WO2013143319A1

WO2013143319A1 - Quinazoline derivative and usage thereof

Info

Publication number: WO2013143319A1
Application number: PCT/CN2012/086251
Authority: WO
Inventors: 卢灿忠; 雍建平
Original assignee: 中国科学院福建物质结构研究所
Priority date: 2012-03-26
Filing date: 2012-12-10
Publication date: 2013-10-03
Also published as: CN103360382B; CN103360382A

Abstract

The present invention provides a quinazoline compound shown in formula (I), or pharmaceutically acceptable salt thereof. R1, R2 and R7 are independently and respectively selected from hydrogen, C1-6 alkyl, C1-6 alkoxy, halogenate C1-6 alkyl, halogenate C1-6 alkoxy, hydroxyl C1-6 alkyl, hydroxyl C1-6 alkoxy, C1-6 alkoxy C1-6 alkoxy, C3-8 cycloalkyloxy, optional aryl or heteroaryl substituted by R6, nitryl, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino; it comprises at least one C3-8 heterocycloalkyloxy selected from N, O, S heteroatoms; Z is -NR4-, C(R5)2, S or -O-, R4 being hydrogen or C1-3 alkyl, and R5 being selected from hydrogen or C1-3 alkyl; R3 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy or halogenate C1-6 alkyl; R6 is selected from hydrogen, C1-3 alkyl, hydroxyl, halogen, C1-3 alkoxy; and n is 0 to 5. The present invention further provides a preparation method of the compound shown in formula (I) or the pharmaceutically acceptable salt and pharmaceutical usage thereof, which can be used as medicines or lead compounds for curing diseases such as tumour and cancer related to protein tyrosine kinase.

Description

说明书 Instruction manual

喹唑淋衍生物及用途 Quinazoline derivatives and uses

技术领域 Technical field

本发明涉及一类结构新颖的舍异噁唑杂环的喹唑啉衍生物及含该类衍生物的药物组合物及其用途，具体而言，涉及具有抑制表皮生长因子蛋白酪氣酸激 (EGFR-TK)活性的喹唑淋化合物或其药物組合物，该类化合物或其盐具有抑制大肠癌细! &株 (HCT-116)和人肺癌细肐林 (A549) 活性，部分化合物对表皮生长因子受体鉻氣酸激醉 ( EGFR-TK )具有较强的抑制活性，该类物质可作为治疗与蛋白輅氨酸激眸有关的肿瘤、癌症等疾病的药物或先导化合物. 背景技术 The present invention relates to a novel structure of a quinazoline derivative having a heterocyclic oxazole heterocyclic ring, a pharmaceutical composition containing the same, and a use thereof, and more particularly to inhibiting epidermal growth factor protein butter cracking EGFR-TK) active quinazoline compound or a pharmaceutical composition thereof, which inhibits colorectal cancer fineness & strain (HCT-116) and human lung cancer lintel (A549) activity, some compounds on epidermis The growth factor receptor chromium oxyacid ( EGFR-TK ) has strong inhibitory activity, and can be used as a drug or a lead compound for treating diseases such as tumors and cancers associated with protein proline stimulating.

表皮生长因子（ Epidermal Growth Factor, EGF )与表皮生长因子受体（ Epidermal Growth Factor Receptor, EGFR )结合可以激活路氨酸激酶的活性，并因此激活导致细胞增殖的反应. EGFR的过度表达和活性增强可以最终导致不可控的细胞***. Epidermal growth factor (EPF) binds to Epidermal Growth Factor Receptor (EGFR) to activate the activity of alanine kinase and thereby activate the response leading to cell proliferation. Overexpression and activity enhancement of EGFR Can eventually lead to uncontrollable cell division.

表皮生长因子受体鉻氛酸激酵 (EGFR-TK)是最早发现的蛋白路氨酸激醉，广泛地分布于人组织的细胞膜上，其在大多 ¾Jit瘤 (如：膀耽癌、非小细 J ^癌、卵巢癌、乳腺癌、胃癌、食道癌等)中过表达， EGFR的胞内区有三碑 «^(ATP)的结合位点， EGFR抑制剂可以竟争性的与 ATP结合位点相结合，从而抑制 EGFR的磷酸化，阻断下游信号的传导，进而抑制肿瘤细胞的生长、分化和转移.以 EGFR受体为耙点进行耙向***是当今癌症治疗中研究十分活跃的领域之一.在临床研究中也已经取得了显著的疗效. 其中以喹唑啉为母核的小分子化合物研究最为突出. The epidermal growth factor receptor chrome-acid sensitizing enzyme (EGFR-TK) is the first discovered protein, which is widely distributed in the cell membrane of human tissues. It is mostly in 3⁄4Jit tumors (eg, bladder cancer, non-small). Overexpression in fine J ^ cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, etc., the intracellular region of EGFR has a binding site of three monuments (ATP), and EGFR inhibitors can compete with ATP binding sites. The combination of dots inhibits the phosphorylation of EGFR, blocks the signaling of downstream signals, and inhibits the growth, differentiation and metastasis of tumor cells. The treatment of tumors with EGFR receptors as a defect is very active in cancer therapy today. One of the fields. It has also achieved remarkable results in clinical research. Among them, the study of small molecule compounds with quinazoline as the mother core is the most prominent.

专利申请公开号 W096/33977、 W096/33978, W096/33979、 WO%/33980、 W096/33981、 WO97/30034 , WO97/30035、 W097/38994、 W098/13354、 WO00/55141、 WO00/56720、 WO02/41882, WO03/82290, EP566226和 EP837063公开了在 4 上携带苯胺基取代和在 6- 和 /或 7 上携带取^ ^的某些喹唑啉化合物，具有受体酸氣酸激醉抑制活性. 上述所有文献引文作为参考. Patent Application Publication Nos. W096/33977, W096/33978, W096/33979, WO%/33980, W096/33981, WO97/30034, WO97/30035, W097/38994, W098/13354, WO00/55141, WO00/56720, WO02 /41882, WO03/82290, EP566226 and EP837063 disclose certain quinazoline compounds which carry an anilino group on 4 and carry a compound on 6- and/or 7 with an acid sulphate inhibitory activity All the above cited citations are for reference.

3-二卤代苯胺基)喹唑啉化合物，所述化合物是 erbB尤其是 EGFR駱氨酸激醉抑制剂 .上述所有文献引^^文作为参考. a 3-dihaloanilino)quinazoline compound, which is an erbB, especially an EGFR lordine intoxication inhibitor. All of the above references are incorporated by reference.

替换页（细则第 26条) 基于 EGFR受体和以喹唑啉为母核的小分子抗肿瘤药物如：吉非替尼 (易瑞沙)、厄罗替尼和拉帕替尼已相继被 FDA批准用于临床。我国王印祥博士和丁列明博士研发的基于厄罗替尼 (特罗凯)的 EGFR受体抑制剂埃克替尼 (凯美纳)，三期临床研究表明其疗效和厄罗替尼相当，安全性更好，给药剂量和方案更适合中国人，已于 2011年 6月被中国食品药品监督管理局批准用于晚期非小细胞肺癌的治疗。 Replacement page (Article 26) Small molecule anti-tumor drugs based on the EGFR receptor and quinazoline as the mother nucleus such as: gefitinib (Iressa), erlotinib and lapatinib have been approved by the FDA for clinical use. The EGFR receptor inhibitor ectotinib (Kemena) based on erlotinib (Troquet) developed by Dr. King Yinxiang and Dr. Ding Liming, a phase III clinical study showed that its efficacy is comparable to that of erlotinib, safety. Better, the dosage and protocol are more suitable for Chinese people. It was approved by the China Food and Drug Administration in June 2011 for the treatment of advanced non-small cell lung cancer.

本发明基于厄罗替尼和埃克替尼，将异噁唑杂环引入喹唑啉母核，合成了一系列含异噁唑杂环的喹唑啉化合物，体外抑制表皮生长因子蛋白酪氨酸激酶 (EGFR-TK)活性表明该类化合物具有较强的抑 EGFR-TK活性，可作为抗肿瘤药物或者先导化合物。发明内容 The invention is based on erlotinib and ectinib, introducing an isoxazole heterocycle into a quinazoline core, synthesizing a series of quinazoline compounds containing an isoxazole heterocycle, inhibiting epidermal growth factor protein tyrosine in vitro Acid kinase (EGFR-TK) activity indicates that the compound has strong anti-EGFR-TK activity and can be used as an antitumor drug or a lead compound. Summary of the invention

本发明的目的在于，提供了如式 (I)所示的含异噁唑杂环的喹唑啉化合物。经过活性研究表明，以该化合物作为活性成分具有抑制 EGFR-TK活性。以该化合物作为活性成分抗大肠癌细胞株 (HCT-116)和人肺癌细胞株 (A549)活性，可作为抗肿瘤的先导化合物。同时该化合物单独或结合一种或几种药学上可接受的、惰性的、无毒的赋形剂或载体组成药物组合物。 It is an object of the present invention to provide an isoxazole-containing quinazoline compound represented by the formula (I). Activity studies have shown that the compound has an inhibitory effect on EGFR-TK activity as an active ingredient. The compound is used as an active ingredient against the activity of colorectal cancer cell line (HCT-116) and human lung cancer cell line (A549), and can be used as a lead compound for antitumor. At the same time, the compound constitutes a pharmaceutical composition either alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.

本发明通过如下技术方案实现： The invention is achieved by the following technical solutions:

一种式 (I)所示的喹唑啉化合物或上可接受的盐 A quinazoline compound or an acceptable salt represented by the formula (I)

其中， among them,

、和11₇各自独立地选自氢， C_1-6烷基， C_1-6烷氧基，羟基 C 烷基，羟基 C_1-6烷氧基，卤代 C_1-6烷基，卤代 C_1-6烷氧基， C_1-6烷氧基 C_1-6烷氧基， C_3-8环烷氧基，任选被 R6取代的芳基，任选被取代的杂芳基，硝基，氨基， C_1-6烷基二（C_1-6烷基）含有至少一个选自 N， 0， S杂原子的杂环烷氧基； And 11 ₇ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy C alkyl, hydroxy C _1-6 alkoxy, halo C _1-6 alkyl, halo C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _3-8 cycloalkoxy, aryl optionally substituted by R 6 , optionally substituted heteroaryl , nitro, amino, C _1-6 alkyl di(C _1-6 alkyl) containing at least one heterocycloalkoxy selected from the group consisting of N, 0, S heteroatoms;

Z为 -NR4-, C(R₅)₂， S或 -0-, 其中为氢或 C_1-3坑基， R₅相同或不同，选自氢或 C_1-3烷基； Z is -NR4-, C(R ₅ ) ₂ , S or -0-, wherein is hydrogen or C _1-3 pit group, R _{5 is the} same or different and is selected from hydrogen or C _1-3 alkyl;

R₃选自氢、卤素， C_1-6烷基、 C_1-6烷氧基或卤代 C_1-6烷基； R6各自独立地选自氢，羟基，巯基，氰基，硝基，卤素， c_1-6烷基， c_1-6烷氧基； C_1-6烷硫基，卤代 C_1-6烷基，或卤代 C_1-6烷氧基； n为 0-5的整数。 R _{3 is} selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkyl; R6 is each independently selected from the group consisting of hydrogen, hydroxy, decyl, cyano, nitro, halogen, _c1-6 alkyl, _c1-6 alkoxy; _C1-6 alkylthio, halo C _1-6 alkane a group, or a halogenated C _1-6 alkoxy group; n is an integer from 0 to 5.

根据本发明的优选技术方案，式（I ) 中， According to a preferred technical solution of the present invention, in the formula (I),

、和11₇各自独立地选自氢， C_1-3烷基， C_1-3烷氧基， C_1-3烷氧基 C_1-3烷氧基，任选被取代的苯基，任选被取代的吡啶基，硝基，含有至少一个选自 N, O, S杂原子的 C_3-8 杂环烷氧基； And 11 ₇ are each independently selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkoxy C _1-3 alkoxy, optionally substituted phenyl, a substituted pyridyl group, a nitro group, a C _3-8 heterocycloalkoxy group containing at least one hetero atom selected from N, O, S;

Z为 -NH-, CH₂或 -0-; R₃选自氢、氟、氯、溴、甲基、曱氧基或三氟曱基， n优选为 1-4，更优选 2-3。 Z is -NH-, CH ₂ or -0-; R _{3 is} selected from hydrogen, fluorine, chlorine, bromine, methyl, decyloxy or trifluoromethyl, and n is preferably from 1 to 4, more preferably from 2 to 3.

根据本发明的优选技术方案，式（ I ) 中： According to a preferred technical solution of the present invention, in the formula (I):

、和11₇各自独立地选自氢， C_1-3烷基， C_1-3烷氧基， C_1-6烷氧基 C_1-6烷氧基，任选被取代的苯基，硝基； And 11 ₇ are each independently selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, optionally substituted phenyl, nitrate base;

Z为 -NH-, -CH₂或 -0-; R6各自独立选自氢， d~C₃烷基，羟基，卤素， C_1-3烷氧基；Z is -NH-, -CH ₂ or -0-; R6 is each independently selected from the group consisting of hydrogen, d-C ₃ alkyl, hydroxy, halogen, C _1-3 alkoxy;

R₃选自氢、氟、氯、溴、曱基、甲氧基或三氟曱基， n优选为 1-4，更优选 2-3。 R _{3 is} selected from hydrogen, fluorine, chlorine, bromine, decyl, methoxy or trifluoromethyl, and n is preferably from 1 to 4, more preferably from 2 to 3.

根据本发明的更优选技术方案，式（I ) 中： Z为 -NH-或 -0-; 和为氢， C_1-3烷氧基，According to a more preferred embodiment of the present invention, in the formula (I): Z is -NH- or -0-; and is hydrogen, C _1-3 alkoxy group,

Ci_-3烷氧基 d_₃烷氧基或硝基； R₇为氢或苯； Ci _-3 alkoxy d_ ₃ alkoxy or nitro; R ₇ is hydrogen or benzene;

R6各自独立选自氢，坑基，羟基，卤素， C_1-3烷氧基； R₃在异噁唑环的邻位或对位，更优选为 4-氟、 4-氯、 2-氯、 4-溴、 2,4-二氯、 4-曱基、 4-甲氧基、氢、 4-三氟曱基或 2,4-二甲氧基。 R6 is each independently selected from the group consisting of hydrogen, pit, hydroxy, halogen, C _1-3 alkoxy; R ₃ is ortho or para to the isoxazole ring, more preferably 4-fluoro, 4-chloro, 2-chloro 4-bromo, 2,4-dichloro, 4-indenyl, 4-methoxy, hydrogen, 4-trifluorodecyl or 2,4-dimethoxy.

根据本发明，还提供一种式IA)所示的喹唑啉化合物，或其药学上可接受的盐 According to the present invention, there is also provided a quinazoline compound of the formula IA), or a pharmaceutically acceptable salt thereof

其中，和各自独立地选自氢， C_1-6烷基， C_1-6烷氧基，羟基 C_1-6烷基，羟基 C_1-6烷氧基，卤代 C_1-6烷基，卤代 C_1-6烷氧基， C_1-6烷氧基 C_1-6烷氧基， C_3-8环烷氧基，任选被 R6取代的芳基，任选被取代的杂芳基，硝基，氨基， C_1-6烷基氨基，二（C_1-6烷基）氨基；含有至少一个选自 N， O, S杂原子的杂环烷氧基；

Wherein, and each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, halo C _1-6 alkyl , halogenated C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _3-8 cycloalkoxy, aryl optionally substituted by R 6 , optionally substituted Aryl, nitro, amino, C _1-6 alkylamino, bis(C _1-6 alkyl)amino; heterocycloalkoxy containing at least one heteroatom selected from N, O, S;

Z为 -NR4-, C(R₅)₂， S或 -0-, 其中为氢或 C_1-3坑基， R₅相同或不同，选自氢或 C_1-3烷基； Z is -NR4-, C(R ₅ ) ₂ , S or -0-, wherein is hydrogen or C _1-3 pit group, R _{5 is the} same or different and is selected from hydrogen or C _1-3 alkane Base

R₃选自氢、卤素， C_1-6烷基、 C_w烷氧基或卤代 C_1-6烷基； R _{3 is} selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _w alkoxy or halogenated C _1-6 alkyl;

R6各自独立地选自氢，羟基，巯基，氰基， J-, 硝基，卤素， C_1-6烷基， C_1-6烷氧基； C_1-6烷硫基，卤代 C_1-6烷基，或卤代 C_1-6烷氧基； n为 0-5的整数。 R6 is independently selected from hydrogen, a hydroxyl group, a mercapto group, a cyano group, J-, nitro, halo, C _1-6 alkyl, C _1-6 alkoxy; C _1-6 alkylthio group, halogeno C _{1 -6} alkyl, or halogenated C _1-6 alkoxy; n is an integer from 0 to 5.

根据本发明，式（IA )中，和各自独立地选自氢， C_1-6烷基， C_1-6烷氧基，卤代 C_1-6 烷氧基， C_1-6烷氧基 C_1-6烷氧基， C_3-8环烷氧基，含有至少一个选自 N， O, S杂原子的 C_3-8 杂环烷氧基； According to the invention, in formula (IA), and each independently selected from hydrogen, _C1-6 alkyl, _C1-6 alkoxy, halo _C1-6 alkoxy, _C1-6 alkoxy C _1-6 alkoxy, C _3-8 cycloalkoxy group, containing at least one heteroatom selected from N, O, S hetero atoms, C _3-8 heterocycloalkyl group;

Z为 -NR4-, C(R₅)₂， S或 -0-，其中 R4为氢或 d Cs)^基， R₅相同或不同，选自氢或 C_1-3 烷基； Z is -NR4-, C(R ₅ ) ₂ , S or -0-, wherein R 4 is hydrogen or d Cs), R _{5 is the} same or different and is selected from hydrogen or C _1-3 alkyl;

R₃选自氢、卤素， C_w烷基、 C_w烷氧基或卤代 C_w烷基； n为 0-5的整数。 R _{3 is} selected from hydrogen, halogen, C _w alkyl, C _w alkoxy or halogenated C _w alkyl; n is an integer from 0 to 5.

根据本发明的优选技术方案，式（IA ) 中：和 R₂为氢， C_1-3烷氧基， C_1-6烷氧基 C_1-6 烷氧基，含有至少一个选自 N, O, S杂原子的 C_3-8杂环烷氧基； Z为 -NH-, CH₂或 -0-; According to a preferred embodiment of the present invention, in the formula (IA): and R ₂ is hydrogen, a C _1-3 alkoxy group, a C _1-6 alkoxy C _1-6 alkoxy group, and at least one selected from the group consisting of N, a C _3-8 heterocycloalkoxy group of an O, S hetero atom; Z is -NH-, CH ₂ or -0-;

根据本发明的更优选技术方案，式（IA )中： Z为 -NH-或 -0-; 和为氢， C_1-3烷氧基，According to a more preferred embodiment of the present invention, in the formula (IA): Z is -NH- or -0-; and is hydrogen, C _1-3 alkoxy group,

C_1-3烷氧基 C_1-3烷氧基； R₃优选在异噁唑环的邻位或对位，更优选为 4-氟、 4-氯、 2-氯、 4-溴、C _1-3 alkoxy C _1-3 alkoxy; R ₃ is preferably ortho or para to the isoxazole ring, more preferably 4-fluoro, 4-chloro, 2-chloro, 4-bromo,

2,4-二氯、 4-甲基、 4-曱氧基、氢、 4-三氟曱基或 2,4-二甲氧基。 2,4-Dichloro, 4-methyl, 4-decyloxy, hydrogen, 4-trifluorodecyl or 2,4-dimethoxy.

根据本发明，还提供一种式IB)所示的喹唑啉衍生物，或其药学上可接受的盐 According to the present invention, there is further provided a quinazoline derivative of the formula IB), or a pharmaceutically acceptable salt thereof

其中：和11₇各自独立地选自氢， C_1-6烷基， C_1-6烷氧基，羟基 C_1-6烷基，羟基 C_1-6烷氧基，卤代 C_1-6烷基，卤代 C_1-6烷氧基， C_1-6烷氧基 C_1-6烷氧基， C_3-8环烷氧基，任选被 R6取代的芳基，任选被取代的杂芳基，硝基，氨基， C_1-6烷基氨基，二（C_1-6烷基）氨基；含有至少一个选自 N， O, S杂原子的杂环烷氧基； Wherein: and 11 ₇ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, halo C _1-6 Alkyl, halo C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _3-8 cycloalkoxy, aryl optionally substituted by R 6 , optionally substituted Heteroaryl, nitro, amino, C _1-6 alkylamino, bis(C _1-6 alkyl)amino; heterocycloalkoxy containing at least one heteroatom selected from N, O, S;

根据本发明的式（IB )，其中，和 R₇各自独立地选自氢， C_1-6坑基， C_1-6烷氧基，卤代 C_1-6烷基，卤代 C_1-6烷氧基， C_1-6烷氧基 C_1-6烷氧基， C_3-8环烷氧基，任选被 R6取代的芳基，任选被 R6取代的杂芳基，硝基，氨基， C_1-6烷基氨基，二（C_1-6烷基）氨基； According to the formula (IB) of the present invention, wherein R and R ₇ are each independently selected from the group consisting of hydrogen, C _1-6 pit group, C _1-6 alkoxy group, halogenated C _1-6 alkyl group, halogenated C _{1- 6} alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _3-8 cycloalkoxy, aryl optionally substituted by R 6 , heteroaryl optionally substituted by R 6 , nitro , amino, C _1-6 alkylamino, di(C _1-6 alkyl)amino;

Z为 -NR4-, C(R₅)₂, -S-或 -0-, 其中 R4为氢或 C_1-3坑基， R₅相同或不同，选自氢或 C_1-3 烷基； Z is -NR4-, C(R ₅ ) ₂ , -S- or -0-, wherein R 4 is hydrogen or a C _1-3 pit group, and R _{5 is the} same or different and is selected from hydrogen or C _1-3 alkyl;

根据本发明的优选技术方案，式（ IB ) 中： According to a preferred technical solution of the present invention, in the formula (IB):

R₇和 R₂各自独立地选自氢， C_1-3烷基， C_1-3烷氧基， C_1-6烷氧基 C_1-6烷氧基，任选被 R6 取代的苯基，硝基； Z为 -NH -， -CH₂或 -0-; R ₇ and R ₂ are each independently selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, phenyl optionally substituted by R ₆ , nitro; Z is -NH -, -CH ₂ or -0-;

根据本发明的更优选技术方案，式（ IB ) 中： According to a more preferred technical solution of the present invention, in the formula (IB):

Z为 -NH-或 -0-; R₇优选为氢或苯， R₂优选为氢或硝基， Z is -NH- or -0-; R ₇ is preferably hydrogen or benzene, and R ₂ is preferably hydrogen or nitro,

R₃优选在异噁唑环的邻位或对位，更优选为 4-氟、 4-氯、 2-氯、 4-溴、 2,4-二氯、 4-曱基、 4-曱氧基、氢、 4-三氟曱基或 2,4-二甲氧基。 R ₃ is preferably ortho or para to the isoxazole ring, more preferably 4-fluoro, 4-chloro, 2-chloro, 4-bromo, 2,4-dichloro, 4-indenyl, 4-anthracene Base, hydrogen, 4-trifluorodecyl or 2,4-dimethoxy.

根据本发明，更优选所述式 (I)所示的喹唑啉化合物选自下述任一种化合物或其药学上可接受的盐： According to the present invention, it is more preferred that the quinazoline compound represented by the formula (I) is selected from any one of the following compounds or a pharmaceutically acceptable salt thereof:

4-[(3-苯基-异噁唑 -5-基) -甲氧基-】 -喹唑啉； 4-[(3-phenyl-isoxazole-5-yl)-methoxy-]-quinazoline;

4-{[3-(4-氟苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 4-{[3-(4-fluorophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

4-{[3-(4-氯苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 4-{[3-(4-chlorophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

4-{[3-(2-氯苯基) -异噁唑 -5-基卜甲氧基+喹唑啉； 4-{[3-(2-chlorophenyl)-isoxazole-5-ylphenoxy+quinazoline;

4-{[3-(4-溴苯基) -异噁唑 -5-基】-甲氧基+喹唑啉； 4-{[3-(4-bromophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

4-{ [3-(2，4-二氯苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 4-{[3-(2,4-dichlorophenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

4-{[3-(4-曱基苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 4-{[3-(4-mercaptophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

4-{ [3-(4-曱氧基苯基) -异噁唑 -5-基】 -曱氧基 +喹唑啉； 4-{[3-(4-decyloxyphenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

4-{[3-(4-三氟甲基苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基卜甲氧基 +喹唑啉； 4-{[3-(4-trifluoromethylphenyl)-isoxazol-5-yl]-decyloxy+quinazoline; 4-{[3-(2,4-dimethoxyphenyl)-isoxazol-5-ylphenoxy+quinazoline;

6,7-二甲氧基 -4-[(3-苯基-异噁唑 -5-基) -甲氧基-】 -喹唑啉； 6,7-dimethoxy-4-[(3-phenyl-isoxazole-5-yl)-methoxy-]-quinazoline;

6,7-二曱氧基 -4-{[3-(4-氟苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 6,7-dimethoxyoxy-4-{[3-(4-fluorophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

6,7-二甲氧基 -4-{[3-(4-氯苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 6,7-dimethoxy-4-{[3-(4-chlorophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

6,7-二曱氧基 -4-{[3-(2-氯苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 6,7-dimethoxyoxy-4-{[3-(2-chlorophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

6,7-二甲氧基 -4-{[3-(4-溴苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 6,7-dimethoxy-4-{[3-(4-bromophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

6,7-二曱氧基 -4-{[3-(2，4-二氯苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 6,7-dimethoxyoxy-4-{[3-(2,4-dichlorophenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

6,7-二甲氧基 -4-{[3-(4-甲基苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 6,7-dimethoxy-4-{[3-(4-methylphenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

6,7-二曱氧基 -4-{[3-(4-甲氧基苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 6,7-dimethoxyoxy-4-{[3-(4-methoxyphenyl)-isoxazole-5-yl]-methoxy+quinazoline;

6,7-二甲氧基 -4-{[3-(4-三氟甲基苯基) -异噁唑 -5-基卜甲氧基+喹唑啉； 6,7-dimethoxy-4-{[3-(4-trifluoromethylphenyl)-isoxazole-5-yl-methoxy-3-quinazoline;

6,7-二曱氧基 -4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 6,7-dimethoxyoxy-4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

[6,7-二 (2-甲氧乙氧基 )】-4-[(3-苯基-异噁唑 -5-基) -甲氧基-】 -喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-[(3-phenyl-isoxazole-5-yl)-methoxy-]-quinazoline;

[6,7-二 (2-甲氧乙氧基 )】-4-{[3-(4-氟苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-fluorophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

[6,7-二 (2-甲氧乙氧基 )】-4-{[3-(4-氯苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-chlorophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

[6,7-二 (2-甲氧乙氧基 )】-4-{[3-(2-氯苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(2-chlorophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

[6,7-二 (2-甲氧乙氧基 )】-4-{[3-(4-溴苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-bromophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

[6,7-二 (2-甲氧乙氧基 )】-4-{[3-(2，4-二氯苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(2,4-dichlorophenyl)-isoxazol-5-yl]-methoxy+quinazoline ;

[6,7-二 (2-甲氧乙氧基 )】-4-{[3-(4-甲基苯基) -异噁唑 -5-基】 -甲氧基 +喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-methylphenyl)-isoxazole-5-yl]-methoxy+quinazoline;

[6,7-二 (2-甲氧乙氧基 )】-4-{[3-(4-甲氧基苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-methoxyphenyl)-isoxazol-5-yl]-decyloxy+quinazoline;

[6,7-二 (2-甲氧乙氧基 )】-4-{[3-(4-三氟甲基苯基) -异噁唑 -5-基卜甲氧基+喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-trifluoromethylphenyl)-isoxazol-5-ylbumethoxy+quinazoline;

[6,7-二 (2-甲氧乙氧基 )】-4-{[3-(2，4-二曱氧基苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉; [6,7-bis(2-methoxyethoxy)]-4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5-yl]-methoxy+quina Oxazoline

4-[(3-苯基-异噁唑 -5-基) -甲氨基-】 -喹唑啉； 4-[(3-phenyl-isoxazole-5-yl)-methylamino-]-quinazoline;

4-{[3-(4-氟苯基) -异噁唑 -5-基卜甲 -}-喹唑啉； 4-{[3-(4-fluorophenyl)-isoxazole-5-yl-benz-}-quinazoline;

4-{[3-(4-氯苯基) -异噁唑 -5-基】 -甲 -}-喹唑啉； 4-{[3-(4-chlorophenyl)-isoxazole-5-yl]-methyl-}-quinazoline;

4-{[3-(2-氯苯基) -异噁唑 -5-基卜甲氨基+喹唑啉； 4-{[3-(2-chlorophenyl)-isoxazole-5-yl-methylamino+quinazoline;

4-{[3-(4-溴苯基) -异噁唑 -5-基卜甲喹唑啉； 4-{[3-(4-bromophenyl)-isoxazole-5-ylpyridinium quinazoline;

4-{ [3-(2，4-二氯苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉； 4-{[3-(2,4-dichlorophenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

4-{[3-(4-曱基苯基) -异噁唑 -5-基】 -甲喹唑啉； 4-{[3-(4-mercaptophenyl)-isoxazole-5-yl]-quinazoline;

4-{[3-(4-曱氧基苯基) -异噁唑 -5-基】 -曱 -}-喹唑啉； 4-{[3-(4-三氟甲基苯基)-异噁唑 -5-基】 -曱氨基+喹唑啉； 4-{[3-(4-decyloxyphenyl)-isoxazol-5-yl]-indole-}-quinazoline; 4-{[3-(4-trifluoromethylphenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基卜甲喹唑啉； 4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5-ylpyridinium quinazoline;

6,7-二曱氧基 -4-[(3-苯基-异噁唑 -5-基) -甲 JH-喹唑啉； 6,7-dimethoxyoxy-4-[(3-phenyl-isoxazole-5-yl)-methyl JH-quinazoline;

6,7-二甲氧基 -4-{[3-(4-氟苯基) -异噁唑 -5-基】 -甲喹唑啉； 6,7-dimethoxy-4-{[3-(4-fluorophenyl)-isoxazole-5-yl]-quinazoline;

6,7-二曱氧基 -4-{[3-(4-氯苯基) -异噁唑 -5-基】 -甲 -}-喹唑啉； 6,7-dimethoxyoxy-4-{[3-(4-chlorophenyl)-isoxazole-5-yl]-methyl-}-quinazoline;

6,7-二甲氧基 -4-{[3-(2-氯苯基) -异噁唑 -5-基】 -甲喹唑啉； 6,7-dimethoxy-4-{[3-(2-chlorophenyl)-isoxazole-5-yl]-quinazoline;

6,7-二曱氧基 -4-{[3-(4-溴苯基) -异噁唑 -5-基】 -甲 -}-喹唑啉； 6,7-dimethoxyoxy-4-{[3-(4-bromophenyl)-isoxazole-5-yl]-methyl-}-quinazoline;

6,7-二甲氧基 -4-{[3-(2，4-二氯苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 6,7-dimethoxy-4-{[3-(2,4-dichlorophenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

6,7-二曱氧基 -4-{[3-(4-甲基苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉； 6,7-dimethoxyoxy-4-{[3-(4-methylphenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

6,7-二甲氧基 -4-{[3-(4-甲氧基苯基) -异噁唑 -5-基】 -甲喹唑啉； 6,7-dimethoxy-4-{[3-(4-methoxyphenyl)-isoxazole-5-yl]-quinazoline;

6,7-二曱氧基 -4-{[3-(4-三氟曱基苯基) -异噁唑 -5-基卜甲喹唑啉； 6,7-dimethoxyoxy-4-{[3-(4-trifluorodecylphenyl)-isoxazole-5-ylbromoquinazoline;

6,7-二甲氧基 -4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉; 6,7-dimethoxy-4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

[6,7-二 (2-甲氧乙氧基)】 -4-[(3-苯基-异噁唑 -5-基) -甲喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-[(3-phenyl-isoxazole-5-yl)-methylquinazoline;

[6,7-二 (2-甲氧乙氧基)】 -4-{[3-(4-氟-苯基)-异噁唑 -5-基】 -曱氨基+喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-fluoro-phenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

[6,7-二 (2-甲氧乙氧基)】 -4-{[3-(4-氯苯基) -异噁唑 -5-基】 -甲 M^-}-喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-chlorophenyl)-isoxazol-5-yl]-methyl M^-}-quinazoline;

[6,7-二 (2-甲氧乙氧基)】 -4-{[3-(2-氯苯基) -异噁唑 -5-基】 -甲喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(2-chlorophenyl)-isoxazol-5-yl]-quinazoline;

[6,7-二 (2-甲氧乙氧基)】 -4-{[3-(4-溴苯基) -异噁唑 -5-基卜甲 M^-}-喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-bromophenyl)-isoxazole-5-ylbromo M^-}-quinazoline;

[6,7-二 (2-甲氧乙氧基)】 -4-{[3-(2，4-二氯苯基) -异噁唑 -5-基】 -甲喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(2,4-dichlorophenyl)-isoxazole-5-yl]-quinazoline;

[6,7-二 (2-甲氧乙氧基)】 —4-{[3-(4-甲基苯基) -异噁唑 -5-基】 -甲氨基+喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-methylphenyl)-isoxazole-5-yl]-methylamino+quinazoline;

[6,7-二 (2-甲氧乙氧基)】 -4-{[3-(4-甲氧基苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-methoxyphenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

[6,7-二 (2-甲氧乙氧基)】 -4-{[3-(4-三氟曱基苯基) -异噁唑 -5-基卜甲喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-trifluorodecylphenyl)-isoxazole-5-ylbromoquinazoline;

[6,7-二 (2-甲氧乙氧基)】 -4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基】 -甲喹唑啉; [6,7-bis(2-methoxyethoxy)]-4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5-yl]-quinazoline;

2-苯基 -4-[(3-苯基-异噁唑 -5-基) -曱氧基小喹唑啉； 2-phenyl-4-[(3-phenyl-isoxazole-5-yl)-decyloxyquinazoline;

2-苯基 -4-{[3-(4-曱基-苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 2-phenyl-4-{[3-(4-indolyl-phenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

2-苯基 -4-{[3-(4-曱氧基苯基) -异噁唑 -5-基】 -甲氧基 +喹唑啉； 2-phenyl-4-{[3-(4-decyloxyphenyl)-isoxazole-5-yl]-methoxy+quinazoline;

2-苯基 -4-{[3-(4-三氟甲基苯基) -异噁唑 -5-基卜甲氧基+喹唑啉； 2-phenyl-4-{[3-(4-trifluoromethylphenyl)-isoxazole-5-ylphenoxy+quinazoline;

2-苯基 -4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉; 2-phenyl-4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

2-苯基 -4-{[3-(4-氟苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 2-phenyl-4-{[3-(4-fluorophenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

2-苯基 -4-{[3-(4-氯苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； -苯基 -4-{ [3- (2-氯苯基) -异噁唑 -5-基】國曱氧基+喹唑啉；2-phenyl-4-{[3-(4-chlorophenyl)-isoxazol-5-yl]-decyloxy+quinazoline; -Phenyl-4-{[3-(2-chlorophenyl)-isoxazol-5-yl] oximeoxy + quinazoline;

-苯基 -4-{ [3- (2,4-二氯苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉；-苯基 -4-{ [3- (4-溴苯基) -异噁唑 -5-基】國曱氧基+喹唑啉；-phenyl-4-{[3-(2,4-dichlorophenyl)-isoxazol-5-yl]-methoxy+quinazoline;-phenyl-4-{ [3- (4 -Bromophenyl)-isoxazole-5-yl] oximeoxy + quinazoline;

-苯基 -4-[ (3-苯基-异噁唑 -5-基) -曱氨基小喹唑啉；-phenyl-4-[(3-phenyl-isoxazole-5-yl)-nonylamino quinazoline;

-苯基 -4-{ [3- (4-曱基-苯基) -异噁唑 -5-基】 -曱 -}-喹唑啉；-phenyl-4-{[3-(4-indolyl-phenyl)-isoxazole-5-yl]-indole-}-quinazoline;

-苯基 -4-{ [3- (4-曱氧基苯基) -异噁唑 -5-基卜甲喹唑啉；-苯基 -4-{ [3- (4-三氟曱基苯基) -异噁唑 -5-基】 -甲 -}-喹唑啉；-苯基 -4-{ [3- (2,4-二甲氧基苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉;-苯基 -4-{ [3- (4-氟苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉；-Phenyl-4-{[3-(4-decyloxyphenyl)-isoxazol-5-ylbuquinazoline;-phenyl-4-{[3-(4-trifluoromethyl) Phenyl)-isoxazole-5-yl]-methyl-}-quinazoline;-phenyl-4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5- - hydrazine amino + quinazoline; -phenyl-4-{[3-(4-fluorophenyl)-isoxazol-5-yl]-nonylamino + quinazoline;

-苯基 -4-{ [3- (4-氯苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉；-phenyl-4-{[3-(4-chlorophenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

-苯基 -4-{ [3- (2-氯苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉；-phenyl-4-{[3-(2-chlorophenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

-苯基 -4-{ [3- (2,4-二氯苯基) -异噁唑 -5-基】 -甲氨基+喹唑啉；-苯基 -4-{ [3- (4-溴苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉；一硝基一4-[ (3-苯基-异噁唑 -5-基) -曱氧基-】 -喹唑啉；-phenyl-4-{[3-(2,4-dichlorophenyl)-isoxazol-5-yl]-methylamino+quinazoline;-phenyl-4-{ [3- (4- Bromophenyl)-isoxazole-5-yl]-nonylamino+quinazoline; mononitro-4-[(3-phenyl-isoxazol-5-yl)-decyloxy-]-quin Oxazoline

-硝基 -4-{ [3- (4-曱基-苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉；一硝基一4-{ [3- (4-曱氧基苯基) -异噁唑 -5-基卜甲氧基+喹唑啉；-硝基 -4-{ [3- (4-三氟曱基苯基) -异噁唑 -5-基卜甲氧基+喹唑啉；一硝基一4-{ [3- (2,4-二甲氧基苯基) -异噁唑 -5-基】國曱氧基+喹唑啉;-硝基 -4-{ [3- (4-氟苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉；一硝基一4-{ [3- (4-氯苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉；-nitro-4-{[3-(4-indolyl-phenyl)-isoxazol-5-yl]-decyloxy+quinazoline; mononitro-4-{ [3- (4-曱oxyphenyl)-isoxazole-5-yl-methoxy+quinazoline;-nitro-4-{[3-(4-trifluorodecylphenyl)-isoxazole-5- Benzylmethoxy+quinazoline; mononitro-4-{[3-(2,4-dimethoxyphenyl)-isoxazol-5-yl] oximeoxy + quinazoline; -nitro-4-{[3-(4-fluorophenyl)-isoxazol-5-yl]-decyloxy+quinazoline; mononitro-4-{[3-(4-chlorobenzene) -isoxazole-5-yl]-decyloxy+quinazoline;

-硝基 -4-{ [3- (2-氯苯基) -异噁唑 -5-基】國曱氧基+喹唑啉；一硝基一4-{ [3- (2,4-二氯苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉；-硝基 -4-{ [3- (4-溴苯基) -异噁唑 -5-基】國曱氧基+喹唑啉；一硝基一4-[ (3-苯基-异噁唑 -5-基) -曱氨基小喹唑啉；-nitro-4-{[3-(2-chlorophenyl)-isoxazol-5-yl] oximeoxy + quinazoline; mononitro-4-{ [3- (2,4- Dichlorophenyl)-isoxazole-5-yl]-methoxy+quinazoline;-nitro-4-{[3-(4-bromophenyl)-isoxazol-5-yl] Alkoxy+quinazoline; mononitro-4-[(3-phenyl-isoxazol-5-yl)-nonylamino quinazoline;

-硝基 -4-{ [3- (4-曱基-苯基) -异噁唑 -5-基】 -曱 -}-喹唑啉；一硝基一4-{ [3- (4-曱氧基苯基) -异噁唑 -5-基卜甲喹唑啉；-硝基 -4-{ [3- (4-三氟曱基苯基) -异噁唑 -5-基】 -甲 -}-喹唑啉；一硝基一4-{ [3- (2,4-二甲氧基苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉;-硝基 -4-{ [3- (4-氟苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉； ₇_硝基 _4-{[3-(4-氯苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉； -nitro-4-{[3-(4-indolyl-phenyl)-isoxazol-5-yl]-indole-}-quinazoline; mononitro-4-{ [3- (4-曱oxyphenyl)-isoxazol-5-ylbuquinazoline;-nitro-4-{[3-(4-trifluoromethylphenyl)-isoxazole-5-yl] A-}-quinazoline; mononitro-4-{[3-(2,4-dimethoxyphenyl)-isoxazol-5-yl]-nonylamino+quinazoline;-nitro -4-{[3-(4-fluorophenyl)-isoxazol-5-yl]-nonylamino+quinazoline; ₇ _Nitro_4-{[3-(4-chlorophenyl)-isoxazol-5-yl]-nonylamino + quinazoline;

₇—硝基 _4-{[3-(2-氯苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉； ₇ -nitro-4-{[3-(2-chlorophenyl)-isoxazol-5-yl]-nonylamino+quinazoline;

7-硝基 -4-{[3-(2，4-二氯苯基) -异噁唑 -5-基】 -甲 J~-}-喹唑啉；和 7-Nitro-4-{[3-(2,4-dichlorophenyl)-isoxazole-5-yl]-methyl J~-}-quinazoline;

₇-硝基 _4-{[3-(4-溴苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉。 ₇ -Nitro-4-{[3-(4-bromophenyl)-isoxazol-5-yl]-nonylamino + quinazoline.

式 (I)所示的喹唑啉化合物，可以分别选择与药学上可接受的酸形成药学上可接受的盐。其中术语"药学上可接受的盐"包括但不限于与无机酸形成的盐，如盐酸盐、磷酸盐、二磷酸盐、氢溴酸盐、硫酸盐、亚磺酸盐、硝酸盐、及其类似盐；也包括与有机酸形成的盐，如草酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、磺酸盐、对曱苯磺酸盐、 2-羟乙基磺酸盐、苯曱酸盐、水杨酸盐、硬脂酸盐、三氟乙酸或氨基酸和链烷酸盐如醋酸盐， HOOC-(CH2)n-COOH其中 n是 0-4的盐，及其类似盐。类似地，药学上可接受的阳离子包括但不限于钠、钾、钙、铝、锂和铵。 The quinazoline compound represented by the formula (I) may be selected to form a pharmaceutically acceptable salt with a pharmaceutically acceptable acid, respectively. Wherein the term "pharmaceutically acceptable salts" includes, but is not limited to, salts formed with inorganic acids, such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and Similar to salts; also includes salts with organic acids such as oxalates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, sulfonates , p-Toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, trifluoroacetic acid or amino acids and alkanoates such as acetate, HOOC-( CH2)n-COOH wherein n is a salt of 0-4, and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

本发明还提供一种药物组合物，其包括前述任一项的式 (I)所示的喹唑啉化合物，或其药学上可接受的盐，以及至少一种药学上可接受的、惰性的、无毒的赋形剂或载体或稀释剂。 The present invention also provides a pharmaceutical composition comprising the quinazoline compound of the above formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable, inert , non-toxic excipients or carriers or diluents.

本发明还提供一种包括前述任一项的式 (I)所示的喹唑啉衍生物和医学上可接受的一种或多种选自填充剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂和包衣材料形成的药物组合物。 The present invention also provides a quinazoline derivative represented by the formula (I) according to any one of the above and one or more medically acceptable ones selected from the group consisting of a filler, a disintegrant, a lubricant, and a glidant A pharmaceutical composition formed from an effervescent agent, a flavoring agent, a preservative, and a coating material.

本发明还提供一种药物制剂，其包括前述任一项的式 (I)所示的喹唑啉化合物，或其药学上可接受的盐，以及至少一种药学上可接受的、惰性的、无毒的赋形剂或载体或稀释剂。 The present invention also provides a pharmaceutical preparation comprising the quinazoline compound of the above formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable, inert, Non-toxic excipient or carrier or diluent.

根据本发明的药物制剂 , 其特征在于，所述制剂优选为固体口服制剂、液体口服制剂或注射剂。 The pharmaceutical preparation according to the present invention is characterized in that the preparation is preferably a solid oral preparation, a liquid oral preparation or an injection.

根据本发明的药物制剂，所述制剂选自片剂、片、肠溶片、嚼片、口崩片、胶嚢、颗粒剂、口服溶液剂、注射用水针、注射用冻干粉针、大输液或小输液。 According to the pharmaceutical preparation of the present invention, the preparation is selected from the group consisting of a tablet, a tablet, an enteric tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a granule, an oral solution, a water injection needle, a lyophilized powder for injection, and a large Infusion or small infusion.

本发明还提供用作药物的前述任一项的式 (I)所示的喹唑啉化合物或其药学上可接受的盐，尤其是一种用于治疗对于抑制 EGFR过渡表达和 /或活性过高有效的肿瘤的药物。 The present invention also provides a quinazoline compound of the above formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular for the treatment of inhibiting EGFR transient expression and/or activity A highly effective tumor drug.

本发明还提供一种前述任一项的式 (I)所示的喹唑啉化合物或其药学上可接受的盐在制备用于抗肿瘤或癌症药物中的应用。 The present invention also provides the use of the quinazoline compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for antitumor or cancer.

根据本发明，所述的肿瘤或癌症是与 EGFR过渡表达和 /或活性过高的癌症。更优选地，所述肿瘤或癌症选自：膀胱癌，非小细胞肺癌，卵巢癌，乳腺癌，胃癌，食道癌，肺癌，头颈癌，结肠癌，咽癌，和胰腺癌等，更是非小细胞肺癌中的应用。本发明还提供一种前述任一项的式 (I)所示的喹唑啉化合物和 /或药学上可接受的盐在制备抑制 EGFR的过渡表达和 /或活性过高的抑制剂中的应用。 According to the invention, the tumor or cancer is a cancer that is transiently expressed and/or active with EGFR. More preferably, the tumor or cancer is selected from the group consisting of: bladder cancer, non-small cell lung cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer, and pancreatic cancer, etc. Application in cell lung cancer. The present invention also provides the use of a quinazoline compound and/or a pharmaceutically acceptable salt of the formula (I) according to any of the preceding claims for the preparation of an inhibitor which inhibits the transient expression and/or activity of EGFR. .

本发明还提供一种式 (I)所示的含异噁唑杂环的喹唑啉化合物的制备方法，其特征在于，所述方法包括如下步骤： The present invention also provides a process for producing an isoxazole heterocyclic-containing quinazoline compound represented by the formula (I), characterized in that the method comprises the following steps:

以 2， 6, 7-三取代 -4-氯-喹唑啉（式 II )和 3-取代苯基 -5-羟曱基-异噁唑（式 III )或 3-取代苯基 -5-氨基-异噁唑（式 IV )为原料，在干燥的有机溶剂和碱性缚酸剂体系中反应制备。 2, 6, 7-trisubstituted-4-chloro-quinazoline (formula II) and 3-substituted phenyl-5-hydroxyindolyl-isoxazole (formula III) or 3-substituted phenyl-5- Amino-isoxazole (formula IV) is a starting material which is prepared by reaction in a dry organic solvent and a basic acid binding agent system.

其中，各取代基如前述所定义。 Wherein each substituent is as defined above.

如果需要，可以将式（II ) 中的任何官能团予以保护。 Any functional group in formula (II) can be protected if desired.

并且其后，如果有必要（以任何次序）： And then, if necessary (in any order):

( 1 )除去任何保护剂，和 (1) remove any protective agent, and

( 2 )形成式 I化合物的药学上可接受的盐。 (2) forming a pharmaceutically acceptable salt of a compound of formula I.

同时，对于 Z为其他取代基的式（I )化合物，例如 R₅为其他取代基的 -NR₅, C(R6)₂， S 时，可采用（II )与 -NH ( R₅ )或 C1-C(R6)₂或 3-取代苯基 -5-巯基异噁唑通过相应的偶联反应制备，其中 3-取代苯基 -5-巯基异噁唑以丙炔硫醇为原料，采用式（ III )的合成过程制备。 Meanwhile, for the compound of the formula (I) wherein Z is another substituent, for example, -NR ₅ , C(R6) ₂ , S wherein R ₅ is another substituent, (II) and -NH (R ₅ ) or C1 may be employed. -C(R6) ₂ or 3-substituted phenyl-5-mercaptoisoxazole is prepared by a corresponding coupling reaction, wherein 3-substituted phenyl-5-mercaptoisoxazole is prepared from propyne thiol. Preparation of the synthesis process of (III).

根据本发明，所述反应温度为 -20°C至回流条件，优选室温至回流条件。 According to the invention, the reaction temperature is from -20 ° C to reflux conditions, preferably from room temperature to reflux conditions.

根据本发明，所述有机溶剂为芳烃，卤代烃， C_w低级醇类，四氢呋喃或二甲基亚砜（ DMF )。优选所述溶剂为苯、曱苯、二曱苯、二氯曱烷、氯仿、异丙醇、四氢呋喃或 DMF，更优选异丙醇。 According to the invention, the organic solvent is an aromatic hydrocarbon, a halogenated hydrocarbon, a C _w lower alcohol, tetrahydrofuran or dimethyl sulfoxide (DMF). Preferably, the solvent is benzene, toluene, dinonylbenzene, dichlorodecane, chloroform, isopropanol, tetrahydrofuran or DMF, more preferably isopropanol.

根据本发明，所述碱性縛酸剂为有机碱或无机碱，所述有机碱优选为三乙胺、三丙胺、 DMAP、叔丁醇钾等；所述无机碱优选为碳酸钾、氢化钠、碳酸钠等。优选的缚酸剂为三乙胺。 According to the present invention, the basic acid binding agent is an organic base or an inorganic base, and the organic base is preferably triethylamine, tripropylamine, DMAP, potassium t-butoxide or the like; and the inorganic base is preferably potassium carbonate or sodium hydride. , sodium carbonate, etc. A preferred acid binding agent is triethylamine.

本发明还提供一种式 (IA)所示的含异噁唑杂环的喹唑啉化合物的制备方法，其特征在于，所述方法包括如下步骤： The present invention also provides a method for preparing an isoxazole heterocyclic-containing quinazoline compound represented by formula (IA), which is characterized in that The method includes the following steps:

以 6,7-二取代 4-氯-喹唑啉（式 IIA )和 3-取代苯基 -5-羟曱基-异噁唑（式 III )或 3-取代苯基 -5-氨曱基-异噁唑（式 IV )为原料，在干燥的有机溶剂和碱性縛酸剂体系中反应制备。 6,7-disubstituted 4-chloro-quinazoline (formula IIA) and 3-substituted phenyl-5-hydroxyindolyl-isoxazole (formula III) or 3-substituted phenyl-5-aminoindole - Isoxazole (Formula IV) is a starting material which is prepared by reaction in a dry organic solvent and a basic acid binding agent system.

如果需要，可以将式（IIA )中的任何官能团予以保护。并且其后，如果有必要（以任何次序）： Any functional group in formula (IIA) can be protected if desired. And then, if necessary (in any order):

( 1 )除去任何保护剂，和 (1) remove any protective agent, and

( 2 )形成式（IA-1 )或（IA-2 )化合物的药学上可接受的盐。 (2) forming a pharmaceutically acceptable salt of the compound of the formula (IA-1) or (IA-2).

根据本发明，所述有机溶剂为苯、曱苯、二曱苯、二氯曱烷、氯仿、异丙醇、四氢呋喃或 DMF, 更优选异丙醇。 According to the invention, the organic solvent is benzene, toluene, dinonylbenzene, dichlorodecane, chloroform, isopropanol, tetrahydrofuran or DMF, more preferably isopropanol.

根据本发明，所述碱性縛酸剂为有机碱或无机碱，所述有机碱优选为三乙胺、三丙胺、 DMAP、叔丁醇钾等；所述无机碱优选为碳酸鉀、氢化钠、碳酸钠等。优选的缚酸剂为三乙胺。 According to the present invention, the basic acid binding agent is an organic base or an inorganic base, and the organic base is preferably triethylamine, tripropylamine, DMAP, potassium t-butoxide or the like; and the inorganic base is preferably potassium carbonate or sodium hydride. , sodium carbonate, etc. A preferred acid binding agent is triethylamine.

根据本发明，所述式（IIA )的中间体 6,7-二取代 4-氯-喹唑啉可通过如下方法制备：以 6,7- 二取代 -喹唑啉酮为原料，在二氯亚砜或三氯氧磷体系中回流制备 (R_{1 ;} R₂同前述所定义)：

According to the present invention, the intermediate 6,7-disubstituted 4-chloro-quinazoline of the formula (IIA) can be produced by the following method: using 6,7-disubstituted-quinazolinone as a raw material, in dichloro Prepared by reflux in sulfoxide or phosphorus oxychloride system (R _{1 ;} R ₂ as defined above):

式（VA ) 式 (IIA) Formula (VA) (IIA)

根据本发明，所述式（ III ) 的中间体 3-取代苯基 -5-羟甲基 -异噁唑或式（ IV ) 的中间体 3- 取代苯基 -5-氨甲基-异噁唑可通过如下方法制备：以取代苯曱酪为原料，通过合成肟、 1,3-偶极环加成反应、甲磺酰酯化反应、叠氮化、还原反应制备 (R₃如上所述)。 According to the invention, the intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole of formula (III) or the intermediate 3-substituted phenyl-5-aminomethyl-isoxine of formula (IV) The azole can be prepared by the following method: Substituting benzoin as a raw material, by synthesizing ruthenium, 1,3-dipole Cycloaddition reaction, methanesulfonyl esterification reaction, azide, reduction reaction (R ₃ as described above).

根据本发明，所述式（ III )的中间体 3-取代苯基 -5-羟甲基-异噁唑通过如下方法制备： ( 1 ) 以取代苯甲醛为原料，通过和羟胺或盐酸羟胺反应合成肟 (V); ( 2 )将肟（V )和丙炔醇在 N- 氯丁二酰亚胺 (NCS)和三乙胺作用下发生 1,3-偶极环加成反应，生成中间体（111 )。 According to the invention, the intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole of the formula (III) is prepared by the following method: (1) by using a substituted benzaldehyde as a starting material, by reacting with hydroxylamine or hydroxylamine hydrochloride Synthesis of ruthenium (V); (2) 肟(V) and propargyl alcohol undergo 1,3-dipolar cycloaddition reaction under the action of N-chlorosuccinimide (NCS) and triethylamine, forming intermediate Body (111).

根据本发明，式（IV ) 的中间体 3-取代苯基 -5-氨曱基-异噁唑通过如下方法制备： According to the invention, the intermediate 3-substituted phenyl-5-aminoindolyl-isoxazole of formula (IV) is prepared by the following method:

(3) 中间体式（III )和甲磺酖氯反应，合成甲磺酰酯式（VI ); (3) reacting intermediate formula (III) with methanesulfonyl chloride to synthesize methanesulfonyl ester (VI);

(4) 曱磺酰酯式（VI )和叠氮钠反应，生成中间体式 (VII); (4) sulfonyl ester type (VI) and sodium azide react to form intermediate formula (VII);

(5) 中间体式 (VII)在锌粉和氯化铵体系中还原得到中间体式（IV )。 (5) Intermediate formula (VII) is reduced in zinc powder and ammonium chloride system to give intermediate formula (IV).

根据本发明 , 所述式 (III)的中间体 3-取代苯基 -5-羟曱基-异噁唑通过如下的方法制备： ( 1 )取代苯甲醛与羟胺或羟胺盐酸盐在甲醇 /水体系中，在碳酸钠的催化下反应生成相应的苯甲趁肟； According to the present invention, the intermediate 3-substituted phenyl-5-hydroxyindolyl-isoxazole of the formula (III) is prepared by the following method: (1) Substituted benzaldehyde with hydroxylamine or hydroxylamine hydrochloride in methanol/ In the water system, the reaction is carried out under the catalysis of sodium carbonate to form the corresponding benzamidine;

( 2 )将步骤（ 1 )制得的苯甲趁肟与丙炔醇在 TV-溴丁二酰亚胺（ NCS )和碱性縛酸剂的作用下通过 1,3-偶极环加成反应形成式（ III )异噁唑化合物。 (2) The benzamidine and propargyl alcohol obtained in the step (1) are subjected to 1,3-dipolar cycloaddition under the action of TV-bromosuccinimide (NSS) and a basic acid-binding agent. The reaction forms an isoxazole compound of formula (III).

根据本发明，优选地，所述的碱性缚酸剂选自有机碱或无机碱，所述有机碱选自三乙胺、三丙胺、 DMAP、 DMF、 N-甲基吗啉等；所述的无机碱选自碳酸钾、氢化钠、碳酸钠等。更优选的碱性缚酸剂为三乙胺。 According to the present invention, preferably, the basic acid binding agent is selected from the group consisting of an organic base or an inorganic base, and the organic base is selected from the group consisting of triethylamine, tripropylamine, DMAP, DMF, N-methylmorpholine, etc.; The inorganic base is selected from the group consisting of potassium carbonate, sodium hydride, sodium carbonate and the like. A more preferred alkaline acid binding agent is triethylamine.

其中，步骤（1 ) 的反应温度为 -20°C至回流条件，优选室温（25°C )至回流条件。 Wherein the reaction temperature of the step (1) is from -20 ° C to reflux conditions, preferably room temperature (25 ° C) to reflux conditions.

其中，步骤（2 ) 的反应温度为 -20°C至回流条件，优选 0°C至回流条件。 Wherein the reaction temperature of the step (2) is from -20 ° C to reflux conditions, preferably from 0 ° C to reflux conditions.

根据本发明 , 所述式 (IV)的中间体 3-取代苯基 5-氨曱基 -异噁唑通过如下的方法制备： According to the invention, the intermediate 3-substituted phenyl 5-aminoindenyl-isoxazole of the formula (IV) is prepared by the following method:

( 3 )式（III ) 的异噁唑化合物（优选通过前述方法获得）与磺酰氯反应获得式（VI )化合物，； (3) an isoxazole compound of the formula (III) (preferably obtained by the aforementioned method) is reacted with a sulfonyl chloride to obtain a compound of the formula (VI);

根据本发明的优选技术方案，步骤（3 )中，所述磺酰氯选自：曱磺酰氯、苯磺酖氯、取代苯磺酰氯（如卤代苯磺酰氯、烷基苯磺酰氯）等，更优选为甲磺酰氯。所述反应温度为 -5度至回流温度，优选室温至回流温度。所述反应溶剂选自苯、甲苯、卤代芳烃、卤代烷烃（如氯仿或二氯曱烷）、四氢呋喃、乙腈及离子液体。更优选地，所述反应在二氯甲烷体系中回流反应。 According to a preferred embodiment of the present invention, in the step (3), the sulfonyl chloride is selected from the group consisting of: sulfonyl chloride, benzenesulfonyl chloride, substituted benzenesulfonyl chloride (such as halobenzenesulfonyl chloride, alkylbenzenesulfonyl chloride), and the like. More preferably, it is a methanesulfonyl chloride. The reaction temperature is -5 degrees to the reflux temperature, preferably room temperature to reflux temperature. The reaction solvent is selected from the group consisting of benzene, toluene, halogenated aromatic hydrocarbons, halogenated alkanes (e.g., chloroform or dichloromethane), tetrahydrofuran, acetonitrile, and ionic liquids. More preferably, the reaction is refluxed in a dichloromethane system.

( 4 )式（ VI )化合物与叠氮化钠反应 (优选在 DMF体系中， 60°C温度下）反应获得式（ VII ) 化合物； (4) reacting a compound of the formula (VI) with sodium azide (preferably in a DMF system at a temperature of 60 ° C) to obtain a compound of the formula (VII);

( 5 )式（VII )化合物与氯化铵及锌粉、铁粉或钯碳催化还原制备式（IV )化合物，优选所述催化剂在无机酸条件下进行催化，优选为盐酸或硫酸，所述催化剂优选为锌粉和氯化铵。其中，步骤（3 ) 的反应温度为 -20°C至回流条件，优选 0°C至室温条件。 (5) a compound of the formula (VII) is catalytically reduced with ammonium chloride and zinc powder, iron powder or palladium carbon to prepare a compound of the formula (IV), preferably the catalyst is catalyzed under mineral acid conditions, preferably hydrochloric acid or sulfuric acid, The catalyst is preferably zinc powder and ammonium chloride. Wherein the reaction temperature of the step (3) is from -20 ° C to reflux conditions, preferably from 0 ° C to room temperature.

其中，步骤（4 ) 的反应温度为 -20°C至回流条件，优选 0°C至 80°C，更优选室温至 60°C。步骤（5 )中优选的反应溶剂是水或有机溶剂（例如醇类，卤代烃类，芳烃类等）或其混合物，优选为乙醇和水的反应体系。 Wherein the reaction temperature of the step (4) is from -20 ° C to reflux conditions, preferably from 0 ° C to 80 ° C, more preferably from room temperature to 60 ° C. The preferred reaction solvent in the step (5) is water or an organic solvent (e.g., an alcohol, a halogenated hydrocarbon, an aromatic hydrocarbon, etc.) or a mixture thereof, preferably a reaction system of ethanol and water.

更优选地，所述式（III )或式（IV ) 的具体制备方法如下述流程所示： More preferably, the specific preparation method of the formula (III) or the formula (IV) is as follows:

( IV ) ( IV )

更优选地，所述制备方法如下述流程所示: More preferably, the preparation method is as follows:

其中各取代基如前述所定义。同时，对于 Z为其他取代基，例如 CH₂, S时，可采用相应的丙炔基氯，丙炔硫醇进行制备。 Wherein each substituent is as defined above. Meanwhile, when Z is another substituent such as CH ₂ , S, it can be prepared by using the corresponding propynyl chloride, propargyl mercaptan.

本发明还提供一种式 (IB)所示的含异噁唑杂环的喹唑啉衍生物的制备方法，其特征在于，所述方法包括如下步骤： The present invention also provides a method for preparing an isoxazole heterocyclic-containing quinazoline derivative represented by formula (IB), characterized in that the method comprises the following steps:

6或 7-取代 4-氯-喹唑啉 (式 IIB)和 3-取代苯基 -5-羟曱基-异噁唑 (式 III)或 3-取代苯基 -5-氨甲基-异噁唑 (式 IV)在干燥的有机溶剂和碱性縛酸剂体系中反应制备; 6 or 7-substituted 4-chloro-quinazoline (formula IIB) and 3-substituted phenyl-5-hydroxyindolyl-isoxazole (formula III) or 3-substituted phenyl-5-carbam The base-isoxazole (formula IV) is prepared by reacting in a dry organic solvent and a basic acid binding agent system;

其中各取代基如前述所定义。 Wherein each substituent is as defined above.

如果需要，可以将式 (II)中的任何官能团予以保护。 Any functional group in formula (II) can be protected if desired.

并且其后，如果有必要 (以任何次序）： And then, if necessary (in any order):

(1) 除去任何保护剂，和 (1) remove any protective agent, and

(2) 形成式（IB-1 )或式（IB-2 )化合物的药学上可接受的盐。 (2) A pharmaceutically acceptable salt of the compound of the formula (IB-1) or the formula (IB-2).

根据本发明，所述有机溶剂为芳烃或烷基取代的芳烃，卤代烃，醇类（如 C_w—元醇类），四氢咬喃， DMF或例子液体。 According to the present invention, the organic solvent is an aromatic hydrocarbon or alkyl-substituted aromatic hydrocarbons, halogenated hydrocarbons, alcohols (e.g., C _w - monoalcohols), tetrahydro-thiopyran bite, DMF or example of a liquid.

根据本发明，所述有机溶剂优选为苯、甲苯、二甲苯、二氯曱烷、氯仿、异丙醇、四氢呋喃或 DMF或离子液体，更优选异丙醇。 According to the invention, the organic solvent is preferably benzene, toluene, xylene, dichlorodecane, chloroform, isopropanol, tetrahydrofuran or DMF or an ionic liquid, more preferably isopropanol.

根据本发明，所述碱性縛酸剂为有机碱或无机碱，所述有机碱优选为三乙胺、三丙胺、 DMAP、氢化钠、叔丁醇钾等；所述无机碱优选为碳酸钾、氢化钠、碳酸钠等。优选的缚酸剂为三乙胺。 According to the present invention, the basic acid binding agent is an organic base or an inorganic base, and the organic base is preferably triethylamine, tripropylamine, DMAP, sodium hydride, potassium t-butoxide or the like; the inorganic base is preferably potassium carbonate. , sodium hydride, sodium carbonate, and the like. A preferred acid binding agent is triethylamine.

根据本发明，所述式 (IIB)的中间体 2-苯基 -4-氯-喹唑啉可以根据已知方法制备或者商购，例如购自阿拉丁试剂公司。 According to the present invention, the intermediate 2-phenyl-4-chloro-quinazoline of the formula (IIB) can be produced according to known methods or commercially available, for example, from Aladdin Reagent.

式 (IIB)的中间体 7-硝基 -4-氯-喹唑啉可通过如下方法制备：以 2-氨基 -4-硝基-苯甲酸和醋酸曱脒为原料，通过在乙醇中反应（所述反应温度优选为 -20°C至回流条件）制得 7-硝基喹唑啉 -4(1H)-酮，然后在二氯亚砜或三氯氧磷体系中反应（优选反应温度为 -20°C至回流条件）制备 7-硝基 -4-氯-喹唑啉。更具体的反应过程如下述流程式所示： The intermediate 7-nitro-4-chloro-quinazoline of formula (IIB) can be prepared by the following method: 2-amino-4-nitro-benzoic acid and cesium acetate are used as raw materials by reaction in ethanol ( The reaction temperature is preferably from -20 ° C to reflux conditions to obtain 7-nitroquinazolin-4(1H)-one, and then reacted in a thionyl chloride or phosphorus oxychloride system (preferably, the reaction temperature is 7-Nitro-4-chloro-quinazoline was prepared from -20 ° C to reflux conditions. A more specific reaction process is shown in the following scheme:

本发明所述式 I化合物，包括但不限于：它们的光学异构体，外消旋体及其混合物。 The compounds of formula I according to the invention include, but are not limited to, their optical isomers, racemates and mixtures thereof.

本发明所述的环烷氧基中的环烷基可以为环丙基，环丁基，环戊基，环己基，环庚基，环辛基，优选为环丙基，环戊基或环己基。 The cycloalkyl group in the cycloalkoxy group of the present invention may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, preferably cyclopropyl, cyclopentyl or a ring. Heji.

本发明所述的含有至少一个选自 N， O, S杂原子的 C_3-8杂环烷氧基中， C_3-8杂环烷基可以为哌漆基，哌啶基，吗啉基，吡咯烷基，高哌嗪基，优选为旅噪基，吗啉基或哌啶基。 In the C _3-8 heterocycloalkoxy group containing at least one hetero atom selected from N, O, S as described in the present invention, the C _3-8 heterocycloalkyl group may be a piperidinyl group, a piperidinyl group or a morpholinyl group. , pyrrolidinyl, homopiperazinyl, preferably a buffer ring, morpholinyl or piperidinyl.

术语"有效量 "指的是，所述至少一种化合物和 /或至少一种药学上可接受的盐对于能有效 "治疗 "个体的一种疾病或不适的用量。如果是癌症时，有效量能减少癌症或肿瘤细胞的数目；缩小肿瘤的大小；抑制或阻止肿瘤细胞向周边器官的侵入，例如，肿瘤蔓延入软组织或骨骼中；抑制或阻止肿瘤的转移；抑制或阻止肿瘤的生长；一定程度上减轻一种或多种与癌症相关的症状；减少发病率和死亡率；提高生活质量；或者是上述效果的结合。有效量可以是通过抑制 EGFR活性来减少疾病症状的用量。对于癌症治疗，体内实验的效果可以通过评估如存活期、疾病进展时间（Time to DiseaseProgression, TTP)、反应率 (Response Rates, RR)、持续反应期和 /或生活质量来测量。专业人员已经意识到，有效量可以随着给药的途径、赋形剂的剂量、以及与其他药物的合用而变化。 The term "effective amount" refers to an amount of the at least one compound and/or at least one pharmaceutically acceptable salt that is effective to "treat" a disease or condition in an individual. In the case of cancer, an effective amount can reduce the number of cancer or tumor cells; reduce the size of the tumor; inhibit or prevent the invasion of tumor cells into peripheral organs, for example, tumors spread into soft tissues or bones; inhibit or prevent tumor metastasis; Or prevent the growth of tumors; to some extent alleviate one or more symptoms associated with cancer; reduce morbidity and mortality; improve quality of life; or a combination of the above effects. An effective amount can be an amount that reduces the symptoms of the disease by inhibiting EGFR activity. For cancer treatment, the effects of in vivo experiments can be measured by assessing, for example, survival, time to disease progression (TTP), response rate (RR), duration of response, and/or quality of life. The skilled person has recognized that an effective amount can vary with the route of administration, the dosage of the excipient, and the combination with other drugs.

术语"有效量"还可指得是所述至少一种化合物和 /或其至少一种药学上可接受的盐对抑制 EGFR的过度表达和 /或活性过高有效的剂量。 The term "effective amount" may also mean a dose effective to inhibit overexpression and/or hyperactivity of EGFR by said at least one compound and/or at least one pharmaceutically acceptable salt thereof.

本发明的化合物具有抗肿瘤、抗癌活性，尤其是对人肺癌细胞株 A549具有很强的抑制活性。化合物 P-26在 lxl(T⁴M浓度下对人肺癌细胞 Α549珠的抑制率为 91.2%， Ρ-24在 lxl(T⁴M 浓度下对人肺癌细胞 A549珠的抑制率为 84.9%， P-22在 lxl(T⁴M浓度下对人肺癌细胞 A549 珠的抑制率为 81.5%。部分化合物对大肠癌细胞株 HCT-116也显示出较强的抑制活性：化合物 P-27在 lxl(T⁴M浓度下对大肠癌细胞株 HCT-116的抑制率为 63.9%，化合物 P-25在 lxl(T⁴M 浓度下对大肠癌细胞株 HCT-116的抑制率为 55.1%; 部分化合物选择性对 EGFR酶也显示出了抑制活性：化合物 Q-15在 lxl(T⁴M浓度下对 EGFR酶的抑制活性为 30.7%, 化合物 Q-21 在 lxl(T⁴M浓度下对 EGFR酶的抑制活性为 30.9%。 The compound of the present invention has antitumor and anticancer activities, and particularly has strong inhibitory activity against human lung cancer cell line A549. Compound P-26 at lxl (T ⁴ M concentration of human lung cancer cell Α549 beads inhibition rate 91.2%, Ρ-24 at lxl (T ⁴ M concentration on A549 cells was suppressed beads 84.9%, P The inhibition rate of -22 on human lung cancer cell A549 beads was 81.5% at lxl (T ⁴ M concentration). Some compounds also showed strong inhibitory activity against colorectal cancer cell line HCT-116: Compound P-27 at lxl (T inhibition rate of colorectal cancer cell line HCT-116 is 63.9% at a concentration of ⁴ M, P-25 compound in lxl (T ⁴ M concentration inhibitory rate of colorectal cancer cell line HCT-116 is 55.1%; the selectivity of the compound Inhibition activity was also shown for EGFR enzyme: Compound Q-15 inhibited EGFR activity at lxl (T ⁴ M concentration was 30.7%, compound Q-21 The inhibitory activity against EGFR enzyme at lxl (T ⁴ M concentration was 30.9%.

因而本发明的化合物可用作***、癌症的候选药物或先导化合物。具体实施方式 Thus, the compounds of the invention are useful as drug candidates or lead compounds for the treatment of tumors, cancers. detailed description

下面结合实施例对本发明作进一步的说明。需要说明的是，下述实施例不能作为对本发明保护范围的限制，任何在本发明上做出的改进都不违背本发明的精神。 The present invention will be further described below in conjunction with the embodiments. It should be noted that the following embodiments are not intended to limit the scope of the present invention, and any improvements made in the present invention are not inconsistent with the spirit of the present invention.

其中，中间体和目标化合物的合成过程均以实施例中的代表说明，其余的中间体和目标化合物的合成过程同代表化合物。 Wherein, the synthesis process of the intermediate and the target compound are illustrated by the representatives in the examples, and the synthesis process of the remaining intermediates and the target compound is the same as the representative compound.

仪器与试剂： Instruments and reagents:

AVANCE III 核磁共振仪（400MHz, DMSO-d₆,TMS 为内标），离子阱液质连用仪 (DECAX-30000 LCQ Deca XP), Shimadzu FTIR-8400S(日本岛津制作所生产）， XT5数字显示显微熔点测定仪 (北京市科仪电光仪器厂制造，温度未经校正），可调波长式微孔板酶标仪 (Molecular Devies SPECTRAMAX190). AVANCE III NMR (400MHz, DMSO-d ₆ , TMS for internal standard), ion trap liquid chromatography (DECAX-30000 LCQ Deca XP), Shimadzu FTIR-8400S (produced by Shimadzu Corporation, Japan), XT5 digital display Micro-melting point measuring instrument (manufactured by Beijing Keyi Electro-optical Instrument Factory, temperature uncorrected), adjustable wavelength microplate microplate reader (Molecular Devies SPECTRAMAX190).

化学试剂均为市售的分析纯或化学纯试剂， RPMI1640 购自 Gibco 公司，磺酰罗丹明 B(Sulforodamine B, SRB) 购自 Sigma公司，三氯乙酸 (TCA)、醋酸和 Tris base unbuffer 均为国产分析纯试剂。 Chemical reagents are commercially available analytically pure or chemically pure reagents, RPMI1640 from Gibco, Sulforodamine B (SRB) from Sigma, trichloroacetic acid (TCA), acetic acid and Tris base unbuffer Domestic analytical pure reagents.

酪氨酸激酶 (EGFR)利用昆虫杆状病毒表达***表达，用 Νί-ΝΤΑ柱亲和纯化得到，经检验符合实验标准，激酶反应底物 Poly(Glu，Tyr)_4:1(Sigma公司），抗磷酸化酪氨酸的单克隆抗体 PY99(Santa Cruz公司），辣根过氧化酶标记羊抗鼠的 IgG(Calbiochem公司）， ATP 、 DTT 、 OPD(Amresco公司），酶标板 (Corning公司），其它试剂均为市售的分析纯，在使用前没有特殊说明未进行处理，异丙醇在使用前用干燥分子筛处理。 Tyrosine kinase (EGFR) was expressed by the insect baculovirus expression system and purified by affinity purification using Νί-ΝΤΑ column. The test was in accordance with the experimental standard, and the kinase reaction substrate Poly(Glu, Tyr) _4:1 (Sigma). Anti-phosphotyrosine monoclonal antibody PY99 (Santa Cruz), horseradish peroxidase-labeled goat anti-mouse IgG (Calbiochem), ATP, DTT, OPD (Amresco), ELISA plate (Corning) Other reagents were commercially available analytical grades, which were not treated without prior treatment prior to use. Isopropanol was treated with dry molecular sieves prior to use.

实施例 1 6,7-二甲氧基 -4-氯-喹唑啉的合成 Example 1 Synthesis of 6,7-dimethoxy-4-chloro-quinazoline

将 4.12 g (20 mmol) 6,7-二曱氧基-喹唑啉酮加入 500 mL单口圆低烧瓶中，接着緩慢加入含有 1滴 DMF的重蒸的二氯亚砜中 120 mL, 回流反应， TLC检测反应完成后，减压蒸除过量的二氯亚砜，剩余物用 300 mL乙酸乙酯溶解，用饱和的碳酸氢钠溶液洗至中性，有机层无水硫酸钠干燥，浓缩后柱分离（ «: 乙 4: 1-2: 1)即得 6,7-二甲氧基 -4-氯-喹唑啉，产率： 85%, 1H NMR(DMSO-i/₆, 400MHz): 4.01(s， 6H, 2CH₃)， 7.38(s, 1H)， 7.45(s, 1H)， 8.88(s，lH); ESI-MS(100%): 224([M】+， 100). 4.12 g (20 mmol) of 6,7-dimethoxy-quinazolinone was added to a 500 mL single-mouth round low flask, followed by slowly adding 120 mL of re-distilled thionyl chloride containing 1 drop of DMF. After the completion of the TLC reaction, the excess of thionyl chloride was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with saturated sodium hydrogen carbonate solution to neutral, dried over anhydrous sodium sulfate and concentrated. Column separation ( «: B 4: 1-2: 1) gives 6,7-dimethoxy-4-chloro-quinazoline, yield: 85%, 1H NMR (DMSO-i/ ₆ , 400 MHz) : 4.01(s, 6H, 2CH ₃ ), 7.38(s, 1H), 7.45(s, 1H), 8.88(s,lH); ESI-MS(100%): 224([M]+, 100).

实施例 2 7-硝基-喹唑啉酮的合成将 46g (0.25 mol) 2- J^-4-硝基苯曱酸和 52g (0.5 mol)醋酸曱脒加入 500mL单口圆底烧瓶中，加入 200 mL无水乙醇，回流反应 4~6 h，体系中将会有大量的土黄色沉淀析出. 此时停止加热，体系冷却至 50°C左右，真空除去部分乙醇至体系大约 50mL，向体系中加入 30mL水，体系搅拌数分钟后冷藏 1 h, 过滤，滤饼依次用冷藏的乙醇 (3xl0mL)洗涤，水 (2xl0mL)洗涤，真空干燥即得 7-硝基-喹唑啉酮 2，土黄色针状固体 39.6g，收率： 82.8%, m.p: 282-284 °C, IR(KBr) v: 3174, 3064, 2960, 1683, 1613, 1528， 803;此化合物不必进一步纯化可直接用于下步氯取代反应。 Example 2 Synthesis of 7-Nitro-quinazolinone Add 46g (0.25 mol) of 2-J^-4-nitrobenzoic acid and 52g (0.5 mol) of lanthanum acetate to a 500mL single-mouth round bottom flask, add 200mL of absolute ethanol, and reflux for 4~6 hours. There will be a large amount of khaki precipitates. At this point, the heating is stopped, the system is cooled to about 50 ° C, some ethanol is removed by vacuum to about 50 mL of the system, 30 mL of water is added to the system, and the system is stirred for several minutes and then refrigerated for 1 h. The filter cake was washed successively with chilled ethanol (3×10 mL), washed with water (2×10 mL), and dried in vacuo to give 7-nitro-quinazolinone 2, 39.6 g of yellow needle solid, yield: 82.8%, mp: 282-284 ° C, IR (KBr) v: 3174, 3064, 2960, 1683, 1613, 1528, 803; This compound can be used directly in the next step of the chlorine substitution reaction without further purification.

实施例 3 7-硝基 -4-氯-喹唑啉的合成 Example 3 Synthesis of 7-Nitro-4-chloro-quinazoline

取 19.1g (O.lmol)的 7-硝基 -喹唑啉酮于 250mL三口瓶中，搅拌下緩慢滴加入 60 mL含 2 滴 DMF的新蒸的 SOCl₂, 加完后回流反应， TLC监测反应的进程，反应完成后，减压蒸出过量的 SOCl₂，残渣用冷藏的*** (5x20mL)洗涤即得粗产物，粗产物用石油醚和乙酸乙酯重结晶即得化合物中间体 7-硝基 -4-氯-喹唑啉 19.0g,白色针状晶体.收率： 90.6%, m.p: 150-151 °C, 1H NMR(CDC1₃, 400 MHz)<5: 8.55(s, 2H， Ph-H), 8.98(s,lH, Ph-H), 9.23(s，lH，Ar-H); IR(KBr) v: 3057, 2959, 1528, 1469, 1357, 805, 743 . Take 19.1 g (O.lmol) of 7-nitro-quinazolinone in a 250 mL three-necked flask, slowly add 60 mL of freshly steamed SOCl ₂ containing 2 drops of DMF with stirring, and return the reaction after completion. TLC monitoring After the reaction is completed, the excess SOCl _{2 is} distilled off under reduced pressure, and the residue is washed with cold diethyl ether (5×20 mL) to obtain a crude product which is recrystallized from petroleum ether and ethyl acetate to give compound intermediate 7-nit. Base chloro-quinazoline 19.0 g, white needle crystal. Yield: 90.6%, mp: 150-151 ° C, 1H NMR (CDC1 ₃ , 400 MHz) <5: 8.55 (s, 2H, Ph -H), 8.98 (s, lH, Ph-H), 9.23 (s, lH, Ar-H); IR (KBr) v: 3057, 2959, 1528, 1469, 1357, 805, 743 .

实施例 4 中间体 3-取代苯基 -5-羟曱基-异噁唑 (III)及 3-取代苯基 -5-氨曱基-异噁唑 (IV)的合成 EXAMPLE 4 Intermediate Synthesis of 3-substituted phenyl-5-hydroxyindenyl-isoxazole (III) and 3-substituted phenyl-5-aminoindolyl-isoxazole (IV)

其中以 R₃为 H作为示例： Where R ₃ is H as an example:

( 1 )苯甲酪

(1) benzoic acid

10.0 mmol苯甲酪溶解在 30 mL 30% CH₃OH和 H₂0溶液中 ,加入装有磁力搅拌器的三角瓶中，搅拌下加入 10.0 mmol盐酸羟氨，等盐酸羟氨溶解后緩慢加入 5.0 mmol干燥研细的碳酸钠。室温反应， TLC检测反应完成后，体系减压蒸除曱醇后，加入 30 mL H₂0，二氯曱烷 (3x30 mL)萃取，合并有机层，无水硫酸钠干燥有机层. 脱溶剂即得苯曱醛肟粗产物，收率 86.2 %。该粗产物不用分离纯化直接进行下步反应。 10.0 mmol of benzoic acid was dissolved in 30 mL of 30% CH ₃ OH and H ₂ 0 solution, and added to a triangular flask equipped with a magnetic stirrer. Add 10.0 mmol of hydroxylamine hydrochloride under stirring, and then slowly add 5.0 after the hydroxylamine hydrochloride was dissolved. Dry dry fine sodium carbonate. After the reaction was completed at room temperature, after the completion of the TLC reaction, the system was evaporated to dryness under reduced pressure. Then, 30 mL of H ₂ 0, dichloromethane (3×30 mL) was added and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate. The crude product of benzofurald oxime was obtained in a yield of 86.2%. This crude product was directly subjected to the next step without isolation and purification.

( 2 ) 3-苯基 -5-羟曱基-异噁唑

( 2 ) 3-phenyl-5-hydroxydecyl-isoxazole

将 10.0 mmol苯甲趁肟和 30 mL干燥的二氯曱烷加入 250 mL单口圆底烧瓶中，搅拌下加入 1.60g (12.0 mmol) N-氯丁二酖亚胺（ NCS )，啟加热至 NCS全部溶解后，滴加 0.56 g (10.0 mmol)2-丙炔 -1-醇，随后緩慢滴加入 20 mL含 10.1 g (10.0 mmol)三乙胺的二氯甲烷溶液，加完后体系回流. TLC检测反应完成后，母液水洗，无 7«酸钠干燥，柱分离（ 5:1-2:1) 即得 3-苯基 -5-羟曱基-异噁唑，收率 76.8 % Add 10.0 mmol of benzamidine and 30 mL of dry dichloromethane to a 250 mL single-neck round bottom flask with stirring 1.60 g (12.0 mmol) of N-chlorobutanediimide (NSS) was added. After heating to NCS, add 0.56 g (10.0 mmol) of 2-propyn-1-ol, followed by slow addition of 20 mL. The solution containing 10.1 g (10.0 mmol) of triethylamine in dichloromethane was refluxed after the addition. After the TLC detection reaction was completed, the mother liquor was washed with water, without 7« sodium drying, column separation (5:1-2:1) 3-phenyl-5-hydroxydecyl-isoxazole, yield 76.8 %

( 3 ) 3-苯基 -5-氨曱基-异噁唑 (3) 3-phenyl-5-aminodecyl-isoxazole

将 10.0 mmol 5-羟甲基 -3-苯基-异噁唑和 30 mL干燥的二氯甲坑加入 250 mL单口圆底烧瓶中，冰拌下将含 1.01g(10.0 mmol)三乙胺的 20 mL二氯曱烷溶液加入体系中，接着将溶有 1.37g (12.0 mmol) 曱磺酰氯（MsCl )的 5 mL二氯甲烷溶液緩慢滴加入体系中，冰浴反应 2 h后，室温反应。 TLC检测反应完成后，母液水洗， 5 %的碳酸氢钠溶液洗，水洗，无水硫酸钠干燥，减压脱溶剂得粗产物 5-曱磺酸 -3-苯基-异噁唑 -5-曱醇酯，收率 68.0 %。粗产物不必纯化直接进行下步反应。 Add 10.0 mmol of 5-hydroxymethyl-3-phenyl-isoxazole and 30 mL of dry dichloromethane to a 250 mL single-neck round bottom flask containing 1.01 g (10.0 mmol) of triethylamine. 20 mL of dichloromethane solution was added to the system, and then a solution of 1.37 g (12.0 mmol) of sulfonyl chloride (MsCl) in 5 mL of dichloromethane was slowly added dropwise to the system, and the mixture was reacted for 2 hours in an ice bath, and then reacted at room temperature. After the completion of the TLC reaction, the mother liquid was washed with water, washed with a 5% sodium hydrogen carbonate solution, washed with water, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to give the crude product, 5-indolesulfonic acid, 3-phenyl-isoxazole-5- The sterol ester was obtained in a yield of 68.0%. The crude product was directly subjected to the next step without purification.

将 5.0 mmol 5-曱磺酸 -3-苯基-异噁唑 -5-曱醇酯溶解在 20 mL干燥的 DMF中，加入 0.34 g ( 5.20 mmol ) 叠氮化钠，室温搅拌溶解后，置于 45°C-50°C油浴中反应， TLC指示反应完成后，过滤，滤饼用***（ 2x30mL )洗涤，合并有机层，向有机层中加 lOOmL水，用***（ 5x30mL ) 萃取，合并有机层，有机层水洗 2次，无水硫酸钠干燥，脱溶剂后得粗产物 3-苯基 -5-叠氮曱基 -异噁唑，收率 90% ，粗产物直接进行下面的还原反应. Dissolve 5.0 mmol of 5-indolesulfonic acid-3-phenyl-isoxazol-5-nonanol ester in 20 mL of dry DMF, add 0.34 g (5.20 mmol) of sodium azide, stir at room temperature, and set. The reaction was carried out in an oil bath at 45 ° C - 50 ° C. After TLC indicated that the reaction was completed, filtered, and the filter cake was washed with diethyl ether (2×30 mL). The organic layer was combined, and 100 mL of water was added to the organic layer and extracted with diethyl ether (5×30 mL). The organic layer and the organic layer were washed twice with water and dried over anhydrous sodium sulfate, and the solvent was obtained to obtain the crude product 3-phenyl-5-azido-indolyl-isoxazole in a yield of 90%, and the crude product was directly subjected to the following reduction reaction. .

5.0 mmol 5-叠氮甲基 -3-苯基-异噁唑溶解在 80 mL乙醇和 20 mL水的混合溶液中，将 0.17g ( 2.6 mmol )的锌粉和 0.28g ( 5.2 mmol )的 NH₄C1加入体系，回流 lh, 真空脱去乙醇，向体系加入 20mL水，用 20% 的氢氧化钠溶液调至 pH值到 12, 向体系中加入 50mLDCM，搅拌均匀后，过滤，滤渣在用少量的水溶解，过滤，合并两次的滤液，分出有机层，有机层，水洗，无水硫酸钠干燥，真空脱溶剂，残渣柱分离（ V 10: 1 )得产物 3-苯基 -5-氨曱基 -异噁唑，收率 75%. 浅黄色固体， m.p: 39-40 °C 1H-NMR (400MHz,CDCl₃,TMS),6ppm: 1.60 ( s, 2H NH₂ ) 3.91 (s, 2H CH₂), 6.40 (s, 1H), 7.39 (m, 2H Ar-H), 7.76 (m, 2H Ar-H). 实施例 5 5.0 mmol 5-azidomethyl-3-phenyl-isoxazole was dissolved in a mixture of 80 mL ethanol and 20 mL water, 0.17 g (2.6 mmol) of zinc powder and 0.28 g (5.2 mmol) of NH. ₄ C1 was added to the system, refluxed for 1 h, the ethanol was removed by vacuum, 20 mL of water was added to the system, and the pH was adjusted to 12 with 20% sodium hydroxide solution. 50 m LDCM was added to the system, stirred uniformly, filtered, and the filter residue was used in small amounts. The water is dissolved, filtered, and the filtrate is combined twice, and the organic layer is separated, the organic layer is washed with water, dried over anhydrous sodium sulfate, evaporated in vacuo, and the residue is separated (V 10: 1) to give the product 3-phenyl-5- Aminomethyl-isoxazole, yield 75%. Light yellow solid, mp: 39-40 °C 1H-NMR (400MHz, CDCl ₃ , TMS), 6ppm: 1.60 ( s, 2H NH ₂ ) 3.91 (s, 2H CH ₂ ), 6.40 (s, 1H), 7.39 (m, 2H Ar-H), 7.76 (m, 2H Ar-H). Example 5

[6,7-二 (曱氧乙氧基 )】-4-[(3-苯基-异噁唑 -5-基) -曱氧基小喹唑啉 [6,7-di(decyloxy)]-4-[(3-phenyl-isoxazole-5-yl)-decyloxyquinazoline

0.3 g (lmmol)的 [6,7-二（曱氧乙氧基）】-4-氯-喹唑啉溶解在 5 mL干燥的异丙醇中，搅拌下将溶有 0.175g(lmmol) 5-羟甲基 -3-苯基-异噁唑的 5 mL异丙醇溶液緩慢滴加入反应体系，接着加入 0.101 g (lmmol)新蒸的三乙胺，体系室温搅拌 30 rnin后， 60°C反应， TLC检测反应完成后，反应液真空浓缩，残渣直接柱分离油 ): ( n =5:l~2:l )即得目标化合物 [6,7-二（甲氧乙氧基）】-4-{[3-(4-甲基-苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉（下表 Q-15 )。其余的化合物按照 0.3 g (1 mmol) of [6,7-di(decyloxy)]-4-chloro-quinazoline was dissolved in 5 mL of dry isopropanol and dissolved in 0.175 g (lmmol) with stirring. A solution of -hydroxymethyl-3-phenyl-isoxazole in 5 mL of isopropanol was slowly added dropwise to the reaction system, followed by the addition of 0.101 g (1 mmol) of freshly distilled triethylamine, and the system was stirred at room temperature for 30 rnin, 60 ° C. After the reaction is completed by TLC, the reaction solution is concentrated in vacuo, and the residue is directly separated from the oil by column: (n = 5:1 to 2:1) to obtain the target compound [6,7-di(methoxyethoxy)]- 4-{[3-(4-Methyl-phenyl)-isoxazol-5-yl]-methoxy+quinazoline (Table Q-15 below). The remaining compounds are in accordance with

[6,7-二（2-曱氧乙氧基）卜 4-{[3-(4-甲基-苯基) -异噁唑 -5-基卜甲氧基 +喹唑啉的合成过程合成。其结构均通过 IR， 1H NMR, ESI-MS等分析方法进行了表征。优选出的化合物的物性常数及光语数据以列表的形式进行说明： Synthesis of [6,7-bis(2-oximeoxyethoxy)-4-{[3-(4-methyl-phenyl)-isoxazol-5-yl-methoxy+quinazoline synthesis. The structures were characterized by IR, 1H NMR, ESI-MS and other analytical methods. The physical property constants and the optical data of the preferred compounds are described in the form of a list:

优选出的化合物的结构、编号 ^称如下表所示： The structure and number of the preferred compounds are shown in the following table:

表 1-优选化合物表 1-优选化合物 Table 1 - Preferred Compounds Table 1 - Preferred Compounds

4-Br Q-2 6,7-二甲氧基 -4-{[3-(4-溴-苯基) -异噁唑 -5-基】 -甲氧基+喹

4-Br Q-2 6,7-Dimethoxy-4-{[3-(4-bromo-phenyl)-isoxazol-5-yl]-methoxy+quina

N H Q-2 6,7-二甲氧基 -4-[(3-苯基-异噁唑 -5-基) -甲 -卜喹唑啉 N H Q-2 6,7-dimethoxy-4-[(3-phenyl-isoxazole-5-yl)-methyl-quinazoline

4-CH₃ Q-2 6,7-二甲氧基 -4-{[3-(4-曱基-苯基) -异噁唑 -5-基】 -甲氨基+ 啉 4-CH ₃ Q-2 6,7-Dimethoxy-4-{[3-(4-indolyl-phenyl)-isoxazol-5-yl]-methylamino+ porphyrin

4-OCH Q-2 6,7-二曱氧基 -4-{[3-(4-曱氧基-苯基) -异噁唑 -5-基卜曱氨基峻啉 4-OCH Q-2 6,7-didecyloxy-4-{[3-(4-decyloxy-phenyl)-isoxazole-5-ylpyridinium amino porphyrin

2-C1 Q-2 6,7-二甲氧基 -4-{[3-(2-氯-苯基) -异噁唑 -5-基】 -甲氨基+喹 2-C1 Q-2 6,7-dimethoxy-4-{[3-(2-chloro-phenyl)-isoxazole-5-yl]-methylamino+quino

4-C1 Q-2 6,7-二甲氧基 -4-{[3-(4-氯-苯基) -异噁唑 -5-基】 -甲氨基+喹 4-C1 Q-2 6,7-Dimethoxy-4-{[3-(4-Chloro-phenyl)-isoxazole-5-yl]-Methylamino+quino

2,4- 二 Q-2 6,7-二甲氧基 -4-{[3-(2，4-二氯-苯基) -异噁唑 -5-基】 -甲氨基峻啉 2,4-di Q-2 6,7-dimethoxy-4-{[3-(2,4-dichloro-phenyl)-isoxazole-5-yl]-methylamino porphyrin

4-Br Q-2 6,7-二甲氧基 -4-{[3-(4-溴-苯基) -异噁唑 -5-基】 -甲氨基+喹 4-Br Q-2 6,7-dimethoxy-4-{[3-(4-bromo-phenyl)-isoxazole-5-yl]-methylamino+quina

Ri=R₂ O H Q-2 [6,7-二 (2-甲氧乙氧基)】-4-[(3-苯基-异噁唑 -5-基) - 甲氧基Ri=R ₂ OH Q-2 [6,7-bis(2-methoxyethoxy)]-4-[(3-phenyl-isoxazol-5-yl)-methoxy

"峻啉 "Veroline

CH₃0 4-CH₃ Q-3 6,7-二 (2-曱氧乙氧基) -4-{[3-(4-曱基-苯基) -异噁唑 -5-基】 -CH2O- 5-基- } -会峻啉 CH ₃ 0 4-CH ₃ Q-3 6,7-bis(2-decyloxy)-4-{[3-(4-indolyl-phenyl)-isoxazol-5-yl] CH2O- 5-based- }

4-OCH Q-3 6,7-二 (2-甲氧乙氧基) -4-{[3-(4-曱氧基-苯基) -异噁唑 -5-基】 - 基- } -全峻啉 4-OCH Q-3 6,7-bis(2-methoxyethoxy)-4-{[3-(4-decyloxy-phenyl)-isoxazol-5-yl]-yl- } -full porphyrin

2-C1 Q-3 [6,7-二 (2-曱氧乙氧基)】-4-{[3-(2-氯-苯基) -异噁唑 -5-基】 - 曱喹唑啉 2-C1 Q-3 [6,7-bis(2-decyloxy)]-4-{[3-(2-chloro-phenyl)-isoxazol-5-yl]-oxazolium Porphyrin

4-C1 Q-3 [6,7-二 (2-曱氧乙氧基)】-4-{[3-(4-氯-苯基) -异噁唑 -5-基】- 曱喹唑啉 4-C1 Q-3 [6,7-bis(2-decyloxy)]-4-{[3-(4-chloro-phenyl)-isoxazol-5-yl]-quinazoline Porphyrin

2,4- 二 Q-3 [6,7-二 (2-甲氧乙氧基)】 -4-{[3-(2，4-二氯-苯基) -异噁唑 -5- - 曱氧基 -}-喹唑啉 2,4-di-Q-3 [6,7-bis(2-methoxyethoxy)]-4-{[3-(2,4-dichloro-phenyl)-isoxazole-5- -曱oxy-}-quinazoline

4-Br Q-3 [6,7-二 (2-曱氧乙氧基)】-4-{[3-(4-溴-苯基) -异噁唑 -5-基】 - 甲喹唑啉 4-Br Q-3 [6,7-bis(2-decyloxy)]-4-{[3-(4-bromo-phenyl)-isoxazol-5-yl] - A Quinazoline

N H Q-3 [6,7-二 (2-甲氧乙氧基)】-4-[(3-苯基-异噁唑 -5-基) - 甲氨基 N H Q-3 [6,7-bis(2-methoxyethoxy)]-4-[(3-phenyl-isoxazole-5-yl)-methylamino

"峻啉 "Veroline

4-CH₃ Q-3 6,7-二 (2-曱氧乙氧基) -4-{[3-(4-曱基-苯基) -异噁唑 -5-基】 - 一会峻啉 4-CH ₃ Q-3 6,7-bis(2-decyloxy)-4-{[3-(4-indolyl-phenyl)-isoxazol-5-yl] - Yihui Jun Porphyrin

4-OCH Q-3 6,7-二 (2-甲氧乙氧基) -4-{[3-(4-曱氧基-苯基) -异噁唑 -5-基】 - 基- } -会峻啉 4-OCH Q-3 6,7-bis(2-methoxyethoxy)-4-{[3-(4-decyloxy-phenyl)-isoxazol-5-yl]-yl- } - Huijun

4-C1 Q-4 [6,7-二 (2-曱氧乙氧基)】-4-{[3-(4-氯-苯基) -异噁唑 -5-基】- 曱喹唑啉 4-C1 Q-4 [6,7-bis(2-decyloxy)]-4-{[3-(4-chloro-phenyl)-isoxazol-5-yl]-quinazoline Porphyrin

2,4- 二 Q-4 [6,7-二 (2-曱氧乙氧基)】 -4-{[3-(2，4-二氯-苯基) -异噁唑 -5- - 曱氨基+喹唑啉 2,4-di-Q-4 [6,7-bis(2-oximeoxyethoxy)]-4-{[3-(2,4-dichloro-phenyl)-isoxazole-5- - Amidoxime + quinazoline

4-Br Q-4 [6,7-二 (2-曱氧乙氧基)】-4-{[3-(4-溴-苯基) -异噁唑 -5-基】 - 甲喹唑啉实施例 6 7-硝基 -4-[(3-苯基-异噁唑 -5-基) -曱氧基-】 -喹唑啉 4-Br Q-4 [6,7-bis(2-decyloxy)]-4-{[3-(4-bromo-phenyl)-isoxazol-5-yl]-methylquinazole Phenanthristyl Example 6 7-Nitro-4-[(3-phenyl-isoxazol-5-yl)-decyloxy-]-quinazoline

将 0.209 g (lmmol)的 7-硝基 -4-氯-喹唑啉溶解在 5 mL干燥的异丙醇中，搅拌下将溶有 0.175g(lmmol) 5-羟甲基 -3-苯基-异噁唑的 5 mL异丙醇溶液緩慢滴加入反应体系，接着加入 0.101 g (lmmol)新蒸的三乙胺，体系室温搅拌 30 rnin后， 60°C反应， TLC检测反应完成后，反应液真空浓缩，残渣直接柱分离（ y c =5:1~2:1)即得目标化合物 7-硝基 -4-[(3-苯基) -异噁唑 -5-基】 -曱氧基-喹唑啉 (下表 Q-l)。其余的化合物按照 7-硝基 -4-[(3-苯基) -异噁唑 -5- 基】 -甲氧基-喹唑啉。其结构均通过 IR H NM ESI-MS等分析方法进行了表征。优选出的化合物的物性常数及光谱数据以列表的形式进行说明： 0.209 g (lmmol) of 7-nitro-4-chloro-quinazoline was dissolved in 5 mL of dry isopropanol, and 0.175 g (1 mmol) of 5-hydroxymethyl-3-phenyl was dissolved with stirring. - 5 mL of isopropoxazole in isopropanol solution was slowly added dropwise to the reaction system, followed by the addition of 0.101 g (1 mmol) of freshly distilled triethylamine. The system was stirred at room temperature for 30 rnin, and then reacted at 60 ° C. After the TLC reaction was completed, the reaction was completed. The liquid is concentrated in a vacuum, and the residue is directly separated by a column (yc = 5:1 to 2:1) to obtain the target compound 7-nitro-4-[(3-phenyl)-isoxazol-5-yl]-decyloxy - quinazoline (Ql below). The remaining compound was based on 7-nitro-4-[(3-phenyl)-isoxazol-5-yl]-methoxy-quinazoline. The structures were characterized by analytical methods such as IR H NM ESI-MS. The physical property constants and spectral data of the preferred compounds are illustrated in the form of a list:

实施例 7 2-苯基 -4-[(3-苯基-异噁唑 -5-基) -曱氧基-】 -喹唑啉

Example 7 2-Phenyl-4-[(3-phenyl-isoxazol-5-yl)-decyloxy-]-quinazoline

将 0.24 g (lmmol)的 2-苯基 -4-氯-喹唑啉溶解在 5 mL干燥的异丙醇中，搅拌下将溶有 0.175g(lmmol) 5-羟甲基 -3-苯基-异噁唑的 5 mL异丙醇溶液緩慢滴加入反应体系，接着加入 0.101 g (lmmol)新蒸的三乙胺，体系室温搅拌 30 rnin后， 60°C反应， TLC检测反应完成后，反应液真空浓缩，残渣直接柱分离（ y c =5:1~2:1)即得目标化合物 2-苯基 -4-[(3-苯基) -异噁唑 -5-基卜曱氧基-喹唑啉 (下表 Q-ll)。其余的化合物按照 2-苯基 -4-[(3-苯基) -异噁唑 -5- 基】 -曱氧基-喹唑啉。其结构均通过 IR H NM ESI-MS等分析方法进行了表征。优选出的化合物的物性常数及光谱数据以列表的形式进行说明。 0.24 g (lmmol) of 2-phenyl-4-chloro-quinazoline was dissolved in 5 mL of dry isopropanol, and 0.175 g (1 mmol) of 5-hydroxymethyl-3-phenyl was dissolved with stirring. - 5 mL of isopropoxazole in isopropanol solution was slowly added dropwise to the reaction system, followed by the addition of 0.101 g (1 mmol) of freshly distilled triethylamine. The system was stirred at room temperature for 30 rnin, and then reacted at 60 ° C. After the TLC reaction was completed, the reaction was completed. The liquid is concentrated in a vacuum, and the residue is directly separated by a column (yc = 5:1 to 2:1) to obtain the target compound 2-phenyl-4-[(3-phenyl)-isoxazol-5-ylpyridinoxy- Quinazoline (Q-ll, below). The remaining compound was based on 2-phenyl-4-[(3-phenyl)-isoxazol-5-yl]-decyloxy-quinazoline. The structures were characterized by analytical methods such as IR H NM ESI-MS. The physical property constants and spectral data of the preferred compounds are described in the form of a list.

优选出的化合物的结构、编 ^称如下表所示： The structure and the structure of the preferred compounds are shown in the following table:

表 2-优选化合物 Table 2 - Preferred compounds

il 4-CF₃ P-9 ₇—硝基 _4_{[₃_₍₄_三氟曱基-苯基) -异噁唑 -5-基】 -甲氧基+

Il 4-CF ₃ P-9 ₇ —Nitro_4_{[ ₃ _ ₍₄ _Trifluoromethyl-phenyl)-isoxazol-5-yl]-methoxy+

2,4- 二 P-10 ₇·硝基 _4-{[3-[4-(2，4-二曱氧基-苯基)】 -异噁唑 -5-基】 -甲氧基 }一会峻啉 2,4-di-P-10 ₇ ·Nitro_4-{[3-[4-(2,4-dimethoxy-phenyl)]-isoxazole-5-yl]-methoxy} One-time

N H P-ll ₇—硝基 _₄_[(3-苯基-异噁唑 -5-基) -曱氨基-】 -喹唑啉 NH P-ll ₇ -nitro- ₄ _[(3-phenyl-isoxazol-5-yl)-indolyl-]-quinazoline

4-CH₃ P-12 ₇—硝基 _₄_{[3-(4-甲基-苯基) -异噁唑 -5-基】 -甲氨基 +喹唑 4-CH ₃ P-12 ₇ —Nitro_ ₄ _{[3-(4-Methyl-phenyl)-isoxazol-5-yl]-Methylamino+quinazoline

4-OCH P-13 ₇_硝基 _₄_{[₃_₍₄_甲氧基-苯基)—异噁唑 _₅_基】 -曱氨基+喹 4-OCH P-13 ₇ _Nitro_ ₄ _{[ ₃ _ ₍₄ _Methoxy-phenyl)-isoxazole _ ₅ _ group] -Amino group + quinolin

2-C1 P-14 ₇_硝基 _₄_{[3-(2-氯-苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉2-C1 P-14 ₇ _Nitro- ₄ _{[3-(2-chloro-phenyl)-isoxazol-5-yl]-nonylamino+quinazoline

4-C1 P-15 ₇-硝基 _₄_{[3-(4-氯-苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉4-C1 P-15 ₇ -nitro- ₄ _{[3-(4-chloro-phenyl)-isoxazol-5-yl]-nonylamino+quinazoline

2,4- 二 P-16 ₇_硝基 _₄_{[₃_(2，4-二氯-苯基) -异噁唑 -5-基】 -曱氨基+喹 2,4-di-P-16 ₇ _nitro- ₄ _{[ ₃ _(2,4-dichloro-phenyl)-isoxazol-5-yl]-nonylamino + quinine

4-Br P-17 ₇_硝基 _₄_{[3-(4-溴-苯基) -异噁唑 -5-基】 -甲氨基+喹唑啉4-Br P-17 ₇ _Nitro- ₄ _{[3-(4-Bromo-phenyl)-isoxazol-5-yl]-Methylamino+quinazoline

4-F P-18 ₇_硝基 _₄_{[3-(4-氟-苯基) -异噁唑 -5-基】 -甲氨基+喹唑啉4-F P-18 ₇ _Nitro- ₄ _{[3-(4-Fluoro-phenyl)-isoxazol-5-yl]-Methylamino+quinazoline

4-CF₃ P-19 ₇—硝基 _₄_{[₃_₍₄_三氟甲基-苯基)-异噁唑 -5-基】 -甲 -}- 4-CF ₃ P-19 ₇ —Nitro — ₄ _{[ ₃ _ ₍₄ _Trifluoromethyl-phenyl)-isoxazole-5-yl]-A-}-

2,4- 二 P-20 ₇·硝基 _4-{[3-[4-(2，4-二甲氧基-苯基)】 -异噁唑 -5-基】 -甲氨基 }一会峻啉 2,4-di-P-20 ₇ ·Nitro-4-{[3-[4-(2,4-dimethoxy-phenyl)]-isoxazole-5-yl]-methylamino} Will

O H P-21 2-苯基 -4-[(3-苯基-异噁唑 -5-基) -曱氧基-】 -喹唑啉 O H P-21 2-phenyl-4-[(3-phenyl-isoxazole-5-yl)-decyloxy-]-quinazoline

R₂=-H 4-CH₃ P-22 2-苯基 -4-{[3-(4-甲基-苯基) -异噁唑 -5-基】 -甲氧基 +喹唑 R ₂ =-H 4-CH ₃ P-22 2-phenyl-4-{[3-(4-methyl-phenyl)-isoxazol-5-yl]-methoxy+quinazoline

4-OCH P-23 2-苯基 -4-{[3-(4-甲氧基-苯基) -异噁唑 -5-基】 -曱氧基+喹 4-OCH P-23 2-phenyl-4-{[3-(4-methoxy-phenyl)-isoxazole-5-yl]-decyloxy+quino

2-C1 P-24 2-苯基 -4-{[3-(2-氯-苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉2-C1 P-24 2-phenyl-4-{[3-(2-chloro-phenyl)-isoxazole-5-yl]-methoxy+quinazoline

4-C1 P-25 2-苯基 -4-{[3-(4-氯-苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉4-C1 P-25 2-phenyl-4-{[3-(4-chloro-phenyl)-isoxazole-5-yl]-decyloxy+quinazoline

2,4- 二 P-26 2-苯基 -4-{[3-(2，4-二氯-苯基) -异噁唑 -5-基】 -曱氧基+喹 2,4-di-P-26 2-phenyl-4-{[3-(2,4-dichloro-phenyl)-isoxazole-5-yl]-decyloxy+quino

4-Br P-27 2-苯基 -4-{[3-(4-溴-苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉 4-F P-28 2-苯基 -4-{[3-(4-氟-苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉 4-Br P-27 2-phenyl-4-{[3-(4-bromo-phenyl)-isoxazol-5-yl]-decyloxy+quinazoline 4-F P-28 2-phenyl-4-{[3-(4-fluoro-phenyl)-isoxazol-5-yl]-decyloxy+quinazoline

4-CF₃ P-29 2-苯基 -4-{[3-(4-三氟甲基-苯基) -异噁唑 -5-基】 -甲氧基+ 4-CF ₃ P-29 2-phenyl-4-{[3-(4-trifluoromethyl-phenyl)-isoxazol-5-yl]-methoxy+

2,4- 二 P-30 2-苯基 -4-{[3-[4-(2，4-二甲氧基-苯基)】 -异噁唑 -5-基】 -甲氧基 }一会峻啉 2,4-di-P-30 2-phenyl-4-{[3-[4-(2,4-dimethoxy-phenyl)]-isoxazole-5-yl]-methoxy} One-time

N H P-31 2-苯基 -4-[(3-苯基-异噁唑 -5-基) -曱氨基-】 -喹唑啉 N H P-31 2-phenyl-4-[(3-phenyl-isoxazole-5-yl)-indolyl-]-quinazoline

4-CH3 P-32 2-苯基 -4-{[3-(4-曱基-苯基）-异噁唑 -5-基卜甲喹唑 4-CH3 P-32 2-phenyl-4-{[3-(4-mercapto-phenyl)-isoxazole-5-yl-b-methyl quinazoline

4-OCH P-33 2-苯基 -4-{[3-(4-甲氧基 -苯基 ) -异噁唑 -5-基】 -曱氨基+ 4-OCH P-33 2-phenyl-4-{[3-(4-methoxy-phenyl)-isoxazole-5-yl]-nonylamino+

2-C1 P-34 2-苯基 -4-{[3-(2-氯-苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉2-C1 P-34 2-phenyl-4-{[3-(2-chloro-phenyl)-isoxazole-5-yl]-nonylamino+quinazoline

4-C1 P-25 2-苯基 -4-{[3-(4-氯-苯基) -异噁唑 -5-基】 -甲氨基+喹唑啉4-C1 P-25 2-phenyl-4-{[3-(4-chloro-phenyl)-isoxazole-5-yl]-methylamino+quinazoline

2,4- 二 P-36 2-苯基 -4-{[3-(2，4-二氯-苯基) -异噁唑 -5-基】 -曱氨基+喹 2,4-di-P-36 2-phenyl-4-{[3-(2,4-dichloro-phenyl)-isoxazole-5-yl]-nonylamino+quina

4-Br P-37 2-苯基 -4-{[3-(4-溴-苯基) -异噁唑 -5-基】 -甲氨基+喹唑啉4-Br P-37 2-phenyl-4-{[3-(4-bromo-phenyl)-isoxazole-5-yl]-methylamino+quinazoline

4-F P-38 2-苯基 -4-{[3-(4-氟-苯基) -异噁唑 -5-基】 -甲氨基+喹唑啉4-F P-38 2-phenyl-4-{[3-(4-fluoro-phenyl)-isoxazole-5-yl]-methylamino+quinazoline

4-CF₃ P-39 2-苯基 -4-{[3-(4-三氟甲基-苯基) -异噁唑 -5-基】 -甲 -}- 4-CF ₃ P-39 2-phenyl-4-{[3-(4-trifluoromethyl-phenyl)-isoxazol-5-yl]---}-

2,4- 二 P-40 2-苯基 -4-{[3-[4-(2，4-二甲氧基-苯基)】 -异噁唑 -5-基】 -甲氨基 }一全峻啉 2,4-di-P-40 2-phenyl-4-{[3-[4-(2,4-dimethoxy-phenyl)]-isoxazole-5-yl]-methylamino} Total porphyrin

表 3-表 1化合物的物性常数、 IR和 MS数据 Table 3 - Table 1 Physical property constants, IR and MS data for compounds

Q-4 白色固体 104-105 3120,2934,1617,1499,1503,1444, 338 ( [M+l]⁺,100 )

Q-4 white solid 104-105 3120, 2934, 1617, 1499, 1503, 1444, 338 ([M+l] ⁺ , 100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-5 白色固体 145-148 3120,2934,1617,1499,1503,1444, 338 ( [M+l]⁺,100 ) Q-5 white solid 145-148 3120, 2934, 1617, 1499, 1503, 1444, 338 ([M+l] ⁺ ,100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-6 白色固体 146-147 3120,2934,1617,1499,1503,1444, 373 ( [M+2]⁺,20 ) Q-6 white solid 146-147 3120, 2934, 1617, 1499, 1503, 1444, 373 ([M+2] ⁺ , 20 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-7 白色固体 158-160 3120,2934,1617,1499,1503,1444, Q-7 white solid 158-160 3120, 2934, 1617, 1499, 1503, 1444,

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-8 白色固体 3237,3079,2927,1590,1544,1433, 303 ( [M+l]⁺,100 ) Q-8 white solid 3237, 3079, 2927, 1590, 1544, 1433, 303 ([M+l] ⁺ , 100 )

1232,1106,799 1232,1106,799

Q-9 白色固体 3237,3079,2927,1590,1544,1433, 317 ( [M+l]⁺,100 ) Q-9 white solid 3237, 3079, 2927, 1590, 1544, 1433, 317 ([M+l] ⁺ , 100 )

1232,1106,799 1232,1106,799

Q-10 白色固体 3237,3079,2927,1590,1544,1433, 333 ( [M+l]⁺,100 ) Q-10 white solid 3237, 3079, 2927, 1590, 1544, 1433, 333 ([M+l] ⁺ ,100 )

1232,1106,799 1232,1106,799

Q-ll 白色固体 3237,3079,2927,1590,1544,1433, 337 ( [M+l]⁺,100 ) Q-ll white solid 3237, 3079, 2927, 1590, 1544, 1433, 337 ([M+l] ⁺ , 100 )

1232,1106,799 1232,1106,799

Q-12 白色固体 3237,3079,2927,1590,1544,1433, 337 ( [M+l]⁺,100 ) Q-12 white solid 3237, 3079, 2927, 1590, 1544, 1433, 337 ([M+l] ⁺ , 100 )

1232,1106,799 1232,1106,799

Q-13 白色固体 3237,3079,2927,1590,1544,1433, 372 ( [M+2]⁺,20 ) Q-13 white solid 3237, 3079, 2927, 1590, 1544, 1433, 372 ([M+2] ⁺ , 20 )

1232,1106,799 1232,1106,799

Q-14 白色固体 3237,3079,2927,1590,1544,1433, Q-14 white solid 3237,3079,2927,1590,1544,1433,

1232,1106,799 1232,1106,799

Q-15 白色固体 163-164 3120,2934,1617,1499,1503,1444, 364 ( [M+l]⁺,100 ) Q-15 white solid 163-164 3120, 2934, 1617, 1499, 1503, 1444, 364 ([M+l] ⁺ ,100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-16 白色固体 169-171 3120,2934,1617,1499,1503,1444, 378 ( [M+l]⁺,100 ) Q-16 white solid 169-171 3120, 2934, 1617, 1499, 1503, 1444, 378 ([M+l] ⁺ ,100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-17 白色固体 158-161 3121,2934,1617,1570,1503,1444, 394 ( [M+l]⁺,100 ) Q-17 white solid 158-161 3121,2934,1617,1570,1503,1444, 394 ([M+l] ⁺ ,100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-18 白色固体 163-165 3121,2934,1617,1570,1503,1444, 398 ( [M+l]⁺,100 ) 1361,1281,1091,958,817 Q-18 white solid 163-165 3121, 2934, 1617, 1570, 1503, 1444, 398 ([M+l] ⁺ ,100 ) 1361,1281,1091,958,817

Q-19 白色固体 176-178 3121,2934,1617,1570,1503,1444, 398 ( [M+l]⁺,100 ) Q-19 white solid 176-178 3121, 2934, 1617, 1570, 1503, 1444, 398 ([M+l] ⁺ ,100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-20 白色固体 185-187 3120,2934,1617,1499,1503,1444, 432 ( [M+l]⁺,100 ) Q-20 white solid 185-187 3120, 2934, 1617, 1499, 1503, 1444, 432 ([M+l] ⁺ ,100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-21 白色固体 178-179 3121,2934,1617,1570,1503,1444, 442 ( [M+l]⁺,100 ) Q-21 White solid 178-179 3121, 2934, 1617, 1570, 1503, 1444, 442 ([M+l] ⁺ , 100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-22 白色固体 3237,3079,2927,1590,1544,1433, 363 ( [M+l]⁺,100 ) Q-22 white solid 3237, 3079, 2927, 1590, 1544, 1433, 363 ([M+l] ⁺ ,100 )

1232,1106,799 1232,1106,799

Q-23 白色固体 3237,3079,2927,1590,1544,1433, 377 ( [M+l]⁺,100 ) Q-23 white solid 3237, 3079, 2927, 1590, 1544, 1433, 377 ([M+l] ⁺ , 100 )

1232,1106,799 1232,1106,799

Q-24 白色固体 3237,3079,2927,1590,1544,1433, 393 ( [M+l]⁺,100 ) Q-24 white solid 3237, 3079, 2927, 1590, 1544, 1433, 393 ([M+l] ⁺ ,100 )

1232,1106,799 1232,1106,799

Q-25 白色固体 3237,3079,2927,1590,1544,1433, 397 ( [M+l]⁺,100 ) Q-25 white solid 3237, 3079, 2927, 1590, 1544, 1433, 397 ([M+l] ⁺ ,100 )

1232,1106,799 1232,1106,799

Q-26 白色固体 3237,3079,2927,1590,1544,1433, 397 ( [M+l]⁺,100 ) Q-26 white solid 3237, 3079, 2927, 1590, 1544, 1433, 397 ([M+l] ⁺ , 100 )

1232,1106,799 1232,1106,799

Q-27 白色固体 3237,3079,2927,1590,1544,1433, 431 ( [M+l]⁺,100 ) Q-27 white solid 3237, 3079, 2927, 1590, 1544, 1433, 431 ([M+l] ⁺ , 100 )

1232,1106,799 1232,1106,799

Q-28 白色固体 3237,3079,2927,1590,1544,1433, 441 ( [M+l]⁺,100 ) Q-28 white solid 3237, 3079, 2927, 1590, 1544, 1433, 441 ([M+l] ⁺ ,100 )

1232,1106,799 1232,1106,799

Q-29 白色固体 112-113 3120,2934,1617,1499,1503,1444, 452 ( [M+l]⁺,100 ) Q-29 white solid 112-113 3120, 2934, 1617, 1499, 1503, 1444, 452 ([M+l] ⁺ , 100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-30 白色固体 115-117 3120,2934,1617,1499,1503,1444, 466 ( [M+l]⁺,100 ) Q-30 white solid 115-117 3120, 2934, 1617, 1499, 1503, 1444, 466 ([M+l] ⁺ ,100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-31 白色固体 136-137 3121,2934,1617,1570,1503,1444, 482 ( [M+l]⁺,100 ) Q-31 white solid 136-137 3121,2934,1617,1570,1503,1444, 482 ([M+l] ⁺ ,100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-32 白色固体 133-134 3120,2934,1617,1499,1503,1444, 486 ( [M+l]⁺,100 ) Q-32 white solid 133-134 3120, 2934, 1617, 1499, 1503, 1444, 486 ([M+l] ⁺ ,100 )

1361,1281,1091,958,817 Q-33 白色固体 117-118 3121,2934,1617,1570,1503,1444, 586 ( [M+l]⁺,100 ) 1361,1281,1091,958,817 Q-33 white solid 117-118 3121,2934,1617,1570,1503,1444, 586 ([M+l] ⁺ ,100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-34 白色固体 121-122 3120,2934,1617,1499,1503,1444, 520 ( [M+l]⁺,100 ) Q-34 white solid 121-122 3120, 2934, 1617, 1499, 1503, 1444, 520 ([M+l] ⁺ ,100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-35 白色固体 119-120 3121,2934,1617,1570,1503,1444, 530([M+1]⁺,100 ) Q-35 white solid 119-120 3121, 2934, 1617, 1570, 1503, 1444, 530 ([M+1] ⁺ , 100 )

1361,1281,1091,958,817 1361,1281,1091,958,817

Q-36 白色固体 3237,3079,2927,1590,1544,1433, 451 ( [M+l]⁺,100 ) Q-36 white solid 3237, 3079, 2927, 1590, 1544, 1433, 451 ([M+l] ⁺ , 100 )

1232,1106,799 1232,1106,799

Q-37 白色固体 3237,3079,2927,1590,1544,1433, 465 ( [M+l]⁺,100 ) Q-37 white solid 3237, 3079, 2927, 1590, 1544, 1433, 465 ([M+l] ⁺ ,100 )

1232,1106,799 1232,1106,799

Q-38 白色固体 3237,3079,2927,1590,1544,1433, 481 ( [M+l]⁺,100 ) Q-38 white solid 3237, 3079, 2927, 1590, 1544, 1433, 481 ([M+l] ⁺ , 100 )

1232,1106,799 1232,1106,799

Q-39 白色固体 3237,3079,2927,1590,1544,1433, 485 ( [M+l]⁺,100 ) Q-39 white solid 3237, 3079, 2927, 1590, 1544, 1433, 485 ([M+l] ⁺ ,100 )

1232,1106,799 1232,1106,799

Q-40 白色固体 3237,3079,2927,1590,1544,1433, 485 ( [M+l]⁺,100 ) Q-40 white solid 3237, 3079, 2927, 1590, 1544, 1433, 485 ([M+l] ⁺ ,100 )

1232,1106,799 1232,1106,799

Q-41 白色固体 3237,3079,2927,1590,1544,1433, 519 ( [M+l]⁺,100 ) Q-41 white solid 3237, 3079, 2927, 1590, 1544, 1433, 519 ([M+l] ⁺ , 100 )

1232,1106,799 1232,1106,799

Q-42 白色固体 3237,3079,2927,1590,1544,1433, 529([M+1]⁺,100 ) Q-42 white solid 3237, 3079, 2927, 1590, 1544, 1433, 529 ([M+1] ⁺ , 100 )

1232,1106,799 表 4-表 1化合物的物性常数 1H NMR数据 1232,1106,799 Table 4-Table 1 Physical property constants of compounds 1H NMR data

azole-H), 7.37(d, 2H， J=4.8Hz), 7.84(d, 2H， J=7.6Hz), 8.69(s, 1H).

azole-H), 7.37 (d, 2H, J = 4.8 Hz), 7.84 (d, 2H, J = 7.6 Hz), 8.69 (s, 1H).

Q-18 3.97(s, 6H, 2CH₃)， 5.87(s， 2H， CH₂)， 7.16(s, 1H， isoxazole-H), 7.37(m, 2H)， 7.48-7.56(m, 2H)， l-7.73(m,2H), 8.70(s， 1H). Q-18 3.97(s, 6H, 2CH ₃ ), 5.87(s, 2H, CH ₂ ), 7.16(s, 1H, isoxazole-H), 7.37(m, 2H), 7.48-7.56(m, 2H), L-7.73 (m, 2H), 8.70 (s, 1H).

Q-19 3.97(s, 6H,2CH₃), 5.85(s， 2H， CH₂)， 7.30(s, 1H， isoxazole-H), 7.37(d, 2H， J=6.4Hz),7.60(d, 2H， .4Hz),7.94(d, 2H， J=8.8Hz), 8.69(s, 1H). Q-19 3.97(s, 6H, 2CH ₃ ), 5.85(s, 2H, CH ₂ ), 7.30(s, 1H, isoxazole-H), 7.37(d, 2H, J=6.4Hz), 7.60(d, 2H, .4Hz), 7.94(d, 2H, J=8.8Hz), 8.69(s, 1H).

Q-20 3.91(s, 6H,2CH₃), 5.87(s， 2H， CH₂)， 7.17(s， 1H， isoxazole-H), 7.37(m, 2H),7.58-7.60(m,lH), i(d， 1H， J=8.4Hz), 7.84-7.85(m, 1H)， 8.70(s，lH). Q-20 3.91(s, 6H, 2CH ₃ ), 5.87(s, 2H, CH ₂ ), 7.17(s, 1H, isoxazole-H), 7.37(m, 2H), 7.58-7.60(m,lH), i(d, 1H, J=8.4Hz), 7.84-7.85(m, 1H), 8.70(s,lH).

Q-21 3.97 (s, 6H,2CH₃), 5.84 (s, 2H， CH₂)， 7.29 (s, 1H， isoxazole-H), 7.37(d, 2H， J=8.0Hz), 7.73 (d，lH， .4Hz )， 7.86 (d, 1H， J=8.4Hz), 8.69 (s，lH). Q-21 3.97 (s, 6H, 2CH ₃ ), 5.84 (s, 2H, CH ₂ ), 7.29 (s, 1H, isoxazole-H), 7.37 (d, 2H, J=8.0Hz), 7.73 (d, lH, .4Hz ), 7.86 (d, 1H, J=8.4Hz), 8.69 (s,lH).

Q-22 3.95(s, 6H, 3CH₃), 4.29(t, J=6.6Hz,lH, NH), 5.84-5.85(m, 2H, CH₂), 7.24 (s, 1H, isoxazole-H), l(d, 2H, J=6.8Hz), 7.51-7.53 (m, 2H), 7.65-7.72(m, 1H), 7.89-7.91(m, 2H), 8.70(s, 1H). Q-22 3.95(s, 6H, 3CH ₃ ), 4.29(t, J=6.6Hz, lH, NH), 5.84-5.85(m, 2H, CH ₂ ), 7.24 (s, 1H, isoxazole-H), l(d, 2H, J=6.8Hz), 7.51-7.53 (m, 2H), 7.65-7.72(m, 1H), 7.89-7.91(m, 2H), 8.70(s, 1H).

Q-23 2.36(s, 3H, CH₃), 3.97(s, 6H, 2CH₃), 4.29(t, J=6.6Hz,lH, NH), 5.83-5.85(m, 2H, CH₂), 7.23(s, 1H, azole-H), 7.33(d, 2H， J=8.0Hz), 7.37(d, 2H， J=6.0Hz), 7.79(d, 2H， J=8.0Hz), 8.70(s，lH). Q-23 2.36(s, 3H, CH ₃ ), 3.97(s, 6H, 2CH ₃ ), 4.29(t, J=6.6Hz, lH, NH), 5.83-5.85(m, 2H, CH ₂ ), 7.23 (s, 1H, azole-H), 7.33 (d, 2H, J = 8.0 Hz), 7.37 (d, 2H, J = 6.0 Hz), 7.79 (d, 2H, J = 8.0 Hz), 8.70 (s, lH).

Q-24 3.82(s,3H, OCH₃), 3.97( s, 6H, 2CH₃)， 4.29(t, J=6.6Hz,lH, NH), 5.82-5.83(m, 2H， CH₂)， 7.07(d， J=7.6Hz), 7.20(s， 1H， isoxazole-H), 7.37(d, 2H， J=4.8Hz), 7.84(d, 2H， J=7.6Hz), 8.69(s, 1H).Q-24 3.82(s,3H, OCH ₃ ), 3.97( s, 6H, 2CH ₃ ), 4.29(t, J=6.6Hz, lH, NH), 5.82-5.83(m, 2H, CH ₂ ), 7.07 (d, J = 7.6 Hz), 7.20 (s, 1H, isoxazole-H), 7.37 (d, 2H, J = 4.8 Hz), 7.84 (d, 2H, J = 7.6 Hz), 8.69 (s, 1H) .

Q-25 3.97(s, 6H, 2CH₃), 4.3 l(t, J=6.6Hz,lH, NH), 5.87-5.89(m, 2H, CH₂), 7.16(s, 1H, isoxazole-H), (m, 2H)， 7.48-7.56(m, 2H)， 7.64-7.73(m,2H), 8.70(s， 1H). Q-25 3.97(s, 6H, 2CH ₃ ), 4.3 l(t, J=6.6Hz, lH, NH), 5.87-5.89(m, 2H, CH ₂ ), 7.16(s, 1H, isoxazole-H) , (m, 2H), 7.48-7.56 (m, 2H), 7.64-7.73 (m, 2H), 8.70 (s, 1H).

Q-26 3.97(s, 6H,2CH₃), 4.31(t, J=6.6Hz,lH, NH), 5.85-5.86(m, 2H, CH₂), 7.30(s, 1H, isoxazole-H), (d, 2H， J=6.4Hz),7.60(d, 2H， J=8.4Hz),7.94(d, 2H， J=8.8Hz), 8.69(s, 1H). Q-26 3.97(s, 6H, 2CH ₃ ), 4.31(t, J=6.6Hz, lH, NH), 5.85-5.86(m, 2H, CH ₂ ), 7.30(s, 1H, isoxazole-H), (d, 2H, J = 6.4 Hz), 7.60 (d, 2H, J = 8.4 Hz), 7.94 (d, 2H, J = 8.8 Hz), 8.69 (s, 1H).

Q-27 3.91(s, 6H,2CH₃), 4.31(t, J=6.6Hz,lH, NH), 5.87-5.88(m, 2H, CH₂), 7.17(s， 1H, isoxazole-H), (m, 2H),7.58-7.60(m,lH), 7.76(d, 1H， J=8.4Hz), 7.84-7.85(m, 1H)， 8.70(s，lH). Q-27 3.91(s, 6H, 2CH ₃ ), 4.31(t, J=6.6Hz, lH, NH), 5.87-5.88(m, 2H, CH ₂ ), 7.17(s, 1H, isoxazole-H), (m, 2H), 7.58-7.60 (m, lH), 7.76 (d, 1H, J = 8.4 Hz), 7.84-7.85 (m, 1H), 8.70 (s, lH).

Q-28 3.97 (s, 6H,2CH₃), 4.31(t, J=6.6Hz,lH, NH), 5.84-5.85 (m, 2H， CH₂)， 7.29 (s, 1H， isoxazole-H), (d, 2H， J=8.0Hz), 7.73 (d，lH， J=8.4Hz )， 7.86 (d, 1H， J=8.4Hz), 8.69 (s，lH). Q-28 3.97 (s, 6H, 2CH ₃ ), 4.31 (t, J = 6.6 Hz, lH, NH), 5.84-5.85 (m, 2H, CH ₂ ), 7.29 (s, 1H, isoxazole-H), (d, 2H, J=8.0Hz), 7.73 (d,lH, J=8.4Hz), 7.86 (d, 1H, J=8.4Hz), 8.69 (s,lH).

Q-29 3.35(s, 6H, 2CH₃), 3.72-3.76(m, 4H, 2CH₂)， 4.26-4.33(m, 4H, 2CH₂),5.83(s, 2H， CH₂)， 7.23 (s, isoxazole-H),7.42(d, 2H， J=12.0Hz),7.50-7.54(m, 3H),7.89-7.91(m, 2H),8.69(s,lH). Q-29 3.35(s, 6H, 2CH ₃ ), 3.72-3.76(m, 4H, 2CH ₂ ), 4.26-4.33(m, 4H, 2CH ₂ ), 5.83(s, 2H, CH ₂ ), 7.23 (s , isoxazole-H), 7.42 (d, 2H, J = 12.0 Hz), 7.50-7.54 (m, 3H), 7.89-7.91 (m, 2H), 8.69 (s, lH).

Q-30 2.36(s, 3H, Ph-CH₃),3.36(s, 6H, 2CH₃),3.72-3.76(m, 4H, 2CH₂), 4.25-4.33(m, 4H, 2CH₂), 5.81 (s, CH₂), 7.23 (s, 1H, isoxazole-H),7.31-7.35(m, 2H), 7.38-7.41(m, 2H), 7.77-7.79(m, 2H), 8.68(s,lH).Q-30 2.36(s, 3H, Ph-CH ₃ ), 3.36(s, 6H, 2CH ₃ ), 3.72-3.76(m, 4H, 2CH ₂ ), 4.25-4.33(m, 4H, 2CH ₂ ), 5.81 (s, CH ₂ ), 7.23 (s, 1H, isoxazole-H), 7.31-7.35 (m, 2H), 7.38-7.41 (m, 2H), 7.77-7.79 (m, 2H), 8.68 (s, lH ).

Q-31 3.34 (s, 6H, 2CH₃), 3.72-3.76 (m, 4H, 2CH₂)， 3.81 (s, 3H, Ph-OCH₃), 4.25-4.33 (m, 4H, 2CH₂)， Q-31 3.34 (s, 6H, 2CH ₃ ), 3.72-3.76 (m, 4H, 2CH ₂ ), 3.81 (s, 3H, Ph-OCH ₃ ), 4.25-4.33 (m, 4H, 2CH ₂ ),

1 (s, 2H， CH₂)， 7.07(d， 2H， J=8.8 Hz), 7.20 (s, 1H， isoxazole-H), 7.41 (d, 2H， J=12.0Hz), 8.69 1 (s, 2H, CH ₂ ), 7.07 (d, 2H, J = 8.8 Hz), 7.20 (s, 1H, isoxazole-H), 7.41 (d, 2H, J = 12.0 Hz), 8.69

l-5.85(m, 2H, CH₂)， 7.30(s, 1H， isoxazole-H),7.40(d, 2H， J=12.8Hz),7.72-7.74(m, 2H)， i-7.87(m, 2H)， 8.68(s, IH). 表 5-表 2部分化合物的 NMR数据 L-5.85 (m, 2H, CH ₂ ), 7.30 (s, 1H, isoxazole-H), 7.40 (d, 2H, J = 12.8 Hz), 7.72 - 7.74 (m, 2H), i-7.87 (m, 2H), 8.68(s, IH). NMR data of some compounds in Table 5 - Table 2

编号 ^JH NMR ( 400MHz, DMSO-< ₆ ) No. ^J H NMR (400MHz, DMSO-< ₆ )

P-11 4.28 (t, J= 6.5 Hz, IH, NH), 4.99 (s, 2H, CH₂), 7.04 (s, IH, isoxazole-H), 7.18-7.92 (m, 4H, Ph-H), -8.62 (s, 3H,Ph-H), 8.67 (s，lH). P-11 4.28 (t, J = 6.5 Hz, IH, NH), 4.99 (s, 2H, CH ₂ ), 7.04 (s, IH, isoxazole-H), 7.18-7.92 (m, 4H, Ph-H) , -8.62 (s, 3H, Ph-H), 8.67 (s, lH).

P-12 3.17 (s, 3H, CH₃), 4.22(t, J= 6.6 Hz, 1H， NH), 5.00(s, 2H, CH₂), 7.01 P-12 3.17 (s, 3H, CH ₃ ), 4.22(t, J= 6.6 Hz, 1H, NH), 5.00(s, 2H, CH ₂ ), 7.01

(s, 1H， isoxazole-H), 7.67-7.75(m, 4H, Ph-H),8.28-8.51(m, 3H, Ph-H), 8.71(s， IH). (s, 1H, isoxazole-H), 7.67-7.75 (m, 4H, Ph-H), 8.28-8.51 (m, 3H, Ph-H), 8.71 (s, IH).

P-13 3.65 (s, 3H, CH₃)， 4.35 (t, J= 6.3 Hz, 1H， NH), 4.96 (s, 2H， CH₂)， 7.10 (s, 1H， isoxazole-H), :-7.91(m, 4H, Ph-H), 8.31-8.62 (m, 3H, Ph-H), 8.68 (s, IH). P-13 3.65 (s, 3H, CH ₃ ), 4.35 (t, J = 6.3 Hz, 1H, NH), 4.96 (s, 2H, CH ₂ ), 7.10 (s, 1H, isoxazole-H), :- 7.91 (m, 4H, Ph-H), 8.31-8.62 (m, 3H, Ph-H), 8.68 (s, IH).

P-14 4.35 (t, J= 6.8 Hz, IH, NH), 4.98 (s, 2H, CH₂), 7.04(s, IH, isoxazole-H ), 7.18-7.91(m, 4H, Ph-H), L-8.62 (m, 3H, Ph-H), 8.67(s,lH). P-14 4.35 (t, J = 6.8 Hz, IH, NH), 4.98 (s, 2H, CH ₂ ), 7.04 (s, IH, isoxazole-H), 7.18-7.91 (m, 4H, Ph-H) , L-8.62 (m, 3H, Ph-H), 8.67 (s, lH).

P-19 4.29(t, J= 6.4 Hz, 1H， NH), 4.99 (s, 2H， CH₂)， 7.13(s, 1H， isoxazole-H )， 7.84-8.09(dd, 4H, J=8.0, Hz, Ph-H), 8.25-8.47 (m, 3H, Ph-H), 8.66 (s, IH). P-19 4.29 (t, J = 6.4 Hz, 1H, NH), 4.99 (s, 2H, CH ₂ ), 7.13(s, 1H, isoxazole-H ), 7.84-8.09 (dd, 4H, J=8.0, Hz, Ph-H), 8.25-8.47 (m, 3H, Ph-H), 8.66 (s, IH).

P-21 6.04(s, 2H, CH₂), 7.37(s, IH, isoxazole-H), 7.52-7.62(m, 5H)， 7.71-7.78(m, IH), 7.90-7.92(m, 2H), L-8.03(m, 2H)， 8.14-8.20(m, 1H)， 8.26-8.32(m, 1H)， 8.50-8.59(m, 2H). P-21 6.04(s, 2H, CH ₂ ), 7.37(s, IH, isoxazole-H), 7.52-7.62(m, 5H), 7.71-7.78(m, IH), 7.90-7.92(m, 2H) , L-8.03(m, 2H), 8.14-8.20(m, 1H), 8.26-8.32(m, 1H), 8.50-8.59(m, 2H).

P-22 2.37(s, 3H, Ph-CH₃), 6.02(s, 2H, CH₂)， 7.32(m, 2H)， 7.34(s, IH, isoxazole-H), 7.56-7.59(m, 3H), J-7.81(m, 3H), 8.01-8.03(m, 2H), 8.26-8.28(m, IH), 8.57-8.59(m, 2H). P-22 2.37(s, 3H, Ph-CH ₃ ), 6.02(s, 2H, CH ₂ ), 7.32(m, 2H), 7.34(s, IH, isoxazole-H), 7.56-7.59(m, 3H ), J-7.81(m, 3H), 8.01-8.03(m, 2H), 8.26-8.28(m, IH), 8.57-8.59(m, 2H).

P-23 2.82(s, 3H, Ph-OCH₃), 6.02(s, 2H, CH₂), 7.32(m, 2H)， 7.34(s, IH, isoxazole-H), 7.56-7.59(m, 3H), J-7.81(m, 3H), 8.01-8.03(m, 2H), 8.26-8.28(m, IH), 8.57-8.59(m, 2H). P-23 2.82(s, 3H, Ph-OCH ₃ ), 6.02(s, 2H, CH ₂ ), 7.32(m, 2H), 7.34(s, IH, isoxazole-H), 7.56-7.59(m, 3H ), J-7.81(m, 3H), 8.01-8.03(m, 2H), 8.26-8.28(m, IH), 8.57-8.59(m, 2H).

P-24 6.04(s, 2H, CH₂), 7.34(s, IH, isoxazole-H), 7.47-7.59(m, 5H)， 7.63-7.73(m, 3H), 7.99-8.04(m, 2H), l-8.25(m, 1H)， 8.58-8.60(m, 2H). P-24 6.04(s, 2H, CH ₂ ), 7.34(s, IH, isoxazole-H), 7.47-7.59(m, 5H), 7.63-7.73(m, 3H), 7.99-8.04(m, 2H) , l-8.25(m, 1H), 8.58-8.60(m, 2H).

P-25 6.04(s, 2H, CH₂), 7.40(s, IH, isoxazole-H), 7.56-7.62(m, 5H)， 7.69-7.73(m, IH), 7.93-7.96(m, 2H), >-8.059(m, 2H)， 8.18-8.28(m, 1H)， 8.57-8.59(m, 2H). P-25 6.04(s, 2H, CH ₂ ), 7.40(s, IH, isoxazole-H), 7.56-7.62(m, 5H), 7.69-7.73(m, IH), 7.93-7.96(m, 2H) , >-8.059(m, 2H), 8.18-8.28(m, 1H), 8.57-8.59(m, 2H).

P-26 6.07(s, 2H, CH₂)， 7.28(s， IH, isoxazole-H), 7.57-7.57(m, 3H), 7.61(d, IH, J=2.4Hz), 7.68-7.72(m, ， 7.76(d, 1H， J=8.4Hz), 7.86(d, 1H， J=2.0Hz). P-26 6.07(s, 2H, CH ₂ ), 7.28(s, IH, isoxazole-H), 7.57-7.57(m, 3H), 7.61(d, IH, J=2.4Hz), 7.68-7.72(m , , 7.76(d, 1H, J=8.4Hz), 7.86(d, 1H, J=2.0Hz).

P-27 6.04(s, 2H, CH₂), 7.40(s, IH, isoxazole-H), 7.56-7.59(m, 3H), 7.68-7.75(m, 3H), 7.86-7.89(m, 2H), >-8.05(m, 2H)， 8.28(d， 1H， J=8.0Hz).

P-27 6.04(s, 2H, CH ₂ ), 7.40(s, IH, isoxazole-H), 7.56-7.59(m, 3H), 7.68-7.75(m, 3H), 7.86-7.89(m, 2H) , >-8.05(m, 2H), 8.28(d, 1H, J=8.0Hz).

TSZ980/Zl0ZN3/X3d 6ΐεε /ειοζ OAV 表 6-表 2部分化合物的 MS数据 TSZ980/Zl0ZN3/X3d 6ΐεε /ειοζ OAV Table 6 - MS data for some of the compounds in Table 2

实施例 8 4-[(3-苯基-异噁唑 -5-基) -甲氧基-】 -喹唑啉的盐酸盐和醋酸盐的制备

Example 8 Preparation of 4-[(3-Phenyl-isoxazol-5-yl)-methoxy-]-quinazoline hydrochloride and acetate

( 1 ) 4-[(3-苯基-异噁唑 -5-基) -甲氧基-】 -喹唑啉盐酸盐 (1) 4-[(3-Phenyl-isoxazole-5-yl)-methoxy-]-quinazoline hydrochloride

将 O.Smmol 4- [(3-苯基-异噁唑 -5-基) -曱氧基-】 -喹唑啉加入 20 mL ( V： V, 1:1 ) 5%的盐酸溶液和甲醇混合溶液中，微热搅拌使其溶解后，室温緩慢蒸发结晶即得 4-[(3-苯基-异噁唑 -5-基) - 曱氧基-】 -喹唑啉盐酸盐，白色固体，收率： 68%。 Add O.Smmol 4-[(3-phenyl-isoxazol-5-yl)-decyloxy-]-quinazoline to 20 mL (V: V, 1:1) 5% hydrochloric acid solution and methanol In the mixed solution, after dissolving it by gentle stirring, it is slowly evaporated to crystallize at room temperature to obtain 4-[(3-phenyl-isoxazol-5-yl)-decyloxy-]-quinazoline hydrochloride, white Solid, yield: 68%.

( 2 ) 4-[(3-苯基-异噁唑 -5-基) -甲氧基-】 -喹唑啉乙酸盐的制备： (2) Preparation of 4-[(3-phenyl-isoxazole-5-yl)-methoxy-]-quinazoline acetate:

将 0.5mmol 4-[(3-苯基-异噁唑 -5-基) -曱氧基-】 -喹唑啉加入盛有 10 mL干燥二氯甲烷的 50mL单口圆底烧瓶中，搅拌下加入 2mL冰乙酸， 30°C~40°C搅拌 l~2h，冷却后冷藏结晶，过滤，真空干燥后即得 4-[(3-苯基-异噁唑 -5-基) -甲氧基小喹唑啉乙酸盐，无色固体，收率： 58%。实施例 9 部分化合物盐的制备 Add 0.5 mmol of 4-[(3-phenyl-isoxazol-5-yl)-decyloxy-]-quinazoline to a 50 mL single-mouth round bottom flask containing 10 mL of dry dichloromethane, and add with stirring. 2mL glacial acetic acid, stirring at 30 ° C ~ 40 ° C for l ~ 2h, cooling, crystallizing, filtration, vacuum drying, then get 4-[(3-phenyl-isoxazol-5-yl)-methoxy Quinazoline acetate, colorless solid, yield: 58%. Example 9 Preparation of Partial Compound Salt

以 2-苯基 -4- [(3-苯基-异噁唑 -5-基) -甲氧基-】 -喹唑啉的盐酸盐和醋酸盐的制备为例说明之，其余化合物盐的制备同该过程。 Taking the preparation of the hydrochloride and acetate of 2-phenyl-4-[(3-phenyl-isoxazol-5-yl)-methoxy-]-quinazoline as an example, the remaining compounds The preparation of the salt is the same as the process.

( 1 ) 2-苯基 -4-[(3-苯基-异噁唑 -5-基) -曱氧基小喹唑啉盐酸盐的制备 (1) Preparation of 2-phenyl-4-[(3-phenyl-isoxazole-5-yl)-decyloxyquinazoline hydrochloride

将 O.Smmol 2-苯基 -4- [(3-苯基-异噁唑 -5-基) -甲氧基-】 -喹唑啉加入 20 mL(K: V, 1:1)5%的盐酸溶液和甲醇混合溶液中，微热搅拌使其溶解后，室温緩慢蒸发结晶即得 2-苯基 -4-[(3-苯基- 异噁唑 -5-基) -甲氧基-】 -喹唑啉盐酸盐，白色固体，收率： 52%。 ( 2 ) 2-苯基 -4-[(3-苯基-异噁唑 -5-基) -曱氧基小喹唑啉乙酸盐的制备 Add O.Smmol 2-phenyl-4-[(3-phenyl-isoxazol-5-yl)-methoxy-]-quinazoline to 20 mL (K: V, 1:1) 5% In a mixed solution of hydrochloric acid solution and methanol, after slightly stirring with heat to dissolve, the crystal is slowly evaporated at room temperature to obtain 2-phenyl-4-[(3-phenyl-isoxazol-5-yl)-methoxy- - quinazoline hydrochloride, white solid, yield: 52%. (2) Preparation of 2-phenyl-4-[(3-phenyl-isoxazol-5-yl)-decyloxyquinazoline acetate

将 0.5mmol 2-苯基 -4- [(3-苯基-异噁唑 -5-基) -曱氧基-】 -喹唑啉加入盛有 10 mL干燥二氯甲烷的 50mL单口圆底烧瓶中，搅拌下加入 2mL冰乙酸， 30°C~40°C搅拌 l~2h，冷却后冷藏结晶，过滤，真空干燥后即得 2-苯基 -4-[(3-苯基-异噁唑 -5-基) -曱氧基-】 -喹唑啉乙酸盐，无色固体，收率： 58%。 Add 0.5 mmol of 2-phenyl-4-[(3-phenyl-isoxazol-5-yl)-decyloxy-]-quinazoline to a 50 mL single-mouth round bottom flask containing 10 mL of dry dichloromethane Add 2mL glacial acetic acid under stirring, stir at 30 ° C ~ 40 ° C for l ~ 2h, cool, crystallize, filter, vacuum drying to obtain 2-phenyl-4-[(3-phenyl-isoxazole) -5-yl)-nonyloxy-]-quinazoline acetate, colorless solid, yield: 58%.

表 7-式（I )所示的化合物分别和有机酸或无机酸所成的盐 Table 7 - Salts of the compounds of formula (I) and organic or inorganic acids, respectively

实施例 10生物活性试验

Example 10 Biological Activity Test

本发明式（I )所示的喹啉化合物或其药学上可接受的盐作为 EGFR酶抑制剂，采用酶联免疫吸附法测定所列举的化合物抑制 EGFR酶活性。 The quinoline compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is used as an EGFR enzyme inhibitor, and the exemplified compounds are assayed for inhibition of EGFR enzyme activity by an enzyme-linked immunosorbent assay.

具体的实验步骤如下： The specific experimental steps are as follows:

(1)酶反应底物 Poly(Glu，Tyr)_4:1用无钾离子的 PBS稀释成 20 g/mL , 包被酶标板，置于 37°C反应 12~16h后，弃去孔中液体。 (1) The enzyme reaction substrate Poly(Glu, Tyr) _4:1 was diluted to 20 g/mL with PBS without potassium ions, coated with the enzyme plate, placed After reacting at 37 ° C for 12 to 16 hours, the liquid in the well was discarded.

(2)接着用 T-PBS洗板三次，每次 10 m i (2) Then wash the plate three times with T-PBS for 10 m i each time.

(3) 于 ³⁷°C烘箱中干燥酶标板 (3) Dry the ELISA plate in an oven at ³⁷ °C

(4) 包被好的酶标板孔内加入受试样品（其中受试样品临用前先用 DMSO配制成 lxl(T²M 的储备液，再用反应緩冲液稀释到所需的浓度后加至实验孔内，使其在 ΙΟΟμί反应体系中达到相应的终浓度。 (4) Add the test sample to the well of the coated ELISA plate (the test sample is first prepared with DMSO to prepare lxl (T ² M stock solution, and then diluted with the reaction buffer to the required sample). The concentration was added to the experimental wells to achieve the corresponding final concentration in the ΙΟΟμί reaction system.

(5)加入 ΑΤΡ和受试酪氨酸激酶，加入用反应緩冲液稀释的 ΑΤΡ溶液 (ΑΤΡ终浓度为 5μΜ) 及用反应緩冲液稀释的受试酪氨酸激酶。反应的总体积为 100μί。同时设立阴性对照孔和无酶对照孔。 (5) Add hydrazine and test tyrosine kinase, add hydrazine solution diluted in reaction buffer (final concentration of ΑΤΡ5 μΜ) and test tyrosine kinase diluted with reaction buffer. The total volume of the reaction is 100 μί. Negative control wells and enzyme-free control wells were also established.

(6)将反应体系置于湿盒内， 37°C摇床避光反应 lh, 反应结束后 T-PBS 反 3次。 (6) The reaction system was placed in a wet box, and shaken at 37 ° C for 1 h, and T-PBS was reversed 3 times after the reaction.

(7)每孔中加入抗体 PY99 ΙΟΟμί, 37°C摇床反应 30min, T-PBS 3次。 (7) Add PY99 ΙΟΟμί to each well, shake for 37 min at 37 °C, and T-PBS 3 times.

(8)每孔中加入辣根过氧化物酶标记的羊抗鼠的 IgG ΙΟΟμί, 37°C摇床反应 30min, T-PBS 洗板 3次。 (8) Horseradish peroxidase-labeled goat anti-mouse IgG ΙΟΟμί was added to each well, and the reaction was shaken at 37 ° C for 30 min, and the plate was washed 3 times with T-PBS.

(9)每孔中加入 OPD显色液 ΙΟΟμί, 室温避光反应 l-10min。 (9) Add OPD coloring solution to each well ΙΟΟμί, and dilute at room temperature for l-10min.

(10)每孔中加入 21^的 H₂S0₄溶液终止反应，用可调波长式微孔板酶标仪测 A₄₉。值。采用如下的公式计算酶抑制率。 (10) The reaction was terminated by adding 21 μ of H ₂ S0 ₄ solution to each well, and A _{49 was} measured with a tunable wavelength microplate reader. value. The enzyme inhibition rate was calculated using the following formula.

化合物的 OD值 -无酶对照孔 OD值 OD value of the compound - no enzyme control well OD value

抑制率（％) = X 100 Inhibition rate (%) = X 100

阴性对照 OD值 -无酶对照孔 OD值 Negative control OD value - no enzyme control well OD value

采用如上的活性测试方法，测得式 (I)所示的化合物或其盐对 EGFR酶的抑制活性。 The inhibitory activity against the EGFR enzyme of the compound of the formula (I) or a salt thereof was measured by the above activity test method.

表 10-部分化合物在 ΙΟΟμΜ浓度下抑制 EGFR酶的活性测试结果 Table 10- Some compounds inhibit the activity of EGFR enzyme test at ΙΟΟμΜ concentration

实施例 11 生物活性试验

Example 11 Biological Activity Test

本发明式 (I)所示的化合物或其盐采用 SRB法进行了抗大肠癌细胞株 (HCT-116)和人肺癌细胞株 (A549)活性筛选，筛选过程参考文献 (Li M. H.; Miao Z. H.; Tan W. F. et al. Clin. Cancer Res. 2004, 10(24): 8266-8274)。 The compound represented by the formula (I) or a salt thereof of the present invention is subjected to the SRB method for screening the activity against the colorectal cancer cell line (HCT-116) and the human lung cancer cell line (A549), and the screening process reference document (Li MH; Miao ZH; Tan WF et al. Clin. Cancer Res. 2004, 10(24): 8266-8274).

具体的实验步骤如下： The specific experimental steps are as follows:

(1)根据肿瘤细胞的生长速率，将处于对数生长期的大肠癌细胞株 (HCT-116)接种于 96孔培养板，贴壁生长 24小时后，将 1χ1(Γ⁴Μ的药品加入，其浓度设 3个复孔，并设相应浓度的生理盐水对照及无细胞调零孔，肿瘤 /癌细胞在 37°C、 5%C0₂条件下培养 72小时。 (1) According to the growth rate of tumor cells, the colon cancer cell line (HCT-116) in the logarithmic growth phase is inoculated into a 96-well culture plate, and after adhering for 24 hours, a drug of 1χ1 (Γ ⁴ Μ is added, The concentration was set to 3 replicate wells, and the corresponding concentration of physiological saline control and cell-free zero-adjustment were set, and the tumor/cancer cells were cultured for 72 hours at 37 ° C and 5% CO ₂ .

(2)取出培养板，每孔用 10%冷三乙酸 (TCA)溶液固定细胞， 4°C放置 1小时。 (2) The plate was taken out, and the cells were fixed with 10% cold triacetic acid (TCA) solution per well, and allowed to stand at 4 ° C for 1 hour.

(3) 弃固定液，用蒸餾水洗涤 5次，空气中自然干燥。 (3) Discard the fixative and wash it with distilled water for 5 times. The air is naturally dry.

(4) 然后加入由 1%的冰乙酸配制的 SRB溶液，室温染色 15分钟。 (4) A SRB solution prepared from 1% glacial acetic acid was then added and stained for 15 minutes at room temperature.

(5)去上清夜，用 1%的醋酸溶液洗涤 5次，空气干燥。 (5) Go to the supernatant, wash 5 times with 1% acetic acid solution, and air dry.

(6) 最后加入 Tris溶液,在平板震荡器上震荡 5分钟。用可调波长式微孔板酶标仪测 560nm 波长下的吸光度值 (A₅₆。)。采用如下的公式计算酶抑制率。采用如下的公式计算酶抑制率。 (6) Finally add the Tris solution and shake it on the plate shaker for 5 minutes. Absorbance values at 560 nm (A ₅₆ Å) were measured using a tunable wavelength microplate reader. The enzyme inhibition rate was calculated using the following formula. The enzyme inhibition rate was calculated using the following formula.

^A 560对照 - ^A 560给药 ^A 560 control - ^A 560 administration

抑制率（％) = X 100 Inhibition rate (%) = X 100

A 560对照 A 560 control

采用如上的活性测试方法，测得式 (I)所示的化合物或其盐在 lxl(T⁴M浓度下抑制大肠癌细胞珠 (HCT-116) 和人肺癌细胞 A549的活性。实验结果见下表。 Using the above activity test method, the compound represented by the formula (I) or a salt thereof was measured for its activity of inhibiting colorectal cancer cell beads (HCT-116) and human lung cancer cell A549 at a concentration of 1× ¹ . table.

表 11- 式 (I)中部分实施例化合物抑制大肠癌细胞珠 (HCT-116)活性测试结果 Table 11 - Test results of some of the compounds of formula (I) for inhibiting colorectal cancer cell beads (HCT-116) activity

Claims

1.一种式 (I)所示的喹唑啉化合物或上可接受的盐 A quinazoline compound or an acceptable salt represented by the formula (I)

其中， among them,

、和11₇各自独立地选自氢， c_1-6烷基， c_1-6烷氧基，羟基 c 烷基，羟基 c_1-6烷氧基，卤代 C_1-6烷基，卤代 C_1-6烷氧基， C_1-6烷氧基 C_1-6烷氧基， C_3-8环烷氧基，任选被 R6取代的芳基，任选被 R6取代的杂芳基，硝基，氨基， C_1-6烷基二（C_1-6烷基）含有至少一个选自 N， 0， S杂原子的杂环烷氧基； And 11 ₇ are each independently selected from the group consisting of hydrogen, c _1-6 alkyl, c _1-6 alkoxy, hydroxy c alkyl, hydroxy c _1-6 alkoxy, halo C _1-6 alkyl, halo C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _3-8 cycloalkoxy, aryl optionally substituted by R 6 , heteroaryl optionally substituted by R 6 a nitro group, an amino group, a C _1-6 alkyl di(C _1-6 alkyl group) containing at least one heterocycloalkoxy group selected from the group consisting of N, 0, S heteroatoms;

R₃选自氢、卤素， C_1-6烷基、 C_1-6烷氧基或卤代 C_1-6烷基； R _{3 is} selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkyl;

R6各自独立地选自氢，羟基，疏基，氰基，硝基，卤素， C_1-6烷基， C_1-6烷氧基； c_w烷硫基，卤代 c_w烷基，或卤代 c_w烷氧基； R6 is independently selected from hydrogen, hydroxy, mercapto, cyano, nitro, halo, C _1-6 alkyl, C _1-6 alkoxy; alkylthio c _w, c _w haloalkyl group, or Halogenated c _w alkoxy;

n为 0-5的整数。 n is an integer from 0 to 5.

2.—种权利要求 1的喹峻啉化合物或其药学上可接受的盐，其为下式（IA ) 2. The quinolin compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is of the following formula (IA)

(IA) (IA)

其中：和 R₂各自独立地选自氢，羟基 C_1-6烷基，羟基 C_1-6烷氧基， C_1-6烷氧基，卤代 C_1-6烷氧基， C_1-6烷氧基 C_1-6烷氧基， C_3-8环烷氧基，含有至少一个选自 N， 0， S杂原子的 C_3-8杂环烷氧基； Wherein: and R ₂ are each independently selected from the group consisting of hydrogen, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy, halo C _1-6 alkoxy, C _{1- 6} alkoxy C _1-6 alkoxy, C _3-8 cycloalkoxy, containing at least one C _3-8 heterocycloalkoxy selected from N, 0, S heteroatoms;

Z为 -NR4-, C(R₅)₂， S或 -0-, 其中 R4为氢或 C_1-3坑基， R₅相同或不同，选自氢或 C_1-3烷基； R₃选自氢、卤素，烷基、 C_w烷氧基或卤代烷基； n为 0-5的整数。 Z is -NR4-, C(R ₅ ) ₂ , S or -0-, wherein R 4 is hydrogen or a C _1-3 pit group, and R _{5 is the} same or different and is selected from hydrogen or C _1-3 alkyl; R _{3 is} selected from hydrogen, halogen, alkyl, C _w alkoxy or haloalkyl; n is an integer from 0 to 5.

3.根据权利要求 1的奎峻啉衍生物或上可接受的盐，其为下式（IB ) The quinuctoline derivative or the above acceptable salt according to claim 1, which is of the following formula (IB)

其中：和11₇各自独立地选自氢， C_1-6烷基， C_1-6烷氧基，羟基 C_1-6烷基，羟基 C_1-6烷氧基，卤代 C_1-6烷基，卤代 C_1-6烷氧基， C_1-6烷氧基 C_1-6烷氧基， C_3-8环烷氧基，任选被 R6取代的芳基，任选被 R6取代的杂芳基，硝基，氨基， C_1-6烷基，二（C_1-6烷基） Wherein: and 11 ₇ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, halo C _1-6 Alkyl, halo C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _3-8 cycloalkoxy, aryl optionally substituted by R 6 , optionally R 6 Substituted heteroaryl, nitro, amino, C _1-6 alkyl, di(C _1-6 alkyl)

Z为 -NR4-, C(R₅)₂, -S-或 -0-，其中 R4为氢或 C_1-3坑基， R₅相同或不同，选自氢或 C_1-3 烷基； Z is -NR4-, C(R ₅ ) ₂ , -S- or -0-, wherein R 4 is hydrogen or a C _1-3 pit group, and R _{5 is the} same or different and is selected from hydrogen or C _1-3 alkyl;

R6各自独立地选自氢，羟基，巯基，氰基， J-, 硝基，卤素， C_1-6烷基， C_1-6烷氧基； C_w烷硫基，卤代 C_w烷基，或卤代 C_w烷氧基； R6 is independently selected from hydrogen, a hydroxyl group, a mercapto group, a cyano group, J-, nitro, halo, C _1-6 alkyl, C _1-6 alkoxy; alkylthio C _w, C _w haloalkyl group Or halogenated C _w alkoxy;

R₃选自氢、卤素，烷基、 C_w烷氧基或卤代烷基； n为 0-5的整数。 R _{3 is} selected from hydrogen, halogen, alkyl, C _w alkoxy or haloalkyl; n is an integer from 0 to 5.

4.根据权利要求 1-3任一项的喹唑啉化合物或其药学上可接受的盐，其中所述化合物选自： The quinazoline compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of:

4-{[3-(4-三氟甲基苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 4-{[3-(4-trifluoromethylphenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基卜甲氧基+喹唑啉； 4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5-yl-methoxy-3-quinazoline;

6,7-二曱氧基 -4-[(3-苯基-异噁唑 -5-基) -甲氧基-】 -喹唑啉； 6,7-dimethoxyoxy-4-[(3-phenyl-isoxazole-5-yl)-methoxy-]-quinazoline;

6,7-二甲氧基 -4-{[3-(4-氟苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 6,7-dimethoxy-4-{[3-(4-fluorophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

6,7-二曱氧基 -4-{[3-(4-氯苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 6,7-二曱氧基 -4-{[3-(2-氯苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 6,7-dimethoxy-4-([3-(4-chlorophenyl)-isoxazol-5-yl]-methoxy+quinazoline; 6,7-dimethoxy-4-([3-(2-chlorophenyl)-isoxazol-5-yl]-methoxy+quinazoline;

4-{[3-(4-曱氧基苯基) -异噁唑 -5-基】 -曱 -}-喹唑啉； 4-{[3-(4-decyloxyphenyl)-isoxazole-5-yl]-hydrazine-}-quinazoline;

4-{[3-(4-三氟甲基苯基)-异噁唑 -5-基】 -曱氨基+喹唑啉； 4-{[3-(4-trifluoromethylphenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

6,7-二甲氧基 -4-[(3-苯基-异噁唑 -5-基) -甲^ 喹唑啉； 6,7-dimethoxy-4-[(3-phenyl-isoxazole-5-yl)-methyl quinazoline;

6,7-二曱氧基 -4-{[3-(4-氟苯基) -异噁唑 -5-基】 -甲 -}-喹唑啉； 6,7-二曱氧基 -4-{[3-(4-氯苯基) -异噁唑 -5-基】 -甲 -}-喹唑啉； 6,7-dimethoxy-4-([3-(4-fluorophenyl)-isoxazol-5-yl]-methyl-}-quinazoline; 6,7-dimethoxy-4-([3-(4-chlorophenyl)-isoxazol-5-yl]-methyl-}-quinazoline;

6,7-二甲氧基 -4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉； 6,7-dimethoxy-4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

[6,7-二 (2-甲氧乙氧基)】-4-[(3-苯基-异噁唑 -5-基) -甲氨基-】 -喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-[(3-phenyl-isoxazole-5-yl)-methylamino-]-quinazoline;

[6,7-二 ( 2-甲氧乙氧基)】-4-{[3-(4-氟-苯基) -异噁唑 -5-基】 -甲喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-fluoro-phenyl)-isoxazol-5-yl]-quinazoline;

[6,7-二 (2-甲氧乙氧基)】-4-{[3-(4-氯苯基) -异噁唑 -5-基】 -甲喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-chlorophenyl)-isoxazol-5-yl]-quinazoline;

[6,7-二 (2-甲氧乙氧基)】-4-{[3-(2-氯苯基) -异噁唑 -5-基】 -甲喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(2-chlorophenyl)-isoxazol-5-yl]-quinazoline;

[6,7-二 (2-甲氧乙氧基)】-4-{[3-(4-溴苯基) -异噁唑 -5-基】 -甲喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-bromophenyl)-isoxazole-5-yl]-quinazoline;

[6,7-二 (2-甲氧乙氧基)】-4-{[3-(2，4-二氯苯基) -异噁唑 -5-基卜甲喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(2,4-dichlorophenyl)-isoxazole-5-ylbromoquinazoline;

[6,7-二 (2-甲氧乙氧基)】-4-{[3-(4-甲基苯基) -异噁唑 -5-基】 -甲 -}-喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-methylphenyl)-isoxazole-5-yl]-methyl-}-quinazoline;

[6,7-二 (2-甲氧乙氧基)】-4-{[3-(4-甲氧基苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-methoxyphenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

[6,7-二 (2-甲氧乙氧基)】-4-{[3-(4-三氟曱基苯基) -异噁唑 -5-基】 -甲喹唑啉； [6,7-bis(2-methoxyethoxy)]-4-{[3-(4-trifluorodecylphenyl)-isoxazole-5-yl]-quinazoline;

[6,7-二 (2-甲氧乙氧基)】-4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基】 -甲喹唑啉; [6,7-bis(2-methoxyethoxy)]-4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5-yl]-quinazoline;

2-苯基 -4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 2-phenyl-4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

2-苯基 -4-{[3-(4-氯苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 2-phenyl-4-{[3-(4-chlorophenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

2-苯基 -4-{[3-(2-氯苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 2-phenyl-4-{[3-(2-chlorophenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

2-苯基 -4-{[3-(2，4-二氯苯基) -异噁唑 -5-基】 -甲氧基+喹唑啉； 2-phenyl-4-{[3-(2,4-dichlorophenyl)-isoxazole-5-yl]-methoxy+quinazoline;

2-苯基 -4-{[3-(4-溴苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉； 2-phenyl-4-{[3-(4-bromophenyl)-isoxazole-5-yl]-decyloxy+quinazoline;

2-苯基 -4-[(3-苯基-异噁唑 -5-基) -曱氨基小喹唑啉； -苯基 -4-{[3-(4-曱基-苯基) -异噁唑 -5-基】國曱 -}-喹唑啉；2-phenyl-4-[(3-phenyl-isoxazol-5-yl)-nonylamino quinazoline; -phenyl-4-{[3-(4-indolyl-phenyl)-isoxazol-5-yl]-indole-}-quinazoline;

-苯基 -4-{[3-(4-曱氧基苯基) -异噁唑 -5-基】 -甲喹唑啉；-苯基 -4-{[3-(4-三氟曱基苯基) -异噁唑 -5-基卜甲 -}-喹唑啉；-苯基 -4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉;-苯基 -4-{[3-(4-氟苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉；-phenyl-4-{[3-(4-decyloxyphenyl)-isoxazol-5-yl]-methylquinazoline;-phenyl-4-{[3-(4-trifluoroindole) Phenyl)-isoxazole-5-yl-methyl-}-quinazoline;-phenyl-4-{[3-(2,4-dimethoxyphenyl)-isoxazole-5- - hydrazine amino + quinazoline; -phenyl-4-{[3-(4-fluorophenyl)-isoxazol-5-yl]-nonylamino + quinazoline;

-苯基 -4-{[3-(4-氯苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉；-phenyl-4-{[3-(4-chlorophenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

-苯基 -4-{[3-(2-氯苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉；-phenyl-4-{[3-(2-chlorophenyl)-isoxazole-5-yl]-nonylamino+quinazoline;

-苯基 -4-{[3-(2，4-二氯苯基) -异噁唑 -5-基】 -甲喹唑啉；-苯基 -4-{[3-(4-溴苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉；一硝基 _4-[(3-苯基-异噁唑 -5-基) -曱氧基小喹唑啉；-phenyl-4-{[3-(2,4-dichlorophenyl)-isoxazol-5-yl]-methylquinazoline;-phenyl-4-{[3-(4-bromobenzene) -isoxazole-5-yl]-nonylamino+quinazoline; mononitro-4-[(3-phenyl-isoxazol-5-yl)-decyloxyquinazoline;

—硝基 _4-{[3-(4-曱基-苯基) -异噁唑 -5-基】國曱氧基+喹唑啉；—硝基 _₄_{[3-(4-曱氧基苯基) -异噁唑 -5-基卜甲氧基+喹唑啉；—硝基 _₄_{[3-(4-三氟曱基苯基)-异噁唑 -5-基】-甲氧基+喹唑啉；—硝基 _4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉;—硝基 _4-{[3-(4-氟苯基) -异噁唑 -5-基】國曱氧基+喹唑啉；-nitro-4-{[3-(4-indolyl-phenyl)-isoxazol-5-yl] oxime oxy-quinazoline; -nitro- ₄ _{[3-(4-曱oxyphenyl)-isoxazole-5-yl-methoxy-3-quinazoline;-nitro- ₄ _{[3-(4-trifluorodecylphenyl)-isoxazole-5- -Methoxy+quinazoline;-Nitro-4-{[3-(2,4-dimethoxyphenyl)-isoxazol-5-yl]-decyloxy+quinazoline ;-nitro-4-{[3-(4-fluorophenyl)-isoxazol-5-yl] oximeoxy + quinazoline;

-硝基 _4-{[3-(4-氯苯基) -异噁唑 -5-基】 -曱氧基+喹唑啉；—硝基 _4-{[3-(2-氯苯基) -异噁唑 -5-基】國曱氧基+喹唑啉；一硝基 _4-{[3-(2，4-二氯苯基) -异噁唑 -5-基卜甲氧基+喹唑啉；—硝基 _4-{[3-(4-溴苯基) -异噁唑 -5-基】國曱氧基+喹唑啉；—硝基 _4-[(3-苯基-异噁唑 -5-基) -曱氨基小喹唑啉；-nitro-4-{[3-(4-chlorophenyl)-isoxazol-5-yl]-decyloxy+quinazoline;-nitro-4-{[3-(2-chlorobenzene) -isoxazole-5-yl] oximeoxy + quinazoline; mononitro-4-{[3-(2,4-dichlorophenyl)-isoxazole-5-yl b Oxy+quinazoline;-nitro-4-{[3-(4-bromophenyl)-isoxazol-5-yl] oximeoxy + quinazoline; -nitro-4-[( 3-phenyl-isoxazol-5-yl)-nonylamino quinazoline;

—硝基 _4-{[3-(4-曱基-苯基) -异噁唑 -5-基】國曱 -}-喹唑啉；—硝基 _₄_{[3-(4-曱氧基苯基) -异噁唑 -5-基卜甲喹唑啉；—硝基 _₄_{[3-(4-三氟曱基苯基)-异噁唑 -5-基】 -甲 J^-}-喹唑啉；—硝基 _4-{[3-(2，4-二甲氧基苯基) -异噁唑 -5-基】 -曱氨基+喹唑啉;—硝基 _4-{ [3-(4-氟苯基) -异噁唑 -5-基】國曱氨基+喹唑啉；—硝基 _4-{[3-(4-氯苯基) -异噁唑 -5-基】國曱氨基+喹唑啉；—硝基 _4-{ [3-(2-氯苯基) -异噁唑 -5-基】國曱氨基+喹唑啉；一硝基 _4-{[3-(2，4-二氯苯基) -异噁唑 -5-基卜甲喹唑啉；—硝基 _4-{[3-(4-溴苯基) -异噁唑 -5-基】國曱氨基+喹唑啉。 -nitro-4-[[3-(4-indolyl-phenyl)-isoxazole-5-yl]-indole-}-quinazoline; -nitro- ₄ _{[3-(4-曱oxyphenyl)-isoxazole-5-ylbuquinazoline;-nitro- ₄ __[[3-(4-trifluoromethylphenyl)-isoxazole-5-yl] AJ^-}-quinazoline;-nitro-4-{[3-(2,4-dimethoxyphenyl)-isoxazol-5-yl]-nonylamino+quinazoline; Nitro-4-{[3-(4-fluorophenyl)-isoxazol-5-yl] oxime amino + quinazoline; -nitro-4-{[3-(4-chlorophenyl) -isoxazole-5-yl] guanidine amino + quinazoline; -nitro-4-{[3-(2-chlorophenyl)-isoxazole-5-yl] guanidine amino + quinazoline ; mononitro-4-{[3-(2,4-dichlorophenyl)-isoxazol-5-yl-b-quinazoline;-nitro-4-{[3-(4-bromobenzene) Base) -isoxazol-5-yl] guanidine amino + quinazoline.

5.—种药物组合物，其包括权利要求 1-4任一项的喹唑啉化合物或其药学上可接受的盐，以及至少一种药学上可接受的、惰性的、无毒的赋形剂或载体。 5. A pharmaceutical composition comprising the quinazoline compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable, inert, non-toxic form Agent or carrier.

6.用作药物的权利要求 1-4任一项的的喹唑啉化合物或其药学上可接受的盐，尤其是一种用于治疗对于抑制 EGFR过渡表达和 /或活性过高有效的肿瘤的药物。 A quinazoline compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, particularly for use in the treatment of a tumor effective for inhibiting EGFR transient expression and/or activity Drug.

7. 一种权利要求 1-4任一项的喹唑啉化合物或其药学上可接受的盐在制备用于抗肿瘤或癌症药物中的应用。 Use of a quinazoline compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in antitumor or cancer.

8.根据权利要求 7所述的应用，其中所述的肿瘤或癌症是与 EGFR过渡表达和 /或活性过高的癌症。更优选地，所述肿瘤或癌症选自：膀胱癌，非小细胞肺癌，卵巢癌，乳腺癌，胃癌，食道癌，肺癌，头颈癌，结肠癌，咽癌，和胰腺癌等，更是非小细胞肺癌中的应用。 The use according to claim 7, wherein the tumor or cancer is a cancer that is transiently expressed and/or active with EGFR. More preferably, the tumor or cancer is selected from the group consisting of: bladder cancer, non-small cell lung cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer, and pancreatic cancer, etc. Application in cell lung cancer.

9. 一种权利要求 1-4任一项的喹唑啉化合物和 /或药学上可接受的盐在制备抑制 EGFR的过渡表达和 /或活性过高的抑制剂。 A quinazoline compound and/or a pharmaceutically acceptable salt according to any one of claims 1 to 4 for the preparation of an inhibitor which inhibits the transient expression and/or activity of EGFR.

10.—种权利要求 1-4任一项的喹唑啉化合物的制备方法，其特征在于，所述方法包括如下步骤： A method of producing a quinazoline compound according to any one of claims 1 to 4, characterized in that the method comprises the steps of:

以 2， 6, 7-三取代 -4-氯-喹唑啉（式 II )和 3-取代苯基 -5-羟甲基-异噁唑（式 III )或 3-取代苯基 -5-氨曱基-异噁唑（式 IV )为原料，在干燥的有机溶剂和碱性縛酸剂体系中反应制备。 2, 6, 7-trisubstituted-4-chloro-quinazoline (formula II) and 3-substituted phenyl-5-hydroxymethyl-isoxazole (formula III) or 3-substituted phenyl-5- Aminoguanidine-isoxazole (formula IV) is a raw material prepared by reacting in a dry organic solvent and a basic acid binding agent system.

如果需要，可以将式（II ) 中的任何官能团予以保护; Any functional group in formula (II) can be protected if necessary;

( 1 )除去任何保护剂，和 (1) remove any protective agent, and