CN115477639A - 一种以fgfr1为靶点的多取代嘧啶类化合物及其制备方法和用途 - Google Patents
一种以fgfr1为靶点的多取代嘧啶类化合物及其制备方法和用途 Download PDFInfo
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- CN115477639A CN115477639A CN202211035617.8A CN202211035617A CN115477639A CN 115477639 A CN115477639 A CN 115477639A CN 202211035617 A CN202211035617 A CN 202211035617A CN 115477639 A CN115477639 A CN 115477639A
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- chloro
- pyrimidine
- ethyl acetate
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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Abstract
本发明属于药物化学领域，具体涉及一类以FGFR1为靶点的多取代嘧啶类化合物及其制备方法和用途，该化合物可以选择性地抑制FGFR1激酶的磷酸化从而用于治疗与此激酶密切联系的恶性肿瘤，同时能减少不良反应；能够用于治疗FGFR1激酶相关的肿瘤或相关的疾病。多取代嘧啶类化合物的通式为A～D,其中：以上R1、R2、R3、R4、R5、R6可以多种取代基选择，R1、R2、R3、R4、R5、R6取代基可以任意组合。本发明所述的以FGFR1为靶点的多取代嘧啶类化合物对FGFR1激酶具有良好的抑制作用；可用于制备抗肿瘤药物，且抗肿瘤效果较好。A
B
C
D
Description
技术领域
本发明属于药物化学领域，具体涉及一类以FGFR1为靶点的多取代嘧啶类化合物及其制备方法和用途。
背景技术
在蛋白激酶这个领域，成纤维细胞生长因子受体FGFR1家族在肿瘤治疗中是一个非常有吸引力的靶点。受体酪氨酸激酶的FGFR1家族包括四个成员，分别是FGFR1I,FGFR12,FGFR13和FGFR14。它们具有高度相似的序列同源性。FGFR1激酶的过表达与多种恶性肿瘤密切相关，如乳腺癌、膀胱癌、胃癌、前列腺癌、直肠癌等多种癌症，因此肿瘤医学不断对其研宄和对癌症的诊断和治疗。
抑制与疾病相关的蛋白激酶，阻断并破坏肿瘤细胞的信号传递，可通过多种方法来实现，但由于合成的反义寡核苷酸易受核酶的攻击而降解，RNA干扰技术存在安全性、稳定性和脱靶效应等问题，因此新药研发人员尝试从有机合成小分子中筛选FGFR1的化学小分子抑制剂。目前为止已有3款FGFR1抑制剂已经上市。包括厄达替尼(erdafitinib)、英菲格拉替尼(infigrarinib)和培米替尼(pemigatinib)以及处于临床试验中的抑制剂包括AZD4547、LY2874455、BAY-1163877、TAS-120等。但是上述抑制剂同时存在选择性不足、副作用较大等缺点。因此目前开发能够克服上述缺点的新型FGFR1抑制剂是亟待解决的问题。
发明内容
本发明的目的之一是为解决上述技术问题，提供一类以FGFR1为靶点的多取代嘧啶类化合物及其制备方法和用途，该化合物可以选择性地抑制FGFR1激酶的磷酸化从而用于治疗与此激酶密切联系的恶性肿瘤同时能减少不良反应：能够用于治疗FGFR1激酶相关的肿瘤或相关的疾病。
为实现上述技术效果，本发明的技术方案为：
一类以FGFR1为靶点的多取代嘧啶类化合物，具有下列通式：
A系列
B系列
C系列
D系列
其中：R1可以选自下列任一取代基团：
其中：R2可以选自下列任一取代基团：
其中：R3可以选自下列任一取代基团：
-H-Cl-CN-CF3
其中：R4可以选自下列任一取代基团：
其中：R5可以选自下列任一取代基团：
以上R1、R2、R3、R4和R5取代基可以任意组合。
一种制备上述的一类以FGFR1为靶点的多取代嘧啶类化合物的方法，包括以下步骤：
A系列：步骤一：称取2，4-R3-嘧啶，碳酸钠和R1-R2于烧瓶中，搅拌下加入无水乙醇使其溶解，室温反应，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，固体粉末状的2-氯-4-(R1-R2)-R3-嘧啶；
步骤二：称取所述2-氯-4-(R1-R2)-R3-嘧啶和R4-NH于烧瓶中，搅拌下加入甲醇与三氟乙酸使其溶解，120℃回流，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为二氯甲烷-甲醇，得2-(R4-NH)4-(R1-R2)嘧啶
B系列：步骤一：取2,4-二氯吡啶以及R1-R2，碳酸钾溶解于DMSO中。100℃反应。反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为石油醚-乙酸乙酯，得到2-氯-4-(R1-R2)吡啶。
步骤二：取2-氯-4-(R1-R2)吡啶以及NH-R4溶解于无水甲醇中后，加入三氟乙酸催化,反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为二氯甲烷-甲醇得到。4-R4-NH)4-(R1-R2)吡啶。C系列：步骤一：称取5-硝基吲哚、NCS溶解于无水DCM中，50℃反应。反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为石油醚-乙酸乙酯，得到3-氯-5-硝基吲哚。
步骤二：称取3-氯-5-硝基吲哚、铁粉和氯化铵溶解于乙醇：水＝1:1中，80℃反应。反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩。产物不做进一步纯化，得到3-氯-5-胺基吲哚红色固体。
步骤三：称取3-氯-5-胺基吲哚，2-氨基-3-硝基-4-氯吡啶，碳酸钠溶解于无水乙醇中，室温反应。反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为石油醚-乙酸乙酯，得到N4-(3-氯-1H-吲哚-5-基)-3-硝基吡啶-2,4-二胺黄色固体。
步骤四：称取N4-(3-氯-1H-吲哚-5-基)-3-硝基吡啶-2,4-二胺、铁粉和氯化铵溶解于乙醇：水＝1:1(20ml)中，80℃反应2h。反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，产物不做进一步纯化，得到N4-(3-氯-1H-吲哚-5-基)吡啶-2,4-二胺。
步骤五：称取N4-(3-氯-1H-吲哚-5-基)吡啶-2,4-二胺、4-(4-甲基哌嗪)苯甲醛和六水氯化钴溶解与DMF中，并且保持通风状态。110℃反应。反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为二氯甲烷:甲醇＝10:1，得到N-(3-氯-1H-吲哚-5-基)-2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-胺
D系列：步骤一：称取2，4-R5-杂环嘧啶，碳酸钠和R1-R2于烧瓶中，搅拌下加入无水乙醇使其溶解，室温反应，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，固体粉末状的2-氯-4-(R1-R2)-R5-杂环嘧啶；
步骤二：称取所述2-氯-4-(R1-R2)-R5-杂环嘧啶和R4-NH于烧瓶中，搅拌下加入甲醇与三氟乙酸使其溶解，回流，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为二氯甲烷-甲醇，得2-(R4-NH)4-(R1-R2)-R5-杂环嘧啶
本发明还提供了一类以FGFR1为靶点的多取代嘧啶类化合物的用途，所述用途为制备抗肿瘤药物中的应用。
一种药物组合物，包括药用辅料和所述的一类以FGFR1为靶点的多取代嘧啶类化合物。
本发明还提供了含有以FGFR1为靶点的多取代嘧啶类化合物的药物组合物，所述的药物组合物的制剂形式为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂或纳米制剂的任一种。
附图说明
图1为实施例7中tsj41对U87细胞FGFR1及其下游ERK磷酸化水平的抑制作用。
具体实施方式
下文将结合具体实施例详细描述本发明。应当注意的是，下述实施例中描述的技术特征或者技术特征的组合不应当被认为是孤立的，它们可以被相互组合从而达到更好的技术效果。
实施例1N2-(4-(4-乙基哌嗪-1-基)苯基)-N4-(1H-吲哚-5-基)嘧啶-2，4-二胺(化合物tsj01)的制备
(1)N-(2-氯嘧啶-4-基)-1H-吲哚-5-胺的制备
将5-胺基吲哚(200mg,1.57mmol)溶解于无水乙醇(10ml)中，加入碳酸钠(332.8mg，3.14mmol)和2，4-二氯嘧啶(233.8mg，1.57mmol),反应混合物在室温下搅拌1h，反应结束后，减压浓缩，残余物用乙酸乙酯萃取3次，有机层用饱和食盐水洗涤，浓缩得固体，产物不做进一步纯化，得到333.25mg黄色固体，产率为90％。
(2)N2-(4-(4-乙基哌嗪-1-基)苯基)-N4-(1H-吲哚-5-基)嘧啶-2，4-二胺(tsj01)的制备
称取N-(2-氯嘧啶-4-基)-1H-吲哚-5-胺(300mg,1.29mmol)、4-(4-乙基-1-哌嗪基)苯胺(398.28mg，1.94mmol)和三氟乙酸(441.25mg,3.87mmol)溶于甲醇(10ml)，加毕120℃反应8h。冷却,减压浓缩体系，得到的油状物倒入水中,加入碳酸氢钠中和至中性，乙酸乙酯萃取,干燥,浓缩有机相得到粗品,柱层析(二氯甲烷:甲醇＝20∶1)得到黄色固体状产物401.12mg,收率75.2％。
按照实施例1,用2,4-二氯-R4嘧啶、4-(4-乙基-1-哌嗪基)苯胺以及不同取代R1为原料，合成了下列化合物
实施例2 4-((1H-吲哚-5-基)氧基)-N-(4-(4-乙基哌嗪-1-基)苯基)吡啶-2-胺(tsj07的制备)
(a)5-hydroxyindole,K2CO3,DMSO,100℃,8h.(b)4-(4-Ethylpiperazin-1-yl)phenylamine,TFA,MeOH,120℃,8h.
(1)N-(2-氯嘧啶-4-基)-1H-吲哚-5-胺的制备
取3 1mmol(147.98mg)以及5-羟基吲哚1mmol(133.15mg)，碳酸钾2mmol(138.20mg)加入到50mL单口圆底烧瓶，溶解于20ml DMSO中。超声待其充分溶解后，100℃反应10h。反应结束后，将反应液倒入水中，用乙酸乙酯(30ml×3)萃取。减压浓缩溶液，加入适量柱层析硅胶，旋干制砂，经过柱层析色谱法分离提纯(石油醚:乙酸乙酯＝2:1)，得到N-(2-氯嘧啶-4-基)-1H-吲哚-5-胺的制备黄色固体。
(2)4-((1H-吲哚-5-基)氧基)-N-(4-(4-乙基哌嗪-1-基)苯基)吡啶-2-胺的制备
取4 0.5mmol(122.33mg)以及4-(4-乙基哌嗪-1-基)苯胺0.75mmol(153.97mg)加入中50ml单口圆底烧瓶中，溶解于20ml无水甲醇中后，加入三氟乙酸1.5mmol(156.3mg)，120℃反应8h,TLC监测反应。反应结束后，减压浓缩溶剂，残余物加入水中，用乙酸乙酯(30ml×3)萃取。减压浓缩溶液，加入适量柱层析硅胶，旋干制砂，经过柱层析色谱法分离提纯(二氯甲烷:甲醇＝20:1)，得到4-((1H-吲哚-5-基)氧基)-N-(4-(4-乙基哌嗪-1-基)苯基)吡啶-2-胺,白色固体。
实施例3N-(3-氯-1H-吲哚-5-基)-2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-胺(tsj08)的制备
(a)NCS,DCM,50℃,5h.(b)Fe,NH4Cl,EtOH:H2O＝1:1,80℃,5h.(c)2-amino-4-chloro-3-nitropyridine,Na2CO3,EtOH,rt,1h.(d)Fe,NH4Cl,EtOH:H2O＝1:1,80℃,5h.(e)cobalt chloride hexahydrate,DMF,120℃,10h.
(1)3-氯5-硝基的制备
将5-硝基吲哚(1g,6.16mmol)与NCS(823.54mg,6.16mmol)溶解于二氯甲烷中，50℃反应5h。反应结束后，将溶液倒入水中，二氯甲烷萃取3次，有机层用饱和食盐水洗涤。浓缩硅胶柱层析，洗脱剂为石油醚：乙酸乙酯＝2：1。得到黄色固体粉末1116.16mg，产率为92％
(2)3-氯-1H-吲哚-5-胺的制备
称取3-氯-5-硝基-1H-吲哚(1g,5.08mmol)、铁粉(2840.93mg,50.8mmol)和氯化铵(271.72mg,5.08mmol)溶解于乙醇：水＝1:1(20ml)中，80℃反应2h。反应完全后，硅藻土过滤，减压浓缩；残余物用乙酸乙酯萃取3次，有机层用饱和食盐水洗涤。产物不做进一步纯化，得到806.31mg红色固体，产率为95％。
(3)N4-(3-氯-1H-吲哚-5-基)-3-硝基吡啶-2,4-二胺的制备
称取3-氯-5-硝基-1H-吲哚3mmol(499.8mg)，2-氨基-3-硝基-4-氯吡啶3mmol(520.65mg)，碳酸钠6mmol(635.94mg)溶解于无水乙醇中，室温反应2h。反应结束后，减压浓缩溶剂，残余物加入水中，用乙酸乙酯(30ml×3)萃取。减压浓缩溶液，加入适量柱层析硅胶，旋干制砂，经过柱层析色谱法分离提纯(石油醚:乙酸乙酯＝2:1)，得到N4-(3-氯-1H-吲哚-5-基)-3-硝基吡啶-2,4-二胺黄色固体。
(4)N4-(3-氯-1H-吲哚-5-基)吡啶-2,4-二胺的制备
称取N4-(3-氯-1H-吲哚-5-基)-3-硝基吡啶-2,4-二胺1mmol(286.72mmol)、铁粉10mmol(558.00mg)和氯化铵1mmol(53.8mg)溶解于乙醇：水＝1:1(20ml)中，80℃反应2h。反应完全后，硅藻土过滤，减压浓缩；残余物用乙酸乙酯萃取3次，有机层用饱和食盐水洗涤。柱色谱分离(石油醚：乙酸乙酯＝1:1)，得到N4-(3-氯-1H-吲哚-5-基)吡啶-2,4-二胺红色固体。
(5)N-(3-氯-1H-吲哚-5-基)-2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-胺的制备
称取N4-(3-氯-1H-吲哚-5-基)吡啶-2,4-二胺0.5mmol(143.36mg)、4-(4-甲基哌嗪)苯甲醛0.75mmol(153.20mg)和六水氯化钴1.5mmol(356.89mg)溶解与DMF中，并且保持通风状态。110℃反应8h。反应结束后，将反应液倒入水中，用乙酸乙酯(30ml×3)萃取。减压浓缩溶液，加入适量柱层析硅胶，旋干制砂，经过柱层析色谱法分离提纯(二氯甲烷:甲醇＝10:1)，得到N-(3-氯-1H-吲哚-5-基)-2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-胺，白色固体。
实施例4N4-(3-氯-1H-吲哚-5-基)-N2-(4-(4-乙基哌嗪-1-基)苯基)嘧啶-2,4-二胺(tsj09)的制备
(a)2,4-Dichloro-5-R3 pyrimidine,Na2CO3,EtOH,rt,1h.(b)4-(4-Ethylpiperazin-1-yl)phenylamine,TFA,MeOH,120℃,8h.
(1)3-氯-N-(2-氯嘧啶-4-基)-1H-吲哚-5-胺的制备
称取5-胺基吲哚2mmol(333.25mg)、2,4-二氯-嘧啶2mmol和碳酸钠4mmol(423.96mg)溶解于无水乙醇中，室温反应2h。反应结束后，减压浓缩溶剂，残余物加入水中，用乙酸乙酯(30ml×3)萃取。减压浓缩溶液，加入适量柱层析硅胶，旋干制砂，经过柱层析色谱法分离提纯(石油醚:乙酸乙酯＝2:1)，得到3-氯-N-(2-氯嘧啶-4-基)-1H-吲哚-5-胺，黄色固体。
(2)N4-(3-氯-1H-吲哚-5-基)-N2-(4-(4-乙基哌嗪-1-基)苯基)嘧啶-2,4-二胺的制备
称取3-氯-N-(2-氯嘧啶-4-基)-1H-吲哚-5-胺0.5mmol(139.56mg)、以及4-(4-乙基哌嗪-1-基)苯胺0.75mmol(153.97mg)，溶解于20ml无水甲醇中后，加入三氟乙酸1.5mmol(156.30mg)。120℃反应8h,TLC监测反应。反应结束后，减压浓缩溶剂，残余物加入水中，用乙酸乙酯(30ml×3)萃取。减压浓缩溶液，加入适量柱层析硅胶，旋干制砂，经过柱层析色谱法分离提纯(二氯甲烷:甲醇＝20:1)，得到N4-(3-氯-1H-吲哚-5-基)-N2-(4-(4-乙基哌嗪-1-基)苯基)嘧啶-2,4-二胺,白色固体。
按照实施例2合成下列化合物
实施例4 4-((1-乙酰基-3-氯-1H-吲哚-5-基)(乙基)氨基)-2-((4-(4-乙基哌嗪-1-基)苯基)氨基)嘧啶-5-腈的制备
(a)BOC2O,DMAP,THF,rt,10min.(b)Fe,NH4Cl,EtOH:H2O＝1:1,80℃,5h.(c)BOC2O,Et3N,THF,60℃,6h.(d)IEt,NaOH,DMF,40℃,1h-overnight.(e)TFA:DCM＝3:1,rt,overnight.(f)2,4-Dichloro-5-cyanopyrimi-dine,Na2CO3,EtOH,rt,1h.(g)4-(4-Ethylpiperazin-1-yl)phenylamine,TFA,MeOH,120℃,8h.(h)acetylchloride,t-BuOK,DMF,rt,3h.
(1)3-氯-5-硝基-1H-吲哚-1-羧酸叔丁酯的制备
将3-氯-5-硝基-1H-吲哚(1.5g,7.63mmol)、二碳酸叔二丁酯(1831mg,8.39mmol)、DMAP(92.84mg,0.76mmol)溶解于四氢呋喃中，室温反应0.2h。反应结束后，减压浓缩，乙酸乙酯萃取，有机层用饱和食盐水洗涤。浓缩硅胶柱层析，洗脱剂为石油醚：乙酸乙酯＝10：1，得到黄色固体粉末2150.65mg，产率为95％
(2)5-氨基-3-氯-1H-吲哚-1-羧酸叔丁酯的制备
称取3-氯-5-硝基-1H-吲哚-1-羧酸叔丁酯(2150.65mg,7.24mmol)、铁粉(4048.32mg,72.4mmol)和氯化铵(387.26mg,7.24mmol)溶解于乙醇：水＝1:1(30ml)中，80℃反应2h。反应完全后，硅藻土过滤，减压浓缩；残余物用乙酸乙酯萃取3次，有机层用饱和食盐水洗涤。产物不做进一步纯化，得到1642.59mg红色液体，产率为85.2％。
(3)5-((叔丁氧基羰基)氨基)-3-氯-1H-吲哚-1-羧酸叔丁酯的制备
将5-氨基-3-氯-1H-吲哚-1-羧酸叔丁酯(1642.59g,6.16mmol)、二碳酸叔二丁酯(1479.16mg,6.77mmol)、三乙胺(1246.66mg,12.32mmol)溶解于四氢呋喃(20ml)中，室温反应8h。反应结束后，减压浓缩，乙酸乙酯萃取，有机层用饱和食盐水洗涤。产物不做进一步纯化得到红色液体2011.57mg，产率为89.3％
(4)5-((叔丁氧基羰基)(乙基)氨基)-3-氯-1H-吲哚-1-羧酸叔丁酯的制备
将5-((叔丁氧基羰基)氨基)-3-氯-1H-吲哚-1-羧酸叔丁酯(2011.57mg,5.48mmol)、NaOH(1479.16mg,6.77mmol)、碘乙烷(1246.66mg,12.32mmol)溶解于四氢呋喃(20ml)中，室温反应8h。反应结束后，减压浓缩，乙酸乙酯萃取，有机层用饱和食盐水洗涤。产物不做进一步纯化得到5-((叔丁氧基羰基)(乙基)氨基)-3-氯-1H-吲哚-1-羧酸叔丁酯，红色液体2011.57mg，产率为89.3％
(5)3-氯-N-乙基-1H-吲哚-5-胺的制备
称取5-((叔丁氧基羰基)(乙基)氨基)-3-氯-1H-吲哚-1-羧酸叔丁酯3mmol()溶于DCM:TFA＝1:3中。室温反应下过夜。反应结束后，加入饱和碳酸氢钠调节PH至中性。减压浓缩溶剂。残余物放入水中，用乙酸乙酯萃取。减压浓缩溶液，加入适量柱层析硅胶，旋干制砂，经过柱层析色谱法分离提纯(石油醚:乙酸乙酯＝5:1)，得到3-氯-N-乙基-1H-吲哚-5-胺，红色油状物。
(6)2-氯-4-((3-氯-1H-吲哚-5-基)(乙基)氨基)嘧啶-5-腈的制备
称取3-氯-N-乙基-1H-吲哚-5-胺2.2mmol，2,4-二氯-5-氰基嘧啶1.1mmol(382.77mg)，碳酸钠4.4mmol(466.35mg)溶解于无水乙醇中，室温反应2h。反应结束后，减压浓缩溶剂，残余物加入水中，用乙酸乙酯(30ml×3)萃取。减压浓缩溶液，加入适量柱层析硅胶，旋干制砂，经过柱层析色谱法分离提纯(石油醚:乙酸乙酯＝2:1)，得到2-氯-4-((3-氯-1H-吲哚-5-基)(乙基)氨基)嘧啶-5-腈，黄色固体。
(7)4-((3-氯-1H-吲哚-5-基)(乙基)氨基)-2-((4-(4-乙基哌嗪-1-基)苯基)氨基)嘧啶-5-腈的制备
称取2-氯-4-((3-氯-1H-吲哚-5-基)(乙基)氨基)嘧啶-5-腈0.8mmol、以及4-(4-乙基哌嗪-1-基)苯胺1.2mmol(246.36mg)，溶解于20ml无水甲醇中后，加入三氟乙酸2.4mmol(273.67mg)。120℃反应8h,TLC监测反应。反应结束后，减压浓缩溶剂，残余物加入水中，用乙酸乙酯(30ml×3)萃取。减压浓缩溶液，加入适量柱层析硅胶，旋干制砂，经过柱层析色谱法分离提纯(二氯甲烷:甲醇＝20:1)，得到4-((3-氯-1H-吲哚-5-基)(乙基)氨基)-2-((4-(4-乙基哌嗪-1-基)苯基)氨基)嘧啶-5-腈,黄色固体。
(8)4-((1-乙酰基-3-氯-1H-吲哚-5-基)(乙基)氨基)-2-((4-(4-乙基哌嗪-1-基)苯基)氨基)嘧啶-5-腈的制备
称取4-((3-氯-1H-吲哚-5-基)(乙基)氨基)-2-((4-(4-乙基哌嗪-1-基)苯基)氨基)嘧啶-5-腈0.3mmol(150.30mg)、t-BuOK 0.6mmol(67.36mg)溶解于10ml DMF中,缓慢滴加乙酰氯0.36mmol(28.26mg)。室温反应2h。反应结束后，减压浓缩溶剂，残余物加入水中，用乙酸乙酯(30ml×3)萃取。减压浓缩溶液，加入适量柱层析硅胶，旋干制砂，经过柱层析色谱法分离提纯(二氯甲烷:甲醇＝20:1)，得到4-((1-乙酰基-3-氯-1H-吲哚-5-基)(乙基)氨基)-2-((4-(4-乙基哌嗪-1-基)苯基)氨基)嘧啶-5-腈,白色固体。
按照实施例4合成下列化合物
实施例5化合物对FGFR1激酶活性的测定
通过LANCE ULTRAAssay方法测定化合物对FGFR1的抑制活性，筛选出活性好的化合物。FGFR1为CARNA公司购买。
具体方法：所测试的化合物、ATP、特异性底物以及FGFR1激酶用激酶稀释液稀释。激酶反应混合物中含FGFRI、ATP、底物、HEPES(P1＝7.5)、MgC1g、EGTA、Tween-20。不加任何化合物组作100％磷酸化对照，加入FGFRI激酶后马上加EDTA终止反应组作为0％磷酸化对照。激酶反应混合物室温下共哪育1h后,加EDTA终止反应5分钟。再加入特异性抗体，室温下继续共孵育1h,用PerkinElmer Envision激酶仪检测激发光。根据激酶仪检测所得信号值，用公式计算得抑制率或者GraphPad计算受试化合物IC50值。
表1：FGFR1激酶实验结果
aNT＝Not test
对部分化合物进行FGFR1 IC50测定，得到如下结果
表2部分化合物对FGFR1的IC50
FGFR1测试结果表明，tsj41化合物结构新颖，并且对FGFR1有着非常好的效力。可用于预防和治疗与成纤维细胞成长因子受体激酶1有关的疾病。
实施例6tsj41对肿瘤细胞的活性测试结果与分析
表3 tsj41对细胞的增殖抑制活性
结果表明：tsj41对选择的高表达FGFR1的细胞株都有着较好的活性，而且都高于阳性化合物BGJ398，以此证明，其在细胞上的活性是高于阳性化合物BGJ398的。其中对U87细胞的抑制能力最好，IC50达到了0.92μM。
实施7免疫印迹实验结果以及分析
结果表明：通过对图1免疫印迹的分析可以看出，tsj41能够降低U87FGFR1的蛋白浓度且优于阳性药物BGJ398；同时tsj41对ERK磷酸化也具有抑制作用。说明tsj41对于FGFR1及其下游信号通路具有抑制作用。
部分化合物的性状、产率、熔点、氢谱和质谱数据：
5-Chloro-N2-(4-(4-ethylpiperazin-1-yl)phenyl)-N4-(1H-indol-5-yl)pyrimidine-2,4-diamine(tsj-02)
化学式:C24H26ClN7；收率/％:60.58％；MP:306.9～307.1℃；HPLC:纯度:95.65％；HRESI-MS:448.2025[M+H]+；1H-NMR(400MHz,MeOD)δ(ppm):8.00(s,1H),7.74(d,J＝1.3Hz,1H),7.47(d,J＝8.6Hz,1H),7.38(s,1H),7.30(d,J＝8.8Hz,2H),7.21-7.13(m,1H),6.75(s,2H),3.69(d,J＝31.6Hz,4H),3.28(q,J＝7.3Hz,2H),3.16(t,J＝11.4Hz,2H),3.01(t,J＝12.1Hz,2H),1.41(t,J＝7.3Hz,3H)；13C-NMR(101MHZ,MeOD)δ(ppm):160.48,160.11,158.39,139.53,135.11,127.96,127.81,125.60,120.29,118.76,117.42,117.07,116.80,114.54,111.06,104.89,51.75,51.03,46.63,8.13.
4-((1H-Indol-5-yl)oxy)-N-(4-(4-ethylpiperazin-1-yl)phenyl)pyridin-2-amine(tsj-07)
化学式:C25H27N5O；收率/％:50.32％；MP:313.4～316.9℃；HPLC:纯度:95.65％；HRESI-MS:414.2292[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):11.27(s,1H),8.62(s,1H),7.96(d,J＝5.8Hz,1H),7.49(d,J＝8.7Hz,1H),7.47-7.42(m,3H),7.34(s,1H),6.90(dd,J＝8.6,1.7Hz,1H),6.83(d,J＝8.8Hz,2H),6.47(s,1H),6.38-6.31(m,1H),6.06(d,J＝1.3Hz,1H),3.04(s,4H),2.53(s,4H),2.41(d,J＝6.8Hz,2H),1.05(t,J＝7.1Hz,3H)；13C-NMR(101MHz,DMSO-d6)δ(ppm):167.00,158.48,149.32,146.95,145.97,134.61,134.05,128.76,127.40,120.12,116.61,115.43,113.08,112.13,104.17,101.88,95.44,52.82,52.08,49.52,12.33.
N4-(3-Chloro-1H-indol-5-yl)-N2-(4-(4-ethylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine(tsj-09)
化学式:C24H26ClN7；收率/％:55.6％；MP:308.6～310.4℃；HPLC:纯度:98.73％；HRESI-MS:448.1996[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):11.40(s,1H),9.34(s,1H),9.06(s,1H),7.95(d,J＝5.8Hz,1H),7.70(s,1H),7.64(d,J＝8.9Hz,2H),7.52(d,J＝2.5Hz,1H),7.42(s,2H),6.88(d,J＝9.0Hz,2H),6.18(d,J＝5.9Hz,1H),3.24(s,8H),3.09(d,J＝6.9Hz,2H),1.24(t,J＝7.2Hz,3H)；13C-NMR(101MHz,DMSO-d6)δ(ppm):161.55,159.69,159.21,158.86,155.25,144.81,134.45,132.84,132.18,125.13,123.45,120.74,119.13,118.49,117.10,112.78,109.67,103.42,98.04,51.29,51.11,47.43,9.83.
4-((3-Chloro-1H-indol-5-yl)(propyl)amino)-2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carbonitrile(tsj-27)
化学式:C28H31ClN8；收率/％:24.25％；MP:382.4～385.1℃；HPLC:纯度:99.13％；HRESI-MS:515.2441[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):11.63(d,J＝1.6Hz,1H),9.73(d,J＝0.9Hz,1H),8.20(s,1H),7.63(d,J＝2.5Hz,1H),7.56(d,J＝7.0Hz,2H),7.50(d,J＝8.6Hz,1H),7.42(d,J＝1.1Hz,1H),7.12(dd,J＝8.6,1.7Hz,1H),6.86(d,J＝4.2Hz,2H),3.97-3.83(m,2H),3.11(s,4H,),2.69-2.53(m,4H),2.44(d,J＝1.4Hz,2H),1.66(dd,J＝15.0,7.4Hz,2H),1.06(t,J＝7.1Hz,3H,),0.89(t,J＝7.4Hz,3H)；13C-NMR(101MHz,DMSO-d6)δ(ppm):164.37,161.11,159.66,147.22,135.26,135.01,131.97,125.55,124.36,123.64,121.45,117.60,116.87,115.99,113.86,104.20,52.65,52.03,48.99,31.46,22.57,20.56,14.46,12.22,11.53.
4-((3-Chloro-1H-indol-5-yl)(cyclopropylmethyl)amino)-2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carbonitrile(tsj-29)
化学式:C29H31ClN8；收率/％:15.67％；MP:404.5～407.6℃；HPLC:纯度:98.90％；HRESI-MS:527.2443[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):11.60(d,J＝0.5Hz,1H),9.71(s,1H),8.21(s,1H),7.67-7.54(m,3H),7.53-7.40(m,2H),7.17(d,J＝4.5Hz,1H),6.93(d,J＝1.8Hz,2H),3.90(d,J＝0.6Hz,2H),3.26(d,J＝1.9Hz,4H),3.01(d,J＝1.7Hz,4H),2.87(s,2H),1.18(s,4H),0.48-0.33(m,2H),0.11(s,2H).13C-NMR(101MHz,DMSO-d6)δ(ppm):164.59,161.17,158.51,146.45,135.30,135.07,132.47,125.49,124.30,123.93,121.88,117.86,116.43,113.68,104.22,56.37,51.62,51.56,47.74,10.67,10.02,3.93.
4-((3-Chloro-1H-indol-5-yl)(propyl)amino)-2-((3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carbonitrile(tsj40)
化学式:C27H29ClN8；收率/％:24.2％；MP:410.4～413.6℃；HPLC:纯度:100.00％；HRESI-MS:501.2276[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):11.65(d,J＝2.1Hz,1H),9.75(s,1H),8.25(s,1H),7.63(d,J＝2.6Hz,1H),7.51(d,J＝8.6Hz,1H),7.48(d,J＝7.2Hz,1H),7.44(d,J＝1.6Hz,1H),7.19(d,J＝10.8Hz,2H),7.14(dd,J＝8.6,1.9Hz,1H),6.72(dd,J＝8.2,1.5Hz,1H),4.01-3.90(m,2H),3.35(d,J＝33.1Hz,8H),2.83(s,3H),1.72-1.56(m,2H),0.88(t,J＝7.4Hz,3H)；13C-NMR(101MHz,DMSO-d6)δ(ppm):164.56,161.12,159.84,159.23,158.92,150.53,140.84,135.10,134.97,129.49,125.55,124.45,123.64,119.14,117.67,116.52,116.16,113.90,112.50,111.41,108.43,104.22,54.14,52.89,46.49,42.84,20.49,11.52.
4-((3-Chloro-1H-indol-5-yl)(propyl)amino)-2-((4-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carbonitrile(tsj41)
化学式:C28H31ClN8；收率/％:22.3％；MP:404.4～406.3℃；HPLC:纯度:99.00％；HRESI-MS:515.2447[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):11.62(s,1H),9.70(d,J＝1.2Hz,1H),8.18(s,1H),7.60(d,J＝1.8Hz,1H),7.54(d,J＝7.2Hz,2H),7.49(d,J＝8.6Hz,1H),7.40(d,J＝1.0Hz,1H),7.10(dd,J＝8.6,1.5Hz,1H),6.85(d,J＝3.9Hz,2H),3.88(s,2H),3.51(d,J＝10.7Hz,2H),2.98(d,J＝6.4Hz,2H),2.24(t,J＝11.1Hz,2H),1.63(dt,J＝14.2,7.1Hz,2H),1.10(d,J＝6.3Hz,7H),0.87(t,J＝7.3Hz,3H)；13C-NMR(101MHz,DMSO-d6)δ(ppm):164.37,161.12,159.69,147.00,135.25,135.02,131.96,125.56,124.34,123.65,121.52,117.62,116.89,116.19,113.86,104.23,55.21,50.80,20.58,18.86,11.57.
4-((3-Chloro-1H-indol-5-yl)(propyl)amino)-2-((4-((2-(ethylamino)ethyl)amino)phenyl)amino)pyrimidine-5-carbonitrile(tsj42)
化学式:C26H29ClN8；收率/％:16.3％；MP:399.5～403.2℃；HPLC:纯度:96.68％；HRESI-MS:489.2274[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):11.70(s,1H),9.62(s,1H),8.16(s,1H),7.61(d,J＝1.2Hz,1H),7.51(d,J＝8.4Hz,3H),7.41(s,1H),7.11(d,J＝7.8Hz,1H),6.60(d,J＝7.7Hz,2H),5.72(d,J＝1.6Hz,1H),3.88(s,2H),3.35(s,2H),3.09(t,J＝5.7Hz,2H),3.01(dd,J＝14.2,7.0Hz,2H),1.65(d,J＝6.7Hz,2H),1.22(t,J＝7.1Hz,3H),0.88(t,J＝7.0Hz,3H).；13C-NMR(101MHz,DMSO-d6)δ(ppm):164.27,161.10,159.12,158.81,144.48,135.19,135.04,129.78,125.53,124.36,123.64,122.13,119.07,117.59,116.91,116.10,113.88,112.66,104.17,80.74,54.37,45.90,42.58,20.51,11.42.
4-((3-Chloro-1H-indol-5-yl)(propyl)amino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carbonitrile(tsj43)
化学式:C28H31ClN8O；收率/％:23.7％；MP:455.3～458.2℃；HPLC:纯度:97.40％；HRESI-MS:531.2380[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):11.62(d,J＝1.8Hz,1H),10.27(d,J＝2.5Hz,1H),8.58(s,1H),8.19(s,1H),7.63(d,J＝2.6Hz,2H),7.49(d,J＝8.6Hz,1H),7.40(s,1H),7.11(d,J＝8.5Hz,1H),6.75(d,J＝1.7Hz,1H),6.54(d,J＝7.5Hz,1H),3.86(s,5H),3.79(s,2H),3.56(d,J＝11.0Hz,2H),3.20(d,J＝0.5Hz,2H),2.99(t,J＝11.7Hz,2H),2.89(s,4H),1.57(d,J＝6.5Hz,2H),0.80(s,3H)；13C-NMR(101MHz,DMSO-d6)δ(ppm):164.09,160.92,159.12,158.79,135.05,135.02,125.52,124.43,124.28,123.58,120.65,118.59,117.58,116.51,115.64,113.86,107.52,104.19,101.11,56.22,52.80,46.59,42.56,20.39,11.49.
4-((3-Chloro-1H-indol-5-yl)(propyl)amino)-2-((4-(4-ethylpiperazin-1-yl)-3-methoxyphenyl)amino)pyrimidine-5-carbonitrile(tsj44)
化学式:C29H33ClN8O；收率/％:20.7％；MP:450.2～453.1℃；HPLC:纯度:99.48％；HRESI-MS:545.2546[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):11.62(d,J＝1.8Hz,1H),9.97(d,J＝3.5Hz,1H),8.25(s,1H),7.63(d,J＝2.6Hz,1H),7.51(d,J＝8.6Hz,1H),7.46-7.36(m,2H),7.30(s,1H),7.14(dd,J＝8.6,1.6Hz,1H),6.86(d,J＝7.6Hz,1H),4.00-3.90(m,2H),3.82(s,3H),3.53(dd,J＝33.8,12.0Hz,4H),3.19(dd,J＝22.3,9.3Hz,4H),2.95(t,J＝11.7Hz,2H),1.64(dd,J＝15.1,7.5Hz,2H),1.28(t,J＝7.2Hz,3H),0.87(t,J＝7.2Hz,3H)；13C-NMR(101MHz,DMSO-d6)δ(ppm):164.17,161.11,159.45,159.09,158.74,158.39,152.34,135.97,135.29,135.10,134.93,125.54,124.44,123.64,118.57,117.88,117.69,116.46,114.97,113.88,112.87,105.91,105.80,104.22,55.96,54.11,51.21,47.85,20.49,11.47,9.39,1.62.
上述详细说明是针对发明的可行实施例的具体说明，该实施例并非用以限制本发明的专利范围，凡未脱离本发明的等效实施或变更,均应当包含于本发明的专利范围内。另外，本领域技术人员还可在木发明权利要求公开的范围和精神内做其它形式和细节上的各种修改、添加和替换。当然,这些依据木发明精神所做的各种修改、添加和替换等变化，都应包含在本发明所要求保护的范围之内。
Claims (9)
1.一种以FGFR1为靶点的多取代嘧啶类化合物，其特征在于，具有下列通式：
A系列
B系列
C系列
D系列
其中：R1可以选自下列任一取代基团：
其中：R2可以选自下列任一取代基团：
-NH--O-
其中：R3可以选自下列任一取代基团：
-H-Cl-CN-CF3
其中：R4可以选自下列任一取代基团：
其中：R5可以选自下列任一取代基团：
以上R1、R2、R3、R4和R5取代基可以任意组合。
2.一种以FGFR1为靶点的多取代嘧啶类化合物，其特征在于，为以下化合物中的一种：
3.一种制备权利要求1所述的以FGFR1为靶点的多取代嘧啶类化合物的方法，其特征在于，包括如下步骤：
A系列：步骤一：称取2，4-R3-嘧啶，碳酸钠和R1-R2于烧瓶中，搅拌下加入无水乙醇使其溶解，室温反应，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，固体粉末状的2-氯-4-(R1-R2)-R3-嘧啶；
步骤二：称取所述2-氯-4-(R1-R2)-R3-嘧啶和R4-NH于烧瓶中，搅拌下加入甲醇与三氟乙酸使其溶解，120℃回流，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为二氯甲烷-甲醇，得2-(R4-NH)4-(R1-R2)嘧啶；或者，
B系列：步骤一：取2,4-二氯吡啶以及R1-R2，碳酸钾溶解于DMSO中，100℃反应，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为石油醚-乙酸乙酯，得到2-氯-4-(R1-R2)吡啶；
步骤二：取2-氯-4-(R1-R2)吡啶以及NH-R4溶解于无水甲醇中后，加入三氟乙酸催化,反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为二氯甲烷-甲醇得到，4-R4-NH)4-(R1-R2)吡啶；
C系列：步骤一：称取5-硝基吲哚、NCS溶解于无水DCM中，50℃反应，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为石油醚-乙酸乙酯，得到3-氯-5-硝基吲哚；
步骤二：称取3-氯-5-硝基吲哚、铁粉和氯化铵溶解于乙醇：水＝1:1中，80℃反应，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，产物不做进一步纯化，得到3-氯-5-胺基吲哚红色固体；
步骤三：称取3-氯-5-胺基吲哚，2-氨基-3-硝基-4-氯吡啶，碳酸钠溶解于无水乙醇中，室温反应，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为石油醚-乙酸乙酯，得到N4-(3-氯-1H-吲哚-5-基)-3-硝基吡啶-2,4-二胺黄色固体；
步骤四：称取N4-(3-氯-1H-吲哚-5-基)-3-硝基吡啶-2,4-二胺、铁粉和氯化铵溶解于乙醇：水＝1:1(20ml)中，80℃反应2h，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，产物不做进一步纯化，得到N4-(3-氯-1H-吲哚-5-基)吡啶-2,4-二胺；
步骤五：称取N4-(3-氯-1H-吲哚-5-基)吡啶-2,4-二胺、4-(4-甲基哌嗪)苯甲醛和六水氯化钴溶解与DMF中，并且保持通风状态，110℃反应，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为二氯甲烷:甲醇＝10:1，得到N-(3-氯-1H-吲哚-5-基)-2-(4-(4-甲基哌嗪-1-基)苯基)-3H-咪唑并[4,5-b]吡啶-7-胺；或者，
D系列：步骤一：称取2，4-R5-杂环嘧啶，碳酸钠和R1-R2于烧瓶中，搅拌下加入无水乙醇使其溶解，室温反应，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，固体粉末状的2-氯-4-(R1-R2)-R5-杂环嘧啶；
步骤二：称取所述2-氯-4-(R1-R2)-R5-杂环嘧啶和R4-NH于烧瓶中，搅拌下加入甲醇与三氟乙酸使其溶解，回流，反应完毕后，减压浓缩，加入饱和食盐水，混合物用乙酸乙酯萃取，浓缩，硅胶柱层析，洗脱剂为二氯甲烷-甲醇，得2-(R4-NH)4-(R1-R2)-R5-杂环嘧啶。
4.如权利要求3所述的制备以FGFR1为靶点的多取代嘧啶类化合物的方法，其特征在于，
所述A系列步骤一中，室温反应时间为1h；每lg所述2，4-二氯-5-R3嘧啶用无水乙醇20ml。物质的量之比：2，4-二氯-5-R3嘧啶：碳酸钠：R1-R2＝1：2：1，所述萃取次数为3次；
步骤二中，每500mg所述2-氯-4-(R1-R2)-R3-嘧啶用甲醇15-20m1溶解，再将三氟乙酸滴入烧瓶中，物质的量之比：2-氯-4-(R1-R2)-R3-嘧啶：R4一NH2：三氟乙酸＝1：1.5：3；所述回流时间为8h，所述萃取次数为3次，所述洗脱剂二氯甲烷-甲醇，二氯甲烷与甲醇的体积比为20：1；
所述B系列步骤一中，室温反应时间为1h；每lg所述2，4-二氯吡啶用无水乙醇20ml，物质的量之比：2，4-二氯-5-R3嘧啶：碳酸钠：R1-R2＝1：2：1，所述萃取次数为3次；
步骤二中，每500mg所述2-氯-4-(R1-R2)吡啶用甲醇15-20m1溶解，再将三氟乙酸滴入烧瓶中，物质的量之比：2-氯-4-(R1-R2)吡啶：R4-NH2：三氟乙酸＝1：1.5：3；所述回流时间为8h，所述萃取次数为3次，所述洗脱剂二氯甲烷-甲醇，二氯甲烷与甲醇的体积比为20：1；
所述C系列：步骤一中，反应时间为1h；每lg所述5-硝基吲哚用DCM 20ml溶解；物质的量之比：5-硝基吲哚：NCS＝1：1.1；所述萃取次数为3次；洗脱剂比例石油醚：乙酸乙酯＝2：1；
步骤二中，反应时间为2h；每lg所述3-氯-5-硝基吲哚用乙醇：水＝1:120ml溶解；物质的量之比：3-氯-5-硝基吲哚：铁粉：氯化铵＝1：10：1；所述萃取次数为3次；
步骤三中，室温反应时间为1h；每lg所述3-氯-5-胺基吲哚用无水乙醇20ml溶解，物质的量之比：3-氯-5-胺基吲哚：碳酸钠：2-氨基-3-硝基-4-氯吡啶＝1：2：1，所述萃取次数为3次，洗脱剂比例石油醚：乙酸乙酯＝4：1；
步骤四中，反应时间为2h；每lg所述N4-(3-氯-1H-吲哚-5-基)-3-硝基吡啶-2,4-二胺用乙醇：水＝1:1 20ml溶解；物质的量之比：N4-(3-氯-1H-吲哚-5-基)-3-硝基吡啶-2,4-二胺：铁粉：氯化铵＝1：10：1；所述萃取次数为3次；
步骤五：反应时间为8h；每lg所述N4-(3-氯-1H-吲哚-5-基)吡啶-2,4-二胺用DMF 20ml溶解；物质的量之比：N4-(3-氯-1H-吲哚-5-基)吡啶-2,4- 二胺：4-(4-甲基哌嗪)苯甲醛:六水氯化钴＝1：1.1:1.5；所述萃取次数为3次；洗脱剂比例二氯甲烷：甲醇＝10：1；
所述D系列：步骤一中，室温反应时间为1h；每lg所述2，4-二氯-R4-杂环嘧啶用无水乙醇20ml，物质的量之比：2，4-二氯-R4-杂环嘧啶：碳酸钠：R1-R2＝1：2：1，所述萃取次数为3次；
步骤二中，每500mg所述2-氯-4-(R1-R2)-R5-杂环嘧啶用甲醇15-20m1溶解，再将三氟乙酸滴入烧瓶中，物质的量之比：2-氯-4-(R1-R2)-R5-杂环嘧啶：R4一NH2：三氟乙酸＝1：1.5：3；所述回流时间为8h，所述萃取次数为3次，所述洗脱剂二氯甲烷-甲醇，二氯甲烷与甲醇的体积比为20：1。
5.一种如权利要求1或2所述的以FGFR1为靶点的多取代嘧啶类化合物的用途，其特征在于，所述用途为制备抗肿瘤药物中的应用。
6.根据权利要求5所述的以FGFR1为靶点的多取代嘧啶类化合物的用途，其特征在于，所述化合物为以下化合物：
7.根据权利要求5或6所述的所述的以FGFR1为靶点的多取代嘧啶类化合物的用途，其特征在于，所述的抗肿瘤药物用于以下疾病的治疗或者预防：
胃腺癌、胃癌、人卵巢癌、肺腺癌、胶质瘤中的一种或者多种。
8.一种药物组合物，其特征在于，包括药用辅料和如权利要求1或2所述的以FGFR1为靶点的多取代嘧啶类化合物。
9.根据权利要求8所述的药物组合物，其特征在于，所述的药物组合物的制剂形式为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂或纳米制剂的任一种。
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