WO2021037179A1 - Sting通路调节剂及其用途 - Google Patents

Sting通路调节剂及其用途 Download PDF

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WO2021037179A1
WO2021037179A1 PCT/CN2020/111932 CN2020111932W WO2021037179A1 WO 2021037179 A1 WO2021037179 A1 WO 2021037179A1 CN 2020111932 W CN2020111932 W CN 2020111932W WO 2021037179 A1 WO2021037179 A1 WO 2021037179A1
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cancer
compound
dimethyl
virus
acridone
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赵海峰
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迈德欣国际有限公司
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Definitions

  • the present invention relates to compounds that modulate the activity of STING and their use in treating diseases.
  • the present invention also relates to a method for preparing the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, a pharmaceutical composition containing the compound, and its use in the preparation of medicines.
  • the innate immune response is the host's first line of defense against foreign pathogenic microorganisms.
  • the host can recognize pathogen-related molecular patterns through pattern recognition receptors, and then initiate an antiviral immune response.
  • Interferon activating protein (STING) is an important molecule in the innate immune response, which plays an important role in defending against viral and intracellular bacterial infections and mediating the production of type I interferons.
  • STING can directly recognize cyclic dinucleotides, and can also be used as an adaptor protein to promote the transduction of downstream signal pathways;
  • STING is an important part of the signal transduction cascade, which can be infected by pathogens (viruses, bacteria, parasites, etc.) At the same time play an immune defense role.
  • STING When STING is activated, it can increase the production of interferons and cytokines, and through a series of cascade reactions, activate the adaptive immune system and activate T cells.
  • cGAS cyclic GMP-AMP synthase
  • cGAS can connect two nucleotides to form a cyclic two called cGAMP. Nucleotides, thereby activating STING.
  • DNA in the human body usually does not activate the STING protein, because DNA can exist in the nucleus under normal circumstances (except for mitochondrial DNA). But if DNA leaks into the cytoplasm, it will activate STING and trigger an immune response.
  • STING agonists In addition to fighting foreign pathogen infections, STING agonists also play an important role in tumor immunotherapy.
  • the laboratory of Tim Mitchison of Harvard Medical School is studying a STING agonist, DMXAA, which is extremely effective in mouse anti-tumor models.
  • DMXAA can only bind to the mouse STING protein, which restricts its subsequent clinical application.
  • Cyclic dinucleotide is a natural agonist of STING.
  • researchers from Aduro Biotech found that the synthetic CDN can be injected directly into the tumor of mice to activate STING, thereby activating the innate immune system and triggering a series of stages. Link reaction and activate T cells to fight tumors.
  • Aduro's research team also injected more tumor cells into mice to spread them throughout the lungs.
  • the injection of CDN into a single tumor can activate T cells throughout the mouse and eliminate tumors in other parts including the lungs. If the results can be reproduced in patients, it means that STING agonists will have a very bright future, because most patients will not die from carcinoma in situ, but from tumors formed by cancer cell metastasis.
  • CDNs natural cyclic dinucleotide
  • DMXAA 5′,6′-dimethylxanthenone-4-acetic acid
  • CMA 10-carboxymethyl-9-acridanone
  • the identified human-derived agonists STING mainly include: G10, DSDP, C11, BNBC and ⁇ -mangostin, etc. Although all these compounds have antiviral or anti-tumor effects, the intensity of inducing immune responses is low. In cyclic dinucleotide compounds. In 2018, researchers developed the dimer of aminobenzimidazole (ABZI): Trihydrochloride, a potent non-CDN-like STING agonist that has been publicly reported, but its molecular weight is too large and its drug-making properties are uncertain.
  • STING is a significant drug target. By activating the STING pathway, it can achieve anti-tumor, anti-viral and antibacterial effects.
  • the purpose of the present invention is to develop novel STING pathway agonists for the preparation of novel broad-spectrum antiviral, antibacterial or cancer immunotherapy therapeutic drugs.
  • the inventors unexpectedly found that the compound of formula I as defined below can effectively regulate the activity of the STING pathway, thereby providing the use and pharmaceutical composition of the compound for the treatment of STING-related diseases.
  • the present invention provides the following compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof:
  • R 1 , R 2 and R 3 are independently selected from hydrogen, alkyl, alkoxy, hydroxyl,
  • the compound of formula I is selected from:
  • the alkyl group may be a lower alkyl group, for example, a 1-8C alkyl group. It includes straight and branched chain alkyl groups, such as methyl, ethyl, propyl, isopropyl and tert-butyl, etc., as well as (3-8C) cycloalkyl groups such as cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl and cycloheptyl, etc.
  • the alkoxy group may be a lower alkyloxy group, for example, a 1-8C alkoxy group. Including methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc.
  • the compound of formula I is 2-(5,6-dimethyl-7-methoxy-9-acridone)-4-acetic acid.
  • the compound of formula I is 2-methoxy-5,6-dimethyl-9-acridone.
  • the present invention also provides a method for preparing the above-mentioned compound of formula I.
  • the preparation method of the compound of formula I includes:
  • Suitable pharmaceutically acceptable salts of the compounds of formula I of the present invention are, for example, acid addition salts of the compounds of formula I, for example with inorganic or organic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid or horse Acid); or ammonium salt, or with organic base (such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine), or base Salt formed by metals.
  • inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid or horse Acid
  • organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine
  • Suitable pharmaceutically acceptable solvates of the compound of formula I of the present invention are, for example, hydrates, such as hemihydrate, monohydrate, dihydrate, or trihydrate, or alternative combinations thereof.
  • the compound of the present invention may be administered in the form of a prodrug, which is a modified form of a prodrug known in the industry, which is cleaved in the human or animal body to release the compound of the compound of the present invention.
  • prodrugs include in vivo cleavable ester derivatives and in vivo cleavable amide derivatives.
  • the ester derivatives can be formed on the carboxyl or hydroxyl group of the compound of formula I, and the amide derivative can be formed on the carboxyl group of the compound of formula I. Or formed on the amino group.
  • the pharmaceutically acceptable prodrugs of the compounds of formula I may also be in the form of in vivo cleavable esters or ethers.
  • examples include in vivo cleavable esters or ethers of the compounds of formula I containing a hydroxyl group.
  • the ester-forming groups include inorganic esters such as phosphate esters (including phosphoramidate cyclic esters).
  • suitable pharmaceutically acceptable ester-forming groups also include (1-10C) alkanoyl (such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl), (1- 10C) Alkoxycarbonyl (such as ethoxycarbonyl, N,N-[di-(1-4C)alkyl]carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl).
  • alkanoyl such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl
  • 1- 10C Alkoxycarbonyl (such as ethoxycarbonyl, N,N-[di-(1-4C)alkyl]carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl).
  • ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl And 4-(1-4C)alkylpiperazin-1-ylmethyl.
  • suitable pharmaceutically acceptable ether-forming groups include -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.
  • the pharmaceutically acceptable prodrugs of the compounds of formula I can also be, for example, amide derivatives that are cleavable in vivo.
  • Suitable pharmaceutically acceptable amides formed from amino groups include, for example, amides formed with (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl.
  • Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl And 4-(1-4C)alkylpiperazin-1-ylmethyl.
  • the compound of formula I of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof has STING agonistic activity.
  • the compound of formula I of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof can be used to prevent and/or treat STING pathway related diseases or prepare drugs for the prevention and/or treatment of STING pathway related diseases For example, diseases treated by STING activation or used to prepare drugs for treating diseases by STING activation.
  • a pharmaceutical composition which comprises a compound of formula I as defined above or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable compound mixed with it.
  • Excipients such as diluents or carriers.
  • compositions of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art.
  • the composition intended for oral use may contain one or more coloring agents, sweetening agents, flavoring agents and/or preservatives, etc. as excipients.
  • pharmaceutically acceptable carriers, diluents or excipients refers to pharmaceutical excipients commonly used in the formulation industry, for example in Luo Mingsheng et al., "Pharmaceutical Excipients Encyclopedia", Sichuan Science and Technology Press , Listed in 1995.
  • composition of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art.
  • the composition intended for oral use may contain one or more coloring agents, sweetening agents, flavoring agents and/or preservatives, etc. as excipients.
  • the pharmaceutical composition of the present invention can be in a form suitable for oral administration (e.g. tablets, lozenges, hard or soft capsules, water or oil suspensions, emulsions, dispersible powders or granules, syrups or elixirs), Forms suitable for topical use (e.g. creams, ointments, gels or water or oily solutions or suspensions), forms suitable for inhalation administration (e.g. finely dispersed powders or liquid aerosols), suitable for insufflation
  • the form of medicine e.g. finely divided powder
  • parenteral administration e.g. sterile water or oily solutions for intravenous, subcutaneous, intraperitoneal or intramuscular administration or suppositories for rectal administration ).
  • a formulation intended for oral administration to humans will generally contain, for example, 0.01 mg-1 g (more suitably 0.1-250 mg, such as 0.1-100 mg) active ingredient mixed with an appropriate and convenient amount of excipients, which may It is in the range of about 5-98% by weight of the total composition.
  • the dosage size of the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug for therapeutic or preventive purposes will generally naturally depend on the nature and severity of the disease, the age and sex of the animal or patient, and the route of administration , Changed according to well-known medical principles.
  • the diseases related to the STING pathway are infectious diseases, cancer, inflammation, allergic and autoimmune diseases.
  • the infectious disease is a viral infectious disease or a bacterial infectious disease
  • its infectious agent is, for example, influenza virus, enterovirus, hepatitis B virus, hepatitis C virus, Ebola virus, Marburg virus, SARS virus, Zika virus, Bunya virus, rhinovirus, respiratory nucleocytosis virus, cholera virus and other viral pathogens, as well as Mycobacterium tuberculosis, Escherichia coli, Acinetobacter baumannii, pneumococcus, lactic acid streptococcus, urea spore Sarcina, golden yellow Staphylococcus, Bacillus subtilis, Bacillus anthracis, Bacillus subtilis, Streptobacter, Proteus, Vibrio cholerae, Treponema pallidum and other bacterial pathogens.
  • the cancer is gastric cancer, liver cancer, lung cancer, esophageal cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, nasopharyngeal cancer, ovarian cancer, kidney cancer, bladder cancer, thyroid cancer, skin cancer, etc.; from mesenchymal tissue Malignant tumors such as muscle, fat, bone, blood vessels, lymph, etc., such as rhabdomyosarcoma, leiomyosarcoma, fibrosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, angiosarcoma, lymphosarcoma, etc.
  • leukemia Hodgkin’s disease, Wilm’s tumor (wilms tumor), melanoma, retinocytoma, seminoma, granulosa cell tumor, Kwagenberg’s tumor, Ewing’s tumor, malignant Hemangioendothelioma or Paget's disease of the breast.
  • it is gastrointestinal cancer and respiratory cancer, such as gastric cancer, liver cancer, lung cancer, esophageal cancer, and colorectal cancer.
  • Inflammation represents the blood vessel, cell, and nerve response to trauma. Inflammation can be characterized by the movement of inflammatory cells such as monocytes, neutrophils, and granulocytes into the tissue. This usually involves reduced endothelial barrier function and edema into the tissue. Inflammation can be classified as acute or chronic. Acute inflammation is the body's initial response to harmful stimuli and is achieved by increased movement of plasma and white blood cells from the blood to the damaged tissue. The cascade of biochemical events spreads and matures the inflammatory response, which involves the local vascular system, immune system and various cells in the damaged tissue. Long-term inflammation, called chronic inflammation, leads to progressive changes in the cell types present at the site of inflammation, and is characterized by the simultaneous destruction and healing of tissues from the inflammatory process. Inflammation includes musculoskeletal inflammation, vascular inflammation, neuroinflammation, digestive system inflammation, eye inflammation, reproductive system inflammation, or other inflammations, such as asthma.
  • Autoimmune diseases include, but are not limited to, systemic lupus erythematosus, psoriasis, insulin-dependent diabetes mellitus (IDDM), dermatomyositis, and Sjogren’s syndrome (SS).
  • IDDM insulin-dependent diabetes mellitus
  • SS Sjogren’s syndrome
  • Allergic diseases include, but are not limited to, allergic reactions, contact dermatitis (including caused by poison ivy), urticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis), and gluten-sensitive enteropathy (celiac disease).
  • the present invention can be further described through the following examples and test examples. However, the scope of the present invention is not limited to the following Examples or Test Examples. Those skilled in the art can understand that various changes and modifications can be made to the present invention without departing from the spirit and scope of the present invention.
  • the present invention provides a general and/or specific description of the materials and test methods used in the test. Although many materials and operating methods used to achieve the purpose of the present invention are well known in the art, the present invention is still described here in as much detail as possible.
  • % means mass percentage
  • the starting material 2-amino-3,4-dimethylbenzoic acid was replaced with 2-amino-3,4-dimethyl-5-methoxybenzoic acid, according to the ratio After feeding and obtaining the corresponding intermediate, according to the method in the above-mentioned Example 6, 0.70 g of gray solid was obtained, and the total yield was 27.7%.
  • the compound was co-cultured with the modified cell line, and the agonistic activity of each pathway of STING was verified by measuring the fluorescently labeled immune molecules.
  • All cell lines were from Invivogen: 293T-Dual TM hSTING-R232 Cells; 293T-Dual TM mSTING Cells. There is no STING in 293 human embryonic kidney cells, which is a good verification cell for STING pathway.
  • hSTING-R232 is commonly known as wild-type STING, which accounts for about 70% of the population.
  • mSTING Cells were transfected with mSTING 293T cells.
  • 293T-Dual TM hSTING-R232 Cells or 293T-Dual TM mSTING Cells ( ⁇ 100000 cells/well) and 20 ⁇ L of salt solution or salt solution of the test compound were incubated in a 5% CO2 incubator at 37°C for 48 hours .
  • Use different detection solutions to indirectly measure the activity of each pathway of STING 293T cells use QUANTI-Blue to detect the activity of the IRF pathway, and QUANTI-Blue to detect the activity of the NF- ⁇ B pathway.
  • the test is divided into two steps. The first step is to initially screen for effective compounds.
  • the initial screening concentration of each compound is 10 ⁇ M and 100 ⁇ M, and the concentration of the positive compound cGAMP is 20 ⁇ M.
  • the second step is to set a concentration gradient for the effective small molecules to determine the EC50 value of the compound and compare it with cGAMP to determine the strength of the molecule's activation of the STING pathway.
  • the detection principle is based on Technology, when the dye approaches, the excitation of the donor by the light source (laser or flash lamp) triggers the fluorescence resonance energy transfer (FRET) to the acceptor, which emits fluorescence at a specific wavelength (665nm).
  • the specific anti-6His antibody is labeled with terbium cryptate (donor), which can bind to the human STING protein labeled with 6His and the STING ligand labeled with d2 (acceptor).
  • the human STING ligand is detected by a competitive analysis method.
  • the detection compound competes with the tail ligand labeled with d2, thereby blocking the occurrence of FRET.
  • the strength of the specific signal is inversely proportional to the concentration of the compound.
  • the compound of the present invention has an agonist for different species, especially human STING, and has high activity.

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Abstract

一种式I化合物或其药学上可接受的盐、溶剂合物或前药及其制备方法、含有其的药用组合物和应用。该类化合物可用于制备治疗和预防STING通路相关疾病的药物。

Description

STING通路调节剂及其用途
本申请要求2019年8月28日提交的、申请号为201910803609.5、发明名称为“STING通路调节剂及其用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
发明领域
本发明涉及调节STING活性的化合物和其治疗疾病的用途。本发明还涉及所述化合物或其药学上可接受的盐、溶剂合物或前药的制备方法、含有其的药用组合物及其在制备药物中的用途。
背景技术
固有免疫反应是宿主抵御外来病原微生物的第一道防线。宿主可以通过模式识别受体识别病原体相关的分子模式，进而起始抗病毒免疫反应。干扰素激活蛋白(STING)是固有免疫反应中一个重要分子，其在防御病毒及胞内细菌感染、介导I型干扰素产生过程中发挥重要功能。STING既可以直接识别环二核苷酸，也可以作为接头蛋白促进下游信号通路的转导；STING作为信号转导级联反应中的重要组成部分，在病原体(病毒、细菌、寄生虫等)感染时发挥免疫防御作用。当STING激活之后能够增加干扰素以及细胞因子的生成，并通过一系列的级联反应，激活适应性免疫系统，活化T细胞。
无论DNA是来自于病毒，细菌或者生物体自身，都能与一种叫做cyclic GMP-AMP synthase(cGAS)的酶结合，cGAS能够将两个核苷酸相连，形成一种叫做cGAMP的环状二核苷酸，从而激活STING。人体内的DNA通常不会激活STING蛋白，因为正常情况下DNA能够存在于细胞核之内(线粒体DNA除外)。但如果DNA泄漏到胞浆 之中，则会活化STING，引发免疫反应。
除了对抗外来病原感染，STING激动剂在肿瘤的免疫治疗方面也有着重要的作用。哈佛医学院的Tim Mitchison实验室研究一种STING激动剂-DMXAA，这种化合物在小鼠抗肿瘤模型中的药效极其好。但DMXAA只能结合老鼠的STING蛋白，制约了其后续的临床应用。
环二核苷酸(cyclic dinucleotide，CDN)为STING的天然激动剂，Aduro Biotech公司的研究人员发现合成的CDN直接注射到小鼠的肿瘤内能够激活STING，从而激活固有免疫系统并引发一系列级联反应，并激活T细胞对抗肿瘤。Aduro的科研团队同时也向小鼠体内注射了更多的肿瘤细胞，使其扩散到整个肺部。令人意想不到的是，单个瘤内注射CDN之后能够激活小鼠全身的T细胞，并清除包括肺部在内的其他部位的肿瘤。如果该结果能够在病人身上重现，就意味着STING激动剂将有非常光明的前景，因为多数病人最终并不是死于原位癌，而是死于癌细胞转移所形成的肿瘤。
目前，STING激动剂处于起步阶段，其激动剂的研究主要集中在修饰天然环状二核苷酸(CDNs)类似物的工作上。但是，CDNs类化合物受限于较低的膜渗透性和代谢不稳定性，在临床上难以有效利用。非CDNs类小分子的研究也在同时进行，主要包括5′，6′-dimethylxanthenone-4-acetic acid(DMXAA)和10-carboxymethyl-9-acridanone(CMA)，种属选择性的差异是影响其进一步开发的主要因素。目前，已经确定的人源激动剂STING的主要包括：G10、DSDP、C11、BNBC和α-mangostin等，所有的这些化合物虽然都具有抗病毒或抗肿瘤的作用，但是诱导免疫反应的强度均低于环状二核苷酸类化合物。2018年研究人员发展了aminobenzimidazole(ABZI)的二聚体：Trihydrochloride，是公开报道的强力的非CDNs类STING激动剂，但分子量过大，成药性不确定。
已有的研究结果表明STING是一个意义重大的药物靶点，通过激活STING通路可以实现抗肿瘤、抗病毒以及抗菌的作用。本发明的 目的在于发展新型STING通路激动剂，以用于制备新型广谱抗病毒、抗细菌或癌症免疫治疗的治疗药物。
发明内容
发明人出乎意料地发现如下定义的式I化合物能够有效地调节STING通路的活性，由此提供了所述化合物用于治疗STING相关疾病的用途和药物组合物。
具体的，本发明提供了如下式I化合物或其药学上可接受的盐、溶剂合物或前药：
Figure PCTCN2020111932-appb-000001
其中，
R 1、R 2和R 3独立地选自氢、烷基、烷氧基、羟基，
R4和R5独立地选自氢、烷氧基、乙酰基，或者R4或R5与相邻吡啶环上的N原子相连形成＝N-C(＝O)-C-。
在本发明的其中一个方面，所述式I化合物选自：
9，10-二甲基-6H-吡咯[3，2，1-de]-1，6-吖啶二酮，
2-(5，6-二甲基-9-吖啶酮)-4-乙酸，
2-(5，6-二甲基-7-甲氧基-9-吖啶酮)-4-乙酸，
2-甲氧基-5，6-二甲基-9-吖啶酮-4-甲酸，
3，4-二甲基-9-吖啶酮，
2-甲氧基-5，6-二甲基-9-吖啶酮，
2-甲氧基-3，4-二甲基-9-吖啶酮，和
2，7-二甲氧基-3，4-二甲基-9-吖啶酮。
其中，所述烷基可为低级烷基，例如为1-8C烷基。其包括直链 和支链烷基，如甲基、乙基、丙基、异丙基和叔-丁基等，也包括(3-8C)环烷基，如环丙基、环丁基、环戊基、环己基和环庚基等。
其中，所述烷氧基可为低级烷基氧基，例如为1-8C烷氧基。包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明的其中又一个方面，所述式I化合物为2-(5，6-二甲基-7-甲氧基-9-吖啶酮)-4-乙酸。
在本发明的其中又一个方面，所述式I化合物为2-甲氧基-5，6-二甲基-9-吖啶酮。
本发明还提供了上述式I化合物的制备方法。
在本发明的其中一个方面，所述式I化合物的制备方法包括：
Figure PCTCN2020111932-appb-000002
例如，以式i与式ii化合物为起始原料，在含有铜粉和氧化亚铜混合催化剂的N，N-二甲基甲酰胺中，加热至100-110℃，偶联生成式iii化合物，式iii化合物在适量伊顿试剂中加热搅拌，缩合生成式I化合物，其中R 1、R 2、R 3、R 4、R 5的定义如前定义。
本发明的式I化合物的合适的药学上可接受的盐为例如式I化合物的酸加成盐，例如与无机或有机酸(如盐酸、氢溴酸、硫酸、三氟乙酸、柠檬酸或马来酸)形成的酸加成盐；或铵盐，或与有机碱(如甲胺、二甲胺、三甲胺、哌啶、吗啉或三-(2-羟乙基)胺)，或碱金属形成的盐。
本发明的式I化合物的合适的药学上可接受的溶剂合物为例如 水合物，如半水合物、一水合物、二水合物或三水合物或其可选择的组合量。
本发明化合物可采用前药形式给药，所述前药是业内公知的前药修饰形式，在人或动物体内裂解而释放本发明化合物的化合物。前药的实例包括体内可裂解的酯衍生物和体内可裂解的酰胺衍生物，所述酯衍生物可在式I化合物的羧基或羟基上形成，所述酰胺衍生物可在式I化合物的羧基或氨基上形成。
式I化合物的药学上可接受的前药还可为体内可裂解的酯或醚的形式，实例包括含有羟基的式I化合物的体内可裂解的酯或醚，对于羟基，合适的药学上可接受的成酯基团包括无机酯例如磷酸酯(包括氨基磷酸环酯)。对于羟基，合适的药学上可接受的成酯基团还包括(1-10C)烷酰基(如乙酰基、苯甲酰基、苯乙酰基和取代的苯甲酰基和苯乙酰基)、(1-10C)烷氧基羰基(如乙氧基羰基、N，N-[二-(1-4C)烷基]氨基甲酰基、2-二烷基氨基乙酰基和2-羧基乙酰基)。苯乙酰基和苯甲酰基上环取代基的实例包括氨基甲基、N-烷基氨基甲基、N，N-二烷基氨基甲基、吗啉代甲基、哌嗪-1-基甲基和4-(1-4C)烷基哌嗪-1-基甲基。对于羟基，合适的药学上可接受的成醚基团包括-酰氧基烷基例如乙酰氧基甲基和新戊酰氧基甲基。
式I化合物的药学上可接受的前药还可以为，例如其体内可裂解的酰胺衍生物。由氨基形成的合适的药学上可接受的酰胺包括，例如与(1-10C)烷酰基(如乙酰基、苯甲酰基、苯乙酰基和取代的苯甲酰基和苯乙酰基)形成的酰胺。苯乙酰基和苯甲酰基上环取代基的实例包括氨基甲基、N-烷基氨基甲基、N，N-二烷基氨基甲基、吗啉代甲基、哌嗪-1-基甲基和4-(1-4C)烷基哌嗪-1-基甲基。
本发明的式I化合物或其药学上可接受的盐、溶剂合物或前药具有STING激动的活性。由此，本发明的式I化合物或其药学上可接受的盐、溶剂合物或前药可用于预防和/或治疗STING通路相关疾病或制备用于预防和/或治疗STING通路相关疾病的药物，例如通过STING激活治疗的疾病或用于制备通过STING激活治疗疾病的药物。
在本发明的其中一个方面，提供一种药用组合物，它包含上文限定的式I化合物或其药学上可接受的盐、溶剂合物或前药，以及与之混合的药学上可接受的赋形剂，例如稀释剂或载体。
本发明的药用组合物可用本领域熟知的常规药用赋形剂，经常规方法获得。例如，意欲口服使用的组合物可包含的赋形剂为一种或多种着色剂、甜味剂、矫味剂和/或防腐剂等。如用于本文的，术语“药学上可接受的载体、稀释剂或赋形剂”是指制剂工业领域常用的药用辅料，例如在罗明生等，《药剂辅料大全》，四川科学技术出版社，1995中列举的。
本发明的药用组合物可用本领域熟知的常规药用赋形剂，经常规方法获得。例如，意欲口服使用的组合物可包含的赋形剂为一种或多种着色剂、甜味剂、矫味剂和/或防腐剂等。
本发明的药用组合物可采用适合口服的形式(例如片剂、锭剂、硬或软胶囊、水或油混悬液、乳剂、可分散的粉剂或粒剂、糖浆剂或酏剂)、适合局部使用的形式(例如霜剂、软膏剂、凝胶剂或水或油性溶液或混悬液)、适合吸入给药的形式(例如精细分散的粉剂或液体气雾剂)、适合吹入给药的形式(例如精细分散的粉剂)或适合胃肠外给药的形式(例如用于静脉内、皮下、腹膜内或肌内给药的无菌水或油性溶液或用于直肠给药的栓剂)。
与一种或多种赋形剂组合形成单一剂型的活性成分的量将按需要改变，取决于治疗主体和具体给药途径。例如，意欲口服给予人的制剂通常将含有，例如与适当和方便量的赋形剂混合的0.01mg-1g (更适合为0.1-250mg，例如0.1-100mg)活性成分，所述赋形剂可占约5-98％范围内的总组合物重量。
用于治疗或预防目的的式I化合物或其药学上可接受的盐、溶剂合物或前药的剂量大小将通常自然根据疾病的性质和严重度、动物或患者的年龄和性别以及给药途径，根据众所周知的医学原则改变。
根据本发明的又一个方面，提供上文描述的式I化合物或其药学上可接受的盐、溶剂合物或前药，在制备用于治疗或预防STING通路相关疾病的药物中的用途。
根据本发明的又一方面，所述STING通路相关疾病为感染性疾病、癌症、炎症、过敏性和自身免疫性疾病。
所述感染性疾病为病毒感染性疾病或细菌感染性疾病，其感染原例如为流感病毒、肠道病毒、乙肝病毒、丙肝病毒、埃博拉病毒、马尔堡病毒、SARS病毒、塞卡病毒、布尼亚病毒、鼻病毒、呼吸核胞病毒、霍乱病毒等病毒性病原，以及结核杆菌、大肠杆菌、鲍曼不动杆菌、肺炎双球菌、乳酸链球菌、尿素生孢八叠球菌、金黄色葡萄球菌、枯草芽孢杆菌、炭疽芽孢杆菌、枯草杆菌、链杆菌、变形杆菌、霍乱弧菌、梅毒螺旋体等细菌性病原。
所述癌症为胃癌、肝癌、肺癌、食管癌、子宫颈癌、乳腺癌、结肠癌、直肠癌、鼻咽癌、卵巢癌、肾癌、膀胱癌、甲状腺癌和皮肤癌等；从间叶组织如肌肉、脂肪、骨骼、血管、淋巴等长出来的恶性肿瘤，例如横纹肌肉瘤、平滑肌肉瘤、纤维肉瘤、脂肪肉瘤、骨肉瘤、软骨肉瘤、血管肉瘤、淋巴肉瘤等。另外还有例如白血病、霍奇金病、威尔姆氏瘤(肾母细胞瘤)、黑色素瘤、视网膜细胞瘤、精原细胞瘤、颗粒细胞瘤、枯根勃氏瘤、尤文氏瘤、恶性血管内皮细胞瘤或乳房派杰氏病。优选为消化道癌症和呼吸道癌症，如胃癌、肝癌、肺癌、食管癌、大肠癌。
炎症代表对创伤的血管、细胞和神经响应。炎症可以表征为炎症细胞如单核细胞、嗜中性粒细胞和粒细胞进入组织的运动。这通常涉 及减少的内皮屏障功能和水肿进入组织。炎症可以分为急性或慢性。急性炎症是身体对有害刺激的初始响应，并且通过血浆和白细胞从血液到损伤组织的运动增加来实现。生化事件的级联扩散和成熟炎性响应，其涉及损伤组织内的局部血管系统、免疫系统和各种细胞。称为慢性炎症的长期炎症导致存在于炎症部位的细胞类型的进行性变化，并且其特征在于来自炎性过程的组织的同时破坏和愈合。炎症包括肌肉骨骼炎症、血管炎症、神经炎症、消化系统炎症、眼部炎症、生殖系统炎症或其它炎症，例如为哮喘。
自身免疫性疾病包括但不限于系统性红斑狼疮、牛皮癣、胰岛素依赖性糖尿病(IDDM)、皮肌炎和干燥综合征(SS)。
过敏性疾病包括但不限于敏反应、接触性皮炎(包括由毒葛所致)、荨麻疹、皮肤过敏、呼吸道过敏(枯草热、过敏性鼻炎)和谷蛋白敏感性肠病(乳糜泻)。
具体实施方式
通过下面的实施例和试验例可以对本发明进行进一步的描述。然而，本发明的范围并不限于下述实施例或试验例。本领域的专业人员能够理解，在不背离本发明的精神和范围的前提下，可以对本发明进行各种变化和修饰。本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的，但是本发明仍然在此作尽可能详细描述。
对于以下全部实施例，可以使用本领域技术人员已知的标准操作和纯化方法。除非另有说明，所有温度以℃(摄氏度)表示。化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。化合物熔点m.p.由YRT-3药物熔点仪测定，温度计未经校正，m.p.是以℃给出。 1H NMR由AVANCE III HD-400型核磁共振仪测定。质谱由AB Sciex API 4000型质谱仪测定。所有反应用溶剂未注明都经标准化预处理。
下面实施例中如无特殊说明，％是指质量百分比。
实施例1 10-二甲基-6H-吡咯[3，2，1-de]-1，6-吖啶二酮的制备
Figure PCTCN2020111932-appb-000003
将2-溴苯乙酸(2.16g，10.00mmol)、2-氨基-3，4-二甲基苯甲酸(1.5g，9.1mmol)、铜粉(0.06g)和氧化亚铜(0.06g)加入到N，N-二甲基甲酰胺(18ml)中，在50℃左右条件下物料混合均后，升温至100-110℃反应过夜，薄层层析监测反应进程，至反应完全后，将反应液静置冷却至室温，随后减压蒸除N，N-二甲基甲酰胺，得到深棕色固体。加入1N氢氧化钠溶液(60ml)溶解，过滤去除铜粉，得到黄棕色澄清滤液。向滤液内缓慢滴加浓盐酸，至溶液PH为5，充分搅拌后过滤并用水冲洗，得到浅黄色固体，干燥称重为1.81g，收率66.7％。将浅黄色固体全部加入至9ml伊顿试剂中，90-100℃下加热搅拌3.5h，静置冷却至室温，缓慢倾入到150ml饱和碳酸氢钠溶液中，加毕充分搅拌，析出大量固体。过滤并用大量水冲洗，得到粗品，干燥后用硅胶柱层析纯化，得白色固体，干燥称重为1.52g，总收率为63.3％。 1H NMR(400MHz，DMSO-D6)δ：8.11(d，J＝8.0Hz，1H)，7.97(d，J＝8.1Hz，1H)，7.75(d，J＝7.0Hz，1H)，7.51-7.40(m，2H)，4.05(s，2H)，3.37(s，1H)，2.43(s，3H)，2.33(s，3H).ESI-MS(m/z)：264.1[M+H]+。
实施例2 2-(5，6-二甲基-9-吖啶酮)-4-乙酸的制备
Figure PCTCN2020111932-appb-000004
按上述实施例1中的方法得到9，10-二甲基-6H-吡咯[3，2，1-de] -1，6-吖啶二酮后，取0.8g产物投入至40ml乙醇溶液中，混合均匀后，加入8ml浓度为1N的NaOH溶液，加热至100℃，反应4.5h，减压旋干后用40ml水溶解，随后加入2N盐酸酸化至PH＝7，有大量固体析出。充分搅拌后过滤，得到粗品。真空干燥后用硅胶柱层析纯化，得黄色固体，干燥称重为0.70g，收率为83.2％。 1H NMR(400MHz，DMSO-D6)δ：13.11(s，1H)，9.53(s，1H)，8.14(dd，J＝8.1，1.3Hz，1H)，8.05(d，J＝8.2Hz，1H)，7.66(dd，J＝7.2，1.5Hz，1H)，7.27(m，J＝8.0，7.2Hz，1H)，7.13(d，J＝8.3Hz，1H)，4.10(s，2H)，2.52(s，3H)，2.41(s，3H).13C NMR(101MHz，DMSO-D6)δ：177.44(s)，173.65(s)，142.28(s)，139.63(s)，139.51(s)，135.88(s)，125.76(s)，124.72(s)，123.69(s)，123.23(s)，121.46(s)，121.24(s)，119.31(s)，38.59(s)，21.15(s)，12.63(s).MS(ESI)：m/z 282.11[M+H]+。
实施例3 2-(5，6-二甲基-7-甲氧基-9-吖啶酮)-4-乙酸的制备
Figure PCTCN2020111932-appb-000005
按上述实施例1中的方法，将起始原料2-氨基-3，4-二甲基苯甲酸替换为2-氨基-3，4-二甲基-5-甲氧基苯甲酸，按比例投料，得到相应中间体后，按上述实施例6中的方法，得到灰色固体0.70g，总产率为27.7％。 1H NMR(400MHz，DMSO-D6)δ：9.46(s，1H)，8.18(dd，J＝8.1，1.3Hz，1H)，7.68(dd，J＝7.2，1.3Hz，1H)，7.52(s，1H)，7.24(dd，J＝8.0，7.2Hz，1H)，4.13(s，2H)，3.86(s，3H)，2.51(s，3H)，2.36(s，3H).13C NMR(101MHz，DMSO-D6)δ：176.68，173.72，153.32，139.26，135.57，134.29，133.22，125.76，125.31，123.21，121.45，120.71，119.29，101.53，55.88，38.69，13.40，13.19.MS(ESI)：m/z 312.14[M+H]+。
实施例4 2-甲氧基-5，6-二甲基-9-吖啶酮-4-甲酸的制备
Figure PCTCN2020111932-appb-000006
按上述实施例1中的方法，将起始原料2-溴苯乙酸替换为2-溴-5-甲氧基苯甲酸，按比例投料，得绿色固体0.32g，总收率为45.2％。 1H NMR(400MHz，DMSO-D6)δ：14.09(s，1H)，11.83(s，1H)，7.99-7.83(m，3H)，7.14(d，J＝8.2Hz，1H)，3.82(s，3H)，2.41(s，3H)，2.33(s，3H).13C NMR(101MHz，DMSO-D6)δ：173.72，168.61，148.83，138.47，136.65，133.48，121.22，120.77，120.48，120.09，118.17，117.44，116.13，111.52，59.12，18.17，10.66.MS(ESI)：m/z 298.11[M+H]+。
实施例5 3，4-二甲基-9-吖啶酮的制备
Figure PCTCN2020111932-appb-000007
按上述实施例1中的方法，将起始原料2-溴苯乙酸和2-氨基-3，4-二甲基苯甲酸替换为2-溴苯甲酸和2，3-二甲基苯胺，按比例投料，得到黄绿色固体0.82g，总产率为53.8％。 1H-NMR(400MHz，DMSO-D6)δ：10.46(s，1H)，8.23(dd，J＝8.1，1.3Hz，1H)，8.09(d，J＝8.2Hz，1H)，7.99(d，J＝8.4Hz，1H)，7.76-7.69(m，1H)，7.21(ddd，J＝8.0，7.0，0.9Hz，1H)，7.09(d，J＝8.2Hz，1H)，2.46(s，3H)，2.41(s，3H).13C NMR(101MHz，DMSO-D6)δ：173.75，138.46，137.53，136.68，127.47，121.32，120.64，120.31，120.08，119.31，118.09，117.36，116.01，18.36，10.65.MS(ESI)：m/z 224.11[M+H]+.
实施例6 2-甲氧基-5，6-二甲基-9-吖啶酮的制备
Figure PCTCN2020111932-appb-000008
按上述实施例1中的方法，将起始原料2-溴苯乙酸和2-氨基-3，4- 二甲基苯甲酸替换为2-溴-5-甲氧基苯甲酸和2，3-二甲基苯胺，按比例投料，得到浅黄色固体1.53g，总产率为40.2％。 1H-NMR(400MHz，DMSO-D6)δ：10.49(s，1H)，8.13(d，J＝8.3Hz，1H)，7.93(d，J＝9.1Hz，1H)，7.62(d，J＝3.0Hz，1H)，7.35(dd，J＝9.1，3.0Hz，1H)，7.11(d，J＝8.3Hz，1H)，3.88(s，3H)，2.45(s，3H)，2.36(s，3H).13C NMR(101MHz，DMSO-D6)δ(ppm)：13C NMR(101MHz，DMSO-D6)δ：176.69，154.43，141.59，139.66，136.48，124.17，123.76，123.55，123.04，121.02，120.35，119.23，105.21，55.74，21.16，13.67.MS(ESI)：m/z 254.12[M+H]+。
实施例7 2-甲氧基-3，4-二甲基-9-吖啶酮的制备
Figure PCTCN2020111932-appb-000009
按上述实施例1中的方法，将起始原料2-溴苯乙酸和2-氨基-3，4-二甲基苯甲酸替换为2-溴苯甲酸和2，3-二甲基-4-甲氧基苯胺，按比例投料，得到深绿色固体0.31g，总产率为57.3％。1H-NMR(400MHz，DMSO-D6)δ：10.48(s，1H)，8.21(d，J＝7.9Hz，1H)，7.93(d，J＝8.4Hz，1H)，7.66(t，J＝7.6Hz，1H)，7.53(s，1H)，7.26(t，J＝7.2Hz，1H)，3.84(s，3H)，2.55(s，3H)，2.31(s，3H).13C NMR(101MHz，DMSO-D6)δ：176.73，152.74，141.17，134.65，133.21，132.59，126.22，125.12，121.21，119.85，119.46，118.55，101.67，55.87，14.29，13.38.MS(ESI)：m/z 254.12[M+H]+。
实施例8 2，7-二甲氧基-3，4-二甲基-9-吖啶酮的制备
Figure PCTCN2020111932-appb-000010
按上述实施例1中的方法，将起始原料2-溴苯乙酸和2-氨基-3，4-二甲基苯甲酸替换为2-溴-5-甲氧基苯甲酸和2，3-二甲基-4-甲氧基 苯胺，按比例投料，得到深绿色固体0.42g，总产率为44.4％。1H-NMR(400MHz，DMSO-D6)δ：10.45(s，1H)，7.86(d，J＝9.1Hz，1H)，7.56(d，J＝2.9Hz，1H)，7.51(s，1H)，7.34(dd，J＝9.1，3.0Hz，1H)，3.89(s，3H)，3.83(s，3H)，2.54(s，3H)，2.31(s，3H).13C NMR(101MHz，DMSO-D6)δ：175.69，154.46，152.45，136.21，134.42，132.32，125.13，124.12，120.43，120.26，118.68，104.45，101.33，55.91，55.67，14.28，13.31.MS(ESI)：m/z 284.13[M+H]+。
实施例1-8制备的化合物以及阳性对照药cGAMP、DMXAA和CMA的化学名称及结构式如下表所示。
Figure PCTCN2020111932-appb-000011
Figure PCTCN2020111932-appb-000012
实施例9化合物在细胞模型上激动STING通路活性评价
9.1测试原理：
化合物与改造的细胞系共培养，通过测定被荧光标记的免疫分子来验证STING各通路的激动活性，所有细胞系来源于Invivogen公司：293T-Dual TMhSTING-R232 Cells；293T-Dual TMmSTING Cells。293人胚胎肾细胞内本身没有STING，是很好的STING通路验证细胞。hSTING-R232是俗称野生型STING，约占人口的70％。mSTING Cells 转染mSTING的293T细胞。
9.2.测试方法：
180μL的293T-Dual TMhSTING-R232 Cells或293T-Dual TMmSTING Cells液(～100000细胞/孔)与20μL盐溶液或测试化合物的盐溶液共同在37℃的5％CO2培养箱中培养48小时后，用不同检测液间接测量STING各通路的活性：293T细胞用QUANTI-Blue检测IRF通路的活性，用QUANTI-Blue检测NF-κB通路的活性。测试分为两个步骤进行，第一步初步筛选有效化合物，各化合物的初步筛选浓度为10μM和100μM，阳性化合物cGAMP的浓度为20μM。第二步是对有效小分子分别设定浓度梯度来确定化合物的EC50值并与cGAMP比较，判断分子激活STING通路的强弱。
9.3.测试结果：
表1目标化合物激动STING通路的生物评级测试结果
化合物编号 人源STING活性 鼠源STING活性
Con 1 ++ ++
Con 2 - ++
Con 3 - ++
3 + +
6 ++ ++
表2目标化合物激动STING通路生物活性测试结果
Figure PCTCN2020111932-appb-000013
注：表1和表2中，(1)“-”表示无活性；“+”表示活性良好；“++”表示活性优秀；(2)EC50：药物半数最大效应浓度；Emax：药物发挥效应的最大强度值；nt表示未检测到活性。
实施例10化合物与STING配体竞争结合作用评价
10.1.测试原理：
检测原理基于
Figure PCTCN2020111932-appb-000014
技术，当染料接近时，光源(激光或闪光灯)对供体的激发会触发向受体的荧光共振能量转移(FRET)，在特定波长(665nm)下发出荧光。用穴状铽(供体)标记特异性抗6His抗体，该抗体可与6His标记的人STING蛋白和标记有d2(受体)的STING配体相结合。以竞争性分析的方式检测人STING配体，检测化合物与标记有d2的尾支配体竞争，从而阻断了FRET的发生，特定信号的强弱与化合物的浓度成反比。
10.2.测试方法：
先加入5μL不同浓度的检测化合物或cGAMP或阴性对照液，再加入5μL的6His标记的人源STING(阴性对照孔加入的是检测缓冲液)，最后加入10μL的d2配体和抗6His抗体混合液；密封细胞板并室温培养3h后，酶标仪分别读取665nm和620nm处吸光值，二者比值AU665/AU620为评价化合物结合STING蛋白强弱的依据。
10.3.测试结果：
表3化合物竞争性抑制STING结合测定结果
化合物编号 竞争性抑制浓度
3 1721.54±15.68nM
6 375.25±7.65nM
Con1 333.32±6.89nM
Con2 ＞500μM
实验证明，本发明的化合物具有对不同种属，特别是对人源STING的激动剂，而且活性很高。
上面是对本发明进行的说明，不能将其看成是对本发明进行的限制。除非另外指出，本发明的实践将使用有机化学、聚合物化 学、生物技术等的常规技术，显然除在上述说明和实施例中所特别描述之外，还可以别的方式实现本发明。其它在本发明范围内的方面与改进将对本发明所属领域的技术人员显而易见。根据本发明的教导，许多改变和变化是可行的，因此其在本发明的范围之内。

Claims (10)

  1. 一种式I的化合物，其药学可接受的盐、溶剂合物、水合物或前药，
    Figure PCTCN2020111932-appb-100001
    其中，
    R 1、R 2和R 3独立地选自氢、烷基、烷氧基、羟基，
    R4和R5独立地选自氢、烷氧基、乙酰基，或者R4或R5与相邻吡啶环上的N原子相连形成＝N-C(＝O)-C-。
  2. 根据权利要求1的化合物，其药学可接受的盐、溶剂合物、水合物或前药化合物，其中所述化合物选自：
    9，10-二甲基-6H-吡咯[3，2，1-de]-1，6-吖啶二酮，
    2-(5，6-二甲基-9-吖啶酮)-4-乙酸，
    2-(5，6-二甲基-7-甲氧基-9-吖啶酮)-4-乙酸，
    2-甲氧基-5，6-二甲基-9-吖啶酮-4-甲酸，
    3，4-二甲基-9-吖啶酮，
    2-甲氧基-5，6-二甲基-9-吖啶酮，
    2-甲氧基-3，4-二甲基-9-吖啶酮，和
    2，7-二甲氧基-3，4-二甲基-9-吖啶酮。
  3. 药物组合物，其中包括权利要求1所述的化合物，其药学可接受的盐、溶剂合物、水合物或前药，以及一种或多种药学上可接受的载体或赋形剂。
  4. 根据权利要求3所述的药物组合物，其用于治疗和/或预防STING通路相关疾病。
  5. 权利要求1所述的化合物，其药学可接受的盐、溶剂合物、水合物或前药用于制备治疗和/或预防STING通路相关疾病的药物中的用途。
  6. 根据权利要求5的用途，其中所述STING通路相关疾病为感染性疾病、癌症、炎症、过敏性和自身免疫性疾病。
  7. 根据权利要求6的用途，其中所述感染性疾病为病毒感染性疾病或细菌感染性疾病，其病原例如为流感病毒、肠道病毒、乙肝病毒、丙肝病毒、埃博拉病毒、马尔堡病毒、SARS病毒、塞卡病毒、布尼亚病毒、鼻病毒、呼吸核胞病毒、霍乱病毒等病毒性病原，或是结核杆菌、大肠杆菌、鲍曼不动杆菌、肺炎双球菌、乳酸链球菌、尿素生孢八叠球菌、金黄色葡萄球菌、枯草芽孢杆菌、炭疽芽孢杆菌、枯草杆菌、链杆菌、变形杆菌、霍乱弧菌、梅毒螺旋体等细菌性病原。
  8. 根据权利要求6的用途，其中所述癌症为胃癌、肝癌、肺癌、食管癌、子宫颈癌、乳腺癌、结肠癌、直肠癌、鼻咽癌、卵巢癌、肾癌、膀胱癌、甲状腺癌和皮肤癌等；从间叶组织如肌肉、脂肪、骨骼、血管、淋巴等长出来的恶性肿瘤，例如横纹肌肉瘤、平滑肌肉瘤、纤维肉瘤、脂肪肉瘤、骨肉瘤、软骨肉瘤、血管肉瘤、淋巴肉瘤等。另外还有例如白血病、霍奇金病、威尔姆氏瘤(肾母细胞瘤)、黑色素瘤、视网膜细胞瘤、精原细胞瘤、颗粒细胞瘤、枯根勃氏瘤、尤文氏瘤、恶性血管内皮细胞瘤或乳房派杰氏病。
  9. 根据权利要求6的用途，其中所述炎症、过敏性和自身免疫性疾病为肌肉骨骼炎症、血管炎症、神经炎症、消化系统炎症、眼部炎症、生殖系统炎症或其它炎症，例如为哮喘。
  10. 权利要求1所述的化合物的制备方法，其包括以下步骤：
    Figure PCTCN2020111932-appb-100002
    Figure PCTCN2020111932-appb-100003
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