CN102746292A - Cyclized berberine derivatives, preparation method and uses thereof - Google Patents

Cyclized berberine derivatives, preparation method and uses thereof Download PDF

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CN102746292A
CN102746292A CN201210101607XA CN201210101607A CN102746292A CN 102746292 A CN102746292 A CN 102746292A CN 201210101607X A CN201210101607X A CN 201210101607XA CN 201210101607 A CN201210101607 A CN 201210101607A CN 102746292 A CN102746292 A CN 102746292A
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phenanthridines
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宋丹青
邵荣光
蒋建东
李阳彪
赵午莉
毕重文
汪燕翔
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Institute of Medicinal Biotechnology of CAMS and PUMC
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Abstract

本发明涉及环化的小檗碱衍生物及其制备方法和用途。本发明具体涉及式I化合物或其药学可接受的盐或溶剂合物，其中X为卤素；R选自：氢、C1-6烷基、苯基取代的C1-6烷基、C1-18烷基酰基、苯甲酰基、苯磺酰基、3，4-C1-3亚烷基二氧基苯甲酰基，其中所述的苯基任选被1至4个选自下列的取代基取代：卤素、C1-6烷基、C1-6烷氧基、硝基、氰基、氨基、羟基、C1-4烷基酰基氨基。本发明化合物具有有益的生理学活性。 The present invention relates to a cyclized berberine derivative and a preparation method and use thereof. The present invention specifically relates to a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, wherein X is halogen; R is selected from: hydrogen, C 1-6 alkyl, phenyl substituted C 1-6 alkyl, C 1 -18 Alkanoyl, benzoyl, benzenesulfonyl, 3,4-C 1-3 alkylenedioxybenzoyl, wherein the phenyl is optionally substituted by 1 to 4 selected from the following Base substitution: halogen, C 1-6 alkyl, C 1-6 alkoxy, nitro, cyano, amino, hydroxyl, C 1-4 alkylacylamino. The compounds of the present invention possess beneficial physiological activities.

Description

环化的小檗碱衍生物及其制备方法和用途Cyclized berberine derivative and its preparation method and use

技术领域 technical field

本发明属于医药化学领域，具体涉及一类新的可作为抗肿瘤剂的化合物，特别涉及一类具有抗肿瘤活性的环化小檗碱衍生物及其制备方法，以及此类化合物在作为药物特别是作为抗肿瘤药物例如抗肝脏肿瘤的药物方面的应用。The invention belongs to the field of medicinal chemistry, and in particular relates to a new class of compounds that can be used as antitumor agents, in particular to a class of cyclized berberine derivatives with antitumor activity and a preparation method thereof, and the use of such compounds in particular as drugs It is an application as an anti-tumor drug such as a drug against liver tumors.

背景技术 Background technique

肿瘤和癌症是危害人类健康的最重大疾病之一。肿瘤是机体在各种致癌因素作用下，局部组织的某一个细胞在基因水平上失去对其生长的正常调控，导致其克隆性异常增生而形成的新生物。一般认为，肿瘤细胞是单克隆性的，即一个肿瘤中的所有瘤细胞均是一个突变的细胞的后代。一般将肿瘤分为良性和恶性两大类。所有的恶性肿瘤总称为癌症。医学家指出癌症病因是：机体在环境污染、化学污染(化学毒素)、电离辐射、自由基毒素、微生物(细菌、真菌、病毒等)及其代谢毒素、遗传特性、内分泌失衡、免疫功能紊乱等等各种致癌物质、致癌因素的作用下导致身体正常细胞发生癌变的结果，常表现为：局部组织的细胞异常增生而形成的局部肿块。癌症是机体正常细胞在多原因、多阶段与多次突变所引起的一大类疾病。Tumors and cancers are one of the most serious diseases that endanger human health. Tumor is a new organism formed by the body under the action of various carcinogenic factors when a certain cell in a local tissue loses its normal regulation of its growth at the gene level, resulting in abnormal clonal proliferation. It is generally believed that tumor cells are monoclonal, that is, all tumor cells in a tumor are descendants of a mutant cell. Tumors are generally divided into benign and malignant. All malignant tumors are collectively called cancer. Medical scientists point out that the cause of cancer is: the body's environmental pollution, chemical pollution (chemical toxins), ionizing radiation, free radical toxins, microorganisms (bacteria, fungi, viruses, etc.) and their metabolic toxins, genetic characteristics, endocrine imbalance, immune dysfunction, etc. Under the action of various carcinogens and carcinogenic factors, the result of canceration of normal cells in the body is often manifested as a local mass formed by abnormal cell proliferation in local tissues. Cancer is a large class of diseases caused by normal cells in the body due to multiple reasons, multiple stages and multiple mutations.

已经知道，小檗碱(Berberine，BBR)，又称为黄连素，是一种常见的异喹啉生物碱，其分子式为[C20H18NO4]+。它存在于小檗科等四个科十个属的许多植物中，1826年M.-E.夏瓦利埃和G.佩尔坦首次从Xanthoxylonclava树皮中首次获得。小檗碱是一种季铵生物碱，从乙醚中可析出黄色针状晶体；熔点145℃；溶于水，难溶于苯、乙醚和氯仿。其盐类在水中的溶解度都比较小，例如盐酸盐为1∶500，硫酸盐为1∶30。小檗碱对痢疾杆菌、大肠杆菌、肺炎双球菌、金葡菌、链球菌、伤寒杆菌及阿米巴原虫有抑制作用。临床常用的盐酸小檗碱为其2水合物，主要用于肠道感染及菌痢等。近来还发现小檗碱具有抗心律失常作用以及可以用于治疗糖尿病。小檗碱的抗菌谱广，体外对多种革兰阳性及阴性菌均具抑菌作用，其中对溶血性链球菌、金葡菌、霍乱弧菌。脑膜炎球菌、志贺痢疾杆菌、伤寒杆菌、白喉杆菌等有较强的抑制作用，低浓度时抑菌，高浓度时杀菌。对流感病毒、阿米巴原虫、钩端螺旋体、某些皮肤真菌也有一定抑制作用。体外实验证实黄连素能增强白细胞及肝网状内皮系统的吞噬能力。痢疾杆菌、溶血性链球菌、金葡菌等极易对本品产生耐药性。小檗碱与青霉素、链霉素等并无交叉耐药性。目前小檗碱在临床上主要用于治疗胃肠炎、细菌性痢疾等肠道感染，对于眼结膜炎、化脓性中耳炎等有效。It is known that berberine (BBR), also known as berberine, is a common isoquinoline alkaloid, and its molecular formula is [C 20 H 18 NO 4 ] + . It exists in many plants of ten genera in four families including Berberidaceae, and was first obtained from the bark of Xanthoxylonclava in 1826 by M.-E. Chavalier and G. Peltin. Berberine is a quaternary ammonium alkaloid, yellow needle-like crystals can be precipitated from ether; melting point 145°C; soluble in water, insoluble in benzene, ether and chloroform. The solubility of its salts in water is relatively small, for example, hydrochloride is 1:500, and sulfate is 1:30. Berberine has inhibitory effects on Shigella, Escherichia coli, Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus, Salmonella typhi and amoeba. The commonly used berberine hydrochloride is its 2 hydrate, which is mainly used for intestinal infection and bacillary dysentery. Berberine has also recently been found to have antiarrhythmic effects and can be used in the treatment of diabetes. Berberine has a broad antibacterial spectrum, and has antibacterial effects on a variety of Gram-positive and negative bacteria in vitro, including hemolytic streptococci, Staphylococcus aureus, and Vibrio cholerae. Meningococcus, Shigella dysenteriae, typhoid bacillus, diphtheria bacillus, etc. have a strong inhibitory effect, inhibiting bacteria at low concentrations and sterilizing at high concentrations. It also has a certain inhibitory effect on influenza virus, amoeba, leptospira, and some skin fungi. In vitro experiments confirmed that berberine can enhance the phagocytosis of leukocytes and liver reticuloendothelial system. Shigella, hemolytic streptococci, and Staphylococcus aureus can easily develop resistance to this product. There is no cross-resistance between berberine and penicillin, streptomycin, etc. At present, berberine is mainly used clinically to treat intestinal infections such as gastroenteritis and bacillary dysentery, and is effective for conjunctivitis and suppurative otitis media.

人们仍然期待有新颖而有效的抗肿瘤药物例如抗肝脏肿瘤的药物用于临床。It is still expected that novel and effective anti-tumor drugs such as drugs against liver tumors will be used clinically.

发明内容 Contents of the invention

本发明的目的是寻找具有有效的抗肿瘤例如抗肝脏肿瘤的新化合物。本发明人令人惊奇的发现，具有式I结构的环化小檗碱衍生物具有令人惊奇的效果。本发明基于此发现而得以完成。The object of the present invention is to find new compounds with effective anti-tumor, eg anti-liver tumors. The present inventors surprisingly found that the cyclized berberine derivatives having the structure of formula I have surprising effects. The present invention has been accomplished based on this finding.

为此，本发明第一方面提供了以下式I化合物：To this end, the first aspect of the present invention provides the following compounds of formula I:

Figure BDA0000151312600000021
Figure BDA0000151312600000021

或其药学可接受的盐或溶剂合物，其中or a pharmaceutically acceptable salt or solvate thereof, wherein

X为卤素；X is a halogen;

R1选自：氢、C1-6烷基、苯基取代的C1-6烷基、C1-18烷基酰基、苯甲酰基、苯磺酰基、3，4-C1-3亚烷基二氧基苯甲酰基，其中所述的苯基任选被1至4个选自下列的取代基取代：卤素、C1-6烷基、C1-6烷氧基、硝基、氰基、氨基、羟基、C1-4烷基酰基氨基；R 1 is selected from: hydrogen, C 1-6 alkyl, phenyl substituted C 1-6 alkyl, C 1-18 alkyl acyl, benzoyl, benzenesulfonyl, 3,4-C 1-3 ethylene Alkyldioxybenzoyl, wherein the phenyl is optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, nitro, Cyano, amino, hydroxyl, C 1-4 alkylacylamino;

R2和R3各自独立地选自：氢、C1-6烷基、苯甲酰基，其中所述的苯基任选被1至4个卤素取代；或者R2和R3一起为-CH2-(即R2和R3与它们连接的氧原子一起形成一个二氧杂环戊烯的环)。R 2 and R 3 are each independently selected from: hydrogen, C 1-6 alkyl, benzoyl, wherein the phenyl is optionally substituted by 1 to 4 halogens; or R 2 and R 3 together are -CH 2 - (ie R 2 and R 3 together with the oxygen atom to which they are attached form a dioxole ring).

根据本发明第一方面的化合物，其中R2和R3各自独立地选自：氢、C1-4烷基、卤代苯甲酰基；或者R2和R3一起为-CH2-(即R2和R3与它们连接的氧原子一起形成一个二氧杂环戊烯的环)。The compound according to the first aspect of the present invention, wherein R 2 and R 3 are each independently selected from: hydrogen, C 1-4 alkyl, halobenzoyl; or R 2 and R 3 together are -CH 2 - (ie R 2 and R 3 together with the oxygen atom to which they are attached form a dioxole ring).

根据本发明第一方面的化合物，其为以下式II的化合物：A compound according to the first aspect of the present invention, which is a compound of the following formula II:

或其药学可接受的盐或溶剂合物，其中or a pharmaceutically acceptable salt or solvate thereof, wherein

X为卤素；X is a halogen;

R选自：氢、C1-6烷基、苯基取代的C1-6烷基、C1-18烷基酰基、苯甲酰基、苯磺酰基、3，4-C1-3亚烷基二氧基苯甲酰基，其中所述的苯基任选被1至4个选自下列的取代基取代：卤素、C1-6烷基、C1-6烷氧基、硝基、氰基、氨基、羟基、C1-4烷基酰基氨基。R is selected from: hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted by phenyl, C 1-18 alkyl acyl, benzoyl, benzenesulfonyl, 3,4-C 1-3 alkylene Dioxybenzoyl, wherein the phenyl is optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, nitro, cyano group, amino group, hydroxyl group, C 1-4 alkylacylamino group.

根据本发明第一方面的化合物，其中X选自氟、氯、溴、碘。在一个实施方案中，X选自氯、溴、碘。The compound according to the first aspect of the present invention, wherein X is selected from fluorine, chlorine, bromine and iodine. In one embodiment, X is selected from chlorine, bromine, iodine.

根据本发明第一方面的化合物，其中R选自氢、C1-4烷基、苯基取代的C1-4烷基、C1-16烷基酰基、苯甲酰基、苯磺酰基、3，4-C1-2亚烷基二氧基苯甲酰基，其中所述的苯基任选被1至4个选自下列的取代基取代：卤素、C1-4烷基、C1-4烷氧基、硝基、氰基、氨基、羟基、C1-4烷基酰基氨基。According to the compound of the first aspect of the present invention, wherein R is selected from hydrogen, C 1-4 alkyl, C 1-4 alkyl substituted by phenyl, C 1-16 alkyl acyl, benzoyl, benzenesulfonyl, 3 , 4-C 1-2 alkylenedioxybenzoyl, wherein the phenyl is optionally substituted by 1 to 4 substituents selected from the group consisting of: halogen, C 1-4 alkyl, C 1- 4 alkoxy, nitro, cyano, amino, hydroxyl, C 1-4 alkylacylamino.

根据本发明第一方面的化合物，其中R选自氢、C1-4烷基、苯基取代的C1-4烷基、C1-16烷基酰基、苯甲酰基、苯磺酰基、3，4-亚甲二氧基苯甲酰基，其中所述的苯基任选被1至4个选自下列的取代基取代：卤素、C1-4烷基、C1-4烷氧基、硝基、氰基、氨基、羟基、C1-4烷基酰基氨基。According to the compound of the first aspect of the present invention, wherein R is selected from hydrogen, C 1-4 alkyl, C 1-4 alkyl substituted by phenyl, C 1-16 alkyl acyl, benzoyl, benzenesulfonyl, 3 , 4-methylenedioxybenzoyl, wherein the phenyl is optionally substituted by 1 to 4 substituents selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, Nitro, cyano, amino, hydroxyl, C 1-4 alkylacylamino.

根据本发明第一方面的化合物，其为下式化合物，According to the compound of the first aspect of the present invention, it is a compound of the following formula,

Figure BDA0000151312600000031
Figure BDA0000151312600000031

其中R1、R2、R3和X具有以下编号(No1至No51)任一项所述含义：Wherein R 1 , R 2 , R 3 and X have the meanings described in any one of the following numbers (No1 to No51):

Figure BDA0000151312600000032
Figure BDA0000151312600000032

Figure BDA0000151312600000041
Figure BDA0000151312600000041

根据本发明第一方面的化合物，其为选自下列的化合物：A compound according to the first aspect of the present invention, which is a compound selected from the group consisting of:

9，10-二甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9,10-Dimethoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino[8,1,2- cde]phenanthridine-7-ium chloride;

9-羟基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-Hydroxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino[8,1,2 -cde]phenanthridin-7-ium chloride;

9-乙氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓溴化物；9-ethoxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino[8,1 , 2-cde]phenanthridine-7-ium bromide;

9-丁氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓碘化物；9-butoxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino[8,1 , 2-cde]phenanthridine-7-ium iodide;

9-苯甲氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓溴化物；9-Benzyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino[8, 1,2-cde]phenanthridine-7-ium bromide;

9-(2，4-二氟苯基)甲氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓溴化物；9-(2,4-difluorophenyl)methoxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6, 7] isoquinolino[8,1,2-cde]phenanthridin-7-ium bromide;

9-乙酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-acetyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino[8, 1,2-cde]phenanthridine-7-ium chloride;

9-苯甲酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-benzoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino[8 , 1,2-cde]phenanthridine-7-ium chloride;

9-对甲基苯甲酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-p-methylbenzoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinoline And [8,1,2-cde]phenanthridin-7-ium chloride;

9-对甲氧基苯甲酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-p-methoxybenzoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinone Phino[8,1,2-cde]phenanthridin-7-ium chloride;

9-对氟苯甲酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-p-fluorobenzoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino [8,1,2-cde]phenanthridin-7-ium chloride;

9-对氟间硝基苯甲酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-p-Fluorom-nitrobenzoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]iso Quinolino[8,1,2-cde]phenanthridin-7-ium chloride;

9-对甲基间硝基苯甲酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-p-methyl-m-nitrobenzoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7] Isoquinolino[8,1,2-cde]phenanthridin-7-ium chloride;

9-对甲氧基间硝基苯甲酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-p-methoxym-nitrobenzoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7 ]isoquinolino[8,1,2-cde]phenanthridin-7-ium chloride;

9-(3，4-亚甲二氧基苯甲酰基氧基)-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-(3,4-methylenedioxybenzoyloxy)-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′ : 6,7]isoquinolino[8,1,2-cde]phenanthridin-7-ium chloride;

9-(3，4，5-三甲氧基苯甲酰基氧基)-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-(3,4,5-trimethoxybenzoyloxy)-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′ : 6,7]isoquinolino[8,1,2-cde]phenanthridin-7-ium chloride;

9-邻氟苯甲酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-O-fluorobenzoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino [8,1,2-cde]phenanthridin-7-ium chloride;

9-邻氯苯甲酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-o-chlorobenzoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino [8,1,2-cde]phenanthridin-7-ium chloride;

9-(2，4-二氟苯甲酰基氧基)-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-(2,4-Difluorobenzoyloxy)-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6, 7] isoquinolino[8,1,2-cde]phenanthridin-7-ium chloride;

9-对乙酰胺基苯磺酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-p-acetamidobenzenesulfonyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinone Phino[8,1,2-cde]phenanthridin-7-ium chloride;

9-苯磺酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-Benzenesulfonyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino[8 , 1,2-cde]phenanthridine-7-ium chloride;

9-癸酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-decanoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino[8, 1,2-cde]phenanthridine-7-ium chloride;

9-十二烷酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-dodecanoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino[ 8,1,2-cde]phenanthridine-7-ium chloride;

9-十六烷酰基氧基-10-甲氧基-5，6-二氢-[1，3]二氧杂环戊烯并[4′，5′：6，7]异喹啉并[8，1，2-cde]菲啶-7-鎓氯化物；9-hexadecanoyloxy-10-methoxy-5,6-dihydro-[1,3]dioxole[4′,5′:6,7]isoquinolino[ 8,1,2-cde]phenanthridine-7-ium chloride;

或其药学可接受的盐或溶剂合物。or a pharmaceutically acceptable salt or solvate thereof.

根据本发明第一方面的化合物，其是如本发明实施例所制备的化合物或其药学可接受的盐或溶剂合物。The compound according to the first aspect of the present invention is the compound prepared according to the embodiment of the present invention or a pharmaceutically acceptable salt or solvate thereof.

本发明第二方面提供了制备本发明第一方面任一项所述式I化合物的方法，其包括以下步骤：The second aspect of the present invention provides a method for preparing the compound of formula I described in any one of the first aspect of the present invention, which comprises the following steps:

a)在溶剂(例如甲醇)中，在碱(例如碳酸钾、氢氧化钠等或其组合)存在下，使硼氢化钠与小檗碱反应，得到二氢小檗碱；a) in a solvent (such as methanol), in the presence of a base (such as potassium carbonate, sodium hydroxide, etc., or a combination thereof), sodium borohydride is reacted with berberine to obtain dihydroberberine;

b)在溶剂(例如乙腈)中，在酸(例如有机酸，例如乙酸)存在下，使二氢小檗碱与乙二醛反应，得到式Ia所示的环化小檗碱：b) in a solvent (such as acetonitrile), in the presence of an acid (such as an organic acid, such as acetic acid), dihydroberberine is reacted with glyoxal to obtain the cyclized berberine shown in formula Ia:

Figure BDA0000151312600000071
Figure BDA0000151312600000071

任选的，c)使式Ia环化小檗碱在真空(例如10-60mmHg，例如20-40mmHg)下、在高温(例如150～250℃，例如180～230℃)下处理得到式Ib所示的9-羟基环化小檗碱：Optionally, c) treating the cyclized berberine of formula Ia under vacuum (eg 10-60mmHg, eg 20-40mmHg) and high temperature (eg 150-250°C, eg 180-230°C) to obtain formula Ib 9-Hydroxycyclized berberine shown:

Figure BDA0000151312600000072
Figure BDA0000151312600000072

任选的，d)在有机溶剂(例如DMF)中，在碱(例如氢氧化钠、氢氧化钾)存在下，使式Ib的9-羟基环化小檗碱与适宜的试剂(例如卤代烃，例如卤代烷烃、苯基取代的卤代烷烃)反应，得到9-烷基氧基环化小檗碱，其中的烷基任选被苯基或取代的苯基取代；Optionally, d) in an organic solvent (such as DMF), in the presence of a base (such as sodium hydroxide, potassium hydroxide), make the 9-hydroxycyclized berberine of formula Ib with a suitable reagent (such as halogenated Hydrocarbons, such as haloalkane, phenyl substituted haloalkane) react to obtain 9-alkyloxycyclized berberine, wherein the alkyl group is optionally substituted by phenyl or substituted phenyl;

任选的，e)在有机溶剂(例如乙腈)中，在试剂(例如吡啶)存在下，使式Ib的9-羟基环化小檗碱与酰氯或者磺酰氯反应，得到9-酰基氧基环化小檗碱或者9-磺酰基氧基环化小檗碱，其中的酰基为烷酰基或苯甲酰基。Optionally, e) reacting a 9-hydroxycyclized berberine of formula Ib with an acid chloride or a sulfonyl chloride in the presence of a reagent such as pyridine in an organic solvent such as acetonitrile to give the 9-acyloxy ring Berberine or 9-sulfonyloxycyclized berberine, wherein the acyl group is alkanoyl or benzoyl.

在本发明第二方面的制备方法中，在必要情况下，在式I化合物制备过程中，为防止有些基团(如氨基、羟基等)发生不希望的反应，需要对这些基团予以保护，同时，在适当的时候予以去除保护基。这些实施例不胜枚举的，没有具体提及的保护基的使用和脱保护的方法也属于本发明的范围之内。In the preparation method of the second aspect of the present invention, if necessary, during the preparation of the compound of formula I, in order to prevent some groups (such as amino, hydroxyl, etc.) from undesired reactions, these groups need to be protected, At the same time, the protecting group is removed when appropriate. These examples are too numerous to mention, and the use of protecting groups and methods of deprotection not specifically mentioned also fall within the scope of the present invention.

本发明第三方面涉及一种药物组合物，其包含本发明第一方面任一项所述的式I化合物，以及任选的一种或多种药学可接受的载体或赋形剂。The third aspect of the present invention relates to a pharmaceutical composition, which comprises the compound of formula I according to any one of the first aspect of the present invention, and optionally one or more pharmaceutically acceptable carriers or excipients.

本发明第四方面涉及本发明第一方面任一项所述的式I化合物在制备用于治疗和/或预防哺乳动物(包括人)肿瘤或癌症性疾病(例如肝癌)的药物中的用途。The fourth aspect of the present invention relates to the use of the compound of formula I described in any one of the first aspect of the present invention in the preparation of a medicament for treating and/or preventing tumors or cancerous diseases (such as liver cancer) in mammals (including humans).

本发明第五方面涉及一种在有需要的哺乳动物中治疗和/或预防哺乳动物(包括人)肿瘤或癌症性疾病(例如肝癌)的方法，该方法包括给有需要的哺乳动物施用治疗有效量的本发明第一方面任一项所述的式I化合物。The fifth aspect of the present invention relates to a method of treating and/or preventing mammalian (including human) tumors or cancerous diseases (such as liver cancer) in a mammal in need thereof, the method comprising administering to the mammal in need a therapeutically effective Amount of the compound of formula I according to any one of the first aspect of the present invention.

本发明第六方面涉及用于治疗和/或预防哺乳动物(包括人)肿瘤或癌症性疾病(例如肝癌)的药物组合物，该药物组合物包含本发明第一方面任一项所述的式I化合物，以及任选的一种或多种药学可接受的载体或赋形剂。The sixth aspect of the present invention relates to a pharmaceutical composition for treating and/or preventing tumors or cancerous diseases (such as liver cancer) in mammals (including humans), the pharmaceutical composition comprising the formula according to any one of the first aspect of the present invention I compound, and optionally one or more pharmaceutically acceptable carriers or excipients.

本发明第七方面还涉及用于治疗和/或预防哺乳动物(包括人)肿瘤或癌症性疾病(例如肝癌)的本发明第一方面任一项所述的式I化合物。The seventh aspect of the present invention also relates to the compound of formula I according to any one of the first aspect of the present invention for use in the treatment and/or prevention of tumors or cancerous diseases (eg liver cancer) in mammals (including humans).

本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。Any embodiment of any aspect of the present invention may be combined with other embodiments as long as they do not contradict each other. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as there is no contradiction between them.

下面对本发明作进一步的描述。The present invention will be further described below.

本发明所引述的所有文献，它们的全部内容通过引用并入本文，并且如果这些文献所表达的含义与本发明不一致时，以本发明的表述为准。此外，本发明使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本发明仍然希望在此对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本发明所表述的含义为准。All the documents cited in the present invention are incorporated herein by reference in their entirety, and if the meaning expressed in these documents is inconsistent with the present invention, the expression of the present invention shall prevail. In addition, various terms and phrases used in the present invention have common meanings known to those skilled in the art. Even so, the present invention still hopes to make a more detailed description and explanation of these terms and phrases here. The terms and phrases mentioned are as follows: If there is any inconsistency with the known meaning, the meaning expressed in the present invention shall prevail.

本领域技术人员知晓，小檗碱的主要环和环原子可按如下示例性的顺序编号：Those skilled in the art know that the main rings and ring atoms of berberine can be numbered in the following exemplary order:

Figure BDA0000151312600000081
Figure BDA0000151312600000081

类似地，对于本发明式I化合物而言，例如对于对于本发明式Ia化合物而言，其中相应的五个环及部分环原子的编号可以示例如下：Similarly, for the compound of formula I of the present invention, for example, for the compound of formula Ia of the present invention, the numbering of the corresponding five rings and some ring atoms can be exemplified as follows:

Figure BDA0000151312600000082
Figure BDA0000151312600000082

因此在本发明中，提及“环化小檗碱”时，是指以上式Ia的小檗碱衍生物。进一步的，提及“9-羟基环化小檗碱”时，是指以下式Ib所示的小檗碱衍生物：Therefore, in the present invention, when referring to "cyclized berberine", it refers to the berberine derivative of the above formula Ia. Further, when referring to "9-hydroxycyclized berberine", it refers to the berberine derivative shown in the following formula Ib:

Figure BDA0000151312600000091
Figure BDA0000151312600000091

又例如，在提及“9-乙氧基环化小檗碱”时是指9-位是乙氧基的本发明化合物。As another example, the reference to "9-ethoxycyclized berberine" refers to the compound of the present invention in which the 9-position is an ethoxy group.

在本发明中，术语“卤素”或“卤代”是指氟、氯、溴、和碘。在本发明中，基团“3，4-C1-3亚烷基二氧基苯甲酰基”中的基团部分“C1-3亚烷基”是指具有1至3个碳原子的亚烷基。In the present invention, the term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine. In the present invention, the group part "C 1-3 alkylene" in the group "3,4-C 1-3 alkylenedioxybenzoyl" refers to a group having 1 to 3 carbon atoms alkylene.

本发明中，当提及时，所采用的术语“烃基”包括烷基、烯基和炔基，以及环状基团，例如芳环(如苯环)或非芳环(例如环己烷环)的基团。在本发明中，提及C1-6烷基时，其包括其任意子集，例如包括C1-5烷基、C1-4烷基、C1-3烷基，以及甲基、乙基、正丙基、异丙基、正丁基等。In the present invention, when referred to, the term "hydrocarbyl" is used to include alkyl, alkenyl and alkynyl groups, as well as cyclic groups, such as aromatic rings (such as benzene rings) or non-aromatic rings (such as cyclohexane rings) group. In the present invention, when referring to C 1-6 alkyl, it includes any subset thereof, for example including C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, and methyl, ethyl base, n-propyl, isopropyl, n-butyl, etc.

在本发明合成式I化合物的方法中，反应所用的各种原材料是本领域技术人员根据已有知识可以制备得到的，或者是可以通过文献公知的方法制得的，或者是可以通过商业购得的。以上反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识可以作适当改变的。或者，本领域技术人员也可以根据本发明第二方面方法合成本发明未具体列举的其它式I化合物。In the method for synthesizing the compound of formula I of the present invention, various raw materials used in the reaction can be prepared according to prior knowledge by those skilled in the art, or can be prepared by methods known in the literature, or can be purchased commercially of. The intermediates, raw materials, reagents, and reaction conditions used in the above reaction schemes can be appropriately changed according to the existing knowledge of those skilled in the art. Alternatively, those skilled in the art can also synthesize other compounds of formula I not specifically listed in the present invention according to the method of the second aspect of the present invention.

本发明的式I化合物可以与其它活性成分组合使用，只要它不产生其他不利作用，例如过敏反应。The compound of the formula I according to the invention can be used in combination with other active ingredients, provided it does not produce other adverse effects, such as allergic reactions.

本发明式I所示的活性化合物可作为唯一的抗肿瘤/抗癌药物使用，或者可以与一种或多种其他抗菌药物联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。The active compound represented by formula I of the present invention can be used as the only antitumor/anticancer drug, or can be used in combination with one or more other antibacterial drugs. Combination therapy is achieved by simultaneous, sequential or spaced administration of the individual therapeutic components.

本文所用的术语“组合物”意指包括包含指定量的各指定成分的产品，以及直接或间接从指定量的各指定成分的组合产生的任何产品。在本发明中，术语“组合物”可以与“药物组合物”互换使用。As used herein, the term "composition" is meant to include a product comprising the specified amounts of each of the specified ingredients, as well as any product resulting, directly or indirectly, from the combination of the specified amounts of each of the specified ingredients. In the present invention, the term "composition" may be used interchangeably with "pharmaceutical composition".

本发明的化合物可以以衍生自无机酸或有机酸的药学可接受的盐的形式使用。词语“药学可接受的盐”指在可靠的医学判断范围内，适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等，且与合理的效果/风险比相称的盐。药学可接受的盐是本领域公知的。例如，S.M.Berge，et al.，J.Pharmaceutical Sciences，1977，66：1中对药学可接受的盐进行了详细描述。所述盐可通过使本发明化合物的游离碱官能度与合适的有机酸反应，在本发明化合物的最终分离和纯化过程中原位制备或者单独制备。代表性的酸加成盐包括但不限于乙酸盐、己二酸盐、海藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(异硫代硫酸盐，isothionate)、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一烷酸盐。同样，碱性含氮基团可用以下物质季铵化：低级烷基卤化物如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物；硫酸二烷基酯如硫酸二甲酯、二乙酯、二丁酯和二戊酯；长链卤化物如癸基、十二烷基、十四烷基和十八烷基的氯化物、溴化物和碘化物；芳基烷基卤化物如苄基溴和苯乙基溴及其他。因此得到可溶于或分散于水或油的产品。可用来形成药学可接受的酸加成盐的酸实例包括无机酸如盐酸、氢溴酸、硫酸和磷酸，以及有机酸如草酸、马来酸、琥珀酸和柠檬酸。The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salt" means, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and with a reasonable effect/risk ratio Matching salt. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in S.M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66:1. Said salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base functionality of the compounds of the invention with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate Salt, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodic acid salt, 2-hydroxyethanesulfonate (isothiosulfate, isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitic acid Salt, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamic acid salt, bicarbonate, p-toluenesulfonate and undecanoate. Likewise, basic nitrogen-containing groups can be quaternized with: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as disulfate Methyl, diethyl, dibutyl, and dipentyl esters; long-chain halides such as decyl, dodecyl, tetradecyl, and octadecyl chlorides, bromides, and iodides; aryl alkanes Halides such as benzyl bromide and phenethyl bromide and others. Products are thus obtained which are soluble or dispersible in water or oil. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.

碱加成盐可通过使本发明化合物的含羧酸部分与合适的碱反应，在本发明化合物的最终分离和纯化过程中原位制备，所述的碱例如药学可接受的金属阳离子的氢氧化物、碳酸盐和碳酸氢盐，或者氨或有机伯胺、仲胺或叔胺。Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the invention by reacting the carboxylic acid-containing moiety of the compounds of the invention with a suitable base, such as the hydroxide of a pharmaceutically acceptable metal cation. , carbonates and bicarbonates, or ammonia or organic primary, secondary or tertiary amines.

药学可接受的盐包括但不限于基于碱金属或碱土金属的阳离子如锂、钠、钾、钙、镁和铝盐等，以及无毒的季铵和胺阳离子，包括铵、四甲基铵、四乙基铵、甲基铵、二甲基铵、三甲基铵、三乙基铵、二乙基铵和乙基铵等。可用于形成碱加成盐的其他代表性有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶、哌嗪等。Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal based cations such as lithium, sodium, potassium, calcium, magnesium and aluminum salts, etc., as well as non-toxic quaternary ammonium and amine cations, including ammonium, tetramethylammonium, Tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium, etc. Other representative organic amines that can be used to form base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

本发明式I化合物还包括其异构体、消旋体、对映体、非对映体、对映体富集物、溶剂合物、和酯，本发明式I化合物以及它的异构体、消旋体、对映体、非对映体、对映体富集物、溶剂合物、和酯还可以形成溶剂合物，例如水合物、醇合物等。上述化合物还可以是前药或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。一般来说，对于本发明的目的，与药学可接受的溶剂如水、乙醇等的溶剂合物形式与非溶剂合物形式相当。The compound of formula I of the present invention also includes its isomers, racemates, enantiomers, diastereomers, enantiomeric enrichments, solvates, and esters, the compound of formula I of the present invention and its isomers , racemates, enantiomers, diastereomers, enantiomerically enriched substances, solvates, and esters may also form solvates such as hydrates, alcoholates, and the like. The above-mentioned compounds may also be prodrugs or forms that release the active ingredient after metabolic changes in the body. Selection and preparation of appropriate prodrug derivatives is within the skill of those skilled in the art. In general, solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like are equivalent to unsolvated forms for the purposes of the present invention.

本发明的一些示例性化合物的结构及其抗HepG2细胞增殖的活性列于下面，其中的抗增殖活性测定方法见试验例1。The structures of some exemplary compounds of the present invention and their anti-proliferation activity on HepG2 cells are listed below, and the anti-proliferation activity determination method is shown in Test Example 1.

  实施例号 Example number   化合物代号 Compound code   抑制率％ Inhibition rate%   实施例1 Example 1   A A   33.4±3.2a 33.4±3.2 a   实施例2 Example 2   A-30 A-30   50.0±3.1a 50.0±3.1 a   实施例3 Example 3   A-31 A-31   41.9±3.3a 41.9±3.3 a   实施例4 Example 4   A-32 A-32   62.6±1.8a 62.6±1.8 a   实施例5 Example 5   A-33 A-33   53.3±11.5a 53.3±11.5 a   实施例6 Example 6   A-43 A-43   50.7±11.7a 50.7±11.7 a   实施例7 Example 7   A-34 A-34   88.7±1.1a 88.7±1.1 a   实施例8 Example 8   A-35 A-35   86.6±2.4a 86.6±2.4 a   实施例9 Example 9   A-38 A-38   63.7±2.0a 63.7±2.0 a

  实施例10 Example 10   A-40 A-40   84.5±1.9a 84.5±1.9 a   实施例11 Example 11   A-39 A-39   70.3±2.6a 70.3±2.6 a   实施例12 Example 12   A-44 A-44   69.6±2.5a 69.6±2.5 a   实施例13 Example 13   A-45 A-45   50.9±4.3a 50.9±4.3 a   实施例14 Example 14   A-46 A-46   53.6±2.2a 53.6±2.2 a   实施例15 Example 15   A-56 A-56   88.6±10.8a 88.6±10.8 a   实施例16 Example 16   A-49 A-49   86.5±10.6a 86.5±10.6 a   实施例17 Example 17   A-55 A-55   93.7±16.1a 93.7±16.1 a   实施例18 Example 18   A-37 A-37   62.3±2.0a 62.3±2.0 a   实施例19 Example 19   A-58 A-58   92.5±11.4a 92.5±11.4 a   实施例20 Example 20   A-41 A-41   8.9±5.1a 8.9±5.1 a   实施例21 Example 21   A-42 A-42   56.2±2.0a 56.2±2.0 a   实施例22 Example 22   A-50 A-50   87.3±55.5a 87.3±55.5 a   实施例23 Example 23   A-53 A-53   87.6±9.8a 87.6±9.8 a   实施例24 Example 24   A-54 A-54   93.5±2.5a 93.5±2.5 a   实施例25 Example 25   A-61 A-61   86.5±10.6a 86.5±10.6 a   实施例26 Example 26   A-64 A-64   79.0±9.9a 79.0±9.9 a   实施例27 Example 27   A-67 A-67   70.5±2.5a 70.5±2.5 a   实施例28 Example 28   A-68 A-68   63.7±6.1a 63.7±6.1 a   实施例29 Example 29   A-69 A-69   88.6±9.1a 88.6±9.1 a   实施例30 Example 30   A-70 A-70   76.5±8.4a 76.5±8.4 a   实施例31 Example 31   A-71 A-71   58.6±5.3b 58.6± 5.3b   实施例32 Example 32   A-72 A-72   49.7±6.1b 49.7± 6.1b   实施例33 Example 33   A-73 A-73   58.0±5.6b 58.0± 5.6b   实施例34 Example 34   A-74 A-74   59.3±5.1b 59.3± 5.1b   实施例35 Example 35   A-75 A-75   57.6±3.6b 57.6± 3.6b   实施例36 Example 36   A-76 A-76   52.4±2.3b 52.4± 2.3b   实施例37 Example 37   A-77 A-77   52.8±4.1b 52.8± 4.1b   实施例38 Example 38   A-78 A-78   50.9±3.5b 50.9± 3.5b   实施例39 Example 39   A-79 A-79   48.5±4.3b 48.5± 4.3b   实施例40 Example 40   A-80 A-80   49.5±6.0b 49.5± 6.0b   实施例41 Example 41   A-81 A-81   57.3±3.6b 57.3± 3.6b   实施例42 Example 42   A-82 A-82   43.4±3.2b 43.4± 3.2b   实施例43 Example 43   A-83 A-83   56.6±1.2b 56.6± 1.2b   实施例44 Example 44   A-84 A-84   53.5±5.6b 53.5± 5.6b   实施例45 Example 45   A-85 A-85   60.6±1.2b 60.6± 1.2b   实施例46 Example 46   A-86 A-86   54.1±6.0b 54.1± 6.0b   实施例47 Example 47   A-87 A-87   13.0±1.3b 13.0± 1.3b   实施例48 Example 48   A-36 A-36   32.9±3.0a 32.9±3.0 a   实施例49 Example 49   A-60 A-60   5.4±0.9a 5.4±0.9 a   实施例50 Example 50   A-65 A-65   87.3±55.5a 87.3±55.5 a   实施例51 Example 51   A-66 A-66   87.6±9.8a 87.6±9.8 a

注a：0.6μg/mL  b：0.1μg/mLNote a: 0.6μg/mL b: 0.1μg/mL

可改变本发明药物组合物中各活性成分的实际剂量水平，以便所得的活性化合物量能有效针对具体患者、组合物和给药方式得到所需的治疗反应。剂量水平须根据具体化合物的活性、给药途径、所治疗病况的严重程度以及待治疗患者的病况和既往病史来选定。但是，本领域的做法是，化合物的剂量从低于为得到所需治疗效果而要求的水平开始，逐渐增加剂量，直到得到所需的效果。Actual dosage levels of each active ingredient in the pharmaceutical compositions of this invention will be varied so that the amount of active compound obtained is effective to obtain the desired therapeutic response in a particular patient, composition and mode of administration. Dosage levels will be selected based on the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is practice in the art to start doses of the compound at levels lower than that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained.

当用于上述治疗和/或预防或其他治疗和/或预防时，治疗和/或预防有效量的一种本发明化合物可以以纯形式应用，或者以药学可接受的酯或前药形式(在存在这些形式的情况下)应用。或者，所述化合物可以以含有该目的化合物与一种或多种药物可接受赋形剂的药物组合物给药。词语“治疗和/或预防有效量”的本发明化合物指以适用于任何医学治疗和/或预防的合理效果/风险比治疗障碍的足够量的化合物。但应认识到，本发明化合物和组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者，具体的治疗有效剂量水平须根据多种因素而定，所述因素包括所治疗的障碍和该障碍的严重程度；所采用的具体化合物的活性；所采用的具体组合物；患者的年龄、体重、一般健康状况、性别和饮食；所采用的具体化合物的给药时间、给药途径和排泄率；治疗持续时间；与所采用的具体化合物组合使用或同时使用的药物；及医疗领域公知的类似因素。例如，本领域的做法是，化合物的剂量从低于为得到所需治疗效果而要求的水平开始，逐渐增加剂量，直到得到所需的效果。一般说来，本发明式I化合物用于哺乳动物特别是人的剂量可以介于0.001～1000mg/kg体重/天，例如介于0.01～100mg/kg体重/天，例如介于0.01～10mg/kg体重/天。When used for the above treatment and/or prophylaxis or other treatment and/or prophylaxis, a therapeutically and/or prophylactically effective amount of a compound of the present invention may be used in pure form, or in the form of a pharmaceutically acceptable ester or prodrug (in the presence of In case of these forms) apply. Alternatively, the compound may be administered as a pharmaceutical composition comprising the compound of interest together with one or more pharmaceutically acceptable excipients. The phrase "therapeutically and/or prophylactically effective amount" of a compound of the invention refers to a sufficient amount of the compound to treat a disorder with a reasonable effect/risk ratio applicable to any medical treatment and/or prophylaxis. It should be recognized, however, that the total daily dosage of the compounds and compositions of the present invention must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the particular therapeutically effective dosage level will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; The age, weight, general health, sex and diet of the patient; the timing, route of administration, and rate of excretion of the specific compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and Similar factors are well known in the medical arts. For example, it is practice in the art to start doses of the compound at levels lower than that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained. Generally speaking, the dose of the compound of formula I of the present invention for mammals, especially humans, can be 0.001-1000 mg/kg body weight/day, for example, 0.01-100 mg/kg body weight/day, for example, 0.01-10 mg/kg body weight/day.

运用本领域技术人员熟悉的药物载体可以制备成含有效剂量的本发明化合物的药物组合物。因此本发明还提供包含与一种或多种无毒药物可接受载体配制在一起的本发明化合物的药物组合物。所述药物组合物可特别专门配制成以固体或液体形式供口服给药、供胃肠外注射或供直肠给药。Pharmaceutical compositions containing effective doses of the compounds of the present invention can be prepared using pharmaceutical carriers familiar to those skilled in the art. The present invention thus also provides pharmaceutical compositions comprising a compound of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be particularly specially formulated for oral administration, for parenteral injection or for rectal administration in solid or liquid form.

所述的药物组合物可配制成许多剂型，便于给药，例如，口服制剂(如片剂、胶囊剂、溶液或混悬液)；可注射的制剂(如可注射的溶液或混悬液，或者是可注射的干燥粉末，在注射前加入注射水可立即使用)。所述的药物组合物中载体包括：口服制剂使用的粘合剂(如淀粉，通常是玉米、小麦或米淀粉、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮)，稀释剂(如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素，和/或甘油)，润滑剂(如二氧化硅、滑石、硬脂酸或其盐，通常是硬脂酸镁或硬脂酸钙，和/或聚乙二醇)，以及如果需要，还含有崩解剂，如淀粉、琼脂、海藻酸或其盐，通常是藻酸钠，和/或泡腾混合物，助溶剂、稳定剂、悬浮剂、无色素、矫味剂等，可注射的制剂使用的防腐剂、加溶剂、稳定剂等；局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下是不稳定的，可以将其配制成肠衣片剂。Described pharmaceutical composition can be formulated into many dosage forms, convenient administration, for example, oral preparation (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, Or it is an injectable dry powder, which can be used immediately by adding water for injection before injection). Carriers in the pharmaceutical composition include: binders for oral preparations (such as starch, usually corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone) , diluents (such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycerin), lubricants (such as silicon dioxide, talc, stearic acid or its salts, usually stearic acid magnesium or calcium stearate, and/or polyethylene glycol), and if desired, disintegrants such as starch, agar, alginic acid or its salts, usually sodium alginate, and/or effervescent mixtures, Solubilizers, stabilizers, suspending agents, colorants, flavoring agents, etc., preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations. Pharmaceutical preparations can be administered orally or parenterally (eg intravenously, subcutaneously, intraperitoneally or topically), and if certain drugs are unstable under gastric conditions, they can be formulated as enteric-coated tablets.

更具体地说，本发明的药物组合物可通过口服、直肠、胃肠外、池内、阴道内、腹膜内、局部(如通过散剂、软膏剂或滴剂)、口颊给予人类和其他哺乳动物，或者作为口腔喷雾剂或鼻腔喷雾剂给予。本文所用术语“胃肠外”指包括静脉内、肌肉内、腹膜内、胸骨内、皮下和关节内注射和输液的给药方式。More specifically, the pharmaceutical compositions of the present invention may be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as by powder, ointment or drops), buccal , or given as an oral or nasal spray. The term "parenteral" as used herein refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

适合于胃肠外注射的组合物可包括生理上可接受的无菌含水或非水溶液剂、分散剂、混悬剂或乳剂，及供重构成无菌可注射溶液剂或分散剂的无菌散剂。合适的含水或非水载体、稀释剂、溶剂或媒介物的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、植物油(如橄榄油)、可注射有机酯如油酸乙酯及它们的合适混合物。Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. . Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (such as olive oil), injectable organic esters such as oleic acid Ethyl esters and suitable mixtures thereof.

这些组合物也可含有辅料，如防腐剂、湿润剂、乳化剂和分散剂。通过各种抗细菌剂和抗真菌剂，例如尼泊金酯类、三氯叔丁醇、苯酚、山梨酸等，可确保防止微生物的作用。还期望包括等渗剂，例如糖类、氯化钠等。通过使用能延迟吸收的物质，例如单硬脂酸铝和明胶，可达到可注射药物形式的延长吸收。These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms is ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. It is also desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical forms can be brought about by the use of substances which delay absorption, for example, aluminum monostearate and gelatin.

混悬剂中除活性化合物外还可含有悬浮剂，例如乙氧基化异十八醇、聚氧乙烯山梨醇和聚氧乙烯失水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶或者这些物质的混合物等。Suspensions may contain, in addition to the active compounds, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite , agar and tragacanth gum or a mixture of these substances, etc.

在一些情况下，为延长药物的作用，期望减慢皮下或肌内注射药物的吸收。这可通过使用水溶性差的晶体或无定形物质的液体混悬剂来实现。这样，药物的吸收速度取决于其溶解速度，而溶解速度又可取决于晶体大小和晶型。或者，胃肠外给药的药物形式的延迟吸收通过将该药物溶解于或悬浮于油媒介物中来实现。In some instances, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug injected subcutaneously or intramuscularly. This can be achieved by the use of liquid suspensions of poorly water soluble crystalline or amorphous materials. Thus, the rate of absorption of the drug depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

可注射贮库制剂形式可通过在生物可降解聚合物如聚丙交酯-聚乙交酯(polylactide-polyglycolide)中形成药物的微胶囊基质来制备。可根据药物与聚合物之比和所采用的具体聚合物的性质，对药物释放速度加以控制。其他生物可降解聚合物的实例包括聚原酸酯类(poly(orthoesters))和聚酐类(poly(anhydrides))。可注射贮库制剂也可通过将药物包埋于能与身体组织相容的脂质体或微乳中来制备。Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

可注射制剂可例如通过用滤菌器过滤或通过掺入无菌固体组合物形式的灭菌剂来灭菌，所述固体组合物可在临用前溶解或分散于无菌水或其他无菌可注射介质。Injectable preparations can be sterilized, for example, by filtration through a sterile filter or by incorporating a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile Injectable medium.

本发明化合物或其组合物可用口服方法或非胃肠道给药方式。口服给药可以是片剂、胶囊剂、包衣剂，肠道外用药制剂有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟悉的方法制备的。为了制造片剂、胶囊剂、包衣剂所用的辅料是常规用的辅料，例如淀粉、明胶、阿拉伯胶，硅石，聚乙二醇，液体剂型所用的溶剂如水、乙醇、丙二醇、植物油(如玉米油、花生油、橄榄油等)。含有本发明化合物的制剂中还有其它辅料，例如表面活性剂，润滑剂，崩解剂，防腐剂，矫味剂和色素等。在片剂、胶囊剂、包衣剂、注射剂和栓剂中含有本发明式I化合物的剂量是以单元剂型中存在的化合物量计算的。在单元剂型中本发明式I化合物一般含量为0.01-5000mg，优选的单元剂型含有0.1-500mg，更优选的单元剂型含有1-300mg。具体地说，本发明可以提供的供口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在此类固体剂型中，活性化合物可与至少一种惰性的药物可接受赋形剂或载体如柠檬酸钠或磷酸二钙和/或以下物质混合：a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸；b)粘合剂如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯树胶；c)保湿剂如甘油；d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠；e)溶液阻滞剂如石蜡；f)吸收加速剂如季铵化合物；g)湿润剂如鲸蜡醇和甘油单硬脂酸酯；h)吸附剂如高岭土和膨润土以及i)润滑剂如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠和它们的混合物。在胶囊剂、片剂和丸剂的情况下，所述剂型中也可包含缓冲剂。The compound of the present invention or its composition can be administered orally or parenterally. Oral administration can be in the form of tablets, capsules, coated agents, and parenteral preparations include injections and suppositories. These formulations are prepared according to methods familiar to those skilled in the art. The used adjuvant for making tablet, capsule, coating agent is conventional adjuvant, such as starch, gelatin, gum arabic, silica, polyethylene glycol, the used solvent of liquid dosage form such as water, ethanol, propylene glycol, vegetable oil (such as corn oil, peanut oil, olive oil, etc.). There are other auxiliary materials in the preparation containing the compound of the present invention, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents and pigments. Dosages containing compounds of formula I of this invention in tablets, capsules, coatings, injections and suppositories are based on the amount of compound present in the unit dosage form. The general content of the compound of formula I of the present invention in the unit dosage form is 0.01-5000mg, preferably the unit dosage form contains 0.1-500mg, more preferably the unit dosage form contains 1-300mg. Specifically, the solid dosage forms for oral administration provided by the present invention include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound can be admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or the following: a) fillers or bulking agents such as starch, Lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants such as glycerin; d) disintegration e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as spermaceti alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and their mixture. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

相似类型的固体组合物使用赋形剂例如乳糖及高分子量聚乙二醇等，也可用作软胶囊和硬胶囊中的填充物。Solid compositions of a similar type, using excipients such as lactose and high molecular weight polyethylene glycol, etc., can also be used as fillers in soft and hard capsules.

片剂、糖衣丸剂(dragees)、胶囊剂、丸剂和颗粒剂的固体剂型可与包衣和壳料如肠溶衣材和医药制剂领域公知的其他衣材一起制备。这些固体剂型可任选含有遮光剂，且其组成还可使其只是或优先地在肠道的某个部位任选以延迟方式释放活性成分。可以使用的包埋组合物的实例包括高分子物质和蜡类。如果适合，活性化合物也可与一种或多种上述赋形剂配成微囊形式。The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and others well known in the pharmaceutical formulating art. These solid dosage forms may optionally contain opacifying agents and may also be so constituted that they release the active ingredients only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

供口服给药的液体剂型包括药学可接受的乳剂、溶液剂、混悬剂、糖浆剂和酏剂。液体剂型除含有活性化合物外还可含有本领域常用的惰性稀释剂，例如水或其他溶剂，增溶剂和乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1，3-丁二醇、二甲基甲酰胺、油类(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇(tetrahydrofurfuryl alcohol)、聚乙二醇和脱水山梨糖醇的脂肪酸酯及它们的混合物。口服组合物除包含惰性稀释剂外还可包含辅料，例如湿润剂、乳化剂和悬浮剂、甜味剂、矫味剂和香味剂。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain, in addition to the active compound, inert diluents customary in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate Esters, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol alcohol), fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof. Oral compositions can include adjuvants, besides inert diluents, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

供直肠或阴道给药的组合物优选是栓剂。栓剂可通过将本发明化合物与合适的非刺激性赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡混合来制备，它们在室温下为固体，但在体温下则为液体，因此可在直肠腔或阴道腔内熔化而释放出活性化合物。Compositions for rectal or vaginal administration are preferably suppositories. Suppositories can be prepared by mixing the compound of the invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at room temperature but liquid at body temperature and therefore Melts in the rectal or vaginal cavity to release the active compound.

本发明的化合物及其组合物还考虑用于局部给药。供局部给予本发明化合物的剂量形式包括散剂、喷雾剂、软膏剂和吸入剂。在无菌条件下将活性化合物与药学可接受的载体和任何所需的防腐剂、缓冲剂或推进剂混合。眼用制剂、眼软膏剂、散剂和溶液剂也被考虑在本发明范围内。The compounds of the invention and compositions thereof are also contemplated for topical administration. Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers or propellants. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

本发明化合物也可以脂质体形式给药。如本领域所公知，脂质体通常用磷脂或其他脂类物质制得。脂质体由分散于含水介质中的单层或多层水化液晶所形成。任何能够形成脂质体的无毒、生理上可接受和可代谢的脂质均可使用。脂质体形式的本发明组合物除含有本发明化合物外，还可含有稳定剂、防腐剂、赋形剂等。优选的脂类是天然和合成的磷脂和磷脂酰胆碱(卵磷脂)，它们可单独或者一起使用。形成脂质体的方法是本领域公知的。参见例如Prescott，Ed.，Methods in Cell Biology，Volume XIV，Academic Press，New York，N.Y.(1976)，p.33。The compounds of the invention can also be administered in liposome form. Liposomes are generally prepared using phospholipids or other lipid substances, as is known in the art. Liposomes are formed from monolamellar or multilamellar hydrated liquid crystals dispersed in an aqueous medium. Any nontoxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), either alone or together. Methods of forming liposomes are well known in the art. See, eg, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.33.

本发明人惊奇地发现，结构式I所示的环化小檗碱衍生物对HepG2细胞的增殖产生了明显的抑制作用。因此，本发明的化合物可用于治疗和/或预防哺乳动物(包括人)肿瘤或癌症性疾病(例如肝癌)。The present inventors surprisingly found that the cyclized berberine derivatives represented by structural formula I had obvious inhibitory effect on the proliferation of HepG2 cells. Accordingly, the compounds of the present invention are useful in the treatment and/or prevention of neoplastic or cancerous diseases (eg liver cancer) in mammals (including humans).

附图说明 Description of drawings

图1描绘了本发明化合物对耐药肿瘤细胞的活性测定结果。Figure 1 depicts the results of assaying the activity of compounds of the present invention on drug-resistant tumor cells.

图2描绘了本发明化合物的细胞周期分析测定结果。Figure 2 depicts the results of a cell cycle analysis assay for compounds of the invention.

图3描绘了本发明化合物对拓扑异构酶I的抑制活性测定结果。Figure 3 depicts the results of the assay of the inhibitory activity of the compounds of the present invention on topoisomerase I.

具体实施方式 Detailed ways

下面通过具体的制备实施例和生物学试验例进一步说明本发明，但是，应当理解为，这些实施例和试验例仅仅是用于更详细具体地说明之用，而不应理解为用于以任何形式限制本发明。The present invention is further illustrated by specific preparation examples and biological test examples below, but it should be understood that these examples and test examples are only used for more detailed descriptions, and should not be interpreted as being used for any purpose. Form limits the invention.

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。本领域技术人员清楚，在下文中，如果未特别说明，本发明所用材料和操作方法是本领域公知的。The present invention provides general and/or specific descriptions of the materials and test methods used in the tests. While many of the materials and methods of manipulation which are employed for the purposes of the invention are well known in the art, the invention has been described here in as much detail as possible. It will be clear to those skilled in the art that in the following, unless otherwise specified, the materials and operation methods used in the present invention are well known in the art.

实施例1：化合物A的合成Embodiment 1: the synthesis of compound A

将溶有硼氢化钠(1.2g，32mmol)的5％氢氧化钠溶液(10ml)逐滴加入至含小檗碱(7.4g，20mmol)和碳酸钾(8.3g，60mmol)的甲醇(250ml)溶液体系中，室温搅拌2小时，抽滤收集析出的黄绿色固体，滤饼依次用蒸馏水(100ml)和80％乙醇(100ml)洗涤，得到中间体二氢小檗碱(4.2g，62％)。将中间体二氢小檗碱(4.0g，12mmol)溶解在乙腈(160ml)中，然后加入乙酸(40ml)和40％的乙二醛(2ml)，加热至85～95℃回流5小时，板层监测反应完全，将反应液浓缩，得到深红色油状物，加入2％盐酸溶液(200ml)，室温搅拌1小时，过滤，滤液室温搅拌5天，将反应液浓缩，用95％乙醇重结晶，所得产物用乙醚洗涤，得橙色固体A(1.8g，38％)，熔点：185～187℃。Sodium borohydride (1.2 g, 32 mmol) in 5% sodium hydroxide solution (10 ml) was added dropwise to methanol (250 ml) containing berberine (7.4 g, 20 mmol) and potassium carbonate (8.3 g, 60 mmol) In the solution system, stir at room temperature for 2 hours, collect the precipitated yellow-green solid by suction filtration, and wash the filter cake with distilled water (100ml) and 80% ethanol (100ml) successively to obtain the intermediate dihydroberberine (4.2g, 62%) . The intermediate dihydroberberine (4.0g, 12mmol) was dissolved in acetonitrile (160ml), then acetic acid (40ml) and 40% glyoxal (2ml) were added, heated to 85-95°C and refluxed for 5 hours, plate Layer monitoring reaction was complete, the reaction solution was concentrated to obtain dark red oily matter, added 2% hydrochloric acid solution (200ml), stirred at room temperature for 1 hour, filtered, the filtrate was stirred at room temperature for 5 days, the reaction solution was concentrated, recrystallized with 95% ethanol, The obtained product was washed with diethyl ether to obtain orange solid A (1.8 g, 38%), melting point: 185-187°C.

HRMS-ESI(M/Z)：360.1216【M-Cl】+ HRMS-ESI(M/Z): 360.1216【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.8Hz，2H)，4.12(s，3H)，4.16(s，3H)，5.24(t，J＝6.8Hz，2H)，6.39(s，2H)，7.59(s，1H)，8.21(d，J＝9.2Hz，1H)，8.31(d，J＝9.6Hz，1H)，8.85(d，J＝9.6Hz，1H)，8.89(d，J＝9.2Hz，1H)，10.14(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.8Hz, 2H), 4.12(s, 3H), 4.16(s, 3H), 5.24(t, J=6.8Hz, 2H ), 6.39(s, 2H), 7.59(s, 1H), 8.21(d, J=9.2Hz, 1H), 8.31(d, J=9.6Hz, 1H), 8.85(d, J=9.6Hz, 1H ), 8.89(d, J=9.2Hz, 1H), 10.14(s, 1H).

实施例2：化合物A-30的合成Embodiment 2: the synthesis of compound A-30

将A(3.6g，9.1mmol)置于250ml圆底烧瓶中，保持真空度为30～40mmHg，加热至195～210℃反应30分钟，固体颜色逐渐加深，最后全部变为深红色，盐酸乙醇(5ml∶95ml)酸化得到红色产物A-30(3.2g，92％)，熔点：269～271℃。Put A (3.6g, 9.1mmol) in a 250ml round-bottomed flask, keep the vacuum at 30-40mmHg, heat to 195-210°C for 30 minutes, the color of the solid gradually deepens, and finally all become dark red, ethanol hydrochloride ( 5ml:95ml) was acidified to give the red product A-30 (3.2g, 92%), melting point: 269-271°C.

HRMS-ESI(M/Z)：346.1069【M-Cl】+ HRMS-ESI(M/Z): 346.1069【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.56(t，J＝6.8Hz，2H)，4.03(s，3H)，5.10(t，J＝6.8Hz，2H)，6.36(s，2H)，7.52(s，1H)，8.02(d，J＝8.8Hz，1H)，8.10(d，J＝9.2Hz，1H)，8.26(d，J＝8.4Hz，1H)，8.75(d，J＝9.2Hz，1H)，9.96(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.56(t, J=6.8Hz, 2H), 4.03(s, 3H), 5.10(t, J=6.8Hz, 2H), 6.36(s, 2H ), 7.52(s, 1H), 8.02(d, J=8.8Hz, 1H), 8.10(d, J=9.2Hz, 1H), 8.26(d, J=8.4Hz, 1H), 8.75(d, J =9.2Hz, 1H), 9.96(s, 1H).

实施例3：化合物A-31的合成Embodiment 3: the synthesis of compound A-31

将A-30(198mg，0.52mmol)溶于DMF(10ml)，然后加入研细的氢氧化钾(60mg，1.04mmol)和溴乙烷(2ml，27mmol)，加热至60℃反应12小时，减压浓缩除去溶剂，残余物用稀盐酸调PH至3，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-31(52mg，22％)，熔点：216～218℃。A-30 (198mg, 0.52mmol) was dissolved in DMF (10ml), then finely ground potassium hydroxide (60mg, 1.04mmol) and ethyl bromide (2ml, 27mmol) were added, heated to 60°C for 12 hours, and then Concentrate under reduced pressure to remove the solvent, adjust the pH of the residue to 3 with dilute hydrochloric acid, collect the precipitated solid by suction filtration, use dichloromethane/methanol as the mobile phase, and separate and purify with a vacuum silica gel column to obtain the red product A-31 (52mg, 22 %), melting point: 216-218°C.

HRMS-ESI(M/Z)：374.1397【M-Br】+ HRMS-ESI(M/Z): 374.1397【M-Br】 +

1H NMR(CD3SOCD3，400MHz)：δ1.49(t，J＝7.2Hz，3H)，3.62(t，J＝6.8Hz，2H)，4.10(s，3H)，4.44(q，J＝7.2Hz，2H)，5.26(t，J＝6.8Hz，2H)，6.39(s，2H)，7.58(s，1H)，8.20(d，J＝9.2Hz，1H)，8.29(d，J＝9.2Hz，1H)，8.83(d，J＝9.2Hz，1H)，8.88(d，J＝9.2Hz，1H)，10.05(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ1.49(t, J=7.2Hz, 3H), 3.62(t, J=6.8Hz, 2H), 4.10(s, 3H), 4.44(q, J =7.2Hz, 2H), 5.26(t, J=6.8Hz, 2H), 6.39(s, 2H), 7.58(s, 1H), 8.20(d, J=9.2Hz, 1H), 8.29(d, J =9.2Hz, 1H), 8.83(d, J=9.2Hz, 1H), 8.88(d, J=9.2Hz, 1H), 10.05(s, 1H).

实施例4：化合物A-32的合成Embodiment 4: the synthesis of compound A-32

将A-30(198mg，0.52mmol)溶于DMF(10ml)，然后加入研细的氢氧化钾(60mg，1.04mmol)和1-碘丁烷(236μl，2.08mmol)，加热至60℃反应12小时，减压浓缩除去溶剂，残余物用稀盐酸调PH至3，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-32(75mg，27％)，熔点：202～204℃。A-30 (198mg, 0.52mmol) was dissolved in DMF (10ml), then finely ground potassium hydroxide (60mg, 1.04mmol) and 1-iodobutane (236μl, 2.08mmol) were added, heated to 60°C for reaction 12 Hours, concentrated under reduced pressure to remove the solvent, the residue was adjusted to PH to 3 with dilute hydrochloric acid, the precipitated solid was collected by suction filtration, and the mobile phase was separated and purified with a decompressed silica gel column with dichloromethane/methanol to obtain the red product A-32 ( 75mg, 27%), melting point: 202-204°C.

HRMS-ESI(M/Z)：402.1702【M-I】+ HRMS-ESI(M/Z): 402.1702【MI】 +

1H NMR(CD3SOCD3，400MHz)：δ1.00(t，J＝7.2Hz，3H)，1.51-1.57(m，2H)，1.87-1.94(m，2H)，3.62(t，J＝6.8Hz，2H)，4.10(s，3H)，4.37(t，J＝6.8Hz，2H)，5.25(t，J＝6.8Hz，2H)，6.40(s，2H)，7.59(s，1H)，8.22(d，J＝9.2Hz，1H)，8.30(d，J＝9.2Hz，1H)，8.84(d，J＝9.2Hz，1H)，8.89(d，J＝9.2Hz，1H)，9.98(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ1.00(t, J=7.2Hz, 3H), 1.51-1.57(m, 2H), 1.87-1.94(m, 2H), 3.62(t, J= 6.8Hz, 2H), 4.10(s, 3H), 4.37(t, J=6.8Hz, 2H), 5.25(t, J=6.8Hz, 2H), 6.40(s, 2H), 7.59(s, 1H) , 8.22(d, J=9.2Hz, 1H), 8.30(d, J=9.2Hz, 1H), 8.84(d, J=9.2Hz, 1H), 8.89(d, J=9.2Hz, 1H), 9.98 (s, 1H).

实施例5：化合物A-33的合成Embodiment 5: the synthesis of compound A-33

将A-30(99mg，0.26mmol)溶于DMF(5ml)，然后加入研细的氢氧化钾(30mg，0.52mmol)和溴化苄(124μl，1.04mmol)，加热至60℃反应12小时，减压浓缩除去溶剂，残余物用稀盐酸调PH至3，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到橙色产物A-33(81mg，60％)，熔点：131～133℃。A-30 (99mg, 0.26mmol) was dissolved in DMF (5ml), then finely ground potassium hydroxide (30mg, 0.52mmol) and benzyl bromide (124μl, 1.04mmol) were added, heated to 60°C for 12 hours, Concentrate under reduced pressure to remove the solvent, adjust the pH of the residue to 3 with dilute hydrochloric acid, collect the precipitated solid by suction filtration, use dichloromethane/methanol as the mobile phase, and separate and purify with a vacuum silica gel column to obtain the orange product A-33 (81 mg, 60%), melting point: 131-133°C.

HRMS-ESI(M/Z)：436.1562【M-Br】+ HRMS-ESI(M/Z): 436.1562【M-Br】 +

1H NMR(CD3SOCD3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，4.14(s，3H)，5.22(t，J＝6.8Hz，2H)，5.43(s，2H)，6.39(s，2H)，7.35-7.43(m，3H)，7.59(s，1H)，7.62(d，J＝6.8Hz，2H)，8.21(d，J＝9.2Hz，1H)，8.32(d，J＝9.6Hz，1H)，8.86(t，J＝9.2Hz，2H)，9.98(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.61(t, J=6.8Hz, 2H), 4.14(s, 3H), 5.22(t, J=6.8Hz, 2H), 5.43(s, 2H ), 6.39(s, 2H), 7.35-7.43(m, 3H), 7.59(s, 1H), 7.62(d, J=6.8Hz, 2H), 8.21(d, J=9.2Hz, 1H), 8.32 (d, J=9.6Hz, 1H), 8.86(t, J=9.2Hz, 2H), 9.98(s, 1H).

实施例6：化合物A-43的合成Embodiment 6: the synthesis of compound A-43

将A-30(99mg，0.26mmol)溶于DMF(5ml)，然后加入研细的氢氧化钾(30mg，0.52mmol)和2，4-二氟溴苄(134μl，1.04mmol)，加热至60℃反应12小时，减压浓缩除去溶剂，残余物用稀盐酸调PH至3，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-43(79mg，55％)，熔点：138～140℃。Dissolve A-30 (99mg, 0.26mmol) in DMF (5ml), then add finely ground potassium hydroxide (30mg, 0.52mmol) and 2,4-difluorobenzyl bromide (134μl, 1.04mmol), heat to 60 React at ℃ for 12 hours, concentrate under reduced pressure to remove the solvent, adjust the pH of the residue to 3 with dilute hydrochloric acid, collect the precipitated solid by suction filtration, use dichloromethane/methanol as the mobile phase, and separate and purify with a vacuum silica gel column to obtain the red product A -43 (79mg, 55%), melting point: 138-140°C.

HRMS-ESI(M/Z)：472.1347【M-Br】+ HRMS-ESI(M/Z): 472.1347【M-Br】 +

1H NMR(CD3SOCD3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，4.11(s，3H)，5.22(t，J＝6.8Hz，2H)，5.47(s，2H)，6.40(s，2H)，7.14-7.19(m，1H)，7.28-7.33(m，1H)，7.60(s，1H)，7.81(q，J＝8.4Hz，1H)，8.22(d，J＝9.2Hz，1H)，8.33(d，J＝9.6Hz，1H)，8.88(d，J＝4.4Hz，1H)，8.90(d，J＝4.0Hz，1H)，9.93(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.61(t, J=6.8Hz, 2H), 4.11(s, 3H), 5.22(t, J=6.8Hz, 2H), 5.47(s, 2H ), 6.40(s, 2H), 7.14-7.19(m, 1H), 7.28-7.33(m, 1H), 7.60(s, 1H), 7.81(q, J=8.4Hz, 1H), 8.22(d, J=9.2Hz, 1H), 8.33(d, J=9.6Hz, 1H), 8.88(d, J=4.4Hz, 1H), 8.90(d, J=4.0Hz, 1H), 9.93(s, 1H) .

实施例7：化合物A-34的合成Embodiment 7: the synthesis of compound A-34

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入乙酰氯(74μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-34(70mg，64％)，熔点：183～185℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add acetyl chloride (74μl, 1.04mmol), and continue to reflux After 6 hours, the lamellar monitoring reaction was complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-34 (70mg, 64%), melting point: 183-185°C.

HRMS-ESI(M/Z)：388.1188【M-Cl】+ HRMS-ESI(M/Z): 388.1188【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ2.56(s，3H)，3.64(t，J＝6.8Hz，2H)，4.09(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.2Hz，1H)，10.15(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ2.56(s, 3H), 3.64(t, J=6.8Hz, 2H), 4.09(s, 3H), 5.24(t, J=6.8Hz, 2H ), 6.41(s, 2H), 7.61(s, 1H), 8.26(d, J=9.2Hz, 1H), 8.40(d, J=9.2Hz, 1H), 8.95(d, J=9.2Hz, 1H ), 9.09(d, J=9.2Hz, 1H), 10.15(s, 1H).

实施例8：化合物A-35的合成Embodiment 8: the synthesis of compound A-35

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入苯甲酰氯(120μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到橙色产物A-35(84mg，67％)，熔点：228～230℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add benzoyl chloride (120μl, 1.04mmol), continue Reflux for 6 hours, and the plate layer monitors that the reaction is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as mobile phase to obtain the orange product A-35 (84mg, 67%), melting point: 228-230°C.

HRMS-ESI(M/Z)：450.1336【M-Cl】+ HRMS-ESI(M/Z): 450.1336【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，4.07(s，3H)，5.22(t，J＝6.8Hz，2H)，6.41(s，2H)，7.60(s，1H)，7.71(t，J＝7.6Hz，2H)，7.86(t，J＝7.6Hz，1H)，8.26-8.31(m，3H)，8.46(d，J＝9.6Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.15(d，J＝9.2Hz，1H)，10.24(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.61(t, J=6.8Hz, 2H), 4.07(s, 3H), 5.22(t, J=6.8Hz, 2H), 6.41(s, 2H ), 7.60(s, 1H), 7.71(t, J=7.6Hz, 2H), 7.86(t, J=7.6Hz, 1H), 8.26-8.31(m, 3H), 8.46(d, J=9.6Hz , 1H), 8.98(d, J=9.6Hz, 1H), 9.15(d, J=9.2Hz, 1H), 10.24(s, 1H).

实施例9：化合物A-38的合成Embodiment 9: the synthesis of compound A-38

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入对甲基苯甲酰氯(139μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-38(53mg，41％)，熔点：221～223℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add p-toluyl chloride (139μl, 1.04mmol ), continue to reflux for 6 hours, and the plate layer monitors that the reaction is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-38 (53mg, 41%), melting point: 221-223°C.

HRMS-ESI(M/Z)：464.1489【M-Cl】+ HRMS-ESI(M/Z): 464.1489【M-Cl】 +

1H NMR(CD3OD，400MHz)：δ2.47(s，3H)，3.60(t，J＝6.8Hz，2H)，4.06(s，3H)，5.17(t，J＝6.8Hz，2H)，6.29(s，2H)，7.40(s，1H)，7.43(d，J＝8.0Hz，2H)，8.19(d，J＝8.0Hz，2H)，8.27(d，J＝9.6Hz，1H)，8.32(d，J＝9.6Hz，1H)，8.76(d，J＝9.2Hz，1H)，8.96(d，J＝9.2Hz，1H)，9.89(s，1H). 1 H NMR (CD 3 OD, 400MHz): δ2.47(s, 3H), 3.60(t, J=6.8Hz, 2H), 4.06(s, 3H), 5.17(t, J=6.8Hz, 2H) , 6.29(s, 2H), 7.40(s, 1H), 7.43(d, J=8.0Hz, 2H), 8.19(d, J=8.0Hz, 2H), 8.27(d, J=9.6Hz, 1H) , 8.32(d, J=9.6Hz, 1H), 8.76(d, J=9.2Hz, 1H), 8.96(d, J=9.2Hz, 1H), 9.89(s, 1H).

实施例10：化合物A-40的合成Embodiment 10: the synthesis of compound A-40

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入对甲氧基苯甲酰氯(141μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到橙色产物A-40(69mg，51％)，熔点：202～204℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add p-methoxybenzoyl chloride (141μl, 1.04 mmol), continued to reflux for 6 hours, and the plate layer monitoring reaction was complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the orange product A-40 (69 mg, 51%), melting point: 202-204°C.

HRMS-ESI(M/Z)：480.1442【M-Cl】+ HRMS-ESI(M/Z): 480.1442【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，3.92(s，3H)，4.06(s，3H)，5.22(t，J＝6.8Hz，2H)，6.41(s，2H)，7.22(d，J＝8.8Hz，2H)，7.59(s，1H)，8.24(d，J＝8.8Hz，2H)，8.27(d，J＝9.6Hz，1H)，8.44(d，J＝9.2Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.20(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.61(t, J=6.8Hz, 2H), 3.92(s, 3H), 4.06(s, 3H), 5.22(t, J=6.8Hz, 2H ), 6.41(s, 2H), 7.22(d, J=8.8Hz, 2H), 7.59(s, 1H), 8.24(d, J=8.8Hz, 2H), 8.27(d, J=9.6Hz, 1H ), 8.44(d, J=9.2Hz, 1H), 8.98(d, J=9.6Hz, 1H), 9.13(d, J=9.6Hz, 1H), 10.20(s, 1H).

实施例11：化合物A-39的合成Embodiment 11: the synthesis of compound A-39

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入对氟苯甲酰氯(123μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到橙色产物A-39(40mg，31％)，熔点：218～220℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add p-fluorobenzoyl chloride (123μl, 1.04mmol) , continue to reflux for 6 hours, and the plate layer monitors that the reaction is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the orange product A-39 (40mg, 31%), melting point: 218-220°C.

HRMS-ESI(M/Z)：468.1256【M-Cl】+ HRMS-ESI(M/Z): 468.1256【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.08(s，3H)，5.21(t，J＝6.4Hz，2H)，6.41(s，2H)，7.56(t，J＝8.8Hz，2H)，7.60(s，1H)，8.28(d，J＝9.2Hz，1H)，8.35-8.39(m，2H)，8.46(d，J＝9.6Hz，1H)，8.99(d，J＝9.2Hz，1H)，9.16(d，J＝9.6Hz，1H)，10.24(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.61(t, J=6.4Hz, 2H), 4.08(s, 3H), 5.21(t, J=6.4Hz, 2H), 6.41(s, 2H ), 7.56(t, J=8.8Hz, 2H), 7.60(s, 1H), 8.28(d, J=9.2Hz, 1H), 8.35-8.39(m, 2H), 8.46(d, J=9.6Hz , 1H), 8.99(d, J=9.2Hz, 1H), 9.16(d, J=9.6Hz, 1H), 10.24(s, 1H).

实施例12：化合物A-44的合成Embodiment 12: the synthesis of compound A-44

将4-氟-3-硝基苯甲酸(193mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-44(35mg，25％)，熔点：187～189℃。4-Fluoro-3-nitrobenzoic acid (193 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-44 (35mg, 25%), melting point: 187-189°C.

HRMS-ESI(M/Z)：513.1083【M-Cl】+ HRMS-ESI(M/Z): 513.1083【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.09(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，7.93-7.98(m，1H)，8.29(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.67-8.68(m，1H)，8.94(dd，J＝2.0，7.2Hz，1H)，8.99(d，J＝9.2Hz，1H)，9.18(d，J＝9.6Hz，1H)，10.29(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.4Hz, 2H), 4.09(s, 3H), 5.20(t, J=6.4Hz, 2H), 6.41(s, 2H ), 7.61(s, 1H), 7.93-7.98(m, 1H), 8.29(d, J=9.2Hz, 1H), 8.48(d, J=9.2Hz, 1H), 8.67-8.68(m, 1H) , 8.94(dd, J=2.0, 7.2Hz, 1H), 8.99(d, J=9.2Hz, 1H), 9.18(d, J=9.6Hz, 1H), 10.29(s, 1H).

实施例13：化合物A-45的合成Embodiment 13: the synthesis of compound A-45

将4-甲基-3-硝基苯甲酸(188mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到深红色产物A-45(36mg，25％)，熔点：165～167℃。4-Methyl-3-nitrobenzoic acid (188 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the deep red product A-45 (36mg, 25%), melting point: 165-167°C.

HRMS-ESI(M/Z)：509.1343【M-Cl】+ HRMS-ESI(M/Z): 509.1343【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ2.70(s，3H)，3.62(t，J＝6.8Hz，2H)，4.08(s，3H)，5.20(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，7.87(d，J＝8.0Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.47(d，J＝9.2Hz，2H)，8.79(d，J＝1.2Hz，1H)，8.99(d，J＝9.6Hz，1H)，9.17(d，J＝9.2Hz，1H)，10.27(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ2.70(s, 3H), 3.62(t, J=6.8Hz, 2H), 4.08(s, 3H), 5.20(t, J=6.8Hz, 2H ), 6.41(s, 2H), 7.61(s, 1H), 7.87(d, J=8.0Hz, 1H), 8.28(d, J=9.2Hz, 1H), 8.47(d, J=9.2Hz, 2H ), 8.79(d, J=1.2Hz, 1H), 8.99(d, J=9.6Hz, 1H), 9.17(d, J=9.2Hz, 1H), 10.27(s, 1H).

实施例14：化合物A-46的合成Embodiment 14: the synthesis of compound A-46

将4-甲氧基-3-硝基苯甲酸(205mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到深红色产物A-46(22mg，15％)，熔点：158～160℃。4-Methoxy-3-nitrobenzoic acid (205 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the deep red product A-46 (22mg, 15%), melting point: 158-160°C.

HRMS-ESI(M/Z)：525.1295【M-Cl】+ HRMS-ESI(M/Z): 525.1295【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，4.11(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.60(s，1H)，7.68(d，J＝8.8Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.46(d，J＝9.6Hz，1H)，8.51(dd，J＝2.4，8.8Hz，1H)，8.74(d，J＝2.4Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.16(d，J＝9.2Hz，1H)，10.25(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.4Hz, 2H), 4.08(s, 3H), 4.11(s, 3H), 5.20(t, J=6.4Hz, 2H ), 6.41(s, 2H), 7.60(s, 1H), 7.68(d, J=8.8Hz, 1H), 8.28(d, J=9.2Hz, 1H), 8.46(d, J=9.6Hz, 1H ), 8.51(dd, J=2.4, 8.8Hz, 1H), 8.74(d, J=2.4Hz, 1H), 8.98(d, J=9.6Hz, 1H), 9.16(d, J=9.2Hz, 1H ), 10.25(s, 1H).

实施例15：化合物A-56的合成Embodiment 15: the synthesis of compound A-56

将胡椒酸(173mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到橙色产物A-56(29mg，21％)，熔点：192～194℃。Piperic acid (173 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the orange product A-56 (29mg, 21%), melting point: 192-194°C.

HRMS-ESI(M/Z)：494.1239【M-Cl】+ HRMS-ESI(M/Z): 494.1239【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.25(s，2H)，6.41(s，2H)，7.22(d，J＝8.0Hz，1H)，7.60(s，1H)，7.73(d，J＝1.6Hz，1H)，7.91(dd，J＝1.6，8.4Hz，1H)，8.27(d，J＝9.2Hz，1H)，8.44(d，J＝9.6Hz，1H)，8.97(d，J＝9.6Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.19(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.61(t, J=6.4Hz, 2H), 4.07(s, 3H), 5.23(t, J=6.4Hz, 2H), 6.25(s, 2H ), 6.41(s, 2H), 7.22(d, J=8.0Hz, 1H), 7.60(s, 1H), 7.73(d, J=1.6Hz, 1H), 7.91(dd, J=1.6, 8.4Hz , 1H), 8.27(d, J=9.2Hz, 1H), 8.44(d, J=9.6Hz, 1H), 8.97(d, J=9.6Hz, 1H), 9.13(d, J=9.6Hz, 1H ), 10.19(s, 1H).

实施例16：化合物A-49的合成Embodiment 16: the synthesis of compound A-49

将3，4，5-三甲氧基苯甲酸(221mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到橙色产物A-49(31mg，21％)，熔点：210～212℃。3,4,5-Trimethoxybenzoic acid (221 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the orange product A-49 (31mg, 21%), melting point: 210-212°C.

HRMS-ESI(M/Z)：540.1685【M-Cl】+ HRMS-ESI(M/Z): 540.1685【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，3.83(s，3H)，3.92(s，6H)，4.08(s，3H)，5.24(t，J＝6.4Hz，2H)，6.41(s，2H)，7.56(s，2H)，7.60(s，1H)，8.28(d，J＝9.2Hz，1H)，8.46(d，J＝9.6Hz，1H)，8.99(d，J＝9.2Hz，1H)，9.16(d，J＝9.6Hz，1H)，10.20(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.4Hz, 2H), 3.83(s, 3H), 3.92(s, 6H), 4.08(s, 3H), 5.24(t , J=6.4Hz, 2H), 6.41(s, 2H), 7.56(s, 2H), 7.60(s, 1H), 8.28(d, J=9.2Hz, 1H), 8.46(d, J=9.6Hz , 1H), 8.99(d, J=9.2Hz, 1H), 9.16(d, J=9.6Hz, 1H), 10.20(s, 1H).

实施例17：化合物A-55的合成Embodiment 17: the synthesis of compound A-55

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入邻氟苯甲酰氯(124μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-55(35mg，27％)，熔点：181～183℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add o-fluorobenzoyl chloride (124μl, 1.04mmol) , continue to reflux for 6 hours, and the plate layer monitors that the reaction is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-55 (35mg, 27%), melting point: 181-183°C.

HRMS-ESI(M/Z)：468.1247【M-Cl】+ HRMS-ESI(M/Z): 468.1247【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.8Hz，2H)，4.10(s，3H)，5.22(t，J＝6.8Hz，2H)，6.41(s，2H)，7.51-7.57(m，2H)，7.60(s，1H)，7.88-7.92(m，1H)，8.28(d，J＝9.2Hz，1H)，8.30-8.32(m，1H)，8.46(d，J＝9.2Hz，1H)，8.98(d，J＝9.2Hz，1H)，9.16(d，J＝9.2Hz，1H)，10.25(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.8Hz, 2H), 4.10(s, 3H), 5.22(t, J=6.8Hz, 2H), 6.41(s, 2H ), 7.51-7.57(m, 2H), 7.60(s, 1H), 7.88-7.92(m, 1H), 8.28(d, J=9.2Hz, 1H), 8.30-8.32(m, 1H), 8.46( d, J=9.2Hz, 1H), 8.98(d, J=9.2Hz, 1H), 9.16(d, J=9.2Hz, 1H), 10.25(s, 1H).

实施例18：化合物A-37的合成Embodiment 18: Synthesis of compound A-37

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入邻氯苯甲酰氯(132μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-37(31mg，23％)，熔点：164～166℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add o-chlorobenzoyl chloride (132μl, 1.04mmol) , continue to reflux for 6 hours, and the plate layer monitors that the reaction is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-37 (31mg, 23%), melting point: 164-166°C.

HRMS-ESI(M/Z)：484.0952【M-Cl】+ HRMS-ESI(M/Z): 484.0952【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.63(t，J＝6.8Hz，2H)，4.11(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，7.66-7.69(m，1H)，7.79-7.81(m，2H)，8.28(d，J＝9.2Hz，1H)，8.45-8.48(m，2H)，8.99(d，J＝9.6Hz，1H)，9.16(d，J＝9.2Hz，1H)，10.24(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.63(t, J=6.8Hz, 2H), 4.11(s, 3H), 5.24(t, J=6.8Hz, 2H), 6.41(s, 2H ), 7.61(s, 1H), 7.66-7.69(m, 1H), 7.79-7.81(m, 2H), 8.28(d, J=9.2Hz, 1H), 8.45-8.48(m, 2H), 8.99( d, J=9.6Hz, 1H), 9.16(d, J=9.2Hz, 1H), 10.24(s, 1H).

实施例19：化合物A-58的合成Embodiment 19: Synthesis of compound A-58

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入2，4-二氟苯甲酰氯(128μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-58(23mg，17％)，熔点：191～193℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add 2,4-difluorobenzoyl chloride (128μl , 1.04mmol), continued to reflux for 6 hours, and the plate layer monitoring reaction was complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-58 (23mg, 17%), melting point: 191-193°C.

HRMS-ESI(M/Z)：486.1151【M-Cl】+ HRMS-ESI(M/Z): 486.1151【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.10(s，3H)，5.21(t，J＝6.4Hz，2H)，6.41(s，2H)，7.41-7.46(m，1H)，7.61(s，1H)，7.62-7.68(m，1H)，8.28(d，J＝9.2Hz，1H)，8.39(q，J＝8.4Hz，1H)，8.46(d，J＝9.6Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.16(d，J＝9.6Hz，1H)，10.24(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.4Hz, 2H), 4.10(s, 3H), 5.21(t, J=6.4Hz, 2H), 6.41(s, 2H ), 7.41-7.46(m, 1H), 7.61(s, 1H), 7.62-7.68(m, 1H), 8.28(d, J=9.2Hz, 1H), 8.39(q, J=8.4Hz, 1H) , 8.46(d, J=9.6Hz, 1H), 8.98(d, J=9.6Hz, 1H), 9.16(d, J=9.6Hz, 1H), 10.24(s, 1H).

实施例20：化合物A-41的合成Embodiment 20: Synthesis of compound A-41

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入4-乙酰胺基苯磺酰氯(243mg，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-41(23mg，15％)，熔点：205～207℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add 4-acetamidobenzenesulfonyl chloride (243mg, 1.04mmol), continued to reflux for 6 hours, and the plate layer monitoring reaction was complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-41 (23mg, 15%), melting point: 205-207°C.

HRMS-ESI(M/Z)：543.1203【M-Cl】+ HRMS-ESI(M/Z): 543.1203【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ2.12(s，3H)，3.60(t，J＝6.4Hz，2H)，3.81(s，3H)，5.18(t，J＝6.4Hz，2H)，6.42(s，2H)，7.63(s，1H)，7.86(s，4H)，8.28(d，J＝9.2Hz，1H)，8.34(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.15(d，J＝9.6Hz，1H)，9.74(s，1H)，10.61(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ2.12(s, 3H), 3.60(t, J=6.4Hz, 2H), 3.81(s, 3H), 5.18(t, J=6.4Hz, 2H ), 6.42(s, 2H), 7.63(s, 1H), 7.86(s, 4H), 8.28(d, J=9.2Hz, 1H), 8.34(d, J=9.6Hz, 1H), 8.95(d , J=9.2Hz, 1H), 9.15(d, J=9.6Hz, 1H), 9.74(s, 1H), 10.61(s, 1H).

实施例21：化合物A-42的合成Example 21: Synthesis of Compound A-42

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入苯磺酰氯(133μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-42(38mg，28％)，熔点：223～225℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add benzenesulfonyl chloride (133μl, 1.04mmol), continue Reflux for 6 hours, and the plate layer monitors that the reaction is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-42 (38mg, 28%), melting point: 223-225°C.

HRMS-ESI(M/Z)：486.1001【M-Cl】+ HRMS-ESI(M/Z): 486.1001【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.8Hz，2H)，3.76(s，3H)，5.20(t，J＝6.8Hz，2H)，6.42(s，2H)，7.63(s，1H)，7.73(t，J＝8.0Hz，2H)，7.91(t，J＝7.6Hz，1H)，7.97(d，J＝7.2Hz，2H)，8.28(d，J＝9.6Hz，1H)，8.33(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.16(d，J＝9.6Hz，1H)，9.79(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.8Hz, 2H), 3.76(s, 3H), 5.20(t, J=6.8Hz, 2H), 6.42(s, 2H ), 7.63(s, 1H), 7.73(t, J=8.0Hz, 2H), 7.91(t, J=7.6Hz, 1H), 7.97(d, J=7.2Hz, 2H), 8.28(d, J =9.6Hz, 1H), 8.33(d, J=9.6Hz, 1H), 8.95(d, J=9.2Hz, 1H), 9.16(d, J=9.6Hz, 1H), 9.79(s, 1H).

实施例22：化合物A-50的合成Example 22: Synthesis of Compound A-50

将正癸酸(179mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-50(25mg，18％)，熔点：180～182℃。Add n-decanoic acid (179 mg, 1.04 mmol) into thionyl chloride (5 ml), reflux for 2 hours, and distill off excess solvent thionyl chloride under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-50 (25mg, 18%), melting point: 180-182°C.

HRMS-ESI(M/Z)：500.2444【M-Cl】+ HRMS-ESI(M/Z): 500.2444【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ0.85-0.88(m，3H)，1.23-1.49(m，12H)，1.73-1.80(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.08(d，J＝9.6Hz，1H)，10.11(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ0.85-0.88(m, 3H), 1.23-1.49(m, 12H), 1.73-1.80(m, 2H), 2.89(t, J=7.2Hz, 2H), 3.64(t, J=6.8Hz, 2H), 4.07(s, 3H), 5.24(t, J=6.8Hz, 2H), 6.41(s, 2H), 7.61(s, 1H), 8.26( d, J=9.2Hz, 1H), 8.40(d, J=9.2Hz, 1H), 8.95(d, J=9.2Hz, 1H), 9.08(d, J=9.6Hz, 1H), 10.11(s, 1H).

实施例23：化合物A-53的合成Example 23: Synthesis of Compound A-53

将月桂酸(208mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-53(21mg，14％)，熔点：184～186℃。Add lauric acid (208 mg, 1.04 mmol) into thionyl chloride (5 ml), reflux for 2 hours, and distill off excess solvent thionyl chloride under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-53 (21mg, 14%), melting point: 184-186°C.

HRMS-ESI(M/Z)：528.2718【M-Cl】+ HRMS-ESI(M/Z): 528.2718【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ0.85(t，J＝6.8Hz，3H)，1.25-1.47(m，16H)，1.74-1.78(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.23(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.6Hz，1H)，8.40(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.6Hz，1H)，10.09(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ0.85(t, J=6.8Hz, 3H), 1.25-1.47(m, 16H), 1.74-1.78(m, 2H), 2.89(t, J= 7.2Hz, 2H), 3.64(t, J=6.8Hz, 2H), 4.07(s, 3H), 5.23(t, J=6.8Hz, 2H), 6.41(s, 2H), 7.61(s, 1H) , 8.26(d, J=9.6Hz, 1H), 8.40(d, J=9.6Hz, 1H), 8.95(d, J=9.2Hz, 1H), 9.09(d, J=9.6Hz, 1H), 10.09 (s, 1H).

实施例24：化合物A-54的合成Example 24: Synthesis of Compound A-54

将棕榈酸(267mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-54(52mg，32％)，熔点：184～186℃。Palmitic acid (267 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-54 (52mg, 32%), melting point: 184-186°C.

HRMS-ESI(M/Z)：584.3337【M-Cl】+ HRMS-ESI(M/Z): 584.3337【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ0.84(t，J＝6.8Hz，3H)，1.23-1.47(m，24H)，1.74-1.78(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.4Hz，2H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.6Hz，1H)，10.09(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ0.84(t, J=6.8Hz, 3H), 1.23-1.47(m, 24H), 1.74-1.78(m, 2H), 2.89(t, J= 7.2Hz, 2H), 3.64(t, J=6.4Hz, 2H), 4.07(s, 3H), 5.23(t, J=6.4Hz, 2H), 6.41(s, 2H), 7.61(s, 1H) , 8.26(d, J=9.2Hz, 1H), 8.40(d, J=9.6Hz, 1H), 8.95(d, J=9.2Hz, 1H), 9.09(d, J=9.6Hz, 1H), 10.09 (s, 1H).

实施例25：化合物A-61的合成Example 25: Synthesis of Compound A-61

将A-30(99mg，0.26mmol)溶于DMF(5ml)，然后加入研细的氢氧化钾(30mg，0.52mmol)和1，2-二溴乙烷(90μl，1.04mmol)，加热至60℃反应12小时，减压浓缩除去溶剂，残余物用稀盐酸调PH至3，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-61(40mg，29％)，熔点：142～144℃。Dissolve A-30 (99mg, 0.26mmol) in DMF (5ml), then add finely ground potassium hydroxide (30mg, 0.52mmol) and 1,2-dibromoethane (90μl, 1.04mmol), heat to 60 React at ℃ for 12 hours, concentrate under reduced pressure to remove the solvent, adjust the pH of the residue to 3 with dilute hydrochloric acid, collect the precipitated solid by suction filtration, use dichloromethane/methanol as the mobile phase, and separate and purify with a vacuum silica gel column to obtain the red product A -61 (40mg, 29%), melting point: 142-144°C.

HRMS-ESI(M/Z)：452.0476【M-Br】+ HRMS-ESI(M/Z): 452.0476【M-Br】 +

1H NMR(CD3SOCD3，400MHz)：δ3.65(t，J＝6.4Hz，2H)，4.02(t，J＝6.0Hz，2H)，4.13(s，3H)，4.70(t，J＝6.0Hz，2H)，5.25(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.24(d，J＝9.2Hz，1H)，8.34(d，J＝9.2Hz，1H)，8.90(d，J＝8.8Hz，1H)，8.92(d，J＝8.8Hz，1H)，10.11(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.65(t, J=6.4Hz, 2H), 4.02(t, J=6.0Hz, 2H), 4.13(s, 3H), 4.70(t, J =6.0Hz, 2H), 5.25(t, J=6.4Hz, 2H), 6.41(s, 2H), 7.61(s, 1H), 8.24(d, J=9.2Hz, 1H), 8.34(d, J =9.2Hz, 1H), 8.90(d, J=8.8Hz, 1H), 8.92(d, J=8.8Hz, 1H), 10.11(s, 1H).

实施例26：化合物A-64的合成Example 26: Synthesis of Compound A-64

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入溴乙酰溴(91μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-64(42mg，30％)，熔点：154～156℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), raise the temperature to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add bromoacetyl bromide (91μl, 1.04mmol), continue Reflux for 6 hours, and the plate layer monitors that the reaction is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-64 (42mg, 30%), melting point: 154-156°C.

HRMS-ESI(M/Z)：466.0293【M-Br】+ HRMS-ESI(M/Z): 466.0293【M-Br】 +

1H NMR(CD3SOCD3，400MHz)：δ3.65(t，J＝6.8Hz，2H)，4.10(s，3H)，4.78(s，2H)，5.20(t，J＝6.8Hz，2H)，6.41(s，2H)，7.62(s，1H)，8.27(d，J＝9.2Hz，1H)，8.42(d，J＝9.2Hz，1H)，8.96(d，J＝9.2Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.17(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.65(t, J=6.8Hz, 2H), 4.10(s, 3H), 4.78(s, 2H), 5.20(t, J=6.8Hz, 2H ), 6.41(s, 2H), 7.62(s, 1H), 8.27(d, J=9.2Hz, 1H), 8.42(d, J=9.2Hz, 1H), 8.96(d, J=9.2Hz, 1H ), 9.13(d, J=9.6Hz, 1H), 10.17(s, 1H).

实施例27：化合物A-67的合成Example 27: Synthesis of Compound A-67

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入己酰氯(144μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-67(54mg，43％)，熔点：125～127℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add hexanoyl chloride (144μl, 1.04mmol), and continue to reflux After 6 hours, the lamellar monitoring reaction was complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-67 (54mg, 43%), melting point: 125-127°C.

HRMS-ESI(M/Z)：444.1824【M-Cl】+ HRMS-ESI(M/Z): 444.1824【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ0.94(t，J＝7.2Hz，3H)，1.38-1.46(m，4H)，1.76-1.79(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.4Hz，2H)，4.08(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.2Hz，1H)，10.10(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ0.94(t, J=7.2Hz, 3H), 1.38-1.46(m, 4H), 1.76-1.79(m, 2H), 2.89(t, J= 7.2Hz, 2H), 3.64(t, J=6.4Hz, 2H), 4.08(s, 3H), 5.23(t, J=6.4Hz, 2H), 6.41(s, 2H), 7.61(s, 1H) , 8.26(d, J=9.2Hz, 1H), 8.40(d, J=9.2Hz, 1H), 8.95(d, J=9.2Hz, 1H), 9.09(d, J=9.2Hz, 1H), 10.10 (s, 1H).

实施例28：化合物A-68的合成Example 28: Synthesis of Compound A-68

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入庚酰氯(161μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到橙色产物A-68(46mg，36％)，熔点：117～119℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add heptanoyl chloride (161μl, 1.04mmol), and continue to reflux After 6 hours, the lamellar monitoring reaction was complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by vacuum silica gel column with dichloromethane/methanol as mobile phase to obtain orange product A-68 (46mg, 36%), melting point: 117-119°C.

HRMS-ESI(M/Z)：458.1953【M-Cl】+ HRMS-ESI(M/Z): 458.1953【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ0.91(t，J＝7.2Hz，3H)，1.34-1.38(m，4H)，1.46-1.50(m，2H)，1.75-1.78(m，2H)，2.90(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.25(d，J＝9.2Hz，1H)，8.39(d，J＝9.2Hz，1H)，8.94(d，J＝9.6Hz，1H)，9.08(d，J＝9.2Hz，1H)，10.13(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ0.91(t, J=7.2Hz, 3H), 1.34-1.38(m, 4H), 1.46-1.50(m, 2H), 1.75-1.78(m, 2H), 2.90(t, J=7.2Hz, 2H), 3.64(t, J=6.8Hz, 2H), 4.07(s, 3H), 5.24(t, J=6.8Hz, 2H), 6.41(s, 2H), 7.61(s, 1H), 8.25(d, J=9.2Hz, 1H), 8.39(d, J=9.2Hz, 1H), 8.94(d, J=9.6Hz, 1H), 9.08(d, J=9.2Hz, 1H), 10.13(s, 1H).

实施例29：化合物A-69的合成Example 29: Synthesis of Compound A-69

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入辛酰氯(178μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到橙色产物A-69(69mg，52％)，熔点：118～120℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add octanoyl chloride (178μl, 1.04mmol), and continue to reflux After 6 hours, the lamellar monitoring reaction was complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the orange product A-69 (69mg, 52%), melting point: 118-120°C.

HRMS-ESI(M/Z)：472.2121【M-Cl】+ HRMS-ESI(M/Z): 472.2121【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ0.89(t，J＝6.8Hz，3H)，1.31-1.39(m，6H)，1.45-1.49(m，2H)，1.75-1.79(m，2H)，2.90(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.6Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.08(d，J＝9.2Hz，1H)，10.11(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ0.89(t, J=6.8Hz, 3H), 1.31-1.39(m, 6H), 1.45-1.49(m, 2H), 1.75-1.79(m, 2H), 2.90(t, J=7.2Hz, 2H), 3.64(t, J=6.8Hz, 2H), 4.07(s, 3H), 5.24(t, J=6.8Hz, 2H), 6.41(s, 2H), 7.61(s, 1H), 8.26(d, J=9.6Hz, 1H), 8.40(d, J=9.2Hz, 1H), 8.95(d, J=9.2Hz, 1H), 9.08(d, J=9.2Hz, 1H), 10.11(s, 1H).

实施例30：化合物A-70的合成Example 30: Synthesis of Compound A-70

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入壬酰氯(195μl，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-70(39mg，29％)，熔点：126～128℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add nonanoyl chloride (195μl, 1.04mmol), and continue to reflux After 6 hours, the lamellar monitoring reaction was complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-70 (39mg, 29%), melting point: 126-128°C.

HRMS-ESI(M/Z)：486.2262【M-Cl】+ HRMS-ESI(M/Z): 486.2262【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ0.88(t，J＝6.8Hz，3H)，1.23-1.47(m，10H)，1.75-1.78(m，2H)，2.90(t，J＝7.2Hz，2H)，3.64(t，J＝6.4Hz，2H)，4.07(s，3H)，5.25(t，J＝6.4Hz，2H)，6.40(s，2H)，7.60(s，1H)，8.23(d，J＝9.2Hz，1H)，8.38(d，J＝9.6Hz，1H)，8.92(d，J＝9.6Hz，1H)，9.06(d，J＝9.6Hz，1H)，10.14(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ0.88(t, J=6.8Hz, 3H), 1.23-1.47(m, 10H), 1.75-1.78(m, 2H), 2.90(t, J= 7.2Hz, 2H), 3.64(t, J=6.4Hz, 2H), 4.07(s, 3H), 5.25(t, J=6.4Hz, 2H), 6.40(s, 2H), 7.60(s, 1H) , 8.23(d, J=9.2Hz, 1H), 8.38(d, J=9.6Hz, 1H), 8.92(d, J=9.6Hz, 1H), 9.06(d, J=9.6Hz, 1H), 10.14 (s, 1H).

实施例31：化合物A-71的合成Example 31: Synthesis of Compound A-71

将3-硝基-4-氯苯甲酸(209mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-71(63mg，46％)，熔点：211～213℃。3-nitro-4-chlorobenzoic acid (209 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-71 (63mg, 46%), melting point: 211-213°C.

HRMS-ESI(M/Z)：529.07968【M-Cl】+ HRMS-ESI(M/Z): 529.07968【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，5.19(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.15(d，J＝8.4Hz，1H)，8.28(d，J＝9.6Hz，1H)，8.48(d，J＝9.6Hz，1H)，8.53(dd，J＝2.0，8.4Hz，1H)，8.91(d，J＝1.6Hz，1H)，8.99(d，J＝9.6Hz，1H)，9.18(d，J＝9.6Hz，1H)，10.28(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.4Hz, 2H), 4.08(s, 3H), 5.19(t, J=6.4Hz, 2H), 6.41(s, 2H ), 7.61(s, 1H), 8.15(d, J=8.4Hz, 1H), 8.28(d, J=9.6Hz, 1H), 8.48(d, J=9.6Hz, 1H), 8.53(dd, J =2.0, 8.4Hz, 1H), 8.91(d, J=1.6Hz, 1H), 8.99(d, J=9.6Hz, 1H), 9.18(d, J=9.6Hz, 1H), 10.28(s, 1H ).

实施例32：化合物A-72的合成Example 32: Synthesis of Compound A-72

将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入4-氰基苯磺酰氯(210mg，1.04mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-72(74mg，56％)，熔点：216～219℃。Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add 4-cyanobenzenesulfonyl chloride (210mg, 1.04 mmol), continued to reflux for 6 hours, and the plate layer monitoring reaction was complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-72 (74mg, 56%), melting point: 216-219°C.

HRMS-ESI(M/Z)：511.09638【M-Cl】+ HRMS-ESI(M/Z): 511.09638【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.64(t，J＝6.4Hz，2H)，3.75(s，3H)，5.25(t，J＝6.4Hz，2H)，6.42(s，2H)，7.64(s，1H)，8.16-8.24(m，4H)，8.28(d，J＝9.2Hz，1H)，8.33(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.18(d，J＝9.6Hz，1H)，9.88(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.64(t, J=6.4Hz, 2H), 3.75(s, 3H), 5.25(t, J=6.4Hz, 2H), 6.42(s, 2H ), 7.64(s, 1H), 8.16-8.24(m, 4H), 8.28(d, J=9.2Hz, 1H), 8.33(d, J=9.2Hz, 1H), 8.95(d, J=9.2Hz , 1H), 9.18(d, J=9.6Hz, 1H), 9.88(s, 1H).

实施例33：化合物A-73的合成Example 33: Synthesis of Compound A-73

将2-溴-5-硝基苯甲酸(254mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-73(62mg，46％)，熔点：180～183℃。2-Bromo-5-nitrobenzoic acid (254 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), raise the temperature to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), cool separately, collect the precipitated solid by suction filtration, and dichloromethane Methane/methanol was used as mobile phase, separated and purified by vacuum silica gel column to obtain red product A-73 (62mg, 46%), melting point: 180-183°C.

HRMS-ESI(M/Z)：573.02972【M-Cl】+ HRMS-ESI(M/Z): 573.02972【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.23(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.23(d，J＝7.8Hz，1H)，8.28(d，J＝9.6Hz，1H)，8.48(d，J＝9.6Hz，1H)，8.51(dd，J＝1.6，7.8Hz，1H)，8.93(d，J＝1.6Hz，1H)，8.96(d，J＝9.6Hz，1H)，9.18(d，J＝9.6Hz，1H)，10.36(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.64(t, J=6.8Hz, 2H), 4.07(s, 3H), 5.23(t, J=6.8Hz, 2H), 6.41(s, 2H ), 7.61(s, 1H), 8.23(d, J=7.8Hz, 1H), 8.28(d, J=9.6Hz, 1H), 8.48(d, J=9.6Hz, 1H), 8.51(dd, J =1.6, 7.8Hz, 1H), 8.93(d, J=1.6Hz, 1H), 8.96(d, J=9.6Hz, 1H), 9.18(d, J=9.6Hz, 1H), 10.36(s, 1H ).

实施例34：化合物A-74的合成Example 34: Synthesis of Compound A-74

将2-氟-5-硝基苯甲酸(192mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-74(40mg，30％)，熔点：209～211℃。2-Fluoro-5-nitrobenzoic acid (192 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After fully cooling, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-74 (40mg, 30%), melting point: 209-211°C.

HRMS-ESI(M/Z)：513.11096【M-Cl】+ HRMS-ESI(M/Z): 513.11096【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.63(t，J＝6.4Hz，2H)，4.11(s，3H)，5.20(t，J＝6.4Hz，2H)，6.42(s，2H)，7.61(s，1H)，7.89(t，J＝10.0Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.74-8.76(mm，1H)，8.99(d，J＝9.2Hz，1H)，9.02(d，J＝3.2Hz，1H)，9.19(d，J＝9.6Hz，1H)，10.30(s，1H). 1 H NMR (CD3SOCD 3 , 400MHz): δ3.63(t, J=6.4Hz, 2H), 4.11(s, 3H), 5.20(t, J=6.4Hz, 2H), 6.42(s, 2H), 7.61(s, 1H), 7.89(t, J=10.0Hz, 1H), 8.28(d, J=9.2Hz, 1H), 8.48(d, J=9.2Hz, 1H), 8.74-8.76(mm, 1H ), 8.99(d, J=9.2Hz, 1H), 9.02(d, J=3.2Hz, 1H), 9.19(d, J=9.6Hz, 1H), 10.30(s, 1H).

实施例35：化合物A-75的合成Example 35: Synthesis of Compound A-75

将2-呋喃甲酸(117mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-75(29mg，26％)，熔点：186～188℃。2-Furancarboxylic acid (117 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-75 (29mg, 26%), melting point: 186-188°C.

HRMS-ESI(M/Z)：529.07968【M-Cl】+ HRMS-ESI(M/Z): 529.07968【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，5.23(t，J＝6.4Hz，2H)，6.40(s，2H)，6.93(q，J＝1.6Hz，1H)，7.59(s，1H)，7.77(d，J＝3.6Hz 1H)，8.21-8.25(m，2H)，8.42(d，J＝9.6Hz，1H)，8.92(d，J＝9.6Hz，1H)，9.11(d，J＝9.2Hz，1H)，10.22(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.4Hz, 2H), 4.08(s, 3H), 5.23(t, J=6.4Hz, 2H), 6.40(s, 2H ), 6.93(q, J=1.6Hz, 1H), 7.59(s, 1H), 7.77(d, J=3.6Hz 1H), 8.21-8.25(m, 2H), 8.42(d, J=9.6Hz, 1H), 8.92(d, J=9.6Hz, 1H), 9.11(d, J=9.2Hz, 1H), 10.22(s, 1H).

实施例36：化合物A-76的合成Example 36: Synthesis of Compound A-76

将3-硝基苯甲酸(174mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-76(52mg，41％)，熔点：221～223℃。3-Nitrobenzoic acid (174 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After fully cooling, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-76 (52mg, 41%), melting point: 221-223°C.

HRMS-ESI(M/Z)：495.12041【M-Cl】+ HRMS-ESI(M/Z): 495.12041【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.09(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.60(s，1H)，8.01-8.05(m，1H)，8.28(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.69-8.71(m，2H)，8.97-9.0(m，2H)9.18(d，J＝9.2Hz，1H)，10.32(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.4Hz, 2H), 4.09(s, 3H), 5.20(t, J=6.4Hz, 2H), 6.41(s, 2H ), 7.60(s, 1H), 8.01-8.05(m, 1H), 8.28(d, J=9.2Hz, 1H), 8.48(d, J=9.2Hz, 1H), 8.69-8.71(m, 2H) , 8.97-9.0(m, 2H) 9.18(d, J=9.2Hz, 1H), 10.32(s, 1H).

实施例37：化合物A-77的合成Example 37: Synthesis of Compound A-77

将4-氯苯甲酸(163mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-77(48mg，38％)，熔点：198～201℃。4-Chlorobenzoic acid (163 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-77 (48mg, 38%), melting point: 198-201°C.

HRMS-ESI(M/Z)：484.09596【M-Cl】+ HRMS-ESI(M/Z): 484.09596【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.07(s，3H)，5.21(t，J＝6.4Hz，2H)，6.30(s，2H)，7.60(s，1H)，7.80(d，J＝8.4Hz，2H)，8.24(d，J＝9.2Hz，1H)，8.30(d，J＝8.4Hz，2H)，8.44(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.25(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.61(t, J=6.4Hz, 2H), 4.07(s, 3H), 5.21(t, J=6.4Hz, 2H), 6.30(s, 2H ), 7.60(s, 1H), 7.80(d, J=8.4Hz, 2H), 8.24(d, J=9.2Hz, 1H), 8.30(d, J=8.4Hz, 2H), 8.44(d, J =9.2Hz, 1H), 8.95(d, J=9.2Hz, 1H), 9.13(d, J=9.6Hz, 1H), 10.25(s, 1H).

实施例38：化合物A-78的合成Example 38: Synthesis of Compound A-78

将3-甲基苯甲酸(141mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-78(57mg，48％)，熔点：205～208℃。3-Methylbenzoic acid (141 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-78 (57mg, 48%), melting point: 205-208°C.

HRMS-ESI(M/Z)：464.15097【M-Cl】+ HRMS-ESI(M/Z): 464.15097【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ2.49(s，3H)，3.62(t，J＝6.8Hz，2H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.60(s，1H)，7.62-769.(m，2H)，8.09-8.13(m，2H)，8.23(d J＝8.4Hz，1H)，8.43(d，J＝8.4Hz，1H)，8.94(d，J＝8.4Hz，1H)，9.11(d，J＝8.4Hz，1H)，10.24(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ2.49(s, 3H), 3.62(t, J=6.8Hz, 2H), 4.07(s, 3H), 5.23(t, J=6.4Hz, 2H ), 6.41(s, 2H), 7.60(s, 1H), 7.62-769.(m, 2H), 8.09-8.13(m, 2H), 8.23(d J=8.4Hz, 1H), 8.43(d, J=8.4Hz, 1H), 8.94(d, J=8.4Hz, 1H), 9.11(d, J=8.4Hz, 1H), 10.24(s, 1H).

实施例39：化合物A-79的合成Example 39: Synthesis of Compound A-79

将2-甲基苯甲酸(141mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-79(50mg，42％)，熔点：200～202℃。2-Methylbenzoic acid (141 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After fully cooling, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-79 (50mg, 42%), melting point: 200-202°C.

HRMS-ESI(M/Z)：464.15110【M-Cl】+ HRMS-ESI(M/Z): 464.15110【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ2.66(s，3H)，3.62(t，J＝6.0Hz，2H)，4.09(s，3H)，5.24(t，J＝6.0Hz，2H)，6.40(s，2H)，7.51-7.54(m，2H)，7.59(s，1H)，7.69(t，J＝7.6Hz，1H)，8.24(d J＝9.2Hz，1H)，8.37(d J＝7.6Hz，1H)，8.44(d，J＝9.2Hz，1H)，8.95(d，J＝9.6Hz，1H)，9.11(d，J＝9.6Hz，1H)，10.24(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ2.66(s, 3H), 3.62(t, J=6.0Hz, 2H), 4.09(s, 3H), 5.24(t, J=6.0Hz, 2H ), 6.40(s, 2H), 7.51-7.54(m, 2H), 7.59(s, 1H), 7.69(t, J=7.6Hz, 1H), 8.24(d J=9.2Hz, 1H), 8.37( dJ=7.6Hz, 1H), 8.44(d, J=9.2Hz, 1H), 8.95(d, J=9.6Hz, 1H), 9.11(d, J=9.6Hz, 1H), 10.24(s, 1H ).

实施例40：化合物A-80的合成Example 40: Synthesis of Compound A-80

将5-硝基-2-呋喃甲酸(163mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-80(29mg，27％)，熔点：190～192℃。5-Nitro-2-furancarboxylic acid (163 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-80 (29 mg, 27%), melting point: 190-192°C.

HRMS-ESI(M/Z)：485.09969【M-Cl】+ HRMS-ESI(M/Z): 485.09969【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.63(t，J＝6.4Hz，2H)，4.11(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.02-8.06(m，2H)，8.25(d，J＝8.4Hz，1H)，8.46(d，J＝8.4Hz，1H)，8.96(d，J＝8.4Hz，1H)，9.17(d，J＝8.4Hz，1H)，10.30(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.63(t, J=6.4Hz, 2H), 4.11(s, 3H), 5.20(t, J=6.4Hz, 2H), 6.41(s, 2H ), 7.61(s, 1H), 8.02-8.06(m, 2H), 8.25(d, J=8.4Hz, 1H), 8.46(d, J=8.4Hz, 1H), 8.96(d, J=8.4Hz , 1H), 9.17(d, J=8.4Hz, 1H), 10.30(s, 1H).

实施例41：化合物A-81的合成Example 41: Synthesis of Compound A-81

将4-苯氧基苯甲酸(222mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-81(59mg，42％)，熔点：199～202℃。4-Phenoxybenzoic acid (222 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-81 (59mg, 42%), melting point: 199-202°C.

HRMS-ESI(M/Z)：529.07968【M-Cl】+ HRMS-ESI(M/Z): 529.07968【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.06(s，3H)，5.23(t，J＝6.4Hz，2H)，6.40(s，2H)，7.20-7.23(m，4H)，7.30(t，J＝7.6Hz，1H)，7.52(t，J＝8Hz，2H)，7.59(s，1H)，8.22(d，J＝8.8Hz，1H)，8.30(d，J＝8.4Hz，2H)，8.42(d，J＝9.2Hz，1H)，8.92(d，J＝8.8Hz，1H)，9.09(d，J＝9.2Hz，1H)，10.22(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.61(t, J=6.4Hz, 2H), 4.06(s, 3H), 5.23(t, J=6.4Hz, 2H), 6.40(s, 2H ), 7.20-7.23(m, 4H), 7.30(t, J=7.6Hz, 1H), 7.52(t, J=8Hz, 2H), 7.59(s, 1H), 8.22(d, J=8.8Hz, 1H), 8.30(d, J=8.4Hz, 2H), 8.42(d, J=9.2Hz, 1H), 8.92(d, J=8.8Hz, 1H), 9.09(d, J=9.2Hz, 1H) , 10.22(s, 1H).

实施例42：化合物A-82的合成Example 42: Synthesis of Compound A-82

将4-氟苯乙酸(160mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-82(43mg，34％)，熔点：195～198℃。4-Fluorophenylacetic acid (160 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-82 (43mg, 34%), melting point: 195-198°C.

HRMS-ESI(M/Z)：482.14194【M-Cl】+ HRMS-ESI(M/Z): 482.14194【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.66(t，J＝6.8Hz，2H)，4.08(s，3H)，4.31(s，2H)，5.26(t，J＝6.8Hz，2H)，6.41(s，2H)，7.23-7.30(m，2H)，7.51-7.55(m，2H)，7.62(s，1H)，8.26(d，J＝9.6Hz，1H)，8.38(d，J＝9.6Hz，1H)，8.94(d，J＝9.2Hz，1H)，9.09(d，J＝9.6Hz，1H)，10.20(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.66(t, J=6.8Hz, 2H), 4.08(s, 3H), 4.31(s, 2H), 5.26(t, J=6.8Hz, 2H ), 6.41(s, 2H), 7.23-7.30(m, 2H), 7.51-7.55(m, 2H), 7.62(s, 1H), 8.26(d, J=9.6Hz, 1H), 8.38(d, J=9.6Hz, 1H), 8.94(d, J=9.2Hz, 1H), 9.09(d, J=9.6Hz, 1H), 10.20(s, 1H).

实施例43：化合物A-83的合成Example 43: Synthesis of Compound A-83

将3-氯苯甲酸(162mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-83(63mg，50％)，熔点：183～185℃。3-Chlorobenzoic acid (162 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-83 (63mg, 50%), melting point: 183-185°C.

HRMS-ESI(M/Z)：484.09598【M-Cl】+ HRMS-ESI(M/Z): 484.09598【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，5.22(t，J＝6.4Hz，2H)，6.40(s，2H)，7.60(s，1H)，7.74-7.79(m，1H)，7.94-7.97(m，1H)，8.22-8.26(m，2H)，8.30(s，1H)，8.43(d，J＝9.2Hz，1H)，8.93(d，J＝9.2Hz，1H)，9.12(d，J＝9.2Hz，1H)，10.28(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.4Hz, 2H), 4.08(s, 3H), 5.22(t, J=6.4Hz, 2H), 6.40(s, 2H ), 7.60(s, 1H), 7.74-7.79(m, 1H), 7.94-7.97(m, 1H), 8.22-8.26(m, 2H), 8.30(s, 1H), 8.43(d, J=9.2 Hz, 1H), 8.93(d, J=9.2Hz, 1H), 9.12(d, J=9.2Hz, 1H), 10.28(s, 1H).

实施例44：化合物A-84的合成Example 44: Synthesis of Compound A-84

将3-甲氧基苯甲酸(162mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-84(40mg，32％)，熔点：205～208℃。3-Methoxybenzoic acid (162 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-84 (40mg, 32%), melting point: 205-208°C.

HRMS-ESI(M/Z)：484.14417【M-Cl】+ HRMS-ESI(M/Z): 484.14417【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，3.90(s，3H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.74-7.79(m，1H)，7.60-7.65(m，2H)，7.76(s，1H)，7.89(d，J＝7.6Hz，1H)8.26(d，J＝9.2Hz，1H)，8.44(d，J＝9.6Hz，1H)，8.96(d，J＝9.2Hz，1H)，9.14(d，J＝9.2Hz，1H)，10.23(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.61(t, J=6.4Hz, 2H), 3.90(s, 3H), 4.07(s, 3H), 5.23(t, J=6.4Hz, 2H ), 6.41(s, 2H), 7.74-7.79(m, 1H), 7.60-7.65(m, 2H), 7.76(s, 1H), 7.89(d, J=7.6Hz, 1H) 8.26(d, J =9.2Hz, 1H), 8.44(d, J=9.6Hz, 1H), 8.96(d, J=9.2Hz, 1H), 9.14(d, J=9.2Hz, 1H), 10.23(s, 1H).

实施例45：化合物A-85的合成Example 45: Synthesis of Compound A-85

将3-氟苯甲酸(146mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-85(46mg，38％)，熔点：198～201℃。3-Fluorobenzoic acid (146 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-85 (46mg, 38%), melting point: 198-201°C.

HRMS-ESI(M/Z)：468.12509【M-Cl】+ HRMS-ESI(M/Z): 468.12509【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.06(s，3H)，5.23(t，J＝6.4Hz，2H)，6.39(s，2H)，7.59(s，1H)，7.75-7.79(m，2H)，8.09(d，J＝9.2Hz，1H)，8.14-8.19(m，2H)，8.40(d，J＝9.2Hz，1H)，8.87(d，J＝9.2Hz，1H)，9.07(d，J＝9.6Hz，1H)，10.27(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.61(t, J=6.4Hz, 2H), 4.06(s, 3H), 5.23(t, J=6.4Hz, 2H), 6.39(s, 2H ), 7.59(s, 1H), 7.75-7.79(m, 2H), 8.09(d, J=9.2Hz, 1H), 8.14-8.19(m, 2H), 8.40(d, J=9.2Hz, 1H) , 8.87(d, J=9.2Hz, 1H), 9.07(d, J=9.6Hz, 1H), 10.27(s, 1H).

实施例46：化合物A-86的合成Example 46: Synthesis of Compound A-86

将2-甲氧基苯甲酸(162mg，1.04mmol)加入至二氯亚砜(5ml)中，回流2小时，减压蒸馏除去多余的溶剂二氯亚砜。将A-30(99mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入上述酰氯，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到红色产物A-86(30mg，24％)，熔点：183～185℃。2-Methoxybenzoic acid (162 mg, 1.04 mmol) was added to thionyl chloride (5 ml), refluxed for 2 hours, and excess solvent thionyl chloride was distilled off under reduced pressure. Suspend A-30 (99mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add the above acid chloride, continue to reflux for 6 hours, and monitor the plate layer The response is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the red product A-86 (30mg, 24%), melting point: 183-185°C.

HRMS-ESI(M/Z)：484.14358【M-Cl】+ HRMS-ESI(M/Z): 484.14358【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，3.93(s，3H)，4.08(s，3H)，5.24(t，J＝6.4Hz，2H)，6.40(s，2H)，7.18-7.22(m，1H)，7.33-7.35(m，1H)，7.59(s，1H)，7.75-7.79(m，1H)，8.21-8.26(m，2H)，8.43(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.10(d，J＝9.2Hz，1H)，10.12(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.61(t, J=6.4Hz, 2H), 3.93(s, 3H), 4.08(s, 3H), 5.24(t, J=6.4Hz, 2H ), 6.40(s, 2H), 7.18-7.22(m, 1H), 7.33-7.35(m, 1H), 7.59(s, 1H), 7.75-7.79(m, 1H), 8.21-8.26(m, 2H ), 8.43(d, J=9.2Hz, 1H), 8.95(d, J=9.2Hz, 1H), 9.10(d, J=9.2Hz, 1H), 10.12(s, 1H).

实施例47：化合物A-87的合成Example 47: Synthesis of Compound A-87

将A-30(99mg，0.26mmol)溶于DMF(5ml)，然后加入研细的氢氧化钾(30mg，0.52mmol)和4-硝基苄氯(134μl，1.04mmol)，加热至60℃反应12小时，减压浓缩除去溶剂，残余物用稀盐酸调PH至3，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到橙色产物A-87(72mg，57％)，熔点：208～210℃。Dissolve A-30 (99mg, 0.26mmol) in DMF (5ml), then add finely ground potassium hydroxide (30mg, 0.52mmol) and 4-nitrobenzyl chloride (134μl, 1.04mmol), and heat to 60°C for reaction After 12 hours, concentrate under reduced pressure to remove the solvent, adjust the pH of the residue to 3 with dilute hydrochloric acid, collect the precipitated solid by suction filtration, use dichloromethane/methanol as the mobile phase, and separate and purify with a vacuum silica gel column to obtain the orange product A-87 (72mg, 57%), melting point: 208-210°C.

HRMS-ESI(M/Z)：481.13863【M-Cl】+ HRMS-ESI(M/Z): 481.13863【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.11(s，3H)，5.24(t，J＝6.4Hz，2H)，5.57(s，2H)，6.40(s，2H)，7.60(s，1H)，7.92(d，J＝8.4Hz，2H)，8.22(d，J＝9.2Hz，1H)，8.30(d，J＝8.8Hz，2H)，8.34(d，J＝9.2Hz，1H)，8.88-8.91(m，2H)，10.10(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.62(t, J=6.4Hz, 2H), 4.11(s, 3H), 5.24(t, J=6.4Hz, 2H), 5.57(s, 2H ), 6.40(s, 2H), 7.60(s, 1H), 7.92(d, J=8.4Hz, 2H), 8.22(d, J=9.2Hz, 1H), 8.30(d, J=8.8Hz, 2H ), 8.34(d, J=9.2Hz, 1H), 8.88-8.91(m, 2H), 10.10(s, 1H).

实施例48：化合物A-36的合成Example 48: Synthesis of Compound A-36

90℃下将间苯三酚(3.0g，18.5mmol)分批多次加入至60％硫酸(60ml，v/v)中直至形成无色澄清溶液，然后分批加入A(3.0g，7.6mmol)形成深红色混悬液，加完料后保温继续反应10小时，板层监测反应完全。剧烈搅拌下，将反应液趁热倾至饱和食盐水(50ml)中，室温搅拌2小时，然后放入负20℃冰箱充分冷却。抽滤，固体用蒸馏水洗涤，并将之溶于1NNaOH(100ml)，随后用2N HCl(100ml)将体系调成酸性，充分搅拌，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，所得固体再用乙醇∶浓盐酸(V∶V＝95∶5)体系重结晶，得到红色产物A-36(1.8g，62％)，熔点：225～227℃。Phloroglucinol (3.0g, 18.5mmol) was added to 60% sulfuric acid (60ml, v/v) in batches at 90°C until a colorless clear solution was formed, then A (3.0g, 7.6mmol) was added in batches ) to form a deep red suspension, after the addition of the material, the insulation continued to react for 10 hours, and the plate monitoring reaction was complete. Under vigorous stirring, the reaction solution was poured into saturated brine (50ml) while hot, stirred at room temperature for 2 hours, and then placed in a negative 20°C refrigerator to fully cool. Suction filtration, the solid was washed with distilled water, and dissolved in 1N NaOH (100ml), then the system was adjusted to acidic with 2N HCl (100ml), fully stirred, and the precipitated solid was collected by suction filtration, using dichloromethane/methanol as the mobile phase , separated and purified by vacuum silica gel column, and the obtained solid was recrystallized with ethanol:concentrated hydrochloric acid (V:V=95:5) system to obtain red product A-36 (1.8g, 62%), melting point: 225～227°C .

HRMS-ESI(M/Z)：348.1240【M-Cl】+ HRMS-ESI(M/Z): 348.1240【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.54(t，J＝6.4Hz，2H)，4.11(s，3H)，4.15(s，3H)，5.21(t，J＝6.4Hz，2H)，7.34(s，1H)，8.28(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.77(d，J＝9.6Hz，1H)，8.82(d，J＝9.2Hz，1H)，9.61(s，1H)，10.07(s，1H)，10.36(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.54(t, J=6.4Hz, 2H), 4.11(s, 3H), 4.15(s, 3H), 5.21(t, J=6.4Hz, 2H ), 7.34(s, 1H), 8.28(d, J=9.2Hz, 1H), 8.48(d, J=9.2Hz, 1H), 8.77(d, J=9.6Hz, 1H), 8.82(d, J =9.2Hz, 1H), 9.61(s, 1H), 10.07(s, 1H), 10.36(s, 1H).

实施例49：化合物A-60的合成Example 49: Synthesis of Compound A-60

将A-36(100mg，0.26mmol)混悬于干燥乙腈(5ml)中，升温至回流基本溶解，加无水吡啶(84μl，1.04mmol)，然后加入对氟苯甲酰氯(185μl，1.56mmol)，继续回流6小时，板层监测反应完全。充分冷却，抽滤收集析出的固体，以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，得到黄色产物A-60(18mg，11％)，熔点：169～171℃。Suspend A-36 (100mg, 0.26mmol) in dry acetonitrile (5ml), heat up to reflux and basically dissolve, add anhydrous pyridine (84μl, 1.04mmol), then add p-fluorobenzoyl chloride (185μl, 1.56mmol) , continue to reflux for 6 hours, and the plate layer monitors that the reaction is complete. After cooling sufficiently, the precipitated solid was collected by suction filtration, separated and purified by a vacuum silica gel column with dichloromethane/methanol as the mobile phase to obtain the yellow product A-60 (18mg, 11%), melting point: 169-171°C.

HRMS-ESI(M/Z)：592.1569【M-Cl】+ HRMS-ESI(M/Z): 592.1569【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.80(t，J＝6.4Hz，2H)，4.14(s，3H)，4.20(s，3H)，5.38(t，J＝6.4Hz，2H)，7.34-7.44(m，4H)，8.03(s，1H)，8.07(dd，J＝5.6，8.8Hz，2H)，8.23(dd，J＝5.2，8.8Hz，2H)，8.37(d，J＝9.2Hz，1H)，8.48(d，J＝9.6Hz，1H)，8.96(d，J＝9.6Hz，1H)，9.08(d，J＝9.6Hz，1H)，10.31(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.80(t, J=6.4Hz, 2H), 4.14(s, 3H), 4.20(s, 3H), 5.38(t, J=6.4Hz, 2H ), 7.34-7.44(m, 4H), 8.03(s, 1H), 8.07(dd, J=5.6, 8.8Hz, 2H), 8.23(dd, J=5.2, 8.8Hz, 2H), 8.37(d, J=9.2Hz, 1H), 8.48(d, J=9.6Hz, 1H), 8.96(d, J=9.6Hz, 1H), 9.08(d, J=9.6Hz, 1H), 10.31(s, 1H) .

实施例50：化合物A-65的合成Example 50: Synthesis of Compound A-65

将溶有硼氢化钠(1.2g，32mmol)的5％氢氧化钠溶液(10ml)逐滴加入至含黄藤素(7.8g，20mmol)和碳酸钾(8.3g，60mmol)的甲醇(250ml)溶液体系中，室温搅拌2小时，抽滤收集析出的黄绿色固体，滤饼依次用蒸馏水(100ml)和80％乙醇(100ml)洗涤，得到中间体二氢黄藤素(4.4g，62％)。将中间体二氢黄藤素(4.2g，12mmol)溶解在乙腈(160ml)中，然后加入乙酸(40ml)和40％的乙二醛(2ml)，加热至85～95℃回流5小时，板层监测反应完全，将反应液浓缩，得到深红色油状物，加入2％盐酸溶液(200ml)，室温搅拌1小时，过滤，滤液室温搅拌5天，将反应液浓缩，用95％乙醇重结晶，所得产物用乙醚洗涤，得黄色产物A-65(2.9g，59％)，熔点：105～107℃。Sodium borohydride (1.2g, 32mmol) dissolved in 5% sodium hydroxide solution (10ml) was added dropwise to methanol (250ml) containing palmatine (7.8g, 20mmol) and potassium carbonate (8.3g, 60mmol) In the solution system, stir at room temperature for 2 hours, collect the precipitated yellow-green solid by suction filtration, and wash the filter cake successively with distilled water (100ml) and 80% ethanol (100ml) to obtain the intermediate dihydropalatine (4.4g, 62%) . The intermediate dihydropalatine (4.2g, 12mmol) was dissolved in acetonitrile (160ml), then acetic acid (40ml) and 40% glyoxal (2ml) were added, heated to 85-95°C and refluxed for 5 hours, plate Layer monitoring reaction was complete, the reaction solution was concentrated to obtain dark red oily matter, added 2% hydrochloric acid solution (200ml), stirred at room temperature for 1 hour, filtered, the filtrate was stirred at room temperature for 5 days, the reaction solution was concentrated, recrystallized with 95% ethanol, The obtained product was washed with diethyl ether to obtain a yellow product A-65 (2.9 g, 59%), melting point: 105-107°C.

HRMS-ESI(M/Z)：376.1564【M-Cl】+ HRMS-ESI(M/Z): 376.1564【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.67(t，J＝6.8Hz，2H)，3.97(s，3H)，4.06(s，3H)，4.12(s，3H)，4.17(s，3H)，5.27(t，J＝6.8Hz，2H)，7.72(s，1H)，8.32(d，J＝9.2Hz，1H)，8.45(d，J＝9.2Hz，1H)，8.88(d，J＝9.2Hz，1H)，8.92(d，J＝9.6Hz，1H)，10.15(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.67(t, J=6.8Hz, 2H), 3.97(s, 3H), 4.06(s, 3H), 4.12(s, 3H), 4.17(s , 3H), 5.27(t, J=6.8Hz, 2H), 7.72(s, 1H), 8.32(d, J=9.2Hz, 1H), 8.45(d, J=9.2Hz, 1H), 8.88(d , J=9.2Hz, 1H), 8.92(d, J=9.6Hz, 1H), 10.15(s, 1H).

实施例51：化合物A-66的合成Example 51: Synthesis of Compound A-66

将A-65(2.0g，4.9mmol)置于250ml圆底烧瓶中，保持真空度为30～40mmHg，加热至195～210℃反应30分钟，固体颜色逐渐加深，最后全部变为深红色。以二氯甲烷/甲醇为流动相，用减压硅胶柱分离纯化，乙醇∶浓盐酸(V∶V＝95∶5)体系酸化得到红色产物A-66(1.5g，77％)，熔点：110～112℃。Put A-65 (2.0g, 4.9mmol) in a 250ml round bottom flask, keep the vacuum at 30-40mmHg, heat to 195-210°C for 30 minutes, the color of the solid gradually deepens, and finally all of them turn dark red. Use dichloromethane/methanol as the mobile phase, separate and purify with reduced-pressure silica gel column, acidify with ethanol:concentrated hydrochloric acid (V:V=95:5) system to obtain red product A-66 (1.5g, 77%), melting point: 110 ~112°C.

HRMS-ESI(M/Z)：362.1395【M-Cl】+ HRMS-ESI(M/Z): 362.1395【M-Cl】 +

1H NMR(CD3SOCD3，400MHz)：δ3.56(t，J＝6.4Hz，2H)，3.94(s，3H)，3.95(s，3H)，4.02(s，3H)，5.02(t，J＝6.4Hz，2H)，7.61(s，1H)，7.79(d，J＝8.0Hz，1H)，7.92(s，1H)，8.27(d，J＝9.2Hz，1H)，8.66(d，J＝9.2Hz，1H)，9.74(s，1H). 1 H NMR (CD 3 SOCD 3 , 400MHz): δ3.56(t, J=6.4Hz, 2H), 3.94(s, 3H), 3.95(s, 3H), 4.02(s, 3H), 5.02(t , J=6.4Hz, 2H), 7.61(s, 1H), 7.79(d, J=8.0Hz, 1H), 7.92(s, 1H), 8.27(d, J=9.2Hz, 1H), 8.66(d , J=9.2Hz, 1H), 9.74(s, 1H).

试验例1：本发明化合物抗增殖活性测定Test Example 1: Determination of anti-proliferative activity of compounds of the present invention

材料和方法Materials and methods

1、受试药物：本发明一些示例性的化合物，对照药为羟基喜树碱(10-hydroxycamptothecin，HCPT)。1. Test drug: some exemplary compounds of the present invention, and the control drug is 10-hydroxycamptothecin (HCPT).

2、细胞株：HepG2细胞。2. Cell line: HepG2 cells.

3、药液浓度为0.6μg/mL。3. The concentration of the drug solution is 0.6 μg/mL.

4、方法：将对数生长期的HepG2细胞消化计数后接种于96孔培养板，5000个/孔/200μL，24h后加药，每组药物设5个复孔，并设DMSO溶媒对照孔和无细胞调零孔。于37℃、5％CO2条件下培养48h，PBS洗涤后每孔再加入200μL PBS，滴加50μL 50％(m/v)的三氯乙酸(TCA)固定细胞，TCA终浓度为10％，4℃放置1小时。弃固定液，用蒸馏水洗涤5次，空气中自然干燥。每孔加入50μL的磺酰罗丹明溶液，室温下放置10-30min。去上清，用1％的醋酸洗涤5次，空气干燥。最后加入10mmol/l的Tris溶液(pH＝10.5)150μL，在平板振荡器上振荡5min。在酶联免疫检测仪(Model3550，Bio-Rad)测定OD值，用空白对照调零，所用波长为570nm。按以下公式计算肿瘤细胞生长的抑制率：4. Method: HepG2 cells in the logarithmic growth phase were digested and counted and inoculated in a 96-well culture plate, 5000 cells/well/200 μL, and the drug was added after 24 hours. Each group of drugs was set up with 5 replicate wells, and DMSO solvent control wells and wells were set. Zero wells with no cells. Cultured at 37°C and 5% CO2 for 48 h, after washing with PBS, 200 μL of PBS was added to each well, and 50 μL of 50% (m/v) trichloroacetic acid (TCA) was added dropwise to fix the cells. The final concentration of TCA was 10%. Place at 4°C for 1 hour. Discard the fixative, wash 5 times with distilled water, and air dry naturally. Add 50 μL of sulforhodamine solution to each well, and place at room temperature for 10-30 min. Remove the supernatant, wash 5 times with 1% acetic acid, and air dry. Finally, 150 μL of 10 mmol/l Tris solution (pH=10.5) was added and shaken on a plate shaker for 5 min. The OD value was measured in an enzyme-linked immunosorbent detector (Model 3550, Bio-Rad), and zeroed with a blank control, and the wavelength used was 570 nm. The inhibition rate of tumor cell growth was calculated according to the following formula:

抑制率＝[(OD570对照孔-OD570给药孔)/OD570对照孔]×100％。Inhibition rate=[(OD 570 control well -OD 570 administration well )/OD 570 control well ]×100%.

以上实验重复三次，得到平均抑制率。The above experiments were repeated three times to obtain the average inhibition rate.

在相同测定条件下，对照药HCPT的抑制率为85.4％。结果表明本发明化合物在抗增殖方面具有明显效果。Under the same assay conditions, the inhibition rate of the control drug HCPT was 85.4%. The results show that the compounds of the present invention have obvious effects on anti-proliferation.

试验例2：用MCF-7、Hela、HT1080和HCT116四种肿瘤细胞筛选化合物Test Example 2: Screening Compounds with Four Tumor Cells MCF-7, Hela, HT1080 and HCT116

材料和方法Materials and methods

1、受试药物：本发明一些示例性的化合物，对照药为羟基喜树碱(10-hydroxycamptothecin，HCPT)。1. Test drug: some exemplary compounds of the present invention, and the control drug is 10-hydroxycamptothecin (HCPT).

2、细胞株：MCF-7、Hela、HT1080和HCT116。2. Cell lines: MCF-7, Hela, HT1080 and HCT116.

3、药液浓度为0.6μg/mL。3. The concentration of the drug solution is 0.6 μg/mL.

4、方法：将对数生长期的细胞消化计数后接种于96孔培养板，5000个/孔/200μL，24h后加药，每组药物设5个复孔，并设DMSO溶媒对照孔和无细胞调零孔。于37℃、5％CO2条件下培养48h，PBS洗涤后每孔再加入200μL PBS，滴加50μL 50％(m/v)的三氯乙酸(TCA)固定细胞，TCA终浓度为10％，4℃放置1小时。弃固定液，用蒸馏水洗涤5次，空气中自然干燥。每孔加入50μL的磺酰罗丹明溶液，室温下放置10-30min。去上清，用1％的醋酸洗涤5次，空气干燥。最后加入10mmol/l的Tris溶液(pH＝10.5)150μL，在平板振荡器上振荡5min。在酶联免疫检测仪(Model3550，Bio-Rad)测定OD值，用空白对照调零，所用波长为570nm。按以下公式计算肿瘤细胞生长的抑制率：4. Method: Digest and count the cells in the logarithmic growth phase and inoculate them in a 96-well culture plate, 5000 cells/well/200 μL, add drugs after 24 hours, set 5 duplicate holes for each group of drugs, and set DMSO solvent control wells and no Cell zero well. Cultured at 37°C and 5% CO2 for 48 hours, after washing with PBS, 200 μL of PBS was added to each well, and 50 μL of 50% (m/v) trichloroacetic acid (TCA) was added dropwise to fix the cells. The final concentration of TCA was 10%, 4 °C for 1 hour. Discard the fixative, wash 5 times with distilled water, and air dry naturally. Add 50 μL of sulforhodamine solution to each well, and place at room temperature for 10-30 min. Remove the supernatant, wash 5 times with 1% acetic acid, and air dry. Finally, 150 μL of 10 mmol/l Tris solution (pH=10.5) was added and shaken on a plate shaker for 5 min. The OD value was measured in an enzyme-linked immunosorbent detector (Model 3550, Bio-Rad), and zeroed with a blank control, and the wavelength used was 570 nm. The inhibition rate of tumor cell growth was calculated according to the following formula:

抑制率＝[(OD570对照孔-OD570给药孔)/OD570对照孔]×100％。Inhibition rate=[(OD570 control well-OD570 administration well)/OD570 control well]×100%.

以上实验重复三次，得到平均抑制率。本发明部分化合物对肿瘤细胞增殖的活性见下表：The above experiments were repeated three times to obtain the average inhibition rate. The activity of some compounds of the present invention on tumor cell proliferation is shown in the following table:

结果表明，在相同测定条件下，本发明化合物在抗增殖方面具有明显效果。The results show that under the same assay conditions, the compounds of the present invention have obvious effects on anti-proliferation.

试验例3：化合物A-35、A-55、A-40和A-56对细胞HepG2和HCT116的IC50测定Test Example 3: Determination of IC 50 of Compounds A-35, A-55, A-40 and A-56 on HepG2 and HCT116 Cells

材料和方法Materials and methods

1、受试药物：本发明一些示例性的化合物。1. Test drugs: some exemplary compounds of the present invention.

2、细胞株：HepG2和HCT116。2. Cell lines: HepG2 and HCT116.

3、药液浓度为2μg/mL、1μg/mL、0.5μg/mL、0.25μg/mL和0.125μg/mL。3. The concentration of the drug solution is 2μg/mL, 1μg/mL, 0.5μg/mL, 0.25μg/mL and 0.125μg/mL.

4、方法：将对数生长期的细胞消化计数后接种于96孔培养板，5000个/孔/200μL，24h后加药，每组药物设5个复孔，并设DMSO溶媒对照孔和无细胞调零孔。于37℃、5％CO2条件下培养48h，PBS洗涤后每孔再加入200μL PBS，滴加50μL 50％(m/v)的三氯乙酸(TCA)固定细胞，TCA终浓度为10％，4℃放置1小时。弃固定液，用蒸馏水洗涤5次，空气中自然干燥。每孔加入50μL的磺酰罗丹明溶液，室温下放置10-30min。去上清，用1％的醋酸洗涤5次，空气干燥。最后加入10mmol/l的Tris溶液(pH＝10.5)150μL，在平板振荡器上振荡5min。在酶联免疫检测仪(Model3550，Bio-Rad)测定OD值，用空白对照调零，所用波长为570nm。按以下公式计算肿瘤细胞生长的抑制率：4. Method: Digest and count the cells in the logarithmic growth phase and inoculate them in a 96-well culture plate, 5000 cells/well/200 μL, add drugs after 24 hours, set 5 duplicate holes for each group of drugs, and set DMSO solvent control wells and no Cell zero well. Cultured at 37°C and 5% CO2 for 48 hours, after washing with PBS, 200 μL of PBS was added to each well, and 50 μL of 50% (m/v) trichloroacetic acid (TCA) was added dropwise to fix the cells. The final concentration of TCA was 10%, 4 °C for 1 hour. Discard the fixative, wash 5 times with distilled water, and air dry naturally. Add 50 μL of sulforhodamine solution to each well, and place at room temperature for 10-30 min. Remove the supernatant, wash 5 times with 1% acetic acid, and air dry. Finally, 150 μL of 10 mmol/l Tris solution (pH=10.5) was added and shaken on a plate shaker for 5 min. The OD value was measured in an enzyme-linked immunosorbent detector (Model 3550, Bio-Rad), and zeroed with a blank control, and the wavelength used was 570 nm. The inhibition rate of tumor cell growth was calculated according to the following formula:

IC50采用sigmaplot中的IC50计算公式得到。IC50 was obtained using the IC50 calculation formula in sigmaplot.

以上实验重复三次，得到IC50。本发明部分化合物对肿瘤细胞的IC50列于下表：The above experiments were repeated three times to obtain IC 50 . The IC of some compounds of the present invention to tumor cells is listed in the following table:

Figure BDA0000151312600000301
Figure BDA0000151312600000301

本发明化合物的IC50均较低，数值均在1μM以下，在抗增殖方面具有明显效果。The compounds of the present invention have low IC 50 values below 1 μM, and have obvious effects on anti-proliferation.

试验例4：化合物A-35对耐药细胞IC50的测定Test Example 4: Determination of IC 50 of Compound A-35 on drug-resistant cells

材料和方法Materials and methods

1、受试药物：本发明的化合物A-35和阿霉素。1. Test drug: compound A-35 of the present invention and doxorubicin.

2、细胞株：MCF-7和耐阿霉素的细胞株MCF-7/DOX。2. Cell lines: MCF-7 and doxorubicin-resistant cell line MCF-7/DOX.

3、药液浓度为0.5μg/mL、1μg/mL、2μg/mL、4μg/mL、8μg/Ml、16μg/mL、32μg/mL和64μg/mL。3. The concentration of the drug solution is 0.5 μg/mL, 1 μg/mL, 2 μg/mL, 4 μg/mL, 8 μg/Ml, 16 μg/mL, 32 μg/mL and 64 μg/mL.

4、方法：将对数生长期的细胞消化计数后接种于96孔培养板，5000个/孔/200μL，24h后加药，每组药物设5个复孔，并设DMSO溶媒对照孔和无细胞调零孔。于37℃、5％CO2条件下培养48h，PBS洗涤后每孔再加入200μL PBS，滴加50μL 50％(m/v)的三氯乙酸(TCA)固定细胞，TCA终浓度为10％，4℃放置1小时。弃固定液，用蒸馏水洗涤5次，空气中自然干燥。每孔加入50μL的磺酰罗丹明溶液，室温下放置10-30min。去上清，用1％的醋酸洗涤5次，空气干燥。最后加入10mmol/l的Tris溶液(pH＝10.5)150μL，在平板振荡器上振荡5min。在酶联免疫检测仪(Model3550，Bio-Rad)测定OD值，用空白对照调零，所用波长为570nm。按以下公式计算肿瘤细胞生长的抑制率：4. Method: Digest and count the cells in the logarithmic growth phase and inoculate them in a 96-well culture plate, 5000 cells/well/200 μL, add drugs after 24 hours, set 5 duplicate holes for each group of drugs, and set DMSO solvent control wells and no Cell zero well. Cultured at 37°C and 5% CO2 for 48 hours, after washing with PBS, 200 μL of PBS was added to each well, and 50 μL of 50% (m/v) trichloroacetic acid (TCA) was added dropwise to fix the cells. The final concentration of TCA was 10%, 4 °C for 1 hour. Discard the fixative, wash 5 times with distilled water, and air dry naturally. Add 50 μL of sulforhodamine solution to each well, and place at room temperature for 10-30 min. Remove the supernatant, wash 5 times with 1% acetic acid, and air dry. Finally, 150 μL of 10 mmol/l Tris solution (pH=10.5) was added and shaken on a plate shaker for 5 min. The OD value was measured in an enzyme-linked immunosorbent detector (Model 3550, Bio-Rad), and zeroed with a blank control, and the wavelength used was 570 nm. The inhibition rate of tumor cell growth was calculated according to the following formula:

IC50采用sigmaplot中的IC50计算公式得到。IC50 was obtained using the IC50 calculation formula in sigmaplot.

以上实验重复三次，得到IC50。结果见图1。The above experiments were repeated three times to obtain IC 50 . The results are shown in Figure 1.

由结果可见，本发明化合物可逆转耐阿霉素的细胞的耐药性。It can be seen from the results that the compound of the present invention can reverse the drug resistance of doxorubicin-resistant cells.

试验例5：细胞周期分析Test Example 5: Cell Cycle Analysis

材料和方法Materials and methods

1、受试药物：本发明的化合物A-35。1. Test drug: compound A-35 of the present invention.

2、细胞株：HCT116细胞。2. Cell line: HCT116 cells.

3、药液浓度为0.5μg/mL。3. The concentration of the drug solution is 0.5 μg/mL.

4、方法：用0.5μg/mL处理HCT116细胞，分别在4h、12h和24h收集药物处理后的细胞，PBS洗两次，加入预冷的75％乙醇，-20℃固定过夜，离心除去乙醇，PBS洗两次，加入200mg·mL-1RNA酶，37℃消化30min，加碘化吡啶25mg·mL-1，4℃避光。4. Method: Treat HCT116 cells with 0.5 μg/mL, collect drug-treated cells at 4h, 12h, and 24h respectively, wash twice with PBS, add pre-cooled 75% ethanol, fix at -20°C overnight, and centrifuge to remove ethanol. Wash twice with PBS, add 200mg·mL-1 RNase, digest at 37°C for 30min, add 25mg·mL-1 pyridinium iodide, and protect from light at 4°C.

结果见图2。结果表明本发明化合物将细胞阻滞在G2/M期。The results are shown in Figure 2. The results show that the compounds of the present invention arrest cells in G2/M phase.

试验例6：拓扑异构酶实验Experiment 6: Topoisomerase experiment

材料和方法Materials and methods

1、受试药物：本发明的化合物A-35。1. Test drug: compound A-35 of the present invention.

2、实验对象：拓扑异构酶I以及其底物pBR322DNA。2. Experimental object: topoisomerase I and its substrate pBR322DNA.

3、药液浓度为30μg/mL、3μg/mL和0.3μg/mL。3. The concentration of the drug solution is 30μg/mL, 3μg/mL and 0.3μg/mL.

4、方法：拓扑异构酶I活性的测定在20μl的反应体系中含有10×反应缓冲液(350mmol/L Tris-HCl pH8.0mmol/L，720mmol/L氯化钾，5mmol/L氯化镁，50mmol/L DTT，50mmol/L Spermidine)2μl，0.1％BAS 2μl，PBR3220.36μg，阳性对照管(羟基喜树碱)终浓度为212.5μg/ml，10.6μg/ml。各试管分别加入不同浓度的A-35(终浓度分别为30μg/mL、3μg/mL和0.3μg/mL)。拓扑异构酶I，各管用蒸馏水补充至20μl，混匀后置37℃反应30min，加入5μl终止液(5％的SDD，40％的蔗糖，0.25mg/ml溴酚兰)终止反应。在TBE电泳缓冲液中进行琼脂糖电泳，40V电压下，电泳4h。溴化乙啶溶液(1μg/μl)染色30min，置260nm紫外线下观察DNA的电泳区带，并摄片记录。4. Method: Determination of topoisomerase I activity in a 20 μl reaction system containing 10× reaction buffer (350mmol/L Tris-HCl pH8.0mmol/L, 720mmol/L potassium chloride, 5mmol/L magnesium chloride, 50mmol /L DTT, 50mmol/L Spermidine) 2μl, 0.1% BAS 2μl, PBR3220.36μg, positive control tube (hydroxycamptothecin) final concentration of 212.5μg/ml, 10.6μg/ml. Different concentrations of A-35 were added to each test tube (final concentrations were 30 μg/mL, 3 μg/mL and 0.3 μg/mL, respectively). For topoisomerase I, each tube was replenished to 20 μl with distilled water, mixed evenly and placed at 37°C for 30 min, and 5 μl of stop solution (5% SDD, 40% sucrose, 0.25 mg/ml bromophenol blue) was added to terminate the reaction. Carry out agarose electrophoresis in TBE electrophoresis buffer, under 40V voltage, electrophoresis 4h. Stain with ethidium bromide solution (1 μg/μl) for 30 minutes, observe the electrophoresis zone of DNA under 260nm ultraviolet light, and take pictures for records.

结果见图3。结果表明本发明化合物对拓扑异构酶I具有抑制作用。The results are shown in Figure 3. The results show that the compound of the present invention has inhibitory effect on topoisomerase I.

Claims (10)

1. formula I compound:
Figure FDA0000151312590000011
Or its pharmacologically acceptable salts or solvate, wherein
X is a halogen;
R 1Be selected from: hydrogen, C 1-6Alkyl, the substituted C of phenyl 1-6Alkyl, C 1-18Alkyl acyl, benzoyl-, benzenesulfonyl, 3,4-C 1-3The alkylenedioxy group benzoyl-, wherein said phenyl is optional to be selected from following substituting group replacement by 1 to 4: halogen, C 1-6Alkyl, C 1-6Alkoxyl group, nitro, cyanic acid, amino, hydroxyl, C 1-4Alkyl acyl is amino;
R 2And R 3Be selected from independently of one another: hydrogen, C 1-6Alkyl, benzoyl-, wherein said phenyl is optional to be replaced by 1 to 4 halogen; Perhaps R 2And R 3Be together-CH 2-.
2. the compound of claim 1, wherein X is selected from fluorine, chlorine, bromine, iodine.
3. each compound of claim 1 to 2, wherein R is selected from hydrogen, C 1-4Alkyl, the substituted C of phenyl 1-4Alkyl, C 1-16Alkyl acyl, benzoyl-, benzenesulfonyl, 3,4-C 1-2The alkylenedioxy group benzoyl-, wherein said phenyl is optional to be selected from following substituting group replacement by 1 to 4: halogen, C 1-4Alkyl, C 1-4Alkoxyl group, nitro, cyanic acid, amino, hydroxyl, C 1-4Alkyl acyl is amino.
4. each compound of claim 1 to 3, wherein R 2And R 3Be selected from independently of one another: hydrogen, C 1-4Alkyl, halogeno-benzene formyl radical; Perhaps R 2And R 3Be together-CH 2-.
5. each compound of claim 1 to 4, it is a following formula: compound,
Figure FDA0000151312590000021
R wherein 1, R 2, R 3Have following each said implication of numbering No1 to No51 with X:
Figure FDA0000151312590000022
Figure FDA0000151312590000031
6. each compound of claim 1 to 5, it is to be selected from following compound:
9,10-dimethoxy-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-hydroxyl-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-oxyethyl group-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide;
9-butoxy-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-iodide;
9-benzyloxy-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide;
9-(2,4 difluorobenzene base) methoxyl group-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide;
9-ethanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-benzoyl-Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methyl benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to anisoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to fluoro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to fluorine m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methyl m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methoxyl group m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(3,4-methylene-dioxy benzoyl-oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(3,4,5-trimethoxy benzoyl-oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
The adjacent fluoro benzoyl Oxy-1 of 9-0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
The adjacent chlorobenzene formacyl Oxy-1 of 9-0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(2,4 difluorobenzene formyl radical oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to acetamido benzenesulfonyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole and 4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-benzenesulfonyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquinoline 99.9 [8,1,2-cde] phenanthridines-7-muriate;
9-decanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-lauroyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-hexadecanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
Or its pharmacologically acceptable salts or solvate.
7. prepare the method for each said compound of claim 1 to 6, it may further comprise the steps:
A) in solvent, in the presence of alkali, make the reaction of Peng Qinghuana and Berberine, obtain dihydroberberine;
B) in solvent, in the presence of acid, make dihydroberberine and glyoxal reaction, obtain the cyclisation Berberine shown in the formula Ia:
Figure FDA0000151312590000051
Choose wantonly, c) make formula Ia cyclisation Berberine under vacuum, at high temperature handle and to obtain the 9-hydroxyl cyclisation Berberine shown in the formula Ib:
Figure FDA0000151312590000052
Choose wantonly, d) in organic solvent, in the presence of alkali, make 9-hydroxyl cyclisation Berberine and the suitable reagent reaction of formula Ib, obtain 9-alkyl oxy cyclisation Berberine, alkyl wherein is optional to be replaced by phenyl or substituted phenyl;
Choose wantonly; E) in organic solvent, in the presence of reagent, make 9-hydroxyl cyclisation Berberine and acyl chlorides or the SULPHURYL CHLORIDE reaction of formula Ib; Obtain 9-acyloxy cyclisation Berberine or 9-alkylsulfonyl oxygen basic ring Berberine, acyl group wherein is alkyloyl or benzoyl-.
8. pharmaceutical composition, it comprises each said compound of claim 1 to 6, and optional one or more pharmaceutically acceptable carriers or vehicle.
9. each said compound of claim 1 to 6 is used for treating and/or preventing the purposes of the medicine of mammal tumor or cancer property disease in preparation.
10. the purposes of claim 9, wherein said tumour or cancer property disease are liver cancer.
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WO2018068769A1 (en) * 2016-10-14 2018-04-19 中国医学科学院药物研究所 Use of dihydroberberine type compounds in preparation of product for treating tumour diseases associated with stat3 signaling pathway
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CN109928967A (en) * 2017-11-28 2019-06-25 中国医学科学院医药生物技术研究所 A kind of cyclisation berberinc derivate and its preparation method and application
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CN108822095B (en) * 2018-07-25 2020-05-01 山东大学 Benzo [ h ] chromene compound and application thereof as AcrB efflux pump inhibitor in antibiosis
CN116338060A (en) * 2022-01-25 2023-06-27 成都硕德药业有限公司 A method for the determination of genotoxic impurities in chemical raw materials containing amino groups
CN116338060B (en) * 2022-01-25 2025-06-03 成都硕德药业有限公司 A method for determining genotoxic impurities in chemical raw materials containing amino groups
CN114736202A (en) * 2022-04-20 2022-07-12 四川大学 Preparation and use of berberine derivatives with IDO1/TDO inhibitory activity

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