WO2019201255A1 - 异吲哚衍生物 - Google Patents

异吲哚衍生物 Download PDF

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Publication number
WO2019201255A1
WO2019201255A1 PCT/CN2019/082943 CN2019082943W WO2019201255A1 WO 2019201255 A1 WO2019201255 A1 WO 2019201255A1 CN 2019082943 W CN2019082943 W CN 2019082943W WO 2019201255 A1 WO2019201255 A1 WO 2019201255A1
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optionally substituted
propanoate
dioxoisoindolin
methyl
group
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PCT/CN2019/082943
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English (en)
French (fr)
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张和胜
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天津合美医药科技有限公司
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Priority to CA3094029A priority Critical patent/CA3094029A1/en
Priority to EP19788517.1A priority patent/EP3782983A4/en
Priority to AU2019254962A priority patent/AU2019254962C1/en
Priority to JP2021506028A priority patent/JP2021522315A/ja
Priority to BR112020020800-0A priority patent/BR112020020800A2/pt
Priority to US17/048,914 priority patent/US11767295B2/en
Priority to KR1020207031475A priority patent/KR102646322B1/ko
Publication of WO2019201255A1 publication Critical patent/WO2019201255A1/zh
Priority to JP2024030224A priority patent/JP2024063138A/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present disclosure generally relates to the fields of organic chemistry and medicinal chemistry.
  • Immunoglobulin E is a secreted immunoglobulin composed of two light chains and two heavy chains. It is produced by plasma cells in the lamina basement of the nasopharynx, tonsil, bronchi, and gastric mucosa, and is the main antibody causing type I allergy. Although this antibody is the least abundant in human serum, it plays an important role in allergic diseases and can cause an inflammatory immune response 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 increasing attention.
  • Eczema is a chronic relapsing, inflammatory skin disease that occurs in babies and children and can also occur in adults. According to research, the prevalence of eczema in Western countries is as high as 10% or more, and in the United States is 10.7%. In recent years, epidemiological studies have shown that the prevalence rate of the general population in China is close to that of Western countries, and the incidence rate in industrialized countries has been reduced in the past 20 years. Is rising. While China continues to promote the process of industrialization, the people's living standards have improved significantly, infectious skin diseases have gradually decreased, and allergic skin diseases have gradually increased. Its pathogenesis is complex, mainly related to genetic background, environmental stimuli, epidermal barrier defects, immune disorders and other factors.
  • Asthma also known as bronchial asthma, is a chronic airway disease characterized by tracheal fistula. It is a chronic airway inflammation involving a variety of cells and cellular components. Airway inflammation is a common feature of all types of asthma and is also a clinical symptom. And the basis of high reactivity of the airway. IgE plays a very important role in the inflammatory response of asthma (Zhao Xinyu et al., Journal of Clinical Pulmonology, 2018, 23(7), pp. 1325-1328). When allergens first enter the body, a series of inflammatory cascades are triggered by the presentation of dendritic cells.
  • IgE IgE high-affinity receptors
  • Fc ⁇ RI IgE high-affinity receptors
  • the Fc ⁇ RI-IgE complex is formed; when the allergen re-enters the body, it can rapidly bind to the complex, causing a large amount of inflammatory mediators such as histamine, leukotrienes, and prostaglandins to be released, causing mucus secretion, airway smooth muscle contraction, and vascular communication.
  • Increased permeability inflammatory cells can cascade to expand the production of IgE under the action of the above inflammatory mediators, causing delayed phase allergic reactions and accelerating asthma progression.
  • IgE can also bind to dendritic cells, which enhances antigen presentation and up-regulates the expression of Fc ⁇ RI receptors on the surface of mast cells and basophils.
  • IgE can Airway remodeling is caused by increased extracellular matrix (ECM) and is also involved in viral-induced asthma exacerbations.
  • COPD Asthma-Chronic Obstructive Pulmonary Disease
  • COPD Asthma-Chronic Obstructive Pulmonary Disease
  • AHR airway hyperresponsiveness
  • Urticaria (Xu Yawei et al., Journal of Shanghai Second Medical University, Vol.14, Suppl. 1994, 118-120), commonly known as “Rubella Block”, is a limitation due to the expansion of skin and mucosal small blood vessels and increased permeability. Sexual edema reaction. It is clinically characterized by whistles of varying sizes. It usually resolves within 2 to 24 hours, but a new rash occurs repeatedly. Chronic urticaria refers to the above-mentioned wheal with pruritus occurring almost every day for more than 6 weeks. Although the pathogenesis of urticaria is more complicated, it is related to mast cell activation. Mast cell activation has two types of pathways, immunological and non-immune. The former skin edema wheal is either in the process of IgE-dependent or complement system-mediated immune response.
  • Allergic rhinitis ie allergic rhinitis
  • IgE-mediated mediators mainly histamine
  • Non-infectious inflammatory disease of the nasal mucosa Allergic rhinitis is common in all ages and seasonality. It is most common in adolescents. The symptoms of the patient are sneezing, tearing, clearing, itching, and loss of sense of smell.
  • IgE-mediated type I allergic reaction is the basis of allergic reactions.
  • IgE levels in patients with allergic rhinitis were significantly higher than those in normal people. IgE plays an important role in the pathogenesis of allergic rhinitis. IgE is involved in the immune mechanism of allergic rhinitis and can be used as an effective monitoring index for allergic rhinitis. It has important clinical significance.
  • Common diseases associated with elevated IgE include: seasonal allergic rhinitis (Holgate S T, World Allergy Organization Journal, 2014, 7, 17 and Wang Hanmei, Sun Renshan, Journal of Clinical Military Medicine, 2017 (8), 872-874 ), drug-induced interstitial pneumonia (Yin Wenjie, etc., China Pharmaceutical Conference and Chinese Pharmacist Zhou, 2010), bronchopulmonary aspergillosis (Holgate S T, World Allergy Organization Journal, 2014, 7, 17), leprosy (He Haoming, etc.) , Chinese Journal of Leprosy and Dermatology, 1989 (4), 210-211), cytoplasmic sore (Yin Yue, Li Li, Chinese Journal of Laboratory Medicine, 2018, 41 (3), 242-245) and certain parasitic infections Wait.
  • seasonal allergic rhinitis Holgate S T, World Allergy Organization Journal, 2014, 7, 17 and Wang Hanmei, Sun Renshan, Journal of Clinical Military Medicine, 2017 (8), 872-874
  • IgE molecules An in-depth understanding of the mechanism of action of IgE molecules has facilitated drug development with therapeutic targets for the IgE inflammatory pathway.
  • Anti-IgE treatment reduces the level of free IgE, resulting in a decrease in the high-affinity IgE receptor (Fc ⁇ RI) expressed in mast cells, basophils and dendritic cells, reducing inflammation markers and thus exerting therapeutic effects.
  • Omalizumab is the first monoclonal antibody that targets IgE, a humanized IgE.
  • Omazhudan is resistant to the treatment of severe persistent allergic asthma in children, adolescents and adults aged 6 or older, reducing the number of acute asthma attacks, reducing the use of inhaled hormones, and improving asthma-related quality of life.
  • the disclosure relates to a compound of formula (I), a stereoisomer thereof:
  • R 1 is selected from one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 8 hydrocarbyl, amino, C 1 -C 8 hydrocarbylcarbonylamino, C 1 -C 8 hydrocarbyloxycarbonylamino, One or more C 1 -C 4 hydrocarbyl-substituted amino, substituted aminocarbonyl C 1 -C 8 hydrocarbyl groups;
  • R 2 is selected from a carboxyl group or an ester group
  • R 3 is selected from hydrogen, hydroxy, halogen, C 1 -C 8 alkoxy, C 5 -C 12 aryloxy or C 5 -C 12 cycloaryloxy;
  • R 4 is selected from hydrogen, halogen, hydroxy, C 1 -C 8 alkoxy or C 5 -C 12 aryloxy.
  • the present disclosure is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof, and a pharmaceutically acceptable carrier:
  • R 1 is selected from one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 8 hydrocarbyl, amino, C 1 -C 8 hydrocarbylcarbonylamino, C 1 -C 8 hydrocarbyloxycarbonylamino, One or more C 1 -C 4 hydrocarbyl-substituted amino, substituted aminocarbonyl C 1 -C 8 hydrocarbyl groups;
  • R 2 is selected from a carboxyl group or an ester group
  • R 3 is selected from hydrogen, hydroxy, halogen, C 1 -C 8 alkoxy, C 5 -C 12 aryloxy or C 5 -C 12 cycloaryloxy;
  • R 4 is selected from hydrogen, halogen, hydroxy, C 1 -C 8 alkoxy or C 5 -C 12 aryloxy.
  • the present disclosure relates to a pharmaceutical composition of the formula (I) or a stereoisomer thereof or a pharmaceutical composition comprising a compound of the formula (I) or a stereoisomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a dermatological treatment, silver Uses in medicines for psoriasis, eczema and atopic dermatitis:
  • R 1 is selected from one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 8 hydrocarbyl, amino, C 1 -C 8 hydrocarbylcarbonylamino, C 1 -C 8 hydrocarbyloxycarbonylamino, One or more C 1 -C 4 hydrocarbyl-substituted amino, substituted aminocarbonyl C 1 -C 8 hydrocarbyl groups;
  • R 2 is selected from a carboxyl group or an ester group
  • R 3 is selected from hydrogen, hydroxy, halogen, C 1 -C 8 alkoxy, C 5 -C 12 aryloxy or C 5 -C 12 cycloaryloxy;
  • R 4 is selected from hydrogen, halogen, hydroxy, C 1 -C 8 alkoxy or C 5 -C 12 aryloxy.
  • the present disclosure relates to a process for the preparation of a compound of formula (I) or a stereoisomer thereof:
  • R 1 is selected from one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 8 hydrocarbyl, amino, C 1 -C 8 hydrocarbylcarbonylamino, C 1 -C 8 hydrocarbyloxycarbonylamino, One or more C 1 -C 4 hydrocarbyl-substituted amino, substituted aminocarbonyl C 1 -C 8 hydrocarbyl groups;
  • R 2 is selected from a carboxyl group or an ester group
  • R 3 is selected from hydrogen, hydroxy, halogen, C 1 -C 8 alkoxy, C 5 -C 12 aryloxy or C 5 -C 12 cycloaryloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 8 alkoxy or C 5 -C 12 aryloxy;
  • the preparation method described therein includes:
  • R 3 ' and R 4 ' in the formula (A-II) and the formula (A-III) are the same as those defined for R 3 and R 4 in the formula (I), and R 2 ' Selected from hydrogen, C 1 -C 4 alkyl;
  • R 1 ', R 3', R group in the general formula (I) is represented by R '4 1, R 3, R 4
  • R 2 ' is selected from hydrogen or C 1 -C 4 alkyl.
  • the present disclosure relates to a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • the disclosure relates to the following compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof:
  • the present disclosure is directed to a pharmaceutical composition
  • 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:
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • the present disclosure relates to methods of treating or preventing immunoglobulin E (IgE)-mediated, preferably immunoglobulin E (IgE) mediated, diseases comprising administering to a subject in need thereof a therapeutically effective amount a compound of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount comprising a compound of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt
  • Pharmaceutical composition of carrier, diluent or excipient are examples of carrier, diluent or excipient:
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • the present disclosure relates to a compound of formula (II), a stereoisomer thereof, or a stereoisomer thereof, for use in the treatment or prevention of immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE) mediated diseases
  • a compound of formula (II) for use in the treatment or prevention of immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE) mediated diseases
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • the present disclosure relates to a therapeutically effective amount of a compound of formula (II), for use in the treatment or prevention of immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE) mediated diseases,
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • the present disclosure relates to the treatment or prevention of skin diseases, psoriasis, eczema, atopic dermatitis, urticaria, asthma, asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), allergic rhinitis a compound of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, cerebral venom, and parasitic infection :
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • the present disclosure relates to the use in the treatment or prevention of immunoglobulin E (IgE)-mediated skin diseases, psoriasis, eczema, atopic dermatitis, urticaria associated with immunoglobulin E (IgE) , asthma, asthma - chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), allergic rhinitis, seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, acne-like and parasitic
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • the present disclosure is directed to a process for the preparation of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising:
  • R 3 ' and R 4 ' in the formula (B-II) and the formula (B-III) is the same as the definition of R 3 and R 4 in the formula (II), and R 2 ' Selected from hydrogen or a hydrocarbon group;
  • X is -CR 5 R 6 -, wherein R 5 is hydrogen, R 6 is hydrogen, and n is 1.
  • Figure 1 shows a model animal induction and administration method of Biological Example 1 of the present disclosure.
  • Example 2 shows a model animal induction and administration method of Biological Example 2 of the present disclosure.
  • Figure 3 shows a model animal induction and administration method of Biological Example 3 of the present disclosure.
  • Figure 4 is a graph showing the trend of body weight change of male animals of each test group of Biological Example 7 of the present disclosure.
  • Figure 5 is a graph showing the trend of body weight changes of female animals of each test group of Biological Example 7 of the present disclosure.
  • Fig. 6 is a graph showing the trend of body weight change of male animals of each test group of Biological Example 8 of the present disclosure.
  • Figure 7 is a graph showing the trend of body weight changes of female animals of each test group of Biological Example 8 of the present disclosure.
  • Figure 8 is a graph showing the trend of body weight change of male animals of each test group of Biological Example 9 of the present disclosure.
  • Figure 9 is a graph showing the trend of body weight change of female animals of each test group of Biological Example 9 of the present disclosure.
  • references to “an embodiment” or “another embodiment” or “an embodiment” or “some embodiments” throughout this specification are meant to include, in at least one embodiment, the Specific reference to elements, structures or features.
  • the appearance of the phrase “a” or “an embodiment” or “an embodiment” Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a pharmaceutical composition comprising a “geneic compound of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof" includes a compound of the formula (II), a stereoisomer thereof or a medicament thereof An acceptable salt, or two or more of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • C 1 -C 4 alkyl describes an alkyl group having a total of 1 to 4 carbon atoms as defined below
  • C 3 -C 10 cycloalkyl is described as having a total of 3 to 10 carbon atoms as defined below.
  • Cycloalkyl The total number of carbons in the abbreviated symbols does not include carbon that may be present in the substituents of the group.
  • halogen means fluoro, chloro, bromo or iodo.
  • hydroxy refers to an -OH group.
  • amino refers to a -NH 2 group.
  • carboxy refers to a -COOH group.
  • hydrocarbyl refers to an aliphatic hydrocarbon group.
  • the hydrocarbyl moiety can be a "saturated hydrocarbyl” group, meaning that it does not contain any alkene or alkyne moieties.
  • the hydrocarbyl moiety may also be an "unsaturated hydrocarbyl” moiety, meaning that it contains at least one alkene or alkyne moiety.
  • Alkene moiety refers to a group consisting of two to eight carbon atoms and at least one carbon-carbon double bond, and a straight or branched hydrocarbon chain group, such as a vinyl group, attached to the remainder of the molecule by a single bond.
  • alkyne means from two to eight carbon atoms and at least one a group consisting of a carbon-carbon triple bond, and a linear or branched hydrocarbon chain group bonded to the remainder of the molecule by a single bond.
  • Hydrocarbyl moieties, whether saturated or unsaturated, may be branched or straight chain.
  • the hydrocarbyl group may have 1 to 8 carbon atoms (in each occurrence of the present disclosure, a numerical range such as “1 to 8” refers to each integer in a given range; as “1 to 8” means The hydrocarbyl group may 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" in the unspecified range of values) .
  • the hydrocarbyl group can be optionally substituted, that is, substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, Sulfhydryl, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanate Isothiocyanato), nitro, silyl, trihalomethanesulfonyl, -NR
  • Typical hydrocarbyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, ethynyl, Propynyl and butynyl.
  • substituents may be substituted by one of the above substituents.
  • C 1 -C 4 hydrocarbyl refers to a hydrocarbyl group as defined above containing one to four carbon atoms.
  • the C 1 -C 4 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
  • C 1 -C 6 hydrocarbyl refers to a hydrocarbyl group as defined above containing one to six carbon atoms.
  • the C 1 -C 6 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
  • C 1 -C 12 hydrocarbyl refers to a hydrocarbyl group as defined above containing one to twelve carbon atoms.
  • the C 1 -C 12 hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.
  • C 2 -C 6 hydrocarbyl means as defined above containing two to six carbon atoms in the hydrocarbyl group.
  • the C 2 -C 6 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
  • C 3 -C 6 hydrocarbon group means as defined above containing three to six carbon atoms.
  • the C 3 -C 6 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
  • C 3 -C 12 hydrocarbyl means as defined above containing three to twelve carbon atoms.
  • the C 3 -C 12 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
  • C 6 -C 12 hydrocarbyl refers to a hydrocarbyl group as defined above containing six to twelve carbon atoms.
  • the C 6 -C 12 hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.
  • C 7 -C 12 hydrocarbyl refers to a hydrocarbyl group as defined above containing seven to twelve carbon atoms.
  • the C 7 -C 12 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
  • hydrocarbyloxy refers to a radical of the formula -O-hydrocarbyl, wherein the hydrocarbyl radical is as defined in the present disclosure.
  • hydrocarbyloxy include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec Oxyl, tert-butoxy, pentyloxy and tert-pentyloxy.
  • aryl refers to a carbocyclic ring (all carbon) or two or more fused rings (a ring sharing two adjacent carbon atoms) having a completely delocalized Pi electronic system.
  • Aryl groups include, but are not limited to, anthracenyl, phenyl, and naphthyl.
  • the aryl group may have, for example, five to twelve carbon atoms.
  • the aryl groups of the present disclosure may be substituted or unsubstituted.
  • the hydrogen atom is substituted with one or more groups independently selected from the group consisting of: hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, alkoxy Base, aryloxy, fluorenyl, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, anthracene- Thiocarbamoyl, C-amido, oxime-amido, S-sulfonamido, oxime-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, Cyanothiol, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R"
  • arylhydrocarbyloxy refers to the formula -O-alkylaryl, wherein the hydrocarbyl and aryl are as defined in the present disclosure, respectively.
  • Illustrative examples of arylhydrocarbyloxy include, but are not limited to, benzyloxy, phenethyloxy, and phenylpropyloxy.
  • C 6 -C 16 arylalkyloxy refers to an arylalkyloxy group as defined above containing from six to sixteen carbon atoms.
  • the C 6 -C 16 arylhydrocarbyloxy group may be optionally substituted as defined for the hydrocarbyl group and the aryl group, respectively.
  • C 6 -C 18 arylalkyloxy refers to an arylalkyloxy group as defined above containing from six to eighteen carbon atoms.
  • the C 6 -C 18 arylhydrocarbyloxy group may be optionally substituted as defined for the hydrocarbyl group and the aryl group, respectively.
  • C 7 -C 18 arylalkyloxy refers to an arylalkyloxy group as defined above containing seven to eighteen carbon atoms.
  • the C 7 -C 18 arylhydrocarbyloxy group may be optionally substituted as defined for the hydrocarbyl group and the aryl group, respectively.
  • C 8 -C 18 arylalkyloxy refers to an arylalkyloxy group as defined above containing eight to eighteen carbon atoms.
  • the C 8 -C 18 arylhydrocarbyloxy group may be optionally substituted as defined for the hydrocarbyl group and the aryl group, respectively.
  • C 8 -C 24 arylalkyloxy refers to an arylalkyloxy group as defined above containing eight to twenty four carbon atoms.
  • the C 8 -C 24 arylhydrocarbyloxy group may be optionally substituted as defined for the hydrocarbyl group and the aryl group, respectively.
  • C 11 -C 24 arylalkyloxy refers to an arylalkyloxy group as defined above containing eleven to twenty four carbon atoms.
  • the C 11 -C 24 arylhydrocarbyloxy group may be optionally substituted as defined for the hydrocarbyl group and the aryl group, respectively.
  • C 12 -C 24 arylalkyl group means as defined above containing twelve to twenty-four carbon atoms, aryl hydrocarbon group.
  • the C 12 -C 24 arylhydrocarbyloxy group may be optionally substituted as defined for the hydrocarbyl group and the aryl group, respectively.
  • C 6 -C 24 arylalkyloxy refers to an arylalkyloxy group as defined above containing from six to twenty four carbon atoms.
  • the C 6 -C 24 arylhydrocarbyloxy group may be optionally substituted as defined for the hydrocarbyl group and the aryl group, respectively.
  • heteroaryl refers to a 5- to 18-membered aromatic ring group consisting of one to seventeen carbon atoms and one to ten heteroatoms selected from nitrogen, oxygen and sulfur.
  • a heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused or bridged ring system; and a nitrogen, carbon or sulfur atom in the heteroaryl group can be Optionally oxidized; the nitrogen atom can optionally be quaternized.
  • heteroaryl groups include, but are not limited to, azathiol, acridinyl, benzimidazolyl, benzothiazolyl, benzindenyl, benzodioxolyl, benzofuranyl , benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxanyl, 1,4-benzodioxanyl, benzonaphthalene Furanyl, benzoxazolyl, benzodioxolyl, benzodioxanyl, benzopyranyl, benzopyranone, benzofuranyl, benzofuran Keto, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, oxazolyl, porphyrinyl, dibenzofuranyl, dibenzo Thienyl, furyl, furanone, isothi
  • the heteroaryl groups of the present disclosure may be substituted or unsubstituted.
  • the hydrogen atom is substituted with one or more groups independently selected from the group consisting of: hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, alkoxy Base, aryloxy, fluorenyl, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, anthracene- Thiocarbamoyl, C-amido, oxime-amido, S-sulfonamido, oxime-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, Cyanothiol, isothiocyanato, nitro, silyl, trihalome
  • cycloalkyl refers to a composition consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, in some embodiments having from three to twelve carbon atoms, and which is A stable, non-aromatic monocyclic or bicyclic hydrocarbon group which is saturated or unsaturated and which is bonded to the remainder of the molecule by a single bond, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl and the like.
  • cycloalkyl is intended to include a cyclic hydrocarbon group as defined above optionally substituted by one or more groups selected from substituents: cycloalkyl, aryl, heteroaryl.
  • heteroalicyclic hydroxy, alkoxy, aryloxy, fluorenyl, thiol, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-acylamino, S-sulfinylamino, N-sulfonamido, C-carboxy, O-carboxy, isocyanide Acidate, thiocyanato, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl groups as defined in the disclosure) or include mono- An amino group, and a di-substituted amino group, and a protected derivative thereof.
  • C 3 -C 6 cycloalkyl refers to a cyclic hydrocarbon radical as defined above three to six carbon atoms.
  • the C 3 -C 6 cycloalkyl group may be optionally substituted as defined for the above cyclic hydrocarbon group.
  • C 3 -C 10 cycloalkyl means as defined above having three to ten carbon atoms in the cycloalkyl group.
  • the C 3 -C 10 cycloalkyl group may be optionally substituted as defined for the above cyclic hydrocarbon group.
  • C 3 -C 12 cycloalkyl refers to a cyclic hydrocarbon radical as defined above of three to twelve carbon atoms.
  • the C 3 -C 12 cycloalkyl group may be optionally substituted as defined for the above cyclic hydrocarbon group.
  • cycloalkyloxy refers to an -O-cycloalkyl group, wherein the cycloalkyl group is as defined in the present disclosure.
  • Illustrative examples of cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and cyclodecyloxy.
  • hydrocarbylcarbonylamino include, but are not limited to, acetylamino, propionylamino, butyrylamino, and pentanoylamino.
  • hydrocarbylcarbonyloxy include, but are not limited to, acetoxy, propionyloxy, butyryloxy, and valeryloxy.
  • hydrocarbyloxycarbonylamino include, but are not limited to, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, and t-butoxycarbonylamino.
  • hydrocarbyloxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and butoxycarbonyl.
  • a compound of the present disclosure, a stereoisomer thereof or a pharmaceutically acceptable salt thereof means a compound of the formula (I), a stereoisomer thereof and a pharmaceutically acceptable salt thereof, of the present disclosure, a compound of the formula (II), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, and any specific compound, stereoisomer thereof, and pharmaceutically acceptable thereof, which fall within the formula (I) and formula (II) Salt.
  • the term "mammal” refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans. In certain embodiments, the mammal comprises a human.
  • the term "patient” refers to an animal (eg, a human), a companion animal (eg, a dog, a cat, or a horse), and a domestic animal (eg, a cow, a pig, and a sheep).
  • the patient is a mammal comprising males and females.
  • the patient is a human.
  • the term "pharmaceutically acceptable” refers to carriers, carriers, diluents, excipients and/or salts which must be compatible with the other ingredients of the formulation and which are not deleterious to the recipient.
  • the term "arbitrary” or “arbitrarily” means that the subsequently described event or condition may or may not occur, and the specification includes the occurrence of the event or condition and the situation that did not occur.
  • the term "pharmaceutically acceptable carrier, diluent or excipient” includes, but is not limited to, any adjuvant, carrier, excipient that has been approved by the U.S. Food and Drug Administration for use in humans or animals. , Glidants, sweeteners, thinners, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers
  • the agent or the like has various forms of carriers which do not have side effects in constituting the pharmaceutical composition.
  • carrier is defined as a compound that facilitates the introduction of a compound into a cell or tissue.
  • DMSO dimethyl sulfoxide
  • carrier because it is easy to introduce certain organic compounds into cells or tissues of an organism.
  • pharmaceutically acceptable salts includes “acceptable acid addition salts” and “acceptable base addition salts.”
  • the term "acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and which are inorganic in nature.
  • an acid or an organic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid Alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, octanoic acid, carbonic acid, cinnamic acid , citric acid, cyclohexanesulfamic acid, dodecyl sulfate, ethane-1,2-d
  • the term "acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic base or an 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, and the like. 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, salts of cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, Caffeine, procaine, seabamin, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, Anthraquinone, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like.
  • the like such
  • solvent or solvent mixture means any and all solvents.
  • 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, positive Heptane, n-pentane, toluene, o-xylene, p-xylene, dimethyl sulfoxide (DMSO), pyridine, acetic acid, anisole, butyl acetate, cumene, e
  • DMSO dimethyl sulfoxide
  • the term "pharmaceutical composition” refers to a formulation of a compound described in the present disclosure and a medium which is generally accepted in the art to deliver a biologically activating compound to a mammal such as a human.
  • Such media include all pharmaceutically acceptable carriers, diluents or excipients.
  • the term "therapeutically effective amount” refers to a compound or compound that ameliorates, attenuates or eliminates the symptoms of a particular disease or condition and a particular disease or condition, or avoids or delays the onset of a particular disease or condition or the symptoms of a particular disease or condition.
  • the amount of combination The amount of the compound described in the present disclosure which constitutes a “therapeutically effective amount” will vary depending on the compound, the state of the disease and its severity, and the age, body weight, etc. of the mammal to be treated, but the skilled person will The knowledge and the disclosure herein can be used to determine the amount of the compounds described in this disclosure.
  • treating encompasses a treatment-related disease or condition in a mammal, such as a human, having a related disease or condition, and includes:
  • disease and “disease state” may be used interchangeably or may be different, as a particular disease or condition may not have a known causative agent (and therefore cannot be explained by etiology) Therefore, it is not recognized as a disease, but is considered to be an undesired disease state or condition in which the clinician has identified more or less specific series of symptoms.
  • physiologically acceptable refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • the compound described in the present disclosure or a pharmaceutically acceptable salt thereof may contain one or more asymmetric centers, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms, and may be Absolute stereochemistry defines it as (R)- or (S)-, or (D)- or (L)- of an amino acid.
  • the present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or Resolution is carried out using conventional techniques, such as HPLC using a chiral column.
  • a compound described in this disclosure contains an olefinic double bond or other geometrically asymmetric center, unless otherwise stated, it is meant that the compound includes both E and Z geometric isomers. Again, it is meant to include all tautomeric forms.
  • stereoisomer refers to a compound composed of the same atoms bonded by the same bond, but having different three-dimensional structures that are not interchangeable.
  • the present disclosure encompasses various stereoisomers and mixtures thereof.
  • the disclosure relates to a compound of formula (I), a stereoisomer thereof:
  • R 1 is selected from one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 8 hydrocarbyl, amino, C 1 -C 8 hydrocarbylcarbonylamino, C 1 -C 8 hydrocarbyloxycarbonylamino, One or more C 1 -C 4 hydrocarbyl-substituted amino, substituted aminocarbonyl C 1 -C 8 hydrocarbyl groups;
  • R 2 is selected from a carboxyl group or an ester group
  • R 3 is selected from hydrogen, hydroxy, halogen, C 1 -C 8 alkoxy, C 5 -C 12 aryloxy or C 5 -C 12 cycloaryloxy;
  • R 4 is selected from hydrogen, halogen, hydroxy, C 1 -C 8 alkoxy or C 5 -C 12 aryloxy.
  • R 1 is selected from one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 8 alkyl, amino, C 1 -C 8 alkylcarbonylamino, C 1 -C 8 alkyloxycarbonylamino, one or more C 1 -C 4 alkyl substituted amino, substituted aminocarbonyl C 1 -C 8 alkyl.
  • R 3 is selected from hydrogen, hydroxy, halo, C 1 -C 8 alkoxy, C 5 -C 12 aryloxy or C 5 -C 12 cycloaryloxy.
  • R 4 is selected from hydrogen, hydroxy, halo, C 1 -C 8 alkoxy, C 5 -C 12 aryloxy or C 5 -C 12 cycloaryloxy.
  • R 1 is selected from hydrogen, -OH, -F, -Cl, -CH 3, -CH 2 CH 3, -CH 2 CH 2 CH 3, -NH 2, -NHCH 3, -N (CH 3 ) 2 , -NHCOCH 3 , -NHCOOCH 3 , -NHCOCH 2 OH, -NHCOCH 2 Cl, -NHCOCH 2 F or -NCH 3 COCH 3 .
  • R 2 is selected from the group consisting of -COOH, -COOCH 3 , -COOCH 2 CH 3 , -COOCH 2 CH 2 CH 3 or -COOCH(CH 3 ) 2 .
  • R 3 is selected from hydrogen, hydroxy, halo, benzyloxy, C 1 -C 4 alkoxy, C 5 -C 12 aryloxy or C 5 -C 12 cycloaryloxy .
  • R 3 is selected from -H, -OH, -Cl, -F, -OCH 3, -OCH 2 CH 3, -OCH 2 CH 2 CH 3, -OCH (CH 3) 2 or benzyl Oxygen.
  • R 4 is selected from hydrogen, halogen, hydroxy, C1-C4 alkoxy, benzyloxy or C5-C12 aryl group.
  • R 4 is selected from -H, -Cl, -F, -OH, -OCH 3, -OCH 2 CH 3, -OCH 2 CH 2 CH 3, -OCH (CH 3) 2 or benzyl Oxygen.
  • the present disclosure is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof, and a pharmaceutically acceptable carrier:
  • R 1 is selected from one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 8 hydrocarbyl, amino, C 1 -C 8 hydrocarbylcarbonylamino, C 1 -C 8 hydrocarbyloxycarbonylamino, One or more C 1 -C 4 hydrocarbyl-substituted amino, substituted aminocarbonyl C 1 -C 8 hydrocarbyl groups;
  • R 2 is selected from the group consisting of -COOH, -COOCH 3 , -COOCH 2 CH 3 , -COOCH 2 CH 2 CH 3 or -COOCH(CH 3 ) 2 ;
  • R 3 is selected from the group consisting of hydrogen, hydroxy, halogen, benzyloxy, C 1 -C 4 alkoxy, C 5 -C 12 aryloxy or C 5 -C 12 cycloaryloxy;
  • R 4 is selected from hydrogen, halogen, hydroxy, C 1 -C 4 alkoxy, benzyloxy or C 5 -C 12 aryloxy.
  • the present disclosure relates to a pharmaceutical composition of the formula (I) or a stereoisomer thereof or a pharmaceutical composition comprising a compound of the formula (I) or a stereoisomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a dermatological treatment, silver Uses in medicines for psoriasis, eczema and atopic dermatitis:
  • R 1 is selected from one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 8 hydrocarbyl, amino, C 1 -C 8 hydrocarbylcarbonylamino, C 1 -C 8 hydrocarbyloxycarbonylamino, One or more C 1 -C 4 hydrocarbyl-substituted amino, substituted aminocarbonyl C 1 -C 8 hydrocarbyl groups;
  • R 2 is selected from the group consisting of -COOH, -COOCH 3 , -COOCH 2 CH 3 , -COOCH 2 CH 2 CH 3 or -COOCH(CH 3 ) 2 ;
  • R 3 is selected from the group consisting of hydrogen, hydroxy, halogen, benzyloxy, C 1 -C 4 alkoxy, C 5 -C 12 aryloxy or C 5 -C 12 cycloaryloxy;
  • R 4 is selected from hydrogen, halogen, hydroxy, C 1 -C 4 alkoxy, benzyloxy or C 5 -C 12 aryloxy.
  • the present disclosure relates to a process for the preparation of a compound of formula (I) or a stereoisomer thereof:
  • R 1 is selected from one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 8 hydrocarbyl, amino, C 1 -C 8 hydrocarbylcarbonylamino, C 1 -C 8 hydrocarbyloxycarbonylamino, One or more C 1 -C 4 hydrocarbyl-substituted amino, substituted aminocarbonyl C 1 -C 8 hydrocarbyl groups;
  • R 2 is selected from the group consisting of -COOH, -COOCH 3 , -COOCH 2 CH 3 , -COOCH 2 CH 2 CH 3 or -COOCH(CH 3 ) 2 ;
  • R 3 is selected from the group consisting of hydrogen, hydroxy, halogen, benzyloxy, C 1 -C 4 alkoxy, C 5 -C 12 aryloxy or C 5 -C 12 cycloaryloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 4 alkoxy, benzyloxy or C 5 -C 12 aryloxy;
  • the preparation method described therein includes:
  • R 3 ' and R 4 ' in the formula (A-II) and the formula (A-III) are the same as those defined for R 3 and R 4 in the formula (I), and R 2 ' Selected from hydrogen, C 1 -C 4 alkyl;
  • R 1 ', R 3', R group in the general formula (I) is represented by R '4 1, R 3, R 4
  • R 2 ' is selected from hydrogen or C 1 -C 4 alkyl.
  • the method of reacting a compound of formula (A-I) with malonic acid and ammonium acetate to give a compound of formula (A-II) is carried out in an organic solvent.
  • illustrative examples of suitable organic solvents that can be used in the present disclosure to react a compound of formula (AI) with malonic acid and ammonium acetate to provide a compound of formula (A-II) include but Limited to methanol, ethanol, isopropanol and water.
  • the compound of formula (A-I) is reacted with malonic acid and ammonium acetate at a temperature of from about 50 ° C to about 130 ° C to provide a compound of formula (A-II).
  • esterification agents that can be used to prepare the compounds of formula (A-III) from the compounds of formula (A-II) include, but are not limited to, thionyl chloride, oxalyl chloride, HCl gas and acetyl chloride.
  • the method of reacting a compound of the formula (A-II) with an alcohol compound to give a compound of the formula (A-III) is carried out in an organic solvent.
  • illustrative examples of suitable organic solvents that can be used in the present disclosure to react a compound of formula (A-II) with an alcohol compound to provide a compound of formula (A-III) include, but are not limited to, Alcohols, tetrahydrofuran, dichloromethane, ethyl acetate and methyl tert-butyl ether.
  • illustrative examples of suitable alcohols that can be used in the present disclosure to react a compound of formula (A-II) with an alcohol compound to provide a compound of formula (A-III) include, but are not limited to, Methanol, ethanol and isopropanol.
  • the compound of formula (A-II) is reacted with an alcohol compound at a temperature of from about -20 ° C to about 30 ° C to provide a compound of formula (A-III).
  • a catalyst is added to the process of reacting a compound of formula (A-IV) with a compound of formula (A-III) to provide a compound of formula (I).
  • illustrative examples of suitable catalysts that can be used in the present disclosure to react a compound of formula (A-IV) with a compound of formula (A-III) to provide a compound of formula (I) include It is not limited to sodium acetate, potassium acetate, sodium carbonate, and potassium carbonate.
  • the method of reacting a compound of formula (A-IV) with a compound of formula (A-III) to give a compound of formula (I) is carried out in an organic solvent.
  • illustrative examples of suitable organic solvents that can be used in the present disclosure to react a compound of formula (A-IV) with a compound of formula (A-III) to provide a compound of formula (I) include However, it is not limited to acetic acid, formic acid, dimethylformamide, and dimethylacetamide.
  • a compound of formula (A-IV) is reacted with a compound of formula (A-III) at a temperature of from about 50 ° C to about 180 ° C to provide a compound of formula (I).
  • the present disclosure relates to a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • R 1 is selected from one or more of the following substituents which may be the same or different: halo, hydroxy, optionally substituted C 1 -C 6 hydrocarbyl, optionally substituted amino, optionally substituted C 1 -C 6 A hydrocarbylcarbonylamino group, an optionally substituted C 1 -C 6 hydrocarbylcarbonyloxy group, an optionally substituted C 1 -C 6 hydrocarbyloxycarbonylamino group, an optionally substituted C 1 -C 6 hydrocarbylcarbonylamino group.
  • R 1 is selected from one or more of the following substituents which may be the same or different: halo, hydroxy, optionally substituted alkyl, optionally substituted amino, optionally substituted alkylcarbonylamino, optionally substituted alkane A carbonyloxy group, an optionally substituted alkyloxycarbonylamino group, an optionally substituted alkylcarbonylamino group.
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted C 1 -C 6 alkyl, optionally substituted amino, optionally substituted C 1 -C 6 alkylcarbonylamino, optionally substituted C 1 -C 6 alkylcarbonyloxy, optionally substituted C 1 -C 6 alkyloxycarbonylamino, optionally substituted C 1 -C 6 alkylcarbonylamino.
  • R 1 is selected from one or more identical or different of the following substituents: halogen, hydroxy, optionally substituted methyl, optionally substituted amino, optionally substituted acetylamino, optionally substituted acetyloxy- Any optionally substituted tert-butoxycarbonylamino group.
  • R 1 is selected from one or more of the following substituents which may be the same or different: fluoro, chloro, hydroxy, methyl, amino, C 1 -C 6 alkyl substituted amino, acetylamino, halo Acetylamino, C 1 -C 6 alkyl substituted acetylamino, hydroxy substituted acetylamino, C 1 -C 6 alkyl substituted amino substituted acetylamino, NC 1 -C 6 alkyl substituted acetylamino, acetoxy a tert-butoxycarbonylamino group, a C 1 -C 6 alkyl-substituted tert-butoxycarbonylamino group.
  • R 1 is selected from one or more of the following substituents which may be the same or different: fluoro, chloro, hydroxy, methyl, amino, methylamino, dimethylamino, acetylamino, 2-chloroacetamido, 2-hydroxyacetamido, N-methylacetamido, 2-(dimethylamino)acetamido, acetoxy, tert-butoxycarbonylamino, N-methyl-tert-butoxycarbonylamino.
  • R 1 is selected from the group consisting of acetylamino.
  • R 2 is selected from an optionally substituted C 1 -C 6 hydrocarbyloxycarbonyl or carboxyl group.
  • R 2 is selected from an optionally substituted alkyloxycarbonyl or carboxyl group.
  • R 2 is selected from an optionally substituted C 1 -C 6 alkyloxycarbonyl or carboxyl group.
  • R 2 is selected from an optionally substituted methoxycarbonyl group, an optionally substituted ethoxycarbonyl group, an optionally substituted propoxycarbonyl group, an optionally substituted butoxycarbonyl group, an optionally substituted isopropoxycarbonyl group, or a carboxyl group.
  • R 2 is selected from methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isopropoxycarbonyl or carboxy.
  • R 2 is selected from methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl.
  • R ⁇ 3> is selected from hydrogen, halo, hydroxy, optionally substituted alkyloxy, optionally substituted arylalkyloxy, or optionally substituted cycloalkyloxy.
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C 1 -C 6 hydrocarbyloxy, optionally substituted C 6 -C 18 aryl hydrocarbyloxy, or optionally substituted C 3 -C 10 cyclic hydrocarbyloxy.
  • R ⁇ 3> is selected from hydrogen, halo, hydroxy, optionally substituted alkyloxy, optionally substituted arylalkyloxy, or optionally substituted cycloalkyloxy.
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C 1 -C 6 alkyloxy, optionally substituted C 6 -C 18 arylalkyloxy, or optionally substituted C 3 -C 10 cycloalkyloxy.
  • R 3 is selected from hydrogen, halogen, hydroxy, optionally substituted methoxy, optionally substituted ethoxy, optionally substituted propoxy, optionally substituted iso-propoxy, optionally substituted benzyl Oxyl or optionally substituted cyclopentyloxy.
  • R 3 is selected from the group consisting of hydrogen, chloro, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, benzyloxy or Cyclopentyloxy.
  • R 3 is selected from methoxy or ethoxy.
  • R 4 is selected from hydrogen, halogen, hydroxy, optionally substituted alkyloxy, optionally substituted arylalkyl group or an optionally substituted cycloalkyl group.
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C 1 -C 6 hydrocarbyloxy, optionally substituted C 6 -C 18 aryl hydrocarbyloxy, or optionally substituted C 3 -C 10 cyclic hydrocarbyloxy.
  • R 4 is selected from hydrogen, halogen, hydroxy, optionally substituted alkyloxy, optionally substituted arylalkyl group or an optionally substituted cycloalkyl group.
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C 1 -C 6 alkyloxy, optionally substituted C 6 -C 18 arylalkyloxy, or optionally substituted C 3 -C 10 cycloalkyloxy.
  • R 4 is selected from hydrogen, halogen, hydroxy, optionally substituted methoxy, optionally substituted ethoxy, optionally substituted propoxy, optionally substituted iso-propoxy, optionally substituted benzyl Oxyl or optionally substituted cyclopentyloxy.
  • R 4 is selected from the group consisting of hydrogen, chloro, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, benzyloxy or Cyclopentyloxy.
  • R 4 is selected from methoxy or ethoxy.
  • R 5 is selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 5 is selected from hydrogen, halogen, optionally substituted C 1 -C 6 hydrocarbyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 5 -C 12 aryl group or optionally substituted Heteroaryl.
  • R 5 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted C 5 -C 12 aryl, or optionally substituted heteroaryl.
  • R 5 is selected from hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 5 -C 12 aryl or any Substituted heteroaryl.
  • R 6 is selected from hydrogen, halogen, optionally substituted hydrocarbon group, an optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.
  • R 6 is selected from hydrogen, halogen, optionally substituted C 1 -C 6 hydrocarbyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 5 -C 12 aryl, or optionally substituted Heteroaryl.
  • R 6 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted C 5 -C 12 aryl or optionally substituted heteroaryl.
  • R 6 is selected from hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 5 -C 12 aryl or any Substituted heteroaryl.
  • n 0, 1, 2, 3 or 4.
  • R 5 , R 6 and the carbon atom to which they are attached form an optionally substituted cyclic hydrocarbon group, and n is 1.
  • R 5 , R 6 and the carbon atom to which they are attached form an optionally substituted C 3 -C 12 cycloalkyl group, and n is 1.
  • R 5 , R 6 and the carbon atom to which they are attached form an optionally substituted cycloalkyl, and n is 1.
  • R 5 , R 6 and the carbon atom to which they are attached form an optionally substituted C 3 -C 12 cycloalkyl, and n is 1.
  • R 5 , R 6 and the carbon atom to which they are attached form a C 3 -C 12 cycloalkyl group, and n is 1.
  • R 5 is selected from hydrogen, halogen, or C 1 -C 4 hydrocarbyl.
  • R 6 is selected from hydrogen, halogen, or C 1 -C 4 hydrocarbyl.
  • n 1 or 2.
  • R 5 is selected from hydrogen, halogen, or C 1 -C 4 hydrocarbyl
  • R 6 is selected from hydrogen, halogen, or C 1 -C 4 hydrocarbyl
  • n is 1 or 2.
  • R 5 is hydrogen
  • R 6 is hydrogen
  • n is one.
  • R 5 is hydrogen
  • R 6 is hydrogen
  • n is 1.
  • the compounds of the present disclosure have immunoglobulin E (IgE) inhibitory activity.
  • IgE immunoglobulin E
  • the compounds of the present disclosure have low toxicity.
  • the compounds of the present disclosure have good safety.
  • the compounds of the present disclosure are well tolerated.
  • the disclosure relates to the following compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof:
  • Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-isopropoxyphenyl)propanoate; 3- Methyl (4-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoate;
  • the present disclosure relates to a pharmaceutical composition
  • 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:
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; R 6 is selected from hydrogen, halo , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When a cyclic hydrocarbon group is formed together, n is 1.
  • the present disclosure relates to methods of treating or preventing immunoglobulin E (IgE)-mediated, preferably immunoglobulin E (IgE) mediated, diseases comprising administering to a subject in need thereof a therapeutically effective amount a compound of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount comprising a compound of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt
  • Pharmaceutical composition of carrier, diluent or excipient are examples of carrier, diluent or excipient:
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • a method of treating or preventing an immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE) mediated disease comprising administering to a subject in need of the method 1 mg to 10 g of the present invention A disclosed compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • a method of treating or preventing immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE) mediated comprises administering 10 mg to 3000 mg of the subject to an individual in need thereof.
  • a disclosed compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof comprises administering 10 mg to 3000 mg of the subject to an individual in need thereof.
  • a method of treating or preventing an immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE) mediated disease comprising administering 100 mg to 1000 mg of the subject to an individual in need of the method A disclosed compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • a method of treating or preventing immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE) mediated comprises administering 100 mg, 200 mg, 250 mg to an individual in need of the method. , 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.
  • the present disclosure relates to a compound of formula (II), a stereoisomer thereof, or a stereoisomer thereof, for use in the treatment or prevention of immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE) mediated diseases
  • a compound of formula (II) for use in the treatment or prevention of immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE) mediated diseases
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • the present disclosure relates to a therapeutically effective amount of a compound of formula (II), for use in the treatment or prevention of immunoglobulin E (IgE)-related, preferably immunoglobulin E (IgE) mediated diseases,
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • the present disclosure relates to the treatment or prevention of skin diseases, psoriasis, eczema, atopic dermatitis, urticaria, asthma, asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), allergic rhinitis a compound of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, cerebral venom, and parasitic infection :
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • the present disclosure relates to the use in the treatment or prevention of immunoglobulin E (IgE)-mediated skin diseases, psoriasis, eczema, atopic dermatitis, urticaria associated with immunoglobulin E (IgE) , asthma, asthma - chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), allergic rhinitis, seasonal allergic rhinitis, drug-induced interstitial pneumonia, bronchopulmonary aspergillosis, leprosy, acne-like and parasitic
  • R 1 is selected from one or more of the following substituents which may be the same or different: halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxy a carbonylamino group, an optionally substituted hydrocarbylcarbonylamino group;
  • R 2 is selected from an optionally substituted hydrocarbyloxycarbonyl group or a carboxyl group
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted aryl hydrocarbyloxy or optionally substituted cycloalkyloxy;
  • X is -CR 5 R 6 -, wherein when R 5 is selected from hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 6 is selected from hydrogen, halogen , optionally substituted hydrocarbyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; when R 5 , R 6 and the carbon atom attached thereto When an optionally substituted cyclic hydrocarbon group is formed together, n is 1.
  • a pharmaceutical composition comprises a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compounds of the present disclosure, stereoisomers thereof, or pharmaceutically acceptable salts thereof are used to treat or prevent immunoglobulin E (IgE)-mediated, preferably immunoglobulin E (IgE)-mediated, immunoglobulin E (IgE)-mediated
  • immunoglobulin E (IgE)-mediated preferably immunoglobulin E (IgE)-mediated, immunoglobulin E (IgE)-mediated
  • the route of administration of the disease to a mammal can be either a gastrointestinal route or a parenteral route.
  • the compounds of the present disclosure, stereoisomers thereof, or pharmaceutically acceptable salts thereof are used to treat or prevent immunoglobulin E (IgE)-mediated, preferably immunoglobulin E (IgE)-mediated, immunoglobulin E (IgE)-mediated
  • immunoglobulin E (IgE)-mediated preferably immunoglobulin E (IgE)-mediated, immunoglobulin E (IgE)-mediated
  • the route of administration of the disease to a mammal can be an oral route.
  • the compounds of the present disclosure, stereoisomers thereof, or pharmaceutically acceptable salts thereof are used to treat or prevent immunoglobulin E (IgE)-mediated, preferably immunoglobulin E (IgE)-mediated, immunoglobulin E (IgE)-mediated
  • immunoglobulin E (IgE)-mediated preferably immunoglobulin E (IgE)-mediated, immunoglobulin E (IgE)-mediated
  • the route of administration of the disease to a mammal can be an intrarectal route.
  • the compounds described in the present disclosure may be obtained in any suitable form such as tablets, capsules, powders, oral solutions, suspensions, rectal gels, rectal foams, rectal enemas or rectal suppositories.
  • suitable form such as tablets, capsules, powders, oral solutions, suspensions, rectal gels, rectal foams, rectal enemas or rectal suppositories.
  • Illustrative examples of such tablets include, but are not limited to, plain tablets, sugar coated tablets, and film coated tablets.
  • Examples of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, any adjuvants, carriers, excipients, aids that have been approved by the U.S. Food and Drug Administration for use in humans or animals. Flowing agents, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, osmotic pressure agents, solvents or emulsifiers, etc.
  • Various forms of carriers that have no side effects on the composition of the pharmaceutical composition are well known in the pharmaceutical arts and are for example found in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990). The description is hereby incorporated by reference in its entirety.
  • the pharmaceutical composition of the present disclosure can be administered by any method that achieves its intended purpose.
  • administration can be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal or oral. get on.
  • the route of administration may be a parenteral route, an oral route, and an intrarectal route.
  • the dosage administered will depend on the age, health and weight of the recipient, and, if concurrent, depends on the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.
  • Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, drages, semisolid preparations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, lozenges. , gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which may be prepared according to methods known in the art.
  • Particularly suitable for oral administration are ordinary tablets (primary tablets), sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration, suppositories, suitable Parenteral administration is a solution, an oil-based solution or an aqueous solution, in addition to a suspension, emulsion or implant, and suitable for topical use are ointments, creams or powders.
  • the product of the present disclosure may also be lyophilized, and the resulting lyophilizate is used, for example, to prepare an injection.
  • the formulations given may be sterilized and/or contain adjuvants such as wetting agents, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying osmotic pressure, buffer substances, Dyestuffs, flavoring agents and/or numerous additional active ingredients, such as one or more vitamins.
  • adjuvants such as wetting agents, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying osmotic pressure, buffer substances, Dyestuffs, flavoring agents and/or numerous additional active ingredients, such as one or more vitamins.
  • compositions of the present disclosure are prepared as tablets, solutions, granules, patches, for parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral use. Ointment, capsule, aerosol or suppository.
  • Preservatives can be provided in the pharmaceutical compositions.
  • sodium benzoate, ascorbic acid, and an ester of p-hydroxybenzoic acid can be added as a preservative.
  • antioxidants and suspending agents can be used.
  • alcohols, esters, sulfated aliphatic alcohols, and the like can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate , magnesium aluminate aluminate, synthetic aluminum silicate, calcium carbonate, calcium hydrogencarbonate, calcium hydrogen phosphate, calcium hydroxymethyl cellulose, etc. can be used as an excipient; magnesium stearate, talc, hardened oil, etc.
  • coconut oil olive oil, sesame oil, peanut oil, soybean can be used as a suspension or lubricant; vinegar cellulose as a derivative of sugars such as cellulose or sugar, or as a derivative of polyethylene
  • a methyl acetate-methacrylate copolymer of the substance can be used as a suspension; and a plasticizer such as a phthalate ester can be used as a suspension.
  • Suitable routes of administration may, for example, include oral administration, rectal administration, transmembrane administration, parenteral delivery, topical administration or enteral administration; parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary. Injection and intrathecal injection, direct intraventricular injection, intraperitoneal injection, intranasal injection or intraocular injection.
  • the compounds can also be extended at a predetermined rate and/or in a sustained release or controlled release dosage form including depot injections, osmotic pumps, pills, transdermal (including electromigration) patches, and the like. Timing, pulsed administration.
  • compositions of the present disclosure can be produced in a known manner, for example, by conventional methods of mixing, dissolving, granulating, making tablets, grinding, emulsifying, encapsulating, entrapping or tableting.
  • the pharmaceutical composition used can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants, which facilitate the treatment of the active compound into A pharmaceutically acceptable formulation.
  • physiologically acceptable carriers comprising excipients and adjuvants, which facilitate the treatment of the active compound into A pharmaceutically acceptable formulation.
  • suitable formulations will depend on the route of administration chosen. Any of the well-known techniques, carriers, and excipients can be used as appropriate and understood in the art.
  • the injection can be prepared in the following conventional form: as a solution or suspension, a solid dosage form suitable as a solution or suspension prior to injection, or as an emulsion.
  • Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like.
  • the injectable pharmaceutical compositions may contain minor amounts of non-toxic adjuvants such as wetting agents, pH buffering agents and the like.
  • Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer.
  • Absorption enhancing formulations e.g., liposomes
  • the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • a carrier enables the compound of the present invention to be formulated into tablets, pills, troches, capsules, liquids, gels, syrups, ointments, suspensions, solutions, powders and the like.
  • the pharmaceutical preparation for oral administration can be obtained by mixing the active compound with a solid excipient, grinding the resulting mixture arbitrarily and processing the granule mixture, if necessary, after adding a suitable adjuvant to obtain a tablet or Lozenge core.
  • 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, a Cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP).
  • a disintegrating agent such as crosslinked polyvinylpyrrolidone, agar or alginic acid or alginate such as sodium alginate may be added if necessary.
  • the coating core is suitably coated.
  • a concentrated sugar solution may optionally be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer A solution and a suitable organic solvent or solvent mixture.
  • a dye or pigment may be added to the tablet or lozenge coating.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable Organic solvent or solvent mixture.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol.
  • the push-fit capsules can comprise the active ingredient in admixture 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.
  • the active ingredient can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol.
  • a stabilizer may be added. All formulations for oral administration should achieve a dosage suitable for such administration.
  • compositions of the present disclosure may comprise from 0.1% to 95% of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • compositions of the present disclosure may comprise from 1% to 70% of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • composition or formulation to be administered will contain an amount of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disease/condition of the subject being treated.
  • At least one compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can be used in any A suitable systemic and/or topical method of delivering a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered to a patient.
  • Non-limiting examples of methods of administration include (a) administration by the oral route, including administration in the form of capsules, tablets, granules, sprays, syrups, or the like; (b) by non- Oral administration, for example, rectal, vaginal, intraurethral, intraocular, intranasal or intraaural, the administration includes an aqueous suspension, an oily preparation, or the like, or in the form of drops, sprays, suppositories, ointments, ointments, and the like.
  • a suitable mode of administration is considered to be the contact of the compound described in the present disclosure with living tissue.
  • compositions suitable for administration include those in which an effective amount of the active ingredient is included in such compositions.
  • the dose required for a therapeutically effective amount of the pharmaceutical composition described in this disclosure depends on the route of administration, the type of animal being treated, including the human, and the physical characteristics of the particular animal in question. The dosage can be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent medical therapy, and other factors recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to an amount of a compound that is effective to prevent, alleviate or ameliorate the symptoms of the disease, or to prolong the life of the individual being treated. The actual ability of a person skilled in the art can well determine a therapeutically effective amount, particularly in accordance with the detailed disclosure provided by the present disclosure.
  • the dosage and specific mode of administration for in vivo administration will vary depending on the age, weight and type of mammal being treated, the particular compound employed, and the compound employed. Specific use. Those skilled in the art will be able to achieve the objective of determining an effective dosage level, i.e., the dosage level necessary to achieve the desired effect, using conventional pharmacological methods. Typically, human clinical application of the product begins at a lower dosage level as the dosage level increases until the desired effect is achieved. Alternatively, an established in vitro study can be used to establish an effective dosage and route of administration of the compositions identified by the methods using established pharmacological methods.
  • the application of potential products begins at a higher dose level, as the dose is reduced until the desired effect is no longer achieved or the undesirable side effects disappear.
  • the dosage range can be broader depending on the desired effect and therapeutic indication.
  • the dosage can be from about 10 [mu]g/kg body weight to 1000 mg/kg body weight, and in certain embodiments from about 100 [mu]g/kg body weight to 300 mg/kg body weight.
  • the dosage can be based on and calculated from the body surface area of the patient.
  • the dosage of the composition to be administered to a patient can range from about 0.5 mg/kg to 1000 mg/kg of patient body weight.
  • the dose may be administered once or two or more times during one or several days depending on the needs of the patient.
  • the human dosage of the compound is established by at least some of the conditions, the present disclosure will use those same dosages, or dosages ranging from about 0.1% to 500% of the determined human dose, in certain embodiments the dosage. The range of 25% to 250% of the determined human dose.
  • a suitable human dose can be administered from a half effective dose or a median dose of the infectious dose, or from other suitable values from in vitro or in vivo studies. Inferred, as quantified in the Institute of Toxicity Research and Performance in Animals.
  • the attending physician will know how and when to terminate, interrupt or adjust the administration. 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 condition of interest will vary with the severity of the condition being treated and the route of administration. The severity of the disease state can be assessed, for example, in part by standard prognostic evaluation methods.
  • the dosage and possible dosage frequency will also vary depending on the age, weight, and response of the individual patient. A protocol comparable to the above discussed protocol can be used in veterinary medicine.
  • the daily dosing regimen for an adult patient is, for example, an oral dose of from 0.1 mg to 2000 mg of each active ingredient, and in certain embodiments from 1 mg to 2000 mg of each active ingredient, for example from 5 mg to 1500 mg of each active ingredient.
  • the intravenous, subcutaneous or intramuscular dose of each active ingredient used is from 0.01 mg to 1000 mg, and in certain embodiments from 0.1 mg to 1000 mg, such as from 1 mg to 800 mg.
  • the dosage can be calculated as the free base.
  • the composition is administered from 1 to 4 times daily.
  • compositions described in this disclosure may be administered by continuous intravenous infusion, in certain embodiments at doses up to 2000 mg of each active ingredient per day.
  • doses up to 2000 mg of each active ingredient per day.
  • the compound is administered during continuous treatment, such as one week or weeks, or months or years.
  • the dose and dosing interval can be adjusted individually to provide a plasma level sufficient to maintain an adjustment effect or an active fraction of the lowest effective concentration (MEC).
  • MEC lowest effective concentration
  • the MEC of each compound is different, but the MEC can be evaluated from in vitro data.
  • the dosage required to achieve MEC will depend on the individual characteristics and route of administration. However, plasma concentration can be determined using HPLC (High Performance Liquid Chromatography) assay or bioassay.
  • the medication interval can also be determined using the MEC value. Treatments that maintain plasma levels above the MEC over a period of 10-90% of the time, in some embodiments, 30-90% of the time, and in some embodiments, 50-90% of the time should be used.
  • the regimen is administered to the composition.
  • the effective local concentration of the drug is independent of plasma concentration.
  • the amount of the composition to be administered depends on the individual to be treated, depending on the weight of the individual, the severity of the pain, the mode of administration, and the judgment of the prescribing physician.
  • the potency and toxicity of the compounds described in this disclosure can be assessed using known methods.
  • the toxicology of a particular compound or a subset of such compounds that share certain chemical moieties such as a mammalian cell line and, in certain embodiments, a human cell line
  • the toxicology of a particular compound or a subset of such compounds that share certain chemical moieties can be established by measuring the toxicity of the cell line in vitro.
  • the results of such studies are generally predictive of toxicity in animals such as mammals, or more specifically, toxicity in humans.
  • the toxicity of a particular compound in an animal model such as a mouse, rat, rabbit or monkey can be determined using known methods.
  • the efficacy of a particular compound can be determined using a number of accepted methods, such as in vitro methods, animal models, or human clinical trials.
  • the composition can be placed into a pack or dispenser device, which can contain one or more unit dosage forms containing the active ingredient.
  • the package may for example comprise a metal or plastic foil, such as a blister pack.
  • the pack or dispenser device can be provided with instructions for administration.
  • the packaging or dispensing device may also carry precautions associated with the container, the precautions being prescribed by a government agency that manages the manufacture, use or sale of the drug, the precaution reflecting that the drug form has been Approved for human or veterinary administration. Such considerations, for example, may be labels for prescription drugs approved by the State Food and Drug Administration or the US Food and Drug Administration, or approved product specifications.
  • Compositions comprising a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in a compatible pharmaceutical carrier may also be prepared in a suitable container and labeled for use. Treatment for a given disease state.
  • the present disclosure relates to a process for the preparation of a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising:
  • R 3" and R 4" in the formula (B-II) and the formula (B-III) is the same as the definition of R 3 and R 4 in the formula (II), and R 2 ' Selected from hydrogen or a hydrocarbon group;
  • X is -CR 5 R 6 -, wherein R 5 is hydrogen, R 6 is hydrogen, and n is 1.
  • the method of reacting a compound of the formula (B-I) with malonic acid and ammonium acetate to give a compound of the formula (B-II) is carried out in an organic solvent.
  • illustrative examples of suitable organic solvents that can be used in the present disclosure to react a compound of formula (BI) with malonic acid and ammonium acetate to provide a compound of formula (B-II) include but Limited to methanol, ethanol, isopropanol and water.
  • the compound of formula (B-I) is reacted with malonic acid and ammonium acetate at a temperature of from about 50 ° C to about 130 ° C to provide a compound of formula (B-II).
  • illustrative examples of suitable esterification agents that can be used to prepare a compound of formula (B-III) from a compound of formula (B-II) include, but are not limited to, thionyl chloride, oxalyl chloride, HCl gas and acetyl chloride.
  • the method of reacting a compound of the formula (B-II) with an alcohol compound to give a compound of the formula (B-III) is carried out in an organic solvent.
  • illustrative examples of suitable organic solvents that can be used in the present disclosure to react a compound of formula (B-II) with an alcohol compound to provide a compound of formula (B-III) include, but are not limited to, Alcohols, tetrahydrofuran, dichloromethane, ethyl acetate and methyl tert-butyl ether.
  • illustrative examples of suitable alcohols that can be used in the present disclosure to react a compound of formula (B-II) with an alcohol compound to provide a compound of formula (B-III) include, but are not limited to, Methanol, ethanol and isopropanol.
  • the compound of formula (B-II) is reacted with an alcohol compound at a temperature of from about -20 ° C to about 30 ° C to provide a compound of formula (B-III).
  • a catalyst is added to the process of reacting a compound of the formula (B-IV) with a compound of the formula (B-III) to give a compound of the formula (II).
  • illustrative examples of suitable catalysts that can be used in the present disclosure to react a compound of formula (B-IV) with a compound of formula (B-III) to provide a compound of formula (II) include It is not limited to sodium acetate, potassium acetate, sodium carbonate, and potassium carbonate.
  • the method of reacting a compound of formula (B-IV) with a compound of formula (B-III) to give a compound of formula (II) is carried out in an organic solvent.
  • illustrative examples of suitable organic solvents that can be used in the present disclosure to react a compound of formula (B-IV) with a compound of formula (B-III) to provide a compound of formula (II) include However, it is not limited to acetic acid, formic acid, dimethylformamide, and dimethylacetamide.
  • the compound of formula (B-IV) is reacted with a compound of formula (B-III) at a temperature of from about 50 ° C to about 180 ° C to provide a compound of formula (II).
  • PE petroleum ether
  • 3-amino-3-(3,4-dimethyl) was obtained by the reaction of 3-amino-3-(3,4-dimethoxyphenyl)propanoic acid (4.28 g) by the synthesis method in Example 1.
  • Methyloxyphenyl)propionic acid methyl ester hydrochloride (4.4 g, HPLC purity 99.89%); yield 96.7%.
  • 3-amino-3-(3,4-diethyl) was prepared by the synthesis method of Example 1 from 3-amino-3-(3,4-diethoxyphenyl)propionic acid (4.0 g). Methyloxyphenyl)propionic acid methyl ester hydrochloride (2.9 g, HPLC purity 99.26%); yield 60.9%. MS (m/e): 268.15 (M+H + ).
  • aqueous phase was back-extracted with EA (30 ml), the organic phase was combined, washed with a saturated aqueous solution of NaCI, and then filtered, dried over anhydrous MgSO4, filtered and dried to give 3-(4-(2-(dimethylamino)acetyl) Amino)-1,3-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid methyl ester.
  • 3-amino-3-(3-) was obtained by the reaction of 3-amino-3-(3-ethoxy-4-isopropoxyphenyl)propionic acid (2.7 g). Methyl ethoxy-4-isopropoxyphenyl)propanoate hydrochloride (2.4 g, HPLC purity 98.69%); yield 75%. MS (m/e): 282.16 (M+H + ).
  • 3-ethoxy-4-cyclopentyloxybenzaldehyde was obtained by the reaction of 3-ethoxy-4-hydroxybenzaldehyde (3.0 g) with bromocyclopentane by the synthesis method in Example 3. g, HPLC purity 96.97%); yield 99%.
  • 3-amino-3-(3-) was obtained by the reaction of 3-amino-3-(3-ethoxy-4-cyclopentyloxyphenyl)propanoic acid (2.78 g). Methyl ethoxy-4-cyclopentyloxyphenyl)propanoate hydrochloride (3.25 g, HPLC purity 99.60%); yield 100%. MS (m/e): 308.18 (M+H + ).
  • Methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoate 505 mg Methyl iodide (177 mg) and potassium carbonate (314 mg) were added to a reaction flask, DMF (5 ml) was added, and the mixture was stirred at room temperature for 100 hr. Water (30 ml) and DCM (200 ml) were added to the mixture.
  • the obtained crude product was purified by silica gel chromatography eluting elut elut elut elut elut elut eluting MS (m / e): 477.25 (M + Na + ).
  • Example 3 Using the synthesis method of Example 3, the title compound (403 mg, HPLC purity 96.38%) was obtained from the compound 3-hydroxy-4-methoxybenzaldehyde (5.0 g) and bromoisopropane; MS (m) /e): 477.15 (M + Na + ).
  • Example 2 Using the synthesis method of Example 1, from (R)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propanoic acid hydrochloride (6.5 g) and ethanol (25 ml) The reaction produces (R)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propanoic acid ethyl ester hydrochloride. A white solid product (3.15 g, HPLC purity 94.51%, used directly in the next step) was obtained.
  • DNCB induces pharmacodynamic evaluation of Balb/c mouse atopic dermatitis model
  • mice Sixty healthy male SPF Balb/c mice, weighing 19-21 g, were randomly divided into 6 groups according to body weight, with 10 rats in each group.
  • DNCB is dinitrochlorobenzene; BID means twice a day.
  • the hair around the right ear of the mouse should be removed to reduce the interference of the drug on the experiment due to adhesion to the hair.
  • the experiment was started as the first day, and the administration schedules and induction schemes of each group are shown in Fig. 1.
  • the specific ear thickness measurement time is slightly adjusted from Figure 1.
  • each animal was subjected to blood sampling to measure the concentration of immunoglobulin (IgE) in the serum (according to the kit instructions).
  • the animal's ears were cut, and the 8mm puncher was used to weigh the equal area ear in the fixed position of the ear to calculate the difference in swelling degree between the ears.
  • IgE immunoglobulin
  • mice in different groups were measured by One-Way Anova in SPSS 17.
  • the ear weight in the same area on the 18th day and the IgE concentration in the serum were statistically analyzed.
  • the abnormal value was deleted by G test, which was expressed as p ⁇ 0.05. There are statistical differences.
  • Ear swelling degree (mg) right ear weight (mg) - left ear weight (mg);
  • Ear thickness change (mm) right ear thickness (mm) - left ear thickness (mm);
  • Ear swelling degree inhibition rate (%) 1 - (early ear swelling degree - blank control ear swelling degree) / (model control ear swelling degree - blank control ear swelling degree) ⁇ 100%;
  • Ear thickness change inhibition rate (%) 1 - (change in ear thickness of the drug-administered 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%;
  • IgE inhibition rate (%) 1 - (IgE concentration in the administration group - IgE concentration in the blank control group) / (IgE concentration in the model control group - IgE concentration in the blank control group) ⁇ 100%.
  • DNCB induces pharmacodynamic evaluation of Balb/c mouse atopic dermatitis model
  • mice Seventy healthy male SPF Balb/c mice, weighing 19-21 g, were randomly divided into 7 groups according to body weight, with 10 rats in each group.
  • the hair around the right ear of the mouse should be removed to reduce the interference of the drug on the experiment due to adhesion to the hair.
  • the experiment was started as the first day, and the administration schedules and induction schemes of each group are shown in Fig. 2.
  • each animal was subjected to blood sampling to measure the concentration of immunoglobulin (IgE) in the serum (according to the kit instructions).
  • the animal's ears were cut, and the 8mm puncher was used to weigh the equal area ear in the fixed position of the ear to calculate the difference in swelling degree between the ears.
  • IgE immunoglobulin
  • Ear swelling degree (mg) right ear weight (mg) - left ear weight (mg);
  • Ear swelling degree inhibition rate (%) 1 - (early ear swelling degree - blank control ear swelling degree) / (model control ear swelling degree - blank control ear swelling degree) ⁇ 100%;
  • IgE inhibition rate (%) 1 - (IgE concentration in the administration group - IgE concentration in the blank control group) / (IgE concentration in the model control group - IgE concentration in the blank control group) ⁇ 100%.
  • DNCB induces pharmacodynamic evaluation of Balb/c mouse atopic dermatitis model
  • mice Thirty healthy male SPF Balb/c mice, weighing 19-21 g, were randomly divided into 3 groups according to body weight, with 10 rats in each group.
  • the hair around the right ear of the mouse should be removed to reduce the interference of the drug on the experiment due to adhesion to the hair.
  • the experiment was started as the first day, and the administration schedules and induction schemes of each group are shown in Fig. 3.
  • the specific ear thickness and weight measurement time are slightly adjusted as shown in Figure 3.
  • each animal was subjected to blood sampling to measure the concentration of immunoglobulin (IgE) in the serum (according to the kit instructions).
  • the animal's ears were cut, and the 8mm puncher was used to weigh the equal area ear in the fixed position of the ear to calculate the difference in swelling degree between the ears.
  • IgE immunoglobulin
  • mice in different groups were measured by One-Way Anova in SPSS 17.
  • the ear weight in the same area on the 19th day and the IgE concentration in serum were statistically analyzed.
  • the abnormal value was deleted by G test, which was expressed as p ⁇ 0.05. There are statistical differences.
  • Ear swelling degree (mg) right ear weight (mg) - left ear weight (mg);
  • Ear thickness change (mm) right ear thickness (mm) - left ear thickness (mm);
  • Ear swelling degree inhibition rate (%) 1 - (early ear swelling degree - blank control ear swelling degree) / (model control ear swelling degree - blank control ear swelling degree) ⁇ 100%;
  • Ear thickness change inhibition rate (%) 1 - (change in ear thickness of the drug-administered 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%;
  • IgE inhibition rate (%) 1 - (IgE concentration in the administration group - IgE concentration in the blank control group) / (IgE concentration in the model control group - IgE concentration in the blank control group) ⁇ 100%.
  • ICR mice Forty male ICR mice were divided into 5 groups, 8 in each group.
  • TPA preparation method 2mg/mL TPA mother liquor (dissolved in DMSO) 40 ⁇ L + 600 ⁇ L acetone mixed and used, ready to use;
  • mice Prior to the experiment, animals were grouped to remove hair around the right ear of the mouse.
  • a dose of 40 ⁇ L means a total of 40 ⁇ L for two administrations.
  • the one-Way ANOVA multi-group detection index in SPSS17.0 was used to analyze and test the ear swelling degree and ear swelling rate 5 hours after model administration, and the difference was statistically significant at P ⁇ 0.05.
  • Ear swelling degree (mg) right ear weight (mg) - left ear weight (mg);
  • Ear swelling rate (%) (right ear weight - left ear weight) / left ear weight ⁇ 100%;
  • Inhibition rate of ear swelling degree (%) 1 - (degree of ear swelling in the administration group - ear swelling degree in the blank control group) / (model control ear swelling degree - blank control ear swelling degree) ⁇ 100%.
  • TPA preparation method 2mg/mL TPA mother liquor (dissolved in DMSO) 40 ⁇ L + 600 ⁇ L acetone mixed and used, ready to use;
  • mice Prior to the experiment, animals were grouped to remove hair around the right ear of the mouse.
  • a dose of 40 ⁇ L means a total of 40 ⁇ L for two administrations.
  • the one-Way ANOVA multi-group test index in SPSS17.0 was used to analyze and test the ear swelling degree and ear swelling rate 5 hours after the model administration, and the difference was statistically significant at P ⁇ 0.05.
  • Ear swelling degree (mg) right ear weight (mg) - left ear weight (mg);
  • Ear swelling rate (%) (right ear weight - left ear weight) / left ear weight ⁇ 100%;
  • Inhibition rate of ear swelling degree (%) 1 - (degree of ear swelling in the administration group - ear swelling degree in the blank control group) / (model control ear swelling degree - blank control ear swelling degree) ⁇ 100%.
  • TPA preparation method 2mg/mL TPA mother liquor (dissolved in DMSO) 40 ⁇ L + 600 ⁇ L acetone mixed and used, ready to use;
  • mice Prior to the experiment, animals were grouped to remove hair around the right ear of the mouse.
  • a dose of 40 ⁇ L means a total of 40 ⁇ L for two administrations.
  • the one-Way ANOVA multi-group detection index in SPSS17.0 was used to analyze and test the ear swelling degree and ear swelling rate 5 hours after model administration, and the difference was statistically significant at P ⁇ 0.05.
  • Ear swelling degree (mg) right ear weight (mg) - left ear weight (mg);
  • Ear swelling rate (%) (right ear weight - left ear weight) / left ear weight ⁇ 100%;
  • Inhibition rate of ear swelling degree (%) 1 - (swelling degree of the administration group - swelling degree of the blank control group) / (swelling degree of the model control group - swelling degree of the blank control group) ⁇ 100%.
  • Oral gavage administration was carried out once a day for 22 days, and each administration group was administered with 300 mg/kg of the corresponding compound, and the vehicle control group was given an equal volume of sodium carboxymethylcellulose (CMC-Na).
  • CMC-Na sodium carboxymethylcellulose
  • the behavior and state of the rats after administration were observed daily for abnormality, whether or not poisoning occurred, and the animal reaction was recorded.
  • 3 animals/sex/group animals were sacrificed, and the organ index was observed and collected. The other 3 animals/sex/group animals were sacrificed after one week of observation. The organs were observed and collected.
  • the above compounds were administered orally to SD rats once a day for 22 consecutive days, and no significant drug-related toxicity was observed.
  • SPF healthy SD rats male and female, were randomly divided into 7 groups according to gender groups, 6 rats/sex/group, respectively, vehicle control group and compound administration group, 12 rats in each group, male and female. .
  • Oral gavage administration was carried out once a day for 22 days, and 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 continuous administration for 22 days, the behavior and state of the rats after administration were observed daily for abnormality, whether or not poisoning occurred, and the animal reaction was recorded. After 22 days of continuous administration, 3 animals/sex/group animals were sacrificed, and the organ index was observed and collected. The other 3 animals/sex/group animals were sacrificed after one week of observation. The organs were observed and collected.

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Abstract

公开了通式(I)化合物、其立体异构体： (I) 其中，R1、R2、R3和R4如本公开中定义。

Description

异吲哚衍生物
相关申请的引用
本公开要求2018年4月17日向中华人民共和国国家知识产权局提交的申请号为201810341153.0、发明名称为“具有抗炎作用的异吲哚类衍生物及其制备和应用”的发明专利申请的全部权益，并通过引用的方法将上述发明专利申请的全部内容并入本公开。
领域
本公开大体上涉及有机化学与药物化学领域。
背景
免疫球蛋白E(IgE)是一种分泌型免疫球蛋白，由两条轻链和两条重链组成。它是由鼻咽、扁桃体、支气管、胃粘膜等处固有层的浆细胞产生，是引起I型变态反应的主要抗体。尽管这种抗体在人类血清中含量最少，但其在过敏性疾病中扮演着重要的角色，可以在不同的组织和器官中引起炎症免疫反应。IgE相关的疾病临床表现从轻微症状到危及生命的事件等，可明显影响患者身体和心理健康，导致生活质量下降，受到越来越多的重视。
湿疹是一种慢性复发性、炎症性皮肤疾病，好发于婴儿和儿童，也可发生于成人。据研究，湿疹在西方国家患病率高达10％以上，美国为10.7％，近年来流行病学研究表明，我国一般人群患病率已经接近西方国家，近20年来在工业化国家中的发病率还在升高。我国不断推进工业化进程的同时人民的生活水平明显提高，感染性皮肤病逐渐减少，而过敏性皮肤病却逐渐增加。其发病机制复杂，主要与遗传背景、环境刺激、表皮屏障缺陷、免疫失调等因素有关。表皮屏障的破坏刺激炎症反应，急性期B细胞产生IgE，导致肥大细胞、嗜碱性粒细胞脱颗粒。急性期表皮增厚，神经纤维增生，趋化因子表达增加。该病常伴有剧烈瘙痒、反复发作，时轻时重，病程迁延难愈的特点，是临床上一种慢性、复发性、炎症性皮肤病，可持续数月、数年甚至 数十年，最显著的症状是瘙痒剧烈，可明显影响患者的学习、工作和生活，严重者还可影响睡眠。该类过敏性皮肤类疾病对患者及其家人生活质量的影响以及对社会造成的经济负担的逐渐增加，迫切要求对于疾病致病因素、发病机制的探讨以及在社会层面建立合适的应对措施，缓解或消除临床症状，消除诱发和/或加重因素，减少和预防复发，提高患者的生活质量，消退或改善症状，使患者可享受正常生活。
特应性皮炎患者中有80％以上血清总IgE显著高于正常人(张金桃等，广东医学，2007，28(10)，1688-1690)，特应性皮炎患者血清总IgE浓度与病情严重程度呈正相关，提示血清IgE是特应性皮炎病情活动性的指标。在特应性皮炎发病机制中，IgE起着很重要的作用，外界抗原与IgE结合后通过两种途径促使血嗜酸性粒细胞增多：①与肥大细胞上的IgE受体结合，刺激肥大细胞释放嗜酸性粒细胞趋化因子。②被表皮内的朗格汉斯细胞吞噬处理，将抗原呈递给T细胞，使之活化进而产生多种细胞因子包括嗜酸性粒细胞趋化因子，大量嗜酸性粒细胞脱颗粒所释放的碱性蛋白造成组织损伤。
哮喘又名支气管哮喘，是以气管痉挛为主要病理特点的慢性气管疾病，是由多种细胞及细胞组分参与的慢性气道炎症，气道炎症几乎是所有类型哮喘的共同特征，也是临床症状和气道高反应性的基础。IgE在哮喘的炎症反应中发挥着非常重要的作用(赵鑫玉等，临床肺科杂志，2018，23(7)，1325-1328页)。当过敏原首次进入机体时，通过树突状细胞的递呈引发一系列炎症级联反应，B细胞产生大量IgE，IgE与肥大细胞和嗜碱粒细胞表面的IgE高亲和力受体(FcεRI)结合形成FcεRI-IgE复合物；过敏原再次进入机体时，可迅速与该复合物结合，致使组胺、白三烯、前列腺素等炎性介质大量释放，引起黏液分泌、气道平滑肌收缩、血管通透性增高；炎症细胞在上述炎性介质的作用下又可级联扩大IgE的生成，发生迟发相变态反应，加速哮喘进展。而另有研究指出，特异性的IgE分子还可与树突状细胞结合，使其抗原递呈作用加强，上调肥大细胞、嗜碱粒细胞表面的FcεRI受体表达；有研究结果显示，IgE可通过增加细胞外基质(ECM)导致气道重塑，还参与病毒诱导的哮喘急性发作过程。
哮喘-慢性阻塞性肺病(COPD)重叠综合征(ACOS)是一种同时包括哮喘和COPD在内的阻塞性气道疾病(何忠等，国际呼吸杂志，2017，37(16)，1207-1210页)，通常存在以下3种常见的病理生理改变，即：气道炎症，气道阻塞(AO)，以及气道高反应性(AHR)。西班牙专家共识认为COPD患者若出现支气管舒张试验强阳性、痰液中检出嗜酸粒细胞、总IgE含量增高、40岁以前患有哮喘以及个人过敏史即可考虑诊断ACOS。
荨麻疹(徐亚伟等，上海第二医科大学学报，Vol.14，Suppl.1994，118-120)，俗称“风疹块”，是由于皮肤、黏膜小血管扩张及渗透性增加而出现的一种局限性水肿反应。临床上表现为大小不等的风团伴瘙痒。通常在2至24h内消退，但反复发生新的皮疹。慢性荨麻疹是指上述风团伴瘙痒几乎每天发生，持续6周以上。荨麻疹的发病机制虽然较为复杂，但都与肥大细胞活化有关。肥大细胞活化有免疫性和非免疫性两类途径，前者皮肤水肿风团或是发生在IgE依赖的抑或是补体系统介导的免疫反应过程中。
过敏性鼻炎即变应性鼻炎，是指特应性个体接触变应原后，主要由IgE介导的介质(主要是组胺)的释放，并有多种免疫活性细胞和细胞因子等参与的鼻粘膜非感染性炎性疾病。过敏性鼻炎常年性与季节性，在任何年龄段均有发生，以青少年最为多见，患者症状为打喷嚏、流泪、清涕、臂痒、嗅觉减退等。IgE介导的I型变态反应为过敏反应发生的基础，李朝晖等(李朝晖等，解放军预防医学杂志，2018，36(10)，13-15)研究发现过敏性鼻炎患者IgE水平明显高于正常人，IgE在过敏性鼻炎的发病机理中具有重要的作用，IgE参与了过敏性鼻炎的免疫发生机理，可以作为过敏性鼻炎的有效监测指标，具有重要的临床意义。
与IgE升高相关的常见疾病还包括：季节性过敏性鼻炎(Holgate S T，World Allergy Organization Journal，2014，7，17和王寒梅，孙仁山，临床军医杂志，2017(8)，872-874)、药物性间质性肺炎(尹文杰等，中国药学大会暨中国药师周，2010)、支气管肺曲霉菌病(Holgate S T，World Allergy Organization Journal，2014，7，17)、麻风(何浩明等， 中国麻风皮肤病杂志，1989(4)，210-211)、类天胞疮(尹悦，李莉，中华检验医学杂志，2018，41(3)，242-245)及某些寄生虫感染等。
对于IgE分子作用机制的深入理解促进了以IgE炎症途径为治疗靶点的药物研发。抗抗IgE治疗通过减少游离IgE水平，导致表达于肥大细胞，嗜碱性粒细胞和树突状细胞的高亲和力IgE受体(FcεRI)减少，减少炎症标志物，从而发挥疗效。奥马珠单抗是第一个靶向针对IgE，人源化的IgE单克隆抗体。奥马珠单可抗用于6岁或12岁及以上的儿童、青少年和成人的重度持续性过敏性哮喘患者的治疗，减少哮喘急性发作次数，减少吸入激素的使用，改善哮喘相关的生命质量，减少住院及急诊次数，并具有良好的安全性。最常见的不良事件是短暂的注射部位反应。但是作为蛋白质抗体类药物，不但生产难度高、工艺复杂，而且在保存、运输方面要求也极为苛刻。更为重要的是，它们作为治疗用蛋白质，必然存在潜在的免疫原性。小分子的IgE抑制剂，是过敏性疾病药物开发的一个方向，小分子化合物具有良好的药理学性质，安全性更佳，并且价格低廉，患者依从性好等优点。
概述
一方面，本公开涉及通式(I)化合物、其立体异构体：
Figure PCTCN2019082943-appb-000001
其中，
R 1选自一个或多个取代基，该取代基选自氢、卤素、羟基、C 1-C 8烃基、氨基、C 1-C 8烃基羰基氨基、C 1-C 8烃基氧羰基氨基、一个或多个C 1-C 4烃基取代的氨基、取代的氨基羰基C 1-C 8烃基；
R 2选自羧基或酯基；
R 3选自氢、羟基、卤素、C 1-C 8烃氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基；
R 4选自氢、卤素、羟基、C 1-C 8烃氧基或C 5-C 12芳基氧基。
另一方面，本公开涉及药物组合物，其包含通式(I)化合物或其立体异构体以及药物可接受的载体：
Figure PCTCN2019082943-appb-000002
其中，
R 1选自一个或多个取代基，该取代基选自氢、卤素、羟基、C 1-C 8烃基、氨基、C 1-C 8烃基羰基氨基、C 1-C 8烃基氧羰基氨基、一个或多个C 1-C 4烃基取代的氨基、取代的氨基羰基C 1-C 8烃基；
R 2选自羧基或酯基；
R 3选自氢、羟基、卤素、C 1-C 8烃氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基；
R 4选自氢、卤素、羟基、C 1-C 8烃氧基或C 5-C 12芳基氧基。
再一方面，本公开涉及通式(I)化合物或其立体异构体或包含通式(I)化合物或其立体异构体以及药物可接受的载体的药物组合物在制备治疗皮肤病、银屑病、湿疹和特应性皮炎的药物中的用途：
Figure PCTCN2019082943-appb-000003
其中，
R 1选自一个或多个取代基，该取代基选自氢、卤素、羟基、C 1-C 8烃基、氨基、C 1-C 8烃基羰基氨基、C 1-C 8烃基氧羰基氨基、一个或多个C 1-C 4烃基取代的氨基、取代的氨基羰基C 1-C 8烃基；
R 2选自羧基或酯基；
R 3选自氢、羟基、卤素、C 1-C 8烃氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基；
R 4选自氢、卤素、羟基、C 1-C 8烃氧基或C 5-C 12芳基氧基。
又一方面，本公开涉及制备通式(I)化合物或其立体异构体的方法：
Figure PCTCN2019082943-appb-000004
其中，
R 1选自一个或多个取代基，该取代基选自氢、卤素、羟基、C 1-C 8烃基、氨基、C 1-C 8烃基羰基氨基、C 1-C 8烃基氧羰基氨基、一个或多个C 1-C 4烃基取代的氨基、取代的氨基羰基C 1-C 8烃基；
R 2选自羧基或酯基；
R 3选自氢、羟基、卤素、C 1-C 8烃氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基；
R 4选自氢、卤素、羟基、C 1-C 8烃氧基或C 5-C 12芳基氧基；
其中所述的制备方法包括：
(1)将通式(A-I)化合物与丙二酸及醋酸铵进行反应得到通式(A-II)化合物，
Figure PCTCN2019082943-appb-000005
其中，通式(A-I)和通式(A-II)中的R 3’、R 4’表示的基团与通式(I)中的R 3、R 4的定义相同，
(2)将通式(A-II)化合物与醇进行酯化反应得到通式(A-III)化合物，
Figure PCTCN2019082943-appb-000006
其中，通式(A-II)和通式(A-III)中的R 3’、R 4’表示的基团与通式(I)中的R 3、R 4的定义相同，R 2’选自氢、C 1-C 4烷基；
(3)将通式(A-IV)化合物与通式(A-III)化合物进行反应得到通式(I)化合物，
Figure PCTCN2019082943-appb-000007
其中，通式(A-III)和通式(A-IV)中的R 1’、R 3’、R 4’表示的基团与通式(I)中的R 1、R 3、R 4的定义相同，R 2’选自氢或C 1-C 4烷基。
另一方面，本公开涉及通式(II)化合物、其立体异构体或其药物可接受的盐：
Figure PCTCN2019082943-appb-000008
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
再一方面，本公开涉及下列化合物、其立体异构体或其药物可接受的盐：
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3,4-二甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3,4-二乙氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯；
(R)-3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
(S)-3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
(R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
(S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯 基)丙酸丙酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸异丙酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸丁酯；
3-(4-(2-氯乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-(2-(二甲氨基)乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-(二甲氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-(2-羟基乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-异丙氧基苯基)丙酸甲酯；
3-(4-氟-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-环戊氧基苯基)丙酸甲酯；
3-(4-甲基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(5-氟-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4,7-二氯-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-(N-甲基乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(5-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-(苄氧基)-4-甲氧基 苯基)丙酸甲酯；
3-(4-(N-甲基叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-(甲基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-丙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-环戊氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-丙氧基苯基)丙酸甲酯；
3-(4-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氧基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-氨基-7-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-氨基-5-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-羟基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-(苄氧基)苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-羟基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-甲氧基-4-(苄氧基)苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-甲氧基-4-羟基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-苯基丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-氯苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-乙氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-氯苯基)丙酸甲酯；
3-(4-(叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-(二氟甲氧基)-3-乙氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-(三氟甲氧基)苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-(二氟甲氧基)-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-甲氧基-3-(三氟甲氧基)苯基)丙酸甲酯；
(R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯；
(S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯；
(R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯；
(S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(苯并[d][1,3]二氧杂环戊烯-5-基)丙酸甲酯；以及
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(2,3-二氢苯并[b][1,4]二氧杂芑-6-基)丙酸甲酯。
又一方面，本公开涉及药物组合物，其含有通式(II)化合物、其立体异构体或其药物可接受的盐以及药物可接受的载体、稀释剂或赋形 剂：
Figure PCTCN2019082943-appb-000009
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
另一方面，本公开涉及治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的方法，其包括向需要所述方法的个体给予治疗有效量的通式(II)化合物、其立体异构体或其药物可接受的盐，或者给予治疗有效量的包含通式(II)化合物、其立体异构体或其药物可接受的盐以及药物可接受的载体、稀释剂或赋形剂的药物组合物：
Figure PCTCN2019082943-appb-000010
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
再一方面，本公开涉及用于治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的通式(II)化合物、其立体异构体或其药物可接受的盐：
Figure PCTCN2019082943-appb-000011
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
又一方面，本公开涉及用于治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的包含治疗有效量的通式(II)化合物、其立体异构体或其药物可接受的盐以及药物可接受的载体、稀释剂或赋形剂的药物组合物：
Figure PCTCN2019082943-appb-000012
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基 烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
另一方面，本公开涉及用于治疗或预防皮肤病、银屑病、湿疹、特应性皮炎、荨麻疹、哮喘、哮喘-慢性阻塞性肺病(COPD)重叠综合征(ACOS)、过敏性鼻炎、季节性过敏性鼻炎、药物性间质性肺炎、支气管肺曲霉菌病、麻风、类天胞疮以及寄生虫感染的通式(II)化合物、其立体异构体或其药物可接受的盐：
Figure PCTCN2019082943-appb-000013
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤 素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
再一方面，本公开涉及用于治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的皮肤病、银屑病、湿疹、特应性皮炎、荨麻疹、哮喘、哮喘-慢性阻塞性肺病(COPD)重叠综合征(ACOS)、过敏性鼻炎、季节性过敏性鼻炎、药物性间质性肺炎、支气管肺曲霉菌病、麻风、类天胞疮以及寄生虫感染的通式(II)化合物、其立体异构体或其药物可接受的盐：
Figure PCTCN2019082943-appb-000014
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
又一方面，本公开涉及制备通式(II)化合物、其立体异构体或其药 物可接受的盐的方法，其包括：
(1)将通式(B-I)化合物与丙二酸及醋酸铵进行反应得到通式(B-II)化合物，
Figure PCTCN2019082943-appb-000015
其中，通式(B-I)和通式(B-II)中的R 3’、R 4’表示的基团与通式(II)中的R 3、R 4的定义相同，
(2)将通式(B-II)化合物与醇进行酯化反应得到通式(B-III)化合物，
Figure PCTCN2019082943-appb-000016
其中，通式(B-II)和通式(B-III)中的R 3’、R 4’表示的基团与通式(II)中的R 3、R 4的定义相同，R 2’选自氢或烃基；
(3)将通式(B-IV)化合物与通式(B-III)化合物进行反应得到通式(II)化合物
Figure PCTCN2019082943-appb-000017
其中，通式(B-III)和通式(B-IV)中的R 1’、R 3’、R 4’表示的基团与通式(II)中的R 1、R 3、R 4的定义相同，R 2’选自氢或烃基；
其中X为-CR 5R 6-，其中R 5为氢，R 6为氢，n为1。
附图简要说明
图1示出了本公开生物学实施例1的模型动物诱导及给药方法。
图2示出了本公开生物学实施例2的模型动物诱导及给药方法。
图3示出了本公开生物学实施例3的模型动物诱导及给药方法。
图4示出了本公开生物学实施例7的各试验组雄性动物体重变化趋势。
图5示出了本公开生物学实施例7的各试验组雌性动物体重变化趋势。
图6示出了本公开生物学实施例8的各试验组雄性动物体重变化趋势。
图7示出了本公开生物学实施例8的各试验组雌性动物体重变化趋势。
图8示出了本公开生物学实施例9的各试验组雄性动物体重变化趋势。
图9示出了本公开生物学实施例9的各试验组雌性动物体重变化趋势。
详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其他方法、部件、材料等的情况下可实现实施方案。
除非本公开中另外要求，在整个说明书和其后的权利要求书中，词语“包括”和“包含”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个本说明书中提及的“一实施方案”或“另一实施方案”或“实施方案”或“某些实施方案”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“一实施方案”或“实施方案”或“另一实施方案”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当 的方式在一个或多个实施方案中结合。
应当理解，在本公开的说明书和所附的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包含“通式(II)化合物、其立体异构体或其药物可接受的盐”的药物组合物包括一种通式(II)化合物、其立体异构体或其药物可接受的盐，或两种或多种通式(II)、其立体异构体或其药物可接受的盐。
定义
因此，除非另有相反的说明，否则说明书及所附权利要求中所用的下列术语具有以下的意思：
本公开中命名的某些化学基团前面所置的简写符号表示在所指示的化学基团存在的碳原子总数。例如，C 1-C 4烷基描述如下文所定义的具有总共1至4个碳原子的烷基，而C 3-C 10环烷基描述如下文所定义的具有总共3至10个碳原子的环烷基。简写符号中的碳总数不包含可能存在于所述基团的取代基中的碳。
在本公开中，术语“卤素”系指氟、氯、溴或碘。
在本公开中，术语“羟基”系指-OH基团。
在本公开中，术语“氨基”系指-NH 2基团。
在本公开中，术语“羧基”系指-COOH基团。
在本公开中，术语“烃基”系指脂肪族烃基团。烃基部分可以是“饱和的烃基”基团，意为其不包含任何烯或炔部分。烃基部分还可以是“不饱和的烃基”部分，意为其包含至少一个烯或炔部分。“烯”部分是指由两至八个碳原子和至少一个碳-碳双键组成的基团，并且由单键与分子的其余部分连接的直链或支链烃链基团，例如乙烯基、丙-1-烯基、丁-1-烯基、戊-1-烯基、戊-1,4-二烯基等，并且“炔”部分是指由两至八个碳原子和至少一个碳-碳三键组成的基团，并且由单键与分子的其余部分连接的直链或支链烃链基团。烃基部分，无论饱和的或不饱和的，可以是支链的或直链的。
烃基基团可具有1至8个碳原子(在本公开中每次出现时，诸如“1 至8”的数值范围是指给定范围中的每一整数；如“1至8”意为所述烃基基团可由1个碳原子、2个碳原子、3个碳原子、4个碳原子等直至并包括8个碳原子，尽管本定义还涵盖未指定数值范围的术语“烃基”的出现)。
烃基基团可以是任意取代的，亦即取代或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：环烃基、芳基、杂芳基、杂脂环基、羟基、烃氧基、芳氧基、巯基、烃硫基、芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合(isocyanato)、氰硫基、异硫氰酸根合(isothiocyanato)、硝基、甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。通常烃基基团包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、乙烯基、丙烯基、丁烯基、乙炔基、丙炔基和丁炔基。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
在某些实施方案中，“C 1-C 4烃基”系指含有一至四个碳原子的上述定义的烃基基团。C 1-C 4烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C 1-C 6烃基”系指含有一至六个碳原子的上述定义的烃基基团。C 1-C 6烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C 1-C 12烃基”系指含有一至十二个碳原子的上述定义的烃基基团。C 1-C 12烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C 2-C 6烃基”系指含有二至六个碳原子的上述定义的烃基基团。C 2-C 6烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C 3-C 6烃基”系指含有三至六个碳原子的上述 定义的烃基。C 3-C 6烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C 3-C 12烃基”系指含有三至十二个碳原子的上述定义的烃基。C 3-C 12烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C 6-C 12烃基”系指含有六至十二个碳原子的上述定义的烃基。C 6-C 12烃基基团可以如对烃基基团定义的那样被任意地取代。
在某些实施方案中，“C 7-C 12烃基”系指含有七至十二个碳原子的上述定义的烃基。C 7-C 12烃基基团可以如对烃基基团定义的那样被任意地取代。
在本公开中，术语“烃基氧基”系指通式-O-烃基，其中烃基如本公开中所定义。烃基氧基的示例性实例包括但不限于甲氧基、乙氧基、正丙氧基、1-甲基乙氧基(异丙氧基)、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基和叔戊氧基。
在本公开中，术语“芳基”是指具有完全离域的Pi电子体系的碳环(全碳)或两个或多个稠合环(共享两个相邻碳原子的环)。芳基基团包括但不限于芴基、苯基及萘基。芳基基团例如可以具有五至十二个碳原子。本公开的芳基基团可以是取代的或未取代的。当被取代时，氢原子被一个或多个独立地选自下列取代基的基团取代：烃基、环烃基、芳基、杂芳基、杂脂环基、羟基、被保护的羟基、烃氧基、芳氧基、巯基、烃硫基、芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、Ν-硫代氨基甲酰基、C-酰氨基、Ν-酰氨基、S-亚磺酰氨基、Ν-亚磺酰氨基、C-羧基、被保护的C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或被保护的氨基。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
在本公开中，术语“芳基烃基氧基”系指通式-O-烃基芳基，其中烃基和芳基分别如本公开中所定义。芳基烃基氧基的示例性实例包括但 不限于苄氧基、苯乙基氧基和苯丙基氧基。
在某些实施方案中，“C 6-C 16芳基烃基氧基”系指含有六至十六个碳原子的上述定义的芳基烃基氧基。C 6-C 16芳基烃基氧基基团可以如对烃基基团和芳基基团定义的那样分别被任意地取代。
在某些实施方案中，“C 6-C 18芳基烃基氧基”系指含有六至十八个碳原子的上述定义的芳基烃基氧基。C 6-C 18芳基烃基氧基基团可以如对烃基基团和芳基基团定义的那样分别被任意地取代。
在某些实施方案中，“C 7-C 18芳基烃基氧基”系指含有七至十八个碳原子的上述定义的芳基烃基氧基。C 7-C 18芳基烃基氧基基团可以如对烃基基团和芳基基团定义的那样分别被任意地取代。
在某些实施方案中，“C 8-C 18芳基烃基氧基”系指含有八至十八个碳原子的上述定义的芳基烃基氧基。C 8-C 18芳基烃基氧基基团可以如对烃基基团和芳基基团定义的那样分别被任意地取代。
在某些实施方案中，“C 8-C 24芳基烃基氧基”系指含有八至二十四个碳原子的上述定义的芳基烃基氧基。C 8-C 24芳基烃基氧基基团可以如对烃基基团和芳基基团定义的那样分别被任意地取代。
在某些实施方案中，“C 11-C 24芳基烃基氧基”系指含有十一至二十四个碳原子的上述定义的芳基烃基氧基。C 11-C 24芳基烃基氧基基团可以如对烃基基团和芳基基团定义的那样分别被任意地取代。
在某些实施方案中，“C 12-C 24芳基烃基氧基”系指含有十二至二十四个碳原子的上述定义的芳基烃基氧基。C 12-C 24芳基烃基氧基基团可以如对烃基基团和芳基基团定义的那样分别被任意地取代。
在某些实施方案中，“C 6-C 24芳基烃基氧基”系指含有六至二十四个碳原子的上述定义的芳基烃基氧基。C 6-C 24芳基烃基氧基基团可以如对烃基基团和芳基基团定义的那样分别被任意地取代。
在本公开中，术语“杂芳基”系指是指由一至十七个碳原子和一至十个选自氮、氧及硫的杂原子组成的5元至18元芳族环基。在某些实施方案中，杂芳基可为单环、双环、三环或四环环系统，其可包含经稠合或桥接的环系统；且杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。杂芳基的示例性实例包括但不限于氮杂卓 基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并二氧杂环戊烯基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、苯并[b][1,4]二氧杂环庚基、1,4-苯并二噁烷基、苯并萘呋喃基、苯并噁唑基、苯并二氧杂环戊烯基、苯并二氧杂环己烯基、苯并吡喃基、苯并吡喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、噌啉基、二苯并呋喃基、二苯并噻吩基、呋喃基、呋喃酮基、异噻唑基、咪唑基、吲唑基、吲哚基、吲唑基、异吲哚基、吲哚啉基、异吲哚啉基、异喹啉基、吲哚嗪基、异噁唑基、萘啶基、噁二唑基、2-氧代氮杂卓基、噁唑基、环氧乙基、1-苯基-1H-吡咯基、菲嗪基、菲噻嗪基、菲噁嗪基、酞嗪基、喋啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、喹唑啉基、喹噁啉基、喹啉基、奎宁环基、异喹啉基、四氢喹啉基、噻唑基、噻二唑基、三唑基、四唑基、三嗪基和噻吩基。本公开的杂芳基基团可以是取代的或未取代的。当被取代时，氢原子被一个或多个独立地选自下列取代基的基团取代：烃基、环烃基、芳基、杂芳基、杂脂环基、羟基、被保护的羟基、烃氧基、芳氧基、巯基、烃硫基、芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、Ν-硫代氨基甲酰基、C-酰氨基、Ν-酰氨基、S-亚磺酰氨基、Ν-亚磺酰氨基、C-羧基、被保护的C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或被保护的氨基。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
在本公开中，术语“环烃基”系指仅由碳和氢原子组成的，具有三至十五个碳原子的，在某些实施方案中具有三至十二个碳原子的，并且其为饱和或不饱和的，并且通过单键与分子的其余部分相连的稳定的非芳香族单环或双环烃基团，例如环丙基、环丁基、环戊基、环己基、环癸基等。除非本公开中另有明确说明，否则术语“环烃基”旨在包括被一个或多个选自如下取代基的基团所任意取代的上述定义的环烃基：环烃基、芳基、杂芳基、杂脂环基、羟基、烃氧基、芳氧基、 巯基、烃硫基、芳硫基、氰基、卤代、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰基氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、-NR’R”(R’和R”为本公开中定义的烃基)或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。
在某些实施方案中，“C 3-C 6环烃基”系指具有三至六个碳原子的上述定义的环烃基基团。C 3-C 6环烃基基团可以如对上述环烃基的定义那样被任意地取代。
在某些实施方案中，“C 3-C 10环烃基”系指具有三至十个碳原子的上述定义的环烃基基团。C 3-C 10环烃基基团可以如对上述环烃基的定义那样被任意地取代。
在某些实施方案中，“C 3-C 12环烃基”系指具有三至十二个碳原子的上述定义的环烃基基团。C 3-C 12环烃基基团可以如对上述环烃基的定义那样被任意地取代。
在本公开中，术语“环烃基氧基”系指-O-环烃基，其中环烃基如本公开中所定义。环烃基氧基的示例性的实例包括但不限于环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基和环癸基氧基。
在本公开中，术语“烃基羰基氨基”系指-NHC(＝O)-烃基，其中烃基如本公开中所定义。烃基羰基氨基的示例性的实例包括但不限于乙酰氨基、丙酰氨基、丁酰氨基和戊酰氨基。
在本公开中，术语“烃基羰基氧基”系指-OC(＝O)-烃基，其中烃基如本公开中所定义。烃基羰基氧基的示例性的实例包括但不限于乙酰氧基、丙酰氧基、丁酰氧基和戊酰氧基。
在本公开中，术语“烃基氧基羰基氨基”系指-NHC(＝O)O-烃基，其中烃基如本公开中所定义。烃基氧基羰基氨基的示例性实例包括但不限于甲氧基羰基氨基、乙氧基羰基氨基、丙氧基羰基氨基和叔丁氧羰基氨基。
在本公开中，术语“烃基氧基羰基”系指-C(＝O)O-烃基，其中烃基如本公开中所定义。烃基氧基羰基的示例性实例包括但不限于甲氧羰 基、乙氧羰基、丙氧羰基、异丙氧羰基和丁氧羰基。
在本公开中，术语“本公开的化合物、其立体异构体或其药物可接受的盐”系指本公开的通式(I)化合物、其立体异构体及其药物可接受的盐，通式(II)化合物、其立体异构体及其药物可接受的盐，以及任何落入通式(I)和通式(II)中的具体化合物、其立体异构体及其药物可接受的盐。
在本公开中，术语“哺乳动物”是指包括例如狗、猫、牛、羊、马和人类等的动物。在某些实施方案中，哺乳动物包括人类。
在本公开中，术语“患者”系指动物(例如，人)、伴侣动物(例如，狗、猫或马)和家畜(例如，牛、猪和羊)。在某些实施方案中，患者是包括雄性和雌性的哺乳动物。在某些实施方案中，患者为人类。
在本公开中，术语“药物可接受的”系指必须与制剂的其它成分相容并且不会对其接受者有害的载体、载剂、稀释剂、赋形剂和/或盐。
在本公开中，术语“任意的”或“任意地”意为随后描述的事件或状况可以发生也可以不发生，且说明书包括该事件或状况发生的情况及未发生的情况。
在本公开中，术语“药物可接受的载体、稀释剂或赋形剂”包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。
在本公开中，术语“载体”定义为有利于将化合物引入细胞或组织的化合物。例如二甲亚砜(DMSO)通常用作载体，这是因为它易于将某些有机化合物引入生物体的细胞或组织中。
在本公开中，术语“药物可接受的盐”包括“可以接受的酸加合盐”和“可以接受的碱加合盐”。
在本公开中，术语“可以接受的酸加合盐”系指保持游离碱的生物学有效性和性质的那些盐，所述酸加合盐是在生物学或其它方面合适的并且是使用无机酸或有机酸来形成的，所述无机酸例如但不限于盐 酸、氢溴酸、硫酸、硝酸、磷酸等，所述有机酸例如但不限于乙酸、2,2-二氯乙酸、己二酸、褐藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯羧酸、4-乙酰胺基苯羧酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷基氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、甲酸、富马酸、粘酸、龙胆酸、葡庚糖酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖醛酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲烷磺酸、黏酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
在本公开中，术语“可以接受的碱加合盐”系指保持游离酸的生物学有效性和性质的那些盐，所述碱加合盐是在生物学或其它方面合适的。向游离酸中加入无机碱或有机碱来制备这些盐。由无机碱衍生的盐包括但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。在某些实施方案中，无机盐为铵、钠、钾、钙及镁盐。由有机碱衍生的盐包括但不限于伯、仲和叔胺的盐、包括天然存在的取代的胺在内的取代的胺、环胺和碱性离子交换树脂的盐，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、苄胺、苯乙二胺、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。在某些实施方案中，有机碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
在本公开中，术语“溶剂或溶剂混合物”系指任何和所有溶剂。在某些实施方案中，溶剂或溶剂混合物为有机溶剂和水，其包括但不限于甲醇、乙醇、2-丙醇、正丁醇、异丁醇、丙酮、甲基乙基酮、乙酸乙酯、1,4-二噁烷、乙醚、甲基叔丁基醚、四氢呋喃、乙腈、二氯甲烷、氯仿、N,N-二甲基甲酰胺、环己烷、环戊烷、正己烷、正庚烷、 正戊烷、甲苯、邻二甲苯、对二甲苯、二甲基亚砜(DMSO)、吡啶、乙酸、苯甲醚、乙酸丁酯、异丙基苯、甲酸乙酯、甲酸、乙酸异丁酯、乙酸异丙酯、乙酸甲酯、3-甲基-1-丁醇、甲基异丁基酮、2-甲基-1-丙醇、1-戊醇、乙酸丙酯、乙二醇和1-甲基-2-吡咯烷酮，以及任何和所有两种或更多种这类溶剂的混合物。在某些实施方案中，溶剂或溶剂混合物为单一溶剂和二元混合物。在某些实施方案中，溶剂或溶剂混合物为水和有机溶剂的单一溶剂以及水和有机溶剂的二元混合物。
在本公开中，术语“药物组合物”系指本公开中所述的化合物与通常被本领域所接受的将生物活化化合物输送至诸如人类等哺乳动物的介质所形成的制剂。这样的介质包括所有药物可接受的载体、稀释剂或赋形剂。
在本公开中，术语“治疗有效量”指改善、减弱或消除特定疾病或病况和特定疾病或病况的症状、或者避免或延迟特定疾病或病况或者特定疾病或病况的症状的发病的化合物或化合物组合的量。根据化合物、疾病状态及其严重性、以及待治疗哺乳动物的年龄、体重等，构成“治疗有效量”的本公开中所述的化合物的量将会不同，但是本领域的技术人员根据其自身的知识以及本公开可以依惯例确定本公开中所述的化合物的量。
本公开所用的“进行治疗”或“治疗”涵盖患有相关疾病或病症的哺乳动物例如人类中治疗相关的疾病或疾病状态，并且包括：
(i)预防疾病或疾病状态在哺乳动物中发生，尤其是当该哺乳动物易感于所述疾病状态，但尚未被诊断出患有这种疾病状态时；
(ii)抑制疾病或疾病状态，即阻止其发生；或者
(iii)缓解疾病或疾病状态，即使疾病或疾病状态消退或不进展。
正如本公开所用的那样，术语“疾病”和“疾病状态”可以相互交换使用，或者可以是不同的，因为特殊的疾病或疾病状态可能并没有已知的致病因子(因此不能用病因学解释)，因此其不被公认为是疾病，而是被认为是不期望的疾病状态或病症，其中临床医生已经鉴定出或多或少的特定系列的症状。
在本公开中，术语“生理可接受的”系指不消除化合物的生物活性 和性质的载体或稀释剂。
本公开中所述的化合物或其药物可接受的盐可以含一个或多个不对称中心，并且因此可以产生对映异构体、非对映异构体、以及其它立体异构形式，可以根据绝对立体化学将其定义为(R)-或(S)-，或氨基酸的(D)-或(L)-。本公开旨在包括所有这些可能的异构体，以及其外消旋形式和光学纯的形式。可使用手性合成子(chiral synthon)或手性试剂制备旋光的(+)和(-)、(R)-和(S)-、或(D)-和(L)-异构体，或使用常规技术进行拆分，如使用手性柱的HPLC。当本公开中所述的化合物含有烯双键或其它几何不对称中心时，除非另有说明，否则意味着化合物包括E和Z几何异构体。同样，还意味着包括所有的互变异构形式。
在本公开中，术语“立体异构体”系指由相同的键键合的相同的原子组成的，但具有不可互换的不同三维结构的化合物。本公开涵盖各种立体异构体及其混合物。
具体实施方案
一方面，本公开涉及通式(I)化合物、其立体异构体：
Figure PCTCN2019082943-appb-000018
其中，
R 1选自一个或多个取代基，该取代基选自氢、卤素、羟基、C 1-C 8烃基、氨基、C 1-C 8烃基羰基氨基、C 1-C 8烃基氧羰基氨基、一个或多个C 1-C 4烃基取代的氨基、取代的氨基羰基C 1-C 8烃基；
R 2选自羧基或酯基；
R 3选自氢、羟基、卤素、C 1-C 8烃氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基；
R 4选自氢、卤素、羟基、C 1-C 8烃氧基或C 5-C 12芳基氧基。
在某些实施方案中，R 1选自一个或多个取代基，该取代基选自氢、 卤素、羟基、C 1-C 8烷基、氨基、C 1-C 8烷基羰基氨基、C 1-C 8烷基氧羰基氨基、一个或多个C 1-C 4烷基取代的氨基、取代的氨基羰基C 1-C 8烷基。
在某些实施方案中，R 3选自氢、羟基、卤素、C 1-C 8烷氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基。
在某些实施方案中，R 4选自氢、羟基、卤素、C 1-C 8烷氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基。
在某些实施方案中，R 1选自氢、-OH、-F、-Cl、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-NH 2、-NHCH 3、-N(CH 3) 2、-NHCOCH 3、-NHCOOCH 3、-NHCOCH 2OH、-NHCOCH 2Cl、-NHCOCH 2F或-NCH 3COCH 3。
在某些实施方案中，R 2选自-COOH、-COOCH 3、-COOCH 2CH 3、-COOCH 2CH 2CH 3或-COOCH(CH 3) 2。
在某些实施方案中，R 3选自氢、羟基、卤素、苄氧基、C 1-C 4烷氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基。
在某些实施方案中，R 3选自-H、-OH、-Cl、-F、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2或苄氧基。
在某些实施方案中，R 4选自氢、卤素、羟基、C1-C4烃氧基、苄氧基或C5-C12芳基氧基。
在某些实施方案中，R 4选自-H、-Cl、-F、-OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2或苄氧基。
另一方面，本公开涉及药物组合物，其包含通式(I)化合物或其立体异构体以及药物可接受的载体：
Figure PCTCN2019082943-appb-000019
其中，
R 1选自一个或多个取代基，该取代基选自氢、卤素、羟基、C 1-C 8烃基、氨基、C 1-C 8烃基羰基氨基、C 1-C 8烃基氧羰基氨基、一个或多 个C 1-C 4烃基取代的氨基、取代的氨基羰基C 1-C 8烃基；
R 2选自-COOH、-COOCH 3、-COOCH 2CH 3、-COOCH 2CH 2CH 3或-COOCH(CH 3) 2；
R 3选自氢、羟基、卤素、苄氧基、C 1-C 4烷氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基；
R 4选自氢、卤素、羟基、C 1-C 4烃氧基、苄氧基或C 5-C 12芳基氧基。
再一方面，本公开涉及通式(I)化合物或其立体异构体或包含通式(I)化合物或其立体异构体以及药物可接受的载体的药物组合物在制备治疗皮肤病、银屑病、湿疹和特应性皮炎的药物中的用途：
Figure PCTCN2019082943-appb-000020
其中，
R 1选自一个或多个取代基，该取代基选自氢、卤素、羟基、C 1-C 8烃基、氨基、C 1-C 8烃基羰基氨基、C 1-C 8烃基氧羰基氨基、一个或多个C 1-C 4烃基取代的氨基、取代的氨基羰基C 1-C 8烃基；
R 2选自-COOH、-COOCH 3、-COOCH 2CH 3、-COOCH 2CH 2CH 3或-COOCH(CH 3) 2；
R 3选自氢、羟基、卤素、苄氧基、C 1-C 4烷氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基；
R 4选自氢、卤素、羟基、C 1-C 4烃氧基、苄氧基或C 5-C 12芳基氧基。
又一方面，本公开涉及制备通式(I)化合物或其立体异构体的方法：
Figure PCTCN2019082943-appb-000021
其中，
R 1选自一个或多个取代基，该取代基选自氢、卤素、羟基、C 1-C 8烃基、氨基、C 1-C 8烃基羰基氨基、C 1-C 8烃基氧羰基氨基、一个或多个C 1-C 4烃基取代的氨基、取代的氨基羰基C 1-C 8烃基；
R 2选自-COOH、-COOCH 3、-COOCH 2CH 3、-COOCH 2CH 2CH 3或-COOCH(CH 3) 2；
R 3选自氢、羟基、卤素、苄氧基、C 1-C 4烷氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基；
R 4选自氢、卤素、羟基、C 1-C 4烃氧基、苄氧基或C 5-C 12芳基氧基；
其中所述的制备方法包括：
(1)将通式(A-I)化合物与丙二酸及醋酸铵进行反应得到通式(A-II)化合物，
Figure PCTCN2019082943-appb-000022
其中，通式(A-I)和通式(A-II)中的R 3’、R 4’表示的基团与通式(I)中的R 3、R 4的定义相同，
(2)将通式(A-II)化合物与醇进行酯化反应得到通式(A-III)化合物，
Figure PCTCN2019082943-appb-000023
其中，通式(A-II)和通式(A-III)中的R 3’、R 4’表示的基团与通式(I)中的R 3、R 4的定义相同，R 2’选自氢、C 1-C 4烷基；
(3)将通式(A-IV)化合物与通式(A-III)化合物进行反应得到通式(I)化合物
Figure PCTCN2019082943-appb-000024
其中，通式(A-III)和通式(A-IV)中的R 1’、R 3’、R 4’表示的基团与通式(I)中的R 1、R 3、R 4的定义相同，R 2’选自氢或C 1-C 4烷基。
在某些实施方案中，将通式(A-I)化合物与丙二酸及醋酸铵进行反应得到通式(A-II)化合物的方法是在有机溶剂中进行的。
在某些实施方案中，能够用于本公开的将通式(A-I)化合物与丙二酸及醋酸铵进行反应得到通式(A-II)化合物的合适的有机溶剂的示例性实例包括但不限于甲醇、乙醇、异丙醇和水。
在某些实施方案中，在约50℃至约130℃下将通式(A-I)化合物与丙二酸及醋酸铵进行反应得到通式(A-II)化合物。
在某些实施方案中，能够用于由通式(A-II)化合物制备通式(A-III)化合物的合适的酯化剂的示例性实例包括但不限于氯化亚砜、草酰氯、HCl气体和乙酰氯。
在某些实施方案中，将通式(A-II)化合物与醇类化合物进行反应得到通式(A-III)化合物的方法是在有机溶剂中进行的。
在某些实施方案中，能够用于本公开的将通式(A-II)化合物与醇类化合物进行反应得到通式(A-III)化合物的合适的有机溶剂的示例性实例包括但不限于醇类、四氢呋喃、二氯甲烷、乙酸乙酯和甲基叔丁基 醚。
在某些实施方案中，能够用于本公开的将通式(A-II)化合物与醇类化合物进行反应得到通式(A-III)化合物的合适的醇类的示例性实例包括但不限于甲醇、乙醇和异丙醇等。
在某些实施方案中，在约-20℃至约30℃下将通式(A-II)化合物与醇类化合物进行反应得到通式(A-III)化合物。
在某些实施方案中，在将通式(A-IV)化合物与通式(A-III)化合物进行反应得到通式(I)化合物的方法中加入催化剂。
在某些实施方案中，能够用于本公开的将通式(A-IV)化合物与通式(A-III)化合物进行反应得到通式(I)化合物的合适的催化剂的示例性实例包括但不限于醋酸钠、醋酸钾、碳酸钠和碳酸钾。
在某些实施方案中，将通式(A-IV)化合物与通式(A-III)化合物进行反应得到通式(I)化合物的方法是在有机溶剂中进行的。
在某些实施方案中，能够用于本公开的将通式(A-IV)化合物与通式(A-III)化合物进行反应得到通式(I)化合物的合适的有机溶剂的示例性实例包括但不限于醋酸、甲酸、二甲基甲酰胺和二甲基乙酰胺。
在某些实施方案中，在约50℃至约180℃下将通式(A-IV)化合物与通式(A-III)化合物进行反应得到通式(I)化合物。
另一方面，本公开涉及通式(II)化合物、其立体异构体或其药物可接受的盐：
Figure PCTCN2019082943-appb-000025
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
在某些实施方案中，R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的C 1-C 6烃基、任意取代的氨基、任意取代的C 1-C 6烃基羰基氨基、任意取代的C 1-C 6烃基羰基氧基、任意取代的C 1-C 6烃基氧基羰基氨基、任意取代的C 1-C 6烃基羰基氨基。
在某些实施方案中，R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烷基、任意取代的氨基、任意取代的烷基羰基氨基、任意取代的烷基羰基氧基、任意取代的烷基氧基羰基氨基、任意取代的烷基羰基氨基。
在某些实施方案中，R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的C 1-C 6烷基、任意取代的氨基、任意取代的C 1-C 6烷基羰基氨基、任意取代的C 1-C 6烷基羰基氧基、任意取代的C 1-C 6烷基氧基羰基氨基、任意取代的C 1-C 6烷基羰基氨基。
在某些实施方案中，R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的甲基、任意取代的氨基、任意取代的乙酰氨基、任意取代的乙酰基氧基、任意取代的叔丁氧基羰基氨基。
在某些实施方案中，R 1选自一个或者多个下列相同或者不同的取代基：氟、氯、羟基、甲基、氨基、C 1-C 6烷基取代的氨基、乙酰氨基、卤代乙酰氨基、C 1-C 6烷基取代的乙酰氨基、羟基取代的乙酰氨基、C 1-C 6烷基取代的氨基取代的乙酰氨基、N-C 1-C 6烷基取代的乙酰氨基、乙酰氧基、叔丁氧基羰基氨基、C 1-C 6烷基取代的叔丁氧基羰基氨基。
在某些实施方案中，R 1选自一个或者多个下列相同或者不同的取代基：氟、氯、羟基、甲基、氨基、甲氨基、二甲氨基、乙酰氨基、2-氯乙酰氨基、2-羟基乙酰氨基、N-甲基乙酰氨基、2-(二甲氨基)乙酰氨基、乙酰氧基、叔丁氧基羰基氨基、N-甲基叔丁氧基羰基氨基。
在某些实施方案中，R 1选自乙酰氨基。
在某些实施方案中，R 2选自任意取代的C 1-C 6烃基氧基羰基或羧基。
在某些实施方案中，R 2选自任意取代的烷基氧基羰基或羧基。
在某些实施方案中，R 2选自任意取代的C 1-C 6烷基氧基羰基或羧基。
在某些实施方案中，R 2选自任意取代的甲氧羰基、任意取代的乙氧羰基、任意取代的丙氧羰基、任意取代的丁氧羰基、任意取代的异丙氧羰基或羧基。
在某些实施方案中，R 2选自甲氧羰基、乙氧羰基、丙氧羰基、丁氧羰基、异丙氧羰基或羧基。
在某些实施方案中，R 2选自甲氧羰基、乙氧羰基或丙氧羰基。
在某些实施方案中，R 3选自氢、卤素、羟基、任意取代的烷基氧基、任意取代的芳基烷基氧基或任意取代的环烷基氧基。
在某些实施方案中，R 3选自氢、卤素、羟基、任意取代的C 1-C 6烃基氧基、任意取代的C 6-C 18芳基烃基氧基或任意取代的C 3-C 10环烃基氧基。
在某些实施方案中，R 3选自氢、卤素、羟基、任意取代的烷基氧基、任意取代的芳基烷基氧基或任意取代的环烷基氧基。
在某些实施方案中，R 3选自氢、卤素、羟基、任意取代的C 1-C 6烷基氧基、任意取代的C 6-C 18芳基烷基氧基或任意取代的C 3-C 10环烷基氧基。
在某些实施方案中，R 3选自氢、卤素、羟基、任意取代的甲氧基、任意取代的乙氧基、任意取代的丙氧基、任意取代的异丙氧基、任意取代的苄氧基或任意取代的环戊基氧基。
在某些实施方案中，R 3选自氢、氯、羟基、甲氧基、二氟甲氧基、 三氟甲氧基、乙氧基、丙氧基、异丙氧基、苄氧基或环戊基氧基。
在某些实施方案中，R 3选自甲氧基或乙氧基。
在某些实施方案中，R 4选自氢、卤素、羟基、任意取代的烷基氧基、任意取代的芳基烷基氧基或任意取代的环烷基氧基。
在某些实施方案中，R 4选自氢、卤素、羟基、任意取代的C 1-C 6烃基氧基、任意取代的C 6-C 18芳基烃基氧基或任意取代的C 3-C 10环烃基氧基。
在某些实施方案中，R 4选自氢、卤素、羟基、任意取代的烷基氧基、任意取代的芳基烷基氧基或任意取代的环烷基氧基。
在某些实施方案中，R 4选自氢、卤素、羟基、任意取代的C 1-C 6烷基氧基、任意取代的C 6-C 18芳基烷基氧基或任意取代的C 3-C 10环烷基氧基。
在某些实施方案中，R 4选自氢、卤素、羟基、任意取代的甲氧基、任意取代的乙氧基、任意取代的丙氧基、任意取代的异丙氧基、任意取代的苄氧基或任意取代的环戊基氧基。
在某些实施方案中，R 4选自氢、氯、羟基、甲氧基、二氟甲氧基、三氟甲氧基、乙氧基、丙氧基、异丙氧基、苄氧基或环戊基氧基。
在某些实施方案中，R 4选自甲氧基或乙氧基。
在某些实施方案中，R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基。
在某些实施方案中，R 5选自氢、卤素、任意取代的C 1-C 6烃基、任意取代的C 3-C 10环烃基、任意取代的C 5-C 12芳基或任意取代的杂芳基。
在某些实施方案中，R 5选自氢、卤素、任意取代的烷基、任意取代的环烷基、任意取代的C 5-C 12芳基或任意取代的杂芳基。
在某些实施方案中，R 5选自氢、卤素、任意取代的C 1-C 6烷基、任意取代的C 3-C 10环烷基、任意取代的C 5-C 12芳基或任意取代的杂芳基。
在某些实施方案中，R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基。
在某些实施方案中，R 6选自氢、卤素、任意取代的C 1-C 6烃基、任意取代的C 3-C 10环烃基、任意取代的C 5-C 12芳基或任意取代的杂芳基。
在某些实施方案中，R 6选自氢、卤素、任意取代的烷基、任意取代的环烷基、任意取代的C 5-C 12芳基或任意取代的杂芳基。
在某些实施方案中，R 6选自氢、卤素、任意取代的C 1-C 6烷基、任意取代的C 3-C 10环烷基、任意取代的C 5-C 12芳基或任意取代的杂芳基。
在某些实施方案中，n为0、1、2、3或4。
在某些实施方案中，R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基，并且n为1。
在某些实施方案中，R 5、R 6和与其相连的碳原子一起形成任意取代的C 3-C 12环烃基，并且n为1。
在某些实施方案中，R 5、R 6和与其相连的碳原子一起形成任意取代的环烷基，并且n为1。
在某些实施方案中，R 5、R 6和与其相连的碳原子一起形成任意取代的C 3-C 12环烷基，并且n为1。
在某些实施方案中，R 5、R 6和与其相连的碳原子一起形成C 3-C 12环烷基，并且n为1。
在某些实施方案中，R 5选自氢、卤素或C 1-C 4烃基。
在某些实施方案中，R 6选自氢、卤素或C 1-C 4烃基。
在某些实施方案中，n为1或2。
在某些实施方案中，R 5选自氢、卤素或C 1-C 4烃基，R 6选自氢、卤素或C 1-C 4烃基，并且n为1或2。
在某些实施方案中，R 5为氢。
在某些实施方案中，R 6为氢。
在某些实施方案中，n为1。
在某些实施方案中，R 5为氢，R 6为氢，并且n为1。
在某些实施方案中，本公开的化合物具有免疫球蛋白E(IgE)抑制活性。
在某些实施方案中，本公开的化合物具有低毒性。
在某些实施方案中，本公开的化合物具有良好的安全性。
在某些实施方案中，本公开的化合物具有良好的耐受性。
再一方面，本公开涉及下列化合物、其立体异构体或其药物可接受的盐：
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3,4-二甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3,4-二乙氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯；
(R)-3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
(S)-3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
(R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
(S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸丙酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸异丙酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯 基)丙酸丁酯；
3-(4-(2-氯乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-(2-(二甲氨基)乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-(二甲氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-(2-羟基乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-异丙氧基苯基)丙酸甲酯；3-(4-氟-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-氟-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-环戊氧基苯基)丙酸甲酯；
3-(4-甲基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(5-氟-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4,7-二氯-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-(N-甲基乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(5-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-(苄氧基)-4-甲氧基苯基)丙酸甲酯；
3-(4-(N-甲基叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-(甲基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-丙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-环戊氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-丙氧基苯基)丙酸甲酯；
3-(4-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氧基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-氨基-7-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-氨基-5-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-羟基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-(苄氧基)苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-羟基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-甲氧基-4-(苄氧基)苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-甲氧基-4-羟基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-苯基丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-氯苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-乙氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-氯苯基)丙酸甲酯；
3-(4-(叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-(二氟甲氧基)-3-乙氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-(三氟甲氧基)苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-(二氟甲氧基)-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-甲氧基-3-(三氟甲氧基)苯基)丙酸甲酯；
(R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯；
(S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯；
(R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯；以及
(S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯；
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(苯并[d][1,3]二氧杂环戊烯-5-基)丙酸甲酯；以及
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(2,3-二氢苯并[b][1,4]二氧杂芑-6-基)丙酸甲酯。
又一方面，本公开涉及药物组合物，其含有通式(II)化合物、其立体异构体或其药物可接受的盐以及药物可接受的载体、稀释剂或赋形剂：
Figure PCTCN2019082943-appb-000026
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基、任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基、任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成环烃基时，n为1。
另一方面，本公开涉及治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的方法，其包括向需要所述方法的个体给予治疗有效量的通式(II)化合物、其立体异构体或其药物可接受的盐，或者给予治疗有效量的包含通式(II)化合物、其立体异构体或其药物可接受的盐以及药物可接受的载体、稀释剂或赋形剂的药物组合物：
Figure PCTCN2019082943-appb-000027
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
在某些实施方案中，治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的方法，包括对需要所述方法的个体给予1mg-10g的本公开的化合物、其立体异构体或其药物可接受的盐。
在某些实施方案中，治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的方法，包括对需要所述方法的个体给予10mg-3000mg的本公开的化合物、其立体异构体或其药物可接受的盐。
在某些实施方案中，治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的方法，包括对需要所述方法的个体给予100mg-1000mg的本公开的化合物、其立体异构体或其药物可接 受的盐。
在某些实施方案中，治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的方法，包括对需要所述方法的个体给予100mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、650mg、700mg、750mg、800mg、850mg、900mg或1000mg的本公开的化合物、其立体异构体或其药物可接受的盐。
再一方面，本公开涉及用于治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的通式(II)化合物、其立体异构体或其药物可接受的盐：
Figure PCTCN2019082943-appb-000028
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
又一方面，本公开涉及用于治疗或预防与免疫球蛋白E(IgE)相关 的，优选免疫球蛋白E(IgE)介导的疾病的包含治疗有效量的通式(II)化合物、其立体异构体或其药物可接受的盐以及药物可接受的载体、稀释剂或赋形剂的药物组合物：
Figure PCTCN2019082943-appb-000029
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
另一方面，本公开涉及用于治疗或预防皮肤病、银屑病、湿疹、特应性皮炎、荨麻疹、哮喘、哮喘-慢性阻塞性肺病(COPD)重叠综合征(ACOS)、过敏性鼻炎、季节性过敏性鼻炎、药物性间质性肺炎、支气管肺曲霉菌病、麻风、类天胞疮以及寄生虫感染的通式(II)化合物、其立体异构体或其药物可接受的盐：
Figure PCTCN2019082943-appb-000030
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
再一方面，本公开涉及用于治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的皮肤病、银屑病、湿疹、特应性皮炎、荨麻疹、哮喘、哮喘-慢性阻塞性肺病(COPD)重叠综合征(ACOS)、过敏性鼻炎、季节性过敏性鼻炎、药物性间质性肺炎、支气管肺曲霉菌病、麻风、类天胞疮以及寄生虫感染的通式(II)化合物、其立体异构体或其药物可接受的盐：
Figure PCTCN2019082943-appb-000031
其中，
R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
R 2选自任意取代的烃基氧基羰基或羧基；
R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；
R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
药物组合物
在某些实施方案中，药物组合物包含本公开的化合物、其立体异构体或其药物可接受的盐，以及药物可接受的载体、稀释剂或赋形剂。
在某些实施方案中，本公开的化合物、其立体异构体或其药物可接受的盐用于治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病给予哺乳动物时的给药途径可以为肠胃途径或非肠胃途径。
在某些实施方案中，本公开的化合物、其立体异构体或其药物可接受的盐用于治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋 白E(IgE)介导的疾病给予哺乳动物时的给药途径可以为口服途径。
在某些实施方案中，本公开的化合物、其立体异构体或其药物可接受的盐用于治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病给予哺乳动物时的给药途径可以为直肠内途径。
可以以任何合适的形式如片剂、胶囊剂、粉剂、口服溶液、悬浮液、直肠凝胶、直肠泡沫、直肠灌肠剂或直肠栓剂等获得本公开中所述的化合物。所述的片剂的示例性实例包括但不限于素片、糖衣片和薄膜衣片。
能够用于本公开的药物组合物中的药物可接受的载体的实例包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗透压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。用于治疗用途的可接受载体或稀释剂在药物领域是公知的，并且例如在Remington’s Pharmaceutical Sciences(雷明顿制药学),18th Ed.,Mack Publishing Co.,Easton,PA(1990))中有描述，本文将其全部内容引入作为参考。
本公开中的药物组合物可以通过任何实现其预期目的的方法被施用。例如，施用可以通过口服、胃肠外、局部、肠内、静脉内、肌内、吸入、鼻、关节内、脊柱内、经气管、经眼、皮下、腹膜内、经皮或口含等途径进行。给药途径可以为非肠胃途径、口服途径以及直肠内途径。所施用的剂量将取决于接受者的年龄、健康状况和体重，如果有并行治疗，还取决于并行治疗的种类、治疗的频率，以及所需效果的性质。
合适的剂型包括但不限于胶囊剂、片剂、小丸、糖锭剂(dragee)、半固体制剂、散剂、颗粒剂、栓剂、软膏剂、乳膏剂、洗剂、吸入剂、注射剂、泥罨剂、凝胶剂、带剂(tape)、滴眼剂、溶液剂、糖浆剂、气雾剂、混悬剂、乳剂，其可以根据本领域已知的方法制备。
特别适合口服施用的是普通片剂(素片)、糖衣片、薄膜衣片、丸剂、胶囊剂、散剂、颗粒剂、糖浆剂、汁液(juice)或滴剂，适合直肠 施用的是栓剂，适合胃肠外施用的是溶液剂，也可以是基于油的溶液或水溶液，此外还有混悬剂、乳剂或植入剂，适合局部使用的是软膏剂、乳膏剂或散剂。本公开中的产品也可以被冻干，生成的冻干物用于例如制备注射剂。所给出的制剂可以被灭菌和/或包含辅助剂(assistant)，如润湿剂、防腐剂、稳定剂和/或润湿剂、乳化剂、用于改变渗透压的盐、缓冲物质、染料、矫味剂和/或众多另外的活性成分，例如一种或多种维生素。
在某些实施方案中，本公开中的药物组合物被制备成胃肠外、经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、胶囊剂、气雾剂或栓剂。
在药物组合物中可以提供防腐剂、稳定剂、染料、甜味剂、芳香剂、香料等。例如，可加入作为防腐剂的苯甲酸钠、抗坏血酸以及对羟基苯甲酸的酯。另外，可以使用抗氧化剂和混悬剂。
在不同的实施方案中，醇、酯、硫酸化脂族醇等可用作表面活性剂；蔗糖、葡萄糖、乳糖、淀粉、结晶纤维素、甘露醇、轻质无水硅酸盐、铝酸镁、铝酸甲基硅酸镁、合成硅酸铝、碳酸钙、碳酸氢钙、磷酸氢钙、羟甲基纤维素钙等可用作赋形剂；硬脂酸镁、滑石、硬化油等可用作光滑剂；椰子油、橄榄油、麻油、花生油、大豆可用作混悬剂或润滑剂；作为诸如纤维素或糖等糖类的衍生物的醋酞纤维素、或作为聚乙烯的衍生物的乙酸甲酯-异丁烯酸酯共聚物可用作混悬剂；以及诸如酞酸酯等的增塑剂可用作混悬剂。
合适的给药途径可以例如包括口服给药、直肠给药、透膜给药、肠胃外输送、局部给药或肠内给药；肠胃外输送包括肌内注射、皮下注射、静脉注射、髓内注射以及鞘内注射、直接心室内注射、腹膜内注射、鼻内注射或眼内注射。化合物也能够在包括储库型注射(depot injections)、渗透泵、丸剂、透皮(包括电迁移)贴片等在内的缓释或控释的剂型中以预先确定的速率进行延长和/或定时、脉冲给药。
本公开中的药物组合物可按已知的方法进行生产，例如，通过常规的混合、溶解、粒化、制造锭剂、研磨、乳化、包囊、截留或压片等操作方法进行生产。
因此根据本公开，所使用的药物组合物可使用一种或多种包含赋形剂和辅助剂的生理可接受的载体以常规方法配制，该赋形剂和辅助剂有利于将活性化合物处理成为药学可用的制剂。合适的制剂取决于所选的给药途径。可以如本领域中适合的并理解的那样使用任何公知的技术、载体和赋形剂。
能够将注射剂制备成下列常规形式：作为溶液或混悬液，在注射前适合制成溶液或混悬液的固体剂型，或作为乳剂。合适的赋形剂是，例如水、盐水、葡萄糖、甘露醇、乳糖、卵磷脂、白蛋白、谷氨酸钠、盐酸半胱氨酸等。另外，如果需要，注射剂药物组合物可以含有少量无毒的辅助物，例如湿润剂、pH缓冲剂等。生理适合的缓冲剂包括但不限于Hank溶液、Ringer溶液或生理盐水缓冲液。如果需要，可使用吸收增强制剂(例如脂质体)。
对于口服给药，通过组合所述活性化合物与本领域公知的药物可接受的载体，能够容易地组方所述化合物。为了使待治疗患者口服摄取，这样的载体能使本发明化合物被配制为片剂、丸剂、锭剂、胶囊、液体、凝胶、糖浆、膏剂、混悬液、溶液、粉剂等。能够通过下述方法获得用于口服的药物制剂：将活性化合物与固体赋形剂混合，任意研磨所得混合物并且将加工颗粒混合物，如果需要，在加入合适的辅助剂后进行加工以获得片剂或锭剂核。合适的赋形剂特别是诸如糖等的填充剂，包括乳糖、蔗糖、甘露醇或山梨醇；纤维素制剂，例如玉米淀粉、小麦淀粉、米淀粉、马铃薯淀粉、明胶、西黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯酮(PVP)。如果需要可加入崩解剂，例如交联的聚乙烯吡咯烷酮、琼脂或海藻酸或诸如海藻酸钠的海藻酸盐。对锭剂核进行合适的包被。出于该目的，可使用浓缩的糖溶液，该糖溶液可任选地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶(carbopol gel)、聚乙二醇和/或二氧化钛、紫胶漆溶液以及合适的有机溶剂或溶剂混合物。为了识别或表征活性化合物剂量的不同组合，可向片剂或锭剂包衣中加入染料或色素。出于该目的，可使用浓缩的糖溶液，该糖溶液可任选地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶、聚乙二醇和/或二氧化钛、紫胶漆 溶液、以及合适的有机溶剂或溶剂混合物。
能够用于口服的药物制剂包括明胶制成的推入配合胶囊，以及诸如甘油或山梨醇的明胶和增塑剂制成的软的、密封的胶囊。推入配合胶囊能够包含与诸如乳糖的填充剂、诸如淀粉的粘合剂和/或诸如滑石或硬脂酸镁的润滑剂以及任选的稳定剂混合的活性成分。在软胶囊中，活性成分可溶解或悬浮在合适的液体中，例如脂肪油、液状石蜡或液状聚乙二醇。另外，可加入稳定剂。所有口服给药的制剂应该达到适于这种给药的剂量。
在某些实施方案中，本公开的药物组合物可以包含0.1％-95％的本公开的化合物、其立体异构体或其药物可接受的盐。
在某些实施方案中，本公开的药物组合物可以包含1％-70％的本公开的化合物、其立体异构体或其药物可接受的盐。
在任何情况下，待施用的组合物或制剂将含有一定量的本公开的化合物、其立体异构体或其药物可接受的盐，其量可有效治疗受治疗的受试对象疾病/病况。
给药方法
可将本公开的至少一种化合物、其立体异构体或其药物可接受的盐或包含至少一种本公开的化合物、其立体异构体或其药物可接受的盐的药物组合物以任何适宜系统的和/或局部的输送本公开的化合物、其立体异构体或其药物可接受的盐的任何方法进行的方法对患者进行给药。给药方法的非限制性实例包括(a)通过口服途径给药，该给药包括以胶囊、片剂、颗粒剂、喷雾剂、糖浆剂或其它这类形式进行给药；(b)通过非口服途径给药，例如直肠、阴道、尿道内、眼内、鼻内或耳内，所述给药包括以水性悬浮液、油性制剂等或以滴剂、喷雾剂、栓剂、药膏、软膏等方式进行给药；(c)经皮下注射、腹膜内注射、静脉内注射、肌内注射、皮内注射、眶内注射、囊内注射、脊柱内注射、胸骨内注射等进行给药，包括输液泵输送；(d)诸如直接在肾脏区域或心脏区域中进行注射的局部(locally)给药，例如通过储库型植入；以及(e)局部(topically)给药；如本领域中技术人员所认为的适当的给药方式 是本公开中所述的化合物与活组织接触。
最适合途径取决于被治疗疾病状态的性质与严重性。本领域技术人员也熟悉确定给药方法(口腔、静脉内、吸入、皮下、直肠等)、剂型、适当医药赋形剂及与将化合物、其立体异构体或其药物可接受的盐传递至有需要的对象有关的其它事项。
适于给药的药物组合物包括其中含有有效量的活性成分以达到其预期效果的组合物。本公开中所述的药物组合物的治疗有效量所需的剂量取决于给药途径、包括人在内的被治疗动物的类型以及所考虑的特定动物的身体特征。可以调整剂量以达到期望的效果，但是这将取决于下列因素：体重、饮食、同时的药物治疗以及其它医学领域的技术人员公认的其它因素。更具体地，治疗有效量指有效阻止、减轻或改善疾病症状，或延长接受治疗个体寿命的化合物的量。本领域技术人员的实际能力可很好地确定治疗有效量，特别是按照本公开所提供的详细公开。
正如本领域技术人员所显而易见的，用于体内给药的剂量和具体的给药方式的变化将取决于年龄、体重和所治疗的哺乳动物的种类、所使用的具体化合物以及所使用的这些化合物的具体用途。本领域技术人员使用常规的药理学方法可达到确定有效剂量水平的目的，即达到确定预期效果所必需的剂量水平的目的。通常，以较低剂量水平开始进行产物的人体临床应用，随着剂量水平的增加直至达到所期望的效果。或者，采用已确立的药理学方法，能够使用可接受的体外研究来建立本方法鉴定的组合物的有效剂量和给药途径。
在非人动物研究中，潜在产物的应用以较高剂量水平开始，随着剂量的减少直至不再实现所期望的效果或者不良副作用消失。取决于预期效果和治疗适应症，剂量范围可较宽泛。通常，剂量可为约10μg/kg体重至1000mg/kg体重，在某些实施方案中为约100μg/kg体重至300mg/kg体重。或者，正如本领域技术人员所理解的，剂量可基于患者的体表面积并且按照其计算。
各医师能够根据患者的状况来选择本公开中所述的药物组合物的确切制剂、给药途径和剂量。通常，向患者给药的组合物的剂量范围 可以为约0.5mg/kg至1000mg/kg患者体重。根据患者需要，剂量可在一天或数天期间单独一次给予或两次或多次给予。在化合物的人用剂量因至少某些条件已确立的情况下，本公开将使用那些相同的剂量，或剂量范围为约0.1％至500％的确定的人用剂量，在某些实施方案中剂量范围为25％至250％已确定的人用剂量。在没有确定的人用剂量的情况下，如新发现的药物化合物的情况，适宜的人用剂量能够从半数有效量或感染剂量中位数数值，或来自体外或体内研究的其它合适的值进行推断，正如在动物中的毒性研究和效能研究所定量化的。
应当指出，由于毒性和器官功能障碍，主治医师将知道如何且何时终止、中断或调整给药。相反，如果临床反应不充分(排除毒性)，则主治医生也将知道将治疗调整至较高水平。在所关注病症的治疗中给药剂量的大小将随着待治疗疾病状态的严重性和给药途径的变化而变化。例如部分通过标准的预后评价方法可评价所述疾病状态的严重性。此外，所述剂量和可能的剂量频率也将根据个体患者的年龄、体重、以及反应的变化而变化。与上述讨论方案相当的方案可用于兽医学中。
虽然可基于逐一的药物分析(drug-by-drug)可决定确切的剂量，但是在大多数情况下，能够就药剂进行某些概括。成人患者的日给药方案为，例如口服剂量为0.1mg至2000mg各活性成分，在某些实施方案中为1mg至2000mg各活性成分，例如5mg至1500mg各活性成分。在其它实施方案中，所使用的各活性成分的静脉内、皮下或肌内剂量为0.01mg至1000mg，在某些实施方案中为0.1mg至1000mg，例如1mg至800mg。在给予药物可接受盐的情况下，可按照游离碱来计算剂量。在某些实施方案中，每日1至4次将所述组合物进行给药。或者，本公开中所述的组合物可通过连续的静脉输注进行给药，在某些实施方案中以每日高达2000mg的各活性成分的剂量进行给药。正如本领域技术人员所理解的，在某些情形中，为了有效且迅速地治疗迅速发展的疾病或感染，以超过或远远超过上述剂量范围的量给予本公开中所述的化合物是必要的。在某些实施方案中，将所述化合物在连续治疗期间进行给药，例如一周或数周、或数月或数年。
可以个别地调整剂量和用药间隔以提供足以维持调整效果或最低有效浓度(MEC)的活性部分的血浆水平。每种化合物的MEC不同，但是能够从体外数据评估MEC。达到MEC的所需剂量取决于个体特征和给药途径。然而，能够使用HPLC(高效液相色谱)测定或生物测定来确定血浆浓度。
使用MEC值还能够测定用药间隔。应使用在10-90％的时间内、在某些实施方案中在30-90％的时间内、以及在某些实施方案中在50-90％的时间内将血浆水平维持在MEC以上的治疗方案对组合物进行给药。
在局部给药或选择性吸收的情况下，药物的有效局部浓度与血浆浓度无关。
当然，被给药的组合物的量取决于待治疗的个体，取决于所述个体的体重、痛苦的严重性、给药方式以及开处方医师的判断。
使用已知的方法能够对本公开中所述的化合物的效能和毒性进行评估。例如，通过在体外测定细胞系的毒性可建立特定化合物或共享某些化学部分的该化合物子集的毒理学，所述细胞系例如哺乳动物细胞系并且在某些实施方案中为人的细胞系。这类研究的结果通常可预测诸如哺乳动物等的动物体内的毒性，或更具体地，可预测人体内的毒性。或者，使用已知方法可测定特定化合物在诸如小鼠、大鼠、家兔或猴等动物模型中的毒性。使用若干公认的方法，例如体外方法、动物模型或人体临床试验，可确定特定化合物的效能。几乎对每类疾病状态都存在着公认的体外模型，该疾病状态包括但不限于癌症、心血管疾病和多种免疫机能障碍。类似地，可接受的动物模型可用于确定治疗这些疾病状态的化学药物的效能。当选择模型测定效能时，技术人员能够在本领域现有技术的指导下选择合适的模型、剂量和给药途径以及治疗方案。当然，人体临床试验还能够用于测定化合物在人体内的效能。
如果需要，可将所述组合物置于包装或分配装置中，该包装或分配装置可以包含一种或多种含有活性成分的单位剂型。所述包装可以例如包括金属或塑料箔，例如泡罩包装。所述包装或分配装置可带有 给药说明书。所述包装或分配装置还可以带有与所述容器相关的注意事项，该注意事项是由管理药物生产、使用或销售的政府机构规定的，该注意事项反映了所述药物形式已经由该机构批准用于人类或兽类给药。这类注意事项，例如，可以是由国家食品药品监督管理总局或美国食品和药物管理局批准的用于处方药的标签，或者是批准的产品说明书。还可以在合适的容器中制备、放置在相容的药物载体中组方的包含本公开的化合物、其立体异构体或其药物可接受的盐在内的组合物，并对其标记以用于指定的疾病状态的治疗。
又一方面，本公开涉及制备通式(II)化合物、其立体异构体或其药物可接受的盐的方法，其包括：
(1)将通式(B-I)化合物与丙二酸及醋酸铵进行反应得到通式(B-II)化合物，
Figure PCTCN2019082943-appb-000032
其中，通式(B-I)和通式(B-II)中的R 3”、R 4”表示的基团与通式(II)中的R 3、R 4的定义相同，
(2)将通式(B-II)化合物与醇进行酯化反应得到通式(B-III)化合物，
Figure PCTCN2019082943-appb-000033
其中，通式(B-II)和通式(B-III)中的R 3”、R 4”表示的基团与通式(II)中的R 3、R 4的定义相同，R 2’选自氢或烃基；
(3)将通式(B-IV)化合物与通式(B-III)化合物进行反应得到通式 (II)化合物
Figure PCTCN2019082943-appb-000034
其中，式(B-III)和通式(B-IV)中的R 1”、R 3”、R 4”表示的基团与通式(II)中的R 1、R 3、R 4的定义相同，R 2’选自氢或烃基；
其中X为-CR 5R 6-，其中R 5为氢，R 6为氢，n为1。
在某些实施方案中，将通式(B-I)化合物与丙二酸及醋酸铵进行反应得到通式(B-II)化合物的方法是在有机溶剂中进行的。
在某些实施方案中，能够用于本公开的将通式(B-I)化合物与丙二酸及醋酸铵进行反应得到通式(B-II)化合物的合适的有机溶剂的示例性实例包括但不限于甲醇、乙醇、异丙醇和水。
在某些实施方案中，在约50℃至约130℃下将通式(B-I)化合物与丙二酸及醋酸铵进行反应得到通式(B-II)化合物。
在某些实施方案中，能够用于由通式(B-II)化合物制备通式(B-III)化合物的合适的酯化剂的示例性实例包括但不限于氯化亚砜、草酰氯、HCl气体和乙酰氯。
在某些实施方案中，将通式(B-II)化合物与醇类化合物进行反应得到通式(B-III)化合物的方法是在有机溶剂中进行的。
在某些实施方案中，能够用于本公开的将通式(B-II)化合物与醇类化合物进行反应得到通式(B-III)化合物的合适的有机溶剂的示例性实例包括但不限于醇类、四氢呋喃、二氯甲烷、乙酸乙酯和甲基叔丁基醚。
在某些实施方案中，能够用于本公开的将通式(B-II)化合物与醇类化合物进行反应得到通式(B-III)化合物的合适的醇类的示例性实例包括但不限于甲醇、乙醇和异丙醇等。
在某些实施方案中，在约-20℃至约30℃下将通式(B-II)化合物与醇类化合物进行反应得到通式(B-III)化合物。
在某些实施方案中，在将通式(B-IV)化合物与通式(B-III)化合物进 行反应得到通式(II)化合物的方法中加入催化剂。
在某些实施方案中，能够用于本公开的将通式(B-IV)化合物与通式(B-III)化合物进行反应得到通式(II)化合物的合适的催化剂的示例性实例包括但不限于醋酸钠、醋酸钾、碳酸钠和碳酸钾。
在某些实施方案中，将通式(B-IV)化合物与通式(B-III)化合物进行反应得到通式(II)化合物的方法是在有机溶剂中进行的。
在某些实施方案中，能够用于本公开的将通式(B-IV)化合物与通式(B-III)化合物进行反应得到通式(II)化合物的合适的有机溶剂的示例性实例包括但不限于醋酸、甲酸、二甲基甲酰胺和二甲基乙酰胺。
在某些实施方案中，在约50℃至约180℃下将通式(B-IV)化合物与通式(B-III)化合物进行反应得到通式(II)化合物。
下文中，本公开将通过如下实施例进行详细解释以便更好地理解本申请的各个方面及其优点。然而，应当理解，以下的实施例是非限制性的而且仅用于说明本申请的某些实施方案。
实施例
缩写语：
DMF：N,N-二甲基甲酰胺
DCM：二氯甲烷
THF：四氢呋喃
PE：石油醚
EA：乙酸乙酯
AcOH：乙酸
DMAP：4-二甲氨基吡啶
CDCl 3：氘代氯仿
HPLC：高效液相色谱
TLC：薄层色谱
实施例1
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将3-硝基邻苯二甲酸(10.0克)、钯碳(1.0克，Pd含量10％)和四氢呋喃(200毫升)加入反应瓶中，以氢气球置换空气三次，室温下搅拌反应16小时，高效液相色谱监测显示反应完全。将反应液过滤，滤液以水泵减压浓缩得到粗产品。粗产品用二氯甲烷打浆纯化得到黄色固体3-氨基邻苯二甲酸(4.0克，HPLC纯度81.88％)；收率47％。MS(m/e)：182.24(M+H +)。
将3-氨基邻苯二甲酸(1.0克)和乙酸酐(2.5毫升)加入反应瓶中，加热至105摄氏度反应2小时，TLC显示反应完全。将反应液降至室温，减压抽滤，收集滤饼；将滤饼加入乙醚打浆纯化，减压过滤，收集滤饼即为黄色固体N-(1,3-二氧代-1,3-二氢异苯并呋喃-4-基)乙酰胺(0.67克，HPLC纯度98.94％)；收率59％。
将3-乙氧基-4-甲氧基苯甲醛(200克)、醋酸铵(171克)和丙二酸(150克)加入反应瓶中，加入乙醇(1235毫升)和水(65毫升)，体系在搅拌下升温至回流(内温80摄氏度)，回流温度下搅拌反应16小时，析出大量固体，HPLC显示反应完全。将反应液减压抽滤，收集滤饼；滤饼以乙酸乙酯打浆纯化，过滤收集滤饼，以真空干燥箱(40摄氏度)干燥，得到白色固体3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸(168克，HPLC纯度80.48％)；收率65.5％。MS(m/e)：240.12(M+H +)。
将3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸(83克)加入反应瓶中，加入甲醇(581毫升)，体系降至0摄氏度，搅拌下缓慢滴加氯化亚砜(53.65克)，滴加完毕后缓慢升至室温，搅拌反应过夜，高效液相色谱监测显示反应完全。将反应液加入甲基叔丁基醚(2.9升)，室温搅拌过夜，将析出的大量固体减压抽滤，收集滤饼，以真空干燥箱(45摄氏度)干燥，得到白色固体3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(86克，HPLC纯度99.36％)；收率87％。MS(m/e)：254.13(M+H +)。
将3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(50.73克)、N-(1,3-二氧代-1,3-二氢异苯并呋喃-4-基)乙酰胺(30克)、醋酸钠(24克)和AcOH(300毫升)加入反应瓶中，置于油浴中加热至140度，搅拌反 应6小时，HPLC显示反应完全。将反应液依次以水泵减压浓缩，得到粗产品。向粗产品中加入DCM和水，溶解并萃取，收集有机相并以饱和食盐水洗涤两次；将有机相以无水硫酸钠干燥，水泵减压浓缩，所得粗产品用硅胶柱层析(洗脱液为石油醚：乙酸乙酯＝15:1至1:1)纯化，得到标题化合物(41.3克，HPLC纯度99.24％)；收率64.1％。
1HNMR(CDCl 3,400MHz)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 +)。
实施例2
3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
用实施例1中的合成方法，由3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐和3-硝基邻苯二甲酸酐反应制得3-(3-乙氧基-4-甲氧基苯基)-3-(4-硝基-1,3-二氧代异吲哚啉-2-基)丙酸甲酯(16.2克，HPLC纯度95.15％)；收率75％。MS(m/e)：429.12(M+H +)。
将3-(3-乙氧基-4-甲氧基苯基)-3-(4-硝基-1,3-二氧代异吲哚啉-2-基)丙酸甲酯(6.0克)、钯碳(3.0克，钯含量10％)和四氢呋喃(200毫升)加入反应瓶中，以氢气球置换空气三次，室温下搅拌反应16小时，TLC显示反应完全。将反应液过滤，滤液以水泵减压浓缩得到粗产品。粗产品用硅胶柱层析(洗脱液PE:EA＝3:1)纯化得到黄色标题化合物(3.87克，HPLC纯度96.49％)；收率74.1％。MS(m/e)：399.15(M+H +)。
实施例3
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3,4-二甲氧基苯基)丙酸甲酯
将3-羟基-4-甲氧基苯甲醛(5.0克)、碳酸钾(4.56克)投入反应瓶，以DMF溶解，再加入碘甲烷(3.1毫升)。将反应移至油浴中65摄氏度 搅拌反应15小时，HPLC显示反应完全。将反应液稀释至乙酸乙酯中，然后用饱和食盐水洗涤分液，收集有机相以无水硫酸镁干燥，以水泵40摄氏度缩干得到粗品。粗产品用硅胶柱层析(洗脱液PE:EA＝8:1)纯化得到无色油状产品(3,4-二甲氧基苯甲醛)(4.95克，HPLC纯度99.94％)，收率90％。
用实施例1中的合成方法，由3,4-二甲氧基苯甲醛(4.9克)反应制得3-氨基-3-(3,4-二甲氧基苯基)丙酸(4.28克，HPLC纯度98.54％)；收率79％。MS(m/e)：226.10(M+H +)。
用实施例1中的合成方法，由3-氨基-3-(3,4-二甲氧基苯基)丙酸(4.28克)反应制得3-氨基-3-(3,4-二甲氧基苯基)丙酸甲酯盐酸盐(4.4克，HPLC纯度99.89％)；收率96.7％。MS(m/e)：240.12(M+H +)。
用实施例1中的合成方法，由3-氨基-3-(3,4-二甲氧基苯基)丙酸甲酯盐酸盐(1.16克)和N-(1,3-二氧代-1,3-二氢异苯并呋喃-4-基)乙酰胺(1.0克)反应制得标题化合物(0.68克，HPLC纯度96.49％)；收率32.6％。MS(m/e)：427.14(M+H +)。
实施例4
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3,4-二乙氧基苯基)丙酸甲酯
用实施例3中的合成方法，由3-乙氧基-4-羟基苯甲醛(3.0克)与碘乙烷反应制得化合物油状产品(3,4-二乙氧基苯甲醛)(3.48克，HPLC纯度98.99％)；收率99.3％。
用实施例3中的合成方法，由3,4-二乙氧基苯甲醛(3.48克)反应制得3-氨基-3-(3,4-二乙氧基苯基)丙酸(4.0克，HPLC纯度97.68％)；收率88.1％。MS(m/e)：254.13(M+H +)。
用实施例1中的合成方法，由3-氨基-3-(3,4-二乙氧基苯基)丙酸(4.0克)反应制得3-氨基-3-(3,4-二乙氧基苯基)丙酸甲酯盐酸盐(2.9克，HPLC纯度99.26％)；收率60.9％。MS(m/e)：268.15(M+H +)。
用实施例1中的合成方法，由3-氨基-3-(3,4-二乙氧基苯基)丙酸甲酯盐酸盐(1.48克)和N-(1,3-二氧代-1,3-二氢异苯并呋喃-4-基)乙酰胺 (1.0克)反应制得标题化合物(0.38克，HPLC纯度98.79％)；收率17.2％。MS(m/e)：455.17(M+H +)。
实施例5
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸
用实施例1中的合成方法，由3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸(2.1克)和N-(1,3-二氧代-1,3-二氢异苯并呋喃-4-基)乙酰胺(2.05克)反应制得标题化合物(2.73克，HPLC纯度98.81％)；收率76.7％。MS(m/e)：425.14(M-H -)。
实施例6
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯
将3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸(0.3克)、6-氯-1-羟基苯并三氮唑(0.18克)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.2克)加入反应瓶中，加入DCM(4毫升)，室温下搅拌溶清后，加入乙醇(0.25毫升)，室温搅拌过夜。HPLC显示反应完全，加水淬灭反应；将反应液以水泵减压浓缩，所得粗品用硅胶柱层析(洗脱液为DCM:EA＝30:1至20:1)纯化，得到浅黄色标题化合物(0.17克，HPLC纯度99.65％)；收率54.4％。MS(m/e)：477.28(M+Na +)。
实施例7
(R)-3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(5.0克)溶于水(100毫升)中，用饱和碳酸钠水溶液调至pH＝9，以DCM(50毫升×4)萃取水相；合并有机相，以饱和氯化钠水溶液(40毫升)洗涤一次，用无水硫酸钠干燥，过滤，滤液以水泵减压浓缩得到油状产品3-氨基 -3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(4.4克，直接用于下一步反应)；收率100％。
将3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(14.0克)、N-(叔丁氧羰基)-L-亮氨酸一水合物(7.15克)加入反应瓶中，加入甲基叔丁基醚(490毫升)，体系升温至35摄氏度搅拌1小时；然后缓慢降至室温搅拌过夜，析出大量白色固体，将反应液减压抽滤，滤饼以甲基叔丁基醚(30毫升)洗涤1次，收集滤饼自然晾干，得到白色固体产品(R)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯N-(叔丁氧羰基)-L-亮氨酸盐(11克，光学纯度为98.64％)；收率41.1％。
将(R)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯N-(叔丁氧羰基)-L-亮氨酸盐(12.1克)溶于水(100毫升)中，用饱和碳酸钠水溶液调至pH＝9，以乙酸乙酯(50毫升×4)萃取水相；合并有机相，以饱和氯化钠水溶液(60毫升)洗涤一次，用无水硫酸钠干燥，过滤，滤液以水泵减压浓缩(35度)得到油状产品(R)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(5.62克，测定旋光为[α] D 20＝-14.5°(C＝0.02,EtOH)，直接用于下一步反应)；收率100％。
用实施例1中的合成方法，由(R)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(4.9克)和3-硝基邻苯二甲酸酐(4.48克)反应制得(R)-3-(3-乙氧基-4-甲氧基苯基)-3-(4-硝基-1,3-二氧代异吲哚啉-2-基)丙酸甲酯(5.28克，HPLC纯度98.62％)；收率63.7％。MS(m/e)：429.12(M+H +)。
用实施例2中的合成方法，由(R)-3-(3-乙氧基-4-甲氧基苯基)-3-(4-硝基-1,3-二氧代异吲哚啉-2-基)丙酸甲酯(5.06克)反应制得标题化合物(3.2克，HPLC纯度97.26％，光学纯度99.05％)，旋光测定为[α] D 20＝+12.55°(C＝0.02，乙腈)；收率69％。MS(m/e)：399.15(M+H +)。
实施例8
(S)-3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
用实施例7中的合成方法，由3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(14.0克)和N-(叔丁氧羰基)-D-亮氨酸一水合物(7.15克)反应 制得(S)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯N-(叔丁氧羰基)-D-亮氨酸盐(10克，HPLC纯度98.83％，光学纯度99.15％)；收率37.3％。
用实施例7中的合成方法，由(S)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯N-(叔丁氧羰基)-D-亮氨酸盐(10克)反应制得油状产品(S)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(5.3克，旋光测定为[α] D 20＝+14.1°(C＝0.02，乙醇)，直接用于下一步反应)。
用实施例1中的合成方法，由(S)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(3.92克)和3-硝基邻苯二甲酸酐(3.1克)反应制得(S)-3-(3-乙氧基-4-甲氧基苯基)-3-(4-硝基-1,3-二氧代异吲哚啉-2-基)丙酸甲酯(3.84克，HPLC纯度98.13％)；收率58％。MS(m/e)：429.12(M+H +)。
用实施例2中的合成方法，由(S)-3-(3-乙氧基-4-甲氧基苯基)-3-(4-硝基-1,3-二氧代异吲哚啉-2-基)丙酸甲酯(2.63克)反应制得标题化合物(1.92克，HPLC纯度99.32％，光学纯度99.25％)；旋光测定为[α] D 20＝-11.93°(C＝0.02，乙腈)；收率48％。MS(m/e)：399.15(M+H +)。
实施例9
(R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
用实施例1中的合成方法，由(R)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(10.44克)和N-(1,3-二氧代-1,3-二氢异苯并呋喃-4-基)乙酰胺)(8.5克)反应制得标题化合物(12.0克，HPLC纯度99.40％，光学纯度99.60％)，旋光测定为[α] D 20＝+11.2°(C＝0.02，乙腈)；收率66.1％。
1HNMR(CDCl 3,400MHz)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 +)。
实施例10
(S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
用实施例1中的合成方法，由(S)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯和N-(1,3-二氧代-1,3-二氢异苯并呋喃-4-基)乙酰胺(4.1克)反应制得标题化合物(6.6克，HPLC纯度98.83％，光学纯度99.73％)，旋光测定为[α] D 20＝-11.6°(C＝0.02,ACN)；收率76.1％。
1HNMR(CDCl 3,400MHz)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 +)。
实施例11
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸丙酯
用实施例6中的合成方法，由3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸(0.3克)和正丙醇反应制得标题化合物(0.12克，HPLC纯度99.32％)；收率36％。MS(m/e)：491.17(M+Na +)。
实施例12
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸异丙酯
用实施例6中的合成方法，由3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸(0.3克)和异丙醇反应制得标题化合物(0.14克，HPLC纯度98.93％)；收率42％。MS(m/e)：491.16(M+Na +)。
实施例13
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基) 丙酸丁酯
用实施例6中的合成方法，由3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸(0.3克)和正丁醇反应制得标题化合物(0.22克，HPLC纯度99.46％)；收率61％。MS(m/e)：505.20(M+Na +)。
实施例14
3-(4-(2-氯乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(700毫克)、氯乙酰氯(218毫克)、碳酸钾(486毫克)和DCM(12毫升)加入反应瓶中，室温搅拌反应过夜，HPLC显示反应完全。向反应液中加入水(30毫升)和DCM(50毫升)，萃取分液。再用DCM(2×50毫升)反萃水相，合并DCM。再用饱和NaCl水溶液清洗，分液，无水MgSO4干燥，过滤，缩干得到3-(4-(2-氯乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯粗品。所得粗产品用硅胶柱层析(洗脱液为PE:EA＝10:1至4:1)纯化，得到标题化合物纯品(220毫克，HPLC纯度99.78％)；收率26％。MS(m/e)：497.19(M+Na +)。
实施例15
3-(4-(2-(二甲氨基)乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将3-(4-(2-氯乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(200毫克)、二甲胺盐酸盐(52毫克)、碳酸钾(116毫克)和丙酮(10毫升)加入反应瓶中，室温搅拌反应50小时，HPLC显示反应完全。向反应液中加入水(40毫升)和EA(40毫升)，萃取分液。再用EA(30毫升)反萃水相，合并有机相，再用饱和NaCl水溶液清洗，分液，无水MgSO4干燥，过滤，缩干得到3-(4-(2-(二甲氨基)乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯粗 品。所得粗产品用硅胶柱层析(洗脱液为DCM:MeOH＝200:1)纯化，得到标题化合物纯品(100毫克，HPLC纯度96.44％)；收率49％。MS(m/e)：484.27(M+H +)。
实施例16
3-(4-(二甲氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(500毫克)、甲醛水溶液(9毫升)、Pd/C(50毫克，Pd含量10％)和甲醇(20毫升)加入反应瓶中，以氢气球置换空气三次，室温下搅拌反应100小时，TLC显示反应完全。将反应液过滤，滤液以水泵减压浓缩得到3-(4-(二甲氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯粗产品。粗产品用硅胶柱层析(洗脱液PE:EA＝4:1)纯化得到标题化合物纯品(176毫克，HPLC纯度96.67％)；收率32.9％。MS(m/e)：427.18(M+H +)。
实施例17
3-(4-(2-羟基乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将2-(苄氧基)乙酸(318毫克)和DCM(10毫升)加入反应瓶中，室温搅拌下加入氯化亚砜(0.27毫升)，然后加入DMF(1毫升)，室温搅拌反应18小时。将反应液依次以水泵、油泵减压浓缩得到油状产品2-(苄氧基)乙酰氯(347毫克)，直接用于下步反应。
将2-(苄氧基)乙酰氯(347毫克)、3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(500毫克)、碳酸钾(191毫克)和DCM(10毫升)加入反应瓶中，室温下搅拌反应18小时，HPLC显示反应完全。向反应液中加入水(40毫升)和DCM(100毫升)，萃取分液。再用DCM(2×30毫升)反萃水相，合并DCM。再用饱和NaCl水溶液清洗，分液，无水MgSO 4干燥，过滤，缩干得粗品。粗产品用硅胶柱层析(洗脱液PE:EA＝4:1)纯化得到3-(4-(2-(苄氧基)乙酰氨基)-1,3-二 氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(234毫克，HPLC纯度95.88％)；收率34.2％。MS(m/e)：569.21(M+Na +)。
将3-(4-(2-(苄氧基)乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(234毫克)、Pd/C(24毫克，Pd含量10％)、甲醇(17毫升)和EA(7毫升)加入反应瓶中，以氢气球置换空气三次，室温下搅拌反应40小时，HPLC显示反应完全。将反应液过滤，滤液以水泵减压浓缩得到3-(4-(2-羟基乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯粗产品。粗产品用硅胶柱层析(洗脱液PE:EA＝2:1)纯化得标题化合物(89毫克，HPLC纯度98.70％)；收率45.6％。MS(m/e)：479.17(M+Na +)。
实施例18
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-异丙氧基苯基)丙酸甲酯
用实施例3中的合成方法，由3-乙氧基-4-羟基苯甲醛(3.0克)与溴代异丙烷反应制得3-乙氧基-4-异丙氧基苯甲醛(2.8克，HPLC纯度98.56％)；收率76％。
用实施例1中的合成方法，由3-乙氧基-4-异丙氧基苯甲醛(2.8克)反应制得3-氨基-3-(3-乙氧基-4-异丙氧基苯基)丙酸(2.7克，HPLC纯度99.43％)；收率74％。MS(m/e)：268.15(M+H +)。
用实施例1中的合成方法，由3-氨基-3-(3-乙氧基-4-异丙氧基苯基)丙酸(2.7克)反应制得3-氨基-3-(3-乙氧基-4-异丙氧基苯基)丙酸甲酯盐酸盐(2.4克，HPLC纯度98.69％)；收率75％。MS(m/e)：282.16(M+H +)。
用实施例1中的合成方法，由3-氨基-3-(3-乙氧基-4-异丙氧基苯基)丙酸甲酯盐酸盐(1.5克)和N-(1,3-二氧代-1,3-二氢异苯并呋喃-4-基)乙酰胺(1.0克)反应制得标题化合物(237毫克，HPLC纯度97.30％)；收率10.4％。MS(m/e)：491.20(M+Na +)。
实施例19
3-(4-氟-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
用实施例1中的合成方法，由3-氟酞酐(275毫克)和3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(526毫克)反应制得标题化合物(546毫克，HPLC纯度99.85％)；收率82％。MS(m/e)：424.16(M+Na +)。
实施例20
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-环戊氧基苯基)丙酸甲酯
用实施例3中的合成方法，由3-乙氧基-4-羟基苯甲醛(3.0克)与溴代环戊烷反应制得3-乙氧基-4-环戊氧基苯甲醛(4.2克，HPLC纯度96.97％)；收率99％。
用实施例1中的合成方法，由3-乙氧基-4-环戊氧基苯甲醛(4.2克)反应制得3-氨基-3-(3-乙氧基-4-环戊氧基苯基)丙酸(2.78克，HPLC纯度99.60％)；收率52.9％。MS(m/e)：294.16(M+H +)。
用实施例1中的合成方法，由3-氨基-3-(3-乙氧基-4-环戊氧基苯基)丙酸(2.78克)反应制得3-氨基-3-(3-乙氧基-4-环戊氧基苯基)丙酸甲酯盐酸盐(3.25克，HPLC纯度99.60％)；收率100％。MS(m/e)：308.18(M+H +)。
用实施例1中的合成方法，由3-氨基-3-(3-乙氧基-4-环戊氧基苯基)丙酸甲酯盐酸盐(1.8克)和N-(1,3-二氧代-1,3-二氢异苯并呋喃-4-基)乙酰胺(1.0克)反应制得标题化合物(606毫克，HPLC纯度94.97％)；收率25.1％。MS(m/e)：517.23(M+Na +)。
实施例21
3-(4-甲基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
用实施例1中的合成方法，由3-甲基邻苯二甲酸酐(330毫克)和3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(648毫克)反应制得标题化合物(609毫克，HPLC纯度99.58％)；收率75％。MS(m/e)： 420.16(M+Na +)。
实施例22
3-(5-氟-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
用实施例1中的合成方法，由4-氟邻苯二甲酸酐(271毫克)和3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(526毫克)反应制得标题化合物(350毫克，HPLC纯度98.02％)；收率53％。MS(m/e)：424.14(M+Na +)。
实施例23
3-(4,7-二氯-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
用实施例1中的合成方法，由3,6-二氯邻苯二甲酸酐(500毫克)和3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(666毫克)反应制得标题化合物(100毫克，HPLC纯度99.20％)；收率7.2％。
1HNMR(CDCl 3,400MHz)δ7.530-7.527(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 +)。
实施例24
3-(4-(N-甲基乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(505毫克)、碘甲烷(177毫克)和碳酸钾(314毫克)加入反应瓶中，加入DMF(5毫升)，体系在室温下搅拌反应100小时，HPLC显示反应完全。向反应液中加入水(30毫升)和DCM(200毫升)，萃取分液，收集有机相，减压浓缩得到粗产品。所得粗产品用硅胶柱层析(洗脱液为PE:EA＝20:1至1:1)纯化，得到标题化合物(410毫克， HPLC纯度98.12％)；收率79.5％。MS(m/e)：477.25(M+Na +)。
实施例25
3-(5-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将4-硝基邻苯二甲酸(1.5克)和乙酸酐(15毫升)加入反应瓶中，于125摄氏度下搅拌反应2小时。将反应液依次以水泵、油泵减压浓缩得到4-硝基邻苯二甲酸酐(1.4克)，直接用于下步反应。
用实施例1中的合成方法，由4-硝基邻苯二甲酸酐(1.4克)和3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(1.58克)反应制得3-(3-乙氧基-4-甲氧基苯基)-3-(5-硝基-1,3-二氧代异吲哚啉-2-基)丙酸甲酯(2.2克，HPLC纯度97.65％)；收率94％。MS(m/e)：429.12(M+H +)。
用实施例2中的合成方法，由3-(3-乙氧基-4-甲氧基苯基)-3-(5-硝基-1,3-二氧代异吲哚啉-2-基)丙酸甲酯(678毫克)反应制得3-(3-乙氧基-4-甲氧基苯基)-3-(5-氨基-1,3-二氧代异吲哚啉-2-基)丙酸甲酯(500毫克，HPLC纯度98.25％)；收率79.2％。MS(m/e)：421.25(M+Na +)。
将3-(3-乙氧基-4-甲氧基苯基)-3-(5-氨基-1,3-二氧代异吲哚啉-2-基)丙酸甲酯(250毫克)、乙酸酐(83毫克)、三乙胺(190毫克)、DMAP(8毫克)和DCM(2.5毫升)加入反应瓶中，室温搅拌反应过夜。HPLC检测反应完全，向反应液中加入一滴水淬灭反应，将反应液依次以水泵减压浓缩得到粗产品。粗产品用硅胶柱层析(洗脱液PE:EA＝1:1)纯化得到标题化合物(170毫克，HPLC纯度98.39％)；收率61.6％。MS(m/e)：463.22(M+Na +)。
实施例26
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-(苄氧基)-4-甲氧基苯基)丙酸甲酯
用实施例3中的合成方法，用溴苄代替碘甲烷，由3-羟基-4-甲氧基苯甲醛(5.0克)反应制得标题化合物(806毫克，HPLC纯度99.46％)；MS(m/e)：525.14(M+Na +)。
实施例27
3-(4-(N-甲基叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(500毫克)、Boc 2O(958毫克)和DMAP(31毫克)加入反应瓶中，加入THF(15毫升)，室温搅拌反应过夜，TLC显示原料反应完全。将反应液以水泵减压浓缩得到粗产品。粗产品用硅胶柱层析(洗脱液为PE:EA＝15:1至5:1)纯化得到3-(4-(二叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(634毫克，HPLC纯度98.28％)；收率84.4％。MS(m/e)：599.25(M+H +)。
将3-(4-(二叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(634毫克)溶于DCM(200毫升)，加入三氟乙酸(1毫升)，室温搅拌反应15分钟，TLC显示反应完全。向反应液中加入饱和NaHCO 3(30毫升)淬灭反应，搅拌10分钟；以分液漏斗分液，有机相以无水MgSO 4干燥、过滤，收集滤液依次以水泵、油泵减压浓缩得到粗产品。粗产品用硅胶柱层析(洗脱液为PE:EA＝15:1至5:1)纯化得到3-(4-(叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(354毫克，HPLC纯度99.41％)；收率67％。
将3-(4-(叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(300毫克)、碘甲烷(171毫克)和碳酸钾(250毫克)加入反应瓶中，加入DMF(6毫升)，室温搅拌反应过夜，HPLC显示反应完全。将反应液以EA(250毫升)稀释，先用水(40毫升)洗涤有机相；再以饱和NaCl水溶液(30毫升×4)洗涤有机相，有机相以无水MgSO 4干燥、过滤、依次以水泵、油泵减压浓缩得到标题化合物(201毫克，HPLC纯度95.54％)；收率65.3％。MS(m/e)：513.22(M+H +)。
实施例28
3-(4-(甲基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将化合物3-(4-(N-甲基叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(201毫克)溶于DCM(2毫升)，加入三氟乙酸(2毫升)，室温搅拌反应2小时，TLC显示反应完全。将反应液以水泵减压浓缩得到粗产品，粗产品用硅胶柱层析(洗脱液为PE:EA＝10:1至5:1)纯化得到标题化合物(120毫克，HPLC纯度99.95％)；收率74％。MS(m/e)：435.14(M+Na +)。
实施例29
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-丙氧基-4-甲氧基苯基)丙酸甲酯
用实施例3中的合成方法，由3-羟基-4-甲氧基苯甲醛(5.0克)与正溴丙烷反应制得标题化合物(886毫克，HPLC纯度98.496％)；MS(m/e)：477.14(M+Na +)。
实施例30
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-环戊氧基-4-甲氧基苯基)丙酸甲酯
用实施例3中的合成方法，由3-羟基-4-甲氧基苯甲醛(5.0克)与溴代环戊烷反应制得标题化合物(1.086克，HPLC纯度98.51％)。
1HNMR(CDCl 3,400MHz)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 +)。
实施例31
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-丙氧基苯基)丙酸甲酯
用实施例3中的合成方法，由3-乙氧基-4-羟基苯甲醛)(3.0克)与 正溴丙烷反应制得标题化合物(227毫克，HPLC纯度96.34％)。
1HNMR(CDCl 3,400MHz)δ9.529(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 +)。
实施例32
3-(4-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
用实施例1中的合成方法，由3-羟基邻苯二甲酸酐(300毫克)和3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(580毫克)反应制得标题化合物(340毫克，HPLC纯度97.97％)；收率46％。MS(m/e)：422.16(M+Na +)。
实施例33
3-(4-乙酰氧基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将3-(4-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(300毫克)、乙酰氯(177毫克)、三乙胺(228毫克)和DCM(5毫升)加入反应瓶中，室温搅拌反应过夜，HPLC显示反应完全。向反应液中加入1N盐酸水溶液(30毫升)和DCM(100毫升)，萃取分液。有机相用饱和NaCl水溶液清洗，分液，无硫酸镁干燥，过滤，缩干得到粗品。所得粗产品用硅胶柱层析(洗脱液为PE:EA＝10:1至2:1)纯化，得到标题化合物(179毫克，HPLC纯度97.95％)；收率53.9％。MS(m/e)：464.14(M+Na +)。
实施例34
3-(4-氨基-7-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯 基)丙酸甲酯
将3-叔丁氧羰基氨基-6-羟基邻苯二甲酸二甲酯(2.0克)、3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(3.56克)和吡啶(40毫升)加入反应瓶中，置于油浴中加热至100摄氏度，搅拌反应38小时。将反应液降至室温，以水泵减压浓缩得到粗产品。粗产品用硅胶柱层析(洗脱液为PE:EA＝5:1)纯化，得到3-(4-(叔丁氧羰基氨基)-7-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(2.149克，HPLC纯度99.22％)；收率67.9％。MS(m/e)：515.20(M+H +)。
将3-(3-乙氧基-4-甲氧基苯基)-3-(4-(叔丁氧羰基氨基)-7-羟基-1,3-二氧代异吲哚啉-2-基)丙酸甲酯(2.148克)溶于二氯甲烷(50毫升)，加入三氟乙酸(6毫升)，室温搅拌反应6小时，TLC显示反应完全。将反应液以水泵减压浓缩得到粗产品，粗产品以PE/DCM＝1:1(10毫升)打浆纯化，得到标题化合物(1.28克，HPLC纯度99.36％)；收率74％。MS(m/e)：437.21(M+Na +)。
实施例35
3-(4-氨基-5-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将4-羟基邻苯二甲酸二甲酯(125克)和浓H 2SO4(600毫升)加入反应瓶中，搅拌下降温至0摄氏度；向体系中缓慢滴加发烟HNO 3(39.44克)，控制体系温度小于5摄氏度，约1小时滴加完毕。撤掉冰浴，升至室温，搅拌反应22小时，HPLC显示反应完全。将反应液缓慢倒入冰水(1.4千克)中淬灭反应，加EA(600毫升×5)萃取水相；合并有机相，以无水MgSO 4(25克)干燥、过滤，收集滤液，依次以水泵、油泵减压浓缩得到4-羟基-3-硝基邻苯二甲酸二甲酯粗产品(169克，HPLC纯度36.54％)，直接用于下步反应。MS(m/e)：254.07(M-H -)。
将4-羟基-3-硝基邻苯二甲酸二甲酯(164克)、溴化苄(135.9克)、碳酸钾(400克)和丙酮(1730毫升)加入反应瓶中，置于油浴中加热至70摄氏度，搅拌反应23小时，TLC确认反应完全。将反应体系降至室温，将反应液减压抽滤，滤饼以DCM(2000毫升)淋洗，收集滤液； 将滤液减压浓缩，向浓缩物中加入DCM(2000毫升)和饱和NaCl水溶液(1000毫升)萃取分液，有机相以无水MgSO 4(100克)干燥、过滤、以水泵减压浓缩得到黄色固体粗品。粗品以EA重结晶纯化，得到白色固体产品4-苄氧基-3-硝基邻苯二甲酸二甲酯(40克，HPLC纯度96.96％)；收率18.1％。MS(m/e)：346.14(M+H +)。
将4-苄氧基-3-硝基邻苯二甲酸二甲酯(1.335克)和EtOH(14毫升)加入反应瓶中，将预配制好的NaOH水溶液(1.089克NaOH溶于7毫升水中)加入反应瓶中，置于油浴中加热至70摄氏度，搅拌反应7小时，TLC确认反应完全。将反应体系降至室温，反应液以水泵减压浓缩，至缩出大部分EtOH；室温下，向浓缩物中加入4mol/l HCl水溶液酸化，至pH＝2，有大量白色固体析出；将此混合物减压抽滤，收集滤饼，以油泵减压干燥，得到白色固体产品4-苄氧基-3-硝基邻苯二甲酸(1.089克，HPLC纯度99.72％)；收率88.8％。MS(m/e)：316.15(M-H -)。
将4-苄氧基-3-硝基邻苯二甲酸(1.089克)和乙酸酐(11毫升)加入反应瓶中，置于油浴中加热至140摄氏度，搅拌反应6小时。将反应体系降至室温，反应液以水泵减压浓缩得到粗产品4-苄氧基-3-硝基邻苯二甲酸酐粗产品1.02克，直接用于下一步反应。
用实施例1中的合成方法，由4-苄氧基-3-硝基邻苯二甲酸酐(1.02克)和3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(1.09克)反应制得3-(4-硝基-5-苄氧基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(1.48克，HPLC纯度97.92％)；收率78.1％。MS(m/e)：557.21(M+Na +)。
用实施例2中的合成方法，由3-(4-硝基-5-苄氧基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(1.48克)反应制得标题化合物(950毫克，HPLC纯度98.45％)；收率82.8％。MS(m/e)：437.10(M+Na +)。
实施例36
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-羟基-4-甲氧基苯基)丙酸甲酯
将3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-(苄氧基)-4-甲氧基苯基)丙酸甲酯(200毫克)、Pd/C(57毫克，Pd含量10％)和THF(10毫升)加入反应瓶中，以氢气球置换空气三次，室温下搅拌反应16小时，TLC显示反应完全。将反应液过滤，滤液以水泵减压浓缩得到粗产品；所得粗产品用硅胶柱层析(洗脱液为PE:EA＝5:1至1:1)纯化，得到标题化合物(116毫克，HPLC纯度99.81％)；收率70.7％。MS(m/e)：435.13(M+Na +)。
实施例37
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-(苄氧基)苯基)丙酸甲酯
用实施例3中的合成方法，用溴苄代替碘甲烷，由3-乙氧基-4-羟基苯甲醛(3.0克)反应制得标题化合物(881毫克，HPLC纯度97.54％)；MS(m/e)：539.21(M+Na +)。
实施例38
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-羟基苯基)丙酸甲酯
用实施例36中的合成方法，由3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-(苄氧基)苯基)丙酸甲酯(765毫克)反应制得标题化合物(600毫克，HPLC纯度97.25％)；收率95％。MS(m/e)：449.18(M+Na +)。
实施例39
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-甲氧基-4-(苄氧基)苯基)丙酸甲酯
用实施例3中的合成方法，用溴苄代替碘甲烷，由3-甲氧基-4-羟基苯甲醛(3.0克)反应制得标题化合物(1.615克，HPLC纯度96.81％)；MS(m/e)：525.18(M+Na +)。
实施例40
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-甲氧基-4-羟基苯基)丙酸甲酯
用实施例36中的合成方法，由3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-甲氧基-4-(苄氧基)苯基)丙酸甲酯(1.468克)反应制得标题化合物(856毫克，HPLC纯度98.37％)；MS(m/e)：435.15(M+Na +)。
实施例41
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-苯基丙酸甲酯
用实施例1中的合成方法，由苯甲醛(3.0克)反应制得标题化合物(1.46克，HPLC纯度98.71％)；MS(m/e)：389.13(M+Na +)。
实施例42
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-氯苯基)丙酸甲酯
用实施例1中的合成方法，由3-氯苯甲醛(500毫克)反应制得标题化合物(263毫克，HPLC纯度98.54％)；MS(m/e)：423.14(M+Na +)。
实施例43
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-乙氧基苯基)丙酸甲酯
用实施例1中的合成方法，由4-乙氧基苯甲醛(1.9克)反应制得标题化合物(0.86克，HPLC纯度97.83％)；MS(m/e)：411.15(M+H +)。
实施例44
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-氯苯基)丙酸甲酯
用实施例1中的合成方法，由4-氯苯甲醛(500毫克)反应制得标题化合物(260毫克，HPLC纯度98.78％)；MS(m/e)：423.14(M+Na +)。
实施例45
3-(4-(叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯
将3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(500毫克)、Boc 2O(958毫克)和DMAP(31毫克)加入反应瓶中，加入THF(15毫升)，室温搅拌反应过夜，TLC显示原料反应完全。将反应液以水泵减压浓缩得到粗产品。粗产品用硅胶柱层析(洗脱液为PE:EA＝15:1至5:1)纯化得到3-(4-(二叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(634毫克，HPLC纯度98.28％)；收率84.4％。MS(m/e)：599.25(M+H +)。
将3-(4-(二叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯(634毫克)溶于DCM(200毫升)，加入三氟乙酸(1毫升)，室温搅拌反应15分钟，TLC显示反应完全。向反应液中加入饱和NaHCO 3(30毫升)淬灭反应，搅拌10分钟；以分液漏斗分液，有机相以无水MgSO 4干燥、过滤，收集滤液依次以水泵、油泵减压浓缩得到粗产品。粗产品用硅胶柱层析(洗脱液为PE:EA＝15:1至5:1)纯化得到标题化合物(354毫克，HPLC纯度99.41％)；收率67％。MS(m/e)：499.20(M+H +)。
实施例46
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯
用实施例3中的合成方法，由化合物3-羟基-4-甲氧基苯甲醛(5.0克)与溴代异丙烷反应制得标题合物(403毫克，HPLC纯度96.38％)；MS(m/e)：477.15(M+Na +)。
实施例47
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-(二氟甲氧基)-3-乙氧基苯基)丙酸甲酯
用实施例3中的合成方法，由化合物3-乙氧基-4-羟基苯甲醛(5.0克)与二氟碘甲烷反应制得标题化合物(158毫克，HPLC纯度95.36％)；MS(m/e)：477.14(M+H +)。
实施例48
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-(三氟甲氧基)苯基)丙酸甲酯
用实施例3中的合成方法，由化合物3-乙氧基-4-羟基苯甲醛(5.0克)与三氟碘甲烷反应制得标题化合物(105毫克，HPLC纯度95.18％)；MS(m/e)：495.13(M+H +)。
实施例49
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-(二氟甲氧基)-4-甲氧基苯基)丙酸甲酯
用实施例3中的合成方法，由化合物3-羟基-4-甲氧基苯甲醛(5.0克)与二氟碘甲烷反应制得标题化合物(109毫克，HPLC纯度96.37％)；MS(m/e)：463.12(M+H +)。
实施例50
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-甲氧基-3-(三氟甲氧基)苯基)丙酸甲酯
用实施例3中的合成方法，由化合物3-羟基-4-甲氧基苯甲醛(5.0克)与三氟碘甲烷反应制得标题化合物(116毫克，HPLC纯度96.11％)；MS(m/e)：481.11(M+H +)。
实施例51
(R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯
将(R)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(3.0克)加入反应瓶，加入四氢呋喃(30毫升)溶解，室温下加入配置好的氢氧化钠水溶液(2.5克氢氧化钠，30毫升水)，室温搅拌反应3小时，TLC检测至水解反应完全。将反应液降温至0度，以浓盐酸(12N，5.25毫升)调至pH＝1-2，减压浓缩反应液，浓缩物以乙腈(25毫升)共沸除水两次，得到粗品(R)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸盐酸盐(6.5 克，HPLC纯度98.66％)，收率以100％计，直接用于下步反应。
用实施例1中的合成方法，由(R)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸盐酸盐(6.5克)与乙醇(25毫升)反应制得(R)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯盐酸盐。得到白色固体产品(3.15克，HPLC纯度94.51％，直接用于下一步反应)。
用实施例1中的合成方法，由(R)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯盐酸盐(3.15克)和N-(1,3-二氧代-1,3-二氢异苯并呋喃-4-基)乙酰胺(1.8克)反应制得标题化合物(2.227克，HPLC纯度97.75％，光学纯度100％)；收率56.7％。MS(m/e)：477.18(M+Na +)。
实施例52
(S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯
用实施例51中的合成方法，由化合物(S)-3-氨基-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(3.0克)反应制得标题化合物(1.62克，HPLC纯度94.39％)；MS(m/e)：477.20(M+Na +)。
实施例53
(R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯
用实施例7中的合成方法，由3-氨基-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(6.0克)反应制得标题化合物(1.86克，HPLC纯度96.96％，光学纯度99.03％)；MS(m/e)：477.18(M+Na +)。
实施例54
(S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯
用实施例8中的合成方法，由3-氨基-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯盐酸盐(6.0克)反应制得标题化合物(1.62克，HPLC纯度96.44％，光学纯度97.82％)；MS(m/e)：477.18(M+Na +)。
实施例55
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(苯并[d][1,3]二氧杂环戊烯-5-基)丙酸甲酯
用实施例1中的合成方法，由苯并[d][1,3]二氧杂环戊烯-5-甲醛(按照文献RSC Advances,2015，5(91),74425-74437报道的方法制备)(450毫克)反应制得标题化合物(207毫克，HPLC纯度96.32％)；MS(m/e)：411.14(M+H +)。
实施例56
3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(2,3-二氢苯并[b][1,4]二氧杂芑-6-基)丙酸甲酯
用实施例1中的合成方法，由2,3-二氢苯并[b][1,4]二氧杂芑-6-甲醛(按照文献Journal ofMedicinal Chemistry,2007,50(17),4122-4134报道的方法制备)(492毫克)反应制得标题化合物(235毫克，HPLC纯度97.58％)；MS(m/e)：425.18(M+H +)。
生物学实施例
生物学实施例1
DNCB诱导Balb/c小鼠特应性皮炎模型的药效评估实验
1.1试验方法
1.1.1分组
取健康雄性SPF级Balb/c小鼠60只，体重19-21g，按体重随机分为6组，每组10只。
表1.分组表
Figure PCTCN2019082943-appb-000035
Figure PCTCN2019082943-appb-000036
注：DNCB为二硝基氯苯；BID表示一天给药两次。
1.1.2剃毛
试验前，需对小鼠右耳周围毛发进行去除，减少药物由于附着在毛发上对实验的干扰。
1.1.3造模及给药
实验开始记为第1天，各组给药方案以及诱导方案详见图1。具体耳厚测量时间与图1略有调整。实验第18天结束后对每只动物进行取血检测血清中免疫球蛋白(IgE)浓度(按试剂盒说明书进行)。动物双耳剪下，8mm打孔器于耳固定位置打下相等面积耳片称重，计算双耳肿胀度差异。
1.2评价指标及统计方法
应用SPSS 17中One-Way Anova对多组间小鼠耳厚变化，第18天相同面积下耳重以及血清中IgE浓度分别进行统计学分析比较，G检验法删除异常值，以p<0.05表示有统计学差异。
耳肿胀度(mg)＝右耳重量(mg)-左耳重量(mg)；
耳厚变化(mm)＝右耳厚(mm)-左耳厚(mm)；
耳肿胀度抑制率(％)＝1-(给药组耳肿胀度-空白对照组耳肿胀度)/(模型对照组耳肿胀度-空白对照组耳肿胀度)×100％；
耳厚变化抑制率(％)＝1-(给药组耳厚变化-空白对照组耳厚变化)/(模型对照组耳厚变化-空白对照组耳厚变化)×100％；
IgE抑制率(％)＝1-(给药组IgE浓度-空白对照组IgE浓度)/(模型对照组IgE浓度-空白对照组IgE浓度)×100％。
1.3实验结果
表2.各组动物体重变化，单位：g，Mean±S.D.
组别 第1天 第10天 第17天 第18天
空白对照组 21.1±0.9 22.3±0.9 23.0±0.7 23.9±0.7
模型对照组 20.8±0.7 21.9±1.1 22.1±1.1 22.3±1.3
实施例10 20.6±0.8 22.3±1.1 21.8±1.3 22.4±1.3
实施例1 21.0±0.8 22.4±0.8 21.9±1.1 22.0±1.3
实施例3 20.6±0.8 22.3±1.4 22.1±1.8 21.7±1.8
实施例11 20.3±1.3 21.6±1.1 21.2±1.2 21.1±1.3
表3.各组耳厚变化单位：mm，Mean±S.D.
组别 第1天 第10天 第17天 第18天
空白对照组 0.21±0.01 0.23±0.02 0.22±0.02 0.21±0.01
模型对照组 0.21±0.01 0.50±0.22 0.74±0.22 0.77±0.12
实施例10 0.21±0.01 0.35±0.07 0.46±0.10 0.44±0.07
实施例1 0.22±0.02 0.47±0.02 0.60±0.08 0.64±0.07
实施例3 0.21±0.01 0.38±0.10 0.58±0.09 0.58±0.10
实施例11 0.22±0.01 0.33±0.09 0.35±0.04 0.48±0.06
表4.各组动物耳指标比较
Figure PCTCN2019082943-appb-000037
Figure PCTCN2019082943-appb-000038
注：与空白对照组比较，*P<0.05，***P<0.001；
与模型对照组比较，#P<0.05，##P<0.01，###P<0.001；
生物学实施例2
DNCB诱导Balb/c小鼠特应性皮炎模型的药效评估实验
2.1试验方法
2.1.1分组
取健康雄性SPF级Balb/c小鼠70只，体重19-21g，按体重随机分为7组，每组10只。
表5分组表
Figure PCTCN2019082943-appb-000039
Figure PCTCN2019082943-appb-000040
2.1.2剃毛
试验前，需对小鼠右耳周围毛发进行去除，减少药物由于附着在毛发上对实验的干扰。
2.1.3造模及给药
实验开始记为第1天，各组给药方案以及诱导方案详见图2。实验第18天结束后对每只动物进行取血检测血清中免疫球蛋白(IgE)浓度(按试剂盒说明书进行)。动物双耳剪下，8mm打孔器于耳固定位置打下相等面积耳片称重，计算双耳肿胀度差异。
2.2评价指标及统计方法
应用SPSS 17中One-Way Anova对多组间第18天血清中IgE浓度分别进行统计学分析比较，G检验法删除异常值，以p<0.05表示有统计学差异。
耳肿胀度(mg)＝右耳重量(mg)-左耳重量(mg)；
耳肿胀度抑制率(％)＝1-(给药组耳肿胀度-空白对照组耳肿胀度)/(模型对照组耳肿胀度-空白对照组耳肿胀度)×100％；
IgE抑制率(％)＝1-(给药组IgE浓度-空白对照组IgE浓度)/(模型对照组IgE浓度-空白对照组IgE浓度)×100％。
2.3实验结果
表6.各组动物体重变化，单位：g，Mean±S.D.
时间/组别 第1天 第10天 第17天 第18天
空白对照组 22.0±0.8 22.7±1.0 24.3±1.4 24.5±1.4
模型对照组 21.8±0.4 22.4±0.7 23.0±0.9 22.8±0.8
实施例46 21.6±0.7 22.6±0.6 23.0±0.7 23.1±0.7
实施例51 21.8±0.7 22.8±1.2 23.1±1.1 22.9±1.3
实施例52 21.8±0.5 22.6±0.9 24.3±5.6 24.2±6.0
实施例6 21.4±0.7 22.8±1.4 23.3±1.4 22.7±1.5
实施例54 21.6±0.6 22.6±0.8 23.3±1.2 23.1±1.2
表7.各组动物耳指标比较
Figure PCTCN2019082943-appb-000041
注：与空白对照组比较，**P<0.01，***P<0.001；
与模型对照组比较，#P<0.05，##P<0.01；
生物学实施例3
DNCB诱导Balb/c小鼠特应性皮炎模型的药效评估实验
3.1试验方法
3.1.1分组
取健康雄性SPF级Balb/c小鼠30只，体重19-21g，按体重随机分为3组，每组10只。
表8.分组表
Figure PCTCN2019082943-appb-000042
Figure PCTCN2019082943-appb-000043
3.1.2剃毛
试验前，需对小鼠右耳周围毛发进行去除，减少药物由于附着在毛发上对实验的干扰。
3.1.3造模及给药
实验开始记为第1天，各组给药方案以及诱导方案详见图3。具体耳厚、体重测量时间与图3略有调整。实验第19天结束后对每只动物进行取血检测血清中免疫球蛋白(IgE)浓度(按试剂盒说明书进行)。动物双耳剪下，8mm打孔器于耳固定位置打下相等面积耳片称重，计算双耳肿胀度差异。
3.2评价指标及统计方法
应用SPSS 17中One-Way Anova对多组间小鼠耳厚变化，第19天相同面积下耳重以及血清中IgE浓度分别进行统计学分析比较，G检验法删除异常值，以p<0.05表示有统计学差异。
耳肿胀度(mg)＝右耳重量(mg)-左耳重量(mg)；
耳厚变化(mm)＝右耳厚(mm)-左耳厚(mm)；
耳肿胀度抑制率(％)＝1-(给药组耳肿胀度-空白对照组耳肿胀度)/(模型对照组耳肿胀度-空白对照组耳肿胀度)×100％；
耳厚变化抑制率(％)＝1-(给药组耳厚变化-空白对照组耳厚变化)/(模型对照组耳厚变化-空白对照组耳厚变化)×100％；
IgE抑制率(％)＝1-(给药组IgE浓度-空白对照组IgE浓度)/(模型对照组IgE浓度-空白对照组IgE浓度)×100％。
3.3实验结果
表9.各组动物体重变化，单位：g，Mean±S.D.
组别 第1天 第8天 第12天 第14天 第16天 第19天
空白对照组 20.4±0.7 21.5±1.0 22.0±1.2 22.1±1.3 22.3±1.3 22.8±1.3
模型对照组 20.2±0.7 21.7±0.7 22.1±0.8 22.0±0.8 21.9±0.7 22.7±0.6
实施例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
表10.各组耳厚变化单位：mm，Mean±S.D.
组别 第1天 第10天 第17天 第19天
空白对照组 0.24±0.01 0.25±0.01 0.25±0.01 0.27±0.02
模型对照组 0.26±0.01 0.54±0.12 0.76±0.16 0.77±0.14
实施例10 0.26±0.01 0.52±0.11 0.65±0.09 0.63±0.05
表11.各组动物耳指标比较
Figure PCTCN2019082943-appb-000044
Figure PCTCN2019082943-appb-000045
注：与空白对照组比较，**P<0.01，***P<0.001。
生物学实施例4
抑制佛波酯(TPA)诱导小鼠耳肿胀实验
4.1试验方法
4.1.1分组
选取40只雄性ICR小鼠分为5组，每组8只。
表12.分组造模信息表
Figure PCTCN2019082943-appb-000046
注：a.125μg/mL TPA配制方法：2mg/mL TPA母液(溶于DMSO)40μL+600μL丙酮混匀使用，现用现配；
b.丙酮与DMSO混合比例为15:1(v/v)。
4.1.2剃毛
试验前，对动物进行分组，去除小鼠右耳周围毛发。
4.1.3造模及给药
实验各组动物右耳分别给予20μL各自药物(模型对照组给予空白溶剂)进行涂抹，并于1h10min后进行建模诱导，除空白组外，均给予 动物右耳20μL浓度为125μg/mL的TPA进行诱导；诱导后10分钟实验各组动物第二次右耳分别给予20μL各自药物(模型对照组给予空白溶剂)进行涂抹。
表13.分组给药信息表
Figure PCTCN2019082943-appb-000047
注：给药体积40μL系指2次给药共计40μL。
4.1.4结果观察
建模后5h各组动物用打孔器取双侧耳部同一部位的耳片，称重后计算耳肿胀度、耳肿胀率以及抑制率。
4.2评价指标及统计方法
应用SPSS17.0中One-Way ANOVA多组间检测指标进行对造模给药后5h的耳肿胀度、耳肿胀率等进行分析、检验，以P<0.05表示具有统计学差异。
耳肿胀度(mg)＝右耳重量(mg)-左耳重量(mg)；
耳肿胀率(％)＝(右耳重量-左耳重量)/左耳重量×100％；
耳肿胀度抑制率(％)＝1-(给药组耳肿胀度-空白对照组耳肿胀度)/(模型对照组耳肿胀度-空白对照组耳肿胀度)×100％。
4.3实验结果
表14.各组小鼠抑制率等指标：
组别/指标 耳肿胀度抑制率％
空白对照组 —
模型对照组 —
实施例10 71.7
实施例9 54.5
实施例1 60.1
生物学实施例5
抑制佛波酯(TPA)诱导小鼠耳肿胀实验
5.1试验方法
5.1.1分组
选取72只雄性ICR小鼠分为9组，每组8只。
表15.分组造模信息表
Figure PCTCN2019082943-appb-000048
注：a.125μg/mL TPA配制方法：2mg/mL TPA母液(溶于DMSO)40μL+600μL丙酮混匀使用，现用现配；
b.丙酮与DMSO混合比例为15:1(v/v)。
5.1.2剃毛
试验前，对动物进行分组，去除小鼠右耳周围毛发。
5.1.3造模及给药
实验各组动物右耳分别给予20μL各自药物(模型对照组给予空白溶剂)进行涂抹，并于1h10min后进行建模诱导，除空白组外，均给予动物右耳20μL浓度为125μg/mL的TPA进行诱导；诱导后10分钟实验各组动物第二次右耳分别给予20μL各自药物(模型对照组给予空白溶剂)进行涂抹。
表16.分组给药信息
Figure PCTCN2019082943-appb-000049
注：给药体积40μL系指2次给药共计40μL。
5.1.4结果观察
建模后5h各组动物用打孔器取双侧耳部同一部位的耳片，称重后计算耳肿胀度、耳肿胀率以及抑制率等。
5.2评价指标及统计方法
应用SPSS17.0中One-Way ANOVA多组间检测指标进行对造模 给药后5h的耳肿胀度、耳肿胀率等进行分析、检验，以P<0.05表示具有统计学差异。
耳肿胀度(mg)＝右耳重量(mg)-左耳重量(mg)；
耳肿胀率(％)＝(右耳重量-左耳重量)/左耳重量×100％；
耳肿胀度抑制率(％)＝1-(给药组耳肿胀度-空白对照组耳肿胀度)/(模型对照组耳肿胀度-空白对照组耳肿胀度)×100％。
5.3实验结果
表17.各组小鼠抑制率等指标：
组别 耳肿胀度mg 耳肿胀率％ 耳肿胀度抑制率％
实施例6 5.1±1.6### 36.4±11.9### 87.3
实施例3 6.0±2.5### 42.1±19.3### 83.7
实施例4 4.8±2.1### 34.3±18.2### 88.8
实施例12 5.8±2.3### 39.6±14.0### 84.8
实施例24 5.9±1.7### 43.0±11.8### 84.2
实施例25 8.5±2.7### 59.1±17.5### 73.6
实施例11 6.5±5.0### 46.3±35.7### 81.7
模型对照组 26.6±3.9*** 197.5±30.0*** —
空白对照组 2.0±1.5 14.7±12.2 —
注：与空白对照组比较，***P<0.001；
与模型对照组比较，###P<0.001。
生物学实施例6
抑制佛波酯(TPA)诱导小鼠耳肿胀实验
5.1试验方法
5.1.1分组
选取72只雄性ICR小鼠分为9组，每组8只。
表18.分组造模信息表
Figure PCTCN2019082943-appb-000050
Figure PCTCN2019082943-appb-000051
注：a.125μg/mL TPA配制方法：2mg/mL TPA母液(溶于DMSO)40μL+600μL丙酮混匀使用，现用现配；
b.丙酮与DMSO混合比例为15:1(v/v)。
5.1.2剃毛
试验前，对动物进行分组，去除小鼠右耳周围毛发。
5.1.3造模及给药
实验各组动物右耳分别给予20μL各自药物(模型对照组给予空白溶剂)进行涂抹，并于1h10min后进行建模诱导，除空白组外，均给予动物右耳20μL浓度为125μg/mL的TPA进行诱导；诱导后10分钟实验各组动物第二次右耳分别给予20μL各自药物(模型对照组给予空白溶剂)进行涂抹。
表19.分组给药信息
Figure PCTCN2019082943-appb-000052
Figure PCTCN2019082943-appb-000053
注：给药体积40μL系指2次给药共计40μL。
5.1.4结果观察
建模后5h各组动物用打孔器取双侧耳部同一部位的耳片，称重后计算耳肿胀度、耳肿胀率以及抑制率等。
5.2评价指标及统计方法
应用SPSS17.0中One-Way ANOVA多组间检测指标进行对造模给药后5h的耳肿胀度、耳肿胀率等进行分析、检验，以P<0.05表示具有统计学差异。
耳肿胀度(mg)＝右耳重量(mg)-左耳重量(mg)；
耳肿胀率(％)＝(右耳重量-左耳重量)/左耳重量×100％；
耳肿胀度抑制率(％)＝1-(给药组肿胀度-空白对照组肿胀度)/(模型对照组肿胀度-空白对照组肿胀度)×100％。
5.3实验结果
表20.各组小鼠抑制率等指标：
Figure PCTCN2019082943-appb-000054
Figure PCTCN2019082943-appb-000055
注：与空白对照组比较，***P<0.001；
与模型对照组比较，###P<0.001。
生物学实施例7
大鼠连续灌胃22天的亚急毒试验
7.1试验方法
7.1.1分组
SPF级健康SD大鼠96只，雌雄各半，按照性别区段随机分为8组，6只/性别/组，分别为溶媒对照组及各化合物给药组，每组12只，雌雄各半。
表21.分组表
Figure PCTCN2019082943-appb-000056
Figure PCTCN2019082943-appb-000057
注：
Figure PCTCN2019082943-appb-000058
表示雄性；♀表示雌性。
7.1.2给药
口服灌胃给药，每天1次连续给药22天，各给药组给予300mg/Kg相应化合物，溶媒对照组给予等体积的羧甲基纤维素钠(CMC-Na)。连续给药22天，每天观察大鼠给药后的行为、状态是否异常，有无中毒现象，并记录动物反应。连续给药22天后3只/性别/组动物处死，解剖大体观察及采集脏器指数，其余3只/性别/组动物停药观察一周后处死，解剖大体观察及采集脏器指数。
7.1.3观察指标
体重、外观、呼吸、行为、反射、排便。
7.2实验结果
7.2.1临床观察
试验期间，各组动物外观、呼吸、行为、反射以及排便等未观察到与药物相关的明显异常。
7.2.2体重
试验期间动物体重未见明显异常，体重变化趋势见图4和图5。
7.2.3解剖大体观察
各组动物给药结束及恢复期结束解剖大体观察，均未观察到各脏器与化合物相关的明显异常。
7.2.4脏器指数
动物脏器指数未观察到明显异常。
7.3实验结论
上述化合物反复灌胃给予SD大鼠，每天1次，连续22天，未见 明显与药物相关的毒性表现。
生物学实施例8
大鼠连续灌胃22天的亚急毒试验
8.1试验方法
8.1.1分组
SPF级健康SD大鼠84只，雌雄各半，按照性别区段随机分为7组，6只/性别/组，分别为溶媒对照组及各化合物给药组，每组12只，雌雄各半。
表22.分组表
Figure PCTCN2019082943-appb-000059
注：
Figure PCTCN2019082943-appb-000060
表示雄性；♀表示雌性。
8.1.2给药
口服灌胃给药，每天1次连续给药22天，各给药组给予300mg/Kg相应化合物，溶媒对照组给予等体积的CMC-Na。连续给药22天，每天观察大鼠给药后的行为、状态是否异常，有无中毒现象，并记录动物反应。连续给药22天后3只/性别/组动物处死，解剖大体观察及采集脏器指数，其余3只/性别/组动物停药观察一周后处死，解剖大体观察及采集脏器指数。
8.1.3观察指标
体重、外观、呼吸、行为、反射、排便。
8.2实验结果
8.2.1临床观察
试验期间，各组动物外观、呼吸、行为、反射以及排便等未观察到与药物相关的明显异常。
8.2.2体重
试验期间动物体重未见明显异常，体重变化趋势见图6和图7。
8.2.3解剖大体观察
各组动物给药结束及恢复期结束解剖大体观察，均未观察到各脏器与化合物相关的明显异常。
8.2.4脏器指数
动物脏器指数未观察到明显异常。
8.3实验结论
上述化合物反复灌胃给予SD大鼠，每天1次，连续22天，未见明显与药物相关的毒性表现。
生物学实施例9
小鼠单次灌胃的急毒试验
9.1试验方法
9.1.1分组
SPF级健康ICR小鼠30只，雌雄各半，按照性别区段随机分为5组，3只/性别/组，每组6只，雌雄各半。
表23.分组表
Figure PCTCN2019082943-appb-000061
注：
Figure PCTCN2019082943-appb-000062
表示雄性；♀表示雌性。
9.1.2给药
单次灌胃给药，给药后观察所有动物的症状反应并如实记录。实验连续观察15天，记录动物的症状。实验结束后所有动物均进行组织脏器的称重，观察，记录，标本留样。
9.1.3观察指标
体重、外观、呼吸、行为、反射、排便。
9.2实验结果
9.2.1临床观察
表24
Figure PCTCN2019082943-appb-000063
Figure PCTCN2019082943-appb-000064
9.2.2体重
试验期间动物体重未见明显异常，体重变化趋势见图8和图9。
9.2.3解剖大体观察
各组动物给药结束及恢复期结束解剖大体观察，均未观察到各脏器与化合物相关的明显异常。
9.2.4脏器指数
动物脏器指数未观察到明显异常。
9.3实验结论
上述化合物以2000mg/Kg单次灌胃给予ICR小鼠，未见明显与药 物相关的毒性表现。
在本公开中，诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来，而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。
从前述中可以理解，尽管为了示例性说明的目的描述了本公开的具体实施方案，但是在不偏离本公开的精神和范围的条件下，本领域所述技术人员可以作出各种变形或改进。这些变形或修改都应落入本公开所附权利要求的范围。

Claims (39)

  1. 通式(I)化合物、其立体异构体：
    Figure PCTCN2019082943-appb-100001
    其中，
    R 1选自一个或多个取代基，该取代基选自氢、卤素、羟基、C 1-C 8烃基、氨基、C 1-C 8烃基羰基氨基、C 1-C 8烃基氧羰基氨基、一个或多个C 1-C 4烃基取代的氨基、取代的氨基羰基C 1-C 8烃基；
    R 2选自羧基或酯基；
    R 3选自氢、羟基、卤素、C 1-C 8烃氧基、C 5-C 12芳基氧基或C 5-C 12环芳基氧基；
    R 4选自氢、卤素、羟基、C 1-C 8烃氧基或C 5-C 12芳基氧基。
  2. 如权利要求1所述的通式(I)化合物，
    Figure PCTCN2019082943-appb-100002
    其中，
    R 1选自一个或多个取代基，该取代基选自氢、卤素、羟基、C 1-C 8烃基、氨基、C 1-C 8烃基羰基氨基、C 1-C 8烃基氧羰基氨基、一个或多个C 1-C 4烃基取代的氨基、取代的氨基羰基C 1-C 8烃基；
    R 2选自-COOH、-COOCH 3、-COOCH 2CH 3、-COOCH 2CH 2CH 3或-COOCH(CH 3) 2；
    R 3选自氢、羟基、卤素、苄氧基、C 1-C 4烷氧基、C 5-C 12芳基氧基 或C 5-C 12环芳基氧基；
    R 4选自氢、卤素、羟基、C 1-C 4烃氧基、苄氧基或C 5-C 12芳基氧基。
  3. 如权利要求1所述的通式(I)化合物，
    Figure PCTCN2019082943-appb-100003
    其中，
    R 1选自氢、-OH、-F、-Cl、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-NH 2、-NHCH 3、-N(CH 3) 2、-NHCOCH 3、-NHCOOCH 3、-NHCOCH 2OH、-NHCOCH 2Cl、-NHCOCH 2F或-NCH 3COCH 3；
    R 2选自-COOH、-COOCH 3、-COOCH 2CH 3、-COOCH 2CH 2CH 3或-COOCH(CH 3) 2；
    R 3选自-H、-OH、-Cl、-F、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2或苄氧基；
    R 4选自-H、-Cl、-F、-OH、-OCH3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2或苄氧基。
  4. 如权利要求1至3中任一权利要求所述的通式(I)化合物、其立体异构体，其选自：
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3,4-二甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3,4-二乙氧基苯基)丙 酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯；
    (R)-3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    (S)-3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    (R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    (S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸丙酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸异丙酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸丁酯；
    3-(4-(2-氯乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-(2-(二甲氨基)乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-(二甲氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-(2-羟基乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-异丙氧基苯基)丙酸甲酯；
    3-(4-氟-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙 酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-环戊氧基苯基)丙酸甲酯；
    3-(4-甲基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(5-氟-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4，7-二氯-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-(N-甲基乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(5-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-(苄氧基)-4-甲氧基苯基)丙酸甲酯；
    3-(4-(N-甲基叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-(甲基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-丙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-环戊氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-丙氧基苯基)丙酸甲酯；
    3-(4-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氧基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-(叔丁氧羰基氨基)-7-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙 氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-氨基-5-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-羟基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-(苄氧基)苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-羟基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-甲氧基-4-(苄氧基)苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-甲氧基-4-羟基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-苯基丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-氯苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-乙氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-氯苯基)丙酸甲酯；以及
    3-(4-(叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯。
  5. 药物组合物，其包括权利要求1至4中任一权利要求所述的化合物或其立体异构体以及药物可接受的载体。
  6. 如权利要求5所述的药物组合物，其被制备为胃肠外、经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、胶囊剂、气雾剂或栓剂。
  7. 权利要求1-4中任一权利要求所述的化合物或其立体异构体或 权利要求5-6中任一权利要求所述的药物组合物在制备治疗皮肤病、银屑病、湿疹和特应性皮炎的药物中的用途。
  8. 制备权利要求1中通式(I)化合物或其立体异构体的方法：
    Figure PCTCN2019082943-appb-100004
    其中，
    R 1选自一个或多个取代基，该取代基选自氢、卤素、羟基、C 1-C 4烷基、氨基、C 1-C 8烃基羰基氨基、C 1-C 8烃基氧羰基氨基、一个或多个C 1-C 4烷基取代的氨基、卤素取代的氨基羰基C 1-C 4烷基、羟基取代的氨基羰基C 1-C 4烷基；
    R 2选自-COOH、-COOCH 3、-COOCH 2CH 3、-COOCH 2CH 2CH 3、-COOCH(CH 3) 2；
    R 3选自氢、羟基、卤素、苄氧基、C 1-C 4烷氧基、C 5-C 12芳基氧基、C 5-C 12环芳基氧基；
    R 4选自氢、卤素、羟基、C 1-C 4烃氧基、苄氧基、C 5-C 12芳基氧基；
    其中所述的制备方法包括：
    (1)将通式(A-I)化合物与丙二酸及醋酸铵进行反应得到通式(A-II)化合物，
    Figure PCTCN2019082943-appb-100005
    其中，通式(A-I)和通式(A-II)中的R 3’、R 4’表示的基团与通式(I)中的R 3、R 4的定义相同，
    (2)将通式(A-II)化合物与醇进行酯化反应得到通式(A-III)化合 物，
    Figure PCTCN2019082943-appb-100006
    其中，通式(A-II)和通式(A-III)中的R 3’、R 4’表示的基团与通式(I)中的R 3、R 4的定义相同，R 2’选自氢、C 1-C 4烷基；
    (3)将通式(A-IV)化合物与通式(A-III)化合物进行反应得到通式(I)化合物，
    Figure PCTCN2019082943-appb-100007
    其中，通式(A-III)和通式(A-IV)中的R 1’、R 3’、R 4’表示的基团与通式(I)中的R 1、R 3、R 4的定义相同，R 2’选自氢或C 1-C 4烷基。
  9. 通式(II)化合物、其立体异构体或其药物可接受的盐：
    Figure PCTCN2019082943-appb-100008
    其中，
    R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的烃基、任意取代的氨基、任意取代的烃基羰基氨基、任意取代的烃基羰基氧基、任意取代的烃基氧基羰基氨基、任意取代的烃基羰基氨基；
    R 2选自任意取代的烃基氧基羰基或羧基；
    R 3选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基 烃基氧基或任意取代的环烃基氧基；
    R 4选自氢、卤素、羟基、任意取代的烃基氧基、任意取代的芳基烃基氧基或任意取代的环烃基氧基；以及
    X为-CR 5R 6-，其中当R 5选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基；R 6选自氢、卤素、任意取代的烃基、任意取代的环烃基、任意取代的芳基或任意取代的杂芳基时，n为0、1、2、3或4；当R 5、R 6和与其相连的碳原子一起形成任意取代的环烃基时，n为1。
  10. 如权利要求9所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 2选自任意取代的C 1-C 6烃基氧基羰基或羧基，优选任意取代的烷基氧基羰基或羧基，更优选任意取代的C 1-C 6烷基氧基羰基或羧基。
  11. 如权利要求9或10所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 3选自氢、卤素、羟基、任意取代的C 1-C 6烃基氧基、任意取代的C 6-C 18芳基烃基氧基或任意取代的C 3-C 10环烃基氧基，优选氢、卤素、羟基、任意取代的烷基氧基、任意取代的芳基烷基氧基或任意取代的环烷基氧基，更优选氢、卤素、羟基、任意取代的C 1-C 6烷基氧基、任意取代的C 6-C 18芳基烷基氧基或任意取代的C 3-C 10环烷基氧基。
  12. 如权利要求9至11中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 4选自氢、卤素、羟基、任意取代的C 1-C 6烃基氧基、任意取代的C 6-C 18芳基烃基氧基或任意取代的C 3-C 10环烃基氧基，优选氢、卤素、羟基、任意取代的烷基氧基、任意取代的芳基烷基氧基或任意取代的环烷基氧基，更优选氢、卤素、羟基、任意取代的C 1-C 6烷基氧基、任意取代的C 6-C 18芳基烷基氧基或任意取代的C 3-C 10环烷基氧基。
  13. 如权利要求9至12中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 1选自一个或者多个下列相同或者不同的取代基：卤素、羟基、任意取代的C 1-C 6烃基、任意取代的氨基、任意取代的C 1-C 6烃基羰基氨基、任意取代的C 1-C 6烃基羰基氧基、任意取代的C 1-C 6烃基氧基羰基氨基、任意取代的C 1-C 6烃基羰基氨基；优选卤素、羟基、任意取代的烷基、任意取代的氨基、任意取代的烷基羰基氨基、任意取代的烷基羰基氧基、任意取代的烷基氧基羰基氨基、任意取代的烷基羰基氨基；更优选卤素、羟基、任意取代的C 1-C 6烷基、任意取代的氨基、任意取代的C 1-C 6烷基羰基氨基、任意取代的C 1-C 6烷基羰基氧基、任意取代的C 1-C 6烷基氧基羰基氨基、任意取代的C 1-C 6烷基羰基氨基。
  14. 如权利要求9至13中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 2选自任意取代的甲氧羰基、任意取代的乙氧羰基、任意取代的丙氧羰基、任意取代的丁氧羰基、任意取代的异丙氧羰基或羧基；优选R 5选自氢、卤素或C 1-C 4烃基，R 6选自氢、卤素或C 1-C 4烃基，并且n为1或2。
  15. 如权利要求9至14中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 3选自氢、卤素、羟基、任意取代的甲氧基、任意取代的乙氧基、任意取代的丙氧基、任意取代的异丙氧基、任意取代的苄氧基或任意取代的环戊基氧基。
  16. 如权利要求9至15中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 4选自氢、卤素、羟基、任意取代的甲氧基、任意取代的乙氧基、任意取代的丙氧基、任意取代的异丙氧基、任意取代的苄氧基或任意取代的环戊基氧基。
  17. 如权利要求9至16中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 1选自一个或者多个下列相 同或者不同的取代基：卤素、羟基、任意取代的甲基、任意取代的氨基、任意取代的乙酰氨基、任意取代的乙酰氧基、任意取代的叔丁氧基羰基氨基。
  18. 如权利要求9至17中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 1选自一个或多个取代基，该取代基选自卤素、羟基、C 1-C 6烷基、氨基、C 1-C 4烷基取代的氨基、C 1-C 6烷基羰基氨基、C 1-C 6烷基羰基氧基、C 1-C 6烷基氧基羰基氨基、C 1-C 6烷基取代的氨基取代的C 1-C 6烷基羰基氨基、N-C 1-C 6烷基取代的C 1-C 6烷基羰基氨基。
  19. 如权利要求9至18中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 2选自C 1-C 6烷基氧基羰基或羧基；优选R 5为氢，R 6为氢，并且n为1。
  20. 如权利要求9至19中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 3选自氢、羟基、卤素、C 1-C 8烷氧基、C 5-C 12芳基氧基或C 5-C 12环烃基氧基。
  21. 如权利要求9至20中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 4选自氢、羟基、卤素、C 1-C 8烷氧基、C 5-C 12芳基氧基或C 5-C 12环烃基氧基。
  22. 如权利要求9至21中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 1选自一个或者多个下列相同或者不同的取代基：氟、氯、羟基、甲基、氨基、甲氨基、二甲氨基、乙酰氨基、2-氯乙酰氨基、2-羟基乙酰氨基、N-甲基乙酰氨基、2-(二甲氨基)乙酰氨基、乙酰氧基、叔丁氧基羰基氨基、N-甲基叔丁氧基羰基氨基。
  23. 如权利要求9至22中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 3选自氢、氯、羟基、甲氧基、二氟甲氧基、三氟甲氧基、乙氧基、丙氧基、异丙氧基、苄氧基或环戊基氧基。
  24. 如权利要求9至23中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 4选自氢、氯、羟基、甲氧基、二氟甲氧基、三氟甲氧基、乙氧基、丙氧基、异丙氧基、苄氧基或环戊基氧基。
  25. 如权利要求9至24中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中R 2选自甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基或丁氧基羰基；优选R 5为氢，R 6为氢，并且n为1。
  26. 如权利要求9至25中任一权利要求所述的通式(II)化合物、其立体异构体或其药物可接受的盐，其中：
    R 1为乙酰氨基；
    R 2选自甲氧基羰基、乙氧基羰基或丙氧基羰基；
    R 3选自甲氧基或乙氧基；
    R 4选自甲氧基或乙氧基；
    R 5为氢；
    R 6为氢；并且
    n为1。
  27. 下列化合物、其立体异构体或其药物可接受的盐：
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3,4-二甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3,4-二乙氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯；
    (R)-3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    (S)-3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    (R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    (S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸丙酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸异丙酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸丁酯；
    3-(4-(2-氯乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-(2-(二甲氨基)乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-(二甲氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-(2-羟基乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-异丙氧基苯基)丙酸甲酯；
    3-(4-氟-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-环戊氧基苯基)丙酸甲酯；
    3-(4-甲基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(5-氟-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4,7-二氯-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-(N-甲基乙酰氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(5-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-(苄氧基)-4-甲氧基苯基)丙酸甲酯；
    3-(4-(N-甲基叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-(甲基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-丙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-环戊氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-丙氧基苯基)丙酸甲酯；
    3-(4-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氧基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-氨基-7-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-氨基-5-羟基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-羟基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-(苄氧基)苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-羟基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-甲氧基-4-(苄氧基)苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-甲氧基-4-羟基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-苯基丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-氯苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-乙氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-氯苯基)丙酸甲酯；
    3-(4-(叔丁氧羰基氨基)-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-(二氟甲氧基)-3-乙氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-(三氟甲氧基)苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-(二氟甲氧基)-4-甲 氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(4-甲氧基-3-(三氟甲氧基)苯基)丙酸甲酯；
    (R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯；
    (S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-乙氧基-4-甲氧基苯基)丙酸乙酯；
    (R)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯；
    (S)-3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(3-异丙氧基-4-甲氧基苯基)丙酸甲酯；
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(苯并[d][1,3]二氧杂环戊烯-5-基)丙酸甲酯；以及
    3-(4-乙酰氨基-1,3-二氧代异吲哚啉-2-基)-3-(2,3-二氢苯并[b][1,4]二氧杂芑-6-基)丙酸甲酯。
  28. 药物组合物，其含有权利要求9至27中任一权利要求所述的化合物、其立体异构体或其药物可接受的盐以及药物可接受的载体、稀释剂或赋形剂。
  29. 如权利要求28所述的药物组合物，其被制备为胃肠外、经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、凝胶剂、胶囊剂、气雾剂或栓剂。
  30. 治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的方法，其包括向需要所述方法的个体给予治疗有效量的权利要求9至27中任一权利要求所述的化合物、其立体异构体或其药物可接受的盐，或者给予治疗有效量的权利要求28或29所述的药物组合物。
  31. 如权利要求30所述的方法，其中所述个体为哺乳动物，优选为人类。
  32. 如权利要求30或31所述的方法，其中所述疾病选自皮肤病、银屑病、湿疹、特应性皮炎、荨麻疹、哮喘、哮喘-慢性阻塞性肺病(COPD)重叠综合征(ACOS)、过敏性鼻炎、季节性过敏性鼻炎、药物性间质性肺炎、支气管肺曲霉菌病、麻风、类天胞疮以及寄生虫感染。
  33. 用于治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的权利要求9至27中任一权利要求所述的化合物、其立体异构体或其药物可接受的盐。
  34. 用于治疗或预防与免疫球蛋白E(IgE)相关的，优选免疫球蛋白E(IgE)介导的疾病的包含治疗有效量的权利要求9至27中任一权利要求所述的化合物、其立体异构体或其药物可接受的盐以及药物可接受的载体、稀释剂或赋形剂的药物组合物。
  35. 制备权利要求9至27中任一权利要求所述的化合物、其立体异构体或其药物可接受的盐的方法，其包括：
    (1)将通式(B-I)化合物与丙二酸及醋酸铵进行反应得到通式(B-II)化合物，
    Figure PCTCN2019082943-appb-100009
    其中，通式(B-I)和通式(B-II)中的R 3’、R 4’表示的基团与通式(II)中的R 3、R 4的定义相同，
    (2)将通式(B-II)化合物与醇进行酯化反应得到通式(B-III)化合物，
    Figure PCTCN2019082943-appb-100010
    其中，通式(B-II)和通式(B-III)中的R 3’、R 4’表示的基团与通式(II)中的R 3、R 4的定义相同，R 2’选自氢或烃基；
    (3)将通式(B-IV)化合物与通式(B-III)化合物进行反应得到通式(II)化合物，
    Figure PCTCN2019082943-appb-100011
    其中，通式(B-III)和通式(B-IV)中的R 1’、R 3’、R 4’表示的基团与通式(II)中的R 1、R 3、R 4的定义相同，R 2’选自氢或烃基；
    其中X为-CR 5R 6-，其中R 5为氢，R 6为氢，n为1。
  36. 如权利要求35所述的方法，其中在溶剂，优选甲醇、乙醇、异丙醇、水或其混合物中，更优选在50℃至130℃下，将通式(B-I)化合物与丙二酸及醋酸铵进行反应得到通式(B-II)化合物。
  37. 如权利要求35或36所述的方法，其中由通式(B-II)化合物与醇在有机溶剂，优选醇类、四氢呋喃、二氯甲烷、乙酸乙酯、甲基叔丁基醚或其混合物中进行酯化反应得到通式(B-III)化合物，优选在-20℃至30℃下进行反应，所述醇类优选甲醇、乙醇、异丙醇或其混合物。
  38. 如权利要求35至37中任一权利要求所述的方法，其中酯化剂选自氯化亚砜、草酰氯、HCl气体、乙酰氯或其混合物。
  39. 如权利要求35至38中任一权利要求所述的方法，其中在通式(B-IV)化合物与通式(B-III)化合物进行反应得到通式(II)化合物的过程中加入催化剂，优选醋酸钠、醋酸钾、碳酸钠、碳酸钾或其混合物，更优选在50℃至180℃下进行反应，更优选在有机溶剂中进行反应，所述有机溶剂优选醋酸、甲酸、二甲基甲酰胺、二甲基乙酰胺或其混合物。
PCT/CN2019/082943 2018-04-17 2019-04-16 异吲哚衍生物 WO2019201255A1 (zh)

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