CN113372267A - 一种c-Met激酶抑制剂 - Google Patents
一种c-Met激酶抑制剂 Download PDFInfo
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- CN113372267A CN113372267A CN202010160921.XA CN202010160921A CN113372267A CN 113372267 A CN113372267 A CN 113372267A CN 202010160921 A CN202010160921 A CN 202010160921A CN 113372267 A CN113372267 A CN 113372267A
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- Prior art keywords
- acid
- compound
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- alkyl
- halogen
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- 238000002360 preparation method Methods 0.000 claims abstract description 35
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- 239000013078 crystal Substances 0.000 claims abstract description 10
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000001188 haloalkyl group Chemical group 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
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- 238000000034 method Methods 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 10
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明提供了一种结构新颖的式(I)磺酰脒类化合物及其制备方法与应用。该磺酰脒类化合物为式(I)所示的化合物，或其多晶型物、前药、溶剂化物、水合物、共晶体、药学可接受的盐等。本发明提供的磺酰脒类化合物对多种癌细胞都具有较好的增殖抑制作用，具有较低的肿瘤细胞抑制浓度，化合物活性显著提升，并且对肿瘤细胞具有较好的选择性，有望成为靶向c‑Met激酶的特效抗肿瘤药物。
Description
技术领域
本发明属于生物医药技术领域，特别涉及一种c-Met激酶抑制剂。
背景技术
c-Met或称HGFR，是一种由c-Met原癌基因编码的蛋白产物，是一类具有高度亲和性的受体酪氨酸激酶，是唯一一个己知的肝细胞生长因子(HGF)高亲和力的受体。HGF/c-Met信号通路的激活对于细胞的增殖、运动、迁移和存活具有十分重要的作用。但是在众多常见恶性肿瘤中，c-Met和HGF异常高表达，造成HGF/c-Met信号通路异常活化，这与肿瘤细胞的增殖、转移、侵袭、抗凋亡和肿瘤血管新生有着密不可分的联系。因此，c-Met激酶及其相关信号通路已经成为抗肿瘤药物研究的一个重要靶点。现在许多c-Met激酶抑制剂中，尤以靶向小分子抑制剂的研究最为突出。构效关系表明，该类抑制剂主要由三部分组成，即易于同c-Met激酶形成氢键的骨架，可延伸到疏水囊中的芳基片段以及中间桥链部分，并且其中间桥链部分对其活性的影响尤为显著。然而，随着c-Met激酶抑制剂的大量使用，机体内肿瘤细胞产生继发性的基因突变或亚克隆选择，造成含有新突变基因的耐药性肿瘤细胞的产生和扩增，最终导致该类药物耐药性的产生。因此，急需研究并开发具有新型结构的c-Met激酶抑制剂，以寻找解决药物耐药的治疗方法。
磺酰脒片段是一种重要的药效团，能与药物靶标形成氢键相互作用，被广泛应用于抗癌药物的设计中。基于该片段在抗肿瘤药物设计中的应用，本研究试将磺酰脒片段作为c-Met抑制剂的中间桥链部分，以期得到具有较好抗肿瘤活性的先导化合物。
以下化合物为一部分已报道的化合物：
发明内容
鉴于现有技术的不足，本申请一方面提供一种c-Met激酶抑制剂。
具体而言，本发明提供了一种由通式I表示的化合物或其多晶型物、前药、溶剂化物、水合物、共晶体、药学可接受的盐：
其中，
R1是C1-6的烷基、C3-6的环烷基、C3-6的杂环烷基、芳基、氮杂芳基，所述的芳基和氮杂芳基可任选被以下基团取代：烷氧基、卤素、烷基、卤代烷基,所述的C3-6的杂环烷基中的杂元素为O、N、S；
R2是芳基、氮杂芳基、C3-6的环烷基、C3-6的杂环烷基，所述的芳基和氮杂芳基可任选被以下基团取代：烷氧基、卤素、烷基、卤代烷基、硝基，所述的C3-6的杂环烷基中的杂元素为O、N、S；
R3是芳基、杂芳基、Het，所述的Het选自哌啶基、吡咯基、吡唑基、哌啶基、咪唑基、呋喃基、吗啉基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、哌嗪基、取代哌嗪基、吡嗪基或哒嗪基的单环杂环；或选自喹啉基、喹喔啉基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并呋喃基、噻吩[3,2-B]吡啶基、7H-吡咯并[2,3-d]嘧啶基、苯并噻吩基、2，3-二氢苯并[b][1,4]二氧六环基或苯并[d][1,3]二氧戊环基的双环杂环；所述的各单环或双环杂环任选被1、2或3个取代基取代，各取代基独立选自卤素、卤代烷基、烷基或烷氧基，或选自C3-C8的脂肪族碳环，或下列的脂肪族杂环：四氢吡咯基、吗啉基、烷氧基吗啉基、哌嗪基、哌啶基、烷氨基哌啶基；哌啶取代的烷基、哌嗪取代的烷基；各单环或双环杂环任选被1、2或3个取代基取代，所述的杂芳基、单环杂环、脂肪族杂环、双环杂环中杂元素为O、N、S；
X为氢或者卤素，卤素选自氟、氯和溴中的一种。
优选地，R1为C1-6的烷基、C3-6的环烷基、C3-6的杂环烷基、芳基、氮杂芳基，所述的芳基和氮杂芳基可任选被以下基团取代：C1-3烷氧基、卤素、C1-3烷基、卤代烷基，所述的C3-6的杂环烷基中杂元素为O、N、S；
R2为芳基、氮杂芳基，所述的芳基和氮杂芳基可任选被以下基团取代：烷氧基、卤素、烷基、卤代烷基、硝基；
R3为喹啉基、噻吩[3,2-B]吡啶基、7H-吡咯并[2,3-d]嘧啶基，喹啉基、噻吩[3,2-B]吡啶基和7H-吡咯并[2,3-d]嘧啶基任选被1、2或3个取代基取代，各取代基独立选自卤素、卤代烷基、烷基或烷氧基；哌啶取代的烷基、哌嗪取代的烷基；
X为卤素，卤素选自氟、氯和溴中的一种。
进一步优选地，R1为C1-6的烷基、C3-6的环烷基、苯基、吡啶基，所述的苯基和吡啶基可任选被以下0、1、2个基团取代：C1-3烷氧基、卤素、C1-3烷基、卤代烷基；
R2为苯基、吡啶基，所述的苯基和吡啶基可任选被以下0、1或2个基团取代：C1-6的烷氧基、卤素、C1-6的烷基、卤代烷基、硝基；
R3为喹啉基，喹啉基任选被1、2或3个取代基取代，各取代基独立选自卤素、卤代烷基、C1-5的烷基或C1-5的烷氧基；2-(1-哌啶)-乙烷基、2-(1-哌嗪)-乙烷基；
X为氟。
更加优选地，所述化合物选自以下化合物：
本发明的第二方面提供一种式I化合物的制备方法，所述方法包括使式IV化合物、式III化合物和式II化合物反应，得到式I化合物的步骤：
其中X、R1、R2和R3如前文所定义。
优选地，该合成方法具体包括以下步骤：式IV化合物溶于有机溶剂中，加入有机碱，搅拌，惰性气体保护，加入式III化合物、式II化合物和催化剂反应得到式I化合物。
进一步优选地，有机碱选自三乙胺、吡啶、三乙醇胺、3-甲基吡啶、DMAP和三异辛胺中的一种；有机溶剂选自二氯甲烷、1,4-二氧六环、MeCN、THF、DMF和甲苯中的一种或几种；惰性气体为氩气或氮气；催化剂为CuX，X选自Cl、I和Br中的一种。
所述方法还包括还原式V化合物的硝基得到式IV化合物的步骤：
其中R3如前文所定义。
优选地，还原式V化合物所使用的还原剂选自铁粉或锌粉。
所述方法还包括使式VII化合物和式VI化合物反应，得到式V化合物的步骤：
其中X、R3如前文所定义。
优选地，本反应中式VII化合物与式VI化合物的摩尔比为1:1.0～1.5。
所述方法还包括使式VIII化合物与氯代试剂反应获得式VI化合物的反应：
R3-OH
VIII，
其中R3如前文所定义。
以下内容进一步详述本发明式I的化合物的制备方法：
室温下，式IV化合物溶于有机溶剂中，加入有机碱，搅拌，惰性气体保护，加入式III化合物、式II化合物和催化剂于室温下反应，向反应溶液中加入二氯甲烷和饱和NH4Cl水溶液，继续搅拌，分液，水相用二氯甲烷萃取，合并有机相，干燥，过滤，减压浓缩，柱层析得式I化合物。
优选地，催化剂选自碘化亚铜、溴化亚铜和氯化亚铜中的一种。
优选地，有机碱选自三乙胺、DMAP和吡啶中的一种。
优选地，式IV化合物与有机碱的摩尔比为1:2～3；式IV化合物与式III化合物的摩尔比为1:1.0～1.1；式IV化合物与式II化合物的摩尔比为1:1.1～1.3。
在一个实施例中，式IV化合物与有机碱的摩尔比为1:2.4；式IV化合物与式III化合物的摩尔比为1:1；式IV化合物与式II化合物的摩尔比为1:1.2。
式IV化合物的制备包括以下步骤：将式V化合物溶于质子溶剂中，加热升温后加入饱和NH4Cl溶液和还原剂，加热回流反应。
优选地，质子溶剂选自乙醇、水或二者的混合溶剂；还原剂选自铁粉或锌粉。
在一个实施例中，乙醇与水的体积比为9:1；还原剂为铁粉。
式V化合物的制备包括以下步骤：将式VI化合物与式VII化合物溶于有机溶剂，加热回流，反应15～32小时。
优选地，有机溶剂选自氯苯，乙二醇二甲醚，对二甲苯，二苯醚，1,4-二恶烷，吡啶/1,4-二恶烷混合溶剂，NMP/1,4-二恶烷混合溶剂，DMF/吡啶混合溶剂中的一种。
优选地，式VII化合物与式VI化合物的摩尔比为1:1.0～1.5；反应时间为28～32小时。
在一个实施例中，式VII化合物与式VI化合物的摩尔比为1:1.2；反应时间为30小时。
式VI化合物的制备包括以下步骤：将式VIII化合物和氯代试剂溶于反应溶剂中，加热回流反应。
优选地，反应溶剂为POCl3或乙腈。
优选地，式VIII化合物和氯代试剂的摩尔比为1:15～28。
进一步优选地，氯代试剂选自三氯氧磷、三氯化磷和五氯化磷中的一种。
在一个实施例中，式VIII化合物和氯代试剂的摩尔比为1:21.5；氯代试剂为三氯氧磷。
在一个优选方案中，式I化合物的制备方法包括如下步骤：式VIII化合物上的羟基经氯代后与式VII化合物反应得到式V化合物；还原式V化合物上硝基得到式IV化合物；最后，式IV化合物、式III化合物和式II化合物三组分反应得到式I化合物。
其合成路线如下：
本发明化合物都可以用上述或类似上述的制备方法制备得到，根据取代基的不同和取代基位置的不同选用相应的原料即可。
本发明中化合物I-1的合成路线如下：
本发明的第三方面提供一种药物组合物，所述药物组合物包括式I的化合物或其多晶型物、前药、溶剂化物、水合物、共晶体、药学可接受的盐和其他药学上可接受的成分。
本发明所述组合物指包括治疗有效量的规定成分的药物产品，以及直接或间接地由规定量的规定成分的组合产生的任何产品。
本发明所述的组合物尤其指药物组合物，其通常是安全、无毒且为生物学上所需要的，因此，本发明中所述药学上可接受的载体或辅料是无毒且安全的，而且其与本发明所述化合物的组合也是无毒且安全的。本发明所述的药学上可接受的载体和辅料通常为本领域人员所熟知的，或者可由本领域技术人员根据实际情况能够确定的。合适的载体和辅料的实例包括葡萄糖、水、甘油、乙醇、丙二醇、玉米淀粉、明胶、乳糖、蔗糖、海藻酸、微晶纤维素、高岭土、甘露醇、磷酸二钙、氯化钠、交联羧甲基纤维素钠、淀粉羟乙酸钠、聚山梨酯80、聚乙二醇300、聚乙二醇400、环糊精或其衍生物，比如((2-羟基丙基)-环糊精)和(2-羟基乙基)-环糊精，其又称为HPCD、聚乙二醇化蓖麻油、泊洛沙姆(比如泊洛沙姆407或188)；亲水载体、疏水载体，或其组合等。疏水载体包括，例如脂肪乳剂、脂质、聚乙二醇化磷脂、生物相容的聚合物、脂质球、脂质体、小囊泡、聚合物基质、颗粒等等。
载体在药物组合物中的含量可以是1wt％～98wt％，通常大约占到80wt％。
本发明所述的组合物，可以以选自以下任意方式施与：口服、喷雾吸入、直肠给药、鼻腔给药、***给药、局部给药、非肠道给药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内或颅内注射或输入，或借助一种外植的储器用药，其中优选口服、肌注、腹膜内或静脉内用药方式。
本发明化合物或含有它的组合物或药物制剂可以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混旋剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、填埋剂、贴剂、擦剂等。
本发明第四方面，提供一种式I化合物或其多晶型物、前药、溶剂化物、水合物、共晶体、药学可接受的盐在制备抗肿瘤药物中的应用。
优选地，所述肿瘤选自：非小细胞肺癌、肝癌、***状肾细胞癌、胃癌、食道癌、恶性胶质瘤、头颈部鳞状细胞、肾癌、急性白血病、***癌、甲状腺癌、皮肤癌、结肠直肠癌、胰腺癌、卵巢癌、乳腺癌、骨髓增生异常综合症或间皮瘤等。
术语解释
以下列出了用于描述本申请的各种术语的定义。这些定义适用于整个说明书和权利要求书中使用的术语，除非在特定情况下单独地或作为较大组的一部分另有限制。
本发明中的术语“烷基”是指饱和的直链或支链烃基，在某些实施方案中，分别含有1至6个或1至3个碳原子，C1-6烷基的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、叔丁基、新戊基、正己基或类似基团，并且C1-3烷基的实例包括但不限于甲基、乙基、丙基、异丙基或类似基团。
本发明中的术语“卤代”是指卤素原子取代碳原子上的氢原子所形成的基团，其中卤素原子包括但不限于F、Cl、Br、I。
本发明中的术语“烷氧基”是指-O-烷基，其中所述烷基包括但不限于C1-3烷基、C1-6烷基和C3-6环烷基，具体的实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基及其卤代形式的基团。
本发明中的术语“芳基”是指单环或多环碳环***，其具有一个或多个稠合或非稠合的芳环，包括但不限于苯基、萘基、四氢萘基等类似基团，并且其环碳上的氢原子还可以被一至多个取代基取代，所述取代基包括但不限于烷基、烷氧基、卤代、卤代烷氧基。
本发明的术语“杂环烷基”指含有2至6个环碳原子和1至3个环杂原子的单环或多环非芳香族环体系，其中所述杂原子选自N、O、S。
本发明的术语“环烷基”是指单环或多环的饱和或部分不饱和碳环化合物的单价基团，C3-6环烷基的包括但不限于环丙基、环丁基、环戊基、环己基等，并且其环碳上的氢原子还可以被一至多个取代基取代，所述取代基包括但不限于烷基、烷氧基、卤代。
本发明的术语“杂芳基”是指含有1至6个碳和至少一个杂原子的芳香环体系，其中所述杂原子选自N、S、O；并且其环碳上的氢原子还可以被一至多个取代基取代，所述取代基包括但不限于烷基、烷氧基、卤代、硝基。
本发明所述的“药学上可接受的盐”指本发明化合物的盐，有本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。本发明中含有相对碱性的官能团，可通过在纯的溶液或者合适的惰性溶剂中用足量的酸与这类化合物的中性形式接触的方式获得酸加成盐，药学上可接受的酸加成盐包括无机盐和有机酸盐。所述无机酸盐包括但不限于盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸、氨基磺酸、乙酰水杨酸，此外还包括无机碱的酸式盐等。
本发明所述的“溶剂合物”是指含有化学计量或非化学计量的溶剂加成形式，溶剂可选自甲醇、乙醇、丙酮、DMF、DMSO等。
本发明所述的“水合物”是指含有化学计量或非化学计量的水加成形式。
本发明所述的“前药”是指通过代谢的方式在体内可转化的化合物，以提供通过本申请化学式所描述的任何化合物，且各种形式的药物是本领域已知的。
本发明所述的“有效量”是指能够在所需的对象中达到所需的治疗效果，但不会造成过度的负面影响的剂量，具体的剂量通常可以由本领域的技术人员根据需要确定。
本发明所述的“治疗”是指减轻或缓和疾病及其并发症状的方法；所述的预防是指减少或消除疾病、病状或病症的症状或并发症的发作。
应该理解的是在上文中未解释的，但出现在本发明中的其它术语，应按照本领域专业技术人员的通常理解来定义。
应该理解的是，在本发明的范围内，本发明的上述各技术特征和在下文中(包括实施例)具体描述的各技术特征之间都可以相互结合，从而构成新的或优选的技术方案。
与现有技术相比，本发明的主要优点包括：
(1)本发明提供了一种结构新颖的磺酰脒类化合物，与现有的化合物相比，本发明的化合物具有更低的肿瘤细胞抑制浓度，化合物的抗肿瘤活性具有显著的增强。
(2)本发明提供的式I磺酰脒类化合物，与已知的相近化合物相比，合成路线较短，操作更为简单，适合工业化放大生产。
具体实施方式
现通过以下实施例来进一步描述本发明的有益效果，实施例仅用于例证的目的，不限制本发明的范围，同时本领域普通技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明范围之内。
本发明式I-1化合物的合成路线如下：
实施例1：式Ⅵ化合物的制备
将4-羟基-6,7-二甲氧基喹啉(Ⅷ)(4.10g，20.0mmol)和POCl3(40mL)置于反应瓶中，并将反应瓶置于油浴中回流6h。TLC检测反应完全后冷却至室温，减压浓缩。向所得残留物中倒入冰水(100mL)并剧烈搅动，再用浓NH4OH调节pH至8，控制温度20℃以内。混合液用二氯甲烷(320mL×2)萃取两次。合并有机相依次用饱和NaCl水溶液和水洗涤，无水Na2SO4干燥，过滤，浓缩得白色固体，为式Ⅵ化合物，收率:68.3％，HPLC纯度:98.11％。m.p.134-136℃；ESI-HRMS(m/z):246.0413[M+Na]+。
实施例2：式Ⅵ化合物的制备
将4-羟基-6,7-二甲氧基喹啉(Ⅷ)(4.10g，20.0mmol)和PCl3(40ml，0.458mol)溶于干燥乙腈(40ml)中，并将反应瓶置于油浴中加热回流反应5h。TLC检测反应完全后冷却至室温，减压浓缩。向所得残留物中倒入冰水(100ml)并剧烈搅动，再用浓NH4OH调节pH至8，温度控制在20℃以内。混合液用二氯甲烷萃取两次(320ml×2)。合并有机相依次用饱和NaCl水溶液和水洗涤，无水Na2SO4干燥，过滤，浓缩得白色固体，收率：66.2％，HPLC纯度：98.06％。m.p.134-136℃；ESI-HRMS(m/z):246.0415[M+Na]+。
实施例3：式Ⅵ化合物的制备
将4-羟基-6,7-二甲氧基喹啉(Ⅷ)(4.10g，20.0mmol)和PCl5(40ml，0.307mol)溶于干燥乙腈(40ml)中，并将反应瓶置于油浴中加热回流反应7h。TLC检测反应完全后冷却至室温，减压浓缩。向所得残留物中倒入冰水(100ml)并剧烈搅动，再用浓NH4OH调节pH至8，温度控制在20℃以内。混合液用二氯甲烷萃取两次(320ml×2)。合并有机相依次用饱和NaCl水溶液和水洗涤，无水Na2SO4干燥，过滤，浓缩得白色固体，收率：65.1％，HPLC纯度：98.97％。m.p.134-136℃；ESI-HRMS(m/z):246.0412[M+Na]+。
实施例4：式V化合物的制备
将式Ⅵ化合物(4.46g，20.0mmol)和2-氟-4-硝基苯酚(Ⅶ)(4.78g，24.1mmol)溶于氯苯(40mL)中，混合物加热回流反应20h。式Ⅵ化合物剩余低于5％时即可停止反应。待冷却至室温，减压蒸馏。将残留物溶于二氯甲烷(80mL)，用饱和K2CO3(20mL×2)水溶液洗涤两次，水(20mL)洗涤一次。无水Na2SO4干燥有机相，过滤，浓缩所得固体经无水乙醇重结晶得淡黄色固体，收率：80.4％，HPLC纯度:98.90％。m.p.161-163℃；ESI-HRMS(m/z):367.0809[M+Na]+。
实施例5：式V化合物的制备
将式Ⅵ化合物(4.46g，20.0mmol)和2-氟-4-硝基苯酚(式Ⅶ化合物)(3.14g，20.0mmol)溶于对二甲苯(40ml)中，混合物加热回流反应32h。式Ⅵ化合物剩余低于5％时即可停止反应。待冷却至室温，减压蒸馏。将残留物溶于二氯甲烷(80ml)，用饱和K2CO3溶液(20ml×2)洗涤两次后再用水(20ml)洗涤一次。有机相用无水Na2SO4干燥，过滤，浓缩所得固体经无水乙醇重结晶得淡黄色固体，收率:78.9％，HPLC纯度:98.09％。m.p.161-163℃；ESI-HRMS(m/z):367.0811[M+Na]+。
实施例6：式V化合物的制备
将式Ⅵ化合物(4.46g，20.0mmol)和2-氟-4-硝基苯酚(式Ⅵ化合物)(4.71g，30.0mmol)溶于乙二醇二甲醚(40ml)中，混合物加热回流反应28h。式Ⅵ化合物剩余低于5％时即可停止反应。待冷却至室温，减压蒸馏。将残留物溶于二氯甲烷(80ml)，用饱和K2CO3溶液(20ml×2)洗涤两次后再用水(20ml)洗涤一次。有机相用无水Na2SO4干燥，过滤，浓缩所得固体经无水乙醇重结晶得淡黄色固体，收率:77.2％，HPLC纯度:98.79％。m.p.161-163℃；ESI-HRMS(m/z):367.0808[M+Na]+。
实施例7：式IV化合物的制备
将式Ⅴ化合物(6.88g，20.0mmol)溶于乙醇/水(90mL，9:1v/v)中，待油浴温度升至78℃时加入饱和NH4Cl溶液(90mL)和铁粉(11.17g，0.2mol)，混合液回流5h。TLC检测反应完全后立即过滤，滤饼用乙醇淋洗，滤液减压浓缩得白色固体，收率:90.6％，HPLC纯度:99.06％。m.p.193-195℃；ESI-HRMS(m/z):337.1105[M+Na]+。
实施例8：式IV化合物的制备
将式Ⅴ化合物(6.88g，20.0mmol)溶于乙醇(90ml)中，待油浴温度升至78℃时加入饱和NH4Cl溶液(90ml)和Fe粉(11.17g，0.2mol)，混合液回流4h。TLC检测反应完全后立即过滤，滤饼用乙醇淋洗，滤液减压浓缩得白色固体，收率：88.2％，HPLC纯度：99.05％。m.p.193-195℃；ESI-HRMS(m/z):337.1108[M+Na]+。
实施例9：式IV化合物的制备
将式Ⅴ化合物(6.88g，20.0mmol)溶于乙醇/水(90ml，9:1v/v)中，待油浴温度升至78℃时加入饱和NH4Cl溶液(90ml)和Zn粉(13.08g，0.2mol)，混合液回流6h。TLC检测反应完全后立即过滤，滤饼用乙醇淋洗，滤液减压浓缩得白色固体，收率：89.6％，HPLC纯度：99.16％。m.p.193-195℃；ESI-HRMS(m/z):337.1109[M+Na]+。
实施例10：化合物I-1的制备
室温下将三乙胺(2.42g，24.0mmol)缓慢滴加到式Ⅳ化合物(3.14g，10.0mmol)的二氯甲烷溶液(400mL)中，搅拌10min，待溶清后，在N2保护下向反应瓶中加入环丙乙炔(Ⅲ)(0.66g，10.0mmol)、苯磺酰叠氮(Ⅱ)(2.20g，12.0mmol)和碘化亚酮(190.45mg，1.0mmol)。混合液在室温下反应2～6h，TLC检测反应结束后，用DCM(45mL)和饱和NH4Cl水溶液(66mL)稀释，继续搅拌30min至分层，水相用DCM(40mL×3)萃取三次。合并有机相用无水Na2SO4干燥，过滤，减压浓缩，柱层析(PE:EA＝10:1)，柱层析纯化产物得目标化合物I-1。白色固体，收率82.1％，HPLC纯度：98.87％，熔点189-191℃，1H NMR(400Hz,CDCl3)δ:9.89(s,1H,-NH-),9.03(d,J＝8.1Hz,1H,-N＝CH-CH＝),7.80-7.59(m,6H,Ph-H,-N＝CH-CH＝),7.30(s,1H,quinoline-H),7.07(s,1H,quinoline-H),6.55-6.53(m,3H,Ph-H),3.92(s,3H,-OCH3),3.83(s,3H,-OCH3),2.20(d,J＝6.3Hz,2H,-CH2-cyclopropare),1.02(m,1H,cyclopropare-H),0.40(m,4H,cyclopropare-H)；13C NMR(100MHz,CDCl3)δ:157.7,156.7,151.3,150.9,150.6,146.2,145.2,144.1,136.0,133.7,129.7(2C),125.5(2C),120.0(2C),117.3(2C),114.5,107.9,106.2,100.7,56.1(2C),42.6,6.1(2C),1.2.ESI-HRMS(m/z):558.1577[M+Na]+
实施例11：化合物I-1的制备
室温下将DMAP(2.93g，24.0mmol)缓慢滴加到式Ⅳ化合物(3.14g，10.0mmol)的乙腈溶液(400mL)中，搅拌10min，待溶清后，在氩气保护下向反应瓶中加入环丙乙炔(Ⅲ)(0.66g，10.0mmol)、苯磺酰叠氮(Ⅱ)(2.20g，12.0mmol)和溴化亚酮(143.45mg，1.0mmol)。混合液在室温下反应2～6h，TLC检测反应结束后，用DCM(45mL)和饱和NH4Cl水溶液(66mL)稀释，继续搅拌30min至分层，水相用DCM(40mL×3)萃取三次。合并有机相用无水Na2SO4干燥，过滤，减压浓缩，柱层析(PE:EA＝10:1)，柱层析纯化产物得目标化合物I-1，收率：83.25％，HPLC纯度：99.13％。
实施例12：化合物I-1的制备
室温下将吡啶(1.90g，24.0mmol)缓慢滴加到式Ⅳ化合物(3.14g，10.0mmol)的THF溶液(400mL)中，搅拌10min，待溶清后，在N2保护下向反应瓶中加入环丙乙炔(Ⅲ)(0.66g，10.0mmol)、苯磺酰叠氮(Ⅱ)(2.20g，12.0mmol)和氯化亚酮(99.0mg，1.0mmol)。混合液在室温下反应2～6h，TLC检测反应结束后，用DCM(45mL)和饱和NH4Cl水溶液(66mL)稀释，继续搅拌30min至分层，水相用DCM(40mL×3)萃取三次。合并有机相用无水Na2SO4干燥，过滤，减压浓缩，柱层析(PE:EA＝10:1)，柱层析纯化产物得目标化合物I-1，收率：82.03％，HPLC纯度：99.00％。
实施例13：化合物I-2的制备
合成方法同I-1，白色固体,收率81.6％，HPLC纯度：99.07％，熔点177-179℃。1HNMR(400Hz,CDCl3)δ:9.87(s,1H,-NH-),9.22(d,J＝8.3Hz,1H,-N＝CH-CH＝),8.11-7.97(m,3H,quinoline-H),7.80(d,J＝5.1Hz,1H,quinoline-H),7.48(dd,J＝0.6Hz,8.1Hz,2H,Ph-H),7.24(dd,J＝1.3Hz,12.0Hz,2H,Ph-H),6.73(t,J＝4.5Hz,1H,Ph-H),6.64(t,J＝6.0Hz,1H,Ph-H),6.20(d,J＝4.3Hz,1H,Ph-H),2.43(s,3H,-Ph-CH3),2.20(s,2H,-CH2-cyclopropare),1.02(m,1H,cyclopropare-H),0.40-0.15(m,4H,cyclopropare-H)；13C NMR(100MHz,CDCl3)δ:159.8,158.1,156.7,152.6,148.6,141.9,141.1,139.4,132.6,132.0,131.3,130.0,128.2(2C),125.5(2C),123.7,119.2,118.5,112.9,110.7,105.8,42.6,6.1(2C),1.2.ESI-HRMS(m/z):546.1133[M+Na]+。
实施例14：化合物I-3的制备
合成方法同I-1，白色固体,收率80.1％，HPLC纯度：98.76％，熔点193-195℃。1HNMR(400Hz,CDCl3)δ:10.01(s,1H,-NH-),9.03(d,J＝7.0Hz,1H,-N＝CH-CH＝),7.80-7.59(m,6H,Ph-H,-N＝CH-CH＝),7.30(s,1H,quinoline-H),7.08(s,1H,quinoline-H),6.55-6.53(m,3H,Ph-H),3.92(s,3H,-OCH3),3.83(s,3H,-OCH3),3.81(s,3H,-OCH3),2.20(d,J＝8.1Hz,2H,-CH2-cyclopropare),1.02(m,1H,cyclopropare-H),0.40(m,4H,cyclopropare-H)；13C NMR(100MHz,CDCl3)δ:157.7,156.1,151.3,150.7,150.4,146.2,145.2,144.1,136.0,133.7,129.7(2C),125.5(2C),120.0(2C),117.3(2C),114.5,107.9,106.2,100.7,56.1(2C),55.8,42.6,6.1(2C),1.2.ESI-HRMS(m/z):588.1683[M+Na]+。
实施例15：化合物I-4的制备
合成方法同I-1。白色固体,收率81.2％，HPLC纯度：98.75％，熔点179-181℃。1HNMR(400Hz,CDCl3)δ:9.88(s,1H,-NH-),9.03(d,J＝8.4Hz,1H,-N＝CH-CH＝),7.78(m,2H,Ph-H),7.59-7.50(m,2H,Ph-H,-N＝CH-CH＝),7.31(s,1H,quinoline-H),7.05(s,1H,quinoline-H),6.73(t,J＝6.0Hz,1H,Ph-H),6.64(t,J＝8.1Hz,1H,Ph-H),6.20(t,J＝4.5Hz,1H,Ph-H),3.92(s,3H,-OCH3),3.83(s,3H,-OCH3),2.20(d,J＝5.3Hz,2H,-CH2-cyclopropare),1.02(m,1H,cyclopropare-H),0.40-0.15(m,4H,cyclopropare-H)；13C NMR(100MHz,CDCl3)δ:167.9,159.9,157.7,156.5,151.3,150.7,150.6,146.2,141.9,139.7,131.3,129.9(2C),123.7,116.5(2C),114.5,112.0,107.9,106.2,105.8,100.7,56.1(2C),42.6,6.1(2C),1.2.ESI-HRMS(m/z):576.1483[M+Na]+。
实施例16：化合物I-5的制备
合成方法同I-1。白色固体，收率82.4％，HPLC纯度：98.89％，熔点148-150℃。1HNMR(400Hz,CDCl3)δ:9.86(s,1H,-NH-),9.04(d,J＝8.1Hz,1H,-N＝CH-CH＝),7.80(d,J＝7.0Hz,2H,Ph-H),7.59(d,J＝8.6Hz,1H,quinoline-H),7.59(d,J＝4.7Hz,1H,quinoline-H),7.32(s,1H,quinoline-H),7.12(t,J＝12.1Hz,2H,Ph-H),7.06(s,1H,quinoline-H),6.73(d,J＝3.8Hz,1H,Ph-H),6.64(d,J＝4.3Hz,1H,Ph-H),6.21(d,J＝6.5Hz,1H,Ph-H),3.92(s,3H,-OCH3),3.84(s,3H,-OCH3),2.14(s,2H,-CH2 -C(CH3)3),0.94(s,9H,-C(CH3)3)；13C NMR(100MHz,CDCl3)δ:159.9,157.7,156.9,152.9,151.3,150.7,150.5,146.2,141.9,136.4,131.3,128.6,129.3(2C),123.7,115.3(2C),114.5,113.2,107.9,106.3,105.8,100.7,56.2(2C),45.1,32.9,29.6(3C).ESI-HRMS(m/z):658.1713[M+Na]+。
实施例17：化合物I-6的制备
合成方法同I-1。白色固体，收率82.7％，HPLC纯度：99.20％，熔点149-151℃。1HNMR(400Hz,CDCl3)δ:9.85(s,1H,-NH-),9.14(d,J＝8.2Hz,1H,-N＝CH-CH＝),8.48(d,J＝7.1Hz,2H,Ph-H),8.10(s,1H,quinoline-H),8.06(d,J＝6.4Hz,2H,Ph-H),7.70(d,J＝8.5Hz,1H,quinoline-H),7.37(s,1H,quinoline-H),6.73(d,J＝4.2Hz,1H,Ph-H),6.64(d,J＝5.0Hz,1H,Ph-H),6.29(d,J＝5.8Hz,1H,Ph-H),2.63(t,J＝8.0Hz,4H,CH3-CH2-CH2 -),2.14(s,2H,-CH2 -(CH3)3),2.14(s,2H,-CH2 -C(CH3)3),1.64(m,4H,CH3-CH2 -CH2-),0.94(t,15H,-CH2-CH2-CH3 ,-CH2-(CH3)3 )；13C NMR(100MHz,CDCl3)δ:159.8,158.1,156.7,152.9,151.1,150.8,145.6,141.9,141.0,137.9,131.3,129.2(2C),127.6,124.9(2C),123.7,119.2,115.7,112.9,108.3,105.8,45.1,36.1,35.7,29.6(3C),26.7,24.4(2C),13.7(2C).ESI-HRMS(m/z):643.2469[M+Na]+。
实施例18：化合物I-7的制备
合成方法同I-1。白色固体,收率86.3％，HPLC纯度：98.88％，熔点198-200℃。1HNMR(400Hz,CDCl3)δ:9.91(s,1H,-NH-),9.01(d,J＝8.5Hz,1H,-N＝CH-CH＝),8.14(d,J＝7.0Hz,1H,Pyridine-H),8.35(dd,J＝1.3Hz,8.3Hz,1H,Pyridine-H),7.80(d,J＝4.7Hz,2H,Pyridine-H,Ph-H),7.75(t,J＝6.0Hz,1H,Ph-H),7.68(t,J＝4.1Hz,2H,Ph-H),7.67(t,J＝5.0Hz,1H,Ph-H),7.68(t,J＝3.3Hz,2H,Ph-H),7.59(d,J＝6.4Hz,1H,Pyridine-H),7.30(s,1H,quinoline-H),7.24(t,J＝5.7Hz,1H,Pyridine-H),7.08(s,1H,quinoline-H),6.73(d,J＝12.0Hz,1H,Ph-H),6.64(t,J＝4.1Hz,1H,Ph-H),6.30(d,J＝8.0Hz,1H,Ph-H),3.92(s,3H,-OCH3),3.92(s,3H,-OCH3),3.83(s,2H,Ph-CH2-),3.58(s,2H,Pyridine-CH2 -)；13C NMR(100MHz,CDCl3)δ:157.9,157.0,151.5,150.7,150.3,146.0,145.2,143.9,136.3,135.6,134.0,129.7(2C),129.0(2C),125.7,125.5(2C),120.0(2C),117.3(2C),114.5,107.9,106.2,100.7,56.1(2C),39.5.ESI-HRMS(m/z):595.1530[M+Na]+。
实施例19：化合物I-8的制备
合成方法同I-1。白色固体,收率84.1％，HPLC纯度：98.96％，熔点190-192℃。1HNMR(400Hz,CDCl3)δ:9.87(s,1H,-NH-),9.17(d,J＝8.3Hz,1H,-N＝CH-CH＝),8.55(d,J＝7.0Hz,2H,Pyridine-H),7.89(d,J＝4.4Hz,1H,quinoline-H),7.73(d,J＝4.7Hz,2H,Ph-H),7.69(d,J＝6.3Hz,1H,quinoline-H),7.63(s,H,quinoline-H),7.56(t,J＝5.0Hz,2H,Ph-H),7.45(d,J＝8.6Hz,1H,quinoline-H),7.22(dd,J＝1.9Hz,8.5Hz,2H,Pyridine-H),6.73(d,J＝12.0Hz,1H,Ph-H),6.64(t,J＝7.1Hz,1H,Ph-H),6.30(d,J＝8.4Hz,1H,Ph-H),4.46(s,2H,-OCH2 -CF3),4.36(s,2H,Pyridine-CH2 -)；13C NMR(100MHz,CDCl3)δ:160.0,158.0,157.5,156.7,150.2,149.8(2C),146.5,143.8,142.2,141.9,139.3,131.3,130.0,129.8(2C),127.7(2C),124.2(2C),123.7,122.8,122.4,118.8,112.9,110.1,105.7,99.2,82.5,39.5.ESI-HRMS(m/z):667.0908[M+Na]+。
实施例20：化合物I-9的制备
合成方法同I-1。白色固体,收率78.1％，HPLC纯度：98.37％，熔点203-205℃。1HNMR(400Hz,CDCl3)δ:9.84(s,1H,-NH-),9.18(d,J＝8.5Hz,1H,-N＝CH-CH＝),8.33(d,J＝7.0Hz,1H,quinoline-H),7.77(d,J＝6.1Hz,1H,quinoline-H),7.52(t,J＝3.9Hz,1H,quinoline-H),7.49(d,J＝9.0Hz,1H,quinoline-H),7.46(m,2H,Ph-H),7.24(m,2H,Ph-H),7.14(m,2H,Ph-H),6.73-6.64(m,4H,Ph-H),6.30(t,J＝5.6Hz,1H,Ph-H),4.64(s,2H,Cl-CH2-),3.81(s,3H,Ph-OCH3),3.58(s,2H,Ph-CH2-),2.43(s,1H,Ph-CH3)；13C NMR(100MHz,CDCl3)δ:159.7,158.6,157.6,156.9,152.2,147.6,141.9,141.1,139.4,139.0,131.3,130.0(2C),128.8,128.4,128.2(2C),127.7,125.5(2C),123.7,120.9,115.8,114.2(2C),112.9,108.5,105.8,55.8,46.2,39.5,21.3.ESI-HRMS(m/z):626.1395[M+Na]+。
实施例21：化合物I-10的制备
合成方法同I-1。白色固体,收率78.4％，HPLC纯度：98.73％，熔点201-203℃。1HNMR(400Hz,CDCl3)δ:9.82(s,1H,-NH-),9.05(d,J＝8.1Hz,1H,-N＝CH-CH＝),7.59(d,J＝7.0Hz,1H,quinoline-H),7.46(dd,J＝1.7Hz,6.4Hz,2H,Ph-H),7.34(s,1H,quinoline-H),7.24(dd,J＝2.9Hz,8.6Hz,2H,Cl-Ph-H),7.14(m,2H,Ph-H),7.09(s,1H,quinoline-H),6.72(dd,J＝2.2Hz,7.4Hz,2H,Ph-H),6.55-6.53(m,4H,Ph-H),3.92(s,3H,-OCH3),3.83(s,3H,-OCH3),3.81(s,3H,Ph-OCH3),3.58(s,2H,Ph-CH2-),2.43(s,1H,Ph-CH3)；13C NMR(100MHz,CDCl3)δ:157.8,157.1,156.6,150.9,150.7,150.4,147.4,145.7,145.2,136.4(2C),129.8(2C),128.5(2C),127.8(2C),127.6,124.1,120.6(2C),116.9(2C),114.5,114.2(2C),108.3,106.6,100.5,55.9(2C),55.7,39.8.ESI-HRMS(m/z):692.1557[M+Na]+。
实施例22：化合物I-11的制备
合成方法同I-1。白色固体,收率78.5％，HPLC纯度：98.54％，熔点212-213℃。1HNMR(400Hz,CDCl3)δ:9.84(s,1H,-NH-),9.19(d,J＝8.4Hz,1H,-N＝CH-CH＝),8.37(d,J＝7.0Hz,1H,quinoline-H),7.78(d,J＝5.3Hz,1H,quinoline-H),7.60(t,J＝4.2Hz,2H,Ph-H),7.55(dd,J＝2.7Hz,6.4Hz,2H,Ph-H),7.52(t,J＝5.7Hz,1H,quinoline-H),7.51(d,J＝3.9Hz,1H,quinoline-H),6.73(d,J＝6.1Hz,1H,Ph-H),6.64(d,J＝6.0Hz,1H,Ph-H),2.72(m,2H,-CH2 -CH3),2.69(t,J＝8.2Hz,2H,Piperidine-CH2 -CH2-),2.67(t,J＝7.6Hz,2H,Piperidine-CH2-CH2 -),2.42(m,4H,Piperidine-H),2.20(d,J＝4.8Hz,2H,Cyclohexane-H),1.53-1.37(m,17H,Piperidine-H,Cyclohexane-H),1.18(t,J＝4.6Hz,3H,-CH2-CH3 )；13C NMR(100MHz,CDCl3)δ:159.5,158.8,156.9,152.2,149.3,147.6,141.9,141.3,139.0,131.3,128.8,128.7(2C),128.4,128.2(2C),123.7,120.9,115.8,112.9,108.5,105.8,60.7,57.1(2C),37.9,33.4(2C),28.2,26.4,26.0,25.9(2C),25.5(2C),24.5,14.5.ESI-HRMS(m/z):679.3196[M+Na]+。
实施例23：化合物I-12的制备
合成方法同I-1。白色固体,收率82.1％，HPLC纯度：98.85％，熔点186-188℃。1HNMR(400Hz,CDCl3)δ:9.93(s,1H,-NH-),9.13(d,J＝8.3Hz,1H,-N＝CH-CH＝),8.91(d,J＝4.9Hz,1H,Pyridine-H),8.89(t,J＝6.0Hz,1H,Pyridine-H),8.43(t,J＝7.5Hz,1H,Pyridine-H),8.37(t,J＝5.5Hz,1H,quinoline-H),7.78(d,J＝7.1Hz,1H,quinoline-H),7.69(m,1H,Pyridine-H),7.52(t,J＝8.3Hz,1H,quinoline-H),7.51(s,1H,quinoline-H),6.73(d,J＝4.6Hz,1H,Ph-H),6.64(d,J＝6.0Hz,1H,Ph-H),6.20(t,J＝4.4Hz,1H,Ph-H),2.69-2.65(m,8H,Piperazine-H,-CH2-CH2-),2.34(m,4H,Piperazine-H),2.20(d,J＝8.7Hz,2H,-CH2-cyclopropare),1.07(s,1H,-NH-),1.02(m,1H,cyclopropare-H),0.40-0.15(m,4H,cyclopropare-H)；13C NMR(100MHz,CDCl3)δ:159.7,158.7,156.7,154.6,152.2,147.8,147.6,141.9,139.0,133.7,133.6,131.3,128.8,128.4,124.8,123.7,120.9,115.8,114.2,108.5,105.8,60.4,57.6(2C),46.2(2C),42.6,33.4,6.3(2C),1.4.ESI-HRMS(m/z):611.2319[M+Na]+。
生物活性研究
1、体外抑制肿瘤细胞增殖实验
为了研究本次实验中所合成的目标化合物抑制肿瘤细胞增殖的能力，我们测定了本发明化合物对人结肠癌细胞(HT-29)、人非小细胞肺癌细胞(A549)、人大细胞肺癌细胞(H460)、人胃癌细胞(MKN-45)四种肿瘤细胞的体外细胞毒性，并以Foretinib作为阳性对照。实验采用的检测方法是标准的MTT法。
实验方法具体为：
从液氮中取出细胞冻存管，于39℃快速融化，并转移至15mL离心管中，加入含10％FBS的培养液10mL，离心5min(1000rpm)，后去除培养基，重新加入含10％FBS和双抗的培养液，转移至培养瓶中培养。取对数生长期细胞，去除培养瓶中的培养液，用PBS润洗细胞一次，胰酶消化离心收集，用含10％胎牛血清的培养基重悬，计数并调整到合适浓度(细胞密度5×104个/mL，细胞活力﹥90％)，将细胞悬液加入到每孔100μL的96微孔板中。目标化合物均用DMSO稀释成20μL溶液，将待测目标化合物用DMSO 3倍梯度稀释。分别取5μL稀释好的化合物溶液加入到495μL含10％FBS的培养基中，配制成待测化合物。取100μL含待测化合物的溶液加到96微孔板相应孔中，在二氧化碳细胞培养箱中培养72h。去除培养基，每孔加入0.3mg·mL-1MTT工作液(0.00265mg·mL-1PMS)150μL，在二氧化碳培养箱中放置2h。96微孔板于振荡器中震荡5min，用酶标仪读取吸光值A450(450nm)。所有试验设3个平行组或重复三次。最后，计算待测化合物的半数抑制浓度(IC50)。试验结果为三次实验的平均值±标准差(SD)。
化合物I-1～12对人结肠癌细胞(HT29)、人非小细胞肺癌细胞(A549)、人大细胞肺癌细胞(H460)、人胃癌细胞(MKN-45)四种癌细胞增殖抑制的体外毒性试验结果见表1。
表1
注：(1)筛选方法：MTT法；(2)作用时间：72小时。(3)*P＜0.05。
体外实验表明，本发明所述的化合物I-1～12对人结肠癌细胞(HT29)、人非小细胞肺癌细胞(A549)、人大细胞肺癌细胞(H460))、人胃癌细胞(MKN-45)四种癌细胞均表现出较强的抑制活性，且大部分化合物活性与临床药物Foretinib相当，其中化合物I-8对人非小细胞肺癌细胞(A549)、人大细胞肺癌细胞(H460)生长抑制活性显著优于对照药物，化合物I-11对人结肠癌细胞(HT29)、人大细胞肺癌细胞(H460)、人胃癌细胞(MKN-45)生长抑制活性显著优于对照药物，表现出较好的应用前景。
2、体外对正常细胞的细胞毒性实验
本发明挑选对肿瘤细胞抗增殖活性较好的化合物I-8和I-11，测试了其对人脐带间充质干细胞(正常细胞)的抑制作用，发现化合物在100uM浓度下，细胞存活率分别为76.2％和84.5％，说明化合物对正常细胞无明显的毒性，化合物对肿瘤细胞有一定的细胞选择性。
总的来说，本发明系列化合物对肿瘤细胞HT29、A549、H460和MKN-45都有有较强的抑制增殖能力，部分化合物的活性优于阳性对照药Foretinib，且对正常细胞没有毒性作用，是一类非常有开发前景的化合物。
Claims (10)
1.一种由通式I表示的化合物或其多晶型物、前药、溶剂化物、水合物、共晶体、药学上可接受的盐：
其中，
R1是C1-6的烷基、C3-6的环烷基、C3-6的杂环烷基、芳基、氮杂芳基，所述的芳基和氮杂芳基可任选被以下基团取代：烷氧基、卤素、烷基、卤代烷基，所述的C3-6的杂环烷基中的杂元素为O、N、S；
R2是芳基、氮杂芳基、C3-6的环烷基、C3-6的杂环烷基，所述的芳基和氮杂芳基可任选被以下基团取代：烷氧基、卤素、卤代烷基、烷基、硝基，所述的C3-6的杂环烷基中的杂元素为O、N、S；
R3是芳基、杂芳基、Het，所述的Het选自哌啶基、吡咯基、吡唑基、哌啶基、咪唑基、呋喃基、吗啉基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、哌嗪基、取代哌嗪基、吡嗪基或哒嗪基的单环杂环；或选自喹啉基、喹喔啉基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并呋喃基、噻吩[3,2-B]吡啶基、7H-吡咯并[2,3-d]嘧啶基、苯并噻吩基、2，3-二氢苯并[b][1,4]二氧六环基或苯并[d][1,3]二氧戊环基的双环杂环；所述的各单环或双环杂环任选被1、2或3个取代基取代，各取代基独立选自卤素、卤代烷基、烷基或烷氧基，或选自C3-C8的脂肪族碳环，或下列的脂肪族杂环：四氢吡咯基、吗啉基、烷氧基吗啉基、哌嗪基、哌啶基、烷氨基哌啶基；哌啶取代的烷基、哌嗪取代的烷基；各单环或双环杂环任选被1、2或3个取代基取代，所述的杂芳基、单环杂环、脂肪族杂环、双环杂环中杂元素为O、N、S；
X为氢或者卤素，卤素选自氟、氯和溴中的一种。
2.如权利要求1所述化合物，其特征在于，
R1为C1-6的烷基、C3-6的环烷基、C3-6的杂环烷基、芳基、氮杂芳基，所述的芳基和氮杂芳基可任选被以下基团取代：C1-3烷氧基、卤素、C1-3烷基、卤代烷基，所述的C3-6的杂环烷基中杂元素为O、N、S；
R2为芳基、氮杂芳基，所述的芳基和氮杂芳基可任选被以下基团取代：烷氧基、卤素、烷基、卤代烷基、硝基；
R3为喹啉基、噻吩[3,2-B]吡啶基、7H-吡咯并[2,3-d]嘧啶基，喹啉基、噻吩[3,2-B]吡啶基和7H-吡咯并[2,3-d]嘧啶基任选被1、2或3个取代基取代，各取代基独立选自卤素、卤代烷基、烷基或烷氧基；哌啶取代的烷基、哌嗪取代的烷基；
X为卤素，卤素选自氟、氯和溴中的一种。
3.如权利要求2所述化合物，其特征在于，
R1为C1-6的烷基、C3-6的环烷基、苯基、吡啶基，所述的苯基和吡啶基可任选被以下0、1、2个基团取代：C1-3烷氧基、卤素、C1-3烷基、卤代烷基；
R2为苯基、吡啶基，所述的苯基和吡啶基可任选被以下0、1或2个基团取代：C1-6的烷氧基、卤素、C1-6的烷基、卤代烷基、硝基；
R3为喹啉基，喹啉基任选被1、2或3个取代基取代，各取代基独立选自卤素、卤代烷基、C1-5的烷基或C1-5的烷氧基；2-(1-哌啶)-乙烷基、2-(1-哌嗪)-乙烷基；
X为氟。
4.如权利要求3所述化合物，其特征在于，所述化合物为以下化合物：
5.权利要求1-4任一项所述化合物或其多晶型物、前药、溶剂化物、水合物、共晶体、药学可接受的盐，其特征在于，药学上可接受的盐包括通式I化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸、氨基磺酸或乙酰水杨酸，此外还包括无机碱的酸式盐；溶剂化物包括通式I化合物与以下溶剂结合形成的化合物：甲醇、乙醇、丙酮、DMF、DMSO；共晶体包括通式I化合物与以下化合物结合形成的共晶：对羟基苯甲酸、香草酸、丁香酸、3,4-二羟基苯甲酸、香豆酸、阿魏酸、咖啡酸、芥子酸、草酸、丙二酸、戊二酸、没食子酸、白藜芦醇、白杨素、大黄素或2-吲哚甲酸。
6.一种权利要求1所述化合物的制备方法，其特征在于，所述方法包括式IV化合物、式III化合物和式II化合物反应，得到式I化合物的步骤；
其中X、R1、R2和R3如权利要求1-4任一项所定义。
7.如权利要求6所述的制备方法，其特征在于，所述方法包括还原式V化合物的硝基得到式IV化合物的步骤：
其中X、R3如权利要求1-4任一项所定义。
8.如权利要求7所述的制备方法，其特征在于，所述方法包括使式VII化合物和式VI化合物反应，得到式V化合物的步骤：
其中X、R3如权利要求1-4任一项所定义。
9.一种药物组合物，所述药物组合物包括权利要求1-4中任意一项所述的化合物或其多晶型物、前药、溶剂化物、水合物、共晶体、药学可接受的盐和其他药学上可接受的成分。
10.一种权利要求1所述化合物或其多晶型物、前药、溶剂化物、水合物、共晶体、药学可接受的盐在制备抗肿瘤药物中的应用，优选地，所述肿瘤可以是非小细胞肺癌、肝癌、***状肾细胞癌、胃癌、食道癌、恶性胶质瘤、头颈部鳞状细胞、肾癌、急性白血病、***癌、甲状腺癌、皮肤癌、结肠直肠癌、胰腺癌、卵巢癌、乳腺癌、骨髓增生异常综合症或间皮瘤。
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