CN1313449C - New quinazoline hind derivative, medicinal composition containing same and their use - Google Patents

New quinazoline hind derivative, medicinal composition containing same and their use Download PDF

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CN1313449C
CN1313449C CN 200510012181 CN200510012181A CN1313449C CN 1313449 C CN1313449 C CN 1313449C CN 200510012181 CN200510012181 CN 200510012181 CN 200510012181 A CN200510012181 A CN 200510012181A CN 1313449 C CN1313449 C CN 1313449C
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CN1724521A (en
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史秀兰
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沈阳中海生物技术开发有限公司
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Abstract

本发明涉及通式I所示的喹唑啉类衍生物,及其光学活性体或消旋体、非对映异构体混合物或其药学上可接受的盐、水合物或溶剂化物,其中取代基R The present invention relates to the general formula I shown quinazoline derivatives, their pharmaceutically optically active or racemic, diastereomeric mixture or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the substituents group R

Description

新的喹唑啉类衍生物、含有其的药物组合物以及它们的用途 The new quinazoline derivatives, pharmaceutical compositions containing them and their use

技术领域 FIELD

本发明涉及4-取代的苯胺基喹唑啉类衍生物,以及以该衍生物为活性成分的药物组合物,以及其在制备蛋白酪氨酸激酶抑制剂以及用于治疗和/或预防各种癌症和其它增生性疾病的药物中的用途。 The present invention relates to 4-substituted anilino quinazoline derivatives, and derivatives as an active ingredient of pharmaceutical compositions, and their use in the preparation of protein tyrosine kinase inhibitor and in the treatment and / or prevention of various drugs for cancer and other proliferative diseases of use.

背景技术 Background technique

癌症,又称为恶性肿瘤,是严重威胁人类健康的一类常见病,目前癌症的死亡率仍在上升,对常见的实体瘤还缺乏有效的药物。 Cancer, also known as cancer is a serious threat to human health of a class of common diseases, the current mortality rate of cancer is still rising, for common solid tumors also lack of effective drugs. 现有的化疗药物大多通过干扰细胞分裂过程的某些环节杀死癌细胞,其作用靶点在癌细胞和正常细胞中并无本质区别,在杀死癌细胞的同时,也会产生毒副作用。 Certain aspects of most existing chemotherapy drugs by interfering with cell division process of killing cancer cells, it is not fundamentally different targets in cancer cells and normal cells while killing cancer cells also produce toxic side effects.

蛋白酪氨酸激酶(protein tyrosine kinase)是一种能选择性地使不同底物的酪氨酸残基磷酸化的一种酶。 Protein tyrosine kinases (protein tyrosine kinase) is an enzyme capable of selectively phosphorylated tyrosine residues of different substrates. 酪氨酸磷酸化在许多细胞调节过程中起着重要作用。 Tyrosine phosphorylation plays an important role in regulating many cellular processes. 这些作用体现在T细胞和B细胞的活化、对外来刺激的反应、有丝分裂、细胞分化和形成、血管增生、神经递质的转导、细胞周期的生长控制、转录调节、葡萄糖的摄取、肿瘤的产生以及细胞凋亡等过程。 These effects are reflected in the activation of T cells and B cells to external stimuli, mitosis, cell differentiation and formation, angiogenesis, neurotransmitter transduction, cell cycle, growth control, transcriptional regulation, glucose uptake, tumor generating processes and apoptosis. 正常情况下,细胞的酪氨酸激酶磷酸化作用是由酪氨酸激酶和酪氨酸磷酸酶拮抗调节而维持平衡的。 Under normal circumstances, cell tyrosine kinase phosphorylation is regulated by antagonizing tyrosine phosphatases and tyrosine kinases maintain balance. 但是,如基因突变、基因融合、自分泌和旁分泌循环等病理机制,会导致蛋白酪氨酸激酶的持续活化,从而阻断了其对细胞分化、生长和凋亡等的调节功能,诱发肿瘤。 However, as mutation, genetic fusion, since the mechanism of autocrine and paracrine pathological circulation, leads to persistent activation of protein tyrosine kinases, thereby blocking its cell differentiation, apoptosis and growth regulatory function, induced tumors . 鉴于酪氨酸激酶在肿瘤分子病原学上的重要作用,强效的酪氨酸激酶抑制剂在肿瘤的治疗中有着重要意义。 In view of the tyrosine kinase molecule in the etiology of the important role of tumor, a potent inhibitor of tyrosine kinase has an important significance in the treatment of tumors. 近年来,蛋白酪氨酸激酶广泛地被作为抗肿瘤药物的靶点。 In recent years, the protein tyrosine kinases are widely used as a target for antitumor drugs.

4-苯胺基喹唑啉类衍生物是AstraZeneca公司在其化合物库中筛选出来的一类新型的酪氨酸激酶抑制剂,其中Iressa(化学名为4-(3-氯-4-氟苯胺基)-7-甲氧基-6-[3-(4-吗啉基)丙氧基]喹唑啉)已于2003年在日本正式上市,用于治疗非小细胞肺癌。 4-anilino-quinazoline derivatives are screened AstraZeneca's compound library in which a new class of tyrosine kinase inhibitor, wherein Iressa (3- chloro-4-fluorophenyl amine (chemical name 4- ) -7-methoxy-6- [3- (4-morpholinyl) propoxy] quinazoline) officially listed in 2003 in Japan for the treatment of non-small cell lung cancer. 体外实验证实,Iressa可诱导细胞周期停滞、促进凋亡和抗血管生成,对一系列肿瘤细胞株显示出生长抑制作用,如前列腺癌、乳腺癌、卵巢癌、结肠癌、小细胞肺癌和非小细胞肺癌等。 In vitro experiments confirmed, Iressa can induce cell cycle arrest, apoptosis and anti-angiogenesis, inhibition of growth of tumor cell lines showed a series, such as prostate cancer, breast cancer, ovarian cancer, colon cancer, small cell lung cancer and non-small cell lung cancer.

本发明合成了一系列的4-取代的苯胺基喹唑啉类衍生物,经体外蛋白酪氨酸激酶抑制活性筛选和体外抗肿瘤活性筛选,表明具有抑制蛋白酪氨酸激酶活性和抗肿瘤活性。 The present inventors have synthesized a series of 4-substituted anilino quinazoline derivatives, in vitro screening of protein tyrosine kinase inhibitory activity and antitumor activity screening, showed that inhibit protein tyrosine kinase activity and antitumor activity .

发明内容 SUMMARY

本发明涉及定义如下的通式I的衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物, The present invention relates to general formula I as defined derivatives, or their racemates, diastereomeric mixture of optically active isomers thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, 其中R1、R2其中之一为C1-C6烷基,另外一个为-R3YR4Q2;A为C1-C4烷基,H;X为一个直接键或C1-C4亚烷基,所述亚烷基可以被1-3个选自羟基、卤素、硝基、C1-C4烷氧基的取代基任选取代;Q1为苯基、萘基或5-10元杂芳基,所述杂芳基可以含有1-3个选自O、N和S的杂原子,且Q1可任选1-3个R5取代;R3、R4为C1-C6亚烷基,所述亚烷基可以被1-3个选自羟基、卤素、硝基、C1-C4烷氧基的取代基任选取代;Y为-S-, Wherein R1, R2, one of which is a C1-C6 alkyl and the other is -R3YR4Q2; A is C1-C4 alkyl, H; X is a direct bond or C1-C4 alkylene group, the alkylene group may be optionally 1 to 3 substituents selected from hydroxy, halo, nitro, C1-C4 alkoxy substituents; Ql is phenyl, naphthyl or 5-10 membered heteroaryl, the heteroaryl may contain 1 -3 selected from O, N, and S, and Q1 optionally substituted with 1-3 R5; R3, R4 is C1-C6 alkylene group, the alkylene group may be selected from 1 to 3 substituted with hydroxy, halogen, nitro, C1-C4 alkoxy group optionally substituted; Y is -S-, Q2为呋喃基、吡咯基、噻吩基,可任选1-3个R6取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、(C1-C4)烷基硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷基酰基、氨基甲酰基、N-C1-C4烷基氨基甲酰基、N,N-二C1-C4烷基氨基甲酰基、氨基磺酰基、N-C1-C4烷基氨基磺酰基、N,N-二C1-C4烷基氨基磺酰基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基,并且该饱和杂环基可以带有1-2个选自氧代、羟基、卤素、C1-C3烷基、C1-C3烷氧基、三氟甲基、硝基的取代基;R6为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-C1-C4烷基氨基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺 Q2 is furyl, pyrrolyl, thienyl, optionally substituted with 1-3 R6; R5 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1- C4 alkyl, C1-C4-alkoxy, N, N- two amino C1-C4 alkyl, (C1-C4) alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl group, C1-C4 alkoxymethyl, C1-C4 alkyl group, carbamoyl, N-C1-C4 alkyl-carbamoyl, N, N- C1-C4 two alkylcarbamoyl, sulfamoyl group, N -C1-C4 alkylaminosulfonyl, N, N- two aminosulfonyl C1-C4 alkyl group, C1-C3 alkylenedioxy group, and group selected from morpholinyl, pyrrolidinyl, piperazinyl, piperazine, piperidinyl, imidazolidinyl and pyrazolidinyl a saturated heterocyclic group, and a saturated heterocyclic group which may have 1-2 substituents selected from oxo, hydroxy, halogen, C1-C3 alkyl, C1-C3 alkoxy group, trifluoromethyl group, nitro group; R6 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, C1-C4 alkyl, C1- C4-alkoxy, N-C1-C4 alkylamino, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkylsulfinyl 酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷基酰基、氨基甲酰基、N-C1-C4烷基氨基甲酰基、N,N-二C1-C4烷基氨基甲酰基、氨基磺酰基、N-C1-C4烷基氨基磺酰基、N,N-二C1-C4烷基氨基磺酰基,或者R6为-CH2NR7R8;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-10元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Acyl, C1-C4 alkylsulfonyl, C1-C4 alkoxymethyl, C1-C4 alkyl group, carbamoyl, N-C1-C4 alkylcarbamoyl, N, N- C1-C4 alkoxy two carbamoyl group, sulfamoyl group, N-C1-C4 alkylaminosulfonyl, N, N- two aminosulfonyl C1-C4 alkyl group, or R6 is -CH2NR7R8; R7, R8 are the same or different, each independently is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, which may be substituted with 1 to 3 identical or different optionally R5, or R7 and R8 together with the nitrogen atom to which they are attached together form a 5-10 membered saturated heterocyclic group, a saturated heterocyclic group except the nitrogen atom to which R7 and R8 are attached, may contain 1-3 heteroatoms selected from O, N and S heteroatoms may be 1 to 3 identical or different R5 is optionally substituted.

本发明优选涉及定义如下的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为C1-C6烷基,另外一个为-R3YR4Q2;A为H;X为一个直接键或C1-C4亚烷基;Q1为苯基、萘基或5-10元杂芳基,所述杂芳基可以含有1-3个选自O、N和S的杂原子,且Q1可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, The present invention preferably relates to the general formula defined below I derivatives, and optically active or racemic, diastereomeric mixtures thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1, R2 wherein one of the C1-C6 alkyl and the other is -R3YR4Q2; a is H; X is a direct bond or C1-C4 alkylene group; Ql is phenyl, naphthyl or 5-10 membered heteroaryl group, the said heteroaryl group may contain 1-3 heteroatoms selected from heteroatoms of O, N and S, and Q1 is optionally substituted with 1-3 R5; R3, R4 is C1-C4 alkylene group; Y is -S-, Q2为呋喃基、吡咯基、噻吩基,可任选1-3个R6取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷基酰基、氨基甲酰基、N-C1-C4烷基氨基甲酰基、N,N-二C1-C4烷基氨基甲酰基、氨基磺酰基、N-C1-C4烷基氨基磺酰基、N,N-二C1-C4烷基氨基磺酰基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基,并且该饱和杂环基可以带有1-2个选自氧代、羟基、卤素、C1-C3烷基、C1-C3烷氧基、三氟甲基、硝基的取代基;R6为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-C1-C4烷基氨基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺 Q2 is furyl, pyrrolyl, thienyl, optionally substituted with 1-3 R6; R5 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1- C4 alkyl, C1-C4-alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1- C4-alkoxymethyl, C1-C4 alkyl group, carbamoyl, N-C1-C4 alkylcarbamoyl, N, N- C1-C4 two alkylcarbamoyl, sulfamoyl group, N-C1 -C4 alkylaminosulfonyl, N, N- two aminosulfonyl C1-C4 alkyl group, C1-C3 alkylenedioxy group, and group selected from morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl , imidazolidinyl and pyrazolidinyl a saturated heterocyclic group, and a saturated heterocyclic group which may have 1-2 substituents selected from oxo, hydroxy, halogen, C1-C3 alkyl, C1-C3 alkoxy group, trifluoromethyl, nitro substituent; R6 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, C1-C4 alkyl, C1-C4 alkyl group, N-C1-C4 alkylamino, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkylsulfinyl 基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷基酰基、氨基甲酰基、N-C1-C4烷基氨基甲酰基、N,N-二C1-C4烷基氨基甲酰基、氨基磺酰基、N-C1-C4烷基氨基磺酰基、N,N-二C1-C4烷基氨基磺酰基,或者R6为-CH2NR7R8;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-10元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Group, C1-C4 alkylsulfonyl, C1-C4 alkoxymethyl, C1-C4 alkyl group, carbamoyl, N-C1-C4 alkylcarbamoyl, N, N- C1-C4 alkoxy two carbamoyl group, sulfamoyl group, N-C1-C4 alkylaminosulfonyl, N, N- two aminosulfonyl C1-C4 alkyl group, or R6 is -CH2NR7R8; R7, R8 are the same or different, each independently is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, which may be substituted with 1 to 3 identical or different optionally R5, or R7 and R8 together with the nitrogen atom to which they are attached together form a 5-10 membered saturated heterocyclic group, a saturated heterocyclic group except the nitrogen atom to which R7 and R8 are attached, may contain 1-3 heteroatoms selected from O, N and S heteroatoms may be 1 to 3 identical or different R5 is optionally substituted.

本发明特别优选涉及定义如下的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为C1-C4烷基,另外一个为-R3YR4Q2;A为H;X为一个直接键或C1-C4亚烷基;Q1是苯基,可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, The present invention particularly preferably relates to derivatives of formula I defined below, its optically active substance or racemate, mixture of diastereomers thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1, wherein one of R2 is C1-C4 alkyl and the other is -R3YR4Q2; a is H; X is a direct bond or C1-C4 alkylene group; Ql is phenyl, optionally substituted with 1-3 R5; R3 , R4 is C1-C4 alkylene group; Y is -S-, Q2为呋喃基、吡咯基、噻吩基,可任选1-3个R6取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、4-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基; Q2 is furyl, pyrrolyl, thienyl, optionally substituted with 1-3 R6; R5 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1- C4 alkyl, C1-C4-alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, and selected from morpholinyl, pyrrolidinyl, piperazinyl, 4-methyl-piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl saturated heterocyclic group;

R6为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-C1-C4烷基氨基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷基酰基、氨基甲酰基、N-C1-C4烷基氨基甲酰基、N,N-二C1-C4烷基氨基甲酰基、氨基磺酰基、N-C1-C4烷基氨基磺酰基、N,N-二C1-C4烷基氨基磺酰基,或者R6为-CH2NR7R8;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-10元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 R6 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, C1-C4 alkyl, C1-C4-alkoxy, N-C1-C4 alkylamino , N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxymethyl, C1-C4 alkyl acyl, carbamoyl, N-C1-C4 alkylcarbamoyl, N, N- C1-C4 two alkylcarbamoyl, sulfamoyl group, N-C1-C4 alkylaminosulfonyl, N, N- two C1-C4 alkylaminosulfonyl group, or R6 is -CH2NR7R8; R7, R8 are the same or different, each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, which may be 1- 3 identical or different optionally substituted by R5, or R7 and R8 together with the nitrogen atom to which they are attached form a 5-10 membered saturated heterocyclic group, a saturated heterocyclic group with the nitrogen atom, R7 and R8 connected in addition , selected may contain 1 to 3 heteroatoms of O, N and S, may be substituted with 1 to 3 identical or different optionally R5.

本发明特别优选涉及定义如下的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为C1-C4烷基,另外一个为-R3YR4Q2;X为一个直接键或亚甲基;Q1是苯基,可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, The present invention particularly preferably relates to derivatives of formula I defined below, its optically active substance or racemate, mixture of diastereomers thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1, wherein one of R2 is C1-C4 alkyl and the other is -R3YR4Q2; X is a direct bond or methylene; Ql is phenyl, optionally substituted with 1-3 R5; R3, R4 is C1-C4 alkylene alkyl group; Y is -S-, Q2为呋喃基、吡咯基、噻吩基,可任选1-3个R6取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、N-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基;R6为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-C1-C4烷基氨基、N,N-二C1-C4烷基氨基、或者R6为-CH2NR7R8;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Q2 is furyl, pyrrolyl, thienyl, optionally substituted with 1-3 R6; R5 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1- C4 alkyl, C1-C4-alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, and selected from morpholinyl, pyrrolidinyl, piperazinyl, N- methylpiperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl a saturated heterocyclic group of; R6 is hydrogen, halogen, hydroxy, tris fluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, C1-C4 alkyl, C1-C4-alkoxy, N-C1-C4 alkylamino, N, N- C1-C4 two alkylamino, or R6 is -CH2NR7R8; R7, R8 are the same or different, each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, which may be the same or different to any one of R5 1-3 optionally substituted, or R7 and R8 with the nitrogen atom to which they are attached form a 5-6 membered saturated heterocyclic group, a saturated heterocyclic group in addition to the nitrogen atom and R7 and R8 attached, may contain 1 to 3 selected from since hetero atoms O, N and S, may be substituted with 1 to 3 identical or different optionally R5.

本发明特别优选还涉及定义如下的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为C1-C4烷基,另外一个为-R3YR4Q2;A为H;X为一个直接键或亚甲基;Q1是苯基,可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, Particularly preferred formula of the present invention also relates to derivatives I defined below, its optically active substance or racemate, mixture of diastereomers thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 , wherein one R2 is C1-C4 alkyl and the other is -R3YR4Q2; a is H; X is a direct bond or methylene; Ql is phenyl, optionally substituted with 1-3 R5; R3, R4 a C1-C4 alkylene group; Y is -S-, Q2为含有呋喃基,可任选1-3个R6取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、4-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基;R6为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-C1-C4烷基氨基、N,N-二C1-C4烷基氨基、或者R6为-CH2NR7R8;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Q2 is a group comprising furyl, optionally substituted with 1-3 R6; R5 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1-C4 alkyl, C1 -C4 alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, selected from morpholinyl and , pyrrolidinyl, piperazinyl, 4-methyl-piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl a saturated heterocyclic group of; R6 is hydrogen, halo, hydroxy, trifluoromethyl, tri difluoromethoxy, carboxy, amino, nitro, cyano, C1-C4 alkyl, C1-C4-alkoxy, N-C1-C4 alkylamino, N, N- two amino C1-C4 alkyl, or R6 is -CH2NR7R8; R7, R8 are the same or different, each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, which may be substituted with 1 to 3 identical or different optionally R5, or R7 and R8 with the nitrogen atom to which they are attached form a 5-6 membered saturated heterocyclic group, a saturated heterocyclic group in addition to the nitrogen atom and R7 and R8 attached, may contain 1-3 heteroatoms selected from O, N and heteroatom S may be substituted with 1 to 3 identical or different optionally R5.

本发明特别优选还涉及定义如下的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为C1-C4烷基,另外一个为-R3YR4Q2;A为H;X为一个直接键或亚甲基;Q1是苯基,可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, Particularly preferred formula of the present invention also relates to derivatives I defined below, its optically active substance or racemate, mixture of diastereomers thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 , wherein one R2 is C1-C4 alkyl and the other is -R3YR4Q2; a is H; X is a direct bond or methylene; Ql is phenyl, optionally substituted with 1-3 R5; R3, R4 a C1-C4 alkylene group; Y is -S-, Q2为呋喃基,且在5位上被-CH2NR7R8取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、4-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Q2 is a furan group, and is substituted at the 5 position -CH2NR7R8; R5 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1-C4 alkyl, C1- C4 alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, selected from morpholinyl and , pyrrolidinyl, piperazinyl, 4-methyl-piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl saturated heterocyclic group; R7, R8 are the same or different, each independently selected from hydrogen, a C1 -C6 alkyl, C3-C6 cycloalkyl, which may be substituted with 1 to 3 identical or different optionally R5, or R7 form a 5-6 membered saturated heterocyclic group and R8, together with the nitrogen atom to which they are attached the saturated heterocyclic group in addition to the nitrogen atom to which R7 and R8, may contain 1 to 3 selected from O, N and S heteroatoms may be substituted with 1 to 3 identical or different optionally R5.

本发明特别优选还涉及定义如下的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为甲基,另外一个为-R3YR4Q2;A为H;X为一个直接键; Particularly preferred formula of the present invention also relates to derivatives I defined below, its optically active substance or racemate, mixture of diastereomers thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 , wherein one R2 is methyl and the other is -R3YR4Q2; a is H; X is a direct bond;

Q1是苯基,可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, Q1 is phenyl, optionally substituted with 1-3 R5; R3, R4 is C1-C4 alkylene group; Y is -S-, Q2为呋喃基,且在5位上被-CH2NR7R8取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、4-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,或R7和R8与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Q2 is a furan group, and is substituted at the 5 position -CH2NR7R8; R5 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1-C4 alkyl, C1- C4 alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, selected from morpholinyl and , pyrrolidinyl, piperazinyl, 4-methyl-piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl saturated heterocyclic group; R7, R8 are the same or different, each independently selected from hydrogen, a C1 -C6 alkyl, C3-C6 cycloalkyl or R7 and R8 together with the nitrogen atom to which they are attached form a 5-6 membered saturated heterocyclic group, a saturated heterocyclic group connected to the nitrogen atom in addition R7 and R8 in addition, selected may contain 1 to 3 heteroatoms of O, N and S, may be substituted with 1 to 3 identical or different optionally R5.

本发明特别优选还涉及定义如下的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为甲基,另外一个为-R3YR4Q2;A为H;X为一个直接键;Q1是苯基,可任选1-3个R5取代;R3为C1-C3亚烷基;R4为亚甲基;Y为-S-, Particularly preferred formula of the present invention also relates to derivatives I defined below, its optically active substance or racemate, mixture of diastereomers thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 , wherein one R2 is methyl and the other is -R3YR4Q2; a is H; X is a direct bond; Ql is phenyl, optionally substituted with 1-3 R5; R3 is C1-C3 alkylene group; R4 It is a methylene group; Y is -S-, Q2为呋喃基,且在5位上被-CH2NR7R8取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、4-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,或R7和R8与和它们所连接的氮原子一起形成吡咯烷基、吗啉基、哌啶基和4-甲基哌嗪基。 Q2 is a furan group, and is substituted at the 5 position -CH2NR7R8; R5 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1-C4 alkyl, C1- C4 alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, selected from morpholinyl and , pyrrolidinyl, piperazinyl, 4-methyl-piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl saturated heterocyclic group; R7, R8 are the same or different, each independently selected from hydrogen, a C1 -C6 alkyl, C3-C6 cycloalkyl or R7 and R8 with the nitrogen atom to which they are attached form pyrrolidinyl, morpholinyl, piperidinyl and 4-methyl-piperazinyl.

本发明非常特别优选的下列通式I衍生物及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物:4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[(5-二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉(实施例1);4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉(实施例2)4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉(实施例3)4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉(实施例4)4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉(实施例5)4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉(实施例6)4-(3-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(二甲胺基)甲基呋喃-2-]甲 Very particularly preferred derivatives of the present invention, the following I and optically active or racemic formula, a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof: 4- (3- chloro-4-fluoroanilino) -6-methoxy-7 - [[3 - [(5-dimethylamino) methyl-furan-2] methylthio] propoxy] quinazoline (embodiment Example 1); 4- (3-chloro-4-fluoroanilino) -6-methoxy -7 - [[3- [5- (N- methyl-ethylamino) methyl-furan-2] A thio] propoxy] quinazoline (Example 2) 4- (3-chloro-4-fluoroanilino) -6-methoxy-7 - [[3- [5- (1-pyrrolidinyl ) furan-2-methyl] methylthio] propoxy] quinazoline (Example 3) 4- (4-methoxyphenoxy) -6-methoxy-7 - [[3- [5- (dimethylamino) methyl-furan-2] methylthio] propoxy] quinazoline (Example 4) 4- (4-methoxyphenoxy) -6-methoxy -7 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] propoxy] quinazoline (Example 5) 4- (4-trifluoromethoxy phenyl) -6-methoxy -7 - [[3- [5- (N- ethylamino-methyl) furan-2-methyl] methylthio] propoxy] quinazoline (Example 6) 4- (3-methoxyphenoxy) -6-methoxy-7 - [[3- [5- (dimethylamino) methyl-furan-2] A 硫基]丙氧基]喹唑啉(实施例12)4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(4-甲基-1-哌嗪基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉(实施例15)4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉(实施例16)4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉(实施例18)4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(1-哌啶基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉(实施例19)4-(4-氟苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉(实施例20)4-(3,5-二氟苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉(实施例27)4-(3,5-二氟苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐(实施例28)4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[2-[5-(二甲胺基)甲基呋哺-2-]甲硫基]乙氧基 Thio] propoxy] quinazoline (Example 12) 4- (3-trifluoromethylanilino) -6-methoxy-7 - [[2- [5- (4-methyl-1 - piperazin-yl) furan-2-methyl] methylthio] ethoxy] quinazoline (Example 15) 4- (3-trifluoromethylanilino) -6-methoxy-7- [ [2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy] quinazoline (Example 16) 4- (3-trifluoromethylanilino) -6 - methoxy -7 - [[2- [5- (N- ethylamino-methyl) furan-2-methyl] methylthio] ethoxy] quinazoline (Example 18) 4- (3 - trifluoromethylanilino) -6-methoxy-7 - [[2- [5- (1-piperidinyl) methyl-furan-2] methylthio] ethoxy] quinazoline ( Example 19) 4- (4-fluoroanilino) -6-methoxy-7 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy ] quinazoline (Example 20) 4- (3,5-difluorophenyl) -6-methoxy-7 - [[2- [5- (1-pyrrolidinyl) methyl-furan-2 ] methylthio] ethoxy] quinazoline (Example 27) 4- (3,5-difluorophenyl) -6-methoxy -7 - [[2- [5- (N- methyl ethylamine yl) furan-2-methyl] methylthio] ethoxy] quinazoline oxalate (Example 28) 4- (3-chloro-4-fluoroanilino) -6-methoxy - 7 - [[2- [5- (dimethylamino) -2- furosemide feeding methyl] methylthio] ethoxy ]喹唑啉(实施例29)4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基丙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉(实施例30)4-(3,4-二氟苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉(实施例31)4-(3,4-二氟苯胺基)-6-甲氧基-7-[[2-[5-(二甲胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉(实施例32)4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基丙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉(实施例35)4-(3-三氟甲基苯胺基)-7-甲氧基-6-[[3-[5-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉(实施例45)4-(3-三氟甲基苯胺基)-7-甲氧基-6-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉(实施例46)4-(3,4-二氟苯胺基)-7-甲氧基-6-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉(实施例48)而且,按照本发明所属领域的一些通常方法,本发明的上式I的喹唑啉类衍生物可以与酸生 ] Quinazoline 4- (3-chloro-4-fluoroanilino) (Example 29) 6-methoxy -7 - [[2- [5- (N- methyl-propylamino) methyl furan - 2-] methylthio] ethoxy] quinazoline (Example 30) 4- (3,4-difluorophenyl) -6-methoxy-7 - [[2- [5- (1- pyrrolidinyl) methyl furan-2] methylthio] ethoxy] quinazoline (Example 31) 4- (3,4-difluorophenyl) -6-methoxy-7 - [[ 2- [5- (dimethylamino) methyl-furan-2] methylthio] ethoxy] quinazoline (Example 32) 4- (4-methoxyphenoxy) -6- methoxy -7 - [[2- [5- (N- methyl-propylamino) methyl-furan-2] methylthio] ethoxy] quinazoline (Example 35) 4- (3- fluoro-methylanilino) -7-methoxy-6 - [[3- [5- (dimethylamino) methyl-furan-2] methylthio] propoxy] quinazoline (Example 45 ) 4- (3-trifluoromethylanilino) -7-methoxy-6 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] propoxy ] quinazoline (Example 46) 4- (3,4-difluorophenyl) -7-methoxy-6 - [[3- [5- (1-pyrrolidinyl) methyl-furan-2 ] methylthio] propoxy] quinazoline (Example 48) Further, according to some conventional methods of ordinary skill in the present invention, the quinazoline derivative of formula I of the present invention may be generated with an acid 它的药学上可接受的盐。 Its pharmaceutically acceptable salt thereof. 酸可以包括无机酸或有机酸,与下列酸形成的盐是特别优选的:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、洒石酸、苯磺酸、苯甲酸或对甲苯磺酸等。 The acid may include inorganic or organic acids, salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid , acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzenesulfonic acid, benzoic acid or p-toluenesulfonic acid and the like.

本发明衍生物可以以立体异构体形式存在,这些立体异构形式可以是对映体或非对映体。 Derivatives of the present invention can exist in stereoisomeric forms, stereoisomeric forms which may be enantiomers or diastereomers. 本发明既涉及对映体或非对映体,也涉及它们各自的混合物,象非对映体一样,可按照自身已知的方法将外消旋形式分离成为立体异构的单一组分。 The present invention relates both to the enantiomers or diastereomers, and also to their respective mixtures, as diastereomers, as racemates may be separated stereoisomeric forms become a single component in accordance with a method known per se.

此外,本发明还包括本发明衍生物的前药。 Further, the present invention further includes a prodrug derivative of the present invention. 依据本发明,前药是通式I的衍生物,它们自身可能具有较弱的活性或甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。 According to the present invention, prodrugs are derivatives of the general formula I, which itself may have weaker activity or even no activity, but after administration, under physiological conditions (e.g., by metabolic, solvolysis or otherwise) is converted to the corresponding biologically active form.

除非另外指出,本发明所用的术语“卤素”是指氟、氯、溴或碘代;“烷基”是指直链或支链的烷基;“亚烷基”是指直链或支链的亚烷基;“环烷基”是指取代或未取代的环烷基;杂芳基包括含有一个或多个选自O、N和S的杂原子,其中每个杂芳基的环状体系可以是单环或多环的,环状体系是芳香性的,可以举出例如咪唑基、吡啶基、嘧啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噁唑基、吡唑基、吡咯基、噻唑基、苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并噻唑基、吲哚基、喹啉基等;饱和杂环基包括含有一个或多个选自O、N和S的杂原子,环状体系可以是单环或多环的,可以举出例如吡咯烷基、吗啉基、哌嗪基、哌啶基、吡唑烷基、咪唑烷基和噻唑啉基等。 Unless otherwise indicated, as used herein, the term "halo" refers to fluoro, chloro, bromo or iodo; "alkyl" means a straight or branched alkyl chain; "alkylene" refers to a straight or branched chain alkylene; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; heteroaryl groups include those containing one or more selected from O, N and S heteroatoms, wherein each ring of the heteroaryl group system may be monocyclic or polycyclic, aromatic ring system is, for example, can include imidazolyl, pyridinyl, pyrimidinyl, pyrazolyl, (1,2,3) - and (1,2,4 ) - triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, benzofuranyl, phenyl benzimidazolyl, benzothiazolyl, indolyl, quinolyl and the like; saturated heterocyclic groups include those containing one or more selected from O, N, and S, the ring system may be monocyclic or polycyclic includes, for example pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, and the like thiazolinyl.

本发明的特定衍生物可具有不对称中心,因此以不同的对映体和非对映体的形式存在。 Certain derivatives of the present invention may have asymmetric centers, and thus the non-enantiomeric forms exist in different enantiomeric. 本发明涉及本发明衍生物的所有旋光异构体、消旋体及其混合物。 The present invention relates to derivatives of the present invention are all optical isomers, racemates and mixtures thereof. “消旋体”是指含有等量的一对对映异构体的混合物。 "Racemate" refers to a mixture containing a pair of enantiomers in equal amounts.

本发明包括药物组合物,该组合物含有上式I的喹唑啉类衍生物,及其光学活性体或消旋体、非对映异构体混合物或其药学上可接受的盐、水合物或溶剂化物作为活性成分,以及药学上可接受的赋型剂。 The present invention includes a pharmaceutical composition, the composition comprising the quinazoline derivative of Formula I, and pharmaceutically optically active or racemic, diastereomeric mixture or a pharmaceutically acceptable salt, hydrate or a solvate thereof as an active ingredient, excipient and pharmaceutically acceptable. 所述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。 The pharmaceutically acceptable excipient refers to any diluent can be used in the pharmaceutical art, adjuvants and / or carriers. 本发明的衍生物可以与其他活性成分组合使用,只要它们不产生其他不利的作用,例如过敏反应。 Derivatives of the invention may be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions.

本发明的药物组合物可配制成若干种剂型,其中含有药学领域中常用的一些赋形剂;例如,口服制剂(如片剂,胶囊剂,溶液或混悬液);可注射的制剂(如可注射的溶液或混悬液,或者是可注射的干燥粉末,在注射前加入注射用水可立即使用);局部制剂(例如软膏或溶液)。 The pharmaceutical compositions of the invention may be formulated into several dosage forms containing some common pharmaceutical excipients in the art; e.g., oral preparations (e.g., tablets, capsules, solutions or suspensions); Injectable preparations (e.g. injectable solution or suspension, or injectable dry powder, was added prior to injection water for injection immediately available); topical preparations (e.g. ointments or solutions).

用于本发明药物组合物的载体是药学领域中可得到的常见类型,包括:口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂等;可注射制剂用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。 Carriers for the pharmaceutical compositions of the present invention are common types available in the pharmaceutical field, comprising: an oral formulation with binders, lubricants, disintegrants, co-solvents, diluents, stabilizers, suspending agents, non-pigmented , flavoring agents; injectable formulation with preservatives, solubilizers, stabilizers and the like; topical formulation with a substrate, diluents, lubricants, preservatives and the like. 药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可将其配制成肠衣片剂。 The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenous, subcutaneous, intraperitoneal or topical) administration, if certain drugs are unstable under the conditions of the stomach, which may be formulated as enteric coated tablets.

我们已发现本发明化合物具有抑制蛋白酪氨酸激酶活性,因此本发明化合物具有抗增生性质。 We have found that compounds of this invention inhibit the protein tyrosine kinase activity, thus the present invention is a compound having antiproliferative properties. 本发明化合物可以用于蛋白酪氨酸激酶受体抑制剂单独或部分间介的疾病或病症的治疗,即化合物可以在需要这类治疗的哺乳动物体内用于产生蛋白酪氨酸激酶受体抑制作用。 Compounds of the invention may be used in the treatment of protein tyrosine kinase disease or condition mediated alone or in part between the receptor inhibitors, i.e. compounds may be used to produce receptor protein tyrosine kinase inhibition in a mammal in need of such treatment effect.

本发明化合物可以用于提供抗增生作用的癌症的治疗,尤其治疗蛋白酪氨酸激酶受体敏感的癌症如乳腺、肺、结肠、直肠、胃、前列腺、膀胱、胰腺和卵巢的癌。 The treatment of cancer the present compounds may be used to provide anti-proliferative effect, particularly in the treatment of receptor protein tyrosine kinase sensitive cancers such as breast, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovarian cancer. 本发明化合物也被期望可以用于治疗其他细胞增生疾病如牛皮癣、良性前列腺肥大、动脉粥样硬化和再狭窄。 The compounds of this invention are also expected to be useful in the treatment of other cell proliferative disorders such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis. 另外预期本发明的喹唑啉衍生物将具有抗白血病、淋巴恶性和固体肿瘤如在组织如肝、肾、前列腺和胰腺中的癌和肉瘤范围的活性。 Also contemplated quinazoline derivatives of the present invention will have anti-leukemia, lymphoid such as liver, kidney, prostate and pancreas activity range of carcinomas and sarcomas and solid tumors such as malignant tissue.

另外,也预期本发明化合物可用于治疗其它细胞增生的疾病,其中包括通过受体蛋白酪氨酸激酶标记,包括还未确定的受体蛋白酪氨酸激酶的畸变细胞。 Further, the compounds of the invention are also contemplated useful for the treatment other proliferative diseases including tyrosine kinase receptor protein labeled by including receptor protein tyrosine kinases has not been determined distortion cells. 这类疾病包括,例如,炎症、血管生成、血管再狭窄,免疫学疾病、胰腺病、肾病和胚成熟和移植。 Such diseases include, for example, inflammation, angiogenesis, vascular restenosis, immunological disorders, pancreatitis, kidney disease and embryo maturation and migration.

体外抗肿瘤活性试验表明本发明的上式I的喹唑啉类衍生物具有抗癌作用,因此,它可以用作制备治疗和/或预防癌症的药物。 Antitumor activity tests in vitro showed that the quinazoline derivative of Formula I of the present invention having anticancer action, therefore, it may be used for treating and / or prophylaxis of cancer.

根据本发明的衍生物可作为活性成分用于制备治疗和/或预防各种癌症,本发明也提供治疗或预防上述疾病的方法,包括给予患有或易患有此病的病人治疗有效量的根据本发明的衍生物。 Preparation of derivatives of the invention according to the treatment can be used as an active ingredient and / or prevention of various cancers, the present invention also provides a method of treating or preventing the above diseases, comprising administering to a patient suffering from or susceptible to disease a therapeutically effective amount of a the derivatives of the invention. 上式I的喹唑啉类衍生物用于患者的临床剂量必需依赖被治疗的主体、给药的具体途径、被治疗疾病的严重性而变化,而最佳剂量由治疗具体患者的医生确定。 Quinazoline derivatives of formula I for clinical dose must rely on the body of the patient being treated, the particular route of administration, severity of the disease being treated varies, the optimal dose is determined by the physician treating a particular patient.

本发明活性化合物可作为唯一的抗癌药物使用,或者可以与一种或多种其它抗肿瘤药物联合使用。 The active compounds of the present invention may be used as the sole anti-cancer drugs, or may be used in combination with one or more other anti-tumor drugs. 联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。 Combination therapy simultaneously, sequentially, or separated administration is achieved by the individual components of the treatment.

下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。 Embodiment examples and preparations provided below further illustrate the compounds of the present invention and illustrate the preparation thereof. 应当理解,下述实施例和制备例的范围并不以任何方式限制本发明的范围。 It should be understood that the scope of the Examples and Preparation Examples below do not limit the scope of the present invention in any way. 在下述实施例中,除非另有说明,否则具有一个手性中心的分子以外消旋混合物的形式存在。 Examples, unless otherwise noted, exist as a chiral center having a racemic mixture of molecules in the following examples. 除非另有说明,否则具有两个或更多个手性中心的分子是作为非对映体的外消旋混合物存在。 Unless otherwise noted, the molecule having two or more chiral centers is present as outer non racemic mixture of diastereomers. 单独的对映体/非对映体可通过本领域技术人员已知的方法获得。 Individual enantiomers may be obtained / diastereomers skilled in the art known methods.

下面合成路线AD描述了本发明的式I衍生物的制备,所有的原料都是通过这些示意图中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。 Scheme AD The following describes the preparation of derivatives of formula I of the present invention, all raw materials by the methods described in these diagrams, prepared by methods of organic chemistry well known to those of ordinary skill in the art or commercially available. 本发明的全部最终衍生物都是通过这些示意图中描述的方法或通过与其类似的方法制备的,这些方法是有机化学领域普通技术人员熟知的。 The method of preparing the derivatives of the invention are all ultimately these are described in the diagram, or by methods analogous thereto, which are methods of organic chemistry well known to those of ordinary skill in the art. 这些示意图中应用的全部可变因数如下文的定义或如权利要求中的定义。 Defined herein or as defined in the claims all of these diagrams applied in variable factors are as follows.

按照本发明的式I衍生物,在路线A中,R1为C1-C6烷氧基,R2为-R3YR4Q2,Y为-S-,-SO-,-SO2-,其它取代基如发明内容部分所定义。 Derivatives of formula I according to the present invention, in the route A, R1 is a C1-C6 alkoxy group, R2 is -R3YR4Q2, Y is -S -, - SO -, - SO2-, other substituents are as Summary section definition. 以3-烷氧基-4-羟基苯甲酸甲酯(A-1)为起始原料,以二甲基甲酰胺为反应溶剂,无水碳酸钾存在下,与氯代溴代烷烃发生取代反应,生成3-烷氧基-4-氯代烷氧基苯甲酸甲酯(A-2),然后经硝化、铁酸还原得到2-氨基-4-氯代烷氧基-5-烷氧基苯甲酸甲酯(A-4),该化合物在无水乙醇中与乙酸甲脒进行环合,制备得到6-烷氧基-7-氯代烷氧基喹唑啉-4-酮(A-5),A-5经氯化,然后与取代的胺反应制备得到4-取代的胺基-6-烷氧基-7-氯代烷氧基喹唑啉(A-7),A-7与取代的硫酚或硫醇发生取代反应,可得到衍生物A-8,经氧化反应,通过改变所用氧化剂的量和控制反应条件和时间(以薄层监测反应进行),A-8在乙酸中经过氧化氢氧化制得单氧化产物A-9和双氧化产物A-10。 In 3-alkoxy-4-hydroxybenzoate (A-1) as a starting material, in dimethylformamide as the reaction solvent, the presence of anhydrous potassium carbonate, a substitution reaction occurs with chlorinated brominated alkanes to produce 3-alkoxy-4-chloro-alkoxy-benzoic acid methyl ester (A-2), then by nitration, reduction of iron acid 4-chloro-2-amino-alkoxy-5-alkoxy benzoic acid methyl ester (A-4), the compound in ethanol and cyclization formamidine acetate, prepared 7-chloro-6-alkoxy-alkoxy-quinazolin-4-one (A- 5), a-5 by chlorination and reaction of a substituted amine to give the 4-substituted-7-chloro-6-alkoxy alkoxy quinazoline (a-7), a-7 with a substituted thiophenol or thiol substitution reaction, can be obtained derivative a-8,, and the amount of the oxidizing agent and the reaction conditions are controlled by varying the time (reaction carried out in a thin layer monitoring) by the oxidation reaction, a-8 in acetic acid after the oxidation with hydrogen peroxide to obtain a single product of A-9 and a double oxidation products A-10.

路线A Route A

根据本发明的式I衍生物,在路线B中,R1为C1-C6烷氧基,R2为-R3YR4Q2,Y为-S-,-SO-,-SO2-,Q2为呋喃基,且在5位上的取代基为-CH2NR7R8,R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,或R7和R8与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代,其它取代基如发明内容部分所定义。 The derivatives of the invention of formula I, in Scheme B, R1 is a C1-C6 alkoxy group, R2 is -R3YR4Q2, Y is -S -, - SO -, - SO2-, Q2 is a furan group, and at 5 substituent is at position -CH2NR7R8, R7, R8 are the same or different, each independently selected from hydrogen, together form a C1-C6 alkyl, C3-C6 cycloalkyl or R7 and R8 and the nitrogen atom to which they are attached 5-6 membered saturated heterocyclic group, a saturated heterocyclic group except the nitrogen atom to which R7 and R8, may contain 1 to 3 selected from O, N and S heteroatoms may be substituted with 1 to 3 identical R5 or different optionally substituted, other substituents are as defined in the Summary section. 首先按照路线A制备得到A-7,然后与呋喃取代的硫醇发生取代反应,得到B-1,经Mannich反应,得到化合物B-2,经氧化反应,通过改变所用氧化剂的量和控制反应条件和时间(以薄层监测反应进行),可制备得到B-3和B-4。 First preparative route A according to the obtained A-7, then the substitution reaction with furan substituted thiol occurs, to obtain reaction condition B-1, through the Mannich reaction, to give Compound B-2, by oxidation, by changing the amount of the oxidizing agent and the control and time (reaction was performed in a thin layer monitoring), may be prepared to give B-3 and B-4.

路线B按照本发明的式I衍生物,在路线C中,R1为-R3YR4Q2,R2为C1-C6烷氧基,Y为-S-,-SO-,SO2-,其它取代基如发明内容部分所定义。 Route B derivative according to formula I of the present invention, in Scheme C, R1 is -R3YR4Q2, R2 is C1-C6 alkoxy, Y is -S -, - SO-, SO2-, other substituents are as part Summary defined. 以4-烷氧基-3-羟基苯甲酸甲酯(C-1)为起始原料,以二甲基甲酰胺为反应溶剂,无水碳酸钾存在下,与氯代溴代烷烃发生取代反应,生成4-烷氧基-3-氯代烷氧基苯甲酸甲酯(C-2),然后经硝化、铁酸还原得到2-氨基-5-氯代烷氧基-4-烷氧基苯甲酸甲酯(C-4),该化合物在无水乙醇中与醋酸单甲脒进行环合,制备得到7-烷氧基-6-氯代烷氧基喹唑啉-4-酮(C-5),C-5经氯化,然后与取代的胺反应制备得到4-取代的胺基-7-烷氧基-6-氯代烷氧基喹唑啉(C-7),C-7与取代的硫酚或硫醇发生取代反应,可得到衍生物C-8,经氧化反应,通过改变所用氧化剂的量和控制反应时间(以薄层监测反应进行),C-8在乙酸中经过氧化氢氧化制得单氧化产物C-9和双氧化产物C-10。 To 4-alkoxy-3-hydroxybenzoate (C-1) as a starting material, in dimethylformamide as the reaction solvent, the presence of anhydrous potassium carbonate, a substitution reaction occurs with chlorinated brominated alkanes , to form 4-alkoxy-3-chloro-benzoic acid methyl ester alkoxy (C-2), then by nitration, reduction of ferrite amino-5-chloro-alkoxy-alkoxy-4 benzoate (C-4), the compound in ethanol and cyclization single formamidine acetate, prepared to give 7-chloro-6-alkoxy alkoxy quinazolin-4-one (C -5), C-5 chlorinated, and then prepared to give the amine-substituted 4-substituted amino-6-chloro -7- alkoxy quinazoline alkoxy (C-7), C- 7 with a substituted thiophenol or thiol substitution reaction, can be obtained derivative C-8, by oxidation reaction (reaction carried out in a thin layer monitoring) the amount of oxidant and controlling the reaction time by varying the, C-8 in acetic acid after oxidation with hydrogen peroxide to obtain the product C-9 mono and bis oxidation product C-10.

根据本发明的式I衍生物,在路线D中,R1为-R3YR4Q2,R2为C1-C6烷氧基,Y为-S-,-SO-,-SO2-,Q2为呋喃基,且在5位上的取代基为-CH2NR7R8,R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,或R7和R8与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代,其它取代基如发明内容部分所定义。 The derivatives of the invention of formula I, in Scheme D, R1 is -R3YR4Q2, R2 is C1-C6 alkoxy, Y is -S -, - SO -, - SO2-, Q2 is a furan group, and at 5 substituent is at position -CH2NR7R8, R7, R8 are the same or different, each independently selected from hydrogen, together form a C1-C6 alkyl, C3-C6 cycloalkyl or R7 and R8 and the nitrogen atom to which they are attached 5-6 membered saturated heterocyclic group, a saturated heterocyclic group except the nitrogen atom to which R7 and R8, may contain 1 to 3 selected from O, N and S heteroatoms may be substituted with 1 to 3 identical R5 or different optionally substituted, other substituents are as defined in the Summary section. 首先按照路线C制备得到C-7,然后与呋哺取代的硫醇发生取代反应,得到D-1,经Mannich反应,得到化合物D-2,经氧化反应,通过改变所用氧化剂的量和控制反应时间(以薄层监测反应进行),可制备得到D-3和D-4。 First preparative route C according to obtain C-7, then with furosemide feeding substituted thiol substitution reaction, to give D-1, through the Mannich reaction, to give compound D-2, by oxidation, by changing the amount of the oxidizing agent and to control the reaction time (reaction carried out in a thin layer monitoring), may be prepared to give D-3 and D-4.

路线D Route D

具体实施方式 Detailed ways

实施例旨在阐述而不是限制本发明的范围。 Examples are intended to illustrate and not to limit the scope of the invention. 衍生物的核磁共振氢谱用Bruker ARX-300测定,质谱用Agilent 1100 LC/MSD测定;所用试剂均为分析纯或化学纯。 H NMR spectra were derivative ARX-300 assay Bruker, Agilent 1100 LC / MSD Mass spectra were measured; the reagents were of analytical grade or chemically pure.

实施例1:4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[(5-二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐步骤A:3-甲氧基-4-(3-氯丙氧基)苯甲酸甲酯的制备在二甲基甲酰胺(DMF)150mL中,加入3-甲氧基-4-羟基苯甲酸甲酯9.1g(0.05mol)、1,3-溴氯丙烷15.8g(0.1mol)、无水碳酸钾10.4g(0.075mol),70~80℃左右搅拌反应6h。 - [[3 - [(5-dimethylamino) methyl-furan-2] methylthio] 4- (3-chloro-4-fluoroanilino) -6-methoxy-7: Example 1 propoxy] quinazoline oxalate step a: 3- methoxy-4- (3-chloropropoxy) benzoic acid methyl ester in dimethylformamide (DMF) 150mL was added 3- methoxy-4-hydroxybenzoate 9.1g (0.05mol), 1,3- bromochloropropane 15.8g (0.1mol), anhydrous potassium carbonate 10.4g (0.075mol), about 70 ~ 80 ℃ reaction was stirred 6h. 反应毕,将反应液倾入冰水中,二氯甲烷提取,合并有机相,水洗,无水硫酸镁干燥,蒸除溶剂,干燥,得产物12.3g(收率:95.3%)。 Completion of the reaction, the reaction solution was poured into ice water, extracted with dichloromethane, the organic phases were combined, washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and dried to give 12.3 g of product (yield: 95.3%).

步骤B:2-硝基-4-(3-氯丙氧基)-5-甲氧基苯甲酸甲酯的制备在氯仿100mL中,加入3-甲氧基-4-(3-氯丙氧基)苯甲酸甲酯12.3g(0.048mol),搅拌溶解。 Step B: 2- nitro-4- (3-chloropropoxy) -5-methoxybenzoate in 100mL of chloroform was added 3-methoxy-4- (3-chloropropyl oxygen yl) benzoate 12.3g (0.048mol), stirred and dissolved. 冷至10℃左右,剧烈搅拌下向反应液中缓慢滴入65%浓硝酸6.9g(0.071mol)和98%浓硫酸(10mL)配成的混酸。 Cooled to about 10 ℃, was slowly added dropwise with vigorous stirring under 65% conc. 6.9g (0.071mol) of 98% nitric acid and concentrated sulfuric acid (10 mL) to the reaction mixture in a mixed acid dubbed. 滴毕,20℃下搅拌反应4h。 Dropwise, the reaction stirred for 4h at 20 ℃. 反应毕,将反应液倾入冰水中,分去水层,氯仿层依次用饱和碳酸氢钠水溶液、水洗涤至中性,无水硫酸镁干燥,减压蒸干,得浅黄色产物12.9g(收率:89.6%)。 Completion of the reaction, the reaction solution was poured into ice water, to the water layer, a chloroform layer was washed with saturated aqueous sodium bicarbonate, washed with water until neutral, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give 12.9 g of a pale yellow product ( yield: 89.6%).

步骤C:2-氨基-4-(3-氯丙氧基)-5-甲氧基苯甲酸甲酯的制备在95%乙醇300mL中,加入冰醋酸5mL和还原铁粉28g(0.5mol),室温下静置15min后,加加入2-硝基-4-(3-氯丙氧基)-5-甲氧基苯甲酸甲酯19g(0.063mol),搅拌回流反应12h,反应毕,趁热抽滤,滤液减压蒸干,得固体15.8g(收率:92.4%)。 Step C: 2- Amino-4- (3-chloropropoxy) -5-methoxybenzoate in 300mL of 95% ethanol, 5mL of glacial acetic acid was added reduced iron powder and 28g (0.5mol), after standing for 15min at room temperature, was added 2-nitro-4- (3-chloropropoxy) -5-methoxybenzoate 19g (0.063mol), reaction was stirred at reflux for 12h, the reaction was completed, the hot filtered off with suction, the filtrate is evaporated to dryness under reduced pressure to give a solid 15.8 g (yield: 92.4%).

步骤D:6-甲氧基-7-(3-氯丙氧基)喹唑啉-4-酮的制备将2-氨基-4-(3-氯丙氧基)-5-甲氧基苯甲酸甲酯17.0g(0.06mol)和乙酸甲脒9.7g(0.09mol)加入无水乙醇200mL中,加热回流20h,反应毕,将反应液冷却至室温,抽滤,冷无水乙醇洗涤,干燥,得固体15.2g(收率:91.0%)。 Step D: Preparation of 6-methoxy-7- (3-chloropropoxy) quinazolin-4-one A mixture of 2-amino-4- (3-chloropropoxy) -5-methoxybenzene carboxylate 17.0g (0.06mol) and formamidine acetate 9.7g (0.09mol) in 200mL of absolute ethanol was added, heated to reflux for 20 h, the reaction was complete, the reaction was cooled to room temperature, washed, suction-filtered cold absolute ethanol, and dried to give 15.2 g of solid (yield: 91.0%).

步骤E:4-氯-6-甲氧基-7-(3-氯丙氧基)喹唑啉的制备将6-甲氧基-7-(3-氯丙氧基)喹唑啉-4-酮15.0g(0.056mol)加至新蒸二氯亚砜150mL中,回流反应3h。 Step E: 4- chloro-6-methoxy-7- (3-chloropropoxy) quinazoline A solution of 6-methoxy-7- (3-chloropropoxy) quinazolin-4 - one 15.0g (0.056mol) was added to 150mL of freshly distilled thionyl chloride, and refluxed for 3h. 反应毕,减压蒸除二氯亚砜后,加入冰水200mL,搅拌得浅黄色固体,抽滤,水洗至中性,干燥,得到产物13.4g(收率:83.8%)。 Completion of the reaction, after addition of thionyl chloride was distilled off under reduced pressure, 200 mL of ice water was added, with stirring to give a pale yellow solid was filtered off with suction, washed with water until neutral, and dried to give 13.4 g of product (yield: 83.8%).

步骤F:4-(3-氯-4-氟苯胺基)-6-甲氧基-7-(3-氯丙氧基)喹唑啉的制备在异丙醇150mL中,加入4-氯-6-甲氧基-7-(3-氯丙氧基)喹唑啉7.8g(0.027mol)和3-氯-4-氟苯胺4.7g(0.032mol),搅拌,回流反应3h,反应毕,冷却反应液至室温,抽滤,冷异丙醇洗涤,干燥,得固体8.9g(收率:82.4%)。 Step F: 4- (3- chloro-4-fluoroanilino) -6-methoxy-7- (3-chloropropoxy) quinazoline in 150mL of isopropanol was added 4-chloro - 6-methoxy-7- (3-chloropropoxy) quinazoline 7.8g (0.027mol) of 3-chloro-4-fluoroaniline and 4.7 g (0.032 mol), stirred and refluxed for 3h, the reaction completion, The reaction was cooled to room temperature, washed, filtered off with suction, cold isopropanol, and dried to give 8.9 g of a solid (yield: 82.4%).

步骤G:4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[3-(呋喃-2-甲硫基)丙氧基]喹唑啉的制备在无水乙醇150mL中,加入呋喃甲硫醇3.6g(0.03mol)和氢氧化钠1.7g(0.04mol),微热、搅拌5分钟使固体全溶,向反应液中加入4-(3-氯-4-氟苯胺基)-6-甲氧基-7-(3-氯丙氧基)喹唑啉8.3g(0.02mol),搅拌回流反应1.5h,反应毕,将反应液冷却,倒入冷水中,析出大量固体,抽滤,水洗,干燥后得浅黄色产物9.5g(收率:96.0%)。 Step G: 4- (3- chloro-4-fluoroanilino) -6-methoxy-7- [3- (furan-2-methylthio-yl) propoxy] quinazoline was prepared in absolute ethanol 150mL was added furoyl mercaptan 3.6g (0.03mol) of sodium hydroxide and 1.7g (0.04mol), fever, stirred for 5 minutes to dissolve the whole solid, 4- (3-chloro-4- to the reaction solution fluoroanilino) -6-methoxy-7- (3-chloropropoxy) quinazoline 8.3g (0.02mol), the reaction was stirred at reflux for 1.5h, the reaction was completed, the reaction solution was cooled, poured into cold water, large amount of solid precipitated, filtered off with suction, washed with water, and dried to give 9.5 g of a pale yellow product (yield: 96.0%).

步骤H:4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[(5-二甲胺基甲基)呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐的制备在冰醋酸25mL中,加入33%的二甲胺水溶液0.7g(5mmol)和36%的甲醛水溶液0.2g(2.3mmol),室温搅拌5分钟,加入4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[3-(呋喃-2-甲硫基)丙氧基]喹唑啉1.0g(2mmol),升温至50℃反应24h,反应毕,减压蒸除溶剂,向残留液中加入少量水稀释,以0.1mol/L氢氧化钠水溶液调pH值至10,二氯甲烷提取,合并有机相,水洗,无水硫酸镁干燥。 Step H: 4- (3- chloro-4-fluoroanilino) -6-methoxy-7 - [[3 - [(5-dimethylaminomethyl) furan-2] methylthio] propionic oxy] quinazoline oxalate in 25mL glacial acetic acid was added 33% aqueous dimethylamine solution of 0.7g (5mmol) of 36% aqueous formaldehyde solution and 0.2g (2.3mmol), stirred at room temperature for 5 minutes, 4 - (3-chloro-4-fluoroanilino) -6-methoxy-7- [3- (furan-2-methylthio-yl) propoxy] quinazoline 1.0g (2mmol), warmed to 50 deg.] C the reaction 24h, the reaction was completed, the solvent was distilled off under reduced pressure, water was added to the residue diluted with a small amount of liquid to 0.1mol / L sodium hydroxide aqueous solution to a pH of 10, extracted with dichloromethane, the organic phases were combined, washed with water, dried over anhydrous sulfate magnesium sulfate. 减压蒸干溶剂,得油状物,用少量丙酮溶液油状物,滴加草酸丙酮溶液调节pH值为2-3,静置析出固体,抽滤,少量丙酮洗,干燥,得实施例1化合物1.0g(收率:83.3%)。 The solvent was evaporated under reduced pressure to give an oil, an oil with a small amount of acetone solution was added dropwise a solution of oxalic acid in acetone adjusted to pH 2-3, the precipitated solid was left to stand, filtered by suction, a small amount of acetone, and dried, to give the compound of Example 1 1.0 Embodiment G (yield: 83.3%).

1H-NMR(DMSO):2.09(m,2H),2.69(s,8H),3.85(s,2H),4.05(s,3H),4.24(t,2H),4.33(s,2H),6.41(d,1H),6.65(d,1H),7.50(d,1H),7.56(d,1H),7.81(d,1H),8.07(d,1H),8.54(s,1H),8.88(s,1H),11.86(s,1H);MS:531.1(M+H). 1H-NMR (DMSO): 2.09 (m, 2H), 2.69 (s, 8H), 3.85 (s, 2H), 4.05 (s, 3H), 4.24 (t, 2H), 4.33 (s, 2H), 6.41 (d, 1H), 6.65 (d, 1H), 7.50 (d, 1H), 7.56 (d, 1H), 7.81 (d, 1H), 8.07 (d, 1H), 8.54 (s, 1H), 8.88 ( s, 1H), 11.86 (s, 1H); MS: 531.1 (M + H).

按照实施例1的方法,以3-甲氧基-4-羟基苯甲酸甲酯和1,3-溴氯丙烷或1,2-溴氯乙烷为起始原料,首先制备得到4-氯-6-甲氧基-7-(3-氯烷氧基)喹唑啉,然后与适合的胺发生取代反应,再与呋喃甲硫醇发生取代反应,进而与适合的脂肪胺进行Mannich反应,分别制得实施例2-39化合物:实施例2:4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.20(t,3H),2.05(m,2H),2.62(s,3H),2.68(t,2H),2.99(q,2H),3.82(s,2H),3.96(s,3H),4.19(t,2H),4.29(s,2H),6.39(d,1H),6.61(d,1H),7.20(s,1H),7.44(t,1H),7.81(m,1H),7.86(s,1H),8.13(dd,1H),8.51(s,1H);MS:545.2(M+H). The method of Example 1 to 3-methoxy-4-hydroxybenzoate and 1,3-bromochloropropane or 1,2-bromochloroethane as a starting material, is first prepared 4-chloro - 6-methoxy-7- (3-chloro-alkoxy) quinazoline, and then with the appropriate amine substitution reaction, methanethiol and then furan substitution reaction, further subjected to Mannich reaction with a suitable aliphatic amine, respectively, to obtain the compound of Example 2-39: Example 2: 4- (3-chloro-4-fluoroanilino) -6-methoxy -7 - [[3- [5- (N- methyl-ethylamine ) furan-2-methyl] methylthio] propoxy] quinazoline oxalate 1H-NMR (DMSO): 1.20 (t, 3H), 2.05 (m, 2H), 2.62 (s, 3H), 2.68 (t, 2H), 2.99 (q, 2H), 3.82 (s, 2H), 3.96 (s, 3H), 4.19 (t, 2H), 4.29 (s, 2H), 6.39 (d, 1H), 6.61 (d, 1H), 7.20 (s, 1H), 7.44 (t, 1H), 7.81 (m, 1H), 7.86 (s, 1H), 8.13 (dd, 1H), 8.51 (s, 1H); MS: 545.2 (M + H).

实施例3:4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.89(s,4H),2.06(m,2H),2.67(t,2H),3.22(s,4H),3.83(s,2H),3.97(s,3H),4.21(t,2H),4.38(s,2H),6.38(d,1H),6.60(d,1H),7.22(s,1H),7.46(t,1H),7.82(m,1H),7.88(s,1H),8.15(dd,1H),8.53(s,1H);MS:557.1(M+H). Example 3: 4- (3-chloro-4-fluoroanilino) -6-methoxy-7 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio ] propoxy] quinazoline oxalate 1H-NMR (DMSO): 1.89 (s, 4H), 2.06 (m, 2H), 2.67 (t, 2H), 3.22 (s, 4H), 3.83 (s, 2H), 3.97 (s, 3H), 4.21 (t, 2H), 4.38 (s, 2H), 6.38 (d, 1H), 6.60 (d, 1H), 7.22 (s, 1H), 7.46 (t, 1H ), 7.82 (m, 1H), 7.88 (s, 1H), 8.15 (dd, 1H), 8.53 (s, 1H); MS: 557.1 (m + H).

实施例4:4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.06(m,2H),2.69(s,8H),3.84(s,2H),3.98(s,3H),4.21(t,3H),4.29(s,2H),6.40(d,1H),6.60(d,1H),7.23(s,1H),7.41(d,2H),7.91(s,1H),7.94(d,2H),8.51(s,1H);MS:563.2(M+H). Example 4: 4- (4-methoxyphenoxy) -6-methoxy-7 - [[3- [5- (dimethylamino) methyl-furan-2] methylthio] propoxy] quinazoline oxalate 1H-NMR (DMSO): 2.06 (m, 2H), 2.69 (s, 8H), 3.84 (s, 2H), 3.98 (s, 3H), 4.21 (t, 3H ), 4.29 (s, 2H), 6.40 (d, 1H), 6.60 (d, 1H), 7.23 (s, 1H), 7.41 (d, 2H), 7.91 (s, 1H), 7.94 (d, 2H) , 8.51 (s, 1H); MS: 563.2 (M + H).

实施例5:4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐 [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio ---6- methoxy-7 4- (4-methoxyanilino): Example 5 ] propoxy] quinazoline oxalate

1H-NMR(DMSO):1.89(s,4H),2.05(m,2H),2.68(t,2H),3.22(s,4H),3.83(s,2H),3.98(s,3H),4.21(t,2H),4.38(s,2H),6.39(d,1H),6.59(d,1H),7.23(s,1H),7.41(d,2H),7.90(s,1H),7.94(d,2H),8.52(s,1H);MS:589.1(M+H). 1H-NMR (DMSO): 1.89 (s, 4H), 2.05 (m, 2H), 2.68 (t, 2H), 3.22 (s, 4H), 3.83 (s, 2H), 3.98 (s, 3H), 4.21 (t, 2H), 4.38 (s, 2H), 6.39 (d, 1H), 6.59 (d, 1H), 7.23 (s, 1H), 7.41 (d, 2H), 7.90 (s, 1H), 7.94 ( d, 2H), 8.52 (s, 1H); MS: 589.1 (M + H).

实施例6:4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.22(t,3H),2.09(m,2H),2.68(m,5H),3.03(m,2H),3.84(s,2H),3.98(s,3H),4.20(t,2H),4.33(s,2H),6.41(d,1H),6.64(d,1H),7.26(s,1H),7.42(d,2H),7.92(s,1H),7.94(d,2H),8.54(s,1H);MS:577.2(M+H). - [[3- [5- (N- methyl-ethylamino) methyl-furan-2] A 4- (4-methoxyphenoxy) -6-methoxy-7: Example 6 thio] propoxy] quinazoline oxalate 1H-NMR (DMSO): 1.22 (t, 3H), 2.09 (m, 2H), 2.68 (m, 5H), 3.03 (m, 2H), 3.84 ( s, 2H), 3.98 (s, 3H), 4.20 (t, 2H), 4.33 (s, 2H), 6.41 (d, 1H), 6.64 (d, 1H), 7.26 (s, 1H), 7.42 (d , 2H), 7.92 (s, 1H), 7.94 (d, 2H), 8.54 (s, 1H); MS: 577.2 (M + H).

实施例7:4-(4-三氟甲基苯胺基)-6-甲氧基-7-[[3-[5-(4-吗啉基)甲基呋哺-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.05(m,2H),2.67(t,2H),2.77(s,4H),3.68(s,4H),3.82(s,2H),3.93(s,2H),3.99(s,3H),4.22(t,2H),6.33(d,1H),6.42(d,1H),7.24(s,1H),7.76(d,2H),7.91(s,1H),8.11(d,2H),8.58(s,1H);MS:589.2(M+H). Example 7: 4- (4-methylanilino) -6-methoxy-7 - [[3- [5- (4-morpholinyl) -2- furosemide feeding methyl] methylthio ] propoxy] quinazoline oxalate 1H-NMR (DMSO): 2.05 (m, 2H), 2.67 (t, 2H), 2.77 (s, 4H), 3.68 (s, 4H), 3.82 (s, 2H), 3.93 (s, 2H), 3.99 (s, 3H), 4.22 (t, 2H), 6.33 (d, 1H), 6.42 (d, 1H), 7.24 (s, 1H), 7.76 (d, 2H ), 7.91 (s, 1H), 8.11 (d, 2H), 8.58 (s, 1H); MS: 589.2 (M + H).

实施例8:4-(3-氟苯胺基)-6-甲氧基-7-[[3-[5-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.05(m,2H),2.76(m,8H),3.84(s,2H),3.98(s,2H),4.22(m,4H),6.40(s,1H),6.60(s,1H),6.93(t,3H),7.22(s,1H),7.42(m,1H),7.64(t,1H),7.89(s,1H),7.92(s,1H),8.54(s,1H);MS:497.2(M+H). Example 8: 4- (3-fluoroanilino) -6-methoxy-7 - [[3- [5- (dimethylamino) methyl-furan-2] methylthio] propoxy] oxalate quinazoline 1H-NMR (DMSO): 2.05 (m, 2H), 2.76 (m, 8H), 3.84 (s, 2H), 3.98 (s, 2H), 4.22 (m, 4H), 6.40 ( s, 1H), 6.60 (s, 1H), 6.93 (t, 3H), 7.22 (s, 1H), 7.42 (m, 1H), 7.64 (t, 1H), 7.89 (s, 1H), 7.92 (s , 1H), 8.54 (s, 1H); MS: 497.2 (M + H).

实施例9:4-(3-氟苯胺基)-6-甲氧基-7-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.88(s,4H),2.09(m,2H),2.70(t,2H),3.22(s,4H),3.84(s,2H),3.96(s,3H),4.24(t,2H),4.37(s,2H),6.37(s,1H),6.58(s,1H),7.24(s,1H),7.45(m,1H),7.63(t,1H),7.92(s,1H),8.25(m,2H),8.55(s,1H);MS:523.4(M+H). Example 9: 4- (3-fluoroanilino) -6-methoxy-7 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] propoxy ] quinazolin oxalate 1H-NMR (DMSO): 1.88 (s, 4H), 2.09 (m, 2H), 2.70 (t, 2H), 3.22 (s, 4H), 3.84 (s, 2H), 3.96 (s, 3H), 4.24 (t, 2H), 4.37 (s, 2H), 6.37 (s, 1H), 6.58 (s, 1H), 7.24 (s, 1H), 7.45 (m, 1H), 7.63 ( t, 1H), 7.92 (s, 1H), 8.25 (m, 2H), 8.55 (s, 1H); MS: 523.4 (m + H).

实施例10:4-(3-氟苯胺基)-6-甲氧基-7-[[3-[5-(N-甲基丙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐 Example 10: 4- (3-fluoroanilino) -6-methoxy -7 - [[3- [5- (N- methyl-propylamino) methyl-furan-2] methylthio] propoxy yl] quinazoline oxalate

1H-NMR(DMSO):0.85(t,3H),1.61(m,2H),2.09(m,2H),2.63(s,3H),2.71(t,2H),2.86(t,2H),3.84(s,2H),3.96(s,3H),4.23(t,2H),4.27(s,2H),6.38(d,1H),6.60(d,1H),7.25(s,1H),7.45(d,1H),7.63(t,1H),7.90(s,1H),8.21(m,1H),8.24(s,1H),8.54(s,1H);MS:525.2(M+H). 1H-NMR (DMSO): 0.85 (t, 3H), 1.61 (m, 2H), 2.09 (m, 2H), 2.63 (s, 3H), 2.71 (t, 2H), 2.86 (t, 2H), 3.84 (s, 2H), 3.96 (s, 3H), 4.23 (t, 2H), 4.27 (s, 2H), 6.38 (d, 1H), 6.60 (d, 1H), 7.25 (s, 1H), 7.45 ( d, 1H), 7.63 (t, 1H), 7.90 (s, 1H), 8.21 (m, 1H), 8.24 (s, 1H), 8.54 (s, 1H); MS: 525.2 (m + H).

实施例11:4-(4-氟苯胺基)-6-甲氧基-7-[[3-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.18(t,3H),2.05(m,2H),2.57(s,2H),2.67(m,4H),2.92(s,2H),3.83(s,2H),3.96(s,3H),4.20(t,2H),6.38(s,1H),6.56(s,1H),7.22(m,3H),7.79~7.86(m,3H),8.44(s,1H),9.60(brs,1H);MS:511.4(M+H). Example 11: 4- (4-fluoroanilino) -6-methoxy -7 - [[3- [5- (N- ethylamino-methyl) furan-2-methyl] methylthio] propionic oxy] quinazoline oxalate 1H-NMR (DMSO): 1.18 (t, 3H), 2.05 (m, 2H), 2.57 (s, 2H), 2.67 (m, 4H), 2.92 (s, 2H) , 3.83 (s, 2H), 3.96 (s, 3H), 4.20 (t, 2H), 6.38 (s, 1H), 6.56 (s, 1H), 7.22 (m, 3H), 7.79 ~ 7.86 (m, 3H ), 8.44 (s, 1H), 9.60 (brs, 1H); MS: 511.4 (M + H).

实施例12:4-(3-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐MS:563.3(M+H). Example 12: 4- (3-methoxyphenoxy) -6-methoxy-7 - [[3- [5- (dimethylamino) methyl-furan-2] methylthio] propoxy] quinazoline oxalate MS: 563.3 (M + H).

实施例13:4-(3-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(N-甲基异丙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐MS:591.2(M+H). Example 13: 4- (3-methoxyanilino) -6-methoxy -7 - [[3- [5- (N- isopropylamino-methyl) furan-2-methyl] methanesulfonamide thio] propoxy] quinazoline oxalate MS: 591.2 (M + H).

实施例14:4-[(喹啉-5-)胺基]-6-甲氧基-7-[[3-[5-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.07(m,2H),2.69(m,8H),3.82(s,2H),3.99(s,3H),4.23~4.28(m,4H),6.41(d,1H),6.61(d,1H),7.25(s,1H),7.51(m,1H),7.68(d,1H),7.85(t,1H),7.80(s,1H),8.02(s,1H),8.27(s,1H),8.29(d,1H),8.94(d,1H);MS:529.9(M+H). Example 14: 4 - [(quinolin-5) amino] -6-methoxy-7 - [[3- [5- (dimethylamino) methyl-furan-2] methylthio] propoxy] quinazoline oxalate 1H-NMR (DMSO): 2.07 (m, 2H), 2.69 (m, 8H), 3.82 (s, 2H), 3.99 (s, 3H), 4.23 ~ 4.28 (m , 4H), 6.41 (d, 1H), 6.61 (d, 1H), 7.25 (s, 1H), 7.51 (m, 1H), 7.68 (d, 1H), 7.85 (t, 1H), 7.80 (s, 1H), 8.02 (s, 1H), 8.27 (s, 1H), 8.29 (d, 1H), 8.94 (d, 1H); MS: 529.9 (M + H).

实施例15:4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(4-甲基-1-哌嗪基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉MS:588.3(M+H). Example 15: 4- (3-trifluoromethyl-anilino) -6-methoxy-7 - [[2- [5- (4-methylpiperazin-1-piperazinyl) methyl-furan-2 ] methylthio] ethoxy] quinazoline MS: 588.3 (M + H).

实施例16:4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:559.3(M+H). Example 16: 4- (3-trifluoromethyl-anilino) -6-methoxy-7 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy] quinazoline oxalate MS: 559.3 (M + H).

实施例17:4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基丁胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐 Example 17: 4- (3-trifluoromethylanilino) -6-methoxy -7 - [[2- [5- (N- methylbutan-amino) furan-2-methyl] methylthio yl] ethoxy] quinazoline oxalate

MS:575.2(M+H). MS: 575.2 (M + H).

实施例18:4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:547.2(M+H). - [[2- [5- (N- methyl-ethylamino) methyl-furan-2] methylthio 4- (3-trifluoromethyl-anilino) -6-methoxy-7: Example 18 yl] ethoxy] quinazoline oxalate MS: 547.2 (M + H).

实施例19:4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(1-哌啶基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:573.2(M+H). Example 19: 4- (3-trifluoromethyl-anilino) -6-methoxy-7 - [[2- [5- (1-piperidinyl) methyl-furan-2] methylthio] ethoxy] quinazoline oxalate MS: 573.2 (M + H).

实施例20:4-(4-氟苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:509.2(M+H). Example 20: 4- (4-fluoroanilino) -6-methoxy-7 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy ] quinazoline oxalate MS: 509.2 (M + H).

实施例21:4-(4-氟苯胺基)-6-甲氧基-7-[[2-[5-(4-甲基-1-哌嗪基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.72(m,7H),2.92(t,2H),3.56(m,4H),3.82(s,2H),3.94(s,2H),3.96(s,3H),4.28(t,2H),6.26(d,2H),6.30(d,2H),7.19(s,1H),7.24(t,2H),7.78(dd,2H),7.86(s,1H),8.45(s,1H),9.59(s,1H);MS:538.1(M+H). Example 21: 4- (4-fluoroanilino) -6-methoxy-7 - [[2- [5- (4-methylpiperazin-1-piperazinyl) furan-2-methyl] methylthio yl] ethoxy] quinazoline oxalate 1H-NMR (DMSO): 2.72 (m, 7H), 2.92 (t, 2H), 3.56 (m, 4H), 3.82 (s, 2H), 3.94 (s , 2H), 3.96 (s, 3H), 4.28 (t, 2H), 6.26 (d, 2H), 6.30 (d, 2H), 7.19 (s, 1H), 7.24 (t, 2H), 7.78 (dd, 2H), 7.86 (s, 1H), 8.45 (s, 1H), 9.59 (s, 1H); MS: 538.1 (M + H).

实施例22:4-(4-氟苯胺基)-6-甲氧基-7-[[2-[5-(4-吗啉基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.63(m,4H),2.93(t,2H),3.62(m,4H),3.78(s,2H),3.97(s,3H),4.29(t,2H),6.34(d,1H),6.35(d,1H),7.22(dd,2H),7.24(s,1H),7.77(m,2H),7.87(s,1H),8.47(s,1H),9.64(s,1H);MS:525.1(M+H). Example 22: 4- (4-fluoroanilino) -6-methoxy-7 - [[2- [5- (4-morpholinyl) furan-2-methyl] methylthio] ethoxy ] quinazolin oxalate 1H-NMR (DMSO): 2.63 (m, 4H), 2.93 (t, 2H), 3.62 (m, 4H), 3.78 (s, 2H), 3.97 (s, 3H), 4.29 (t, 2H), 6.34 (d, 1H), 6.35 (d, 1H), 7.22 (dd, 2H), 7.24 (s, 1H), 7.77 (m, 2H), 7.87 (s, 1H), 8.47 ( s, 1H), 9.64 (s, 1H); MS: 525.1 (M + H).

实施例23:4-(2-氟苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.88(m,4H),2.94(t,2H),3.20(m,4H),3.94(s,3H),3.99(s,2H),4.31(t,2H),4.37(s,2H),6.42(d,1H),6.59(d,1H),7.20(s,1H),7.26~7.33(m,3H),7.54(t,1H),7.85(s,1H),8.35(s,1H);MS:509.2(M+H). Example 23: 4- (2-fluoroanilino) -6-methoxy-7 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy ] quinazolin oxalate 1H-NMR (DMSO): 1.88 (m, 4H), 2.94 (t, 2H), 3.20 (m, 4H), 3.94 (s, 3H), 3.99 (s, 2H), 4.31 (t, 2H), 4.37 (s, 2H), 6.42 (d, 1H), 6.59 (d, 1H), 7.20 (s, 1H), 7.26 ~ 7.33 (m, 3H), 7.54 (t, 1H), 7.85 (s, 1H), 8.35 (s, 1H); MS: 509.2 (M + H).

实施例24:4-(2-氟苯胺基)-6-甲氧基-7-[[2-[5-(二甲胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐 Example 24: 4- (2-fluoroanilino) -6-methoxy-7 - [[2- [5- (dimethylamino) methyl-furan-2] methylthio] ethoxy] quinazoline oxalate

1H-NMR(DMSO):2.67(s,6H),2.94(t,2H),3.95(s,3H),3.99(s,2H),4.26(s,2H),4.31(t,2H),6.43(d,1H),6.60(d,1H),7.20(s,1H),7.27~7.34(m,3H),7.52(t,1H),7.85(s,1H),8.36(s,1H);MS:483.1(M+H). 1H-NMR (DMSO): 2.67 (s, 6H), 2.94 (t, 2H), 3.95 (s, 3H), 3.99 (s, 2H), 4.26 (s, 2H), 4.31 (t, 2H), 6.43 (d, 1H), 6.60 (d, 1H), 7.20 (s, 1H), 7.27 ~ 7.34 (m, 3H), 7.52 (t, 1H), 7.85 (s, 1H), 8.36 (s, 1H); MS: 483.1 (M + H).

实施例25:4-(2-氟苯胺基)-6-甲氧基-7-[[2-[5-(4-吗啉基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.60(m,4H),2.93(t,2H),3.61(m,4H),3.74(s,2H),3.95(s,3H),3.96(s,2H),4.29(t,2H),6.34(s,2H),7.19(s,1H),7.29~7.34(m,3H),7.54(t,1H),7.85(s,1H),8.37(s,1H);MS:524.9(M+H). Example 25: 4- (2-fluoroanilino) -6-methoxy-7 - [[2- [5- (4-morpholinyl) furan-2-methyl] methylthio] ethoxy ] quinazolin oxalate 1H-NMR (DMSO): 2.60 (m, 4H), 2.93 (t, 2H), 3.61 (m, 4H), 3.74 (s, 2H), 3.95 (s, 3H), 3.96 (s, 2H), 4.29 (t, 2H), 6.34 (s, 2H), 7.19 (s, 1H), 7.29 ~ 7.34 (m, 3H), 7.54 (t, 1H), 7.85 (s, 1H), 8.37 (s, 1H); MS: 524.9 (M + H).

实施例26:4-(2-氟苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基丙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):0.86(t,3H),1.63(m,2H),2.64(s,3H),2.87(t,2H),2.92(t,2H),3.95(s,3H),4.00(s,2H),4.28(s,2H),4.31(t,2H),6.44(d,1H),6.62(d,1H),7.20(s,1H),7.26~7.33(m,3H),7.54(t,1H),7.85(s,1H),8.36(s,1H);MS:511.2(M+H). Example 26: 4- (2-fluoroanilino) -6-methoxy -7 - [[2- [5- (N- methyl-propylamino) methyl-furan-2] methylthio] ethoxy yl] quinazoline oxalate 1H-NMR (DMSO): 0.86 (t, 3H), 1.63 (m, 2H), 2.64 (s, 3H), 2.87 (t, 2H), 2.92 (t, 2H), 3.95 (s, 3H), 4.00 (s, 2H), 4.28 (s, 2H), 4.31 (t, 2H), 6.44 (d, 1H), 6.62 (d, 1H), 7.20 (s, 1H), 7.26 ~ 7.33 (m, 3H), 7.54 (t, 1H), 7.85 (s, 1H), 8.36 (s, 1H); MS: 511.2 (m + H).

实施例27:4-(3,5-二氟苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:527.2(M+H). Example 27: 4- (3,5-Difluorophenyl) -6-methoxy-7 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy] quinazoline oxalate MS: 527.2 (M + H).

实施例28:4-(3,5-二氟苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:515.1(M+H). Example 28: 4- (3,5-Difluorophenyl) -6-methoxy -7 - [[2- [5- (N- methyl-ethylamino) methyl-furan-2] methylthio yl] ethoxy] quinazoline oxalate MS: 515.1 (M + H).

实施例29:4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[2-[5-(二甲胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉1H-NMR(DMSO):2.50(s,6H),2.94(t,2H),3.97(m,7H),4.31(t,2H),6.40(s,1H);6.49(s,1H),7.21(s,1H),7.45(t,1H),7.79(m,1H),7.84(s,1H),8.13(m,1H),8.52(s,1H),9.58(s,1H);MS:517.1(M+H). - [[2- [5- (dimethylamino) methyl-furan-2] methylthio] 4- (3-chloro-4-fluoroanilino) -6-methoxy-7: example 29 ethoxy] quinazoline 1H-NMR (DMSO): 2.50 (s, 6H), 2.94 (t, 2H), 3.97 (m, 7H), 4.31 (t, 2H), 6.40 (s, 1H); 6.49 (s, 1H), 7.21 (s, 1H), 7.45 (t, 1H), 7.79 (m, 1H), 7.84 (s, 1H), 8.13 (m, 1H), 8.52 (s, 1H), 9.58 ( s, 1H); MS: 517.1 (M + H).

实施例30:4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基丙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:545.1(M+H). Example 30: 4- (3-chloro-4-fluoroanilino) -6-methoxy -7 - [[2- [5- (N- methyl-propylamino) methyl-furan-2] methylthio yl] ethoxy] quinazoline oxalate MS: 545.1 (M + H).

实施例31:4-(3,4-二氟苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.90(m,4H),2.95(t,2H),3.24(m,4H),3.98(m,5H),4.32(t,2H),4.40(t,2H),6.43(s,1H);6.60(s,1H),7.24(s,1H),7.46(m,1H),7.58(m,1H),7.88(s,1H),8.06(m,1H),8.53(s,1H);MS:527.1(M+H). Example 31: 4- (3,4-difluorophenyl) -6-methoxy-7 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy] quinazoline oxalate 1H-NMR (DMSO): 1.90 (m, 4H), 2.95 (t, 2H), 3.24 (m, 4H), 3.98 (m, 5H), 4.32 (t, 2H ), 4.40 (t, 2H), 6.43 (s, 1H); 6.60 (s, 1H), 7.24 (s, 1H), 7.46 (m, 1H), 7.58 (m, 1H), 7.88 (s, 1H) , 8.06 (m, 1H), 8.53 (s, 1H); MS: 527.1 (m + H).

实施例32:4-(3,4-二氟苯胺基)-6-甲氧基-7-[[2-[5-(二甲胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:501.1(M+H). Example 32: 4- (3,4-difluorophenyl) -6-methoxy-7 - [[2- [5- (dimethylamino) methyl-furan-2] methylthio] acetate oxy] quinazoline oxalate MS: 501.1 (M + H).

实施例33:4-(4-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(4-甲基-1-哌嗪基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:588.2(M+H). Example 33: 4- (4-methylanilino) -6-methoxy-7 - [[2- [5- (4-methylpiperazin-1-piperazinyl) methyl-furan-2 ] methylthio] ethoxy] quinazoline oxalate MS: 588.2 (M + H).

实施例34:4-(4-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基环丙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐. Example 34: 4- (4-methylanilino) -6-methoxy -7 - [[2- [5- (N- cyclopropylmethyl-methyl-amino) methyl-furan-2] methylthio yl] ethoxy] quinazoline oxalate.

1H-NMR(DMSO):0.57(m,4H),2.29(m,2H),2.56(s,3H),2.94(t,2H),3.99(m,5H),4.09(s,2H),4.63(t,2H),6.38(s,1H),6.44(s,1H),7.25(s,1H),7.76(d,2H),7.91(s,1H),8.11(d,2H),8.58(s,1H);MS:559.2(M+H). 1H-NMR (DMSO): 0.57 (m, 4H), 2.29 (m, 2H), 2.56 (s, 3H), 2.94 (t, 2H), 3.99 (m, 5H), 4.09 (s, 2H), 4.63 (t, 2H), 6.38 (s, 1H), 6.44 (s, 1H), 7.25 (s, 1H), 7.76 (d, 2H), 7.91 (s, 1H), 8.11 (d, 2H), 8.58 ( s, 1H); MS: 559.2 (M + H).

实施例35:4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基丙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:577.2(M+H). Example 35: 4- (4-methoxyanilino) -6-methoxy -7 - [[2- [5- (N- methyl-propylamino) methyl-furan-2] methylthio yl] ethoxy] quinazoline oxalate MS: 577.2 (M + H).

实施例36:4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[2-[5-(二甲胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:549.1(M+H). Example 36: 4- (4-methoxyphenoxy) -6-methoxy-7 - [[2- [5- (dimethylamino) methyl-furan-2] methylthio] ethoxy] quinazoline oxalate MS: 549.1 (M + H).

实施例37:4-(1-苯基乙胺基)-6-甲氧基-7-[[2-[5-(4-吗啉基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.63(d,3H),2.59(m,4H),2.92(t,2H),3.60(m,4H),3.72(s,2H),3.95(s,5H),4.26(t,2H),5.68(m,1H),6.32(s,2H),7.16(s,1H),7.24(t,1H),7.34(t,2H),7.44(d,2H),7.87(s,1H),8.46(s,1H),8.73(d,1H);MS:535.1(M+H). Example 37: 4- (1-phenylethylamine) -6-methoxy-7 - [[2- [5- (4-morpholinyl) furan-2-methyl] methylthio] acetate oxy] quinazoline oxalate 1H-NMR (DMSO): 1.63 (d, 3H), 2.59 (m, 4H), 2.92 (t, 2H), 3.60 (m, 4H), 3.72 (s, 2H) , 3.95 (s, 5H), 4.26 (t, 2H), 5.68 (m, 1H), 6.32 (s, 2H), 7.16 (s, 1H), 7.24 (t, 1H), 7.34 (t, 2H), 7.44 (d, 2H), 7.87 (s, 1H), 8.46 (s, 1H), 8.73 (d, 1H); MS: 535.1 (M + H).

实施例38:4-(4-甲氧基苯甲胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉 Example 38: 4- (4-Methoxy-benzyloxy) -6-methoxy-7 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio ] ethoxy] quinazoline

MS:535.4(M+H). MS: 535.4 (M + H).

实施例39:4-(4-氟苯甲胺基)-6-甲氧基-7-[[2-[5-(1-哌啶基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉(YL-365)MS:537.5(M+H). Example 39: 4- (4-fluorophenyl methylamino) -6-methoxy-7 - [[2- [5- (1-piperidinyl) methyl-furan-2] methylthio] acetate oxy] quinazoline (YL-365) MS: 537.5 (M + H).

按照实施例1的方法,以3-羟基-4-甲氧基苯甲酸甲酯和1,3-溴氯丙烷或1,2-溴氯乙烷为起始原料,制得实施例40-65化合物: The method of Example 1, to 3-hydroxy-4-methoxybenzoate and 1,3-bromochloropropane or 1,2-bromochloroethane as a starting material, prepared in Example 40-65 compound:

实施例40:4-(3-氟苯胺基)-7-甲氧基-6-[[3-[5-(4-吗啉基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.07(m,2H),2.69~2.72(m,6H),3.65(m,4H),3.82(s,2H),3.87(s,2H),3.95(s,3H),4.22(t,2H),6.31(d,1H),6.38(d,1H),6.94(t,1H),7.24(s,1H),7.43(dd,1H),7.61(d,1H),7.87(d,1H),7.95(s,1H),8.56(s,1H);MS:539.1(M+H). Example 40: 4- (3-fluoroanilino) -7-methoxy-6 - [[3- [5- (4-morpholinyl) furan-2-methyl] methylthio] propoxy ] quinazolin oxalate 1H-NMR (DMSO): 2.07 (m, 2H), 2.69 ~ 2.72 (m, 6H), 3.65 (m, 4H), 3.82 (s, 2H), 3.87 (s, 2H) , 3.95 (s, 3H), 4.22 (t, 2H), 6.31 (d, 1H), 6.38 (d, 1H), 6.94 (t, 1H), 7.24 (s, 1H), 7.43 (dd, 1H), 7.61 (d, 1H), 7.87 (d, 1H), 7.95 (s, 1H), 8.56 (s, 1H); MS: 539.1 (M + H).

实施例41:4-(3-氟苯胺基)-7-甲氧基-6-[[3-[5-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.09(m,2H),2.66(m,8H),3.84(s,2H),3.95(s,3H),4.26(m,4H),6.39(d,1H),6.58(d,1H),6.93(t,1H),7.24(s,1H),7.42(dd,1H),7.61(d,1H),7.87(d,1H),7.91(s,1H),8.53(s,1H);MS:497.3(M+H). Example 41: 4- (3-fluoroanilino) -7-methoxy-6 - [[3- [5- (dimethylamino) methyl-furan-2] methylthio] propoxy] oxalate quinazoline 1H-NMR (DMSO): 2.09 (m, 2H), 2.66 (m, 8H), 3.84 (s, 2H), 3.95 (s, 3H), 4.26 (m, 4H), 6.39 ( d, 1H), 6.58 (d, 1H), 6.93 (t, 1H), 7.24 (s, 1H), 7.42 (dd, 1H), 7.61 (d, 1H), 7.87 (d, 1H), 7.91 (s , 1H), 8.53 (s, 1H); MS: 497.3 (M + H).

实施例42:4-(3-氟苯胺基)-7-甲氧基-6-[[3-[5-(N-甲基丙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):0.85(t,3H),1.60(m,2H),2.07(m,2H),2.61(s,3H),2.67(t,2H),2.84(m,2H),3.82(s,2H),3.93(s,3H),4.21(t,2H),4.25(s,2H),6.38(d,1H),6.59(d,1H),6.94(t,1H),7.22(s,1H),7.40(dd,1H),7.61(d,1H),7.86(s,1H),7.89(d,1H),8.52(s,1H);MS:525.2(M+H). Example 42: 4- (3-fluoroanilino) -7-methoxy -6 - [[3- [5- (N- methyl-propylamino) methyl-furan-2] methylthio] propoxy yl] quinazoline oxalate 1H-NMR (DMSO): 0.85 (t, 3H), 1.60 (m, 2H), 2.07 (m, 2H), 2.61 (s, 3H), 2.67 (t, 2H), 2.84 (m, 2H), 3.82 (s, 2H), 3.93 (s, 3H), 4.21 (t, 2H), 4.25 (s, 2H), 6.38 (d, 1H), 6.59 (d, 1H), 6.94 (t, 1H), 7.22 (s, 1H), 7.40 (dd, 1H), 7.61 (d, 1H), 7.86 (s, 1H), 7.89 (d, 1H), 8.52 (s, 1H); MS: 525.2 (M + H).

实施例43:4-(4-氟苯胺基)-7-甲氧基-6-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.85(m,2H),2.07(m,2H),2.67(t,2H),3.17(m,4H),3.82(s,2H),3.93(s,3H),4.19(t,2H),4.33(s,2H),6.36(d,1H),6.55(d,1H),7.19~7.25(m,3H),7.75(m,2H),7.84(s,1H),8.43(s,1H);MS:523.4(M+H). Example 43: 4- (4-fluoroanilino) -7-methoxy-6 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] propoxy ] quinazolin oxalate 1H-NMR (DMSO): 1.85 (m, 2H), 2.07 (m, 2H), 2.67 (t, 2H), 3.17 (m, 4H), 3.82 (s, 2H), 3.93 (s, 3H), 4.19 (t, 2H), 4.33 (s, 2H), 6.36 (d, 1H), 6.55 (d, 1H), 7.19 ~ 7.25 (m, 3H), 7.75 (m, 2H), 7.84 (s, 1H), 8.43 (s, 1H); MS: 523.4 (M + H).

实施例44:4-(3-溴苯胺基)-7-甲氧基-6-[[3-[5-(1-哌啶基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.47(m,2H),1.70(m,4H),2.08(m,2H),2.72(t,2H),3.03(m,4H),3.84(s,2H),3.95(s,3H),4.26(m,4H),6.38(d,1H),6.58(d,1H),7.24(s,1H),7.30~7.38(m,3H),7.88(m,2H),8.15(s,1H),8.54(s,1H);MS:599.1(M+H). Example 44: 4- (3-bromophenyl) -7-methoxy-6 - [[3- [5- (1-piperidinyl) methyl-furan-2] methylthio] propoxy ] quinazolin oxalate 1H-NMR (DMSO): 1.47 (m, 2H), 1.70 (m, 4H), 2.08 (m, 2H), 2.72 (t, 2H), 3.03 (m, 4H), 3.84 (s, 2H), 3.95 (s, 3H), 4.26 (m, 4H), 6.38 (d, 1H), 6.58 (d, 1H), 7.24 (s, 1H), 7.30 ~ 7.38 (m, 3H), 7.88 (m, 2H), 8.15 (s, 1H), 8.54 (s, 1H); MS: 599.1 (m + H).

实施例45:4-(3-三氟甲基苯胺基)-7-甲氧基-6-[[3-[5-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.09(m,2H),2.67(m,8H),3.84(m,2H),3.96(s,3H),4.26(m,4H),6.39(d,1H),6.59(d,1H),7.24(s,1H),7.44(d,1H),7.62(t,1H),7.89(s,1H),8.24(m,2H),8.55(s,1H);MS:547.3(M+H). Example 45: 4- (3-trifluoromethyl-phenylamino) -7-methoxy-6 - [[3- [5- (dimethylamino) methyl-furan-2] methylthio] propionic oxy] quinazoline oxalate 1H-NMR (DMSO): 2.09 (m, 2H), 2.67 (m, 8H), 3.84 (m, 2H), 3.96 (s, 3H), 4.26 (m, 4H) , 6.39 (d, 1H), 6.59 (d, 1H), 7.24 (s, 1H), 7.44 (d, 1H), 7.62 (t, 1H), 7.89 (s, 1H), 8.24 (m, 2H), 8.55 (s, 1H); MS: 547.3 (M + H).

实施例46:4-(3-三氟甲基苯胺基)-7-甲氧基-6-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.79(m,4H),2.09(m,2H),2.70(t,2H),2.91(m,4H),3.82(m,2H),3.96(s,3H),4.05(s,2H),4.23(t,2H),6.31(d,1H),6.42(d,1H),7.24(s,1H),7.45(d,1H),7.63(t,1H),7.91(s,1H),8.24(m,2H),8.54(s,1H);MS:573.1(M+H). Example 46: 4- (3-trifluoromethyl-phenylamino) -7-methoxy-6 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] propoxy] quinazoline oxalate 1H-NMR (DMSO): 1.79 (m, 4H), 2.09 (m, 2H), 2.70 (t, 2H), 2.91 (m, 4H), 3.82 (m, 2H ), 3.96 (s, 3H), 4.05 (s, 2H), 4.23 (t, 2H), 6.31 (d, 1H), 6.42 (d, 1H), 7.24 (s, 1H), 7.45 (d, 1H) , 7.63 (t, 1H), 7.91 (s, 1H), 8.24 (m, 2H), 8.54 (s, 1H); MS: 573.1 (m + H).

实施例47:4-(3-三氟甲基苯胺基)-7-甲氧基-6-[[3-[5-(N-甲基丙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐MS:575.2(M+H). Example 47: 4- (3-trifluoromethyl-phenylamino) -7-methoxy -6 - [[3- [5- (N- methyl-propylamino) methyl-furan-2] methylthio ] propoxy] quinazoline oxalate MS: 575.2 (M + H).

实施例48:4-(3,4-二氟苯胺基)-7-甲氧基-6-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐MS:541.2(M+H). Example 48: 4- (3,4-difluorophenyl) -7-methoxy-6 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] propoxy] quinazoline oxalate MS: 541.2 (M + H).

实施例49:4-(3,4-二氟苯胺基)-7-甲氧基-6-[[3-[5-(N-甲基丁胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐MS:557.2(M+H). Example 49: 4- (3,4-difluorophenyl) -7-methoxy -6 - [[3- [5- (N- methylbutan-amino) furan-2-methyl] methylthio yl] propoxy] quinazoline oxalate MS: 557.2 (M + H).

实施例50:4-(3,4-二氟苯胺基)-7-甲氧基-6-[[3-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐MS:529.2(M+H). Embodiment 50 cases: 7-methoxy-6 4- (3,4-difluorophenyl amino) - [[3- [5- (N- methyl-ethylamino) methyl-furan-2] methylthio yl] propoxy] quinazoline oxalate MS: 529.2 (M + H).

实施例51:4-(3-氯-4-氟苯胺基)-7-甲氧基-6-[[3-[5-(4-吗啉基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐MS:573.2(M+H). Example 51: 4- (3-chloro-4-fluoroanilino) -7-methoxy-6 - [[3- [5- (4-morpholinyl) furan-2-methyl] methylthio ] propoxy] quinazoline oxalate MS: 573.2 (M + H).

实施例52:4-(3-三氟甲基-4-氟苯胺基)-7-甲氧基-6-[[3-[5-(1-哌啶基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.46(m,2H),1.68(m,4H),2.08(m,2H),2.68(t,2H),3.01(m,4H),3.83(s,2H),3.95(s,3H),4.23(m,4H),6.38(d,1H),6.56(d,1H),7.24(s,1H),7.54(t,1H),7.88(s,1H),8.25(d,2H),8.53(s,1H);MS:605.2(M+H). Example 52: 4- (3-trifluoromethyl-4-fluoroanilino) -7-methoxy-6 - [[3- [5- (1-piperidinyl) methyl-furan-2] methylthio] propoxy] quinazoline oxalate 1H-NMR (DMSO): 1.46 (m, 2H), 1.68 (m, 4H), 2.08 (m, 2H), 2.68 (t, 2H), 3.01 (m, 4H), 3.83 (s, 2H), 3.95 (s, 3H), 4.23 (m, 4H), 6.38 (d, 1H), 6.56 (d, 1H), 7.24 (s, 1H), 7.54 ( t, 1H), 7.88 (s, 1H), 8.25 (d, 2H), 8.53 (s, 1H); MS: 605.2 (M + H).

实施例53:4-(3,5-双三氟甲基苯胺基)-7-甲氧基-6-[[3-[5-(4-吗啉基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐MS:656.8(M+H). Example 53: 4- (3,5-bis-trifluoromethyl-methylanilino) -7-methoxy-6 - [[3- [5- (4-morpholinyl) furan-2-methyl] methanesulfonamide thio] propoxy] quinazoline oxalate MS: 656.8 (M + H).

实施例54:4-(3,4-亚甲基二氧基苯胺基)-7-甲氧基-6-[[3-[5-(1-哌啶基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐. Example 54: 4- (3,4-methylenedioxy aniline-yl) -7-methoxy-6 - [[3- [5- (1-piperidinyl) methyl-furan-2] methylthio] propoxy] quinazoline oxalate.

1H-NMR(DMSO):1.47(m,2H),1.69(m,4H),2.08(m,2H),2.70(t,2H),3.03(m,4H),3.84(s,2H),3.94(s,3H),4.20(t,2H),4.26(s,2H),6.04(s,2H),6.39(d,1H),6.58(d,1H),6.94(d,1H),7.10(d,1H),7.22(s,1H),7.40(s,1H),7.87(s,1H),8.46(s,1H);MS:562.9(M+H). 1H-NMR (DMSO): 1.47 (m, 2H), 1.69 (m, 4H), 2.08 (m, 2H), 2.70 (t, 2H), 3.03 (m, 4H), 3.84 (s, 2H), 3.94 (s, 3H), 4.20 (t, 2H), 4.26 (s, 2H), 6.04 (s, 2H), 6.39 (d, 1H), 6.58 (d, 1H), 6.94 (d, 1H), 7.10 ( d, 1H), 7.22 (s, 1H), 7.40 (s, 1H), 7.87 (s, 1H), 8.46 (s, 1H); MS: 562.9 (M + H).

实施例55:4-(苯甲胺基)-7-甲氧基-6-[[3-[5-(14-吗啉基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.05(m,2H),2.66(m,4H);3.64(m,4H),3.80(m,4H),3.92(s,2H),3.94(s,3H),4.16(t,2H),4.87(s,2H),6.28(d,1H),6.35(d,1H),7.27(s,1H),7.29~7.40(m,5H),7.82(s,1H),8.59(s,1H),9.45(s,1H);MS:535.3(M+H). Example 55: 4- (phenylmethoxy) -7-methoxy-6 - [[3- [5- (morpholin-14- yl) furan-2-methyl] methylthio] propoxy] oxalate quinazoline 1H-NMR (DMSO): 2.05 (m, 2H), 2.66 (m, 4H); 3.64 (m, 4H), 3.80 (m, 4H), 3.92 (s, 2H), 3.94 ( s, 3H), 4.16 (t, 2H), 4.87 (s, 2H), 6.28 (d, 1H), 6.35 (d, 1H), 7.27 (s, 1H), 7.29 ~ 7.40 (m, 5H), 7.82 (s, 1H), 8.59 (s, 1H), 9.45 (s, 1H); MS: 535.3 (M + H).

实施例56:4-(苯甲胺基)-7-甲氧基-6-[[3-[5-(1-哌啶基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.45(m,2H),1.65(m,4H),2.07(m,2H),2.67(t,2H),2.30(m,4H),3.81(s,2H),3.92(s,3H),4.17(m,4H),4.81(s,2H),6.35(d,1H),6.54(d,1H),7.20(s,1H),7.24~7.379m,5H),7.76(s,1H),8.42(s,1H);MS:523.6(M+H). [Furan-2-methyl] methylthio] propoxy [3- [5- (1-piperidinyl)] - 4- (phenylmethoxy) -7-methoxy-6: Example 56 oxalate quinazoline 1H-NMR (DMSO): 1.45 (m, 2H), 1.65 (m, 4H), 2.07 (m, 2H), 2.67 (t, 2H), 2.30 (m, 4H), 3.81 ( s, 2H), 3.92 (s, 3H), 4.17 (m, 4H), 4.81 (s, 2H), 6.35 (d, 1H), 6.54 (d, 1H), 7.20 (s, 1H), 7.24 ~ 7.379 m, 5H), 7.76 (s, 1H), 8.42 (s, 1H); MS: 523.6 (m + H).

实施例57:4-(4-三氟甲基苯胺基)-7-甲氧基-6-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉1H-NMR(DMSO):1.63(m,4H),2.49(m,4H),2.97(t,2H),3.57(s,2H),3.95(m,5H),4.31(t,2H),6.18(d,1H),6.26(d,1H),7.25(s,1H),7.75(d,1H),7.89(s,1H),8.11(d,1H),8.56(s,1H),9.74(s,1H);MS:559.2(M+H). Example 57: 4- (4-methylanilino) -7-methoxy-6 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy] quinazoline 1H-NMR (DMSO): 1.63 (m, 4H), 2.49 (m, 4H), 2.97 (t, 2H), 3.57 (s, 2H), 3.95 (m, 5H), 4.31 (t, 2H), 6.18 (d, 1H), 6.26 (d, 1H), 7.25 (s, 1H), 7.75 (d, 1H), 7.89 (s, 1H), 8.11 (d, 1H), 8.56 ( s, 1H), 9.74 (s, 1H); MS: 559.2 (M + H).

实施例58:4-(4-氟-3-氯苯胺基)-7-甲氧基-6-[[2-[5-(1-哌啶基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉1H-NMR(DMSO):1.29(m,2H),1.42(m,4H),2.27(m,4H),2.96(t,2H),3.35(s,2H),3.94(m,5H),4.29(t,2H),6.15(d,1H),6.24(d,1H),7.22(s,1H),7.44(t,1H),7.81(m,1H),7.87(s,1H),8.13(dd,1H),8.50(s,1H),9.76(s,1H);MS:557.2(M+H). Example 58: 4- (4-fluoro-3-chloroanilino) -7-methoxy-6 - [[2- [5- (1-piperidinyl) methyl-furan-2] methylthio ] ethoxy] quinazoline 1H-NMR (DMSO): 1.29 (m, 2H), 1.42 (m, 4H), 2.27 (m, 4H), 2.96 (t, 2H), 3.35 (s, 2H), 3.94 (m, 5H), 4.29 (t, 2H), 6.15 (d, 1H), 6.24 (d, 1H), 7.22 (s, 1H), 7.44 (t, 1H), 7.81 (m, 1H), 7.87 (s, 1H), 8.13 (dd, 1H), 8.50 (s, 1H), 9.76 (s, 1H); MS: 557.2 (M + H).

实施例59:4-(2,4-二氯苯胺基)-7-甲氧基-6-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉1H-NMR(DMSO):1.61(m,4H),2.40(m,4H),2.95(t,3H),3.50(s,2H),3.93(s,2H),3.94(s,3H),4.25(t,2H),6.15(d,1H),6.24(d,1H),7.20(s,1H),7.50(dd,1H),7.58(d,1H),7.74(s,1H),7.82(s,1H),8.32(s,1H),9.55(s,1H);MS:559.4(M+H). Example 59: 4- (2,4-dichlorophenyl) -7-methoxy-6 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy] quinazoline 1H-NMR (DMSO): 1.61 (m, 4H), 2.40 (m, 4H), 2.95 (t, 3H), 3.50 (s, 2H), 3.93 (s, 2H), 3.94 (s, 3H), 4.25 (t, 2H), 6.15 (d, 1H), 6.24 (d, 1H), 7.20 (s, 1H), 7.50 (dd, 1H), 7.58 (d, 1H), 7.74 ( s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.55 (s, 1H); MS: 559.4 (M + H).

实施例60:4-(3,5-二氟苯胺基)-7-甲氧基-6-[[2-[5-(4-吗啉基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉1H-NMR(DMSO):2.32(m,4H),2.97(t,2H),3.41(s,2H),3.51(m,4H),3.95(m,5H),4.30(t,2H),6.19(d,1H),6.26(d,1H),6.92(t,1H),7.25(s,1H),7.71(d,2H),7.82(s,1H),8.59(s,1H),9.66(s,1H);MS:543.1(M+H). Example 60: 4- (3,5-difluorophenyl) -7-methoxy-6 - [[2- [5- (4-morpholinyl) furan-2-methyl] methylthio] ethoxy] quinazoline 1H-NMR (DMSO): 2.32 (m, 4H), 2.97 (t, 2H), 3.41 (s, 2H), 3.51 (m, 4H), 3.95 (m, 5H), 4.30 (t, 2H), 6.19 (d, 1H), 6.26 (d, 1H), 6.92 (t, 1H), 7.25 (s, 1H), 7.71 (d, 2H), 7.82 (s, 1H), 8.59 ( s, 1H), 9.66 (s, 1H); MS: 543.1 (M + H).

实施例61:4-(3,4-亚甲基二氧基苯胺基)-7-甲氧基-6-[[2-[5-(4-吗啉基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.79(m,4H),2.79(t,2H),3.68(m,4H),3.95(m,7H),4.30(t,2H),6.06(s,2H),6.36(d,1H),6.43(d,1H),6.96(d,1H),7.08(d,1H),7.28(s,1H),7.37(s,1H),7.91(s,1H),8.54(s,1H);MS:551.2(M+H). Example 61: 4- (3,4-methylenedioxy aniline-yl) -7-methoxy -6---2- [[2- [5- (4-morpholinyl) methyl furan] methylthio] ethoxy] quinazoline oxalate 1H-NMR (DMSO): 2.79 (m, 4H), 2.79 (t, 2H), 3.68 (m, 4H), 3.95 (m, 7H), 4.30 (t, 2H), 6.06 (s, 2H), 6.36 (d, 1H), 6.43 (d, 1H), 6.96 (d, 1H), 7.08 (d, 1H), 7.28 (s, 1H), 7.37 ( s, 1H), 7.91 (s, 1H), 8.54 (s, 1H); MS: 551.2 (M + H).

实施例62:4-(3-氟-4-溴苯胺基)-7-甲氧基-6-[[2-[5-(二甲胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.70(s,6H),2.99(t,2H),3.96(s,3H),4.00(s,2H),4.31(m,4H),6.44(d,1H),6.62(d,1H),7.25(s,1H),7.66(m,2H),7.90(s,1H),8.12(d,1H),8.58(s,1H);MS:561.1(M+H). Example 62: 4- (3-fluoro-4-bromophenyl) -7-methoxy-6 - [[2- [5- (dimethylamino) methyl-furan-2] methylthio] ethoxy] quinazoline oxalate 1H-NMR (DMSO): 2.70 (s, 6H), 2.99 (t, 2H), 3.96 (s, 3H), 4.00 (s, 2H), 4.31 (m, 4H ), 6.44 (d, 1H), 6.62 (d, 1H), 7.25 (s, 1H), 7.66 (m, 2H), 7.90 (s, 1H), 8.12 (d, 1H), 8.58 (s, 1H) ; MS: 561.1 (M + H).

实施例63:4-(2,4,5-三氟苯胺基)-7-甲氧基-6-[[2-[5-(4-吗啉基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.80(m,4H),2.98(t,2H),3.68(m,4H),3.96(s,7H),4.30(t,2H),6.37(d,1H),6.44(d,1H),7.26(s,1H),7.39(m,2H),7.84(s,1H),8.43(s,1H);MS:260.9(M+H). Example 63: 4- (2,4,5-fluoroanilino) -7-methoxy-6 - [[2- [5- (4-morpholinyl) furan-2-methyl] methylthio yl] ethoxy] quinazoline oxalate 1H-NMR (DMSO): 2.80 (m, 4H), 2.98 (t, 2H), 3.68 (m, 4H), 3.96 (s, 7H), 4.30 (t , 2H), 6.37 (d, 1H), 6.44 (d, 1H), 7.26 (s, 1H), 7.39 (m, 2H), 7.84 (s, 1H), 8.43 (s, 1H); MS: 260.9 ( M + H).

实施例64:4-[3-氟-4-(4-吗啉基)苯胺基]-7-甲氧基-6-[[2-[5-(N-甲基丁胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:610.0(M+H)实施例65:4-(4-甲氧基苯甲胺基)-7-甲氧基-6-[[2-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐MS:523.2(M+H). Example 64: 4- [3-fluoro-4- (4-morpholinyl) anilino] -7-methoxy -6 - [[2- [5- (N- methylbutoxy) methyl furan-2] methylthio] ethoxy] quinazoline oxalate MS: 610.0 (M + H) Example 65: 4- (4-methoxy-benzyl) -7-methoxy -6 - [[2- [5- (N- ethylamino-methyl) furan-2-methyl] methylthio] ethoxy] quinazoline oxalate MS: 523.2 (M + H).

实施例66:4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[5-(二甲胺基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉按照实施例1方法制备得到4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[(-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉草酸盐,然后将该化合物1.0g(1.8mmol)加入冰醋酸30mL中,搅拌使其溶解,0~10℃向反应液中滴加30%的双氧水0.3g(2.8mmol),0-5℃反应6-8h,薄层监测反应进行。反应毕,减压蒸除冰乙酸,将残留液用少量水稀释,以0.1mol/L氢氧化钠水溶液调pH值到10,二氯甲烷提取,合并有机相,水洗,无水硫酸镁干燥,减压蒸干,得浅黄色固体粉末0.5g(收率:52.1%)。 Example 66: 4- (3-chloro-4-fluoroanilino) -6-methoxy-7 - [[3- [5- (dimethylamino) methyl-furan-2] methylsulfinyl acyl] propoxy] quinazoline was prepared according to Example 1 to give 4- (3-chloro-4-fluoroanilino) -6-methoxy-7 - [[3 - [(- (dimethylamino ) furan-2-methyl] methylthio] propoxy] quinazoline oxalate this compound 1.0g (1.8mmol) in 30mL glacial acetic acid was then added, and dissolved with stirring, 0 ~ 10 ℃ reaction was added dropwise 30% hydrogen peroxide solution 0.3g (2.8mmol), 0-5 ℃ 6-8h the reaction, the reaction monitoring with TLC. the reaction was completed, the acetic acid evaporated under reduced pressure deicing, the residue was diluted with a small amount of water, 0.1 mol / L aqueous sodium hydroxide solution adjusted to pH 10, extracted with dichloromethane, the organic phases were combined, washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give a pale yellow solid powder 0.5g (yield: 52.1%).

1H-NMR(CDCl3):2.23(s,6H),2.35(m,2H),2.91(m,2H),3.42(s,2H),3.94(s,3H),4.09(s,2H),4.22(t,2H),6.20(d,1H),6.35(d,1H),7.12~7.18(m,2H),7.19(s,1H),7.63(m,1H),7.87(dd,1H),7.97(s,1H),8.59(s,1H);MS:547.1(M+H). 1H-NMR (CDCl3): 2.23 (s, 6H), 2.35 (m, 2H), 2.91 (m, 2H), 3.42 (s, 2H), 3.94 (s, 3H), 4.09 (s, 2H), 4.22 (t, 2H), 6.20 (d, 1H), 6.35 (d, 1H), 7.12 ~ 7.18 (m, 2H), 7.19 (s, 1H), 7.63 (m, 1H), 7.87 (dd, 1H), 7.97 (s, 1H), 8.59 (s, 1H); MS: 547.1 (M + H).

选择合适的原料,首先按照实施例1的方法制备得到甲硫基取代的化合物,然后按照实施例66方法进行氧化反应,分别制得实施例67-104化合物:实施例67:4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉1H-NMR(DMSO):1.75(s,4H),2.32(m,2H),2.53(m,2H),2.67(m,2H),2.88(m,2H),3.60(s,2H),3.91(s,3H),4.18(t,2H),4.35(s,2H),6.21(d,1H),6.33(d,1H),7.11(s,1H),7.22(s,1H),7.27(d,2H),7.80(d,2H),8.59(s,1H);MS:605.1(M+H). Selecting the appropriate starting materials, to give first methylthio substituted compound was prepared according to the method of Example 1, followed by oxidation according to Example 66, Example 67-104 were prepared compounds: 4- (4: Embodiment Example 67 trifluoromethyl-methoxyanilino) -6-methoxy-7 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylsulfinyl] propoxy] quinazoline morpholine 1H-NMR (DMSO): 1.75 (s, 4H), 2.32 (m, 2H), 2.53 (m, 2H), 2.67 (m, 2H), 2.88 (m, 2H), 3.60 (s, 2H), 3.91 (s, 3H), 4.18 (t, 2H), 4.35 (s, 2H), 6.21 (d, 1H), 6.33 (d, 1H), 7.11 (s, 1H), 7.22 (s, 1H), 7.27 (d, 2H), 7.80 (d, 2H), 8.59 (s, 1H); MS: 605.1 (M + H).

实施例68:4-(3-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(二甲胺基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉草酸盐MS:579.2(M+H). Example 68: 4- (3-methoxyphenoxy) -6-methoxy-7 - [[3- [5- (dimethylamino) methyl-furan-2] methylsulfinyl acyl] propoxy] quinazoline oxalate MS: 579.2 (M + H).

实施例69:4-(3-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(1-哌啶基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉草酸盐MS:619.2[M+H]. Example 69: 4- (3-methoxyphenoxy) -6-methoxy-7 - [[3- [5- (1-piperidinyl) methyl-furan-2] methylsulfinyl sulfonyl] propoxy] quinazoline oxalate MS: 619.2 [M + H].

实施例70:4-(4-三氟甲基苯胺基)-6-甲氧基-7-[[3-[5-(4-吗啉基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉1H-NMR(CDCl3):2.37(m,2H),2.44(m,4H),2.90(m,2H),3.49(s,2H),3.69(m,4H),3.96(s,3H),4.09(s,2H),4.22(t,2H),6.22(d,1H),6.36(d,1H),7.15(s,1H),7.17(s,1H),7.64(d,2H),7.91(d,2H),8.55(s,1H);MS:605.1[M+H]. Example 70: 4- (4-methylanilino) -6-methoxy-7 - [[3- [5- (4-morpholinyl) furan-2-methyl] methylsulfinyl acyl] propoxy] quinazoline 1H-NMR (CDCl3): 2.37 (m, 2H), 2.44 (m, 4H), 2.90 (m, 2H), 3.49 (s, 2H), 3.69 (m, 4H) , 3.96 (s, 3H), 4.09 (s, 2H), 4.22 (t, 2H), 6.22 (d, 1H), 6.36 (d, 1H), 7.15 (s, 1H), 7.17 (s, 1H), 7.64 (d, 2H), 7.91 (d, 2H), 8.55 (s, 1H); MS: 605.1 [M + H].

实施例71:4-(3-氟苯胺基)-6-甲氧基-7-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.61(m,4H),2.25(m,2H),2.41(m,4H),2.88(m,1H),2.99(m,1H),3.52(s,2H),3.96(s,3H),4.15(d,1H),4.27(d,1H),4.30(d,1H),6.24(d,1H),6.36(d,1H),7.24(d,1H),7.44(d,1H),7.63(t,1H),7.89(d,1H),8.20~8.25(m,2H),8.54(s,1H),9.66(s,1H);MS:539.5[M+H]. Example 71: 4- (3-fluoroanilino) -6-methoxy-7 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylsulfinyl] propionate oxy] quinazoline oxalate 1H-NMR (DMSO): 1.61 (m, 4H), 2.25 (m, 2H), 2.41 (m, 4H), 2.88 (m, 1H), 2.99 (m, 1H) , 3.52 (s, 2H), 3.96 (s, 3H), 4.15 (d, 1H), 4.27 (d, 1H), 4.30 (d, 1H), 6.24 (d, 1H), 6.36 (d, 1H), 7.24 (d, 1H), 7.44 (d, 1H), 7.63 (t, 1H), 7.89 (d, 1H), 8.20 ~ 8.25 (m, 2H), 8.54 (s, 1H), 9.66 (s, 1H) ; MS: 539.5 [M + H].

实施例72:4-(4-氟苯胺基)-6-甲氧基-7-[[3-[5-(N-甲基丙胺基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):0.85(t,3H),1.59(m,2H),2.21(m,2H),2.56(s,3H),2.78(t,2H),2.89(m,1H),2.989(m,1H),3.97(s,3H),4.18(s,2H),4.32~4.37(m,4H),6.52(d,1H),6.64(d,1H),7.23(d,1H),7.27(s,1H),7.78(t,2H),7.87(s,1H),8.45(s,1H);MS:541.2[M+H]. Example 72: 4- (4-fluoroanilino) -6-methoxy -7 - [[3- [5- (N- methyl-propylamino) methyl-furan-2] methylsulfinyl] propoxy] quinazoline oxalate 1H-NMR (DMSO): 0.85 (t, 3H), 1.59 (m, 2H), 2.21 (m, 2H), 2.56 (s, 3H), 2.78 (t, 2H ), 2.89 (m, 1H), 2.989 (m, 1H), 3.97 (s, 3H), 4.18 (s, 2H), 4.32 ~ 4.37 (m, 4H), 6.52 (d, 1H), 6.64 (d, 1H), 7.23 (d, 1H), 7.27 (s, 1H), 7.78 (t, 2H), 7.87 (s, 1H), 8.45 (s, 1H); MS: 541.2 [M + H].

实施例73:4-[(喹啉-5-)胺基]-6-甲氧基-7-[[3-[5-(二甲胺基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉草酸盐1H-NMR(CDCl3):2.24(m,2H),2.71(s,6H),2.90(m,1H),3.01(m,1H),3.40(s,3H),4.19(d,1H),4.34(m,4H),4.36(d,1H),6.55(d,1H),6.71(d,1H),7.31(s,1H),7.51(dd,1H),7.69(d,1H),7.86(t,1H),8.03(d,1H),8.32(s,1H),8.95(d,1H);MS:546.3[M+H]. Example 73: 4 - [(quinolin-5) amino] -6-methoxy-7 - [[3- [5- (dimethylamino) methyl-furan-2] methylsulfinyl acyl] propoxy] quinazoline oxalate 1H-NMR (CDCl3): 2.24 (m, 2H), 2.71 (s, 6H), 2.90 (m, 1H), 3.01 (m, 1H), 3.40 (s , 3H), 4.19 (d, 1H), 4.34 (m, 4H), 4.36 (d, 1H), 6.55 (d, 1H), 6.71 (d, 1H), 7.31 (s, 1H), 7.51 (dd, 1H), 7.69 (d, 1H), 7.86 (t, 1H), 8.03 (d, 1H), 8.32 (s, 1H), 8.95 (d, 1H); MS: 546.3 [M + H].

实施例74:4-(4-氟苯胺基)-6-甲氧基-7-[[2-[5-(4-吗啉基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.58(m,4H),3.16(m,1H),3.42(m,1H),3.61(m,4H),3.73(s,2H),3.97(s,3H),4.27(d,1H),4.43(d,1H),4.47(m,1H),4.58(m,1H),6.42(d,1H),6.46(d,1H),7.24(t,2H),7.30(s,1H),7.77(dd,2H),7.88(s,1H),8.47(s,1H),9.64(s,1H);MS:541.2(M+H). Example 74: 4- (4-fluoroanilino) -6-methoxy-7 - [[2- [5- (4-morpholinyl) furan-2-methyl] methylsulfinyl] acetate oxy] quinazoline oxalate 1H-NMR (DMSO): 2.58 (m, 4H), 3.16 (m, 1H), 3.42 (m, 1H), 3.61 (m, 4H), 3.73 (s, 2H) , 3.97 (s, 3H), 4.27 (d, 1H), 4.43 (d, 1H), 4.47 (m, 1H), 4.58 (m, 1H), 6.42 (d, 1H), 6.46 (d, 1H), 7.24 (t, 2H), 7.30 (s, 1H), 7.77 (dd, 2H), 7.88 (s, 1H), 8.47 (s, 1H), 9.64 (s, 1H); MS: 541.2 (M + H) .

实施例75:4-(4-氟苯胺基)-6-甲氧基-7-[[2-[5-(4-甲基-1-哌嗪基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.72(m,7H),3.13(m,4H),3.16(m,1H),3.42(m,1H),3.59(d,3H),3.83(s,2H),3.97(s,3H),4.24(d,1H),4.39(d,1H),4.43(m,1H),4.58(m,1H),6.36(d,1H),6.43(d,1H),7.24(t,2H),7.30(s,1H),7.78(dd,2H),7.88(s,1H),8.46(s,1H),9.61(s,1H);MS:554.1(M+H). Example 75: 4- (4-fluoroanilino) -6-methoxy-7 - [[2- [5- (4-methylpiperazin-1-piperazinyl) furan-2-methyl] methyl sulfinyl] ethoxy] quinazoline oxalate 1H-NMR (DMSO): 2.72 (m, 7H), 3.13 (m, 4H), 3.16 (m, 1H), 3.42 (m, 1H), 3.59 (d, 3H), 3.83 (s, 2H), 3.97 (s, 3H), 4.24 (d, 1H), 4.39 (d, 1H), 4.43 (m, 1H), 4.58 (m, 1H), 6.36 ( d, 1H), 6.43 (d, 1H), 7.24 (t, 2H), 7.30 (s, 1H), 7.78 (dd, 2H), 7.88 (s, 1H), 8.46 (s, 1H), 9.61 (s , 1H); MS: 554.1 (M + H).

实施例76:4-(4-氟苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基环丙胺基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):0.50~0.56(m,4H),2.14(m,1H),2.48(s,3H),3.20(m,1H),3.43(m,1H),3.96(s,3H),3.99(s,2H),4.27(d,1H),4.45(d,1H),4.48(m,1H),4.59(m,1H),6.47(s,2H),7.25(t,2H),7.31(s,1H),7.77(dd,2H),7.89(s,1H),8.49(s,1H),9.70(s,1H);MS:525.1(M+H). Example 76: 4- (4-fluoroanilino) -6-methoxy -7 - [[2- [5- (N- cyclopropylmethyl-methyl-amino) methyl-furan-2] methylsulfinyl ] ethoxy] quinazoline oxalate 1H-NMR (DMSO): 0.50 ~ 0.56 (m, 4H), 2.14 (m, 1H), 2.48 (s, 3H), 3.20 (m, 1H), 3.43 ( m, 1H), 3.96 (s, 3H), 3.99 (s, 2H), 4.27 (d, 1H), 4.45 (d, 1H), 4.48 (m, 1H), 4.59 (m, 1H), 6.47 (s , 2H), 7.25 (t, 2H), 7.31 (s, 1H), 7.77 (dd, 2H), 7.89 (s, 1H), 8.49 (s, 1H), 9.70 (s, 1H); MS: 525.1 ( M + H).

实施例77:4-(2-氟苯胺基)-6-甲氧基-7-[[2-[5-(二甲胺基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉1H-NMR(CDCl3):2.35(s,6H),3.13(m,1H),3.32(m,1H),3.58(s,2H),4.02(s,3H),4.19(d,1H),4.38(d,1H),4.57(m,1H),4.65(m,1H),6.32(d,1H),6.48(d,1H),7.07(s,1H),7.11~7.23(m,3H),7.30(s,1H),7.39(s,1H),8.51(t,1H),8.69(s,1H);MS:449.2(M+H). Example 77: 4- (2-fluoroanilino) -6-methoxy-7 - [[2- [5- (dimethylamino) methyl-furan-2] methylsulfinyl] ethoxy yl] quinazoline 1H-NMR (CDCl3): 2.35 (s, 6H), 3.13 (m, 1H), 3.32 (m, 1H), 3.58 (s, 2H), 4.02 (s, 3H), 4.19 (d , 1H), 4.38 (d, 1H), 4.57 (m, 1H), 4.65 (m, 1H), 6.32 (d, 1H), 6.48 (d, 1H), 7.07 (s, 1H), 7.11 ~ 7.23 ( m, 3H), 7.30 (s, 1H), 7.39 (s, 1H), 8.51 (t, 1H), 8.69 (s, 1H); MS: 449.2 (m + H).

实施例78:4-(2-氟苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉1H-NMR(CDCl3):1.82(m,4H),2.62(m,4H),3.13(m,1H),3.30(m,1H),3.68(s,2H),4.02(s,3H),4.20(d,1H),4.37(d,1H),4.57(m,1H),4.65(m,1H),6.27(d,1H),6.45(d,1H),7.05(s,1H),7.09~7.21(m,3H),7.30(s,1H),7.34(s,1H),8.53(t,1H),8.71(s,1H);MS:525.2(M+H). Example 78: 4- (2-fluoroanilino) -6-methoxy-7 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylsulfinyl] acetate oxy] quinazoline 1H-NMR (CDCl3): 1.82 (m, 4H), 2.62 (m, 4H), 3.13 (m, 1H), 3.30 (m, 1H), 3.68 (s, 2H), 4.02 ( s, 3H), 4.20 (d, 1H), 4.37 (d, 1H), 4.57 (m, 1H), 4.65 (m, 1H), 6.27 (d, 1H), 6.45 (d, 1H), 7.05 (s , 1H), 7.09 ~ 7.21 (m, 3H), 7.30 (s, 1H), 7.34 (s, 1H), 8.53 (t, 1H), 8.71 (s, 1H); MS: 525.2 (m + H).

实施例79:4-(2-氟苯胺基)-6-甲氧基-7-[[2-[5-(4-吗啉基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉1H-NMR(CDCl3):2.50(m,4H),3.16(m,1H),3.34(m,1H),3.56(s,2H),3.74(m,4H),4.03(s,3H),4.22(d,1H),4.40(d,1H),4.58(m,1H),4.66(m,1H),6.27(d,1H),6.47(d,1H),7.08(s,1H),7.11~7.25(m,3H),7.32(s,1H),7.42(s,1H),8.50(t,1H),8.71(s,1H);MS:541.1(M+H). Example 79: 4- (2-fluoroanilino) -6-methoxy-7 - [[2- [5- (4-morpholinyl) furan-2-methyl] methylsulfinyl] acetate oxy] quinazoline 1H-NMR (CDCl3): 2.50 (m, 4H), 3.16 (m, 1H), 3.34 (m, 1H), 3.56 (s, 2H), 3.74 (m, 4H), 4.03 ( s, 3H), 4.22 (d, 1H), 4.40 (d, 1H), 4.58 (m, 1H), 4.66 (m, 1H), 6.27 (d, 1H), 6.47 (d, 1H), 7.08 (s , 1H), 7.11 ~ 7.25 (m, 3H), 7.32 (s, 1H), 7.42 (s, 1H), 8.50 (t, 1H), 8.71 (s, 1H); MS: 541.1 (m + H).

实施例80:4-(2-氟苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基丙胺基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):0.88(t,3H),1.64(m,2H),2.66(s,3H),2.89(m,2H),3.17(s,2H),3.21(m,1H),3.45(m,1H),3.95(s,3H),4.30(d,1H),4.48(d,1H),4.58(m,2H),6.57(d,1H),6.71(d,1H),7.31(m,4H),7.54(t,1H),7.87(s,1H),8.37(s,1H);MS:527.2(M+H). Example 80: 4- (2-fluoroanilino) -6-methoxy -7 - [[2- [5- (N- methyl-propylamino) methyl-furan-2] methylsulfinyl] ethoxy] quinazoline oxalate 1H-NMR (DMSO): 0.88 (t, 3H), 1.64 (m, 2H), 2.66 (s, 3H), 2.89 (m, 2H), 3.17 (s, 2H ), 3.21 (m, 1H), 3.45 (m, 1H), 3.95 (s, 3H), 4.30 (d, 1H), 4.48 (d, 1H), 4.58 (m, 2H), 6.57 (d, 1H) , 6.71 (d, 1H), 7.31 (m, 4H), 7.54 (t, 1H), 7.87 (s, 1H), 8.37 (s, 1H); MS: 527.2 (m + H).

实施例81:4-[(喹啉-5-)胺基]-6-甲氧基-7-[[2-[5-(N-甲基乙胺基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.23(t,3H),2.69(s,3H),3.05(m,2H),3.21(m,1H),3.47(m,1H),3.99(s,3H),4.32(d,1H),4.37(t,3H),4.49(d,1H),4.52(m,1H),4.61(m,1H),6.59(d,1H),6.74(d,1H),7.37(s,1H),7.51(dd,1H),7.69(d,1H),7.85(t,1H),8.00(s,1H),8.05(m,1H),8.29(m,2H),8.95(m,1H);MS:546.1(M+H). Example 81: - [(quinolin-5) amino] -6-methoxy -7 - 4 [[2- [5- (N- methyl-ethylamino) methyl-furan-2] A sulfinyl] ethoxy] quinazoline oxalate 1H-NMR (DMSO): 1.23 (t, 3H), 2.69 (s, 3H), 3.05 (m, 2H), 3.21 (m, 1H), 3.47 (m, 1H), 3.99 (s, 3H), 4.32 (d, 1H), 4.37 (t, 3H), 4.49 (d, 1H), 4.52 (m, 1H), 4.61 (m, 1H), 6.59 (d, 1H), 6.74 (d, 1H), 7.37 (s, 1H), 7.51 (dd, 1H), 7.69 (d, 1H), 7.85 (t, 1H), 8.00 (s, 1H), 8.05 ( m, 1H), 8.29 (m, 2H), 8.95 (m, 1H); MS: 546.1 (m + H).

实施例82:4-(3,4-二氯苯胺基)-6-甲氧基-7-[[2-[5-(1-哌啶基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉MS:589.0(M+H). Example 82: 4- (3,4-dichlorophenoxy) -6-methoxy-7 - [[2- [5- (1-piperidinyl) methyl-furan-2] methylsulfinyl acyl] ethoxy] quinazoline MS: 589.0 (M + H).

实施例83:4-(3,5-双三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(二丙胺基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉MS:643.1(M+H). Example 83: 4- (3,5-bis-trifluoromethyl-anilino) -6-methoxy-7 - [[2- [5- (dipropylamino) methyl furan-2] methylsulfinyl sulfonyl] ethoxy] quinazoline MS: 643.1 (M + H).

实施例84:4-[3-氟-4-(4-吗啉基)苯胺基]-6-甲氧基-7-[[2-[5-(N-甲基丙胺基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉 Example 84: 4- [3-fluoro-4- (4-morpholinyl) anilino] -6-methoxy -7 - [[2- [5- (N- methyl-propylamino) methyl furan -2-] methylsulfinyl] ethoxy] quinazoline

MS:612.4(M+H). MS: 612.4 (M + H).

实施例85:4-[3-氟-4-(1-哌啶基)苯胺基]-6-甲氧基-7-[[2-[5-(4-甲基-1-哌嗪基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉MS:637.3(M+H). Example 85: 4- [3-fluoro-4- (1-piperidinyl) anilino] -6-methoxy-7 - [[2- [5- (4-methylpiperazin-1-piperazinyl ) furan-2-methyl] methylsulfinyl] ethoxy] quinazoline MS: 637.3 (M + H).

实施例86:4-(3-氟苯胺基)-7-甲氧基-6-[[3-[5-(N-甲基丙胺基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):0.85(t,3H),1.61(m,2H),2.09(m,2H),2.68(s,3H),2.70(t,2H),2.86(t,2H),3.84(s,2H),3.96(s,3H),4.23(t,2H),4.28(s,2H),6.40(d,1H),6.61(d,1H),7.25(s,1H),7.45(d,1H),7.63(t,1H),7.90(s,1H),8.22~8.24(m,2H),8.55(s,1H);MS:541.2(M+H). Example 86: 4- (3-fluoroanilino) -7-methoxy -6 - [[3- [5- (N- methyl-propylamino) methyl-furan-2] methylsulfinyl] propoxy] quinazoline oxalate 1H-NMR (DMSO): 0.85 (t, 3H), 1.61 (m, 2H), 2.09 (m, 2H), 2.68 (s, 3H), 2.70 (t, 2H ), 2.86 (t, 2H), 3.84 (s, 2H), 3.96 (s, 3H), 4.23 (t, 2H), 4.28 (s, 2H), 6.40 (d, 1H), 6.61 (d, 1H) , 7.25 (s, 1H), 7.45 (d, 1H), 7.63 (t, 1H), 7.90 (s, 1H), 8.22 ~ 8.24 (m, 2H), 8.55 (s, 1H); MS: 541.2 (m + H).

实施例87:4-(3-氟苯胺基)-7-甲氧基-6-[[3-[5-(4-吗啉基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉1H-NMR(DMSO):2.26(m,2H),2.33(m,4H),2.88(m,1H),3.01(m,1H),3.44(s,2H),3.51(m,4H),3.96(s,3H),4.15(d,1H),4.27~4.31(m,3H),6.29(d,1H),6.38(d,1H),7.24(s,1H),7.44(d,1H),7.63(t,1H),7.88(s,1H),8.20~8.24(m,2H),8.54(s,1H),9.65(s,1H);MS:555.1(M+H). Example 87: 4- (3-fluoroanilino) -7-methoxy-6 - [[3- [5- (4-morpholinyl) furan-2-methyl] methylsulfinyl] propionate oxy] quinazoline 1H-NMR (DMSO): 2.26 (m, 2H), 2.33 (m, 4H), 2.88 (m, 1H), 3.01 (m, 1H), 3.44 (s, 2H), 3.51 ( m, 4H), 3.96 (s, 3H), 4.15 (d, 1H), 4.27 ~ 4.31 (m, 3H), 6.29 (d, 1H), 6.38 (d, 1H), 7.24 (s, 1H), 7.44 (d, 1H), 7.63 (t, 1H), 7.88 (s, 1H), 8.20 ~ 8.24 (m, 2H), 8.54 (s, 1H), 9.65 (s, 1H); MS: 555.1 (m + H ).

实施例88:4-(4-氟苯胺基)-7-甲氧基-6-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):1.87(m,4H),2.08(m,2H),2.69(t,2H),3.19(m,4H),3.83(s,2H),3.94(s,3H),4.21(t,2H),4.34(s,2H),6.37(d,1H),6.57(d,1H),7.21(s,1H),7.23(d,2H),7.78(t,2H),7.87(s,1H),8.45(s,1H);MS:539.4(M+H). Example 88: 4- (4-fluoroanilino) -7-methoxy-6 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylsulfinyl] propionate oxy] quinazoline oxalate 1H-NMR (DMSO): 1.87 (m, 4H), 2.08 (m, 2H), 2.69 (t, 2H), 3.19 (m, 4H), 3.83 (s, 2H) , 3.94 (s, 3H), 4.21 (t, 2H), 4.34 (s, 2H), 6.37 (d, 1H), 6.57 (d, 1H), 7.21 (s, 1H), 7.23 (d, 2H), 7.78 (t, 2H), 7.87 (s, 1H), 8.45 (s, 1H); MS: 539.4 (M + H).

实施例89:4-(3-溴苯胺基)-7-甲氧基-6-[[3-[5-(1-哌啶基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉1H-NMR(DMSO):1.29(m,2H),1.41(m,4H),2.23(t,2H),2.29(s,2H),2.78(m,1H),2.97(m,1H),3.38(m,4H),3.95(s,3H),4.16(d,1H),4.28(d,1H),4.29(s,2H),6.24(d,1H),6.36(d,1H),7.23(s,1H),7.28(d,1H),7.35(t,1H),7.86~7.89(m,2H),8.16(s,1H),8.53(s,1H),9.51(s,1H);MS:613.5(M+H). Example 89: 4- (3-bromophenyl) -7-methoxy-6 - [[3- [5- (1-piperidinyl) methyl-furan-2] methylsulfinyl] propionate oxy] quinazoline 1H-NMR (DMSO): 1.29 (m, 2H), 1.41 (m, 4H), 2.23 (t, 2H), 2.29 (s, 2H), 2.78 (m, 1H), 2.97 ( m, 1H), 3.38 (m, 4H), 3.95 (s, 3H), 4.16 (d, 1H), 4.28 (d, 1H), 4.29 (s, 2H), 6.24 (d, 1H), 6.36 (d , 1H), 7.23 (s, 1H), 7.28 (d, 1H), 7.35 (t, 1H), 7.86 ~ 7.89 (m, 2H), 8.16 (s, 1H), 8.53 (s, 1H), 9.51 ( s, 1H); MS: 613.5 (M + H).

实施例90:4-(3-三氟甲基苯胺基)-7-甲氧基-6-[[3-[5-(1-吡咯烷基)甲基呋哺-2-]甲基亚磺酰基]丙氧基]喹唑啉MS:589.2(M+H). Example 90: 4- (3-trifluoromethyl-phenylamino) -7-methoxy-6 - [[3- [5- (1-pyrrolidinyl) -2- furosemide feeding methyl] methylsulfinyl sulfonyl] propoxy] quinazoline MS: 589.2 (M + H).

实施例91:4-(3-三氟甲基苯胺基)-7-甲氧基-6-[[3-[5-(N-甲基丙胺基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉MS:591.2(M+H). Example 91: 4- (3-trifluoromethyl-phenylamino) -7-methoxy -6 - [[3- [5- (N- methyl-propylamino) methyl-furan-2] methylsulfinyl sulfonyl] propoxy] quinazoline MS: 591.2 (M + H).

实施例92:4-(3-三氟甲基苯胺基)-7-甲氧基-6-[[3-[5-(二甲胺基)甲基呋哺-2-]甲基亚磺酰基]丙氧基]喹唑啉MS:563.2(M+H). Example 92: 4- (3-trifluoromethyl-phenylamino) -7-methoxy-6 - [[3- [5- (dimethylamino) -2- furosemide feeding methyl] methylsulfinyl acyl] propoxy] quinazoline MS: 563.2 (M + H).

实施例93:4-(3,4-二氟苯胺基)-7-甲氧基-6-[[3-[5-(1-吡咯烷基)甲基呋哺-2-]甲基亚磺酰基]丙氧基]喹唑啉MS:557.2(M+H). Example 93: 4- (3,4-difluorophenyl) -7-methoxy-6 - [[3- [5- (1-pyrrolidinyl) -2- furosemide feeding methyl] methylsulfinyl sulfonyl] propoxy] quinazoline MS: 557.2 (M + H).

实施例94:4-(3-氟-4-溴苯胺基)-7-甲氧基-6-[[3-[5-(4-吗啉基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉1H-NMR(DMSO):2.24(t,2H),2.40(m,4H),2.89(m,1H),3.00(m,1H),3.52(m,6H),3.96(s,3H),4.16(d,1H),4.29(s,2H),4.30(d,1H),6.32(d,1H),6.39(d,1H),7.24(s,1H),7.64(dd,1H),7.69(t,1H),7.86(s,1H),8.12(d,1H),8.56(s,1H),9.62(s,1H);MS:634.8(M+H). Example 94: 4- (3-fluoro-4-bromophenyl) -7-methoxy-6 - [[3- [5- (4-morpholinyl) furan-2-methyl] methylsulfinyl sulfonyl] propoxy] quinazoline 1H-NMR (DMSO): 2.24 (t, 2H), 2.40 (m, 4H), 2.89 (m, 1H), 3.00 (m, 1H), 3.52 (m, 6H ), 3.96 (s, 3H), 4.16 (d, 1H), 4.29 (s, 2H), 4.30 (d, 1H), 6.32 (d, 1H), 6.39 (d, 1H), 7.24 (s, 1H) , 7.64 (dd, 1H), 7.69 (t, 1H), 7.86 (s, 1H), 8.12 (d, 1H), 8.56 (s, 1H), 9.62 (s, 1H); MS: 634.8 (M + H ).

实施例95:4-(3-氯-4-氟苯胺基)-7-甲氧基-6-[[3-[5-(二甲胺基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉MS:547.2(M+H). 95 cases: 4- (3-chloro-4-fluoroanilino) -7-methoxy-6 - [[3- [5- (dimethylamino) methyl-furan-2] methylsulfinyl acyl] propoxy] quinazoline MS: 547.2 (M + H).

实施例96:4-(3-氯-4-氟苯胺基)-7-甲氧基-6-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉MS:573.1(M+H). Example 96: 4- (3-chloro-4-fluoroanilino) -7-methoxy-6 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylsulfinyl sulfonyl] propoxy] quinazoline MS: 573.1 (M + H).

实施例97:4-(3-氯-4-氟苯胺基)-7-甲氧基-6-[[3-[5-(N-甲基乙胺基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉MS:561.2(M+H). Example 97: 4- (3-chloro-4-fluoroanilino) -7-methoxy -6 - [[3- [5- (N- methyl-ethylamino) methyl-furan-2] A sulfinyl] propoxy] quinazoline MS: 561.2 (M + H).

实施例98:4-(3-三氟甲基-4-氟苯胺基)-7-甲氧基-6-[[3-[5-(二甲胺基)甲基呋喃-2-]甲基亚磺酰基]丙氧基]喹唑啉草酸盐1H-NMR(DMSO):2.10(s,6H),2.24(m,2H),2.90(m,1H),2.96(m,1H),3.37(t,2H),3.95(s,3H),4.14(d,1H),4.25-4.29(m,3H),6.26(d,1H),6.37(d,1H),7.22(s,1H),7.53(t,1H),7.92(s,1H),8.26(m,2H),8.51(s,1H);MS:581.3(M+H). Example 98: 4- (3-trifluoromethyl-4-fluoroanilino) -7-methoxy-6 - [[3- [5- (dimethylamino) methyl-furan-2] A sulfinyl] propoxy] quinazoline oxalate 1H-NMR (DMSO): 2.10 (s, 6H), 2.24 (m, 2H), 2.90 (m, 1H), 2.96 (m, 1H), 3.37 (t, 2H), 3.95 (s, 3H), 4.14 (d, 1H), 4.25-4.29 (m, 3H), 6.26 (d, 1H), 6.37 (d, 1H), 7.22 (s, 1H) , 7.53 (t, 1H), 7.92 (s, 1H), 8.26 (m, 2H), 8.51 (s, 1H); MS: 581.3 (m + H).

实施例99:4-(2,4-二氯苯胺基)-7-甲氧基-6-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉1H-NMR(DMSO):1.65(m,4H),2.43(m,4H),3.19(m,1H),3.42(m,1H),3.54(s,2H),3.94(s,3H),4.24(d,1H),4.41(d,1H),4.53(s,2H),6.26(d,1H),6.39(d,1H),7.22(s,1H),7.50(d,1H),7.59(d,1H),7.75(s,1H),7.93(s,1H),8.34(s,1H),9.56(s,1H);MS:547.8(M+H). Example 99: 4- (2,4-dichlorophenyl) -7-methoxy-6 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylsulfinyl acyl] ethoxy] quinazoline 1H-NMR (DMSO): 1.65 (m, 4H), 2.43 (m, 4H), 3.19 (m, 1H), 3.42 (m, 1H), 3.54 (s, 2H) , 3.94 (s, 3H), 4.24 (d, 1H), 4.41 (d, 1H), 4.53 (s, 2H), 6.26 (d, 1H), 6.39 (d, 1H), 7.22 (s, 1H), 7.50 (d, 1H), 7.59 (d, 1H), 7.75 (s, 1H), 7.93 (s, 1H), 8.34 (s, 1H), 9.56 (s, 1H); MS: 547.8 (M + H) .

实施例100:4-(3,5-二氟苯胺基)-7-甲氧基-6-[[2-[5-(4-吗啉基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉1H-NMR(DMSO):2.49(m,4H),3.23(m,1H),3.47(m,1H),3.58(m,6H),3.96(s,3H),4.27(d,1H),4.45(d,1H),4.57(s,2H),6.37(d,1H),6.44(d,1H),6.92(t,1H),7.27(s,1H),7.92(d,2H),8.61(s,1H),9.67(s,1H);MS:559.4(M+H). Example 100: 4- (3,5-difluorophenyl) -7-methoxy-6 - [[2- [5- (4-morpholinyl) furan-2-methyl] methylsulfinyl acyl] ethoxy] quinazoline 1H-NMR (DMSO): 2.49 (m, 4H), 3.23 (m, 1H), 3.47 (m, 1H), 3.58 (m, 6H), 3.96 (s, 3H) , 4.27 (d, 1H), 4.45 (d, 1H), 4.57 (s, 2H), 6.37 (d, 1H), 6.44 (d, 1H), 6.92 (t, 1H), 7.27 (s, 1H), 7.92 (d, 2H), 8.61 (s, 1H), 9.67 (s, 1H); MS: 559.4 (M + H).

实施例101:4-(3-氯-4-氟苯胺基)-7-甲氧基-6-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉1H-NMR(DMSO):1.66(m,4H),2.47(m,4H),3.23(m,1H),3.35(m,1H),3.57(s,2H),3.95(s,3H),4.25(d,1H),4.43(d,1H),4.56(t,2H),6.28(d,1H),6.41(d,1H),7.24(s,1H),7.45(t,1H),7.78(m,1H),7.92(s,1H),8.13(dd,1H),8.52(s,1H),9.57(s,1H);MS:559.1(M+H). Example 101: 4- (3-chloro-4-fluoroanilino) -7-methoxy-6 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylsulfinyl sulfonyl] ethoxy] quinazoline 1H-NMR (DMSO): 1.66 (m, 4H), 2.47 (m, 4H), 3.23 (m, 1H), 3.35 (m, 1H), 3.57 (s, 2H ), 3.95 (s, 3H), 4.25 (d, 1H), 4.43 (d, 1H), 4.56 (t, 2H), 6.28 (d, 1H), 6.41 (d, 1H), 7.24 (s, 1H) , 7.45 (t, 1H), 7.78 (m, 1H), 7.92 (s, 1H), 8.13 (dd, 1H), 8.52 (s, 1H), 9.57 (s, 1H); MS: 559.1 (m + H ).

实施例102:4-[3-氟-4-(1-哌啶基)苯胺基]-7-甲氧基-6-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉MS:608.3(M+H). Example 102: 4- [3-fluoro-4- (1-piperidinyl) anilino] -7-methoxy-6 - [[2- [5- (1-pyrrolidinyl) methyl furan - 2-] methylsulfinyl] ethoxy] quinazoline MS: 608.3 (M + H).

实施例103:4-(4-氟苯甲胺基)-7-甲氧基-6-[[2-[5-(N-甲基丁胺基)甲基呋喃-2-]甲基亚磺酰基]乙氧基]喹唑啉MS:539.6(M+H). Example 103: 4- (4-methylamino-fluorophenyl) -7-methoxy -6 - [[2- [5- (N- methylbutan-amino) furan-2-methyl] methylsulfinyl sulfonyl] ethoxy] quinazoline MS: 539.6 (M + H).

实施例104:4-(3,4-二氟苯胺基)-7-甲氧基-6-[[2-[5-(N-甲基乙胺基)甲基呋喃-2-]甲基磺酰基]乙氧基]喹唑啉按照实施例1方法制备得到4-(3,4-二氟苯胺基)-7-甲氧基-6-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉草酸盐,然后将该化合物1.05g(2.0mmol)加入冰醋酸30mL中,搅拌使其溶解,25-30℃向反应液中滴加30%的双氧水0.6g(2.8mmol),25℃反应8-12h,薄层监测反应进行。 Example 104: 4- (3,4-difluorophenyl) -7-methoxy -6 - [[2- [5- (N- ethylamino-methyl) furan-2-methyl] methyl sulfonyl] ethoxy] quinazoline was prepared according to Example 1 to give 4- (3,4-difluorophenyl) -7-methoxy-6 - [[2- [5- (1-pyrrolidinyl yl) furan-2-methyl] methylthio] ethoxy] quinazoline oxalate this compound 1.05g (2.0mmol) in 30mL glacial acetic acid was then added, stirred and dissolved, 25-30 ℃ to the reaction mixture was added dropwise 30% hydrogen peroxide solution 0.6g (2.8mmol), 25 ℃ reaction 8-12h, TLC monitoring of the reaction carried out. 反应毕,减压蒸除冰乙酸,将残留液用少量水稀释,以0.1mol/L氢氧化钠水溶液调pH值到10,二氯甲烷提取,合并有机相,水洗,无水硫酸镁干燥,减压蒸干,得浅黄色固体粉末0.45g(收率:40.6%)。 Completion of the reaction, evaporated under reduced pressure deicing acetate, the residue was diluted with a little water to 0.1mol / L sodium hydroxide aqueous solution adjusted to pH value to 10, extracted with dichloromethane, the organic phases were combined, washed with water, dried over anhydrous magnesium sulfate, evaporated to dryness under reduced pressure to give 0.45 g of a pale yellow solid powder (yield: 40.6%).

1H-NMR(DMSO):1.69(m,4H),2.57(m,4H),3.70(s,2H),3.79(t,2H),3.95(s,3H),4.56(t,2H),4.82(s,2H),6.38(d,1H),6.55(d,1H),7.27(s,1H),7.47(dd,1H),7.56(m,1H),7.92(s,1H),8.06(m,1H),8.54(s,1H),9.62(s,1H);MS:559.1(M+H). 1H-NMR (DMSO): 1.69 (m, 4H), 2.57 (m, 4H), 3.70 (s, 2H), 3.79 (t, 2H), 3.95 (s, 3H), 4.56 (t, 2H), 4.82 (s, 2H), 6.38 (d, 1H), 6.55 (d, 1H), 7.27 (s, 1H), 7.47 (dd, 1H), 7.56 (m, 1H), 7.92 (s, 1H), 8.06 ( m, 1H), 8.54 (s, 1H), 9.62 (s, 1H); MS: 559.1 (m + H).

实施例105:4-(3-氟-4-溴苯胺基)-7-甲氧基-6-[[2-[5-(4-吗啉基)甲基呋喃-2-]甲基磺酰基]乙氧基]喹唑啉按照实施例104的方法制备。 Example 105: 4- (3-fluoro-4-bromophenyl) -7-methoxy-6 - [[2- [5- (4-morpholinyl) furan-2-methyl] methanesulfonamide acyl] ethoxy] quinazoline was prepared according to the method of Example 104.

1H-NMR(DMSO):2.86(d,2H),3.46(m,4H),3.66(d,2H),3.95(s,3H),4.07(m,2H),4.30(d,1H),4.44~4.51(m,5H),6.55(d,1H),6.68(d,1H),7.25(s,1H),7.66(m,2H),7.95(s,1H),8.12(d,1H),8.56(s,1H),9.77(s,1H);MS:636.7(M+H). 1H-NMR (DMSO): 2.86 (d, 2H), 3.46 (m, 4H), 3.66 (d, 2H), 3.95 (s, 3H), 4.07 (m, 2H), 4.30 (d, 1H), 4.44 ~ 4.51 (m, 5H), 6.55 (d, 1H), 6.68 (d, 1H), 7.25 (s, 1H), 7.66 (m, 2H), 7.95 (s, 1H), 8.12 (d, 1H), 8.56 (s, 1H), 9.77 (s, 1H); MS: 636.7 (M + H).

本发明产物的药理研究对按照本发明的上式I的喹唑啉类衍生物进行了体外蛋白酪氨酸激酶抑制活性筛选和体外抗肿瘤活性筛选。 Pharmacological studies of the products of the present invention is performed in vitro protein tyrosine quinazoline derivative according to formula I of the present invention kinase inhibitory activity in vitro and antitumor activity Screening Screening.

一、蛋白酪氨酸激酶抑制活性筛选(1)在96孔板的每孔中加入50uL的激酶反应液。 A protein tyrosine kinase inhibitory activity screening (1) was added 50uL kinase reaction solution in each well of a 96 well plate. 在96孔板的2-11列加入受试样品10uL(浓度为9μg/mL),用排枪在1和12列加入激酶反应液10uL。 2-11 in column 96 of the test sample was added 10uL (concentration 9μg / mL), added to 10uL kinase reaction solution with discharge gun 1 and 12. 在96孔板的每孔中加入50uL的大鼠脑组织酪氨酸提取液[蛋白质含量约为0.4mg/mL]。 Add 50uL rat brain tissue in each well of a 96 tyrosine extract [protein content of about 0.4mg / mL]. 振荡混匀。 Shakers. 37℃孵育1小时。 37 ℃ for 1 hour. 以200uL的洗脱液洗3次。 With eluent 200uL wash three times.

(2)用personal pipettor在96孔板的每孔中加入100uL的用洗脱液2000倍稀释的连有辣根过氧化物酶(HRP)的抗磷酸多肽抗体液。 (2) Add 100uL personal pipettor with elution with 2000-fold diluted in each well of a 96 well plate attached horseradish peroxidase (HRP) anti-phospho-polypeptide antibody solution. 振荡混匀。 Shakers. 室温孵育30分钟。 Incubate at room temperature for 30 minutes.

(3)以洗脱液洗3次。 (3) washed three times with the eluent.

(4)每孔加入100uL邻苯二胺溶液。 (4) Add 100uL per well of o-phenylenediamine solution. 室温下避光孵育7-10分钟。 Incubated in the dark at room temperature for 7-10 minutes.

(5)每孔中加入100uL 1mol/L硫酸以终止反应。 (5) per well was added 100uL 1mol / L sulfuric acid to terminate the reaction.

(6)在30分钟内用酶标仪测定在492nm处的吸光度。 (6) over 30 minutes using a microplate reader at absorbance was measured at 492nm.

(7)由酶标仪测定的样品吸光度和同板测定的未加药物的对照吸光度计算药物对蛋白酪氨酸激酶的抑制率。 (7) The absorbance control absorbance of the sample not added the drug and the same plate is then determined by measuring inhibition rate of drugs protein tyrosine kinases. 计算方法如下:抑制率%=(对照OD-样品OD)/(对照OD-空白OD)×100%所述对照品是Astra Zeneca公司研制的作为表皮生长因子受体酪胺酸激酶抑制剂的Iressa,结构式如下, Calculated as follows:% inhibition = (control sample OD- OD) / (Control OD- blank OD) × 100% of the reference standard was developed by the company Astra Zeneca as EGFR tyrosine kinase inhibitors Iressa the following structural formula,

体外实验证明其可抑制前列腺癌、乳腺癌、卵巢癌、结肠癌、小细胞肺癌和非小细胞肺癌。 In vitro experiments show that inhibits prostate cancer, breast cancer, ovarian cancer, colon cancer, small cell lung cancer and non-small cell lung cancer.

随机选择的部分化合物抑制蛋白酪氨酸激酶活性结果见表1。 Randomly selected portion of compounds to inhibit protein tyrosine kinase activity (Table 1).

表1 Table 1

二、体外抗口腔癌和胃癌肿瘤活性测试(1)细胞复苏并传代2-3次稳定后,用胰蛋白酶溶液(0.25%)使其从培养瓶底部消化下来。 Second, the in vitro anti-tumor activity of oral cancer and stomach cancer tests (1) and the cells were passaged 2-3 times recovery after stabilization with trypsin solution (0.25%) to digest it down from the bottom of the culture flask. 将细胞消化液倒入离心管中而后加入培养液以终止消化。 The cell digestion solution was poured into a centrifuge tube followed by addition of broth to terminate the digestion. 将离心管在1300r/min下离心3min,轻轻弃去上清液后加入5mL培养液,吹打混匀细胞,吸取10uL细胞混悬液加入细胞计数板中计数,调整细胞浓度为104个/孔。 3min The tubes were centrifuged at 1300r / min, the supernatant was gently added 5mL After discarding the culture liquid, mixed by pipetting the cell, the cell suspension was added 10uL suction plate counts cell counts, adjusting the cell concentration of 104 / well . 96孔板中除A1孔为空白孔不加细胞外,其余皆加入100uL细胞混悬液。 A1 hole 96 in addition to the blank wells without cells, the remaining cell suspension are added 100uL. 将96孔板放入培养箱中培养24h。 Into 96-well plates incubator 24h.

(2)用50μl二甲基亚砜溶解受试样品,然后加入适量培养液,使样品溶解成2mg/mL药液。 (2) the test sample is dissolved with 50μl of dimethylsulfoxide, followed by addition of an appropriate amount of the culture solution, the sample was dissolved into 2mg / mL drug solution. 然后在24孔板中将样品稀释为16,8,4,2,1μg/mL。 Then diluted to 16,8,4,2,1μg / mL in 24-well plates in the sample. 每个浓度加入3孔,其中周围两行两列细胞长势受环境影响较大,只作为空白细胞孔使用。 Each concentration of holes is added 3, wherein the two rows and two columns around growing cells affected by environment, only hole used as a blank cell. 将96孔板放入培养箱中培养24h。 Into 96-well plates incubator 24h.

(3)将96孔板中带药培养液弃去,用磷酸缓冲溶液(PBS)将细胞冲洗两遍,在每孔中加入MTT(四氮唑)(0.5mg/mL)100uL放入培养箱中4h后,弃去MTT溶液,加入二甲基亚砜100uL。 (3) The 96-well plates with broth discarded medicine, with a phosphate buffer solution (PBS) Cells were washed twice, added MTT (tetrazolium) (0.5mg / mL) in each well in the plate was incubated 100uL in after 4h, MTT solution was discarded, dimethyl sulfoxide was added 100uL. 在磁力振荡器上振荡使存活细胞与MTT反应产物甲臜充分溶解,放入酶标仪中测定结果。 On a magnetic oscillator and viable cells are MTT formazan reaction product was sufficiently dissolved, the measurement result into a standard microplate reader. 通过Bliss法可求出药物IC50值。 Bliss method can be obtained by pharmaceutical IC50 values.

化合物的抑制口腔癌和胃癌细胞活性结果见表2。 Oral cancer and gastric cancer cell inhibiting activity of the compound results in Table 2.

表2 Table 2

三、化合物抗肝癌细胞活性测试(1)选用对数生长期的贴壁人肝癌肿瘤细胞Bel-7402,用胰酶消化后,用10%小牛血清的RPMI1640培养液配成40000个/mL的细胞悬液,接种在96孔培养板中,每孔接种200uL,37℃,5%CO2培养24h。 Third, the activity of the test compounds against liver cancer cells (1) selection of the logarithmic growth phase Bel-7402 human hepatoma tumor adherent cells, after digestion with trypsin, washed with 10% calf serum RPMI1640 medium dubbed 40,000 / mL, cell suspensions were seeded in 96-well culture plate, each well was inoculated 200uL, 37 ℃, 5% CO2 culture 24h.

(2)实验组换新的含5ng/mL样品的培养液,对照组则换含等体积溶剂的培养液,每孔设3~5个复孔,37℃,5%CO2培养3d。 (2) get a new experimental group containing 5ng / mL sample medium, transducer control group containing an equal volume of a solvent medium per well is provided three to five wells, 37 ℃, 5% CO2 culture 3d.

(3)弃去上清液,每孔加入100uL新鲜配制的0.5mg/mL MTT的无血清培养液,37℃继续培养4h。 (3) The supernatant was discarded, each well was added 100uL of a freshly prepared 0.5mg / mL MTT in serum-free medium, 37 [deg.] C incubation was continued 4h. 小心弃上清液,并加入200uL二甲基亚砜溶解MTT甲臜沉淀,用微型超声振荡器混匀后,在酶标仪上测定波长544nm处的光密度值。 The supernatant was carefully discarded and added 200uL MTT formazan precipitate was dissolved in dimethylsulfoxide, after mixing using a micro ultrasonic oscillator, the optical density at a wavelength of 544nm on a microplate reader. 结果见表3。 The results are shown in Table 3.

Bel-7402肿瘤细胞生长抑制率(%)=(OD对照-OD实验)/(OD对照-OD空白)×100%表3 Bel-7402 tumor cell growth inhibition rate (%) = (OD control -OD experiment) / (OD control -OD blank) × 100% Table 3

从上述试验结果可以清楚地看出,本发明所要保护的通式(I)的化合物,具有优异的蛋白酪氨酸激酶抑制活性和抗癌活性。 As is clear from the above experimental results, the compounds of the claimed invention of formula (I) has an excellent protein tyrosine kinase inhibitory activity and anticancer activity. 另外,本发明所要保护的通式(I)的化合物,还具有一定的治疗和/或防止动脉硬化以及牛皮癣的药理活性。 Further, the claimed compounds the present invention of formula (I), and also has a therapeutic and / or prevention of atherosclerosis as well as pharmacologically active psoriasis. 因此本发明的化合物具有很好的工业应用前景。 Thus compounds of the invention has good prospects for industrial applications.

Claims (14)

1.通式I的衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物, 1. The derivatives of general formula I, or its racemates, diastereomeric mixture of optically active isomers thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, 其中R1、R2其中之一为C1-C6烷基,另外一个为-R3YR4Q2;A为C1-C4烷基,H;X为一个直接键或C1-C4亚烷基,所述亚烷基可以被1-3个选自羟基、卤素、硝基、C1-C4烷氧基的取代基任选取代;Q1为苯基、萘基或5-10元杂芳基,所述杂芳基可以含有1-3个选自O、N和S的杂原子,且Q1可任选1-3个R5取代;R3、R4为C1-C6亚烷基,所述亚烷基可以被1-3个选自羟基、卤素、硝基、C1-C4烷氧基的取代基任选取代;Y为-S-, Wherein R1, R2, one of which is a C1-C6 alkyl and the other is -R3YR4Q2; A is C1-C4 alkyl, H; X is a direct bond or C1-C4 alkylene group, the alkylene group may be optionally 1 to 3 substituents selected from hydroxy, halo, nitro, C1-C4 alkoxy substituents; Ql is phenyl, naphthyl or 5-10 membered heteroaryl, the heteroaryl may contain 1 -3 selected from O, N, and S, and Q1 optionally substituted with 1-3 R5; R3, R4 is C1-C6 alkylene group, the alkylene group may be selected from 1 to 3 substituted with hydroxy, halogen, nitro, C1-C4 alkoxy group optionally substituted; Y is -S-, Q2为呋喃基、吡咯基、噻吩基,可任选1-3个R6取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、(C1-C4)烷基硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷基酰基、氨基甲酰基、N-C1-C4烷基氨基甲酰基、N,N-二C1-C4烷基氨基甲酰基、氨基磺酰基、N-C1-C4烷基氨基磺酰基、N,N-二C1-C4烷基氨基磺酰基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基,并且该饱和杂环基可以带有1-2个选自氧代、羟基、卤素、C1-C3烷基、C1-C3烷氧基、三氟甲基、硝基的取代基;R6为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-C1-C4烷基氨基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺 Q2 is furyl, pyrrolyl, thienyl, optionally substituted with 1-3 R6; R5 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1- C4 alkyl, C1-C4-alkoxy, N, N- two amino C1-C4 alkyl, (C1-C4) alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl group, C1-C4 alkoxymethyl, C1-C4 alkyl group, carbamoyl, N-C1-C4 alkyl-carbamoyl, N, N- C1-C4 two alkylcarbamoyl, sulfamoyl group, N -C1-C4 alkylaminosulfonyl, N, N- two aminosulfonyl C1-C4 alkyl group, C1-C3 alkylenedioxy group, and group selected from morpholinyl, pyrrolidinyl, piperazinyl, piperazine, piperidinyl, imidazolidinyl and pyrazolidinyl a saturated heterocyclic group, and a saturated heterocyclic group which may have 1-2 substituents selected from oxo, hydroxy, halogen, C1-C3 alkyl, C1-C3 alkoxy group, trifluoromethyl group, nitro group; R6 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, C1-C4 alkyl, C1- C4-alkoxy, N-C1-C4 alkylamino, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkylsulfinyl 酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷基酰基、氨基甲酰基、N-C1-C4烷基氨基甲酰基、N,N-二C1-C4烷基氨基甲酰基、氨基磺酰基、N-C1-C4烷基氨基磺酰基、N,N-二C1-C4烷基氨基磺酰基,或者R6为-CH2NR7R8;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-10元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Acyl, C1-C4 alkylsulfonyl, C1-C4 alkoxymethyl, C1-C4 alkyl group, carbamoyl, N-C1-C4 alkylcarbamoyl, N, N- C1-C4 alkoxy two carbamoyl group, sulfamoyl group, N-C1-C4 alkylaminosulfonyl, N, N- two aminosulfonyl C1-C4 alkyl group, or R6 is -CH2NR7R8; R7, R8 are the same or different, each independently is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, which may be substituted with 1 to 3 identical or different optionally R5, or R7 and R8 together with the nitrogen atom to which they are attached together form a 5-10 membered saturated heterocyclic group, a saturated heterocyclic group except the nitrogen atom to which R7 and R8 are attached, may contain 1-3 heteroatoms selected from O, N and S heteroatoms may be 1 to 3 identical or different R5 is optionally substituted.
2.权利要求1的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为C1-C6烷基,另外一个为-R3YR4Q2;A为H;X为一个直接键或C1-C4亚烷基;Q1为苯基、萘基或5-10元杂芳基,所述杂芳基可以含有1-3个选自O、N和S的杂原子,且Q1可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, Formula I of claim 1 derivatives, and optically active or racemic, diastereomeric mixtures thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1, R2 wherein one of the C1-C6 alkyl and the other is -R3YR4Q2; a is H; X is a direct bond or C1-C4 alkylene group; Ql is phenyl, naphthyl or 5-10 membered heteroaryl, said heteroaryl may contain 1 to 3 selected from O, N, and S, and Q1 optionally substituted with 1-3 R5; R3, R4 is C1-C4 alkylene group; Y is -S-, Q2为呋喃基、吡咯基、噻吩基,可任选1-3个R6取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷基酰基、氨基甲酰基、N-C1-C4烷基氨基甲酰基、N,N-二C1-C4烷基氨基甲酰基、氨基磺酰基、N-C1-C4烷基氨基磺酰基、N,N-二C1-C4烷基氨基磺酰基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基,并且该饱和杂环基可以带有1-2个选自氧代、羟基、卤素、C1-C3烷基、C1-C3烷氧基、三氟甲基、硝基的取代基;R6为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-C1-C4烷基氨基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺 Q2 is furyl, pyrrolyl, thienyl, optionally substituted with 1-3 R6; R5 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1- C4 alkyl, C1-C4-alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1- C4-alkoxymethyl, C1-C4 alkyl group, carbamoyl, N-C1-C4 alkylcarbamoyl, N, N- C1-C4 two alkylcarbamoyl, sulfamoyl group, N-C1 -C4 alkylaminosulfonyl, N, N- two aminosulfonyl C1-C4 alkyl group, C1-C3 alkylenedioxy group, and group selected from morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl , imidazolidinyl and pyrazolidinyl a saturated heterocyclic group, and a saturated heterocyclic group which may have 1-2 substituents selected from oxo, hydroxy, halogen, C1-C3 alkyl, C1-C3 alkoxy group, trifluoromethyl, nitro substituent; R6 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, C1-C4 alkyl, C1-C4 alkyl group, N-C1-C4 alkylamino, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkylsulfinyl 基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷基酰基、氨基甲酰基、N-C1-C4烷基氨基甲酰基、N,N-二C1-C4烷基氨基甲酰基、氨基磺酰基、N-C1-C4烷基氨基磺酰基、N,N-二C1-C4烷基氨基磺酰基,或者R6为-CH2NR7R8;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-10元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Group, C1-C4 alkylsulfonyl, C1-C4 alkoxymethyl, C1-C4 alkyl group, carbamoyl, N-C1-C4 alkylcarbamoyl, N, N- C1-C4 alkoxy two carbamoyl group, sulfamoyl group, N-C1-C4 alkylaminosulfonyl, N, N- two aminosulfonyl C1-C4 alkyl group, or R6 is -CH2NR7R8; R7, R8 are the same or different, each independently is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, which may be substituted with 1 to 3 identical or different optionally R5, or R7 and R8 together with the nitrogen atom to which they are attached together form a 5-10 membered saturated heterocyclic group, a saturated heterocyclic group except the nitrogen atom to which R7 and R8 are attached, may contain 1-3 heteroatoms selected from O, N and S heteroatoms may be 1 to 3 identical or different R5 is optionally substituted.
3.权利要求2的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为C1-C4烷基,另外一个为-R3YR4Q2;A为H;X为一个直接键或C1-C4亚烷基;Q1是苯基,可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, Of the general formula I according to claim 2, derivatives, and optically active or racemic, diastereomeric mixtures thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1, R2 wherein one of the C1-C4 alkyl and the other is -R3YR4Q2; a is H; X is a direct bond or C1-C4 alkylene group; Ql is phenyl, optionally substituted with 1-3 R5; R3, R4 a C1-C4 alkylene group; Y is -S-, Q2为呋喃基、吡咯基、噻吩基,可任选1-3个R6取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、4-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基;R6为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-C1-C4烷基氨基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷基酰基、氨基甲酰基、N-C1-C4烷基氨基甲酰基、N,N-二C1-C4烷基氨基甲酰基、氨基磺酰基、N-C1-C4烷基氨基磺酰基、N,N-二C1-C4烷基氨基磺酰基,或者R6为-CH2NR7R8;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以 Q2 is furyl, pyrrolyl, thienyl, optionally substituted with 1-3 R6; R5 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1- C4 alkyl, C1-C4-alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, and selected from morpholinyl, pyrrolidinyl, piperazinyl, 4-methyl-piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl a saturated heterocyclic group of; R6 is hydrogen, halogen, hydroxy, tris fluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, C1-C4 alkyl, C1-C4-alkoxy, N-C1-C4 alkylamino, N, N- C1-C4 two alkylamino, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxymethyl, C1-C4 alkyl group, carbamoyl, N -C1-C4 alkyl-carbamoyl, N, N- C1-C4 two alkylcarbamoyl, sulfamoyl group, N-C1-C4 alkylaminosulfonyl, N, N- C1-C4 alkylamino two a sulfonyl group, or R6 is -CH2NR7R8; R7, R8 are the same or different, each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, which may be 被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-10元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Substituted with 1 to 3 identical or different optionally R5, or R7 and R8, the saturated heterocyclic group connected to the nitrogen atom in addition to which they are attached form a 5-10 membered saturated heterocyclic group together with R7 and R8 the nitrogen atom may contain 1 to 3 selected from O, N and S heteroatoms may be substituted with 1 to 3 identical or different optionally R5.
4.权利要求3的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为C1-C4烷基,另外一个为-R3YR4Q2;A为H;X为一个直接键或亚甲基;Q1是苯基,可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, Formula 3 wherein R1, R2 claim I wherein the derivative thereof, and optically active or racemic, diastereomeric mixtures thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, one of the C1-C4 alkyl and the other is -R3YR4Q2; a is H; X is a direct bond or methylene; Ql is phenyl, optionally substituted with 1-3 R5; R3, R4 is C1- C4 alkylene group; Y is -S-, Q2为呋喃基、吡咯基、噻吩基,可任选1-3个R6取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、N-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基;R6为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-C1-C4烷基氨基、N,N-二C1-C4烷基氨基,或者R6为-CH2NR7R8;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Q2 is furyl, pyrrolyl, thienyl, optionally substituted with 1-3 R6; R5 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1- C4 alkyl, C1-C4-alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, and selected from morpholinyl, pyrrolidinyl, piperazinyl, N- methylpiperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl a saturated heterocyclic group of; R6 is hydrogen, halogen, hydroxy, tris fluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, C1-C4 alkyl, C1-C4-alkoxy, N-C1-C4 alkylamino, N, N- C1-C4 two alkylamino, or R6 is -CH2NR7R8; R7, R8 are the same or different, each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, which may be the same or different to any one of R5 1-3 optionally substituted, or R7 and R8 with the nitrogen atom to which they are attached form a 5-6 membered saturated heterocyclic group, a saturated heterocyclic group in addition to the nitrogen atom and R7 and R8 attached, may contain 1 to 3 selected from since hetero atoms O, N and S, may be substituted with 1 to 3 identical or different optionally R5.
5.权利要求4的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为C1-C4烷基,另外一个为-R3YR4Q2;A为H;X为一个直接键或亚甲基;Q1是苯基,可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, Of the general formula I according to claim 4 derivatives, and optically active or racemic, diastereomeric mixtures thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1, R2 wherein one of the C1-C4 alkyl and the other is -R3YR4Q2; a is H; X is a direct bond or methylene; Ql is phenyl, optionally substituted with 1-3 R5; R3, R4 is C1- C4 alkylene group; Y is -S-, Q2为含有呋喃基,可任选1-3个R6取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、4-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基;R6为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-C1-C4烷基氨基、N,N-二C1-C4烷基氨基、或者R6为-CH2NR7R8;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Q2 is a group comprising furyl, optionally substituted with 1-3 R6; R5 is hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1-C4 alkyl, C1 -C4 alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, selected from morpholinyl and , pyrrolidinyl, piperazinyl, 4-methyl-piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl a saturated heterocyclic group of; R6 is hydrogen, halo, hydroxy, trifluoromethyl, tri difluoromethoxy, carboxy, amino, nitro, cyano, C1-C4 alkyl, C1-C4-alkoxy, N-C1-C4 alkylamino, N, N- two amino C1-C4 alkyl, or R6 is -CH2NR7R8; R7, R8 are the same or different, each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, which may be substituted with 1 to 3 identical or different optionally R5, or R7 and R8 with the nitrogen atom to which they are attached form a 5-6 membered saturated heterocyclic group, a saturated heterocyclic group in addition to the nitrogen atom and R7 and R8 attached, may contain 1-3 heteroatoms selected from O, N and heteroatom S may be substituted with 1 to 3 identical or different optionally R5.
6.权利要求5的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为C1-C4烷基,另外一个为-R3YR4Q2;A为H;X为一个直接键或亚甲基;Q1是苯基,可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, Of the general formula I according to claim 5 derivatives, and optically active or racemic, diastereomeric mixtures thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1, R2 wherein one of the C1-C4 alkyl and the other is -R3YR4Q2; a is H; X is a direct bond or methylene; Ql is phenyl, optionally substituted with 1-3 R5; R3, R4 is C1- C4 alkylene group; Y is -S-, Q2为呋喃基,且在5位上被-CH2NR7R8取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、4-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,它们可以被1-3个相同或不同的R5任选取代,或R7和R8与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Q2 is a furan group, and is substituted at the 5 position -CH2NR7R8; R5 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1-C4 alkyl, C1- C4 alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, selected from morpholinyl and , pyrrolidinyl, piperazinyl, 4-methyl-piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl saturated heterocyclic group; R7, R8 are the same or different, each independently selected from hydrogen, a C1 -C6 alkyl, C3-C6 cycloalkyl, which may be substituted with 1 to 3 identical or different optionally R5, or R7 form a 5-6 membered saturated heterocyclic group and R8, together with the nitrogen atom to which they are attached the saturated heterocyclic group in addition to the nitrogen atom to which R7 and R8, may contain 1 to 3 selected from O, N and S heteroatoms may be substituted with 1 to 3 identical or different optionally R5.
7.权利要求6的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为甲基,另外一个为-R3YR4Q2;A为H;X为一个直接键;Q1是苯基,可任选1-3个R5取代;R3、R4为C1-C4亚烷基;Y为-S-, Of the general formula I according to claim 6 derivatives, and optically active or racemic, diastereomeric mixtures thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1, R2 wherein one is methyl and the other is -R3YR4Q2; a is H; X is a direct bond; Ql is phenyl, optionally substituted with 1-3 R5; R3, R4 is C1-C4 alkylene group; Y is -S-, Q2为呋喃基,且在5位上被-CH2NR7R8取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、4-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,或R7和R8与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述饱和杂环基除了与R7和R8连接的氮原子外,可以含有1-3个选自O、N和S的杂原子,可以被1~3个相同或不同的R5任选取代。 Q2 is a furan group, and is substituted at the 5 position -CH2NR7R8; R5 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1-C4 alkyl, C1- C4 alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, selected from morpholinyl and , pyrrolidinyl, piperazinyl, 4-methyl-piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl saturated heterocyclic group; R7, R8 are the same or different, each independently selected from hydrogen, a C1 -C6 alkyl, C3-C6 cycloalkyl or R7 and R8 together with the nitrogen atom to which they are attached form a 5-6 membered saturated heterocyclic group, a saturated heterocyclic group connected to the nitrogen atom in addition R7 and R8 in addition, selected may contain 1 to 3 heteroatoms of O, N and S, may be substituted with 1 to 3 identical or different optionally R5.
8.权利要求7的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物,其中R1、R2其中之一为甲基,另外一个为-R3YR4Q2;A为H;X为一个直接键;Q1是苯基,可任选1-3个R5取代;R3为C1-C3亚烷基;R4为亚甲基;Y为-S-, Formula I of claim 7 derivatives, and optically active or racemic, diastereomeric mixtures thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1, R2 wherein one is methyl and the other is -R3YR4Q2; a is H; X is a direct bond; Ql is phenyl, optionally substituted with 1-3 R5; R3 is C1-C3 alkylene; R4 is methylene group; Y is -S-, Q2为呋喃基,且在5位上被-CH2NR7R8取代;R5为氢、卤素、羟基、三氟甲基、三氟甲氧基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N,N-二C1-C4烷基氨基、C1-C4烷基硫基、C1-C4烷氧基甲基、C1-C3亚烷基二氧基,以及选自吗啉基、吡咯烷基、哌嗪基、4-甲基哌嗪基、哌啶基、咪唑烷基和吡唑烷基的饱和杂环基;R7、R8相同或不同,分别独立地选自氢、C1-C6烷基、C3-C6环烷基,或R7和R8与和它们所连接的氮原子一起形成吡咯烷基、吗啉基、哌啶基和4-甲基哌嗪基。 Q2 is a furan group, and is substituted at the 5 position -CH2NR7R8; R5 is hydrogen, halo, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, cyano, C1-C4 alkyl, C1- C4 alkoxy, N, N- two amino C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxymethyl, C1-C3 alkylenedioxy group, selected from morpholinyl and , pyrrolidinyl, piperazinyl, 4-methyl-piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl saturated heterocyclic group; R7, R8 are the same or different, each independently selected from hydrogen, a C1 -C6 alkyl, C3-C6 cycloalkyl or R7 and R8 with the nitrogen atom to which they are attached form pyrrolidinyl, morpholinyl, piperidinyl and 4-methyl-piperazinyl.
9.下列通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物:4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[(5-二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉;4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉;4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉;4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉;4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉;4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉;4-(3-三氟甲氧基苯胺基)-6-甲氧基-7-[[3-[5-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉;4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(4- 9. The following derivatives of formula I, its optically active substance or racemate, mixture of diastereomers thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof: 4- (3-chloro-4 - fluoroanilino) -6-methoxy-7 - [[3 - [(5-dimethylamino) methyl-furan-2] methylthio] propoxy] quinazoline; 4- (3 - chloro-4-fluoroanilino) -6-methoxy -7 - [[3- [5- (N- ethylamino-methyl) furan-2-methyl] methylthio] propoxy] quinolin oxazoline; 4- (3-chloro-4-fluoroanilino) -6-methoxy-7 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] propoxy] quinazoline; 4- (4-methoxyphenoxy) -6-methoxy-7 - [[3- [5- (dimethylamino) methyl-furan-2] methylthio] propoxy] quinazoline; 4- (4-methoxyphenoxy) -6-methoxy-7 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] propoxy] quinazoline; 4- (4-methoxyanilino) -6-methoxy -7 - [[3- [5- (N- A ethylamino-yl) furan-2-methyl] methylthio] propoxy] quinazoline; 4- (3-methoxyphenoxy) -6-methoxy-7 - [[3- [5- (dimethylamino) methyl-furan-2] methylthio] propoxy] quinazoline; 4- (3-trifluoromethyl-anilino) -6-methoxy-7- [ [2- [5- (4- 基-1-哌嗪基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(3-三氟甲基苯胺基)-6-甲氧基-7-[[2-[5-(1-哌啶基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(4-氟苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(3,5-二氟苯胺基)-6-甲氧基-7-[[2-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(3,5-二氟苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基乙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[2-[5-(二甲胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(3-氯-4-氟苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基丙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(3,4-二氟苯胺基)-6-甲氧基-7-[[2-[ Piperazin-1-yl) furan-2-methyl] methylthio] ethoxy] quinazoline; 4- (3-trifluoromethyl-anilino) -6-methoxy-7 - [[ 2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy] quinazoline; 4- (3-trifluoromethyl-anilino) -6-methoxy - 7 - [[2- [5- (N- ethylamino-methyl) furan-2-methyl] methylthio] ethoxy] quinazoline; 4- (3-trifluoromethyl-phenylamino) - 6-methoxy-7 - [[2- [5- (1-piperidinyl) methyl-furan-2] methylthio] ethoxy] quinazoline; 4- (4-fluoroanilino) -6-methoxy-7 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy] quinazoline; 4- (3,5- fluoroanilino) -6-methoxy-7 - [[2- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy] quinazoline; 4- (3 , 5-fluoroanilino) -6-methoxy -7 - [[2- [5- (N- ethylamino-methyl) furan-2-methyl] methylthio] ethoxy] quinazoline morpholine; 4- (3-chloro-4-fluoroanilino) -6-methoxy-7 - [[2- [5- (dimethylamino) methyl-furan-2] methylthio] ethoxy yl] quinazoline; 4- (3-chloro-4-fluoroanilino) -6-methoxy -7 - [[2- [5- (N- methyl-propylamino) methyl-furan-2] methylthio] ethoxy] quinazoline; 4- (3,4-difluorophenyl) -6-methoxy-7 - [[2- [ 5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(3,4-二氟苯胺基)-6-甲氧基-7-[[2-[5-(二甲胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(4-三氟甲氧基苯胺基)-6-甲氧基-7-[[2-[5-(N-甲基丙胺基)甲基呋喃-2-]甲硫基]乙氧基]喹唑啉;4-(3-三氟甲基苯胺基)-7-甲氧基-6-[[3-[5-(二甲胺基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉;4-(3-三氟甲基苯胺基)-7-甲氧基-6-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉;4-(3,4-二氟苯胺基)-7-甲氧基-6-[[3-[5-(1-吡咯烷基)甲基呋喃-2-]甲硫基]丙氧基]喹唑啉。 5- (1-pyrrolidinyl) methyl furan-2] methylthio] ethoxy] quinazoline; 4- (3,4-difluorophenyl) -6-methoxy-7- [ [2- [5- (dimethylamino) methyl-furan-2] methylthio] ethoxy] quinazoline; 4- (4-methoxyanilino) -6-methoxy -7 - [[2- [5- (N- methyl-propylamino) methyl-furan-2] methylthio] ethoxy] quinazoline; 4- (3-trifluoromethyl-phenylamino) - 7-methoxy-6 - [[3- [5- (dimethylamino) methyl-furan-2] methylthio] propoxy] quinazoline; 4- (3-trifluoromethyl-aniline yl) -7-methoxy-6 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] propoxy] quinazoline; 4- (3,4 - difluoroanilino) -7-methoxy-6 - [[3- [5- (1-pyrrolidinyl) methyl furan-2] methylthio] propoxy] quinazoline.
10.权利要求1~9中任一项所述的通式I衍生物,及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物:其中所述盐是草酸盐。 1 to 9 of the general formula according to any one of the pharmaceutically acceptable salt, hydrate or derivative I according to claim 10, or their, diastereomeric racemates optically active mixture thereof, or solvate thereof: wherein the salt is oxalate.
11.一种药用组合物,包含权利要求1-10中任何一项的衍生物及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物作为活性成分以及药学上可接受的赋型剂。 11. A pharmaceutical composition comprising a derivative as claimed in claim its optically active substance or racemate of any one, diastereomeric mixture 1 to 10, or a pharmaceutically acceptable salt thereof, hydrated or solvate thereof as an active ingredient and excipients pharmaceutically acceptable.
12.权利要求1-10中任何一项的衍生物及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物在制备蛋白酪氨酸激酶抑制剂中的应用。 1-10 derivatives and their optically active substance or racemate of any one, mixture of diastereomers, or a pharmaceutically acceptable salt, hydrate or solvate thereof in the manufacture of casein protein as claimed in claim 12. application of tyrosine kinase inhibitor.
13.权利要求1-10中任何一项的衍生物及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物在制备治疗和/或预防各种癌症疾病的药物中的应用。 Or its derivative, a mixture of diastereomers according to any one of 1-10 optically active racemates for the preparation of the treatment and a pharmaceutically acceptable salt, hydrate or solvate thereof as claimed in claim 13, or a / or prevention of various cancers disease applications.
14.权利要求1-10中任何一项的衍生物及其光学活性体或消旋体、非对映异构体混合物,或其药学上可接受的盐、水合物或溶剂化物在制备治疗和/预防基于动脉硬化的疾病和牛皮癣药物中的应用。 Or its derivative, a mixture of diastereomers according to any one of 1-10 optically active racemates for the preparation of the treatment and a pharmaceutically acceptable salt, hydrate or solvate thereof as claimed in claim 14, or a / prophylaxis of diseases based on arteriosclerosis and psoriasis drugs.
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