CN111454229A - Dihydronaphthoisoxazole derivative and application thereof in antitumor drugs - Google Patents

Abstract

Translated fromChinese

本发明属于药物合成技术领域，提供了如通式所示的二氢萘并异噁唑类衍生物及其制备方法，本发明还公开了所述二氢萘并异噁唑类衍生物在制备抗肿瘤药物中的应用，MTT结果显示，该类化合物对多种肿瘤细胞具有显著的抑制作用。

The invention belongs to the technical field of drug synthesis, and provides dihydronaphthoxazole derivatives as shown in the general formula and a preparation method thereof. The invention also discloses that the dihydronaphthoxazole derivatives are prepared in The application of anti-tumor drugs, MTT results show that these compounds have a significant inhibitory effect on a variety of tumor cells.

Description

Translated fromChinese

二氢萘并异噁唑类衍生物及其在抗肿瘤药物中的应用Dihydronaphthoxazole derivatives and their application in antitumor drugs

技术领域technical field

本发明属于药物合成技术领域，尤其涉及一类新型二氢萘并异噁唑类衍生物，以及此类衍生物的制备方法及其作为抗肿瘤药物中的应用。The invention belongs to the technical field of drug synthesis, and in particular relates to a new class of dihydronaphthoisoxazole derivatives, a preparation method of such derivatives and their application as antitumor drugs.

技术背景technical background

癌症是起源于上皮组织的恶性肿瘤，以细胞的快速增殖和转移为特点的疾病，死亡率居于所有疾病的首位。根据国际癌症研究机构公布的全球最新癌症数据，2012年全球新增约1410万例癌症患者，并且还将以11％左右的年增长速度递增。因此，癌症治疗方面的研究一直被全世界所密切关注。Cancer is a malignant tumor originating from epithelial tissue, characterized by rapid proliferation and metastasis of cells, and the mortality rate ranks first among all diseases. According to the latest global cancer data released by the International Agency for Research on Cancer, there were about 14.1 million new cancer patients worldwide in 2012, and the annual growth rate will increase by about 11%. Therefore, research on cancer treatment has been closely watched all over the world.

目前，临床上治疗癌症的方式主要有四种：手术治疗、放射线治疗、化学药物治疗和免疫治疗。与其他三种方法相比，化学药物治疗一般是无痛的，并且对癌细胞的杀伤力是其他治疗癌症的手段所难以达到的。但大多数的化学药物并不具有专一性，在杀死癌细胞的同时，会对肿瘤周围的正常组织细胞造成损伤，这些组织通常只有在化疗后可以自行修复。所以，寻找靶向性强、效果显著、安全性高的抗肿瘤药物已经成为全球医药研发者研究的热点之一。At present, there are four main ways of clinical treatment of cancer: surgery, radiation therapy, chemotherapy and immunotherapy. Compared with the other three methods, chemotherapy treatment is generally painless, and the killing power to cancer cells is difficult to achieve by other methods of treating cancer. But most chemical drugs are not specific. While killing cancer cells, they will cause damage to normal tissue cells around the tumor. These tissues usually repair themselves only after chemotherapy. Therefore, the search for anti-tumor drugs with strong targeting, significant effect and high safety has become one of the hotspots in the research of global pharmaceutical developers.

随着肿瘤分子生物学技术的不断发展，人们对恶性肿瘤发病机制进一步的认识，对多种致癌途径的不断揭示，研制了多种分子靶向治疗药物。分子靶向治疗是针对在肿瘤发生、发展及转移过程中起关键作用的靶分子及其相关信号通路，干扰或阻断其功效，达到抑制肿瘤生长、转移的目的。随着分子生物学的发展，癌症治疗已经进入靶向的治疗时代。因此，进一步研发靶向性强、高效、低毒的新型抗癌药物，己成为当今抗肿瘤药物研究的重要方向。With the continuous development of tumor molecular biology technology, people's further understanding of the pathogenesis of malignant tumors, and the continuous disclosure of various carcinogenic pathways, a variety of molecular targeted therapy drugs have been developed. Molecular targeted therapy is aimed at target molecules and their related signaling pathways that play a key role in the occurrence, development and metastasis of tumors, interfering or blocking their efficacy, and achieving the purpose of inhibiting tumor growth and metastasis. With the development of molecular biology, cancer treatment has entered the era of targeted therapy. Therefore, further research and development of new anti-cancer drugs with strong targeting, high efficiency and low toxicity has become an important direction of current anti-tumor drug research.

发明内容SUMMARY OF THE INVENTION

本发明的目的是针对现有技术的不足，提供一类新型二氢萘并异噁唑类衍生物，以及所述化合物的药学可接受的盐、水合物、溶剂化物或前药，并提供所述衍生物的制备方法以及所述衍生物的用途。The purpose of the present invention is to aim at the deficiencies of the prior art, to provide a new class of dihydronaphthoxazole derivatives, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds, and to provide the The preparation method of the derivative and the use of the derivative.

为实现上述目的，本发明所述的新型二氢萘并异噁唑类衍生物为通式I所示，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，In order to achieve the above purpose, the novel dihydronaphthoxazole derivatives of the present invention are shown in general formula I, and geometric isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or pro-forms thereof. medicine,

所述的R₁选自1-3个选自羟基、卤素、硝基、氨基、氰基、(C₁-C₆)烷基、(C₂-C₆)烯基、(C₂-C₆)炔基、(C₁-C₆)烷氧基。The R₁ is selected from 1-3 selected from hydroxyl, halogen, nitro, amino, cyano, (C₁ -C₆ ) alkyl, (C₂ -C₆ ) alkenyl, (C₂ -C₆ ) Alkynyl, (_C1 -_C6 )alkoxy.

优选的，所述R₁选自1-3个选自羟基、卤素、硝基、氨基、氰基、(C₁-C₆)烷基。Preferably, the R₁ is selected from 1-3 selected from hydroxyl, halogen, nitro, amino, cyano, (C₁ -C₆ )alkyl.

本发明中“卤素”是指氟、氯、溴或碘代；“烷基”是指直链或支链的烷基。In the present invention, "halogen" means fluorine, chlorine, bromine or iodine; "alkyl" means straight or branched chain alkyl.

本发明通式I化合物及其药学上可接受的盐、水合物、溶剂化物或前药优选以下化合物，但这些化合物并不意味着对本发明的任何限制：The compounds of general formula I and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the present invention are preferably the following compounds, but these compounds do not mean any limitation to the present invention:

本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式I的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。The present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are derivatives of general formula I, which themselves may have weak or even no activity, but after administration, are destroyed under physiological conditions (eg by metabolism, solvolysis or otherwise) by into the corresponding biologically active form.

本发明的药用组合物可配制成若干种剂型，其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、滴丸剂等剂型药物。The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field. Several of the above-mentioned dosage forms can be used as injections, tablets, capsules, drop pills and other dosage forms.

本发明可以含有通式I的衍生物可以通过包括化学领域众所周知的方法来合成，尤其根据本发明的说明来制备，均可按照路线的方法:由相应的起始原料1与草酸二乙酯在LiHMDS条件下缩合得到中间体2；中间体2和盐酸羟胺通过关环反应得到中间体3；再经过碱液水解得到中间体4；最后与5-氨基异噁唑通过酰胺反应得到目标产物。The present invention may contain derivatives of general formula I, which can be synthesized by methods including well-known methods in the chemical field, especially prepared according to the description of the present invention. Condensed under LiHMDS conditions to obtain intermediate 2; intermediate 2 and hydroxylamine hydrochloride were subjected to ring closure reaction to obtain intermediate 3; and then hydrolyzed with lye to obtain intermediate 4; finally, the target product was obtained by amide reaction with 5-aminoisoxazole.

本发明所述的二氢萘并异噁唑类衍生物合成路线如下：The synthetic route of the dihydronaphthoisoxazole derivatives of the present invention is as follows:

合成路线试剂和条件:(a)Diethyl oxalate,LiHMDS；(b)Hydroxylaminehydrochloride,EtOH,reflux,2h；(c)NaOH,MeOH/H₂O,rt.,7h；(e)EDCI,HOBt,DIEA,rt.,7h.Synthetic route reagents and conditions: (a) Diethyl oxalate, LiHMDS; (b) Hydroxylaminehydrochloride, EtOH, flux, 2h; (c) NaOH, MeOH/H₂ O, rt., 7h; (e) EDCI, HOBt, DIEA, rt.,7h.

本发明的积极进步效果在于：本发明提供了二氢萘并异噁唑类衍生物，其制备方法、药物组合物和应用。MTT结果显示，本发明的二氢萘并异噁唑类衍生物具有较强的抗肿瘤活性优点，可用于制备抗肿瘤药物。The positive progress effect of the present invention is that the present invention provides dihydronaphthisoxazole derivatives, a preparation method, a pharmaceutical composition and an application thereof. The results of MTT show that the dihydronaphthisoxazole derivatives of the present invention have the advantages of strong anti-tumor activity, and can be used for preparing anti-tumor drugs.

具体实施方式Detailed ways

下面提供的实施例旨在阐述而不是限制本发明的范围。原料一般可以从商业来源获取的或者使用本领域技术人员所熟知的方法来制备，或根据本发明所述的方法制备。未经特殊说明，所用试剂均为分析纯或化学纯。The examples provided below are intended to illustrate, but not limit, the scope of the present invention. Starting materials can generally be obtained from commercial sources or prepared using methods well known to those skilled in the art, or prepared according to the methods described herein. Unless otherwise specified, all reagents used are of analytical or chemical grade.

实施例1。Example 1.

(1)1-氧代-1,2,3,4-四氢萘-2-羧酸乙酯(中间体2)的合成：(1) Synthesis of ethyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (Intermediate 2):

将1-四氢萘酮1.5g(10.2mmol)和草酸二乙酯1.8g(12.3mmol)溶于四氢呋喃中，在氩气保护下，将体系温度在冰浴下降至0℃，然后缓慢滴加LiHMDS溶液14.3mL(1MinTHF，14.3mmol)，滴加完毕升温至室温反应6h，TLC检测反应完成，减压蒸除溶剂，得到的浓缩物直接用于下一步反应。1.5 g (10.2 mmol) of 1-tetralone and 1.8 g (12.3 mmol) of diethyl oxalate were dissolved in tetrahydrofuran, and under argon protection, the temperature of the system was lowered to 0 °C in an ice bath, and then slowly added dropwise 14.3 mL of LiHMDS solution (1MinTHF, 14.3 mmol) was added dropwise, and the temperature was raised to room temperature for 6 h. TLC detected that the reaction was complete. The solvent was evaporated under reduced pressure, and the obtained concentrate was directly used in the next reaction.

(2)4,5-二氢萘并[2,1-d]异噁唑-3-甲酸乙酯(中间体3)的合成。(2) Synthesis of 4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylic acid ethyl ester (intermediate 3).

将上步浓缩物溶于40mL冰醋酸中，然后加入盐酸羟胺0.85g(12.3mmol)，升温至80℃反应10h。TLC检测反应完成，将反应液倒入100mL水中，用乙酸乙酯萃取，饱和食盐水洗涤有机层，Na₂SO₄干燥过夜。滤除干燥剂，减压蒸除溶剂，残余物经硅胶柱层析纯化，得1.70g白色固体，收率67.9％。The concentrate from the previous step was dissolved in 40 mL of glacial acetic acid, then 0.85 g (12.3 mmol) of hydroxylamine hydrochloride was added, and the temperature was raised to 80° C. for 10 h. TLC detected the completion of the reaction, poured the reaction solution into 100 mL of water, extracted with ethyl acetate, washed the organic layer with saturated brine, and dried over Na₂ SO₄ overnight. The drying agent was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.70 g of a white solid with a yield of 67.9%.

(3)4,5-二氢萘并[2,1-d]异噁唑-3-甲酸(中间体4)的合成。(3) Synthesis of 4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylic acid (intermediate 4).

将4,5-二氢萘并[2,1-d]异噁唑-3-甲酸乙酯2g(8.2mmol)溶于30mL甲醇中，然后加入10mL的2NNaOH溶液，室温搅拌3h。TLC检测反应完成，减压除去甲醇，再用1N的盐酸调节pH到5-7，析出白色固体，过滤干燥得得白色固体1.62g，收率92.1％。¹H-NMR(600MHz,DMSO-d6)δ7.63(d,J＝6.5Hz,1H),7.14–7.08(m,2H),7.03(d,J＝6.8Hz,1H),2.64(t,J＝7.0Hz,2H),2.32–2.27(m,2H).2 g (8.2 mmol) of ethyl 4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate was dissolved in 30 mL of methanol, then 10 mL of 2N NaOH solution was added, and the mixture was stirred at room temperature for 3 h. TLC detected the completion of the reaction, removed methanol under reduced pressure, adjusted the pH to 5-7 with 1N hydrochloric acid, and precipitated a white solid, which was filtered and dried to obtain 1.62 g of a white solid with a yield of 92.1%.¹ H-NMR(600MHz, DMSO-d6)δ7.63(d,J=6.5Hz,1H),7.14-7.08(m,2H),7.03(d,J=6.8Hz,1H),2.64(t, J=7.0Hz, 2H), 2.32–2.27 (m, 2H).

(4)将4,5-二氢萘并[2,1-d]异噁唑-3-甲酸1.0g(4.6mmol)溶于干燥得DMF中，再加入EDCI2.20g(5.1mmol)和HOBt0.69g(5.1mmol)。在室温下反应1h后加入5-氨基异噁唑0.43g(5.1mmol)和DIEA2.5mL(15.2mmol)，升温至70℃反应6h。TLC检测反应完成，将温度降至室温，反应液倒入100mL水中，析出固体，过滤、干燥柱层析得0.86g白色固体，即目标产物。(4) Dissolve 1.0 g (4.6 mmol) of 4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylic acid in dried DMF, then add 2.20 g (5.1 mmol) of EDCI and HOBt0 .69 g (5.1 mmol). After reacting at room temperature for 1 h, 0.43 g (5.1 mmol) of 5-aminoisoxazole and 2.5 mL (15.2 mmol) of DIEA were added, and the temperature was raised to 70° C. and reacted for 6 h. TLC detected that the reaction was completed, the temperature was lowered to room temperature, the reaction solution was poured into 100 mL of water, a solid was precipitated, filtered and dried by column chromatography to obtain 0.86 g of a white solid, the target product.

¹H-NMR(600MHz,DMSO-d₆)δ11.23(s,1H),8.09(d,J＝7.5Hz,1H),7.68(d,J＝6.5Hz,1H),7.15–7.07(m,2H),7.04(d,J＝6.8Hz,1H),6.79(d,J＝7.5Hz,1H),2.62(t,J＝7.0Hz,2H),2.32–2.27(m,2H).¹ H-NMR (600MHz, DMSO-d₆ )δ11.23(s, 1H), 8.09(d, J=7.5Hz, 1H), 7.68(d, J=6.5Hz, 1H), 7.15-7.07(m ,2H),7.04(d,J＝6.8Hz,1H),6.79(d,J＝7.5Hz,1H),2.62(t,J＝7.0Hz,2H),2.32–2.27(m,2H).

按照实施例1的方法，分别使用取代的1-四氢萘酮为原料，经缩合、关环、水解、缩合四步反应制备得到实施例2-4。According to the method of Example 1, respectively using substituted 1-tetralone as a raw material, and through four-step reactions of condensation, ring closure, hydrolysis, and condensation, examples 2-4 were prepared.

实施例2。Example 2.

¹H-NMR(600MHz,DMSO-d₆)δ11.24(s,1H),8.09(d,J＝7.5Hz,1H),7.80(d,J＝2.0Hz,1H),7.60(dd,J＝8.1,2.1Hz,1H),7.37(d,J＝8.1Hz,1H),7.20(s,1H),6.79(d,J＝7.5Hz,1H),2.63(t,J＝7.0Hz,2H),2.31–2.28(m,2H).¹ H-NMR (600MHz, DMSO-d₆ )δ11.24(s, 1H), 8.09(d, J=7.5Hz, 1H), 7.80(d, J=2.0Hz, 1H), 7.60(dd, J ＝8.1, 2.1Hz, 1H), 7.37(d, J＝8.1Hz, 1H), 7.20(s, 1H), 6.79(d, J＝7.5Hz, 1H), 2.63(t, J＝7.0Hz, 2H) ), 2.31–2.28 (m, 2H).

实施例3。Example 3.

¹H-NMR(600MHz,DMSO-d₆)δ11.22(s,1H),8.09(d,J＝7.5Hz,1H),7.32(d,J＝8.4Hz,1H),7.19(d,J＝2.7Hz,1H),6.98(dd,J＝8.4,2.7Hz,1H),6.80(d,J＝7.5Hz,1H),3.82(s,3H),2.63(t,J＝7.0Hz,2H),2.31–2.28(m,2H).¹ H-NMR (600MHz, DMSO-d₆ )δ11.22(s, 1H), 8.09(d, J=7.5Hz, 1H), 7.32(d, J=8.4Hz, 1H), 7.19(d, J =2.7Hz,1H),6.98(dd,J=8.4,2.7Hz,1H),6.80(d,J=7.5Hz,1H),3.82(s,3H),2.63(t,J=7.0Hz,2H) ), 2.31–2.28 (m, 2H).

实施例4。Example 4.

¹H-NMR(600MHz,DMSO-d₆)δ11.22(s,1H),8.09(d,J＝7.5Hz,1H),7.60(d,J＝8.7Hz,1H),7.01(d,J＝2.2Hz,1H),6.93(dd,J＝8.4,2.5Hz,1H),6.81(d,J＝7.5Hz,1H),3.81(s,3H),2.63(t,J＝7.0Hz,2H),2.31–2.28(m,2H).¹ H-NMR (600MHz, DMSO-d₆ )δ11.22(s, 1H), 8.09(d, J=7.5Hz, 1H), 7.60(d, J=8.7Hz, 1H), 7.01(d, J =2.2Hz,1H),6.93(dd,J=8.4,2.5Hz,1H),6.81(d,J=7.5Hz,1H),3.81(s,3H),2.63(t,J=7.0Hz,2H) ), 2.31–2.28 (m, 2H).

MTT法抗癌细胞增殖实验Anti-cancer cell proliferation experiment by MTT method

癌症细胞接种至96孔板，应用含5％CO₂、100U/mL青霉素和100μg/mL链霉素的RPMI1640完全培养基37℃培养24h，加入不同浓度的化合物，每个浓度设定5个复孔，药物作用48h后，弃培养液，MTT试剂测定细胞活力。Cancer cells were seeded into 96-well plates, and cultured at 37°C for 24 h in RPMI1640 complete medium containing 5% CO₂ , 100 U/mL penicillin and 100 μg/mL streptomycin, and adding different concentrations of compounds, each concentration was set to 5 replicates. After 48 hours of drug action, the culture medium was discarded, and the cell viability was determined by MTT reagent.

测定方法为：15μL/孔加入预先配制好的MTT反应液，继续培养4h，吸弃上清，100μL/孔加入DMSO溶解还原产物，避光反应5min，490nm波长处读取吸光度值，计算细胞活力，以测定化合物干预孔吸光度值/对照孔吸光度值作为细胞活力。IC₅₀指细胞生长被抑制一半时抑制剂的浓度。上述化合物对癌细胞的抑制活性数据见表1。The assay method is: add 15 μL/well of the pre-prepared MTT reaction solution, continue to culture for 4 h, aspirate the supernatant, add 100 μL/well of DMSO to dissolve the reduction product, react in the dark for 5 min, read the absorbance value at 490 nm wavelength, and calculate the cell viability. , and the cell viability was determined as the absorbance value of the compound intervention well/the absorbance value of the control well._IC50 refers to the concentration of inhibitor at which cell growth is inhibited by half. The inhibitory activity data of the above compounds on cancer cells are shown in Table 1.

表1 MTT法测试化合物对癌细胞的抑制活性。Table 1 The inhibitory activity of compounds on cancer cells was tested by MTT method.

本发明中通式I的化合物可单独施用，但通常是和药用载体混合物给予，所述药用载体的选择要根据所需用药途径和标准药物实践，下面分别用该类化合物的各种药物剂型，例如片剂、胶囊剂、注射剂、滴丸剂的制备方法，说明其在制药领域中的新应用。The compounds of general formula I in the present invention can be administered alone, but are usually administered in admixture with a pharmaceutically acceptable carrier. The choice of the pharmaceutically acceptable carrier depends on the desired route of administration and standard pharmaceutical practice. Various drugs of this type of compound are used below. The preparation methods of dosage forms, such as tablets, capsules, injections, and drop pills, illustrate their new applications in the pharmaceutical field.

实施例5：片剂。Example 5: Tablets.

用含有权利要求1中化合物的化合物(以实施例1化合物为例)10g，按照药剂学一般压片法加辅料20g混匀后，压制成100片，每片重300mg。Using 10 g of the compound containing the compound of claim 1 (taking the compound of Example 1 as an example), adding 20 g of auxiliary materials according to the general pharmaceutical tableting method, and mixing, then compressed into 100 tablets, each weighing 300 mg.

实施例6：胶囊剂。Example 6: Capsules.

用含有权利要求1中化合物的化合物(以实施例1化合物为例)10g，按照药剂学胶囊剂的要求将辅料20g混匀后，装入空心胶囊，每个胶囊重300mg。Using 10 g of the compound containing the compound in claim 1 (taking the compound of Example 1 as an example), after mixing 20 g of the auxiliary material according to the requirements of pharmaceutical capsules, it was put into hollow capsules, and each capsule weighed 300 mg.

实施例7：注射剂。Example 7: Injection.

用含有权利要求1中化合物的化合物(以实施例1化合物为例)10g，按照药剂学常规方法，进行活性炭吸附，经0.65μm微孔滤膜过滤后，填入氮气罐制成水针制剂，每只装2mL，共灌装100瓶。Using 10 g of the compound containing the compound in claim 1 (taking the compound of Example 1 as an example), according to the conventional method of pharmacy, carry out activated carbon adsorption, after filtering through a 0.65 μm microporous membrane, fill in a nitrogen tank to prepare a water injection preparation, Each bottle contains 2mL, and a total of 100 bottles are filled.

实施例8：滴丸剂。Example 8: Dropping pills.

用含有权利要求1中化合物的化合物(以实施例1化合物为例)10g，与明胶等基质50g加热熔化混匀后，滴入低温液体石蜡中，共制得滴丸1000丸。10 g of the compound containing the compound in claim 1 (taking the compound of Example 1 as an example) was heated, melted and mixed with 50 g of a matrix such as gelatin, and then dropped into low-temperature liquid paraffin to obtain 1000 dripping pills.

尽管已经通过特定实施方案描述了本发明，但修改和等价变化对于精通此领域的技术人员而言是显见的，且它们都包含在本发明范围。While the invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims (4)

1. Dihydronaphthoisoxazole derivatives shown in a general formula I, geometric isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,

said R₁Selected from 1-3 selected from hydroxyl, halogen, nitro, amino, cyano and (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, (C)₁-C₆) An alkoxy group.

2. Dihydronaphthoisoxazole derivatives according to claim 1, and geometric isomers thereof or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein R is₁Selected from 1-3 selected from hydroxyl, halogen, nitro, amino, cyano and (C)₁-C₆) An alkyl group.

3. Dihydronaphthoisoxazole derivatives shown in the general formula I, and geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, are selected from:

4. the use of dihydronaphthoisoxazole derivatives and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof according to claim 1 for the preparation of medicaments for the treatment of tumors.