodiments, R2 is selected from methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl.

[0332] In certain embodiments, R3 is selected from hydrogen, halogen, hydroxy, optionally substituted alkyloxy, optionally substituted arylalkyloxy or optionally substituted cycloalkyloxy.

[0333] In certain embodiments, R3 is selected from hydrogen, halogen, hydroxy, optionally substituted C1-C6 hydrocarbyloxy, optionally substituted C6-C 18 arylhydrocarbyloxy or optionally substituted C3-C 10 cyclohydrocarbyloxy.

[0334] In certain embodiments, R3 is selected from hydrogen, halogen, hydroxy, optionally substituted alkyloxy, optionally substituted arylalkyloxy or optionally substituted cycloalkyloxy.

[0335] In certain embodiments, R3 is selected from hydrogen, halogen, hydroxy, optionally substituted C1-C6 alkyloxy, optionally substituted C6-C 18 arylalkylalkyloxy or optionally substituted C3-C 10 cycloalkyloxy.

[0336] In certain embodiments, R3 is selected from hydrogen, halogen, hydroxy, optionally substituted methoxy, optionally substituted ethoxy, optionally substituted propoxy, optionally substituted isopropoxy, optionally substituted benzyloxy or optionally substituted cyclopentyloxy.

[0337] In certain embodiments, R3 is selected from hydrogen, chlorine, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, benzyloxy or cyclopentyloxy.

[0338] In certain embodiments, R3 is selected from methoxy or ethoxy.

[0339] In certain embodiments, R4 is selected from hydrogen, halogen, hydroxy, optionally substituted alkyloxy, optionally substituted arylalkyloxy or optionally substituted cycloalkyloxy.

[0340] In certain embodiments, R4 is selected from hydrogen, halogen, hydroxy, optionally substituted C1-C6 hydrocarbyloxy, optionally substituted C6-C 18 arylhydrocarbyloxy or optionally substituted C3-C 10 cyclohydrocarbyloxy.

[0341] In certain embodiments, R4 is selected from hydrogen, halogen, hydroxy, optionally substituted alkyloxy, optionally substituted arylalkyloxy or optionally substituted cycloalkyloxy.

[0342] In certain embodiments, R4 is selected from hydrogen, halogen, hydroxy, optionally substituted C1-C6 alkyloxy, optionally substituted C6-C 18 arylalkyloxy or optionally substituted C3-C 10 cycloalkyloxy.

[0343] In certain embodiments, R4 is selected from hydrogen, halogen, hydroxy, optionally substituted methoxy, optionally substituted ethoxy, optionally substituted propoxy, optionally substituted isopropoxy, optionally substituted benzyloxy or optionally substituted cyclopentyloxy.

[0344] In certain embodiments, R4 is selected from hydrogen, chlorine, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, benzyloxy or cyclopentyloxy.

[0345] In certain embodiments, R4 is selected from methoxy or ethoxy.

[0346] In certain embodiments, R5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0347] In certain embodiments, R5 is selected from hydrogen, halogen, optionally substituted C1-C6 hydrocarbyl, optionally substituted C3-C 10Cycloalkyl, optionally substituted C5-C 12 aryl or optionally substituted heteroaryl.

[0348] In certain embodiments, R5 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted C5-C 12 aryl or optionally substituted heteroaryl.

[0349] In certain embodiments, R5 is selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C5-C 12 aryl or optionally substituted heteroaryl.

[0350] In certain embodiments, R6 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0351] In certain embodiments, R6 is selected from hydrogen, halogen, optionally substituted C1-C6 hydrocarbyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C5-C 12 aryl or optionally substituted heteroaryl.

[0352] In certain embodiments, R6 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted C5-C 12 aryl or optionally substituted heteroaryl.

[0353] In certain embodiments, R6 is selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C5-C 12 aryl or optionally substituted heteroaryl.

[0354] In certain embodiments, n is 0, 1, 2, 3 or 4.

[0355] In certain embodiments, R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl, and n is 1.

[0356] In certain embodiments, R5, R6 and the carbon atom to which they are attached together form an optionally substituted C3-C 12 cycloalkyl, and n is 1.

[0357] In certain embodiments, R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl, and n is 1.

[0358] In certain embodiments, R5, R6 and the carbon atom to which they are attached together form an optionally substituted C3-C 12a cycloalkyl group, and n is 1.

[0359] In certain embodiments, R5, R6, and the carbon atom to which they are attached together form a C3-C 12 cycloalkyl group, and n is 1.

[0360] In certain embodiments, R5 is selected from hydrogen, halogen, or a C1-C4 hydrocarbyl group.

[0361] In certain embodiments, R6 is selected from hydrogen, halogen, or a C1-C4 hydrocarbyl group.

[0362] In certain embodiments, n is 1 or 2.

[0363] In certain embodiments, R5 is selected from hydrogen, halogen, or a C1-C4 hydrocarbyl group, R6 is selected from hydrogen, halogen, or a C1-C4 hydrocarbyl group, and n is 1 or 2.

[0364] In certain embodiments, R5 is hydrogen.

[0365] In certain embodiments, R6 is hydrogen.

[0366] In certain embodiments, n is 1.

[0367] In certain embodiments, R5 is hydrogen, R6 is hydrogen, and n is 1.

[0368] In certain embodiments, the compounds of the present disclosure have immunoglobulin E (IgE) inhibitory activity.

[0369] In certain embodiments, the compounds of the present disclosure have low toxicity.

[0370] In certain embodiments, the compounds of the present disclosure have good safety.

[0371] In certain embodiments, the compounds of the present disclosure have good tolerance.

[0372] In another aspect, the present disclosure relates to the following compounds, their stereoisomers, or their pharmaceutically acceptable salts:

[0373] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0374] Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0375] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3,4-dimethoxyphenyl)propionate;

[0376] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3,4-diethoxyphenyl)propionate;

[0377] 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid;

[0378] Ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0379] (R)-Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0380] (S)-Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0381] (R)-Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0382] (S)-Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0383] Propyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0384] Isopropyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0385] Butyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0386] Methyl 3-(4-(2-chloroacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0387] Methyl 3-(4-(2-(dimethylamino)acetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0388] Methyl 3-(4-(dimethylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0389] Methyl 3-(4-(2-hydroxyacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0390] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-isopropoxyphenyl)propionate; Methyl 3-(4-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0391] Methyl 3-(4-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0392] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-cyclopentyloxyphenyl)propionate;

[0393] Methyl 3-(4-methyl-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0394] Methyl 3-(5-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0395] Methyl 3-(4,7-dichloro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0396] Methyl 3-(4-(N-methylacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0397] Methyl 3-(5-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0398] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-(benzyloxy)-4-methoxyphenyl)propionate;

[0399] Methyl 3-(4-(N-methyltert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0400] Methyl 3-(4-(methylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0401] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionate;

[0402] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionate;

[0403] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-propoxyphenyl)propionate;

[0404] Methyl 3-(4-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0405] Methyl 3-(4-acetoxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0406] Methyl 3-(4-amino-7-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0407] Methyl 3-(4-amino-5-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0408] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-hydroxy-4-methoxyphenyl)propionate;

[0409] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-(benzyloxy)phenyl)propionate;

[0410] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-hydroxyphenyl)propionate;

[0411] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-methoxy-4-(benzyloxy)phenyl)propionate;

[0412] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-methoxy-4-hydroxyphenyl)propionate;

[0413] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-phenylpropionate;

[0414] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-chlorophenyl)propionate;

[0415] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-ethoxyphenyl)propionate;

[0416] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-chlorophenyl)propionate;

[0417] Methyl 3-(4-(tert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0418] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)propionate;

[0419] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-(difluoromethoxy)-3-ethoxyphenyl)propionate;

[0420] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-(trifluoromethoxy)phenyl)propionate;

[0421] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-(difluoromethoxy)-4-methoxyphenyl)propionate;

[0422] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-methoxy-3-(trifluoromethoxy)phenyl)propionate;

[0423] (R)-Ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0424] (S)-Ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;

[0425] (R)-Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)propionate; and

[0426] (S)-Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)propionate;

[0427] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(benzo[d][1,3]dioxol-5-yl)propionate; and

[0428] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxepin-6-yl)propionate.

[0429] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient:

[0430]

[0431] wherein,

[0432] R1 is selected from one or more of the following same or different substituents: halogen, hydroxy, optionally substituted hydrocarbon group, optionally substituted amino group, optionally substituted hydrocarbon carbonylamino group, optionally substituted hydrocarbon carbonyloxy group, optionally substituted hydrocarbon oxycarbonylamino group, optionally substituted hydrocarbon carbonylamino group;

[0433] R2 is selected from optionally substituted hydrocarbon oxycarbonyl or carboxyl;

[0434] R3 is selected from hydrogen, halogen, hydroxy, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group;

[0435] R4 is selected from hydrogen, halogen, hydroxy, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group; and

[0436] X is -CR5R6-, where n is 0, 1, 2, 3 or 4 when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group; R6 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group; n is 1 when R5, R6 and the carbon atom to which they are attached together form a cycloalkyl group.

[0437] In another aspect, the present disclosure relates to a method for treating or preventing an immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE)-mediated disease, which comprises administering to an individual in need of said method a therapeutically effective amount of a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient:

[0438]

[0439] Among them,

[0440] R1 is selected from one or more of the following identical or different substituents: halogen, hydroxyl, optionally substituted hydrocarbon group, optionally substituted amino group, optionally substituted hydrocarbon carbonylamino group, optionally substituted hydrocarbon carbonyloxy group, optionally substituted hydrocarbon oxycarbonylamino group, optionally substituted hydrocarbon carbonylamino group;

[0441] R2 is selected from optionally substituted hydrocarbon oxycarbonyl or carboxyl;

[0442] R3 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group;

[0443] R4 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group; and

[0444] X is -CR5R6-, where n is 0, 1, 2, 3 or 4 when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group; and R6 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group; n is 1 when R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl group.

[0445] In certain embodiments, a method of treating or preventing an immunoglobulin E (IgE)-related, preferably IgE-mediated, disease comprises administering to an individual in need of said method from 1 mg to 10 g of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0446] In certain embodiments, a method of treating or preventing an immunoglobulin E (IgE)-related, preferably IgE-mediated, disease comprises administering to an individual in need of said method from 10 mg to 3000 mg of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0447] In certain embodiments, a method of treating or preventing an immunoglobulin E (IgE)-related, preferably IgE-mediated, disease comprises administering to an individual in need of said method from 100 mg to 1000 mg of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0448] In certain embodiments, a method of treating or preventing an immunoglobulin E (IgE)-related, preferably IgE-mediated disease, comprises administering to an individual in need of said method 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, or 1000 mg of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0449] In another aspect, the present disclosure relates to a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for treating or preventing an immunoglobulin E (IgE)-related, preferably IgE-mediated disease:

[0450]

[0451] wherein,

[0452] R1 is selected from one or more of the following same or different substituents: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbyloxycarbonyl, optionally substituted hydrocarbyloxycarbonylamino, optionally substituted hydrocarbylcarbonylamino;

[0453] R2 is selected from optionally substituted hydrocarbyloxycarbonyl or carboxy;

[0454] R3 is selected from hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted arylhydrocarbyloxy, or optionally substituted cycloalkyloxy;

[0455] R4 is selected from hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted arylhydrocarbyloxy, or optionally substituted cycloalkyloxy; and

[0456] X is -CR5R6-, where n is 0, 1, 2, 3, or 4 when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R6 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; n is 1 when R5, R6, and the carbon atom to which they are attached together form an optionally substituted cycloalkyl.

[0457] In yet another aspect, the present disclosure relates to a pharmaceutical composition for treating or preventing an immunoglobulin E (IgE)-related, preferably IgE-mediated disease, comprising a therapeutically effective amount of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient:

[0458]

[0459] Among them,

[0460] R1 is selected from one or more of the following same or different substituents: halogen, hydroxyl, optionally substituted hydrocarbon group, optionally substituted amino group, optionally substituted hydrocarbon carbonyl amino group, optionally substituted hydrocarbon carbonyloxy group, optionally substituted hydrocarbon oxycarbonyl amino group, optionally substituted hydrocarbon carbonyl amino group;

[0461] R2 is selected from optionally substituted hydrocarbon oxycarbonyl or carboxyl;

[0462] R3 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group;

[0463] R4 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group; and

[0464] X is -CR5R6-, where when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group; R6 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group, n is 0, 1, 2, 3 or 4; when R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl group, n is 1.

[0465] On the other hand, the present disclosure relates to a compound of general formula (II), its stereoisomer or its pharmaceutically acceptable salt for treating or preventing skin diseases, psoriasis, eczema, atopic dermatitis, urticaria, asthma, asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), allergic rhinitis, seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, pemphigoid and parasitic infections:

[0466]

[0467] Among them,

[0468] R1 is selected from one or more of the following same or different substituents: halogen, hydroxyl, optionally substituted hydrocarbon group, optionally substituted amino group, optionally substituted hydrocarbon carbonyl amino group, optionally substituted hydrocarbon carbonyloxy group, optionally substituted hydrocarbon oxycarbonyl amino group, optionally substituted hydrocarbon carbonyl amino group;

[0469] R2 is selected from optionally substituted hydrocarbon oxycarbonyl or carboxyl;

[0470] R3 is selected from hydrogen, halogen, hydroxyl, optionally substituted hydrocarbon oxy group, optionally substituted aryl hydrocarbon oxy group or optionally substituted cycloalkyl oxy group;

[0471] R4 is selected from hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted arylhydrocarbyloxy or optionally substituted cycloalkyloxy; and

[0472] X is -CR5R6-, where n is 0, 1, 2, 3 or 4 when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R6 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; n is 1 when R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl.

[0473] In another aspect, the present disclosure relates to a compound of general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for treating or preventing immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE)-mediated skin diseases, psoriasis, eczema, atopic dermatitis, urticaria, asthma, asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), allergic rhinitis, seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, pemphigoid and parasitic infections:

[0474]

[0475] wherein,

[0476] R1 is selected from one or more of the following same or different substituents: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbyloxycarbonyl, optionally substituted hydrocarbyloxycarbonylamino, optionally substituted hydrocarbylcarbonylamino;

[0477] R2 is selected from optionally substituted hydrocarbyloxycarbonyl or carboxy;

[0478] R3 is selected from hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted arylhydrocarbyloxy or optionally substituted cycloalkyloxy;

[0479] R4 is selected from hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted arylhydrocarbyloxy or optionally substituted cycloalkyloxy; and

[0480] X is -CR5R6-, where n is 0, 1, 2, 3 or 4 when R5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R6 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; n is 1 when R5, R6 and the carbon atom to which they are attached together form an optionally substituted cycloalkyl.

[0481] Pharmaceutical Compositions

[0482] In certain embodiments, the pharmaceutical composition comprises a compound of the present disclosure, its stereoisomers, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0483] In certain embodiments, when a compound of the present disclosure, its stereoisomers, or a pharmaceutically acceptable salt thereof is used for treating or preventing an immunoglobulin E (IgE)-related, preferably IgE-mediated disease in a mammal, the route of administration can be enteral or parenteral.

[0484] In certain embodiments, when a compound of the present disclosure, its stereoisomers, or a pharmaceutically acceptable salt thereof is used for treating or preventing an immunoglobulin E (IgE)-related, preferably IgE-mediated disease in a mammal, the route of administration can be an oral route.

[0485] In certain embodiments, when a compound of the present disclosure, its stereoisomers, or a pharmaceutically acceptable salt thereof is used for treating or preventing an immunoglobulin E (IgE)-related, preferably IgE-mediated disease in a mammal, the route of administration can be an intrarectal route.

[0486] The compounds described in the present disclosure can be obtained in any suitable form such as tablets, capsules, powders, oral solutions, suspensions, rectal gels, rectal foams, rectal enemas, or rectal suppositories, etc. Exemplary examples of the tablets include but are not limited to plain tablets, sugar-coated tablets, and film-coated tablets.

[0487] Examples of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present disclosure include but are not limited to any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, etc., which are recognized by the US Food and Drug Administration and can be used in humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition. Acceptable carriers or diluents for therapeutic use are well-known in the pharmaceutical field and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), the entire content of which is incorporated herein by reference.

[0488] The pharmaceutical compositions in the present disclosure can be administered by any method that achieves its intended purpose. For example, administration can be carried out by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, trans-tracheal, trans-ocular, subcutaneous, intraperitoneal, transdermal or buccal routes, etc. The administration route can be non-parenteral, oral and rectal routes. The dose administered will depend on the age, health status and weight of the recipient, and if there is concurrent treatment, also on the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.

[0489] Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees, semi-solid preparations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can be prepared by methods known in the art.

[0490] Particularly suitable for oral administration are plain tablets (uncoated tablets), sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, which can also be oil-based solutions or aqueous solutions, in addition to suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders. The products in the present disclosure can also be freeze-dried, and the resulting freeze-dried products are used, for example, in the preparation of injections. The formulations given can be sterilized and / or contain assistants, such as wetting agents, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for altering osmotic pressure, buffer substances, dyes, flavoring agents and / or numerous other active ingredients, such as one or more vitamins.

[0491] In certain embodiments, the pharmaceutical compositions in the present disclosure are prepared as tablets, solutions, granules, patches, ointments, capsules, aerosols or suppositories for parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral use.

[0492] Preservatives, stabilizers, dyes, sweeteners, fragrances, flavorings, etc. can be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid can be added as preservatives. Additionally, antioxidants and suspending agents can be used.

[0493] In different embodiments, alcohols, esters, sulfated aliphatic alcohols, etc. can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methylsilicate aluminate, synthetic aluminum silicate, calcium carbonate, calcium hydrogen carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, etc. can be used as excipients; magnesium stearate, talc, hardened oil, etc. can be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybeans can be used as suspending agents or lubricants; acetyl cellulose as a derivative of saccharides such as cellulose or sugar, or a methyl acetate-isobutyl acrylate copolymer as a derivative of polyethylene can be used as a suspending agent; and plasticizers such as phthalates can be used as suspending agents.

[0494] Suitable routes of administration can include, for example, oral administration, rectal administration, transdermal administration, parenteral delivery, topical administration or enteral administration; parenteral delivery includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection and intrathecal injection, direct intraventricular injection, intraperitoneal injection, intranasal injection or intraocular injection. The compounds can also be administered in extended and / or timed, pulsed fashion at a predetermined rate in sustained release or controlled release dosage forms including depot injections, osmotic pumps, pills, transdermal (including iontophoretic) patches, etc.

[0495] The pharmaceutical compositions in the present disclosure can be produced by known methods, for example, by conventional mixing, dissolving, granulating, making tablets, grinding, emulsifying, encapsulating, entrapping or tabletting and other operating methods.

[0496] Thus, according to the present disclosure, the pharmaceutical compositions used can be formulated by conventional methods using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the processing of the active compounds into pharmaceutically available formulations. Suitable formulations depend on the chosen route of administration. Any known techniques, carriers and excipients can be used as are suitable and understood in the art.

[0497] Injectable preparations can be prepared in the following conventional forms: as solutions or suspensions, solid dosage forms suitable for being made into solutions or suspensions before injection, or as emulsions. Suitable excipients are, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, etc. Additionally, if desired, the injectable pharmaceutical composition can contain a small amount of non-toxic adjuvants, such as wetting agents, pH buffers, etc. Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution or saline buffer. If desired, absorption enhancing formulations (such as liposomes) can be used.

[0498] For oral administration, the compounds can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier well known in the art. To enable oral ingestion by a patient to be treated, such carriers can render the compounds of the invention formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, pastes, suspensions, solutions, powders, etc. Pharmaceutical preparations for oral use can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture and processing the granular mixture, and, if desired, processing it with suitable adjuvants to obtain tablets or lozenge cores. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). Disintegrating agents can be added if desired, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or alginates such as sodium alginate. The lozenge cores are suitably coated. For this purpose, concentrated sugar solutions can be used which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, shellac solution and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablet or lozenge coatings in order to identify or characterize different combinations of the active compound doses. For this purpose, concentrated sugar solutions can be used which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, shellac solution, and suitable organic solvents or solvent mixtures.

[0499] Pharmaceutical preparations that can be used for oral administration include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient admixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate and, optionally, a stabilizer. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol. Additionally, a stabilizer can be added. All preparations for oral administration should be in a dosage suitable for such administration.

[0500] In certain embodiments, the pharmaceutical compositions of the present disclosure can contain from 0.1% to 95% of the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present disclosure.

[0501] In certain embodiments, the pharmaceutical compositions of the present disclosure can contain from 1% to 70% of the compounds, stereoisomers or pharmaceutically acceptable salts thereof of the present disclosure.

[0502] In any case, the composition or formulation to be administered will contain an amount of a compound, stereoisomer, or pharmaceutically acceptable salt thereof of the present disclosure that is effective to treat the disease / condition of the subject being treated.

[0503] Methods of Administration

[0504] At least one compound, stereoisomer, or pharmaceutically acceptable salt thereof of the present disclosure, or a pharmaceutical composition comprising at least one compound, stereoisomer, or pharmaceutically acceptable salt thereof of the present disclosure, can be administered to a patient by any method suitable for systemic and / or local delivery of the compound, stereoisomer, or pharmaceutically acceptable salt thereof of the present disclosure. Non-limiting examples of administration methods include (a) administration by the oral route, which includes administration in the form of capsules, tablets, granules, sprays, syrups, or other such forms; (b) administration by non-oral routes, such as rectal, vaginal, intraurethral, intraocular, intranasal, or intra-aural, which includes administration as an aqueous suspension, an oily preparation, etc., or in the form of drops, sprays, suppositories, ointments, creams, etc.; (c) administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, intrasternal injection, etc., including infusion pump delivery; (d) local administration, such as direct injection in the kidney area or heart area, for example, by depot implantation; and (e) topical administration; as is considered appropriate by those skilled in the art, the mode of administration is contact of the compound described in the present disclosure with living tissue.

[0505] The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining the method of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, appropriate pharmaceutical excipients, and other matters related to delivering the compound, stereoisomer, or pharmaceutically acceptable salt thereof to a subject in need.

[0506] Pharmaceutical compositions suitable for administration include those containing an effective amount of the active ingredient to achieve its intended effect. The dosage required for a therapeutically effective amount of the pharmaceutical compositions described in the present disclosure depends on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal under consideration. The dosage can be adjusted to achieve the desired effect, but this will depend on the following factors: body weight, diet, concurrent drug therapy, and other factors recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to the amount of the compound that is effective to prevent, alleviate, or improve the symptoms of a disease, or to extend the lifespan of the individual being treated. Those skilled in the art can well determine a therapeutically effective amount, especially in accordance with the detailed disclosure provided in the present disclosure.

[0507] As will be apparent to those skilled in the art, variations in the dosage and the specific mode of administration for in vivo administration will depend on the age, weight and species of the mammal being treated, the specific compound being used, and the particular use for which these compounds are used. Those skilled in the art can achieve the purpose of determining the effective dose level, that is, the dose level necessary to achieve the desired effect, by using conventional pharmacological methods. Generally, the human clinical application of the product is started at a lower dose level and increased as the dose level is increased until the desired effect is achieved. Alternatively, using established pharmacological methods, acceptable in vitro studies can be used to establish the effective dose and route of administration of the compositions identified by this method.

[0508] In non-human animal studies, the application of the potential product is started at a higher dose level and decreased as the dose is decreased until the desired effect is no longer achieved or the adverse side effects disappear. Depending on the desired effect and the treatment indication, the dose range can be relatively broad. Generally, the dose can be from about 10 μg / kg body weight to 1000 mg / kg body weight, and in some embodiments from about 100 μg / kg body weight to 300 mg / kg body weight. Alternatively, as will be understood by those skilled in the art, the dose can be based on and calculated according to the patient's body surface area.

[0509] Each physician can select the exact formulation, route of administration and dose of the pharmaceutical composition described in the present disclosure according to the condition of the patient. Generally, the dose range of the composition administered to the patient can be from about 0.5 mg / kg to 1000 mg / kg of the patient's body weight. Depending on the patient's needs, the dose can be administered either once alone or two or more times during one day or several days. Where the human dose of the compound has been established for at least some conditions, the present disclosure will use those same doses, or dose ranges from about 0.1% to 500% of the established human dose, and in some embodiments dose ranges from 25% to 250% of the established human dose. In the case where no established human dose exists, as in the case of newly discovered pharmaceutical compounds, the appropriate human dose can be inferred from the median effective dose or median infective dose values, or other suitable values from in vitro or in vivo studies, as quantified in toxicity and efficacy studies in animals.

[0510] It should be noted that due to toxicity and organ dysfunction, the attending physician will know how and when to terminate, interrupt, or adjust the administration of the drug. Conversely, if the clinical response is inadequate (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The size of the administered dose in the treatment of the disorder of interest will vary with the severity of the disease state to be treated and the route of administration. For example, the severity of the disease state can be evaluated in part by standard prognostic assessment methods. In addition, the dose and possible dosing frequency will also vary according to the age, weight, and response of the individual patient. A protocol equivalent to the above-discussed protocol can be used in veterinary medicine.

[0511] Although the exact dose can be determined based on a drug-by-drug analysis, in most cases, certain generalizations can be made about the pharmaceutical agent. The daily dosing protocol for adult patients is, for example, an oral dose of 0.1 mg to 2000 mg of each active ingredient, in certain embodiments 1 mg to 2000 mg of each active ingredient, for example 5 mg to 1500 mg of each active ingredient. In other embodiments, the intravenous, subcutaneous, or intramuscular dose of each active ingredient used is 0.01 mg to 1000 mg, in certain embodiments 0.1 mg to 1000 mg, for example 1 mg to 800 mg. When a pharmaceutically acceptable salt of the drug is given, the dose can be calculated as the free base. In certain embodiments, the composition is administered 1 to 4 times a day. Alternatively, the composition described in the present disclosure can be administered by continuous intravenous infusion, in certain embodiments at a dose of up to 2000 mg of each active ingredient per day. As will be understood by those skilled in the art, in certain situations, in order to effectively and rapidly treat a rapidly developing disease or infection, it is necessary to administer the compounds described in the present disclosure in an amount that exceeds or far exceeds the above dose range. In certain embodiments, the compound is administered during a continuous treatment period, such as for one week or several weeks, or several months or years.

[0512] The dose and dosing interval can be adjusted individually to provide a plasma level of the active moiety sufficient to maintain the adjusted effect or the minimum effective concentration (MEC). The MEC of each compound is different, but the MEC can be evaluated from in vitro data. The dose required to reach the MEC depends on individual characteristics and the route of administration. However, HPLC (high performance liquid chromatography) assays or bioassays can be used to determine the plasma concentration.

[0513] The dosing interval can also be determined using the MEC value. The composition should be administered using a treatment protocol that maintains the plasma level above the MEC for 10 - 90% of the time, in certain embodiments for 30 - 90% of the time, and in certain embodiments for 50 - 90% of the time.

[0514] In the case of topical administration or selective absorption, the effective local concentration of the drug is independent of the plasma concentration.

[0515] Of course, the amount of the administered composition depends on the individual to be treated, on the weight of the individual, the severity of the affliction, the mode of administration, and the judgment of the prescribing physician.

[0516] The efficacy and toxicity of the compounds described in the present disclosure can be evaluated using known methods. For example, the toxicology of a particular compound or a subset of such compounds sharing certain chemical moieties can be established by determining the toxicity of a cell line in vitro, such as a mammalian cell line and in certain embodiments a human cell line. The results of such studies can generally predict toxicity in animals such as mammals, or more specifically, in humans. Alternatively, the toxicity of a particular compound can be determined in an animal model such as a mouse, rat, rabbit, or monkey using known methods. The efficacy of a particular compound can be determined using several well-recognized methods, such as in vitro methods, animal models, or human clinical trials. There are generally recognized in vitro models for almost every class of disease state, including but not limited to cancer, cardiovascular disease, and various immunological dysfunctions. Similarly, acceptable animal models can be used to determine the efficacy of pharmaceutical agents for treating these disease states. When selecting a model to determine efficacy, one of ordinary skill in the art can select an appropriate model, dose, route of administration, and treatment regimen under the guidance of the prior art in the field. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0517] If desired, the composition can be placed in a package or dispensing device that can contain one or more unit dosage forms containing the active ingredient. The package can include, for example, a metal or plastic foil, such as a blister pack. The package or dispensing device can bear a label for administration. The package or dispensing device can also bear a notice associated with the container that is prescribed by a governmental agency that regulates the manufacture, use, or sale of the medicament, which notice reflects that the form of the medicament has been approved by the agency for administration to humans or animals. Such notice can be, for example, the label approved by the State Food and Drug Administration or the United States Food and Drug Administration for prescription drugs, or the approved product insert. The composition comprising a compound, stereoisomer, or pharmaceutically acceptable salt thereof of the present disclosure formulated in a compatible pharmaceutical carrier can also be prepared in a suitable container and labeled for the treatment of a designated disease state.

[0518] In another aspect, the present disclosure relates to a method for preparing a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which comprises:

[0519] (1) React the compound of general formula (B-I) with malonic acid and ammonium acetate to obtain the compound of general formula (B-II).

[0520]

[0521] Among them, the groups represented by R 3 ” and R 4 ” in the general formula (B-I) and the general formula (B-II) have the same definitions as R3 and R4 in the general formula (II).

[0522] (2) React the compound of general formula (B-II) with an alcohol to carry out an esterification reaction to obtain the compound of general formula (B-III).

[0523]

[0524] Among them, the groups represented by R 3” and R 4 ” in the general formula (B-II) and the general formula (B-III) have the same definitions as R3 and R4 in the general formula (II), and R 2’ is selected from hydrogen or a hydrocarbon group.

[0525] (3) React the compound of general formula (B-IV) with the compound of general formula (B-III) to obtain the compound of general formula (II).

[0526]

[0527] Among them, the groups represented by R 1 ” and R 3 ” and R 4 ” in the formula (B-III) and the general formula (B-IV) have the same definitions as R1, R3, and R4 in the general formula (II), and R 2’ is selected from hydrogen or a hydrocarbon group.

[0528] Among them, X is -CR5R6-, where R5 is hydrogen, R6 is hydrogen, and n is 1.

[0529] In certain embodiments, the method of reacting the compound of general formula (B-I) with malonic acid and ammonium acetate to obtain the compound of general formula (B-II) is carried out in an organic solvent.

[0530] In certain embodiments, exemplary examples of suitable organic solvents that can be used in the present disclosure for reacting the compound of general formula (B-I) with malonic acid and ammonium acetate to obtain the compound of general formula (B-II) include, but are not limited to, methanol, ethanol, isopropanol, and water.

[0531] In certain embodiments, the compound of formula (B-I) is reacted with malonic acid and ammonium acetate at about 50 °C to about 130 °C to obtain the compound of formula (B-II).

[0532] In certain embodiments, exemplary examples of suitable esterifying agents that can be used to prepare the compound of formula (B-III) from the compound of formula (B-II) include, but are not limited to, thionyl chloride, oxalyl chloride, HCl gas, and acetyl chloride.

[0533] In certain embodiments, the method of reacting the compound of formula (B-II) with an alcohol compound to obtain the compound of formula (B-III) is carried out in an organic solvent.

[0534] In certain embodiments, exemplary examples of suitable organic solvents that can be used in the present disclosure for reacting the compound of formula (B-II) with an alcohol compound to obtain the compound of formula (B-III) include, but are not limited to, alcohols, tetrahydrofuran, dichloromethane, ethyl acetate, and methyl tert-butyl ether.

[0535] In certain embodiments, exemplary examples of suitable alcohols that can be used in the present disclosure for reacting the compound of formula (B-II) with an alcohol compound to obtain the compound of formula (B-III) include, but are not limited to, methanol, ethanol, and isopropanol, etc.

[0536] In certain embodiments, the compound of formula (B-II) is reacted with an alcohol compound at about -20 °C to about 30 °C to obtain the compound of formula (B-III).

[0537] In certain embodiments, a catalyst is added in the method of reacting the compound of formula (B-IV) with the compound of formula (B-III) to obtain the compound of formula (II).

[0538] In certain embodiments, exemplary examples of suitable catalysts that can be used in the present disclosure for reacting the compound of formula (B-IV) with the compound of formula (B-III) to obtain the compound of formula (II) include, but are not limited to, sodium acetate, potassium acetate, sodium carbonate, and potassium carbonate.

[0539] In certain embodiments, the method of reacting the compound of formula (B-IV) with the compound of formula (B-III) to obtain the compound of formula (II) is carried out in an organic solvent.

[0540] In certain embodiments, exemplary examples of suitable organic solvents that can be used in the present disclosure for reacting the compound of formula (B-IV) with the compound of formula (B-III) to obtain the compound of formula (II) include, but are not limited to, acetic acid, formic acid, dimethylformamide, and dimethylacetamide.

[0541] In some embodiments, the compound of general formula (B-IV) is reacted with the compound of general formula (B-III) at about 50 °C to about 180 °C to obtain the compound of general formula (II).

[0542] Hereinafter, the present disclosure will be explained in detail by the following examples to better understand various aspects and advantages of the present application. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present application.

[0543] Examples

[0544] Abbreviations:

[0545] DMF: N,N-dimethylformamide

[0546] DCM: Dichloromethane

[0547] THF: Tetrahydrofuran

[0548] PE: Petroleum ether

[0549] EA: Ethyl acetate

[0550] AcOH: Acetic acid

[0551] DMAP: 4-Dimethylaminopyridine

[0552] CDCl3: Deuterochloroform

[0553] HPLC: High performance liquid chromatography

[0554] TLC: Thin layer chromatography

[0555] Example 1

[0556] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0557] 3-Nitrophthalic acid (10.0 g), palladium on carbon (1.0 g, Pd content 10%) and tetrahydrofuran (200 mL) were added to a reaction flask. The air was displaced with a hydrogen balloon three times, and the reaction was stirred at room temperature for 16 hours. HPLC monitoring showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure with a water pump to obtain a crude product. The crude product was purified by trituration with dichloromethane to obtain a yellow solid, 3-aminophthalic acid (4.0 g, HPLC purity 81.88%); yield 47%. MS (m / e): 182.24 (M+H + )

[0558] 3-Aminophthalic acid (1.0 g) and acetic anhydride (2.5 mL) were added to a reaction flask and heated to 105 °C for reaction for 2 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature and filtered under reduced pressure to collect the filter cake. The filter cake was slurried and purified with diethyl ether, filtered under reduced pressure, and the filter cake collected was the yellow solid N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (0.67 g, HPLC purity 98.94%); the yield was 59%.

[0559] 3-Ethoxy-4-methoxybenzaldehyde (200 g), ammonium acetate (171 g) and malonic acid (150 g) were added to a reaction flask, ethanol (1235 mL) and water (65 mL) were added, and the system was heated to reflux (internal temperature 80 °C) with stirring. The reaction was stirred at the reflux temperature for 16 h, and a large amount of solid precipitated. HPLC showed that the reaction was complete. The reaction solution was filtered under reduced pressure to collect the filter cake. The filter cake was slurried and purified with ethyl acetate, filtered to collect the filter cake, and dried in a vacuum drying oven (40 °C) to obtain the white solid 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (168 g, HPLC purity 80.48%); the yield was 65.5%. MS (m / e): 240.12 (M+H + )

[0560] 3-Amino-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (83 g) was added to a reaction flask, methanol (581 mL) was added, the system was cooled to 0 °C, and thionyl chloride (53.65 g) was slowly added dropwise with stirring. After the addition was complete, the temperature was slowly raised to room temperature and the reaction was stirred overnight. HPLC monitoring showed that the reaction was complete. The reaction solution was added to methyl tert-butyl ether (2.9 L), stirred at room temperature overnight, and the large amount of solid precipitated was filtered under reduced pressure to collect the filter cake, which was dried in a vacuum drying oven (45 °C) to obtain the white solid methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanoate hydrochloride (86 g, HPLC purity 99.36%); the yield was 87%. MS (m / e): 254.13 (M+H + )

[0561] Methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (50.73 g), N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (30 g), sodium acetate (24 g) and AcOH (300 mL) were added to a reaction flask, heated to 140 °C in an oil bath, and stirred for 6 hours. HPLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure with a water pump to obtain a crude product. DCM and water were added to the crude product, dissolved and extracted, and the organic phase was collected and washed twice with saturated brine; the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure with a water pump. The resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1 to 1:1) to obtain the title compound (41.3 g, HPLC purity 99.24%); the yield was 64.1%.

[0562] 1 HNMR(CDCl3,400MHz)δ9.519(bs,1H),8.750-8.729(d,1H),7.651-7.612(dd,1H),7.476-7.456(dd,1H),7.081-7.054(m,2H),6.832-6.810(d,1H),5.734-5.695(q,1H),4.130-4.078(q,2H),3.840(s,3H),3.812-3.745(q,1H),3.648(s,3H),3.217-3.162(q,1H),2.258(s,3H),1.475-1.440(t,3H). MS(m / e): 441.16(M+H + )。

[0563] Example 2

[0564] Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0565] Using the synthesis method in Example 1, methyl 3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitro-1,3-dioxoisoindolin-2-yl)propionate (16.2 g, HPLC purity 95.15%) was prepared by reacting methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride with 3-nitrophthalic anhydride; the yield was 75%. MS(m / e): 429.12(M+H + )。

[0566] Methyl 3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitro-1,3-dioxoisoindolin-2-yl)propionate (6.0 g), palladium on carbon (3.0 g, 10% palladium content), and tetrahydrofuran (200 mL) were added to a reaction flask. The air was displaced with a hydrogen balloon three times, and the reaction was stirred at room temperature for 16 hours. TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure with a water pump to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent PE:EA = 3:1) to obtain the yellow title compound (3.87 g, HPLC purity 96.49%); the yield was 74.1%. MS (m / e): 399.15 (M+H + )

[0567] Example 3

[0568] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3,4-dimethoxyphenyl)propionate

[0569] 3-Hydroxy-4-methoxybenzaldehyde (5.0 g) and potassium carbonate (4.56 g) were added to a reaction flask and dissolved in DMF, and then methyl iodide (3.1 mL) was added. The reaction was transferred to an oil bath and stirred at 65 °C for 15 hours. HPLC showed that the reaction was complete. The reaction solution was diluted with ethyl acetate, then washed and separated with saturated brine, and the organic phase was collected and dried over anhydrous magnesium sulfate. It was concentrated to dryness at 40 °C with a water pump to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent PE:EA = 8:1) to obtain a colorless oily product (3,4-dimethoxybenzaldehyde) (4.95 g, HPLC purity 99.94%); the yield was 90%.

[0570] Using the synthesis method in Example 1, 3-amino-3-(3,4-dimethoxyphenyl)propionic acid (4.28 g, HPLC purity 98.54%) was prepared from 3,4-dimethoxybenzaldehyde (4.9 g); the yield was 79%. MS (m / e): 226.10 (M+H + )

[0571] Using the synthesis method in Example 1, methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (4.4 g, HPLC purity 99.89%) was prepared from 3-amino-3-(3,4-dimethoxyphenyl)propionic acid (4.28 g); the yield was 96.7%. MS (m / e): 240.12 (M+H + )

[0572] Using the synthesis method in Example 1, the title compound (0.68 g, HPLC purity 96.49%) was prepared by reacting methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (1.16 g) with N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (1.0 g); the yield was 32.6%. MS (m / e): 427.14 (M+H + )

[0573] Example 4

[0574] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3,4-diethoxyphenyl)propionate

[0575] Using the synthesis method in Example 3, an oily product of the compound (3,4-diethoxybenzaldehyde) (3.48 g, HPLC purity 98.99%) was prepared by reacting 3-ethoxy-4-hydroxybenzaldehyde (3.0 g) with iodoethane; the yield was 99.3%.

[0576] Using the synthesis method in Example 3, 3-amino-3-(3,4-diethoxyphenyl)propionic acid (4.0 g, HPLC purity 97.68%) was prepared by reacting 3,4-diethoxybenzaldehyde (3.48 g); the yield was 88.1%. MS (m / e): 254.13 (M+H + )

[0577] Using the synthesis method in Example 1, methyl 3-amino-3-(3,4-diethoxyphenyl)propionate hydrochloride (2.9 g, HPLC purity 99.26%) was prepared by reacting 3-amino-3-(3,4-diethoxyphenyl)propionic acid (4.0 g); the yield was 60.9%. MS (m / e): 268.15 (M+H + )

[0578] Using the synthesis method in Example 1, the title compound (0.38 g, HPLC purity 98.79%) was prepared by reacting methyl 3-amino-3-(3,4-diethoxyphenyl)propionate hydrochloride (1.48 g) with N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (1.0 g); the yield was 17.2%. MS (m / e): 455.17 (M+H + )

[0579] Example 5

[0580] 3-(4-Acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid

[0581] Using the synthesis method in Example 1, the title compound (2.73 g, HPLC purity 98.81%) was prepared by reacting 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionic acid (2.1 g) with N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (2.05 g); the yield was 76.7%. MS (m / e): 425.14 (M-H - )。

[0582] Example 6

[0583] Ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0584] 3-(4-Acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid (0.3 g), 6-chloro-1-hydroxybenzotriazole (0.18 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.2 g) were added to a reaction flask, DCM (4 mL) was added, and after stirring to dissolve clearly at room temperature, ethanol (0.25 mL) was added, and the mixture was stirred overnight at room temperature. HPLC showed that the reaction was complete, and the reaction was quenched with water; the reaction solution was concentrated under reduced pressure with a water pump, and the obtained crude product was purified by silica gel column chromatography (the eluent was DCM:EA = 30:1 to 20:1) to obtain the light yellow title compound (0.17 g, HPLC purity 99.65%); the yield was 54.4%. MS (m / e): 477.28 (M+Na + )。

[0585] Example 7

[0586] (R)-Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0587] Methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (5.0 g) was dissolved in water (100 mL), and the pH was adjusted to 9 with saturated sodium carbonate aqueous solution, and the aqueous phase was extracted with DCM (50 mL × 4); the organic phases were combined, washed once with saturated sodium chloride aqueous solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with a water pump to obtain the oily product methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate (4.4 g, directly used in the next step reaction); the yield was 100%.

[0588] Methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate (14.0 g) and N-(tert-butoxycarbonyl)-L-leucine monohydrate (7.15 g) were added to a reaction flask, and methyl tert-butyl ether (490 mL) was added. The system was heated to 35 °C and stirred for 1 hour; then it was slowly cooled to room temperature and stirred overnight. A large amount of white solid precipitated. The reaction solution was filtered under reduced pressure. The filter cake was washed once with methyl tert-butyl ether (30 mL), and the filter cake was collected and air-dried to obtain the white solid product methyl (R)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate N-(tert-butoxycarbonyl)-L-leucinate (11 g, optical purity 98.64%); the yield was 41.1%.

[0589] Methyl (R)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate N-(tert-butoxycarbonyl)-L-leucinate (12.1 g) was dissolved in water (100 mL), and the pH was adjusted to 9 with saturated sodium carbonate aqueous solution. The aqueous phase was extracted with ethyl acetate (50 mL × 4); the organic phases were combined, washed once with saturated sodium chloride aqueous solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure with a water pump (35 °C) to obtain the oily product methyl (R)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate (5.62 g, the measured specific rotation was [α] D 20 = -14.5° (C = 0.02, EtOH), and it was directly used for the next reaction); the yield was 100%.

[0590] Using the synthesis method in Example 1, methyl (R)-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitro-1,3-dioxoisoindolin-2-yl)propionate (5.28 g, HPLC purity 98.62%) was prepared by reacting methyl (R)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate (4.9 g) with 3-nitrophthalic anhydride (4.48 g); the yield was 63.7%. MS (m / e): 429.12 (M+H + ).

[0591] Using the synthesis method in Example 2, the title compound (3.2 g, HPLC purity 97.26%, optical purity 99.05%) was prepared from methyl (R)-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitro-1,3-dioxoisoindolin-2-yl)propionate (5.06 g), and the measured specific rotation was [α] D 20 = +12.55° (C = 0.02, acetonitrile); the yield was 69%. MS (m / e): 399.15 (M+H + ).

[0592] Example 8

[0593] (S)-Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0594] Using the synthesis method in Example 7, methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate (14.0 g) and N-(tert-butoxycarbonyl)-D-leucine monohydrate (7.15 g) were reacted to obtain methyl (S)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate N-(tert-butoxycarbonyl)-D-leucinate (10 g, HPLC purity 98.83%, optical purity 99.15%); the yield was 37.3%.

[0595] Using the synthesis method in Example 7, an oily product, methyl (S)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate (5.3 g, determined by polarimetry as [α] D 20 = +14.1° (C = 0.02, ethanol), was obtained by reacting methyl (S)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate N-(tert-butoxycarbonyl)-D-leucinate (10 g) and was directly used for the next reaction).

[0596] Using the synthesis method in Example 1, methyl (S)-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitro-1,3-dioxoisoindolin-2-yl)propionate (3.84 g, HPLC purity 98.13%) was obtained by reacting methyl (S)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate (3.92 g) and 3-nitrophthalic anhydride (3.1 g); the yield was 58%. MS (m / e): 429.12 (M+H + ).

[0597] Using the synthesis method in Example 2, the title compound (1.92 g, HPLC purity 99.32%, optical purity 99.25%) was obtained by reacting methyl (S)-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitro-1,3-dioxoisoindolin-2-yl)propionate (2.63 g); determined by polarimetry as [α] D 20 = -11.93° (C = 0.02, acetonitrile); the yield was 48%. MS (m / e): 399.15 (M+H + ).

[0598] Example 9

[0599] Methyl (R)-3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0600] Using the synthesis method in Example 1, the title compound (12.0 g, HPLC purity 99.40%, optical purity 99.60%) was prepared by reacting methyl (R)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate (10.44 g) with N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (8.5 g). The optical rotation was measured as [α] D 20 = +11.2° (C = 0.02, acetonitrile); the yield was 66.1%.

[0601] 1 HNMR (CDCl3, 400 MHz) δ 9.519 (bs, 1H), 8.750 - 8.729 (d, 1H), 7.651 - 7.612 (dd, 1H), 7.476 - 7.456 (dd, 1H), 7.081 - 7.054 (m, 2H), 6.832 - 6.810 (d, 1H), 5.734 - 5.695 (q, 1H), 4.130 - 4.078 (q, 2H), 3.840 (s, 3H), 3.812 - 3.745 (q, 1H), 3.648 (s, 3H), 3.217 - 3.162 (q, 1H), 2.258 (s, 3H), 1.475 - 1.440 (t, 3H). MS (m / e): 441.16 (M+H + )

[0602] Example 10

[0603] Methyl (S)-3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0604] Using the synthesis method in Example 1, the title compound (6.6 g, HPLC purity 98.83%, optical purity 99.73%) was prepared by reacting methyl (S)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate with N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (4.1 g). The optical rotation was measured as [α] D 20 = -11.6° (C = 0.02, ACN); the yield was 76.1%.

[0605] 1HNMR(CDCl3, 400 MHz) δ 9.519 (bs, 1H), 8.750 - 8.729 (d, 1H), 7.651 - 7.612 (dd, 1H), 7.476 - 7.456 (dd, 1H), 7.081 - 7.054 (m, 2H), 6.832 - 6.810 (d, 1H), 5.734 - 5.695 (q, 1H), 4.130 - 4.078 (q, 2H), 3.840 (s, 3H), 3.812 - 3.745 (q, 1H), 3.648 (s, 3H), 3.217 - 3.162 (q, 1H), 2.258 (s, 3H), 1.475 - 1.440 (t, 3H). MS (m / e): 441.16 (M + H + ).

[0606] Example 11

[0607] Propyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0608] Using the synthesis method in Example 6, the title compound (0.12 g, HPLC purity 99.32%) was prepared by reacting 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid (0.3 g) with n-propanol; yield 36%. MS (m / e): 491.17 (M + Na + ).

[0609] Example 12

[0610] Isopropyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0611] Using the synthesis method in Example 6, the title compound (0.14 g, HPLC purity 98.93%) was prepared by reacting 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid (0.3 g) with isopropanol; yield 42%. MS (m / e): 491.16 (M + Na + ).

[0612] Example 13

[0613] Butyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0614] Using the synthesis method in Example 6, the title compound (0.22 g, HPLC purity 99.46%) was prepared by reacting 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (0.3 g) with n-butanol; the yield was 61%. MS (m / e): 505.20 (M+Na + )

[0615] Example 14

[0616] Methyl 3-(4-(2-chloroacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0617] Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (700 mg), chloroacetyl chloride (218 mg), potassium carbonate (486 mg) and DCM (12 mL) were added to a reaction flask, and the reaction was stirred at room temperature overnight. HPLC showed that the reaction was complete. Water (30 mL) and DCM (50 mL) were added to the reaction solution, and extraction and liquid separation were performed. The aqueous phase was back-extracted with DCM (2×50 mL), and the DCM layers were combined. The combined organic layer was washed with saturated NaCl aqueous solution, separated, dried over anhydrous MgSO4, filtered, and concentrated to obtain the crude product of methyl 3-(4-(2-chloroacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate. The obtained crude product was purified by silica gel column chromatography (eluent: PE:EA = 10:1 to 4:1) to obtain the pure product of the title compound (220 mg, HPLC purity 99.78%); the yield was 26%. MS (m / e): 497.19 (M+Na + )

[0618] Example 15

[0619] Methyl 3-(4-(2-(dimethylamino)acetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0620] Methyl 3-(4-(2-chloroacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (200 mg), dimethylamine hydrochloride (52 mg), potassium carbonate (116 mg) and acetone (10 mL) were added to a reaction flask, and the mixture was stirred at room temperature for 50 h. HPLC showed that the reaction was complete. Water (40 mL) and EA (40 mL) were added to the reaction solution, and extraction and liquid separation were carried out. The aqueous phase was back-extracted with EA (30 mL), the organic phases were combined, washed with saturated NaCl aqueous solution, separated, dried over anhydrous MgSO4, filtered, and concentrated to obtain the crude product of methyl 3-(4-(2-(dimethylamino)acetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate. The obtained crude product was purified by silica gel column chromatography (eluent: DCM:MeOH = 200:1) to obtain the pure product of the title compound (100 mg, HPLC purity 96.44%); the yield was 49%. MS (m / e): 484.27 (M+H + ).

[0621] Example 16

[0622] Methyl 3-(4-(dimethylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0623] Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (500 mg), aqueous formaldehyde solution (9 mL), Pd / C (50 mg, Pd content 10%) and methanol (20 mL) were added to a reaction flask. The air was displaced with a hydrogen balloon three times, and the mixture was stirred at room temperature for 100 h. TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure with a water pump to obtain the crude product of methyl 3-(4-(dimethylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 4:1) to obtain the pure product of the title compound (176 mg, HPLC purity 96.67%); the yield was 32.9%. MS (m / e): 427.18 (M+H + ).

[0624] Example 17

[0625] Methyl 3-(4-(2-hydroxyacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0626] 2-(Benzyloxy)acetic acid (318 mg) and DCM (10 mL) were added to a reaction flask. Thionyl chloride (0.27 mL) was added under stirring at room temperature, and then DMF (1 mL) was added. The reaction was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure successively with a water pump and an oil pump to obtain an oily product, 2-(benzyloxy)acetyl chloride (347 mg), which was directly used in the next step reaction.

[0627] 2-(Benzyloxy)acetyl chloride (347 mg), methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (500 mg), potassium carbonate (191 mg) and DCM (10 mL) were added to a reaction flask. The reaction was stirred at room temperature for 18 hours. HPLC showed that the reaction was complete. Water (40 mL) and DCM (100 mL) were added to the reaction solution, and extraction and liquid separation were carried out. The aqueous phase was back-extracted with DCM (2×30 mL), and the DCM layers were combined. Then it was washed with saturated NaCl aqueous solution, separated, dried over anhydrous MgSO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent PE:EA = 4:1) to obtain methyl 3-(4-(2-(benzyloxy)acetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (234 mg, HPLC purity 95.88%); the yield was 34.2%. MS (m / e): 569.21 (M+Na + )

[0628] Methyl 3-(4-(2-(benzyloxy)acetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (234 mg), Pd / C (24 mg, Pd content 10%), methanol (17 mL) and EA (7 mL) were added to a reaction flask. The air was displaced with a hydrogen balloon three times, and the reaction was stirred at room temperature for 40 hours. HPLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure with a water pump to obtain the crude product of methyl 3-(4-(2-hydroxyacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate. The crude product was purified by silica gel column chromatography (eluent PE:EA = 2:1) to obtain the title compound (89 mg, HPLC purity 98.70%); the yield was 45.6%. MS (m / e): 479.17 (M+Na + )

[0629] Example 18

[0630] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-isopropoxyphenyl)propionate

[0631] Using the synthesis method in Example 3, 3-ethoxy-4-isopropoxybenzaldehyde (2.8 g, HPLC purity 98.56%) was prepared by reacting 3-ethoxy-4-hydroxybenzaldehyde (3.0 g) with isopropyl bromide; the yield was 76%.

[0632] Using the synthesis method in Example 1, 3-amino-3-(3-ethoxy-4-isopropoxyphenyl)propionic acid (2.7 g, HPLC purity 99.43%) was prepared by reacting 3-ethoxy-4-isopropoxybenzaldehyde (2.8 g); the yield was 74%. MS (m / e): 268.15 (M+H + )

[0633] Using the synthesis method in Example 1, methyl 3-amino-3-(3-ethoxy-4-isopropoxyphenyl)propionate hydrochloride (2.4 g, HPLC purity 98.69%) was prepared by reacting 3-amino-3-(3-ethoxy-4-isopropoxyphenyl)propionic acid (2.7 g); the yield was 75%. MS (m / e): 282.16 (M+H + )

[0634] Using the synthesis method in Example 1, the title compound (237 mg, HPLC purity 97.30%) was prepared by reacting methyl 3-amino-3-(3-ethoxy-4-isopropoxyphenyl)propionate hydrochloride (1.5 g) and N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (1.0 g); the yield was 10.4%. MS (m / e): 491.20 (M+Na + )

[0635] Example 19

[0636] Methyl 3-(4-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0637] Using the synthesis method in Example 1, the title compound (546 mg, HPLC purity 99.85%) was prepared by reacting 3-fluorophthalic anhydride (275 mg) and methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (526 mg); the yield was 82%. MS (m / e): 424.16 (M+Na + )

[0638] Example 20

[0639] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-cyclopentyloxyphenyl)propionate

[0640] Using the synthesis method in Example 3, 3-ethoxy-4-cyclopentyloxybenzaldehyde (4.2 g, HPLC purity 96.97%) was prepared by reacting 3-ethoxy-4-hydroxybenzaldehyde (3.0 g) with bromocyclopentane; the yield was 99%.

[0641] Using the synthesis method in Example 1, 3-amino-3-(3-ethoxy-4-cyclopentyloxyphenyl)propanoic acid (2.78 g, HPLC purity 99.60%) was prepared by reacting 3-ethoxy-4-cyclopentyloxybenzaldehyde (4.2 g); the yield was 52.9%. MS (m / e): 294.16 (M+H + )

[0642] Using the synthesis method in Example 1, methyl 3-amino-3-(3-ethoxy-4-cyclopentyloxyphenyl)propanoate hydrochloride (3.25 g, HPLC purity 99.60%) was prepared by reacting 3-amino-3-(3-ethoxy-4-cyclopentyloxyphenyl)propanoic acid (2.78 g); the yield was 100%. MS (m / e): 308.18 (M+H + )

[0643] Using the synthesis method in Example 1, the title compound (606 mg, HPLC purity 94.97%) was prepared by reacting methyl 3-amino-3-(3-ethoxy-4-cyclopentyloxyphenyl)propanoate hydrochloride (1.8 g) with N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (1.0 g); the yield was 25.1%. MS (m / e): 517.23 (M+Na + )

[0644] Example 21

[0645] Methyl 3-(4-methyl-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoate

[0646] Using the synthesis method in Example 1, the title compound (609 mg, HPLC purity 99.58%) was prepared by reacting 3-methylphthalic anhydride (330 mg) with methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanoate hydrochloride (648 mg); the yield was 75%. MS (m / e): 420.16 (M+Na + )

[0647] Example 22

[0648] Methyl 3-(5-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoate

[0649] Using the synthesis method in Example 1, the title compound (350 mg, HPLC purity 98.02%) was prepared by reacting 4-fluorophthalic anhydride (271 mg) with methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (526 mg); the yield was 53%. MS (m / e): 424.14 (M+Na + ).

[0650] Example 23

[0651] Methyl 3-(4,7-dichloro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0652] Using the synthesis method in Example 1, the title compound (100 mg, HPLC purity 99.20%) was prepared by reacting 3,6-dichlorophthalic anhydride (500 mg) with methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (666 mg); the yield was 7.2%.

[0653] 1 HNMR (CDCl3, 400 MHz) δ 7.530 - 7.527 (d, 2H), 7.123 - 7.092 (m, 2H), 6.825 - 6.804 (d, 1H), 5.767 - 5.728 (q, 1H), 4.133 - 4.081 (q, 2H), 3.840 (s, 3H), 3.816 - 3.774 (q, 1H), 3.651 (s, 3H), 3.237 - 3.181 (q, 1H), 1.478 - 1.443 (t, 3H). MS (m / e): 474.12 (M+Na + ).

[0654] Example 24

[0655] Methyl 3-(4-(N-methylacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0656] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (505 mg), methyl iodide (177 mg) and potassium carbonate (314 mg) were added to a reaction flask, and DMF (5 mL) was added. The system was stirred at room temperature for 100 h, and HPLC showed that the reaction was complete. Water (30 mL) and DCM (200 mL) were added to the reaction solution, and the mixture was extracted and separated. The organic phase was collected and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel column chromatography (eluent: PE:EA = 20:1 to 1:1) to obtain the title compound (410 mg, HPLC purity 98.12%); the yield was 79.5%. MS (m / e): 477.25 (M+Na + )。

[0657] Example 25

[0658] Methyl 3-(5-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0659] 4-Nitrophthalic acid (1.5 g) and acetic anhydride (15 mL) were added to a reaction flask, and the mixture was stirred at 125 °C for 2 h. The reaction solution was concentrated under reduced pressure successively with a water pump and an oil pump to obtain 4-nitrophthalic anhydride (1.4 g), which was directly used in the next step of the reaction.

[0660] Using the synthesis method in Example 1, 3-(3-ethoxy-4-methoxyphenyl)-3-(5-nitro-1,3-dioxoisoindolin-2-yl)propionate (2.2 g, HPLC purity 97.65%) was prepared by reacting 4-nitrophthalic anhydride (1.4 g) with methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (1.58 g); the yield was 94%. MS (m / e): 429.12 (M+H + )。

[0661] Using the synthesis method in Example 2, methyl 3-(3-ethoxy-4-methoxyphenyl)-3-(5-amino-1,3-dioxoisoindolin-2-yl)propionate (500 mg, HPLC purity 98.25%) was prepared by reacting methyl 3-(3-ethoxy-4-methoxyphenyl)-3-(5-nitro-1,3-dioxoisoindolin-2-yl)propionate (678 mg); the yield was 79.2%. MS (m / e): 421.25 (M+Na + )。

[0662] Methyl 3-(3-ethoxy-4-methoxyphenyl)-3-(5-amino-1,3-dioxoisoindolin-2-yl)propionate (250 mg), acetic anhydride (83 mg), triethylamine (190 mg), DMAP (8 mg), and DCM (2.5 mL) were added to a reaction flask and stirred at room temperature overnight. The reaction was monitored by HPLC and found to be complete. One drop of water was added to quench the reaction, and the reaction mixture was concentrated under reduced pressure using a water pump to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 1:1) to give the title compound (170 mg, HPLC purity 98.39%); yield 61.6%. MS (m / e): 463.22 (M+Na + ).

[0663] Example 26

[0664] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-(benzyloxy)-4-methoxyphenyl)propionate

[0665] Using the synthetic method in Example 3, substituting bromobenzene for methyl iodide, the title compound (806 mg, HPLC purity 99.46%) was prepared from 3-hydroxy-4-methoxybenzaldehyde (5.0 g); MS (m / e): 525.14 (M+Na + ).

[0666] Example 27

[0667] Methyl 3-(4-(N-methyltert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0668] Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (500 mg), Boc2O (958 mg), and DMAP (31 mg) were added to a reaction flask, THF (15 mL) was added, and the reaction was stirred at room temperature overnight. TLC showed that the raw materials had completely reacted. The reaction mixture was concentrated under reduced pressure using a water pump to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 15:1 to 5:1) to give methyl 3-(4-(di-tert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (634 mg, HPLC purity 98.28%); yield 84.4%. MS (m / e): 599.25 (M+H + ).

[0669] Dissolve methyl 3-(4-(bis(tert-butoxycarbonyl)amino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (634 mg) in DCM (200 mL), add trifluoroacetic acid (1 mL), stir the reaction at room temperature for 15 minutes, and TLC shows that the reaction is complete. Add saturated NaHCO3 (30 mL) to the reaction solution to quench the reaction, and stir for 10 minutes; separate the layers with a separatory funnel, dry the organic phase over anhydrous MgSO4, filter, and collect the filtrate. Concentrate it under reduced pressure with a water pump and then an oil pump to obtain the crude product. Purify the crude product by silica gel column chromatography (the eluent is PE:EA = 15:1 to 5:1) to obtain methyl 3-(4-(tert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (354 mg, HPLC purity 99.41%); the yield is 67%.

[0670] Add methyl 3-(4-(tert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (300 mg), methyl iodide (171 mg), and potassium carbonate (250 mg) to a reaction flask, add DMF (6 mL), stir the reaction at room temperature overnight, and HPLC shows that the reaction is complete. Dilute the reaction solution with EA (250 mL), first wash the organic phase with water (40 mL); then wash the organic phase with saturated NaCl aqueous solution (30 mL × 4), dry the organic phase over anhydrous MgSO4, filter, and concentrate it under reduced pressure with a water pump and then an oil pump to obtain the title compound (201 mg, HPLC purity 95.54%); the yield is 65.3%. MS (m / e): 513.22 (M+H + )。

[0671] Example 28

[0672] Methyl 3-(4-(methylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0673] Dissolve methyl 3-(4-(N-methyltert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (201 mg) in DCM (2 mL), add trifluoroacetic acid (2 mL), stir the reaction at room temperature for 2 hours, and TLC shows that the reaction is complete. Concentrate the reaction solution under reduced pressure with a water pump to obtain the crude product. Purify the crude product by silica gel column chromatography (the eluent is PE:EA = 10:1 to 5:1) to obtain the title compound (120 mg, HPLC purity 99.95%); the yield is 74%. MS (m / e): 435.14 (M+Na + )。

[0674] Example 29

[0675] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionate

[0676] Using the synthesis method in Example 3, the title compound (886 mg, HPLC purity 98.496%) was prepared from 3-hydroxy-4-methoxybenzaldehyde (5.0 g) and n-propyl bromide; MS (m / e): 477.14 (M+Na + )

[0677] Example 30

[0678] 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)

[0679] Methyl propionate

[0680] Using the synthesis method in Example 3, the title compound (1.086 g, HPLC purity 98.51%) was prepared from 3-hydroxy-4-methoxybenzaldehyde (5.0 g) and cyclopentyl bromide

[0681] 1 HNMR (CDCl3, 400 MHz) δ9.537 (bs, 1H), 8.751 - 8.730 (d, 1H), 7.655 - 7.616 (t, 1H), 7.483 - 7.464 (d, 1H), 7.089 - 7.084 (d, 1H), 7.054 - 7.028 (q, 1H), 6.818 - 6.797 (d, 1H), 5.732 - 5.693 (q, 1H), 4.794 - 4.764 (m, 1H), 3.813 (s, 3H), 3.824 - 3.756 (q, 1H), 3.651 (s, 3H), 3.210 - 3.155 (q, 1H), 2.261 (s, 3H), 1.979 - 1.799 (m, 6H), 1.616 - 1.593 (m, 2H). MS (m / e): 503.17 (M+Na + )

[0682] Example 31

[0683] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-propoxyphenyl)propionate

[0684] Using the synthesis method in Example 3, the title compound (227 mg, HPLC purity 96.34%) was prepared from 3-ethoxy-4-hydroxybenzaldehyde)(3.0 g) and n-propyl bromide

[0685] 1 HNMR(CDCl3, 400 MHz) δ 9.529 (bs, 1H), 8.750 - 8.729 (d, 1H), 7.652 - 7.613 (t, 1H), 7.476 - 7.457 (d, 1H), 7.065 - 7.031 (m, 2H), 6.831 - 6.810 (d, 1H), 5.725 - 5.686 (q, 1H), 4.111 - 4.058 (q, 2H), 3.952 - 3.919 (t, 2H), 3.823 - 3.755 (q, 1H), 3.647 (s, 3H), 3.202 - 3.147 (q, 1H), 2.261 (s, 3H), 1.846 - 1.793 (m, 2H), 1.447 - 1.412 (t, 3H), 1.029 - 0.992 (t, 3H). MS (m / e): 491.21 (M + Na + )。

[0686] Example 32

[0687] Methyl 3-(4-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0688] Prepared by reacting 3-hydroxyphthalic anhydride (300 mg) with methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (580 mg) using the synthetic method in Example 1 to obtain the title compound (340 mg, HPLC purity 97.97%); yield 46%. MS (m / e): 422.16 (M + Na + )。

[0689] Example 33

[0690] Methyl 3-(4-acetoxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0691] Methyl 3-(4-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (300 mg), acetyl chloride (177 mg), triethylamine (228 mg) and DCM (5 mL) were added to a reaction flask, and the reaction was stirred overnight at room temperature. HPLC showed that the reaction was complete. 1N hydrochloric acid aqueous solution (30 mL) and DCM (100 mL) were added to the reaction solution for extraction and liquid separation. The organic phase was washed with saturated NaCl aqueous solution, separated, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The obtained crude product was purified by silica gel column chromatography (eluent: PE:EA = 10:1 to 2:1) to obtain the title compound (179 mg, HPLC purity 97.95%); the yield was 53.9%. MS (m / e): 464.14 (M+Na + )。

[0692] Example 34

[0693] Methyl 3-(4-amino-7-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0694] Dimethyl 3-(tert-butoxycarbonylamino)-6-hydroxyphthalate (2.0 g), methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (3.56 g) and pyridine (40 mL) were added to a reaction flask, and the mixture was heated to 100 °C in an oil bath and stirred for 38 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure with a water pump to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 5:1) to obtain methyl 3-(4-(tert-butoxycarbonylamino)-7-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (2.149 g, HPLC purity 99.22%); the yield was 67.9%. MS (m / e): 515.20 (M+H + )。

[0695] Methyl 3-(3-ethoxy-4-methoxyphenyl)-3-(4-(tert-butoxycarbonylamino)-7-hydroxy-1,3-dioxoisoindolin-2-yl)propionate (2.148 g) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (6 mL) was added, and the reaction was stirred at room temperature for 6 hours. TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure with a water pump to obtain the crude product, and the crude product was purified by pulping with PE / DCM = 1:1 (10 mL) to obtain the title compound (1.28 g, HPLC purity 99.36%); the yield was 74%. MS (m / e): 437.21 (M+Na + )。

[0696] Example 35

[0697] Methyl 3-(4-amino-5-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0698] Dimethyl 4-hydroxyphthalate (125 g) and concentrated H2SO4 (600 mL) were added to a reaction flask, and the temperature was lowered to 0 °C with stirring. Fuming HNO3 (39.44 g) was slowly added dropwise to the system, and the temperature of the system was controlled to be less than 5 °C. The addition was completed in about 1 hour. The ice bath was removed, and the temperature was raised to room temperature. The reaction was stirred for 22 hours, and HPLC showed that the reaction was complete. The reaction solution was slowly poured into ice water (1.4 kg) to quench the reaction, and the aqueous phase was extracted with EA (600 mL × 5). The organic phases were combined, dried over anhydrous MgSO4 (25 g), filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure using a water pump and then an oil pump to obtain a crude product of dimethyl 4-hydroxy-3-nitrophthalate (169 g, HPLC purity 36.54%), which was directly used in the next step. MS (m / e): 254.07 (M-H - )

[0699] Dimethyl 4-hydroxy-3-nitrophthalate (164 g), benzyl bromide (135.9 g), potassium carbonate (400 g), and acetone (1730 mL) were added to a reaction flask, and the mixture was heated to 70 °C in an oil bath and stirred for 23 hours. TLC confirmed that the reaction was complete. The reaction system was cooled to room temperature, and the reaction solution was filtered under reduced pressure. The filter cake was washed with DCM (2000 mL), and the filtrate was collected. The filtrate was concentrated under reduced pressure, DCM (2000 mL) and saturated NaCl aqueous solution (1000 mL) were added to the concentrate for extraction and separation, and the organic phase was dried over anhydrous MgSO4 (100 g), filtered, and concentrated under reduced pressure using a water pump to obtain a crude yellow solid. The crude product was purified by recrystallization from EA to obtain a white solid product, dimethyl 4-benzyloxy-3-nitrophthalate (40 g, HPLC purity 96.96%); the yield was 18.1%. MS (m / e): 346.14 (M+H + )

[0700] Dimethyl 4-benzyloxy-3-nitrophthalate (1.335 g) and EtOH (14 mL) were added to a reaction flask, and the pre-prepared aqueous NaOH solution (1.089 g of NaOH dissolved in 7 mL of water) was added to the reaction flask. The mixture was heated to 70 °C in an oil bath and stirred for 7 hours. The reaction was confirmed to be complete by TLC. The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure with a water pump until most of the EtOH was distilled off. At room temperature, the concentrate was acidified with 4 mol / L aqueous HCl to pH = 2, and a large amount of white solid precipitated. The mixture was filtered under reduced pressure, and the filter cake was collected and dried under reduced pressure with an oil pump to obtain the white solid product 4-benzyloxy-3-nitrophthalic acid (1.089 g, HPLC purity 99.72%); the yield was 88.8%. MS (m / e): 316.15 (M-H - ).

[0701] 4-Benzyloxy-3-nitrophthalic acid (1.089 g) and acetic anhydride (11 mL) were added to a reaction flask and heated to 140 °C in an oil bath and stirred for 6 hours. The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure with a water pump to obtain 1.02 g of the crude product of 4-benzyloxy-3-nitrophthalic anhydride, which was directly used in the next step of the reaction.

[0702] Using the synthesis method in Example 1, 3-(4-nitro-5-benzyloxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl) propionic acid methyl ester (1.48 g, HPLC purity 97.92%) was prepared by reacting 4-benzyloxy-3-nitrophthalic anhydride (1.02 g) with methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl) propionate hydrochloride (1.09 g); the yield was 78.1%. MS (m / e): 557.21 (M+Na + ).

[0703] Using the synthesis method in Example 2, the title compound (950 mg, HPLC purity 98.45%) was prepared from 3-(4-nitro-5-benzyloxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl) propionic acid methyl ester (1.48 g); the yield was 82.8%. MS (m / e): 437.10 (M+Na + ).

[0704] Example 36

[0705] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-hydroxy-4-methoxyphenyl) propionate

[0706] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-(benzyloxy)-4-methoxyphenyl)propionate (200 mg), Pd / C (57 mg, 10% Pd content), and THF (10 mL) were added to a reaction flask. The air was displaced with a hydrogen balloon three times, and the reaction was stirred at room temperature for 16 hours. TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure with a water pump to obtain a crude product; the obtained crude product was purified by silica gel column chromatography (eluent: PE:EA = 5:1 to 1:1) to obtain the title compound (116 mg, HPLC purity 99.81%); the yield was 70.7%. MS (m / e): 435.13 (M+Na + ).

[0707] Example 37

[0708] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-(benzyloxy)phenyl)propionate

[0709] Using the synthetic method in Example 3, with benzyl bromide instead of methyl iodide, the title compound (881 mg, HPLC purity 97.54%) was prepared from 3-ethoxy-4-hydroxybenzaldehyde (3.0 g); MS (m / e): 539.21 (M+Na + ).

[0710] Example 38

[0711] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-hydroxyphenyl)propionate

[0712] Using the synthetic method in Example 36, the title compound (600 mg, HPLC purity 97.25%) was prepared from methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-(benzyloxy)phenyl)propionate (765 mg); the yield was 95%. MS (m / e): 449.18 (M+Na + ).

[0713] Example 39

[0714] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-methoxy-4-(benzyloxy)phenyl)propionate

[0715] Using the synthetic method in Example 3, with benzyl bromide instead of methyl iodide, the title compound (1.615 g, HPLC purity 96.81%) was prepared from 3-methoxy-4-hydroxybenzaldehyde (3.0 g); MS (m / e): 525.18 (M+Na + ).

[0716] Example 40

[0717] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-methoxy-4-hydroxyphenyl)propionate

[0718] Using the synthesis method in Example 36, the title compound (856 mg, HPLC purity 98.37%) was prepared by reacting methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-methoxy-4-(benzyloxy)phenyl)propionate (1.468 g); MS (m / e): 435.15 (M+Na + )

[0719] Example 41

[0720] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-phenylpropionate

[0721] Using the synthesis method in Example 1, the title compound (1.46 g, HPLC purity 98.71%) was prepared by reacting benzaldehyde (3.0 g); MS (m / e): 389.13 (M+Na + )

[0722] Example 42

[0723] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-chlorophenyl)propionate

[0724] Using the synthesis method in Example 1, the title compound (263 mg, HPLC purity 98.54%) was prepared by reacting 3-chlorobenzaldehyde (500 mg); MS (m / e): 423.14 (M+Na + )

[0725] Example 43

[0726] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-ethoxyphenyl)propionate

[0727] Using the synthesis method in Example 1, the title compound (0.86 g, HPLC purity 97.83%) was prepared by reacting 4-ethoxybenzaldehyde (1.9 g); MS (m / e): 411.15 (M+H + )

[0728] Example 44

[0729] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-chlorophenyl)propionate

[0730] Using the synthesis method in Example 1, the title compound (260 mg, HPLC purity 98.78%) was prepared by reacting 4-chlorobenzaldehyde (500 mg); MS (m / e): 423.14 (M+Na + )

[0731] Example 45

[0732] Methyl 3-(4-(tert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0733] Methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (500 mg), Boc2O (958 mg) and DMAP (31 mg) were added to a reaction flask, THF (15 mL) was added, and the reaction was stirred at room temperature overnight. TLC showed that the raw materials had completely reacted. The reaction solution was concentrated under reduced pressure with a water pump to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 15:1 to 5:1) to obtain methyl 3-(4-(di-tert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (634 mg, HPLC purity 98.28%); yield 84.4%. MS (m / e): 599.25 (M+H + )

[0734] Methyl 3-(4-(di-tert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate (634 mg) was dissolved in DCM (200 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 15 minutes. TLC showed that the reaction was complete. Saturated NaHCO3 (30 mL) was added to the reaction solution to quench the reaction, and it was stirred for 10 minutes; the layers were separated with a separatory funnel, the organic phase was dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure with a water pump and then an oil pump to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 15:1 to 5:1) to obtain the title compound (354 mg, HPLC purity 99.41%); yield 67%. MS (m / e): 499.20 (M+H + )

[0735] Example 46

[0736] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)propionate

[0737] Using the synthesis method in Example 3, the title compound (403 mg, HPLC purity 96.38%) was prepared by reacting 3-hydroxy-4-methoxybenzaldehyde (5.0 g) with isopropyl bromide; MS (m / e): 477.15 (M+Na + ).

[0738] Example 47

[0739] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-(difluoromethoxy)-3-ethoxyphenyl)propionate

[0740] Using the synthesis method in Example 3, the title compound (158 mg, HPLC purity 95.36%) was prepared by reacting 3-ethoxy-4-hydroxybenzaldehyde (5.0 g) with difluoroiodomethane; MS (m / e): 477.14 (M+H + ).

[0741] Example 48

[0742] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-(trifluoromethoxy)phenyl)propionate

[0743] Using the synthesis method in Example 3, the title compound (105 mg, HPLC purity 95.18%) was prepared by reacting 3-ethoxy-4-hydroxybenzaldehyde (5.0 g) with trifluoroiodomethane; MS (m / e): 495.13 (M+H + ).

[0744] Example 49

[0745] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-(difluoromethoxy)-4-methoxyphenyl)propionate

[0746] Using the synthesis method in Example 3, the title compound (109 mg, HPLC purity 96.37%) was prepared by reacting 3-hydroxy-4-methoxybenzaldehyde (5.0 g) with difluoroiodomethane; MS (m / e): 463.12 (M+H + ).

[0747] Example 50

[0748] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-methoxy-3-(trifluoromethoxy)phenyl)propionate

[0749] Using the synthesis method in Example 3, the title compound (116 mg, HPLC purity 96.11%) was prepared by reacting 3-hydroxy-4-methoxybenzaldehyde (5.0 g) with trifluoroiodomethane; MS (m / e): 481.11 (M+H + ).

[0750] Example 51

[0751] (R)-Ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0752] Methyl (R)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (3.0 g) was added to a reaction flask, dissolved in tetrahydrofuran (30 mL), and an aqueous sodium hydroxide solution (2.5 g of sodium hydroxide, 30 mL of water) prepared at room temperature was added. The reaction was stirred at room temperature for 3 hours, and TLC was used to detect the completion of the hydrolysis reaction. The reaction solution was cooled to 0 °C, adjusted to pH = 1-2 with concentrated hydrochloric acid (12N, 5.25 mL), and the reaction solution was concentrated under reduced pressure. The concentrate was azeotroped with acetonitrile (25 mL) twice to remove water, and the crude product (R)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (6.5 g, HPLC purity 98.66%) was obtained. The yield was calculated as 100% and was directly used in the next step of the reaction.

[0753] Using the synthesis method in Example 1, (R)-ethyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride was prepared by reacting (R)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (6.5 g) with ethanol (25 mL). A white solid product (3.15 g, HPLC purity 94.51%, directly used in the next step of the reaction) was obtained.

[0754] Using the synthesis method in Example 1, the title compound (2.227 g, HPLC purity 97.75%, optical purity 100%) was prepared by reacting (R)-ethyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (3.15 g) with N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide (1.8 g); the yield was 56.7%. MS (m / e): 477.18 (M+Na + ).

[0755] Example 52

[0756] (S)-Ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate

[0757] Using the synthesis method in Example 51, the title compound (1.62 g, HPLC purity 94.39%) was prepared by reacting methyl (S)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (3.0 g); MS (m / e): 477.20 (M+Na + ).

[0758] Example 53

[0759] (R)-Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)propionate

[0760] Using the synthesis method in Example 7, the title compound (1.86 g, HPLC purity 96.96%, optical purity 99.03%) was prepared by reacting methyl 3-amino-3-(3-isopropoxy-4-methoxyphenyl)propionate hydrochloride (6.0 g); MS (m / e): 477.18 (M+Na + ).

[0761] Example 54

[0762] (S)-Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)propionate

[0763] Using the synthesis method in Example 8, the title compound (1.62 g, HPLC purity 96.44%, optical purity 97.82%) was prepared by reacting methyl 3-amino-3-(3-isopropoxy-4-methoxyphenyl)propionate hydrochloride (6.0 g); MS (m / e): 477.18 (M+Na + ).

[0764] Example 55

[0765] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(benzo[d][1,3]dioxol-5-yl)propionate

[0766] Using the synthesis method in Example 1, the title compound (207 mg, HPLC purity 96.32%) was prepared by reacting benzo[d][1,3]dioxole-5-carbaldehyde (prepared according to the method reported in RSC Advances, 2015, 5(91), 74425 - 74437) (450 mg); MS (m / e): 411.14 (M+H + ).

[0767] Example 56

[0768] Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propionate

[0769] Using the synthesis method in Example 1, the title compound (235 mg, HPLC purity 97.58%) was prepared by reacting 2,3-dihydrobenzo[b][1,4]dioxin-6-carbaldehyde (prepared according to the method reported in Journal of Medicinal Chemistry, 2007, 50(17), 4122 - 4134) (492 mg); MS (m / e): 425.18 (M+H + ).

[0770] Biological Examples

[0771] Biological Example 1

[0772] Pharmacodynamic evaluation experiment of DNCB-induced atopic dermatitis model in Balb / c mice

[0773] 1.1 Test method

[0774] 1.1.1 Grouping

[0775] Sixty healthy male SPF-grade Balb / c mice, weighing 19 - 21 g, were randomly divided into 6 groups according to body weight, with 10 mice in each group.

[0776] Table 1. Grouping table

[0777]

[0778]

[0779] Note: DNCB is dinitrochlorobenzene; BID means administered twice a day.

[0780] 1.1.2 Hair removal

[0781] Before the experiment, the hair around the right ear of the mice needs to be removed to reduce the interference of the drug attached to the hair on the experiment.

[0782] 1.1.3 Model establishment and drug administration

[0783] The start of the experiment was recorded as the 1st day. The drug administration plan and induction plan for each group are shown in Figure 1 . The specific ear thickness measurement time was slightly adjusted compared with Figure 1 . After the end of the 18th day of the experiment, blood was taken from each animal to detect the concentration of immunoglobulin (IgE) in the serum (according to the kit instructions). The ears of the animals were cut off, and ear pieces of equal area were punched at the fixed position of the ear with an 8 mm punch and weighed to calculate the difference in ear swelling degree.

[0784] 1.2 Evaluation Indexes and Statistical Methods

[0785] One-Way Anova in SPSS 17 was used to statistically analyze and compare the changes in ear thickness of mice among multiple groups, the ear weight under the same area on the 18th day, and the IgE concentration in serum. The G test method was used to delete outliers, and p < 0.05 indicated statistical differences.

[0786] Ear swelling degree (mg) = Right ear weight (mg) - Left ear weight (mg);

[0787] Change in ear thickness (mm) = Right ear thickness (mm) - Left ear thickness (mm);

[0788] Ear swelling degree inhibition rate (%) = 1 - (Ear swelling degree of the drug administration group - Ear swelling degree of the blank control group) / (Ear swelling degree of the model control group - Ear swelling degree of the blank control group) × 100%;

[0789] Change in ear thickness inhibition rate (%) = 1 - (Change in ear thickness of the drug administration group - Change in ear thickness of the blank control group) / (Change in ear thickness of the model control group - Change in ear thickness of the blank control group) × 100%;

[0790] IgE inhibition rate (%) = 1 - (IgE concentration of the drug administration group - IgE concentration of the blank control group) / (IgE concentration of the model control group - IgE concentration of the blank control group) × 100%.

[0791] 1.3 Experimental Results

[0792] Table 2. Changes in body weight of animals in each group, unit: g, Mean±S.D.

[0793] Group Day 1 Day 10 Day 17 Day 18 Blank Control Group 21.1±0.9 22.3±0.9 23.0±0.7 23.9±0.7 Model Control Group 20.8±0.7 21.9±1.1 22.1±1.1 22.3±1.3 Example 10 20.6±0.8 22.3±1.1 21.8±1.3 22.4±1.3 Example 1 21.0±0.8 22.4±0.8 21.9±1.1 22.0±1.3 Example 3 20.6±0.8 22.3±1.4 22.1±1.8 21.7±1.8 Example 11 20.3±1.3 21.6±1.1 21.2±1.2 21.1±1.3

[0794] Table 3. Changes in ear thickness of each group, unit: mm, Mean±S.D.

[0795] Group Day 1 Day 10 Day 17 Day 18 Blank Control Group 0.21±0.01 0.23±0.02 0.22±0.02 0.21±0.01 Model Control Group 0.21±0.01 0.50±0.22 0.74±0.22 0.77±0.12 Example 10 0.21±0.01 0.35±0.07 0.46±0.10 0.44±0.07 Example 1 0.22±0.02 0.47±0.02 0.60±0.08 0.64±0.07 Example 3 0.21±0.01 0.38±0.10 0.58±0.09 0.58±0.10 Example 11 0.22±0.01 0.33±0.09 0.35±0.04 0.48±0.06

[0796] Table 4. Comparison of ear indexes of animals in each group

[0797]

[0798]

[0799] Note: Compared with the blank control group, *P < 0.05, ***P < 0.001;

[0800] Compared with the model control group, #P < 0.05, ##P < 0.01, P < 0.001;

[0801] Biological Example 2

[0802] Pharmacodynamic Evaluation Experiment of DNCB-Induced Atopic Dermatitis Model in Balb / c Mice

[0803] 2.1 Test Methods

[0804] 2.1.1 Grouping

[0805] Seventy healthy male SPF-grade Balb / c mice, weighing 19 - 21 g, were randomly divided into 7 groups according to body weight, with 10 mice in each group.

[0806] Table 5 Grouping Table

[0807]

[0808]

[0809] 2.1.2 Hair Shaving

[0810] Before the experiment, the hair around the right ear of the mice needs to be removed to reduce the interference of the drug attached to the hair on the experiment.

[0811] 2.1.3 Model Establishment and Drug Administration

[0812] The start of the experiment was recorded as day 1. The drug administration regimens and induction regimens for each group are shown in Figure 2 . After the experiment ended on day 18, blood was collected from each animal to detect the concentration of immunoglobulin (IgE) in the serum (performed according to the kit instructions). The ears of the animals were cut off, and ear pieces of equal area were punched with an 8 mm puncher at the fixed position of the ear and weighed to calculate the difference in ear swelling degree.

[0813] 2.2 Evaluation Indexes and Statistical Methods

[0814] One-Way Anova in SPSS 17 was used to perform statistical analysis and comparison of the IgE concentration in the serum on day 18 among multiple groups. The G test method was used to delete outliers, and p < 0.05 indicated statistical significance.

[0815] Ear swelling degree (mg) = Right ear weight (mg) - Left ear weight (mg);

[0816] Ear swelling degree inhibition rate (%) = 1 - (Ear swelling degree of the drug administration group - Ear swelling degree of the blank control group) / (Ear swelling degree of the model control group - Ear swelling degree of the blank control group) × 100%;

[0817] IgE inhibition rate (%) = 1 - (IgE concentration of the drug administration group - IgE concentration of the blank control group) / (IgE concentration of the model control group - IgE concentration of the blank control group) × 100%.

[0818] 2.3 Experimental Results

[0819] Table 6. Body weight changes of animals in each group, unit: g, Mean±S.D.

[0820] Time / Group Day 1 Day 10 Day 17 Day 18 Blank Control Group 22.0±0.8 22.7±1.0 24.3±1.4 24.5±1.4 Model Control Group 21.8±0.4 22.4±0.7 23.0±0.9 22.8±0.8 Example 46 21.6±0.7 22.6±0.6 23.0±0.7 23.1±0.7 Example 51 21.8±0.7 22.8±1.2 23.1±1.1 22.9±1.3 Example 52 21.8±0.5 22.6±0.9 24.3±5.6 24.2±6.0 Example 6 21.4±0.7 22.8±1.4 23.3±1.4 22.7±1.5 Example 54 21.6±0.6 22.6±0.8 23.3±1.2 23.1±1.2

[0821] Table 7. Comparison of ear indexes of animals in each group

[0822]

[0823] Note: Compared with the blank control group, **P<0.01, ***P<0.001;

[0824] Compared with the model control group, #P<0.05, ##P<0.01;

[0825] Biological Example 3

[0826] Pharmacodynamic evaluation experiment of DNCB-induced atopic dermatitis model in Balb / c mice

[0827] 3.1 Test method

[0828] 3.1.1 Grouping

[0829] Take 30 healthy male SPF-grade Balb / c mice, weighing 19-21 g, and randomly divide them into 3 groups according to body weight, with 10 mice in each group.

[0830] Table 8. Grouping table

[0831]

[0832]

[0833] 3.1.2 Hair shaving

[0834] Before the experiment, the hair around the right ear of the mice needs to be removed to reduce the interference of the drug attached to the hair on the experiment.

[0835] 3.1.3 Modeling and drug administration

[0836] The start of the experiment is recorded as the 1st day. The drug administration plan and induction plan for each group are shown in Figure 3 . The specific measurement times of ear thickness and body weight are Figure 3 Slightly adjusted. After the end of the 19th day of the experiment, blood was taken from each animal to detect the concentration of immunoglobulin (IgE) in the serum (according to the kit instructions). The ears of the animals were cut off, and ear pieces of equal area were punched at the fixed position of the ear with an 8 mm punch and weighed to calculate the difference in ear swelling degree.

[0837] 3.2 Evaluation indexes and statistical methods

[0838] One-Way Anova in SPSS 17 was used to statistically analyze and compare the changes in mouse ear thickness, ear weight under the same area on the 19th day, and IgE concentration in serum among multiple groups. The G-test method was used to delete outliers, and a statistical difference was indicated by p < 0.05.

[0839] Ear swelling degree (mg) = right ear weight (mg) - left ear weight (mg);

[0840] Ear thickness change (mm) = right ear thickness (mm) - left ear thickness (mm);

[0841] Ear swelling degree inhibition rate (%) = 1 - (ear swelling degree of the drug-administered group - ear swelling degree of the blank control group) / (ear swelling degree of the model control group - ear swelling degree of the blank control group) × 100%;

[0842] Ear thickness change inhibition rate (%) = 1 - (ear thickness change of the drug-administered group - ear thickness change of the blank control group) / (ear thickness change of the model control group - ear thickness change of the blank control group) × 100%;

[0843] IgE inhibition rate (%) = 1 - (IgE concentration of the drug-administered group - IgE concentration of the blank control group) / (IgE concentration of the model control group - IgE concentration of the blank control group) × 100%.

[0844] 3.3 Experimental results

[0845] Table 9. Changes in body weight of animals in each group, unit: g, Mean ± S.D.

[0846] Group Day 1 Day 8 Day 12 Day 14 Day 16 Day 19 Blank Control Group 20.4±0.7 21.5±1.0 22.0±1.2 22.1±1.3 22.3±1.3 22.8±1.3 Model Control Group 20.2±0.7 21.7±0.7 22.1±0.8 22.0±0.8 21.9±0.7 22.7±0.6 Example 10 20.5±0.7 21.8±0.9 21.9±0.8 22.2±0.8 22.0±0.8 22.3±0.9

[0847] Table 10. Ear thickness changes in each group, unit: mm, Mean ± S.D.

[0848] Group Day 1 Day 10 Day 17 Day 19 Blank Control Group 0.24±0.01 0.25±0.01 0.25±0.01 0.27±0.02 Model Control Group 0.26±0.01 0.54±0.12 0.76±0.16 0.77±0.14 Example 10 0.26±0.01 0.52±0.11 0.65±0.09 0.63±0.05

[0849] Table 11. Comparison of ear indicators of animals in each group

[0850]

[0851]

[0852] Note: Compared with the blank control group, **P < 0.01, ***P < 0.001.

[0853] Biological Example 4

[0854] Experiment on inhibiting phorbol ester (TPA)-induced mouse ear swelling

[0855] 4.1 Test method

[0856] 4.1.1 Grouping

[0857] Forty male ICR mice were selected and divided into 5 groups, with 8 mice in each group.

[0858] Table 12. Information table of grouping and model establishment

[0859]

[0860] Note: a. Preparation method of 125 μg / mL TPA: 40 μL of 2 mg / mL TPA stock solution (dissolved in DMSO) + 600 μL of acetone were mixed evenly for use, and it was prepared freshly before use;

[0861] b. The mixing ratio of acetone and DMSO was 15:1 (v / v).

[0862] 4.1.2 Hair removal

[0863] Before the experiment, the animals were grouped, and the hair around the right ear of the mice was removed.

[0864] 4.1.3 Model establishment and drug administration

[0865] Each group of experimental animals was smeared with 20 μL of their respective drugs on the right ear (the model control group was given the blank solvent), and modeling induction was carried out 1 hour and 10 minutes later. Except for the blank group, the animals were given 20 μL of TPA with a concentration of 125 μg / mL on the right ear for induction; 10 minutes after the induction, each group of experimental animals was smeared with 20 μL of their respective drugs on the right ear for the second time (the model control group was given the blank solvent).

[0866] Table 13. Information table of grouping and drug administration

[0867]

[0868] Note: The administration volume of 40 μL means a total of 40 μL for 2 administrations.

[0869] 4.1.4 Result observation

[0870] At 5 hours after modeling, ear pieces of the same part on both ears of each group of animals were taken with a puncher, weighed, and the ear swelling degree, ear swelling rate, and inhibition rate were calculated.

[0871] 4.2 Evaluation indexes and statistical methods

[0872] One-Way ANOVA in SPSS 17.0 was used to analyze and test the ear swelling degree, ear swelling rate, etc. 5 hours after modeling and drug administration, and P < 0.05 indicated statistical significance.

[0873] Ear swelling degree (mg) = right ear weight (mg) - left ear weight (mg);

[0874] Ear swelling rate (%) = (right ear weight - left ear weight) / left ear weight × 100%;

[0875] Inhibition rate of ear swelling degree (%) = 1 - (ear swelling degree of the drug administration group - ear swelling degree of the blank control group) / (ear swelling degree of the model control group - ear swelling degree of the blank control group) × 100%.

[0876] 4.3 Experimental results

[0877] Table 14. Indexes such as inhibition rate of each group of mice:

[0878]

[0879]

[0880] Biological Example 5

[0881] Experiment on inhibiting phorbol ester (TPA)-induced ear swelling in mice

[0882] 5.1 Test method

[0883] 5.1.1 Grouping

[0884] Select 72 male ICR mice and divide them into 9 groups, with 8 mice in each group.

[0885] Table 15. Information table of grouping and model establishment

[0886]

[0887] Note: a. Preparation method of 125 μg / mL TPA: 40 μL of 2 mg / mL TPA stock solution (dissolved in DMSO) + 600 μL of acetone are mixed and used, prepared immediately before use;

[0888] b. The mixing ratio of acetone and DMSO is 15:1 (v / v).

[0889] 5.1.2 Hair removal

[0890] Before the experiment, the animals were grouped and the hair around the right ears of the mice was removed.

[0891] 5.1.3 Model establishment and drug administration

[0892] Each group of experimental animals was smeared with 20 μL of their respective drugs on the right ear (the model control group was given the blank solvent), and 1 hour and 10 minutes later, modeling induction was carried out. Except for the blank group, all animals were given 20 μL of TPA with a concentration of 125 μg / mL on the right ear for induction; 10 minutes after induction, each group of experimental animals was smeared with 20 μL of their respective drugs on the right ear for the second time (the model control group was given the blank solvent).

[0893] Table 16. Information on grouping and drug administration

[0894]

[0895] Note: The administration volume of 40 μL means a total of 40 μL for two administrations.

[0896] 5.1.4 Result Observation

[0897] At 5 h after modeling, ear pieces of the same part on both ears of the animals in each group were taken with a puncher. After weighing, the ear swelling degree, ear swelling rate, inhibition rate, etc. were calculated.

[0898] 5.2 Evaluation Indexes and Statistical Methods

[0899] One-Way ANOVA in SPSS 17.0 was used to analyze and test the ear swelling degree, ear swelling rate, etc. at 5 h after modeling and administration for multiple groups. P < 0.05 indicates statistical difference.

[0900] Ear swelling degree (mg) = Right ear weight (mg) - Left ear weight (mg);

[0901] Ear swelling rate (%) = (Right ear weight - Left ear weight) / Left ear weight × 100%;

[0902] Inhibition rate of ear swelling degree (%) = 1 - (Ear swelling degree of the administration group - Ear swelling degree of the blank control group) / (Ear swelling degree of the model control group - Ear swelling degree of the blank control group) × 100%.

[0903] 5.3 Experimental Results

[0904] Table 17. Inhibition rate and other indexes of each group of mice:

[0905] Group Ear Swelling Degree (mg) Ear Swelling Rate (%) Ear Swelling Degree Inhibition Rate (%) Example 6 5.1±1.6### 36.4±11.9### 87.3 Example 3 6.0±2.5### 42.1±19.3### 83.7 Example 4 4.8±2.1### 34.3±18.2### 88.8 Example 12 5.8±2.3### 39.6±14.0### 84.8 Example 24 5.9±1.7### 43.0±11.8### 84.2 Example 25 8.5±2.7### 59.1±17.5### 73.6 Example 11 6.5±5.0### 46.3±35.7### 81.7 Model Control Group 26.6±3.9*** 197.5±30.0*** — Blank Control Group 2.0±1.5 14.7±12.2 —

[0906] Note: Compared with the blank control group, ***P < 0.001;

[0907] Compared with the model control group, P < 0.001.

[0908] Biological Example 6

[0909] Experiment on Inhibiting TPA-Induced Ear Swelling in Mice

[0910] 5.1 Test Method

[0911] 5.1.1 Grouping

[0912] Seventy-two male ICR mice were selected and divided into 9 groups, with 8 mice in each group.

[0913] Table 18. Information Table of Grouping and Modeling

[0914]

[0915]

[0916] Note: a. Preparation method of 125 μg / mL TPA: Mix 40 μL of 2 mg / mL TPA stock solution (dissolved in DMSO) with 600 μL of acetone and use immediately. Prepare it freshly before use.

[0917] b. The mixing ratio of acetone and DMSO is 15:1 (v / v).

[0918] 5.1.2 Hair Shaving

[0919] Before the experiment, the animals were grouped and the hair around the right ear of the mice was removed.

[0920] 5.1.3 Model Establishment and Drug Administration

[0921] Each group of animals in the experiment was smeared with 20 μL of their respective drugs (the model control group was given the blank solvent) on the right ear, and modeling induction was carried out 1 hour and 10 minutes later. Except for the blank group, 20 μL of 125 μg / mL TPA was given to the right ear of the animals for induction; 10 minutes after induction, each group of animals in the experiment was smeared with 20 μL of their respective drugs (the model control group was given the blank solvent) on the right ear for the second time.

[0922] Table 19. Information on Grouping and Drug Administration

[0923]

[0924]

[0925] Note: The administration volume of 40 μL means a total of 40 μL for two administrations.

[0926] 5.1.4 Result Observation

[0927] 5 hours after modeling, ear pieces of the same part on both ears of each group of animals were taken with a puncher, weighed, and the ear swelling degree, ear swelling rate, inhibition rate, etc. were calculated.

[0928] 5.2 Evaluation Indexes and Statistical Methods

[0929] One-Way ANOVA in SPSS 17.0 was used to analyze and test the ear swelling degree, ear swelling rate, etc. 5 hours after modeling and drug administration. P < 0.05 indicates statistical significance.

[0930] Ear swelling degree (mg) = Right ear weight (mg) - Left ear weight (mg);

[0931] Ear swelling rate (%) = (Right ear weight - Left ear weight) / Left ear weight × 100%;

[0932] The ear swelling inhibition rate (%) = 1 - (ear swelling degree of the drug administration group - ear swelling degree of the blank control group) / (ear swelling degree of the model control group - ear swelling degree of the blank control group) × 100%.

[0933] 5.3 Experimental results

[0934] Table 20. Inhibition rate and other indicators of mice in each group:

[0935]

[0936]

[0937] Note: Compared with the blank control group, ***P < 0.001;

[0938] Compared with the model control group, P < 0.001.

[0939] Biological Example 7

[0940] Subacute toxicity test of continuous gavage for 22 days in rats

[0941] 7.1 Test method

[0942] 7.1.1 Grouping

[0943] 96 SPF - level healthy SD rats, half male and half female, were randomly divided into 8 groups according to gender segments, 6 rats / sex / group. They were the vehicle control group and the compound administration groups respectively, with 12 rats in each group, half male and half female.

[0944] Table 21. Grouping table

[0945]

[0946]

[0947] Note: ♂ represents male; ♀ represents female.

[0948] 7.1.2 Administration

[0949] Oral gavage administration was carried out once a day for 22 consecutive days. Each administration group was given 300 mg / Kg of the corresponding compound, and the vehicle control group was given an equal volume of carboxymethyl cellulose sodium (CMC - Na). After 22 consecutive days of administration, the behavior and status of the rats after administration were observed every day to check for abnormalities and poisoning, and the animal responses were recorded. After 22 consecutive days of administration, 3 rats / sex / group were sacrificed, and gross anatomical observations were made and organ indices were collected. The remaining 3 rats / sex / group were sacrificed after one - week withdrawal observation, and gross anatomical observations were made and organ indices were collected.

[0950] 7.1.3 Observation indicators

[0951] Body weight, appearance, respiration, behavior, reflex, defecation.

[0952] 7.2 Experimental results

[0953] 7.2.1 Clinical observation

[0954] During the test period, no obvious drug-related abnormalities were observed in the appearance, respiration, behavior, reflex, and defecation of the animals in each group.

[0955] 7.2.2 Body weight

[0956] No obvious abnormalities were observed in the body weight of the animals during the test period. The trend of body weight change is shown in Figure 4 and Figure 5 .

[0957] 7.2.3 Gross anatomical observation

[0958] At the end of drug administration and the recovery period, no obvious compound-related abnormalities were observed in the organs of the animals in each group during gross anatomical observation.

[0959] 7.2.4 Organ index

[0960] No obvious abnormalities were observed in the organ index of the animals.

[0961] 7.3 Experimental conclusion

[0962] The above-mentioned compound was repeatedly administered to SD rats by gavage once a day for 22 consecutive days, and no obvious drug-related toxic manifestations were observed.

[0963] Biological Example 8

[0964] Subacute toxicity test of rats by continuous gavage for 22 days

[0965] 8.1 Test method

[0966] 8.1.1 Grouping

[0967] 84 SPF-grade healthy SD rats, half male and half female, were randomly divided into 7 groups according to gender segments, 6 rats / sex / group. They were the vehicle control group and the compound administration groups respectively, with 12 rats in each group, half male and half female.

[0968] Table 22. Grouping table

[0969]

[0970] Note: ♂ represents male; ♀ represents female.

[0971] 8.1.2 Drug administration

[0972] Oral gavage administration was carried out once a day for 22 consecutive days. Each administration group was given 300 mg / Kg of the corresponding compound, and the vehicle control group was given an equal volume of CMC-Na. After 22 consecutive days of administration, the behavior and status of the rats were observed daily for any abnormalities or signs of poisoning, and the animal responses were recorded. After 22 consecutive days of administration, 3 animals per sex per group were sacrificed, and gross anatomical observations were made and organ indices were collected. The remaining 3 animals per sex per group were sacrificed after a one-week drug withdrawal observation, and gross anatomical observations were made and organ indices were collected.

[0973] 8.1.3 Observation indicators

[0974] Body weight, appearance, respiration, behavior, reflex, defecation.

[0975] 8.2 Experimental results

[0976] 8.2.1 Clinical observation

[0977] During the test period, no obvious drug-related abnormalities were observed in the appearance, respiration, behavior, reflex, and defecation of the animals in each group.

[0978] 8.2.2 Body weight

[0979] No obvious abnormalities were observed in the body weight of the animals during the test period. The trend of body weight change is shown in Figure 6 and Figure 7 .

[0980] 8.2.3 Gross anatomical observation

[0981] At the end of the administration and the end of the recovery period, gross anatomical observations were made on the animals in each group, and no obvious compound-related abnormalities were observed in each organ.

[0982] 8.2.4 Organ index

[0983] No obvious abnormalities were observed in the organ indices of the animals.

[0984] 8.3 Experimental conclusion

[0985] The above compound was repeatedly administered to SD rats by gavage once a day for 22 days, and no obvious drug-related toxic manifestations were observed.

[0986] Biological Example 9

[0987] Acute toxicity test of single gavage in mice

[0988] 9.1 Test method

[0989] 9.1.1 Grouping

[0990] Thirty SPF-grade healthy ICR mice, half male and half female, were randomly divided into 5 groups according to gender segments, with 3 animals per sex per group and 6 animals per group, half male and half female.

[0991] Table 23. Grouping Table

[0992]

[0993] Note: ♂ represents male; ♀ represents female.

[0994] 9.1.2 Administration of Drugs

[0995] Single intragastric administration was performed, and the symptomatic responses of all animals were observed and recorded truthfully after administration. The experiment was continuously observed for 15 days, and the symptoms of the animals were recorded. After the experiment, all animals were weighed, observed, recorded, and specimens were retained for the tissues and organs.

[0996] 9.1.3 Observation Indicators

[0997] Body weight, appearance, respiration, behavior, reflex, defecation.

[0998] 9.2 Experimental Results

[0999] 9.2.1 Clinical Observation

[1000] Table 24

[1001]

[1002]

[1003] 9.2.2 Body Weight

[1004] During the test period, no obvious abnormalities were observed in the body weight of the animals. The trend of body weight change is shown in Figure 8 and Figure 9 .

[1005] 9.2.3 Gross Anatomical Observation

[1006] At the end of drug administration and the recovery period for each group of animals, no obvious abnormalities related to the compound were observed in each organ during gross anatomical observation.

[1007] 9.2.4 Organ Index

[1008] No obvious abnormalities were observed in the organ index of the animals.

[1009] 9.3 Experimental Conclusion

[1010] The above-mentioned compound was administered to ICR mice by single intragastric administration at 2000 mg / Kg, and no obvious drug-related toxic manifestations were observed.

[1011] In the present disclosure, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations.

[1012] As can be understood from the foregoing, although specific embodiments of the present disclosure have been described for purposes of illustrative illustration, those skilled in the art can make various variations or improvements without departing from the spirit and scope of the present disclosure. These variations or modifications should fall within the scope of the appended claims of the present disclosure.

Claims

1. The following compounds, their stereoisomers or their pharmaceutically acceptable salts: Ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; (S)-Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; Propyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; and Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)propionate.

2. A pharmaceutical composition comprising the compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, and a pharmaceutically acceptable carrier, diluent or excipient.

3. The pharmaceutical composition according to claim 2, which is prepared as tablets, solutions, granules, patches, ointments, gels, capsules, aerosols or suppositories for parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral use.

4. Use of the compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, or the pharmaceutical composition according to claim 2 or 3, in the preparation of a medicament for treating or preventing IgE-related diseases in an individual.

5. The use according to claim 4, wherein the disease is IgE-mediated.

6. The use according to claim 4, wherein the individual is a mammal.

7. The use according to claim 6, wherein the mammal is a human.

8. The use according to any one of claims 4 to 6, wherein the disease is selected from psoriasis, eczema, atopic dermatitis, urticaria, asthma, asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, pemphigoid and parasitic infections.

9. The use according to any one of claims 4 to 6, wherein the disease is selected from skin diseases and allergic rhinitis.

10. A method for preparing the compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, which comprises: (1) Reacting a compound of general formula (B-I) with malonic acid and ammonium acetate to obtain a compound of general formula (B-II), Among them, R 3’ is selected from ethoxy or isopropoxy, R 4’ is methoxy, (2) Esterifying the compound of general formula (B-II) with an alcohol to obtain a compound of general formula (B-III), Among them, R 3’ is selected from ethoxy or isopropoxy, R 4’ is methoxy, R 2’ is selected from methyl, ethyl or propyl; (3) Reacting a compound of general formula (B-IV) with a compound of general formula (B-III) to obtain the compound according to claim 1, Among them, R 1’ is acetamido, R 3’ is selected from ethoxy or isopropoxy, R 4’ is methoxy, R 2’ is selected from methyl, ethyl or propyl; wherein X is -CR5R6-, R5 is hydrogen, R6 is hydrogen, and n is 1.

11. The method according to claim 10, wherein in a solvent, the compound of general formula (B-I) is reacted with malonic acid and ammonium acetate to obtain a compound of general formula (B-II).

12. The method according to claim 11, wherein the solvent is selected from methanol, ethanol, isopropanol, water or a mixture thereof.

13. The method according to claim 10, wherein the compound of general formula (B-I) is reacted with malonic acid and ammonium acetate at 50 °C to 130 °C to obtain the compound of general formula (B-II).

14. The method according to claim 10, wherein the compound of general formula (B-III) is obtained by an esterification reaction of the compound of general formula (B-II) with an alcohol in an organic solvent.

15. The method according to claim 14, wherein the organic solvent is selected from alcohols, tetrahydrofuran, dichloromethane, ethyl acetate, methyl tert-butyl ether or a mixture thereof.

16. The method according to claim 10, wherein the compound of general formula (B-II) is subjected to an esterification reaction with an alcohol at -20 °C to 30 °C to obtain the compound of general formula (B-III).

17. The method according to claim 16, wherein the alcohol is selected from methanol, ethanol or propanol.

18. The method according to any one of claims 10 to 17, wherein the esterifying agent is selected from thionyl chloride, oxalyl chloride, HCl gas, acetyl chloride or a mixture thereof.

19. The method according to claim 10, wherein a catalyst is added during the reaction of the compound of general formula (B-IV) with the compound of general formula (B-III) to obtain the compound according to claim 1.

20. The method according to claim 19, wherein the catalyst is selected from sodium acetate, potassium acetate, sodium carbonate, potassium carbonate or a mixture thereof.

21. The method according to claim 10, wherein the compound of general formula (B-IV) is reacted with the compound of general formula (B-III) at 50 °C to 180 °C to obtain the compound according to claim 1.

22. The method according to claim 10, wherein the reaction of the compound of general formula (B-IV) with the compound of general formula (B-III) to obtain the compound according to claim 1 is carried out in an organic solvent.

23. The method according to claim 22, wherein the organic solvent is selected from acetic acid, formic acid, dimethylformamide, dimethylacetamide or a mixture thereof.

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