WO2008046242A1

WO2008046242A1 - The novel quinazoline derivatives,preparation methods and uses thereof

Info

Publication number: WO2008046242A1
Application number: PCT/CN2006/002708
Authority: WO
Inventors: Zhiqiang Feng; Xiaoguang Chen
Original assignee: Institute Of Mataria Medica, Chinese Academy Of Medical Sciences
Priority date: 2006-10-16
Filing date: 2006-10-16
Publication date: 2008-04-24

Abstract

A kind of novel quinazoline derivatives represented by the general formula (I), their pharmaceutically acceptable salts, hydrates, solvates, polycrystals or eutectic crystals, their precursors or derivatives which have the similar biological functions, their preparation methods and the compositions comprising one or more present compounds are disclosed. The present application also discloses the uses of present compounds which have the antiproliferative activities, for the manufacture of pharmaceutical medicaments for the treatment of relative diseases, such as anticancer.

Description

新的喹唑啉衍生物、及其制法和药物组合物与用途 Novel quinazoline derivatives, their preparation and pharmaceutical compositions and uses

技术领域 Technical field

本发明涉及通式 I所示的的喹唑啉衍生物，其可药用盐，其水合物和溶剂化物，其多晶和共晶，其同样生物功能的前体或衍生物，及其制备方法，含有一个或多个这化合物的组合物，和该类化合物的抗增生活性如抗癌活性等在治疗相关疾病的药物中的应用。背景技术 The present invention relates to a quinazoline derivative of the formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof, a polycrystal and a eutectic thereof, a precursor or derivative of the same biological function, and a preparation thereof A method, a composition comprising one or more of the compounds, and an anti-proliferative activity of the compound, such as an anti-cancer activity, for use in a medicament for treating a disease. Background technique

目前癌症仍是最致命的疾病之一，化疗是抑制肿瘤生长和癌细胞扩散，使肿瘤消退的重要手段。传统的化疗药物多数为直接攻击 DNA 或抑制其合成及功能的细胞毒类药物，杀死癌细胞的同时也杀伤正常细胞，并只对增殖快的肿瘤有效，副作用强。为了提高对癌细胞作用的选择性，人们已在研究不通过抑制 DNA合成机理的抗癌剂的另一途径。 At present, cancer is still one of the most deadly diseases. Chemotherapy is an important means to inhibit tumor growth and cancer cell proliferation, and to make tumors disappear. Most of the traditional chemotherapy drugs are cytotoxic drugs that directly attack DNA or inhibit their synthesis and function. They also kill cancer cells and kill normal cells, and are effective only for tumors with rapid proliferation and strong side effects. In order to increase the selectivity of cancer cells, another way of studying anticancer agents that do not inhibit the mechanism of DNA synthesis has been studied.

近年来，由于肿瘤发生发展的分子机制研究取得了惊人的进展，新药的研究转向在癌的病因学和病理过程中起作用的特异性的分子生物靶点（Science, 260 (5110)： 918-919 (1993) . Science, 267 (5205)： 1782-1787 (1995)。研究表明， 80%以上的癌基因和原癌基因存在于人的癌编码蛋白酪氨酸激酶（PTK) 中，人类各种癌症的产生和发展是和来自于蛋白酪氨酸激酶的异常细胞信号传导有关的，恶性细胞的一个主要特点是酪氨酸激酶活性的增加。另外，正常原致癌酪氨酸激酶的过度表达也可引起增生性疾病。实验室中已经证明：通过过分表达或变异各种受体酪氨酸激酶，增加其活性，正常细胞能够被转化成癌细胞，恶性转变的程度是与酪氨酸激酶活性密切相关；而且，通过利用受体的抗体或专门的激酶抑制剂降低受体中激酶活性又能使癌变逆转 (Drugs, 59 (4)： 753 (2000) . )。因此，抑制酪氨酸激酶活性，阻断其活化的信号传导路径成为控制肿瘤的新途径。 In recent years, the molecular mechanisms of tumor development have made striking progress, and new drug research has turned to specific molecular biological targets that play a role in the etiology and pathology of cancer (Science, 260 (5110): 918- 919 (1993) . Science, 267 (5205): 1782-1787 (1995). Studies have shown that more than 80% of oncogenes and proto-oncogenes are present in human cancer-encoded protein tyrosine kinase (PTK), humans The production and development of cancer is associated with abnormal cellular signaling from protein tyrosine kinases, a major feature of malignant cells is the increase in tyrosine kinase activity. In addition, overexpression of normal proto-oncocantive tyrosine kinases It can also cause proliferative diseases. It has been shown in the laboratory that by overexpressing or mutating various receptor tyrosine kinases, its activity is increased, and normal cells can be transformed into cancer cells. The degree of malignant transformation is related to tyrosine kinase. Activity is closely related; moreover, cancer can be reversed by using receptor antibodies or specialized kinase inhibitors to reduce kinase activity in the receptor (Drugs, 59 (4) 753 (2000).). Thus, inhibition of tyrosine kinase activity, blocking the signaling pathways activated a new way to control tumors.

表皮生长因子受体（EGFR) 是一种具有酪氨酸激酶活性的膜表面转导***，普遍表达于人体的表皮细胞和基质细胞，并在多种人类恶性肿瘤中高表达，促进肿瘤细胞的增殖，血管生成，粘附，侵袭和转移，抑制肿瘤细胞的凋亡 (Pharmacol Ther, 82， 241 (1999) )。 EGFR 由胞外配位区，跨膜区和胞内酪氨酸激酶区三部分组成。当配体与受体 EGFR的外域配位时，导致受体 EGFR间的二聚或与另一 ErbB受体的二聚，二聚体的形成导致受体酪氨酸激酶的活化并与 ATP结合，二聚体内发生自磷酸化和转磷酸化，促使受体 6个特异的酪氨酸残基磷酸化，最后分别依次识别 SH2蛋白的 6个底物酶，将信号传入细胞内，启动一系列的级联反应，将信息进一步传入核内，同时激活众多的下游信号路径，产生多种生物学反应，促进细胞增殖、粘附、浸润转移和血管生成，抑制细胞凋亡等（Nature Rev Drug Discov. 2 (4)： 296-313 (2003) )。 EGFR在多种人类恶性肿瘤中高表达，包括乳腺癌，卵巢癌，非小细胞肺癌和扁平细胞癌。所以 EGFR及其配体在多种肿瘤的发生发展中起重要作用。 Epidermal growth factor receptor (EGFR) is a membrane surface transduction system with tyrosine kinase activity, which is ubiquitously expressed in human epidermal cells and stromal cells, and is highly expressed in various human malignant tumors, promoting tumor cell proliferation. , angiogenesis, adhesion, invasion and metastasis, inhibiting apoptosis of tumor cells (Pharmacol Ther, 82, 241 (1999)). EGFR consists of three parts: the extracellular coordination region, the transmembrane region, and the intracellular tyrosine kinase domain. When the ligand coordinates with the foreign domain of the receptor EGFR, it leads to dimerization between the receptor EGFR or dimerization with another ErbB receptor, and the formation of the dimer leads to activation of the receptor tyrosine kinase and binding to ATP. Autophosphorylation and transphosphorylation occur in the dimer, which promotes the phosphorylation of six specific tyrosine residues in the receptor. Finally, the six substrate enzymes of the SH2 protein are sequentially recognized, and the signal is introduced into the cell. A series of cascade reactions, further information is introduced into the nucleus, and a number of downstream signal pathways are activated to generate a variety of biological reactions, promoting cell proliferation, adhesion, invasion and angiogenesis, and inhibition of apoptosis. Nature Rev Drug Discov. 2 (4): 296-313 (2003)). EGFR is highly expressed in a variety of human malignancies, including breast cancer, ovarian cancer, non-small cell lung cancer, and squamous cell carcinoma. Therefore, EGFR and its ligands play an important role in the development of various tumors.

人们已经发现许多小分子表皮生长因子酪氨酸激酶抑制剂，具有不同的结构特征：黄酮和异黄酮类，喹唑啉类，硫代肉桂酰胺类，吡咯或吡唑并嘧啶类，喹啉类，吡啶并嘧啶和嘧啶并嘧啶类等，其中喹唑啉类是研究的最多抑制 EGFR活性较高的，已用于临床的 Iressa和即将用于临床的 Tarceva都是喹唑啉衍生物。另外，已公开的专利： EP0566226， W09961428， W00051587， W00375947， W00132651， W09633980, W09630347等几乎都具有 4一苯胺基喹唑啉（II) 的结构特征- Many small molecule epidermal growth factor tyrosine kinase inhibitors have been found to have different structural features: flavonoids and isoflavones, quinazolines, thiocinnamamides, pyrrole or pyrazolopyrimidines, quinolines , pyridopyrimidine and pyrimidopyrimidines, etc., wherein quinazolines are the most inhibited EGFR activity, and Iressa, which has been used clinically, and Tarceva, which is to be used clinically, are all quinazoline derivatives. In addition, the disclosed patents: EP0566226, W09961428, W00051587, W00375947, W00132651, W09633980, W09630347, etc. almost all have the structural characteristics of 4-anilinoquinazoline (II) -

还有 W092 I 20642也公开了作为酪氨酸激酶抑制剂的单环或双环的芳基和杂芳基化合物。虽然上述抗癌化合物对本领域作出了很大贡献，但为改进抗癌药物，本领域仍在继续研究。发明内容 Also, W092 I 20642 discloses monocyclic or bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors. Although the above anticancer compounds have contributed greatly to the field, research is continuing in the art to improve anticancer drugs. Summary of the invention

本发明的目的在于提供一种新型 4一酰胺基取代喹唑啉衍生物，其可药用盐，其溶剂化物，其前药，其多晶或共晶。 SUMMARY OF THE INVENTION An object of the present invention is to provide a novel 4-amido-substituted quinazoline derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, polymorph or eutectic.

本发明的另一目的在于提供一种制备 4一酰胺基取代喹唑啉衍生物的方法。 Another object of the present invention is to provide a process for the preparation of a 4-amido-substituted quinazoline derivative.

本发明的再一目的在于提供一种含有一个或多个这种化合物的药物组合物。 A further object of the present invention is to provide a pharmaceutical composition comprising one or more such compounds.

本发明的又一目的在于提供一种该类化合物在抗癌，及与 EGFR有关疾病的药物中的用途。为了完成本发明之目的，可采用如下技术方案- 本发明是涉及具有下列通式 I的新型 4一酰胺取代喹唑啉衍生物：

巾， It is still another object of the present invention to provide a use of such compounds in anti-cancer, and EGFR-related diseases. For the purpose of the present invention, the following technical scheme can be employed - the present invention relates to a novel 4-amide substituted quinazoline derivative having the following general formula I:

towel,

和1¾分别独立的选自氢，甲基，乙基， 2-甲氧基乙基， 3-甲氧基丙基， 4-甲氧基丁基， 2-乙氧基乙基， 3-乙氧基丙基，（N-甲基哌啶- 4-) 甲基， 4-乙氧基丁基，三氟甲基， 2， 2， 2-三氟乙基， 2-羟基乙基， 3- 羟基丙基， 4-羟基丁基， 2- (N，N-二甲基氨基）乙基， 3- (N，N-二甲氨基)丙基， 4- (N，N-二甲氨基)丁基， 2-吗啉代乙基， 3-吗啉代丙基， 4-吗啉代丁基， 5-吗啉代戊基， 2-哌啶子基乙基， 3-哌啶子基丙基， 4-哌啶子基丁基， 5-哌啶子基戊基， 2- (哌嗪 -1-基）乙基， 3- (哌嗪- 1- 基)丙基， 4- (哌嗪 -1-基)丁基， 2- (4-甲基哌嗪- 1-基）乙基， 3- (4-甲基哌嗪 -1 -基)丙基， 4- (4-甲基哌嗪- 1-基)丁基， 2- (2-甲磺酰基乙氧基）乙基， 2- (2-甲磺酰基乙胺基）乙基， 2- (2-甲磺酰基乙巯基）乙基， 2-吡咯烷子基乙基， 3-吡咯烷子基丙基， 4-吡咯垸子基丁基， And independently separated from hydrogen, methyl, ethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 2-ethoxyethyl, 3-ethyl Oxypropyl, (N-methylpiperidine-4-)methyl, 4-ethoxybutyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, 2-hydroxyethyl, 3 - Hydroxypropyl, 4-hydroxybutyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 4-(N,N-dimethylamino) Butyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, 5-morpholinopentyl, 2-piperidinoethyl, 3-piperidino Propyl, 4-piperidinobutyl, 5-piperidinopentyl, 2-(piperazin-1-yl)ethyl, 3-(piperazine-1-yl)propyl, 4- (piperazin-1-yl)butyl, 2-(4-methylpiperazine-1-yl)ethyl, 3-(4-methylpiperazine-1-yl)propyl, 4- (4- Methylpiperazine-1-yl)butyl, 2-(2-methanesulfonylethoxy)ethyl, 2-(2-methanesulfonylethylamino)ethyl, 2-(2-methanesulfonyl) Ethyl, ethyl 2-pyrrolidinoethyl, 3-pyrrolidinylpropyl, 4-pyrrolidinyl butyl,

2- (2-氧代吡咯垸子基）乙基， 3- (2-氧代吡咯烷子基)丙基， 4- (2 -氧代吡咯烷子基)丁基， 2- (咪唑 -1-基) -乙基， 3- (咪唑 -1-基) -丙基， 4- (咪唑 -1-基) -丁基， 2- (二烷氨基）乙基， 3- (二烷氨基)丙基， 4- (二烷氨基)丁基， 2 - (取代苯甲酰氨基）乙基， 3- (取代苯甲酰氨基)丙基， 4 - (取代苯甲酰氨基)丁基， 2-甲磺酰氨基乙基， 3-甲磺酰氨基丙基， 4-甲磺酰氨基丁基， 2-苯磺酰氨基乙基， 3-苯磺酰氨基丙基， 4-苯磺酰氨基丁基， 2-氨磺酰基乙基， 3-氨磺酰基丙基， 4-氨磺酰基丁基；和分别独立优选为：甲基，乙基， 2-甲氧基乙基， 3-甲氧基丙基， 2-乙氧基乙基， 3-乙氧基丙基，三氟甲基，（N-甲基哌啶 -4-) 甲基， 2-羟基乙基， 3-羟基丙基， 2- (N，N-二甲基氨基）乙基， 3- (N, N- 二甲氨基)丙基， 2-吗啉代乙基， 3-吗啉代丙基， 2-哌啶子基乙基，2-(2-oxopyrrolidino)ethyl, 3-(2-oxopyrrolidino)propyl, 4-(2-oxopyrrolidino)butyl, 2-(imidazole- 1-yl)-ethyl, 3-(imidazol-1-yl)-propyl, 4-(imidazol-1-yl)-butyl, 2-(dialkylamino)ethyl, 3-(dialkylamino , propyl, 4-(dialkylamino)butyl, 2-(substituted benzoylamino)ethyl, 3-(substituted benzoylamino)propyl, 4-(substituted benzoylamino)butyl, 2-methanesulfonylaminoethyl, 3-methanesulfonylaminopropyl, 4-methanesulfonylaminobutyl, 2-benzenesulfonylaminoethyl, 3-benzenesulfonylaminopropyl, 4-benzenesulfonyl Aminobutyl, 2-sulfamoylethyl, 3-sulfamoylpropyl, 4-sulfamoylbutyl; and independently, respectively, are preferably: methyl, ethyl, 2-methoxyethyl, 3- Methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, trifluoromethyl, (N-methylpiperidin-4-)methyl, 2-hydroxyethyl, 3-hydroxy Propyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2- Piperidinoethyl,

3-哌啶子基丙基， 2- (哌嗪 -1-基）乙基， 3- (哌嗪 -1-基）丙基， 2- (4- 甲基哌嗪- 1-基）乙基， 3- (4-甲基哌嗪- 1-基)丙基， 2 - (2-甲磺酰基乙氧基）乙基， 2- (2-甲磺酰基乙氨基）乙基， 2- (2-甲磺酰基乙巯基）乙基， 2-吡咯烷子基乙基， 3-吡咯烷子基丙基， 2- (2-氧代吡咯烷子基）乙基， 3- (2-氧代吡咯垸子基)丙基， 2- (咪唑 -卜基) -乙基， 3- (咪唑 -1-基) -丙基， 2- (二烷氨基）乙基， 3- (二垸氨基)丙基， 3-甲磺酰氨基丙基， 4-甲磺酰氨基丁基， 2-氨磺酰基乙基， 3-氨磺酰基丙基；和分别独立更优选为：甲基，乙基， 2-甲氧基乙基， 3-甲氧 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(4-methylpiperazine-1-yl)ethyl , 3-(4-methylpiperazine-1-yl)propyl, 2-(2-methanesulfonylethoxy)ethyl, 2-(2-methanesulfonylethylamino)ethyl, 2- (2-methanesulfonylethyl)ethyl, 2-pyrrolidinylethyl, 3-pyrrolidinylpropyl, 2-(2-oxopyrrolidino)ethyl, 3-(2- Oxopyrrole-yl)propyl, 2-(imidazolium-bu)-ethyl, 3-(imidazol-1-yl)-propyl, 2-(dialkylamino)ethyl, 3-(di) Amino)propyl, 3-methanesulfonylaminopropyl, 4-methanesulfonylaminobutyl, 2-sulfamoylethyl, 3-sulfamoylpropyl; and each independently more preferably: methyl, B Base, 2-methoxyethyl, 3-methoxy

3 基丙基，（N-甲基哌啶- 4-)甲基， 2-乙氧基乙基， 3-乙氧基丙基，3 Propyl, (N-methylpiperidin-4-yl)methyl, 2-ethoxyethyl, 3-ethoxypropyl,

2- (N，N-二甲基氨基）乙基， 3-(N，N -二甲氨基)丙基， 2-吗啉代乙基，2-(N,N-Dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl,

3 -吗啉代丙基， 3-哌啶子基丙基， 3- (哌嗪 -1-基)丙基， 2- (4-甲基哌嗪-卜基）乙基， 3- (4-甲基哌嗪- 1-基)丙基， 2- (2-甲磺酰基乙氧基）乙基， 2- (2-甲磺酰基乙氨基）乙基， 2- (2-甲磺酰基乙巯基）乙基；3-morpholinopropyl, 3-piperidinopropyl, 3-(piperazin-1-yl)propyl, 2-(4-methylpiperazine-bu)ethyl, 3- (4 -methylpiperazine-1-yl)propyl, 2-(2-methanesulfonylethoxy)ethyl, 2-(2-methanesulfonylethylamino)ethyl, 2-(2-methanesulfonyl) Ethyl)ethyl;

R n 分别独立特别优选为：甲基， 2-甲氧基乙基，（N-甲基哌啶- 4-)甲基， 3-吗啉代丙基； R n is particularly preferably independently selected from the group consisting of: methyl, 2-methoxyethyl, (N-methylpiperidin-4-yl)methyl, 3-morpholinopropyl;

和最优选甲基、（N-甲基哌啶- 4-)甲基， 3-吗啉代丙基。 Most preferred are methyl, (N-methylpiperidin-4-)methyl, 3-morpholinopropyl.

R3选自为甲基，乙基，正丙基， 3-羟基丙基， 4-羟基丁基， 3- 乙酰氧丙基， 4-乙酰氧丁基，甲氧基，乙氧基，正丙氧基，异丙氧基，叔丁氧基，乙酰氧甲氧基，叔丁酰氧甲氧基，苄氧基， 3-氟苄氧基，R3 is selected from the group consisting of methyl, ethyl, n-propyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-acetoxypropyl, 4-acetoxybutyl, methoxy, ethoxy, n-propyl Oxyl, isopropoxy, tert-butoxy, acetomethoxymethoxy, tert-butyryloxymethoxy, benzyloxy, 3-fluorobenzyloxy,

2 -吗啉代乙氧基， 3-吗啉代丙氧基， 4-吗啉代丁氧基， 2-哌啶子基乙氧基， 3-哌啶子基丙氧基， 4-哌啶子基丁氧基， 2- (哌嗪 -1-基）乙氧基， 3- (哌嗪 -1-基)丙氧基， 4 - (哌嗪 -1-基)丁氧基， 2- (4-甲基哌嗪 - 1 -基）乙氧基， 3 - (4-甲基哌嗪- 1-基)丙氧基， 4- (4-甲基哌嗪-卜基）丁氧基， 2-吡咯烷子基乙氧基， 3-吡咯烷子基丙氧基， 4-吡咯垸子基丁氧基， 2- (2-氧代吡咯烷子基）乙氧基， 3- (2-氧代吡咯烷子基)丙氧基， 4- (2-氧代吡咯烷子基)丁氧基，2- (咪唑 -1-基) -乙氧基， 3- (咪唑 -1-基) -丙氧基，苯甲酰氧甲氧基； 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piper Pyridylbutoxy, 2-(piperazin-1-yl)ethoxy, 3-(piperazin-1-yl)propoxy, 4-(piperazin-1-yl)butoxy, 2 - (4-Methylpiperazine-1-yl)ethoxy, 3-(4-methylpiperazine-1-yl)propoxy, 4-(4-methylpiperazine-buyl)butoxy Base, 2-pyrrolidinoethoxy, 3-pyrrolidinylpropoxy, 4-pyrrolidinobutoxy, 2-(2-oxopyrrolidino)ethoxy, 3- (2-oxopyrrolidino)propoxy, 4-(2-oxopyrrolidino)butoxy, 2-(imidazol-1-yl)-ethoxy, 3-(imidazole-1 -yl)-propoxy, benzoyloxymethoxy;

R3选自为甲基，正丙基， 3-羟基丙基， 4-羟基丁基， 3-乙酰氧丙基， 4-乙酰氧丁基，甲氧基，乙氧基，异丙氧基，叔丁氧基，叔丁酰氧甲氧基，乙酰氧甲氧基，苄氧基， 3-氟苄氧基， 2-吗啉代乙氧基， R3 is selected from the group consisting of methyl, n-propyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-acetoxypropyl, 4-acetoxybutyl, methoxy, ethoxy, isopropoxy, Tert-butoxy, tert-butyryloxymethoxy, acetoxymethoxy, benzyloxy, 3-fluorobenzyloxy, 2-morpholinoethoxy

3-吗啉代丙氧基， 2-哌啶子基乙氧基， 3-哌啶子基丙氧基， 2- (哌嗪 - 1-基）乙氧基， 3- (哌嗪 -1-基)丙氧基， 2- (4-甲基哌嗪- 1-基）乙氧基， 3- (4-甲基哌嗪 -1-基)丙氧基， 2-吡咯垸子基乙氧基， 3-吡咯烷子基丙氧基， 2- (2-氧代吡咯烷子基）乙氧基， 3- (2-氧代吡咯烷子基)丙氧基， 2- (咪唑 -1 -基) -乙氧基， 3- (咪唑 -1-基) -丙氧基，苯甲酰氧甲氧基. 3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(piperazine-1-yl)ethoxy, 3-(piperazine-1 -yl)propoxy, 2-(4-methylpiperazine-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-pyrrolidino Oxylate, 3-pyrrolidinopropoxy, 2-(2-oxopyrrolidino)ethoxy, 3-(2-oxopyrrolidino)propoxy, 2-(imidazole- 1-yl)-ethoxy, 3-(imidazol-1-yl)-propoxy, benzoyloxymethoxy.

R3更优选为正丙基， 3-乙酰氧丙基，甲氧基，异丙氧基，叔丁氧基，苄氧基， 2-吗啉代乙氧基， 3-吗啉代丙氧基， 3-哌啶子基丙氧基，叔丁酰氧甲氧基， 3- (哌嗪 -1-基)丙氧基， 3- (4-甲基哌嗪- 1- 基)丙氧基， 3-吡咯烷子基丙氧基， 3- (2-氧代吡咯垸子基)丙氧基， 3- (眯唑 -1-基) -丙氧基。乙酰氧甲氧基，异丁酰氧甲氧基，苯甲酰氧甲氧基； R3 is more preferably n-propyl, 3-acetoxypropyl, methoxy, isopropoxy, tert-butoxy, benzyloxy, 2-morpholinoethoxy, 3-morpholinopropoxy , 3-piperidinopropoxy, tert-butyryloxymethoxy, 3-(piperazin-1-yl)propoxy, 3-(4-methylpiperazine-1-yl)propoxy , 3-pyrrolidinopropoxy, 3-(2-oxopyrrolidino)propoxy, 3-(oxazol-1-yl)-propoxy. Acetoxymethoxy, isobutyryloxymethoxy, benzoyloxymethoxy;

R3特别优选为 3-乙酰氧丙基，甲氧基，异丙氧基，叔丁氧基，苄氧基， 2-吗啉代乙氧基， 3-吗啉代丙氧基， 3-哌啶子基丙氧基，叔丁酰氧甲氧基，乙酰氧甲氧基，苯甲酰氧甲氧基； R3最优选为叔丁氧基、乙氧基、甲氧基、乙基、叔丁酰氧甲氧基。 R3 is particularly preferably 3-acetoxypropyl, methoxy, isopropoxy, tert-butoxy, benzyloxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 3-piperidyl Pyridylpropoxy, tert-butyryloxymethoxy, acetoxymethoxy, benzoyloxymethoxy; Most preferably R3 is tert-butoxy, ethoxy, methoxy, ethyl, t-butyryloxymethoxy.

R4选自：单取代或多取代的苯基，单取代或多取代的苄基，单取代或多取代的苯甲酰基，单取代或多取代的苯磺酰基；取代基选自卤素，甲基，三氟甲基，羟甲基，羟基，硝基，氰基，氨基，取代的氨基，酰氨基，羧基，酯基，氨酰基，烷氧基，烷酰氧基，烯基，卤代苄氧基，卤代苄氨基，卤代苯氧基，卤代苯氨基； R4 is selected from the group consisting of: mono- or poly-substituted phenyl, mono- or poly-substituted benzyl, mono- or poly-substituted benzoyl, mono- or poly-substituted benzenesulfonyl; substituent selected from halogen, methyl , trifluoromethyl, hydroxymethyl, hydroxy, nitro, cyano, amino, substituted amino, acylamino, carboxy, ester, aminoacyl, alkoxy, alkanoyloxy, alkenyl, halobenzyl Oxyl, halobenzylamino, halophenoxy, halophenylamino;

R4优选为 3-溴苯基， 3-溴 -4-羟基苯基， 3-羟基苯基， 3-甲氧基苯基， 3-氰基苯基， 3， 5-二溴- 4-羟基苯基， 3-氯苯基， 3-氟苯基， 3 -氯- 4-氟苯基， 3-甲基苯基， 2-氟 -4-溴苯基， 1-苯基乙基， 4-氨甲酰苯基， 3-烯基苯基， 3-炔基苯基， 2-甲基苯磺酰基， 3-氯- 4- (3-氟苄氧基)苯基， N-苄基异吲唑基， 4-氰基- 2-氟苯基， 3-羟基- 4-甲氧基苯基， 2， 4-二氟苯基， 2-氟- 4 甲氧基苯基； R4 is preferably 3-bromophenyl, 3-bromo-4-hydroxyphenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 3-cyanophenyl, 3,5-dibromo-4-hydroxy Phenyl, 3-chlorophenyl, 3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-methylphenyl, 2-fluoro-4-bromophenyl, 1-phenylethyl, 4 -carbamoylphenyl, 3-alkenylphenyl, 3-alkynylphenyl, 2-methylbenzenesulfonyl, 3-chloro-4-(3-fluorobenzyloxy)phenyl, N-benzyl Isoxazolyl, 4-cyano-2-fluorophenyl, 3-hydroxy-4-methoxyphenyl, 2,4-difluorophenyl, 2-fluoro-4-methoxyphenyl;

R4更优选为 3-溴苯基， 3-溴 -4-羟基苯基， 3-羟基苯基， 3， 5- 二溴- 4-羟基苯基， 3-氯苯基， 3-氟苯基， 3-氯 -4-氟苯基， 3-甲基苯基， 2-氟- 4-溴苯基，卜苯基乙基， 2-甲基苯磺酰基， 3-氯- 4- (3 -氟卞本 ; More preferably, R4 is 3-bromophenyl, 3-bromo-4-hydroxyphenyl, 3-hydroxyphenyl, 3, 5-dibromo-4-hydroxyphenyl, 3-chlorophenyl, 3-fluorophenyl , 3-chloro-4-fluorophenyl, 3-methylphenyl, 2-fluoro-4-bromophenyl, phenylethyl, 2-methylbenzenesulfonyl, 3-chloro-4- (3 - fluoroquinone;

R4特别优选为 3-溴苯基， 3-溴- 4-羟基苯基， 3-羟基苯基， 3， 5-二溴- 4-羟基苯基， 3-氯苯基， 3-氯- 4-氟苯基， 2 -氟- 4-溴苯基； R4最优选为 3-溴苯基、 3-氯 -4-氟苯基、 2-氟 -4-溴苯基。最优选的化合物为 R4 is particularly preferably 3-bromophenyl, 3-bromo-4-hydroxyphenyl, 3-hydroxyphenyl, 3,5-dibromo-4-hydroxyphenyl, 3-chlorophenyl, 3-chloro-4 -fluorophenyl, 2-fluoro-4-bromophenyl; R4 is most preferably 3-bromophenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-bromophenyl. The most preferred compound is

N - (6, 7-二甲氧基喹唑啉 -4 -基) -N- (3-溴苯基)叔丁氧甲酰胺 N - (6, 7-Dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)-tert-butoxycarbonylamide

N- (6， 7-二甲氧基喹唑啉 -4 ）乙氧甲酰胺 N-(6,7-dimethoxyquinazoline-4) ethoxyformamide

N - (6， 7-二甲氧基喹唑啉 -4-基) -N- (3-溴苯基）甲氧基甲酰胺 N - (6, 7-二甲氧基喹唑啉 -4 -氟苯基)叔丁氧基甲酰胺 N - (6, 7-Dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)methoxyformamide N - (6, 7-dimethoxyquinazolin-4-fluorophenyl) tert-butoxycarboxamide

N - (6， 7-二甲氧基喹唑啉- 4-基) - N- (3-溴苯基）乙酰胺 N - (6, 7-Dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)acetamide

N- (6-吗啉丙氧基- 7-甲氧基喹唑啉 -4-基) - N- (3-氯 -4-氟苯基）叔丁氧基甲酰胺 N-(6-morpholinepropoxy-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)tert-butoxycarboxamide

N - (6-吗啉丙氧基 -7-甲氧基喹唑啉 -4-基) -N- (3-氯 -4-氟苯基）乙氧基甲酰胺

N - (6-morpholinepropoxy-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)ethoxyformamide

N- (6-吗啉丙氧基 -7-甲氧基喹唑啉 -4-基) -N- (3-氯 -4-氟苯基）异丁氧基甲酰胺 N-(6-morpholinepropoxy-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)isobutoxycarbamide

N- (6-吗啉丙氧基- 7-甲氧基喹唑啉- 4-基) - N- (3-氯 -4-氟苯基)苄氧基甲酰胺

N-(6-morpholinepropoxy-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)benzyloxycarboxamide

N- (6-甲氧基 -7- (N-甲基哌啶 -4-甲氧基）喹唑啉 -4-基） -N- (2-氟一 4一溴苯基)叔丁氧基甲酰胺 N-(6-Methoxy-7-(N-methylpiperidin-4-methoxy)quinazolin-4-yl)-N-(2-fluoro-1,4-bromophenyl)-tert-butoxy Carboxamide

另外，特别优选的本发明化合物为通式 I喹唑啉衍生物或其可药用酸加成盐，更优选的是甲磺酸盐，最优选的是 N- (6-吗啉丙氧基- 7 - 甲氧基喹唑啉- 4-基) - N- (3-氯- 4-氟苯基）叔丁氧基甲酰胺的甲磺酸卜为了制备本发明通式 I所述的化合物，本发明的制备方法是利用取代的苯胺先与酰氯或酯或酐作用给出 N-取代的酰胺，然后再在碱存在下与 4位具有易离去基团的喹唑啉衍生物反应给出 4一酰氨基喹唑啉衍生物 (X是易离去基团）。所述的易离去基团包括卤素取代基、酰氧基、磺酰氧基。 Further, a particularly preferred compound of the present invention is a quinazoline derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof, more preferably a methanesulfonate, and most preferably N-(6-morpholinyloxy) - 7 -Methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)-tert-butoxycarboxamide methanesulfonate to prepare the compound of formula I of the present invention The preparation method of the present invention is to use a substituted aniline to react with an acid chloride or an ester or an anhydride to give an N-substituted amide, and then react with a quinazoline derivative having an easily leaving group at the 4-position in the presence of a base. A 4-aminoamidoquinazoline derivative (X is an easy leaving group). The easy leaving group includes a halogen substituent, an acyloxy group, a sulfonyloxy group.

另外，上述反应中的起始原料及中间体容易得到，或对本领域熟练技术人员来说可以用有机合成中的常规方法很容易合成。通式 I所述喹唑啉衍生物可以溶剂化物或非溶剂化物的形式存在，利用不同的溶剂进行结晶可能得到不同的溶剂化物。通式 I所述药学上可接受的碱性的喹唑啉衍生物的盐包括不同酸加成盐，如下列无机酸或有机酸的酸加成盐：盐酸，氢溴酸，磷酸，硫酸，甲磺酸，对甲苯磺酸，三氟乙酸，枸杞酸，马来酸，酒石酸，富马酸，柠檬酸，乳酸。通式 I 所述药学上可接受的酸性的喹唑啉衍生物的盐包括不同碱金属盐 (锂，钠，钾盐），碱土金属盐（钙，镁盐）及铵盐，和能提供生理上可接受的阳离子的有机碱的盐，如甲胺，二甲胺，三甲胺，哌啶，吗啉及三（2—羟乙基）胺的盐。在本发明范围内的所有这些盐都可采用常规方法制备。在所述的喹唑啉衍生物及其溶剂化物和其盐的制备过程中，不同结晶条件可能出现多晶或共晶。本发明还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和 /或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为 0.1-95重量％。

Further, the starting materials and intermediates in the above reaction are readily available, or can be easily synthesized by a person skilled in the art by a conventional method in organic synthesis. The quinazoline derivatives of the formula I may exist in the form of solvates or unsolvates, and crystallization with different solvents may result in different solvates. Salts of pharmaceutically acceptable basic quinazoline derivatives of the formula I include different acid addition salts, such as the following acid or organic acid addition salts: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, Methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid. Salts of the pharmaceutically acceptable acidic quinazoline derivatives of the formula I include different alkali metal salts (lithium, sodium, potassium salts), alkaline earth metal salts (calcium, magnesium salts) and ammonium salts, and which provide physiological Salts of acceptable organic bases of cations such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris(2-hydroxyethyl)amine. All of these salts within the scope of the invention can be prepared by conventional methods. In the preparation of the quinazoline derivatives and their solvates and salts thereof, polycrystalline or eutectic may occur under different crystallization conditions. The invention further relates to a pharmaceutical composition comprising a compound of the invention as an active ingredient. The pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.

本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、 ***、直肠等。 The compound of the present invention or a pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung, and Respiratory tract, skin, vagina, rectum, etc.

给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂（包括真溶液和胶体溶液）、乳剂（包括 o/w型、 w/o型和复乳）、混悬剂、注射剂（包括水针剂、粉针剂和输液）、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂（包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片）、胶囊剂（包括硬胶囊、软胶囊、肠溶胶囊）、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气（粉）雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。 The dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w, w/o and double emulsions), suspensions, injections (including water injections, powder injections and infusions), eye drops Agent, nasal drops, lotion and expectorant, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.

本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药***。 The compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.

为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、 ***胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯垸酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橡酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。 In order to form the compound of the present invention into tablets, various excipients known in the art, including diluents, binders, wetting agents, disintegrating agents, lubricants, and glidants, can be widely used. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant may be water, ethanol, or different Propyl alcohol, etc.; the binder may be starch pulp, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin pulp, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl Cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium hydrogencarbonate and decanoic acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; The glidant may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.

还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。 Tablets may also be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.

为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、 pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基 -β-环糊精等； pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。 In order to prepare the administration unit as a capsule, the active ingredient compound of the present invention may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule. The various diluents, binders, wetting agents, disintegrants, glidant varieties used to prepare the tablets of the compounds of the invention are also useful in the preparation of capsules of the compounds of the invention. In order to prepare the compound of the present invention as an injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizer, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added. The solubilizer or co-solvent may be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulator may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like. For preparing a lyophilized powder injection, mannitol, glucose or the like may also be added as a proppant.

此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。 In addition, coloring agents, preservatives, perfumes, flavoring agents or other additives may also be added to the pharmaceutical preparations as needed.

为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。 The pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of enhancing the therapeutic effect for the purpose of administration.

本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为 0.001-150mg/Kg体重，优选为 0.1-100mg/Kg体重，更优选为 l-60mg/Kg 体重，最优选为 2-30mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。 The pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like. In general, a suitable daily dose of the compound of the invention will range from 0.001 to 150 mg/kg body weight, preferably from 0.1 to 100 mg/kg body weight, more preferably from 1 to 60 mg/kg body weight, and most preferably from 2 to 30 mg/kg body weight. The above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。本发明化合物是酪氨酸激酶抑制剂或其前体，具有明显的抗肿瘤活性。本发明化合物具有较高的生物利用度，可用于多种人类恶性肿瘤的治疗，包括头颈部癌、非小细胞肺癌、胰腺癌、结直肠癌、膀胱癌及乳腺癌，卵巢癌，扁平细胞癌等。具体实施方式 The compounds or compositions of this invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation. The compound of the present invention is a tyrosine kinase inhibitor or a precursor thereof, and has remarkable antitumor activity. The compound of the invention has high bioavailability and can be used for the treatment of various human malignant tumors, including head and neck cancer, non-small cell lung cancer, pancreatic cancer, colorectal cancer, bladder cancer and breast cancer, ovarian cancer, flat cells. Cancer, etc. detailed description

以下将结合实施例对发明作进一步说明，但并不限制本发明的范围。 The invention is further illustrated by the following examples, without limiting the scope of the invention.

测定仪器：熔点用 Yanaco显微熔点仪，核磁共振光谱用 Vaariaan Mercury 300型核磁共振仪。质谱用 ZAD- 2F和 VG300质谱仪。实施例 1： N- (6， 7-二甲氧基喹唑啉- 4-基) - N- (3-溴苯基)叔丁氧甲酰胺的制备.

Measuring instruments: Yanaco micro melting point apparatus for melting point and Vaariaan Mercury 300 type nuclear magnetic resonance meter for nuclear magnetic resonance spectrum. Mass spectrometry was performed on a ZAD-2F and VG300 mass spectrometer. Example 1: Preparation of N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)tert-butoxycarbonylamide.

将 0. 48克氢化钠 (60%) (12毫摩尔）和 50毫升无水四氢呋喃置于 100毫升烧瓶中，搅拌下滴加 1. 72克（10毫摩尔）间溴苯胺溶于 10毫升无水四氢呋喃的溶液，然后加热回流一小时，冷至室温，加入 2. 6 克（12毫摩尔）二叔丁氧甲酸酐，搅拌 0. 5小时后再加热回流 14小时，冷至室温，加入饱和氯化铵水溶液中和，旋去大部分溶剂，加入乙酸乙酯萃取，用饱和碳酸氢钠洗涤，水洗，饱和盐溶液洗，无水硫酸钠干燥，旋去溶剂得到 N-叔丁氧甲酰基间溴苯胺，干燥后直接用于下一步反应. 0. 48 g of sodium hydride (60%) (12 mmol) and 50 ml of anhydrous tetrahydrofuran were placed in a 100 ml flask, and 1.72 g (10 mmol) of m-bromoaniline was dissolved in 10 ml without stirring. a solution of water tetrahydrofuran, then heated to reflux for one hour, cooled to room temperature, added 2. 6 g (12 mmol) of di-tert-butoxy anhydride, stirred for 0.5 h and then heated to reflux for 14 hours, cooled to room temperature, added to saturation Neutralize with aqueous ammonium chloride solution, remove most of the solvent, extract with ethyl acetate, wash with saturated sodium hydrogencarbonate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and remove solvent to give N-tert-butoxycarbonyl M-bromoaniline, used directly in the next reaction after drying.

¾ NMR (400MHz, CDC1₃) , δ (ρρπι) 7. 66 (d, 1Η， ArH) , 7. 22-7. 12 (m, 3H, ArH) , 6. 46 (S, 1H, 腿）， 1. 49 (S, 9H， CH3) . _3⁄4 NMR (400MHz, CDC1 ₃ ) , δ (ρρπι) 7. 66 (d, 1Η, ArH) , 7. 22-7. 12 (m, 3H, ArH) , 6. 46 (S, 1H, leg), 1. 49 (S, 9H, CH3).

FABMS : (M+l) =273 FABMS : (M+l) =273

将 272毫克 (1毫摩尔） N-叔丁氧甲酰基间溴苯胺和 225毫克（1毫摩尔） 4-氯 -6， 7-二甲氧基喹唑啉溶于 10毫升无水 DMS0中，加入 48毫克 (60%) (1. 2毫摩尔)氢化钠, 40° C搅拌 20分钟，倾入冰冷的碳酸氢钠溶液中，乙酸乙酯萃取 2次，碳酸氢钠溶液洗涤，水洗，饱和盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析分离得到 N- (6， 7-二甲氧基喹唑啉- 4 -基) -N-(3-溴苯基）叔丁氧基甲酰胺，熔点为：153- 155° (。 ¾ NMR(400M, CDC13) , 5 ( ppm) 8. 62 (S, 1H, ArH ) ， 8. 07 (S, 1H, ArH ) ， 7. 77 (S, 1H， ArH) 7. 21 (m, 3H， ArH)， 6. 97 (S, 1H, ArH)， 4. 01 (,S， 3H， -OCHa) , 3. 99 (S, 3H, -OCH3)， 1. 64 (S, 9H, - C ) . FABMS : (M+H) ⁺ =461₀ 实施例 2: N- (6， 7 -二甲氧基喹唑啉 -4-基) - N- (3-溴苯基）乙氧甲酰胺的制备. 272 mg (1 mmol) of N-tert-butoxycarbonyl-m-bromoaniline and 225 mg (1 mmol) of 4-chloro-6,7-dimethoxyquinazoline were dissolved in 10 ml of anhydrous DMSO. Add 48 mg (60%) (1.2 mmol) of sodium hydride, stir at 40 ° C for 20 minutes, pour into ice-cold sodium bicarbonate solution, extract twice with ethyl acetate, wash with sodium bicarbonate solution, wash with water, saturate Wash with brine, dry over anhydrous sodium sulfate, spin off the solvent, and elute with column chromatography to give N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl) tert-butoxy Melamine, melting point: 153-155° (. 3⁄4 NMR (400M, CDC13), 5 (ppm) 8. 62 (S, 1H, ArH), 8. 07 (S, 1H, ArH), 7. 77 (S, 1H, ArH) 7. 21 (m, 3H, ArH), 6. 97 (S, 1H, ArH), 4. 01 (,S, 3H, -OCHa) , 3. 99 (S, 3H, -OCH3), 1. 64 (S, 9H, - C ) . FABMS : (M+H) ⁺ =461 ₀ Example 2: N-(6,7-Dimethoxyquinazolin-4-yl) - Preparation of N-(3-bromophenyl)ethoxyformamide.

将 0. 48克氢化钠（60%) (12毫摩尔)和 50毫升无水四氢呋喃置于 100毫升烧瓶中，搅拌下滴加 1. 72克（10毫摩尔）间溴苯胺溶于 10毫升无水四氢呋喃的溶液，然后加热回流一小时，冷至室温，加入 1. 95 克（12毫摩尔）二乙氧基甲酸酐，搅拌 0. 5小时后再加热回流 10小时，冷至室温，加入饱和氯化铵水溶液中和，旋去大部分溶剂，加入乙酸乙酯萃取，用饱和碳酸氢钠洗涤，水洗，饱和盐溶液洗，无水硫酸钠干燥，旋去溶剂得到 N-乙氧甲酰基间溴苯胺，干燥后直接用于下一步反应. 0. 48 g of sodium hydride (60%) (12 mmol) and 50 ml of anhydrous tetrahydrofuran were placed in a 100 ml flask, and 1.72 g (10 mmol) of m-bromoaniline was dissolved in 10 ml without stirring. A solution of tetrahydrofuran in water, then heated to reflux for one hour, cooled to room temperature, then added 1.95 g (12 mmol) of diethoxycarboxylic anhydride, stirred for 0.5 hours, then heated to reflux for 10 hours, cooled to room temperature, added to sat. Neutralize with aqueous ammonium chloride solution, remove most of the solvent, extract with ethyl acetate, wash with saturated sodium bicarbonate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate Dry, vortex off the solvent to obtain N-ethoxycarbonyl-bromoaniline, which is dried and used directly in the next reaction.

将 244毫克（1毫摩尔） N-乙氧甲酰基间溴苯胺和 316毫克（1毫摩尔） 4-碘- 6， 7-二甲氧基喹唑啉溶于 10毫升无水 DMS0中，加入 48 毫克（60%) (1. 2毫摩尔)氢化钠， 40° C搅拌 10分钟，倾入冰冷的碳酸氢钠溶液中，乙酸乙酯萃取 2 次，碳酸氢钠溶液洗涤，水洗，饱和盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析分离得到 N- (6, 7-二甲氧基喹唑啉- 4-基）- N- (3-溴苯基）乙氧甲酰胺，熔点为： 121. 4-124. 3° C o ¾ MR(400M, CDC13) , δ ( pm) 7. 85 (S， 1H， ArH)， 7. 54 (S， 1H, ArH)， 7. 41 (S, 1H, ArH) , 7. 25 (S， 1H, ArH) ， 7. 18 (m， 2H， ArH)，7. 00 (m，lH, ArH) , 4. 37 (q, 2H,— C 一）， 3. 95 (S， 3H，— 0CH₃) , 3. 92 (S, 3H, -OCHs)，1. 40 (t，3H， - CH₃) . FABMS : (M+H) ⁺二 433。实施例 3: N- (6， 7-二甲氧基喹唑啉 -4 -基) -N- (3-溴苯基）甲氧基甲酰胺的制备. 244 mg (1 mmol) of N-ethoxyformylbromoaniline and 316 mg (1 mmol) of 4-iodo-6,dimethoxyquinazoline were dissolved in 10 ml of anhydrous DMS0, added 48 mg (60%) (1.2 mmol) of sodium hydride, stirred at 40 ° C for 10 minutes, poured into ice-cold sodium bicarbonate solution, extracted twice with ethyl acetate, washed with sodium bicarbonate solution, washed with water, saturated brine Washed, dried over anhydrous sodium sulfate, vortexed and purified by column chromatography to give N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl) ethoxyformamide , melting point: 121. 4-124. 3° C o 3⁄4 MR(400M, CDC13) , δ ( pm) 7. 85 (S, 1H, ArH), 7. 54 (S, 1H, ArH), 7. 41 (S, 1H, ArH) , 7. 25 (S, 1H, ArH) , 7. 18 (m, 2H, ArH), 7. 00 (m, lH, ArH) , 4. 37 (q, 2H, — C a), 3. 95 (S, 3H, — 0CH ₃ ) , 3. 92 (S, 3H, -OCHs), 1. 40 (t, 3H, - CH ₃ ) . FABMS : (M+H) ⁺ two 433. Example 3: Preparation of N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)methoxyformamide.

将 0. 48克氢化钠 (60%) (12毫摩尔）和 50毫升无水四氢呋喃置于 100毫升烧瓶中，搅拌下滴加 1. 72克（10毫摩尔）间溴苯胺溶于 10毫升无水四氢呋喃的溶液，然后加热回流一小时，冷至室温，加入 1. 14 克 (12毫摩尔）甲氧基甲酰氯，室温搅拌至原料点消失，旋去大部分溶剂，加入乙酸乙酯萃取，用饱和碳酸氢钠洗涤，水洗，饱和盐溶液洗，无水硫酸钠干燥，旋去溶剂，柱层析分离得到 N-甲氧甲酰基间溴苯胺。 0. 48 g of sodium hydride (60%) (12 mmol) and 50 ml of anhydrous tetrahydrofuran were placed in a 100 ml flask, and 1.72 g (10 mmol) of m-bromoaniline was dissolved in 10 ml without stirring. A solution of water in tetrahydrofuran, then heated to reflux for one hour, cooled to room temperature, and then added 1.14 g (12 mmol) of methoxycarbonyl chloride, stirred at room temperature until the starting point disappeared, most of the solvent was removed, and extracted with ethyl acetate. It is washed with saturated sodium hydrogencarbonate, washed with water, washed with a saturated aqueous solution, dried over anhydrous sodium sulfate, and evaporated to the solvent to afford N-methoxyformylbromoaniline.

将 230毫克（1毫摩尔） N-甲氧甲酰基间溴苯胺和 316毫克（1毫摩尔） 4-碘- 6， 7-二甲氧基喹唑啉溶于 10毫升无水 DMS0中，加入 48 毫克（60%) (1. 2毫摩尔)氢化钠， 40° C搅拌 10分钟，倾入冰冷的碳酸氢钠溶液中，乙酸乙酯萃取 2次，碳酸氢钠溶液洗涤，水洗，饱和盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析分离得到 N- (6， 7-二甲氧基喹唑啉 -4-基) -N- (3-溴苯基）甲氧甲酰胺，熔点为：97. 2-99. 7° C。 ¾ NMR(400M, CDC13) , 5(ppm) 7. 93 (S, 1H, ArH), 7. 52(S, 1H, ArH), 7. 25 (m，2H， ArH) ，7. 21 (m, 2H, ArH) , 7. 02 (m， 1H, ArH) ，3. 98 (S, 3H, -OCHs) ， 3. 96 (S，3H， - 0C¾) ，3, 93 (S， 3H， - 0C¾) . FABMS : (M+H) ⁺ 二 419。实施例 4: N- (6， 7-二甲氧基喹唑啉- 4-基) -N- (3-氯- 4-氟苯基)叔丁氧基甲酰胺的制备.

230 mg (1 mmol) of N-methoxyformyl m-bromoaniline and 316 mg (1 mmol) of 4-iodo-6,7-dimethoxyquinazoline were dissolved in 10 ml of anhydrous DMS0, added 48 mg (60%) (1.2 mmol) of sodium hydride, stirred at 40 ° C for 10 minutes, poured into ice-cold sodium bicarbonate solution, extracted twice with ethyl acetate, washed with sodium bicarbonate solution, washed with water, saturated brine Washed, dried over anhydrous sodium sulfate, vortexed, and purified by column chromatography to give N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)methoxyformamide , melting point: 97. 2-99. 7 ° C. 3⁄4 NMR (400M, CDC13), 5 (ppm) 7. 93 (S, 1H, ArH), 7. 52 (S, 1H, ArH), 7. 25 (m, 2H, ArH), 7. 21 (m , 2H, ArH) , 7. 02 (m, 1H, ArH) , 3. 98 (S, 3H, -OCHs) , 3. 96 (S, 3H, - 0C3⁄4) , 3, 93 (S, 3H, - 0C3⁄4) . FABMS : (M+H) ⁺ two 419. Example 4: Preparation of N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)-tert-butoxycarboxamide.

将 0.48克氢化钠 (60%) (12毫摩尔）和 50毫升无水四氢呋喃置于 100毫升烧瓶中，搅拌下滴加 1.46克（10毫摩尔)对氟间氯苯胺溶于 10 毫升无水四氢呋喃的溶液，然后加热回流一小时，冷至室温，加入 2.6 克（12毫摩尔）二叔丁氧甲酸酐，搅拌 0.5小时后再加热回流 13小时，冷至室温，加入饱和氯化铵水溶液中和，旋去大部分溶剂，加入乙酸乙酯萃取，用饱和碳酸氢钠洗涤，水洗，饱和盐溶液洗，无水硫酸钠干燥，旋去溶剂得到 N-叔丁氧甲酰基对氟间氯苯胺，干燥后直接用于下一步反应. 0.48 g of sodium hydride (60%) (12 mmol) and 50 ml of anhydrous tetrahydrofuran were placed in a 100 ml flask, and 1.46 g (10 mmol) of p-chloro-chloroaniline dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise with stirring. The solution was heated to reflux for one hour, cooled to room temperature, and 2.6 g (12 mmol) of di-tert-butoxy anhydride was added, stirred for 0.5 hour, then heated to reflux for 13 hours, cooled to room temperature, and neutralized with saturated aqueous ammonium chloride. The solvent is evaporated, the mixture is extracted with ethyl acetate, washed with EtOAc EtOAc (EtOAc)EtOAc.EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj After drying, it is directly used in the next reaction.

¾ MR (400MHz, CDC1₃)， 5(ppm) 7.57(d, 1H， ArH), 7.14—7.00 (m， 2H, ArH), 6.46 (S, 1H, 腿）， 1.51(S， 9H, CH3) . _3⁄4 MR (400MHz, CDC1 ₃ ), 5 (ppm) 7.57(d, 1H, ArH), 7.14—7.00 (m, 2H, ArH), 6.46 (S, 1H, leg), 1.51(S, 9H, CH3) .

FABMS: (M+H)⁺ 二 246.6 将 246毫克（1毫摩尔） N-叔丁氧甲酰基对氟间氯苯胺和 225毫克 (1毫摩尔）4-氯 -6， 7-二甲氧基喹唑啉溶于 10毫升无水 DMS0中，加入 48毫克 (60%) (1.2毫摩尔）氢化钠， 40° C搅拌 20分钟，倾入冰冷的碳酸氢钠溶液中，乙酸乙酯萃取 2次，碳酸氢钠溶液洗涤，水洗，饱和盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析分离得到 N- (6， 7-二甲氧基喹唑啉 -4-基) -N- (3-氯一 4一氟苯基)叔丁氧基甲酰胺，熔点为: 158-159.9°C。 ¾ NMR(400M, CDC13),5 ( ppm) 8.62 (S, 1H, ArH) ， 8.07 (S, 1H， ArH)， 7.76 (S, 1H, ArH)， 7.25 (m， 1H, ArH) , 7.1 (m， 1H, ArH)， 6.95 (S， 1H， ArH)， 4.01 (S， 3H，— 0C )， 3.99 (S， 3H，一 0CH₃)， 1.61(S，9H, - CH₃) . FABMS: (M+H)⁺ = 434。实施例 5: N- (6, 7-二甲氧基喹唑啉- 4-基) -N-(3-溴苯基）乙酰胺的制备. FABMS: (M+H) ⁺ two 246.6 246 mg (1 mmol) N-tert-butoxycarbonyl-fluoro-chloro-chloroaniline and 225 mg (1 mmol) 4-chloro-6, 7-dimethoxy The quinazoline is dissolved in 10 ml of anhydrous DMSO, 48 mg (60%) (1.2 mmol) of sodium hydride is added, stirred at 40 ° C for 20 minutes, poured into ice-cold sodium bicarbonate solution and extracted twice with ethyl acetate. Washing with sodium bicarbonate solution, washing with water, washing with saturated brine, drying over anhydrous sodium sulfate, stirring solvent, column chromatography to give N-(6,7-dimethoxyquinazolin-4-yl)-N- (3-Chloro-tetrafluorophenyl) tert-butoxycarbonylamide, melting point: 158-159.9 ° C. 3⁄4 NMR (400M, CDC13), 5 (ppm) 8.62 (S, 1H, ArH), 8.07 (S, 1H, ArH), 7.76 (S, 1H, ArH), 7.25 (m, 1H, ArH), 7.1 ( m, 1H, ArH), 6.95 (S, 1H, ArH), 4.01 (S, 3H, - 0C), 3.99 (S, 3H, 0CH ₃ ), 1.61 (S, 9H, - CH ₃ ) . FABMS: (M+H) ⁺ = 434. Example 5: Preparation of N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)acetamide.

将 0.48克氢化钠 (60%) (12毫摩尔）和 50毫升无水四氢呋喃置于 100毫升烧瓶中，搅拌下滴加 1.72克（10毫摩尔）间溴苯胺溶于 10毫升无水四氢呋喃的溶液，然后加热回流一小时，冷至室温，加入 1.23 克 (12毫摩尔）乙酸酐，室温搅拌至原料点消失，旋去大部分溶剂，加入乙酸乙酯萃取，用饱和碳酸氢钠洗涤，水洗，饱和盐溶液洗，无水硫酸钠干燥，旋去溶剂，柱层析分离得到 N-乙酰基间溴苯胺。 0.48 g of sodium hydride (60%) (12 mmol) and 50 ml of anhydrous tetrahydrofuran were placed in a 100 ml flask, and a solution of 1.72 g (10 mmol) of m-bromoaniline dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise with stirring. Then, heat to reflux for one hour, cool to room temperature, add 1.23 g (12 mmol) of acetic anhydride, stir at room temperature until the starting point disappears, and rotate most of the solvent, add It is extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to the solvent to afford N-acetyl m-bromoaniline.

将 214毫克（1 毫摩尔） N-乙酰基间溴苯胺和 225 毫克（1 毫摩尔） 4-氯- 6, 7-二甲氧基喹唑啉溶亍 10毫升无水 DMS0中，加入 48毫克 (60%) (1.2毫摩尔）氢化钠， 40° C搅拌 20分钟，倾入冰冷的碳酸氢钠溶液中，乙酸乙酯萃取 2次，碳酸氢钠溶液洗涤，水洗，饱和盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析分离得到 N- (6， 7-二甲氧基喹唑啉- 4-基）- N- (3-溴苯基）乙酰胺，熔点为：202- 205° (：。 ¾ NMR(400M, CDC13),5 (ppm) 8.69 (S, 1H, ArH) ， 7.98(S，1H， ArH) ， 7.65 (S, 1H, ArH) ， 7.27-7.00 (m, 4H， ArH)， 4.04 (S， 6H， - 0CH₃) ， 2.04 (S, 3H, - C¾) . FABMS: (M+H)⁺ =403₀ 实施例 6: N- (6-吗啉丙氧基- 7-甲氧基喹唑啉 -4-基) -N- (3-氯- 4-氟苯基)叔丁氧基甲酰胺的制备. 214 mg (1 mmol) of N-acetyl m-bromoaniline and 225 mg (1 mmol) of 4-chloro-6, 7-dimethoxyquinazoline dissolved in 10 ml of anhydrous DMS0, add 48 mg (60%) (1.2 mmol) sodium hydride, stirred at 40 ° C for 20 minutes, poured into ice-cold sodium bicarbonate solution, extracted twice with ethyl acetate, washed with sodium hydrogen carbonate solution, washed with water, washed with saturated brine, anhydrous Dry over sodium sulfate, vortex off the solvent and elute to give N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)acetamide, m.p. 205° (: 3⁄4 NMR (400M, CDC13), 5 (ppm) 8.69 (S, 1H, ArH), 7.98 (S, 1H, ArH), 7.65 (S, 1H, ArH), 7.27-7.00 (m, 4H, ArH), 4.04 (S, 6H, - 0CH ₃ ) , 2.04 (S, 3H, - C3⁄4) . FABMS: (M+H) ⁺ =403 ₀ Example 6: N-(6-morpholinepropoxy Preparation of benzyl-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)-tert-butoxycarboxamide.

将 0.48克氢化钠（60%) (12毫摩尔）和 50毫升无水四氢呋喃置于 100毫升烧瓶中，搅拌下滴加 1.46克（10毫摩尔)对氟间氯苯胺溶于 10 毫升无水四氢呋喃的溶液，然后加热回流一小时，冷至室温，加入 2.6克（12毫摩尔）二叔丁氧甲酸酐，搅拌 0.5小时后再加热回流 14 小时，冷至室温，加入饱和氯化铵水溶液中和，用饱和碳酸氢钠洗涤，水洗，饱和盐溶液洗，无水硫酸钠干燥，旋去溶剂得到 N-叔丁氧甲酰基对氟间氯苯胺。 0.48 g of sodium hydride (60%) (12 mmol) and 50 ml of anhydrous tetrahydrofuran were placed in a 100 ml flask, and 1.46 g (10 mmol) of p-chloro-chloroaniline dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise with stirring. The solution was heated to reflux for one hour, cooled to room temperature, and then added to 2.6 g (12 mmol) of di-tert-butoxybenzoic anhydride. After stirring for 0.5 hour, it was heated to reflux for further 14 hours, cooled to room temperature, and neutralized with a saturated aqueous solution of ammonium chloride. Washed with saturated sodium bicarbonate, washed with water, washed with saturated brine and dried over anhydrous sodium sulfate.

将 247毫克（1毫摩尔） N-叔丁氧甲酰基对氟间氯苯胺和 338毫克 (1 毫摩尔）4-氯- 6-吗啉丙氧基 -7-甲氧基喹唑啉溶于 10 毫升无水 DMS0中，加入 48毫克 (60%) (1.2毫摩尔）氢化钠，40°C搅拌 30分钟，倾入冰冷的碳酸氢钠溶液中，乙酸乙酯萃取 2 次，碳酸氢钠溶液洗涤，水洗，饱和盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析分离得到 N - (6-吗啉丙氧基 -7-甲氧基喹唑啉 -4-基） -N- (3-氯- 4-氟苯基）叔丁氧基甲酰胺。熔点为： 144一 146°C。 ¾ MR(400M,CDC13),8 (ppm) 8.61 (S， 1H, ArH)， 8.04 (S， 1H, Aril) , 7.77 (S, 1H, ArH) , 7.12 (m, 2H， ArH) ， 6.92(m，lH， ArH) , 4.22 ( m, 2H, -0CH₂ ) , 3.96(S，3H， -0CH₃) ，3.72(m, 4H， - C 0CH₂- )， 2.51(m，6H， N_C ), 2.06 (m, 2H， - CH₂-)， 1.64(S, 9H, -CH₃) . FABMS: (M+H)⁺ 二 548。实施例 7: N- (6-吗啉丙氧基- 7-甲氧基喹唑啉 -4-基)- N- (3-氯- 4 -氟苯基)叔丁氧基甲酰胺的甲磺酸盐的制备 Dissolve 247 mg (1 mmol) of N-tert-butoxycarbonyl-decafluorochloroaniline and 338 mg (1 mmol) of 4-chloro-6-morpholinylpropoxy-7-methoxyquinazoline Add 10 mg of anhydrous DMS0, add 48 mg (60%) (1.2 mmol) of sodium hydride, stir at 40 ° C for 30 minutes, pour into ice-cold sodium bicarbonate solution, extract twice with ethyl acetate, sodium bicarbonate solution Washed, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated and evaporated. (3-Chloro-4-fluorophenyl) tert-butoxycarboxamide. The melting point is: 144 to 146 ° C. 3⁄4 MR (400M, CDC13), 8 (ppm) 8.61 (S, 1H, ArH), 8.04 (S, 1H, Aril), 7.77 (S, 1H, ArH), 7.12 (m, 2H, ArH), 6.92 ( m,lH, ArH) , 4.22 ( m, 2H, -0CH ₂ ) , 3.96 (S, 3H, -0CH ₃ ) , 3.72 (m, 4H, - C 0CH ₂ - ), 2.51 (m, 6H, N_C ) , 2.06 (m, 2H, - CH ₂ -), 1.64 (S, 9H, -CH ₃ ) . FABMS: (M+H) ⁺ two 548. Example 7: N-(6-morpholinepropoxy-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluoro Preparation of methanesulfonate salt of phenyl)tert-butoxyformamide

将 0.547 克（1 毫摩尔） N- (6-吗啉丙氧基- 7-甲氧基喹唑啉- 4 - 基) (3-氯- 4-氟苯基)叔丁氧基甲酰胺溶于 10毫升丙酮，冰浴搅拌下滴加 0.096克（1毫摩尔）甲磺酸,室温放置至结晶析出，滤出晶体。熔点： 170-172°Co ¾ NMR(400M, CD₃C0CD₃) , δ (ppm) 9.75 (S, 1Η， SOH) , 8.56 (S， 1Η, ArH)， 8.32 (m， 1H, ArH)， 8.07 (m， 2H, ArH) , 7.32 (m， 2H, ArH), 4.45 (m, 2H, 一 0C¾)， 3.99(m, 7H, — 0C¾， C — N— C¾)， 4.03 (m， 4H， - CH₂0C - )， 3.52 (m, 2H, N- C¾)， 2.84 (S, 3H， SC¾)， 2.46 (m, 2H, — C — )， 2.04 (S, 9H, — CH₃)。实施例 8: N-(6-吗啉丙氧基- 7-甲氧基喹唑啉 -4-基)- N-(3-氯 -4 -氟苯基）乙氧基甲酰胺的制备 0.547 g (1 mmol) of N-(6-morpholinyloxy-7-methoxyquinazolin-4-yl)(3-chloro-4-fluorophenyl)tert-butoxycarboxamide To 10 ml of acetone, 0.096 g (1 mmol) of methanesulfonic acid was added dropwise with stirring in an ice bath, and the mixture was allowed to stand at room temperature to crystallize, and crystals were filtered. Melting point: 170-172°Co 3⁄4 NMR (400M, CD ₃ C0CD ₃ ) , δ (ppm) 9.75 (S, 1Η, SOH), 8.56 (S, 1Η, ArH), 8.32 (m, 1H, ArH), 8.07 (m, 2H, ArH), 7.32 (m, 2H, ArH), 4.45 (m, 2H, 0C3⁄4), 3.99(m, 7H, — 0C3⁄4, C — N— C3⁄4), 4.03 (m, 4H, - CH ₂ 0C - ), 3.52 (m, 2H, N- C3⁄4), 2.84 (S, 3H, SC3⁄4), 2.46 (m, 2H, - C — ), 2.04 (S, 9H, — CH ₃ ). Example 8: Preparation of N-(6-morpholinepropoxy-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)ethoxyformamide

将 0.48克氢化钠 (60%) (12毫摩尔)和 50毫升无水四氢呋喃置于 100毫升烧瓶中，搅拌下滴加 1.46克（10毫摩尔)对氟间氯苯胺溶于 10 毫升无水四氢呋喃的溶液，然后加热回流一小时，冷至室温，加入 1.95克（12毫摩尔）二乙氧甲酸酐，搅拌 0.5小时后再加热回流 11小时，冷至室温，加入饱和氯化铵水溶液中和，用饱和碳酸氢钠洗涤，水洗，饱和盐溶液洗，无水硫酸钠干燥，旋去溶剂得到 N-乙氧甲酰基对氟间氯苯胺。 ' 0.48 g of sodium hydride (60%) (12 mmol) and 50 ml of anhydrous tetrahydrofuran were placed in a 100 ml flask, and 1.46 g (10 mmol) of p-chloro-chloroaniline dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise with stirring. The solution was heated to reflux for one hour, cooled to room temperature, then added with 1.95 g (12 mmol) of diethoxytoic anhydride, stirred for 0.5 hour and then heated to reflux for 11 hours, cooled to room temperature, and neutralized with a saturated aqueous solution of ammonium chloride. It was washed with saturated sodium hydrogencarbonate, washed with water, washed with brine and dried over anhydrous sodium sulfate. '

将 217毫克（1毫摩尔） N-乙氧甲酰基对氟间氯苯胺和 338毫克（1 毫摩尔）4-氯- 6-吗啉丙氧基 -7-甲氧基喹唑啉溶于 10毫升无水 DMS0 中，加入 48毫克（60%) (1.2毫摩尔）氢化钠，搅拌 20分钟，倾入冰冷的碳酸氢钠溶液中，乙酸乙酯萃取 2次，碳酸氢钠溶液洗涤，水洗，饱和盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析分离得到 N- (6 -吗啉丙氧基- 7-甲氧基喹唑啉 -4 -基） -N- (3-氯- 4-氟苯基）乙氧基甲酰胺。熔点为： 150-151.5°Co 丽 R(300M,CDC13)，5 (ppm) 8.64 (S, 1H， ArH)， 8.06(S，1H， ArH)， 7.76 (S, 1H, ArH) ， 7.14 (dd， 1H， ArH) ， 7.08 (d， lH， ArH) ,6.92 (m, 1H, ArH) ， 4.50 (q，2H，一 0CH₂) ， 4.22 ( t， 2H， -0CH₂), 3, 95 (S， 3H， - 0CH₃)， 3.71 (m， 4H, - C¾0C - )， 2.54 (t， 2H_: N— C )， 2.47 (t,4H, N-CH₂) , 2.07 (m, 2H, — C — ), 1.45 (S, 3H, —C¾) . FABMS: (M+H) ⁺ = 519。实施例 9: N- (6-吗啉丙氧基- 7-甲氧基喹唑啉 -4-基)- N-(3-氯- 4-氟苯基)异丁氧基甲酰胺的制备 217 mg (1 mmol) of N-ethoxycarbonyl p-fluoro-chloroaniline and 338 mg (1 mmol) of 4-chloro-6-morpholinylpropoxy-7-methoxyquinazoline were dissolved in 10 Add 48 mg (60%) (1.2 mmol) of sodium hydride in ML of anhydrous DMS0, stir for 20 minutes, pour into ice-cold sodium bicarbonate solution, extract twice with ethyl acetate, wash with sodium bicarbonate solution, and wash with water. Wash with saturated brine, dry over anhydrous sodium sulfate, and then remove the solvent and elute to give N-(6-morpholinyloxy-7-methoxyquinazolin-4-yl)-N- (3-chloro - 4-fluorophenyl) ethoxyformamide. Melting point: 150-151.5°Co R (300M, CDC13), 5 (ppm) 8.64 (S, 1H, ArH), 8.06(S,1H, ArH), 7.76 (S, 1H, ArH) , 7.14 (dd , 1H, ArH) , 7.08 (d, lH, ArH) , 6.92 (m, 1H, ArH) , 4.50 (q, 2H, 0CH ₂ ) , 4.22 ( t, 2H, -0CH ₂ ), 3, 95 ( S, 3H, - 0CH ₃ ), 3.71 (m, 4H, - C3⁄40C - ), 2.54 (t, 2H _: N- C ), 2.47 (t,4H, N-CH ₂ ) , 2.07 (m, 2H, — C — ), 1.45 (S, 3H, —C3⁄4) . FABMS: (M+H) ⁺ = 519. Example 9: N-(6-morpholinepropoxy-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluoro Preparation of phenyl)isobutoxycarboxamide

将 0.48克氢化钠（60%) (12毫摩尔)和 50毫升无水四氢呋喃置于 100毫升烧瓶中，搅拌下滴加 1.46克（10毫摩尔)对氟间氯苯胺溶于 10 毫升无水四氢呋喃的溶液，然后加热回流一小时，冷至室温，加入 2.62克（12毫摩尔）二异丁氧甲酸酐，搅拌 0.5小时后再加热回流 12 小时，冷至室温，加入饱和氯化铵水溶液中和，用饱和碳酸氢钠洗涤，水洗，饱和盐溶液洗，无水硫酸钠干燥，旋去溶剂得到 N-异丁氧甲酰基对氟间氯苯胺。 0.48 g of sodium hydride (60%) (12 mmol) and 50 ml of anhydrous tetrahydrofuran were placed in a 100 ml flask, and 1.46 g (10 mmol) of p-chloro-chloroaniline dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise with stirring. The solution was heated to reflux for one hour, cooled to room temperature, 2.62 g (12 mmol) of diisobutoxyaldehyde anhydride was added, stirred for 0.5 hour, then heated to reflux for 12 hours, cooled to room temperature, and neutralized with saturated aqueous ammonium chloride. Washed with saturated sodium bicarbonate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated.

将 246毫克（1毫摩尔） N-异丁氧甲酰基对氟间氯苯胺和 338毫克 (1 毫摩尔）4-氯 -6-吗啉丙氧基 -7-甲氧基喹唑啉溶于 10 毫升无水 DMS0中, 加入 48毫克（60%) (1.2毫摩尔）氢化钠，搅拌 30分钟，倾入冰冷的碳酸氢钠溶液中，乙酸乙酯萃取 2次，碳酸氢钠溶液洗涤，水洗，饱和盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析分离得到 N- (6-吗啉丙氧基- 7-甲氧基喹唑啉 -4-基)- N- (3-氯- 4-氟苯基）异丁氧基甲酰胺。熔点为： 105.1-105.9°Co ^NMROOOM, CDC13),5 (ppm) 8.66(S，1H， ArH), 8.08(S，1H， ArH), 7.76 (S, 1H, ArH), 7.13 (dd, 1H, ArH) , 7.10 (dd, 1H, ArH) , 6.92(m, 1H, ArH) ， 4.21 (d，2H，— 0CH₂) , 4.22 ( t， 2H， -0C ) ,3.95 (S， 3H，— 0C¾ ) ， 3.71 (m， 4H，一 C 0C¾— )， 2.54 (t， 2H， N-CH₂)， 2.47 (t， 4H, N- CH₂)， 2.07 (m， 3H， -CH- - C -) , 1.03(S，3H， - C )， 1.01 (S， 3H， - CH₃) . FABMS: (M+H)⁺ = 548₀ 实施例 10: N-(6-吗啉丙氧基 -7-甲氧基喹唑啉 -4-基) -N-(3-氯 -4 -氟苯基)苄氧基甲酰胺的制备 246 mg (1 mmol) of N-isobutoxycarbonyl p-fluoro-chloroaniline and 338 mg (1 mmol) of 4-chloro-6-morpholinepropoxy-7-methoxyquinazoline were dissolved. In 10 ml of anhydrous DMS0, add 48 mg (60%) (1.2 mmol) of sodium hydride, stir for 30 minutes, pour into ice-cold sodium bicarbonate solution, extract twice with ethyl acetate, wash with sodium bicarbonate solution, wash with water Washed with saturated brine, dried over anhydrous sodium sulfate, EtOAc evaporated Chloro-4-fluorophenyl)isobutoxyformamide. Melting point: 105.1-105.9°Co ^NMROOOM, CDC13),5 (ppm) 8.66 (S,1H, ArH), 8.08 (S,1H, ArH), 7.76 (S, 1H, ArH), 7.13 (dd, 1H , ArH) , 7.10 (dd, 1H, ArH) , 6.92 (m, 1H, ArH) , 4.21 (d, 2H, - 0CH ₂ ) , 4.22 ( t, 2H, -0C ) , 3.95 (S, 3H, - 0C3⁄4 ) , 3.71 (m, 4H, a C 0C3⁄4 — ), 2.54 (t, 2H, N-CH ₂ ), 2.47 (t, 4H, N- CH ₂ ), 2.07 (m, 3H, -CH- - C -) , 1.03 (S, 3H, - C ), 1.01 (S, 3H, - CH ₃ ) . FABMS: (M+H) ⁺ = 548 ₀ Example 10: N-(6-morpholinepropoxy- Preparation of 7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)benzyloxycarboxamide

将 0.48克氢化钠（60%) (12毫摩尔）和 50毫升无水四氢呋喃置于 100毫升烧瓶中，搅拌下滴加 1.46克（10毫摩尔)对氟间氯苯胺溶于 10 毫升无水四氢呋喃的溶液，然后加热回流一小时，冷至室温，加入 3.43克（12毫摩尔）二苄氧甲酸酐，搅拌 0.5小时后再加热回流 8小时，冷至室温，加入饱和氯化铵水溶液中和，用饱和碳酸氢钠洗涤，水洗，饱和盐溶液洗，无水硫酸钠干燥，旋去溶剂得到 N-苄氧甲酰基对氟间氯苯安。 0.48 g of sodium hydride (60%) (12 mmol) and 50 ml of anhydrous tetrahydrofuran were placed in a 100 ml flask, and 1.46 g (10 mmol) of p-chloro-chloroaniline dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise with stirring. The solution is then heated to reflux for one hour, cooled to room temperature, added 3.43 g (12 mmol) of dibenzyloxyl anhydride, stirred for 0.5 hours, then heated to reflux for 8 hours, cooled to room temperature, neutralized with a saturated aqueous solution of ammonium chloride, washed with saturated sodium hydrogen carbonate, washed with water, and washed with saturated salt. After drying over anhydrous sodium sulfate, the solvent was evaporated to give N-benzyloxycarbonyl.

将 286毫克（1毫摩尔） N-苄氧甲酰基对氟间氯苯胺和 338毫克（1 毫摩尔）4-氯 -6-吗啉丙氧基 -7-甲氧基喹唑啉溶于 10毫升无水 DMS0 中，加入 48毫克（60%) (1.2毫摩尔）氢化钠，搅拌 50分钟，倾入冰冷的碳酸氢钠溶液中，乙酸乙酯萃取 2次，碳酸氢钠溶液洗涤，水洗，饱和盐水洗涤，无水硫酸钠干燥，旋去溶剂，柱层析分离得到 N-(6-吗啉丙氧基 -7-甲氧基喹唑啉 -4-基) - N- (3-氯 -4-氟苯基）苄氧基甲酰胺。熔点为：176.5-178.6° C₀ NMR(300M， CDC1₃) , δ (ppm) 8.63 (S, 1Η, ArH) ， 7.91(m，lH， ArH) , 7.57 (S, 1H, ArH) , 7.36 (m， 5H， ArH) ， 7.23 (s，lH， ArH) ,7.22 (s, ΙΗ,ΑΓΗ)， 7.13 (t, 1H, ArH)， 5.17 (s, 2H, 0C¾)， 4.20 (t, 2H, 0CH₂), 3.98 (S， 3H， 0CH₃)， 3.74(t,4H, CH₂0CH₂) _; 2.60 (t, 2H, N-CH₂), 2.52(t，4H， N—CH₂)， 2.12 (m， 2H, CH₂) . FABMS: (M+H)' = 582。药理实验 286 mg (1 mmol) of N-benzyloxycarbonyl p-fluoro-chloroaniline and 338 mg (1 mmol) of 4-chloro-6-morpholinepropoxy-7-methoxyquinazoline were dissolved in 10 Add 48 mg (60%) (1.2 mmol) of sodium hydride in ML of anhydrous DMS0, stir for 50 minutes, pour into ice-cold sodium bicarbonate solution, extract twice with ethyl acetate, wash with sodium bicarbonate solution, and wash with water. Wash with saturated brine, dry over anhydrous sodium sulfate, EtOAc (EtOAc) 4-fluorophenyl)benzyloxycarboxamide. Melting point: 176.5-178.6° C ₀ NMR (300M, CDC1 ₃ ), δ (ppm) 8.63 (S, 1Η, ArH), 7.91 (m, lH, ArH), 7.57 (S, 1H, ArH), 7.36 ( m, 5H, ArH) , 7.23 (s,lH, ArH) , 7.22 (s, ΙΗ, ΑΓΗ), 7.13 (t, 1H, ArH), 5.17 (s, 2H, 0C3⁄4), 4.20 (t, 2H, 0CH ₂ ), 3.98 (S, 3H, 0CH ₃ ), 3.74 (t, 4H, CH ₂ 0CH ₂ ) _; 2.60 (t, 2H, N-CH ₂ ), 2.52 (t, 4H, N-CH ₂ ), 2.12 (m, 2H, CH ₂ ) . FABMS: (M+H)' = 582. Pharmacological experiment

体外 MTT法： In vitro MTT method:

将细胞培养在含 10%小牛血清的 RPMI1640培养基中，内含青霉素 100U/ml，链霉素 10(^g/ml，于 37°C、 5%C02培养箱中传代培养。 The cells were cultured in RPMI1640 medium containing 10% calf serum, containing penicillin 100 U/ml, streptomycin 10 (^g/ml, subcultured in a 37 ° C, 5% CO 2 incubator.

取 0.3%胰酶消化贴壁的肿瘤细胞，含 10%小牛血清的 RPMI1640 培养液配制细胞悬液，浓度为 6X10³个细胞 /毫升。于 96孔培养板内每孔接种 200微升（含 1000个肿瘤细胞）， 37°C培养 24小时。给药组加入含有不同浓度药物，每药设 4一 5个剂量组，每组设三个平行孔。对照组加入与药等体积的溶剂。置于 37° (、 5%C02培养箱中培养 4天后弃去培养液，每孔加入 200微升 0.2%MTT溶液（RPMI1640 配制）。 37° C保温 4小时，弃去上层清液，每孔加入 DMS0150微升溶解 Formazon颗粒，轻度振荡后，用酶标仪，在参考波长 450nm、检测波长 570nm条件下测定光密度值（0D)。 SU5271为阳性对照药。 The adherent tumor cells were digested with 0.3% trypsin, and the cell suspension was prepared in RPMI1640 medium containing 10% calf serum at a concentration of 6×10 ³ cells/ml. 200 μl (containing 1000 tumor cells) per well was seeded in a 96-well culture plate, and cultured at 37 ° C for 24 hours. The drug-administered group was added with different concentrations of drugs, and each drug was set to 4 to 5 dose groups, and each group was provided with three parallel holes. The control group was added with an equal volume of solvent. After being placed at 37 ° (4 days in 5% CO 2 incubator, discard the culture solution, add 200 μl of 0.2% MTT solution (RPMI1640) per well. Incubate at 37 ° C for 4 hours, discard the supernatant, each well DMS0150 μl of dissolved Formazon particles were added, and after light shaking, the optical density value (0D) was measured with a microplate reader at a reference wavelength of 450 nm and a detection wavelength of 570 nm. SU5271 was a positive control drug.

结果计算- 以溶剂对照处理的肿瘤细胞为对照组，求药物对肿瘤细胞的抑制率。 W 对照组平均 0D值一给药组平均 0D值 Results Calculation - Tumor cells treated with solvent control were used as a control group to determine the inhibition rate of the drug on tumor cells. W control group average 0D value - administration group average 0D value

肿瘤细胞抑制率二 X 100% Tumor cell inhibition rate II X 100%

对照组平均 0D值 Average 0D value of the control group

以药物的不同浓度及对细胞的抑制率作图可得到剂量反应曲线，从中求出药物的半数抑制度（IC₅。）本发明化合物对不同癌细胞株的 IG 化合物 HT-29 Hela A2780 The dose response curve can be obtained by plotting the different concentrations of the drug and the inhibition rate of the cells, and the half-inhibition degree of the drug is determined therefrom (IC ₅ ). The IG compound HT-29 Hela A2780 of the compound of the present invention for different cancer cell lines.

实施例 1 4. 8 X 10"⁶ 5. 6 X 10—⁶ 4. 1 X 10'⁶ Example 1 4. 8 X 10" ⁶ 5. 6 X 10 - ⁶ 4. 1 X 10' ⁶

SU5271 1. 4 X 10—⁵ 5. O X 10一 ⁶ 6. 7 X 10"⁶ 体内植入肿瘤法： SU5271 1. 4 X 10— ⁵ 5. OX 10-6 ⁶ 7. 7 X 10" ^{6 In} vivo Implantation Tumor Method:

选择肿瘤生长旺盛且无溃破的荷瘤裸鼠，在无菌条件下，将瘤组织剪成 1. 5mm³左右，接种于裸鼠一侧腋窝皮下。实验设阴性对照组、受试药 2mg/kg、阳性药 2mg/kg三个不同剂量的治疗组，每组四只鼠。当移植瘤体积生长至约 120皿 ³时分组并开始给药。均为腹腔注射给药。受试药和阳性药注射每日一次，每周六次，共给药 18 次。给药体积均为 2mg/kg体重。每周两次测瘤径，计算相对瘤体积，同时称体重。末次给药后 24小时，颈椎脱臼处死动物，称体重、瘤重，计算肿瘤抑制率，进行疗效评价。相对瘤体积（mm³) = 1 / 2a²b (a为宽， b 为长）。本发明化合物对人卵巢癌 A2780在裸鼠异体移植生长抑制作用组别剂量体重（克）瘤体积瘤重 The tumor-bearing nude mice with strong tumor growth and no ulceration were selected, and the tumor tissue was cut into 1. 5 mm ³ under sterile conditions, and inoculated into the axilla of one side of the nude mouse. The experiment was divided into three groups: the negative control group, the test drug 2mg/kg, and the positive drug 2mg/kg three different doses of the treatment group, four mice in each group. When the transplanted tumor volume grew to about 120 dishes ³ , the cells were grouped and started to be administered. All were administered by intraperitoneal injection. The test drug and the positive drug were injected once a day, and the drug was administered 18 times a week. The administration volume was 2 mg/kg body weight. The tumor diameter was measured twice a week, the relative tumor volume was calculated, and the body weight was also weighed. At 24 hours after the last administration, the animals were sacrificed by cervical dislocation, and the body weight and tumor weight were weighed. The tumor inhibition rate was calculated and evaluated for efficacy. Relative tumor volume (mm ³ ) = 1 / 2a ² b (a is wide and b is long). Inhibitory effect of the compound of the present invention on human ovarian cancer A2780 in nude mouse xenograft growth group dose body weight (g) tumor volume tumor weight

(rag/kg) 始末 (mm³) 抑瘤率 (g) 空白对照 24 27. 5 3536. 91 3 (rag/kg) beginning and end (mm ³ ) tumor inhibition rate (g) blank control 24 27. 5 3536. 91 3

实施例 1 2 21. 75 23. 17 101. 0415 97. 14% 0. 10 96. 67%Example 1 2 21. 75 23. 17 101. 0415 97. 14% 0. 10 96. 67%

SU5271 2 23 24. 67 ' 247. 16 93. 01% 0. 187 93. 78% 本发明化合物对小鼠*** U14生长的影响

SU5271 2 23 24. 67 ' 247. 16 93. 01% 0. 187 93. 78% Effect of the compound of the present invention on the growth of mouse cervical cancer U14

空白对照一 11/11 21.45+8.45 4.73+1.73 一一环磷酰胺 60x1 10/10 22.50+6.70 1.72+0.98 64 <0.001 实施例 1 2 6/6 20.33+7.84 1.69±1.30 64 >0.05 Blank control A 11/11 21.45+8.45 4.73+1.73 One one cyclophosphamide 60x1 10/10 22.50+6.70 1.72+0.98 64 <0.001 Example 1 2 6/6 20.33+7.84 1.69±1.30 64 >0.05

SU5271 2 6/6 21.67+8.00 4.31+1.48 9 <0.05SU5271 2 6/6 21.67+8.00 4.31+1.48 9 <0.05

SU5271为阳性对照药。本发明化合物对人肺癌 A549裸鼠异体移植瘤的生长抑制作用剂肿瘤体积瘤重组别 SU5271 is a positive control drug. Growth inhibitory effect of the compound of the present invention on human lung cancer A549 xenograft tumor in nude mice

(mg/kg) (mm ) 抑制率 (g) 抑制率空白对照 694.2±461.4 0.55 ±0.36 (mg/kg) (mm) inhibition rate (g) inhibition rate blank control 694.2 ± 461.4 0.55 ± 0.36

Iressa 75mg/kg*10 167.5± 141.6 75.9% 0.16±0.12 71.2% 实施例 6 37.5mg kg*10 137.9+ 148.7* 80.1% 0.16±0.11 * 71.3% 实施例 6 75mg/kg*10 103.5 ±71.8* 85.1% 0.13 + 0.14* 76.2% Iressa 75 mg/kg*10 167.5± 141.6 75.9% 0.16±0.12 71.2% Example 6 37.5 mg kg*10 137.9+ 148.7* 80.1% 0.16±0.11 * 71.3% Example 6 75 mg/kg*10 103.5 ±71.8* 85.1% 0.13 + 0.14* 76.2%

Iressa为阳性对照药， *P〈0. 05 与对照组比较。 Iressa was a positive control drug, *P<0.05 compared with the control group.

本发明化合物对人非小细胞肺癌 H520裸鼠异体移植瘤的生长抑制作用肿瘤体积瘤重剂量 Growth inhibitory effect of the compound of the present invention on human non-small cell lung cancer H520 xenograft tumor in nude mice tumor volume tumor weight dose

组别 Group

(mg/kg) (mm ) 抑制率 (g) (mg/kg) (mm) inhibition rate (g)

抑制率空白对照 2005.2± 820.7 1.79 ±0.61 Inhibition rate blank control 2005.2± 820.7 1.79 ±0.61

Iressa 50mg/kgX 17days 953.0±291.3 52.47% 0.93 +0.27 48.0% 实施例 6小 25mg/kg 17days 934. 5 ±482.9 53.39% 0.78+0.53 56.6% 实施例 6中 50mg/kgX 17days 901.9±353.9 55.02% 0.92±0.37 48.3% 实施例 6大 100mg/kgX 17days 757.7±485.7 62.21% 0.62+0.46 65.1% Iressa 50mg/kgX 17days 953.0±291.3 52.47% 0.93 +0.27 48.0% Example 6 small 25mg/kg 17days 934. 5 ±482.9 53.39% 0.78+0.53 56.6% Example 6 50mg/kgX 17days 901.9±353.9 55.02% 0.92± 0.37 48.3% Example 6 Large 100mg/kgX 17days 757.7±485.7 62.21% 0.62+0.46 65.1%

Claims

权利要求 Rights request

1、通式（I)所示的化合物，及其药用盐、水合物、溶剂化物，单晶型和多晶型 1. A compound of the formula (I), and pharmaceutically acceptable salts, hydrates, solvates thereof, single crystal type and polymorph

和分别独立的选自氢，甲基，乙基， 2-甲氧基乙基， 3-甲氧基丙基， 4-甲氧基丁基, 2-乙氧基乙基, 3-乙氧基丙基，（N-甲基哌啶- 4-) 甲基， 4-乙氧基丁基，三氟甲基， 2,2,2-三氟乙基， 2-羟基乙基， 3-羟基丙基， 4-羟基丁基， 2-(N,N-二甲基氨基)乙基， 3-(N,N-二甲氨基)丙基，

And independently selected from the group consisting of hydrogen, methyl, ethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 2-ethoxyethyl, 3-ethoxy Propyl, (N-methylpiperidin-4-yl)methyl, 4-ethoxybutyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3- Hydroxypropyl, 4-hydroxybutyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl,

4- (N,N-二甲氨基)丁基, 2-吗啉代乙基， 3-吗啉代丙基， 4-吗啉代丁基，4-(N,N-dimethylamino)butyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl,

5-吗啉代戊基， 2-哌啶子基乙基， 3-哌啶子基丙基， 4-哌啶子基丁基， 5-哌啶子基戊基， 2- (哌嗪 -1-基)乙基， 3- (哌嗪 -1-基)丙基， 4- (哌嗪 -1-基) 丁基, 2-(4-甲基哌嗪小基)乙基, 3-(4-甲基哌嗪- 1-基)丙基， 4-(4-甲基哌嗪 -1-基)丁基， 2-(2-甲磺酰基乙氧基)乙基， 2-(2-甲磺酰基乙胺基)乙基， 2-(2-甲磺酰基乙巯基)乙基, 2-吡咯垸子基乙基, 3-吡咯烷子基丙基, 4-吡咯烷子基丁基， 2-(2-氧代吡咯綜子基)乙基， 3-(2-氧代吡咯烷子基)丙基, 4_(2-氧代吡咯烷子基)丁基， 2- (咪唑 -1-基) -乙基， 3- (咪唑 -1-基)-丙基， 4- (咪唑 -1-基) -丁基， 2- (二烷氨基)乙基， 3- (二垸氨基)丙基， 4- (二烷氨基) 丁基， 2- (取代苯甲酰氨基)乙基， 3- (取代苯甲酰氨基)丙基， 4- (取代苯甲酰氨基)丁基, 2-甲磺酰氨基乙基, 3-甲磺酰氨基丙基, 4-甲磺酰氨基丁基, 2-苯磺酰氨基乙基， 3-苯磺酰氨基丙基， 4-苯磺酰氨基丁基， 2-氨磺酰基乙基, 3-氨磺酰基丙基， 4-氨磺酰基丁基； 5-morpholinopentyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 5-piperidinopentyl, 2-(piperazine- 1-yl)ethyl, 3-(piperazin-1-yl)propyl, 4-(piperazin-1-yl)butyl, 2-(4-methylpiperazine small)ethyl, 3- (4-methylpiperazine-1-yl)propyl, 4-(4-methylpiperazin-1-yl)butyl, 2-(2-methanesulfonylethoxy)ethyl, 2-( 2-methanesulfonylethylamino)ethyl, 2-(2-methanesulfonylethyl)ethyl, 2-pyrrolidinylethyl, 3-pyrrolidinylpropyl, 4-pyrrolidinyl Butyl, 2-(2-oxopyrrolidino)ethyl, 3-(2-oxopyrrolidino)propyl, 4-(2-oxopyrrolidino)butyl, 2-( Imidazol-1-yl)-ethyl, 3-(imidazol-1-yl)-propyl, 4-(imidazol-1-yl)-butyl, 2-(dialkylamino)ethyl, 3- (two Amidinoamino)propyl, 4-(dialkylamino)butyl, 2-(substituted benzoylamino)ethyl, 3-(substituted benzoylamino)propyl, 4-(substituted benzoylamino)butyl Base, 2-methanesulfonylaminoethyl, 3-methanesulfonylaminopropyl, 4-methanesulfonylaminobutyl, 2-benzenesulfonylaminoethyl, 3-benzenesulfonylaminopropyl 4-benzenesulfonylamino-butyl, 2-sulfamoylethyl, 3-sulfamoyl-propyl, butyl 4-sulfamoyl;

R3选自为甲基，乙基，正丙基， 3-羟基丙基， 4-羟基丁基， 3- 乙酰氧丙基， 4-乙酰氧丁基，甲氧基，乙氧基，正丙氧基，异丙氧基，叔丁氧基，乙酰氧甲氧基，叔丁酰氧甲氧基，苄氧基， 3-氟苄氧基， 2- 吗啉代乙氧基， 3-吗啉代丙氧基， 4-吗啉代丁氧基， 2-哌啶子基乙氧基， 3-哌啶子基丙氧基， 4-哌啶子基丁氧基， 2- (哌嗪 -1-基)乙氧基， 3- (哌嗪 -1-基)丙氧基， 4 - (哌嗪小基)丁氧基, 2-(4-甲基哌嗪 -1-基)乙氧基, 3-(4-甲基哌嗪 -1-基)丙氧基, 4-(4-甲基哌嗪- 1-基)丁氧基， 2-吡咯烷子基乙氧基, 3-吡咯烷子基丙氧基, 4-吡咯烷子基丁氧基, 2-(2-氧代吡咯烷子基)乙氧基， 3-(2-氧代吡咯烷子基)丙氧基， 4-(2-氧代吡咯垸子基) 丁氧基，2- (咪唑小基) -乙氧基， 3- (咪唑 -1-基) -丙氧基，苯甲酰氧甲氧基； R4选自单取代或多取代的苯基，单取代或多取代的苄基，单取代或多取代的苯甲酰基，单取代或多取代的苯磺酰基；取代基选自卤素，甲基，三氟甲基，羟甲基，羟基，硝基，氰基，氨基，取代的氨基，酰氨基，羧基，酯基，氨酰基，烷氧基，烷酰氧基，烯基，卤代苄氧基，卤代苄氨基，卤代苯氧基，卤代苯氨基。、根据权利要求 1的化合物，其特征在于， R3 is selected from the group consisting of methyl, ethyl, n-propyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-acetoxypropyl, 4-acetoxybutyl, methoxy, ethoxy, n-propyl Oxy, isopropoxy, tert-butoxy, acetoxymethoxy, tert-butyryloxymethoxy, benzyloxy, 3-fluorobenzyloxy, 2-morpholinoethoxy, 3-? Olinylpropoxy, 4-morpholinobutoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, 2-(piperazine) -1-yl)ethoxy, 3-(piperazin-1-yl)propoxy, 4-(piperazinyl)butoxy, 2-(4-methylpiperazin-1-yl) Oxy, 3-(4-methylpiperazin-1-yl)propoxy, 4-(4-methylpiperazine-1-yl)butoxy, 2-pyrrolidinylethoxy, 3 -pyrrolidinopropoxy, 4-pyrrolidinylbutoxy, 2-(2-oxopyridinyl P-alkylene)ethoxy, 3-(2-oxopyrrolidino)propoxy, 4-(2-oxopyrrolidino)butoxy, 2-(imidazolyl)-B Oxyl, 3-(imidazol-1-yl)-propoxy, benzoyloxymethoxy; R4 selected from mono- or polysubstituted phenyl, mono- or poly-substituted benzyl, monosubstituted or poly Substituted benzoyl, monosubstituted or polysubstituted benzenesulfonyl; substituent selected from halogen, methyl, trifluoromethyl, hydroxymethyl, hydroxy, nitro, cyano, amino, substituted amino, acylamino , carboxyl group, ester group, aminoacyl group, alkoxy group, alkanoyloxy group, alkenyl group, halobenzyloxy group, halobenzylamino group, halophenoxy group, halophenylamino group. The compound according to claim 1, characterized in that

和分别独立的选自甲基，乙基， 2-甲氧基乙基， 3-甲氧基丙基， 2-乙氧基乙基, 3-乙氧基丙基，三氟甲基，（N-甲基哌啶- 4-)甲基， And independently selected from methyl, ethyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, trifluoromethyl, ( N-methylpiperidine 4- 4-methyl,

2-羟基乙基， 3-羟基丙基， 2-(N，N-二甲基氨基)乙基， 3-(N,N-二甲氨基)丙基， 2-吗啉代乙基， 3-吗啉代丙基， 2-哌啶子基乙基， 3-哌啶子基丙基， 2- (哌嗪 -1-基)乙基, 3- (哌嗪 -1-基)丙基, 2-(4-甲基哌嗪 -1-基）乙基, 3-(4-甲基哌嗪- 1-基)丙基， 2-(2-甲磺酰基乙氧基)乙基, 2-(2-甲磺酰基乙氨基)乙基, 2-(2-甲磺酰基乙巯基)乙基, 2-吡咯烷子基乙基, 3- 吡咯烷子基丙基, 2-(2-氧代吡咯烷子基)乙基, 3-(2-氧代吡咯烷子基)丙基， 2- (咪唑 -1-基) -乙基， 3- (咪唑 -1-基) -丙基, 2- (二烷氨基)乙基, 3- (二烷氨基)丙基， 3-甲磺酰氨基丙基, 4-甲磺酰氨基丁基， 2-氨磺酰基乙基, 3- 氨磺酰基丙基； 2-hydroxyethyl, 3-hydroxypropyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3 -morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl , 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazine-1-yl)propyl, 2-(2-methanesulfonylethoxy)ethyl, 2-(2-methanesulfonylethylamino)ethyl, 2-(2-methanesulfonylethyl)ethyl, 2-pyrrolidinylethyl, 3-pyrrolidinylpropyl, 2-(2 -oxopyrrolidino)ethyl, 3-(2-oxopyrrolidino)propyl, 2-(imidazol-1-yl)-ethyl, 3-(imidazol-1-yl)-propan Base, 2-(dialkylamino)ethyl, 3-(dialkylamino)propyl, 3-methanesulfonylaminopropyl, 4-methanesulfonylaminobutyl, 2-sulfamoylethyl, 3- Sulfonyl propyl group;

R3选自甲基，正丙基， 3-羟基丙基， 4-羟基丁基， 3-乙酰氧丙基， 4-乙酰氧丁基，甲氧基，乙氧基，异丙氧基，叔丁氧基，叔丁酰氧甲氧基，乙酰氧甲氧基，苄氧基， 3-氟苄氧基， 2-吗啉代乙氧基， 3-吗啉代丙氧基， 2-哌啶子基乙氧基， 3-哌啶子基丙氧基， 2- (哌嗪 -1-基）乙氧基, 3- (哌嗪 -1-基)丙氧基, 2-(4-甲基哌嗪 -1-基)乙氧基, 3-(4-甲基哌嗪 -1-基)丙氧基， 2-吡咯烷子基乙氧基， 3-吡咯烷子基丙氧基， 2- (2-氧代吡咯垸子基)乙氧基, 3-(2-氧代吡咯垸子基)丙氧基， 2- (咪唑 -1-基) -乙氧基, 3- (咪唑小基) -丙氧基，苯甲酰氧甲氧基； R3 is selected from the group consisting of methyl, n-propyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-acetoxypropyl, 4-acetoxybutyl, methoxy, ethoxy, isopropoxy, uncle Butoxy, tert-butyryloxymethoxy, acetoxymethoxy, benzyloxy, 3-fluorobenzyloxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piper Acridine ethoxy, 3-piperidinopropoxy, 2-(piperazin-1-yl)ethoxy, 3-(piperazin-1-yl)propoxy, 2-(4- Methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-pyrrolidinylethoxy, 3-pyrrolidinylpropoxy , 2-(2-oxopyrrolidino)ethoxy, 3-(2-oxopyrroltino)propoxy, 2-(imidazol-1-yl)-ethoxy, 3- ( Imidazolyl)-propoxy, benzoyloxymethoxy;

R4选自 3-溴苯基， 3-溴 -4-羟基苯基， 3-羟基苯基， 3-甲氧基苯基， 3-氰基苯基， 3， 5-二溴 -4-羟基苯基， 3-氯苯基， 3-氟苯基， 3-氯 -4-氟苯基， 3-甲基苯基， 2-氟 -4-溴苯基， 1-苯基乙基， 4-氨甲酰苯基， R4 is selected from the group consisting of 3-bromophenyl, 3-bromo-4-hydroxyphenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 3-cyanophenyl, 3,5-dibromo-4-hydroxyl Phenyl, 3-chlorophenyl, 3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-methylphenyl, 2-fluoro-4-bromophenyl, 1-phenylethyl, 4 - carbamoylphenyl,

3-烯基苯基， 3-炔基苯基， 2-甲基苯磺酰基， 3-氯 -4-(3-氟苄氧基)苯基， N-苄基异吲唑基， 4-氰基 -2-氟苯基， 3-羟基 -4-甲氧基苯基， 2， 4-二氟苯基， 2-氟 -4-甲氧基苯基。 3-alkenylphenyl, 3-alkynylphenyl, 2-methylbenzenesulfonyl, 3-chloro-4-(3-fluorobenzyloxy)phenyl, N-benzylisoxazolyl, 4- Cyano-2-fluorophenyl, 3-hydroxy-4-methoxyphenyl, 2,4-difluorophenyl, 2-fluoro-4-methoxyphenyl.

3、根据权利要求 2的化合物，其特征在于， 3. A compound according to claim 2, characterized in that

和选自甲基，乙基， 2-甲氧基乙基， 3-甲氧基丙基，（N -甲基哌啶 -4-)甲基， 2-乙氧基乙基, 3-乙氧基丙基, 2-(N,N-二甲基氨基）乙基， 3-(N,N-二甲氨基)丙基， 2-吗啉代乙基， 3-吗啉代丙基， 3-哌啶子基丙基， 3- (哌嗪 -1-基)丙基, 2-(4-甲基哌嗪 -1-基)乙基, 3-(4-甲基哌嗪 -1-基)丙基， 2-(2-甲磺酰基乙氧基)乙基, 2-(2-甲磺酰基乙氨基)乙基, 2-(2-甲磺酰基乙巯基)乙基； And selected from methyl, ethyl, 2-methoxyethyl, 3-methoxypropyl, (N-methylpiperidin-4-)methyl, 2-ethoxyethyl, 3-ethyl Oxypropyl, 2-(N,N-dimethylamino) Ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 3-piperidinopropyl, 3-(piperazin-1- Propyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 2-(2-methanesulfonylethoxy) Ethyl, 2-(2-methanesulfonylethylamino)ethyl, 2-(2-methanesulfonylethyl)ethyl;

R3选自正丙基， 3-乙酰氧丙基，甲氧基，异丙氧基，叔丁氧基，苄氧基， 2-吗啉代乙氧基， 3-吗啉代丙氧基， 3-哌啶子基丙氧基，叔丁酰氧甲氧基， 3- (哌嗪小基)丙氧基, 3-(4-甲基哌嗪 -1-基)丙氧基， 3-吡咯烷子基丙氧基, 3-(2-氧代吡咯烷子基)丙氧基, 3- (咪唑 -1-基) -丙氧基。乙酰氧甲氧基，异丁酰氧甲氧基，苯甲酰氧甲氧基； R3 is selected from the group consisting of n-propyl, 3-acetoxypropyl, methoxy, isopropoxy, tert-butoxy, benzyloxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 3-piperidinopropoxy, tert-butyryloxymethoxy, 3-(piperazinyl)propoxy, 3-(4-methylpiperazin-1-yl)propoxy, 3- Pyrrolidinopropoxy, 3-(2-oxopyrrolidino)propoxy, 3-(imidazol-1-yl)-propoxy. Acetoxymethoxy, isobutyryloxymethoxy, benzoyloxymethoxy;

R4选自 3-溴苯基， 3-溴 -4-羟基苯基， 3-羟基苯基， 3， 5-二溴 -4- 羟基苯基， 3-氯苯基， 3-氟苯基， 3-氯 -4-氟苯基， 3-甲基苯基， 2-氟 -4- 溴苯基， 1-苯基乙基， 2-甲基苯磺酰基， 3-氯 -4-(3-氟苄氧基)苯基。 R4 is selected from the group consisting of 3-bromophenyl, 3-bromo-4-hydroxyphenyl, 3-hydroxyphenyl, 3,5-dibromo-4-hydroxyphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-methylphenyl, 2-fluoro-4-bromophenyl, 1-phenylethyl, 2-methylbenzenesulfonyl, 3-chloro-4-(3 -fluorobenzyloxy)phenyl.

4、根据权利要求 3的化合物，其特征在于， 4. A compound according to claim 3, characterized in that

和分别独立的选自甲基， 2-甲氧基乙基，（N-甲基哌 -4-) 甲基， 3-吗啉代丙基； And independently selected from methyl, 2-methoxyethyl, (N-methylpiperidin-4-)methyl, 3-morpholinopropyl;

R3特别优选为甲氧基，异丙氧基，叔丁氧基，苄氧基， 2-吗啉代乙氧基， 3-吗啉代丙氧基， 3-哌啶子基丙氧基，叔丁酰氧甲氧基，乙酰氧甲氧基，苯甲酰氧甲氧基； R3 is particularly preferably methoxy, isopropoxy, tert-butoxy, benzyloxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 3-piperidinopropoxy, Tert-butyryloxymethoxy, acetoxymethoxy, benzoyloxymethoxy;

R4特别优选为 3-溴苯基， 3-溴 -4-羟基苯基， 3-羟基苯基， 3， 5- 二溴 -4-羟基苯基， 3-氯苯基， 3-氯 -4-氟苯基， 2-氟 -4-溴苯基。 R4 is particularly preferably 3-bromophenyl, 3-bromo-4-hydroxyphenyl, 3-hydroxyphenyl, 3, 5-dibromo-4-hydroxyphenyl, 3-chlorophenyl, 3-chloro-4 -fluorophenyl, 2-fluoro-4-bromophenyl.

5、根据权利要求 4的化合物，其特征在于， 5. A compound according to claim 4, characterized in that

R1和 R2选自甲基、（N-甲基哌啶 -4-)甲基， 3-吗啉代丙基； R1 and R2 are selected from the group consisting of methyl, (N-methylpiperidin-4-)methyl, 3-morpholinopropyl;

R3选自叔丁氧基、乙氧基、甲氧基、乙基、叔丁酰氧甲氧基； R4选自 3-溴苯基、 3-氯 -4-氟苯基、 2-氟 -4-溴苯基。 R3 is selected from the group consisting of tert-butoxy, ethoxy, methoxy, ethyl, t-butyryloxymethoxy; R4 is selected from 3-bromophenyl, 3-chloro-4-fluorophenyl, 2-fluoro- 4-bromophenyl.

6、根据权利要求 5的化合物，其特征在于，所述化合物选自 6. A compound according to claim 5 wherein said compound is selected from the group consisting of

N-(6,7-二甲氧基喹唑啉 -4-基) -N-(3-溴苯基)叔丁氧甲酰胺 N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)tert-butoxycarbonylamide

N-(6，7-二甲氧基喹唑啉 -4-基) -N-(3-溴苯基)乙氧甲酰胺 N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)ethoxyformamide

N-(6,7-二甲氧基喹唑啉 -4-基) -N-(3 -溴苯基)甲氧基甲酰胺

N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)methoxyformamide

N-(6,7-二甲氧基喹唑啉 -4- 基)叔丁氧基甲酰胺 N-(6,7-dimethoxyquinazolin-4-yl)-tert-butoxycarboxamide

N-(6,7-二甲氧基喹唑啉 -4-基) -N-(3-溴苯基)乙酰胺 N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)acetamide

_Ν-(6-吗啉丙氧基 -7-甲氧基喹唑啉 -4-基) -Ν-(3-氯 -4-氟苯基)叔丁氧基甲酰胺 _Ν- (6-morpholinepropoxy-7-methoxyquinazolin-4-yl)-indole-(3-chloro-4-fluorophenyl)-tert-butoxycarboxamide

N-(6-吗啉丙氧基 -7-甲氧基喹 ί -4-基) -Ν-(3-氯 -4-氟苯基)乙氧基甲酰胺

N-(6-morpholinepropoxy-7-methoxyquin-4-yl)-indole-(3-chloro-4-fluorophenyl)ethoxyformamide

_Ν_(6-吗啉丙氧基 -7-甲氧基喹唑啉 -4-基) -Ν-(3-氯 -4-氟苯基)异丁氧基甲酰胺

_Ν _ (6- morpholin-propoxy-7-methoxy-quinazolin-4-yl) -Ν- (3- chloro-4-fluorophenyl) isobutoxy carboxamide

_N_(6-吗啉丙氧基 -7-甲氧基喹唑啉 -4-基) -N-(3-氯 -4-氟苯基)苄氧基甲酰胺 _N _(6-morpholinepropoxy-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)benzyloxycarboxamide

N-(6-甲氧基 -7-(N-甲基哌啶 -4-甲氧基)喹唑啉 -4-基) -N-(2-氟— 4一溴苯基)叔丁氧基甲酰胺 N-(6-Methoxy-7-(N-methylpiperidin-4-methoxy)quinazolin-4-yl)-N-(2-fluoro-4-bromophenyl)-tert-butoxy Carboxamide

7、根据权利要求 1一 6的化合物，其特征在于，所述的药用盐是甲磺酸盐。 7. A compound according to claim 1 - 6, wherein the pharmaceutically acceptable salt is a methanesulfonate.

8、权利要求 1-7所述的化合物的制备方法，其特征在于，包括如下步骤-8. A method of preparing a compound according to any of claims 1-7, comprising the steps of -

A )取代的苯胺先与酰氯或酯或酐作用给出 N-取代的酰胺，A) the substituted aniline is first reacted with an acid chloride or ester or anhydride to give an N-substituted amide,

B )在碱存在下与 4位具有易离去基团的喹唑啉衍生物反应给出 4-酰氨基喹唑啉衍生物； B) reacting with a quinazoline derivative having an easily leaving group at the 4-position in the presence of a base to give a 4-acylaminoquinazoline derivative;

其中 X是易离去基团

Where X is an easy leaving group

9、根据权利要求 8的制备方法，其特征在于，所述的易离去基团 X包括卤素取代基、酰氧基、磺酰氧基。 The process according to claim 8, wherein the easily-releasing group X comprises a halogen substituent, an acyloxy group, a sulfonyloxy group.

10、一种药物组合物，其特征在于，含有药物有效剂量的如权利要求 1-7所述的任一化合物及药用载体。 10. A pharmaceutical composition comprising a pharmaceutically effective amount of any of the compounds of claims 1-7 and a pharmaceutically acceptable carrier.

11、根据权利要求 1-7所述的化合物在制备预防和 I或***药物中的应用 11. A compound according to claims 1-7 for use in the manufacture of a medicament for the prophylaxis and treatment of cancer Applications

12、根据权利要求 11的应用，其特征在于，所述的肿瘤包括头颈部癌、非小细胞肺癌、胰腺癌、结直肠癌、膀胱癌、乳腺癌，卵巢癌，宫颈 , 扁平细胞癌。 12. Use according to claim 11, characterized in that said tumor comprises head and neck cancer, non-small cell lung cancer, pancreatic cancer, colorectal cancer, bladder cancer, breast cancer, ovarian cancer, cervix, squamous cell carcinoma.