WO2017198196A1 - 具有抗肿瘤活性的喹啉衍生物 - Google Patents

具有抗肿瘤活性的喹啉衍生物 Download PDF

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WO2017198196A1
WO2017198196A1 PCT/CN2017/084929 CN2017084929W WO2017198196A1 WO 2017198196 A1 WO2017198196 A1 WO 2017198196A1 CN 2017084929 W CN2017084929 W CN 2017084929W WO 2017198196 A1 WO2017198196 A1 WO 2017198196A1
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王子厚
张晓东
曹日晖
荣祖元
陈西敬
王健
杨泽瀚
李忠野
徐�明
王忠奎
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王子厚
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • 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
    • C07D215/18—Halogen atoms or nitro radicals
    • 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
    • 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
    • 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
    • C07D215/38—Nitrogen atoms
    • 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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms

Definitions

  • the present invention relates to a class of quinoline derivatives having antitumor activity, a process for the preparation of the quinoline derivatives, pharmaceutical compositions comprising the quinoline derivatives, and their use in the preparation of antitumor drugs.
  • Quinoline compounds are an important class of nitrogen-containing heterocyclic compounds whose backbone structure exists in the chemical structure of many clinical drugs, such as anti-malarial drugs (quinine, chloroquine, mefequolo, primaquine, etc.), antiviral Drugs (saquinavir), antibacterial drugs (quinolones ciprofloxacin, seroxacin, gatifloxacin, etc.).
  • camptothecin which opened the prelude to the application of quinoline derivatives in anti-tumor research, followed by camptothecin analogs topotecan, irinotecan, ezetacetin, etc.
  • the inventors have unexpectedly discovered that the compounds of the following formula I of the present invention have excellent antitumor activity, and the present invention has been completed based on this finding.
  • the invention provides a quinoline derivative which is a compound of formula I below:
  • R is one, two or three groups each independently selected from the group consisting of: optionally substituted hydrogen, halogen, hydroxy, amino, alkyl, alkoxy, alkanoyloxy, alkylthio, alkyl Amino, cyano, nitro, carboxy, sulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, acylamino, alkoxycarbonyl or alkyl acyl,
  • R 1 is an optionally substituted alkyl, alkenyl or alkynyl group
  • the optional substituents are each independently selected from the group consisting of aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl, alkane a heterocyclic group, an amino group, an alkylamino group, an amide group, an alkyl acylamino group, a hydroxy group, an alkoxy group, an alkyl acyl group, an alkyl acyloxy group, a decyl group, an alkylthio group, said optional substituent Further replaced; and
  • W is selected from NH, O or S.
  • At least one of said R is selected from the group consisting of: optionally substituted halogen, alkoxy, alkanoyloxy, alkylthio, alkylamino, cyano, nitro, carboxy, sulfonyl, alkane a sulfamoyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an acylamino group, an alkoxycarbonyl group or an alkyl acyl group, preferably at least one of said R is selected from the group consisting of an optionally substituted cyano group, a nitro group, a carboxyl group, Sulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, amido, alkoxycarbonyl or alkylacyl.
  • At least one of said R is nitro, methoxy, fluoro, chloro or bromo.
  • the R 1 is optionally substituted C 2 -C 12 alkyl, C 3 -C 12 alkenyl or C 3 -C 12 alkynyl, for example ethyl, propyl, butyl, pentyl, hexyl, Heptyl, octyl, decyl, decyl, allyl, enbutyl, propargyl, or alkynyl butyl.
  • said R 1 is optionally substituted arylalkyl or heteroarylalkyl, preferably arylmethyl, arylethyl, arylpropyl, for example benzyl, Phenylethyl, phenylpropyl, phenylbutyl; the arylalkyl or heteroarylalkyl group optionally being substituted by one or more halogens such as fluorine, chlorine or bromine, alkyl, alkoxy, Substituted by haloalkyl or haloalkoxy, for example, R 1 may be fluorobenzyl, fluorophenethyl or fluorophenyl.
  • the present invention provides a method of preparing the quinoline derivative of the present invention, which comprises:
  • the base is preferably NaH, and/or the acid is preferably concentrated hydrochloric acid.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned quinoline derivative of the present invention and a pharmaceutically acceptable carrier.
  • the invention also provides the use of the quinoline derivative for the manufacture of a medicament for the treatment of a proliferative disorder.
  • the proliferative disorder is a malignant tumor.
  • the proliferative disease may be selected from the group consisting of leukemia, colorectal cancer, liver cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, and gastric cancer.
  • the present invention also provides a method of treating a proliferative disease comprising administering an effective amount of a quinoline derivative of the present invention to a subject in need thereof.
  • the inventors have unexpectedly found that the quinoline derivative of the present invention has excellent antitumor activity and can be used for effectively treating proliferative diseases, especially malignant tumors.
  • alkyl denotes a straight or branched saturated hydrocarbon group, usually the alkyl group has 1 or more carbon atoms, for example, a C1-C12 alkyl group means an alkane having 1 to 12 carbon atoms. base.
  • the alkyl group may also be a C2-C12 alkyl group, a C2-C11 alkyl group, a C2-C10 alkyl group, a C2-C9 alkyl group, a C2-C8 alkyl group, a C2-C7 alkyl group, a C2-C6 alkane.
  • C2-C5 alkyl, C2-C4 alkyl for example C2 alkyl (ie ethyl), C3 alkyl (including n-propyl, isopropyl), C4 alkyl (including n-butyl, isobutyl) , C5 alkyl (including n-pentyl, isopentyl, neopentyl), C6 alkyl (including n-hexyl, various branched hexyl), C7 alkyl (heptyl), C8 alkyl (octyl) ), C9 alkyl (fluorenyl), C10 alkyl (fluorenyl), C11 alkyl (undecyl), C12 alkyl (dodecyl).
  • C2 alkyl ie ethyl
  • C3 alkyl including n-propyl, isopropyl
  • C4 alkyl including n-butyl, isobut
  • alkyl group when mentioned in another group, for example, an alkoxy group, an alkanoyl group, an alkoxycarbonyl group, wherein the alkyl group has the definition of the alkyl group herein, but some groups (such as The alkanoyl group also includes a carbon atom on the structure other than the alkyl group when calculating the number of carbon atoms.
  • alkenyl denotes a straight or branched chain hydrocarbon radical having one or more carbon-carbon double bonds.
  • alkenyl denotes a straight or branched chain hydrocarbon radical having one or more carbon-carbon double bonds.
  • the alkenyl group may be a C3 alkenyl group (such as an allyl group), a C4 alkenyl group (such as a 1,3-butadienyl group), a C5 alkenyl group, a C6 alkenyl group, a C7 alkenyl group, a C8 alkenyl group, C9 alkenyl, C10 alkenyl, C11 alkenyl, C12 alkenyl.
  • a C3 alkenyl group such as an allyl group
  • a C4 alkenyl group such as a 1,3-butadienyl group
  • C5 alkenyl group such as an allyl group
  • a C6 alkenyl group such as a 1,3-butadienyl group
  • C7 alkenyl group such as a 1,3-butadienyl group
  • C8 alkenyl group such as a 1,3-butadienyl group
  • alkynyl denotes a straight or branched chain hydrocarbon radical having one or more carbon to carbon triple bonds.
  • alkynyl denotes a straight or branched chain hydrocarbon radical having one or more carbon to carbon triple bonds.
  • the alkynyl group may be a C3 alkynyl group (such as a propargyl group), a C4 alkynyl group (such as a 1,3-butadiynyl group), a C5 alkynyl group, a C6 alkynyl group, a C7 alkynyl group, a C8 alkynyl group, C9 alkynyl, C10 alkynyl, C11 alkynyl, C12 alkynyl.
  • a C3 alkynyl group such as a propargyl group
  • a C4 alkynyl group such as a 1,3-butadiynyl group
  • a C5 alkynyl group such as a propargyl group
  • a C6 alkynyl group such as a 1,3-butadiynyl group
  • C7 alkynyl group such as a C7 alkynyl group
  • aryl denotes a carbocyclic group having a cyclic conjugated structure.
  • the aryl group may have 6 or more carbon atoms, such as a C6-C14 aryl group, a C6-C12 aryl group, a C6-C10 aryl group.
  • the aryl group may be a phenyl group, a naphthyl group, an anthracenyl group or a phenanthryl group.
  • heteroaryl denotes a cyclic group having one or more heteroatoms selected from N, O and S in a cyclic conjugated structure.
  • the number of ring atoms in the heteroaryl group may be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more.
  • the heteroaryl group may be a pyridyl group, a thienyl group, a pyrazolyl group, a pyrimidinyl group, a fluorenyl group, a fluorenyl group, a thiazolyl group, or a morpholinyl group.
  • heterocyclyl denotes a cyclic group having one or more heteroatoms selected from N, O and S, for example piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, Oxocyclopentyl, dioxane.
  • halogen denotes fluoro, chloro, bromo, iodo.
  • treatment denotes any treatment that allows the health condition of a subject to be treated to alleviate, ameliorate, restore, eliminate, and prevent the risk of disease and improve the prognosis of the disease.
  • treatments include, but are not limited to, medical treatment, radiation therapy, chemotherapy, surgery, and vaccination.
  • Table 1 below shows the correspondence between the compound 8-51 number of the present invention and the structural formula and basic parameters.
  • the quinoline derivative of the present invention is used as a pharmacological study for a medicament for treating cancer. All tested compounds were prepared as the hydrochloride salt prior to the test, using the commonly used anti-tumor drugs, cisplatin and besibutinib, as positive control drugs.
  • HCT116 Human rectal cancer cell line
  • HepG2 human hepatoma cell line
  • HepG2 human non-small cell lung cancer cell line
  • A549 and NCI-H1650 human ovarian cancer cell line
  • human cervical cancer cell line Hela
  • Human gastric cancer cell line BGC-823
  • other human tumor cell lines were tested by MTT assay.
  • the specific method is as follows: various cell lines are cultured according to standard culture methods, and cell lines in good growth state and in logarithmic growth phase are inoculated into 96-well plates at a concentration of 5 ⁇ 10 4 /ml, and 160 ⁇ l is inoculated per well, followed by The 96-well plate was incubated in an incubator containing 5% CO 2 at 37 ° C for 24 hours, the old solution was discarded, the fresh culture solution was replaced, the sterilized quinoline derivative was added, and the culture was continued for 48 hours, and then discarded.
  • the culture medium was added with 20 ul of RPMI-1640 medium containing 5 mg/ml MTT per well, and the culture was continued for 4 hours.
  • the cell survival rate was plotted against the logarithm of the drug concentration, and the IC 50 value of each sample was determined by the mapping method. The results are shown in Table 2 below.
  • reaction solution was cooled and transferred to a 500 mL beaker, and 150 mL of water was added thereto, and the mixture was extracted three times with ethyl acetate.
  • test examples all the tested compounds were prepared into the hydrochloride form before the test, and the commonly used antitumor drugs, cisplatin and besibutinib, were used as positive control drugs.
  • Human rectal cancer cell line (HCT116), human hepatoma cell line (HepG2), human non-small cell lung cancer cell line (A549), human ovarian cancer cell line (A2780), human gastric cancer cell line (BGC-823), etc. Human tumor cell lines were tested using the MTT method.
  • the specific method is as follows: various cell lines are cultured according to standard culture methods, and cell lines in good growth state and in logarithmic growth phase are inoculated into 96-well plates at a concentration of 5 ⁇ 10 4 /ml, and 160 ⁇ l is inoculated per well, followed by The 96-well plate was incubated in an incubator containing 5% CO 2 at 37 ° C for 24 hours, the old solution was discarded, the fresh culture solution was replaced, the sterilized quinoline derivative was added, and the culture was continued for 48 hours, and then discarded.
  • the culture medium was added with 20 ul of RPMI-1640 medium containing 5 mg/ml MTT per well, and the culture was continued for 4 hours.
  • the cell survival rate was plotted against the logarithm of the drug concentration, and the IC 50 value of each sample was determined by the mapping method. The results are shown in Table 3 below.

Abstract

本发明涉及一类具有抗肿瘤活性的喹啉衍生物，所述喹啉衍生物的制备方法，包含所述喹啉衍生物的药物组合物，以及它们在制备抗肿瘤药物中的应用。

Description

具有抗肿瘤活性的喹啉衍生物
本申请要求于2016年5月18日提交中国国家知识产权局，申请号为201610330810.2，发明名称为“具有抗肿瘤活性的喹啉衍生物”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一类具有抗肿瘤活性的喹啉衍生物，所述喹啉衍生物的制备方法，包含所述喹啉衍生物的药物组合物，以及它们在制备抗肿瘤药物中的应用。
背景技术
喹啉类化合物是一类重要的含氮杂环化合物，其骨架结构存在于许多临床药物的化学结构中，例如抗疟疾药物(奎宁、氯喹、甲弗喹、伯氨喹等)，抗病毒药物(沙奎那韦)，抗菌药物(喹诺酮类药物环丙沙星、司氟沙星、加替沙星等)等。
1966年，M.E.Wall和M.C.Wani发现喜树碱，由此拉开了喹啉衍生物应用于抗肿瘤研究的序幕，随后喜树碱类似物拓扑替康，伊立替康，依喜替康等被合成出来，并应用于癌症的治疗；2012年FDA批准了抗癌新药伯舒替尼和卡博替尼上市，这两个药物都是喹啉的衍生物，前者是一种酪氨酸激酶抑制剂，主要治疗对既往治疗耐药或不能耐受的慢性、加速型成年Ph*慢性粒细胞白血病(CML)，后者作为一种抑制MET、血管内皮生长因子受体2(VEGFR2)和RET的酪氨酸激酶抑制剂，可以阻断肿瘤细胞发生和发展，临床上用于进展性、转移性甲状腺髓样癌(MTC)患者的治疗(汤仲明.2012年美国FDA批准药物简介.国际药学研究杂志,2013,40(1):111-123)。目前有较多的喹啉类抗肿瘤先导药物处于不同的临床试验阶段，喹啉衍生物得到了越来越多研究者的关注。
目前仍然需要寻找新型的具有抗肿瘤活性的喹啉化合物以供临床应用。
发明内容
本发明的一个目的是提供新的具有抗肿瘤活性的喹啉衍生物。发明人意外地发现，本发明的以下式I化合物具有优异的抗肿瘤活性，本发明基于此发现而得以完成。
在第一方面，本发明提供了一种喹啉衍生物，其是以下式I化合物：
Figure PCTCN2017084929-appb-000001
或其可药用盐，其中
R是一个、两个或三个各自独立地选自以下的基团：任选取代的氢、卤素、羟基、氨基、烷基、烷氧基、烷酰基氧基、烷基硫基、烷基氨基、氰基、硝基、羧基、磺酰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、酰氨基、烷氧基羰基或烷基酰基，
R1是任选取代的烷基、烯基或炔基，
当存在时所述任选的取代基各自独立地选自芳基、杂芳基、杂环基、烷基芳基、烷基杂芳基、烷 基杂环基、氨基、烷基氨基、酰胺基、烷基酰基氨基、羟基、烷氧基、烷基酰基、烷基酰基氧基、巯基、烷基硫基，所述任选的取代基可进一步被取代；和
W选自NH、O或S。
在一个实施方案中，至少一个所述R选自：任选取代的卤素、烷氧基、烷酰基氧基、烷基硫基、烷基氨基、氰基、硝基、羧基、磺酰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、酰氨基、烷氧基羰基或烷基酰基，优选地，至少一个所述R选自：任选取代的氰基、硝基、羧基、磺酰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、酰氨基、烷氧基羰基或烷基酰基。
在一个具体实施方案中，至少一个所述R是硝基、甲氧基、氟、氯或溴。
在另一个实施方案中，所述R1是任选取代的C2-C12烷基、C3-C12烯基或C3-C12炔基，例如是乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、烯丙基、烯丁基、炔丙基、或炔丁基。
在一个具体实施方案中，所述R1是任选取代的芳烷基或杂芳基烷基，优选地是芳基甲基、芳基乙基、芳基丙基，例如是苯甲基、苯乙基、苯基丙基、苯基丁基；所述芳基烷基或杂芳基烷基任选地被一个或更多个卤素如氟、氯或溴、烷基、烷氧基、卤代烷基或卤代烷氧基所取代，例如所述R1可以是氟代苯甲基、氟代苯乙基、氟代苯丙基。
另一方面，本发明提供一种制备本发明所述喹啉衍生物的方法，其包括：
1)使式II化合物在碱存在下与R1X接触，
Figure PCTCN2017084929-appb-000002
获得式III化合物，和
Figure PCTCN2017084929-appb-000003
2)使式III化合物在酸存在下与R取代苯胺接触，获得式I化合物，
Figure PCTCN2017084929-appb-000004
其中，X各自独立地是卤素，R、R1和W如权利要求1-6中所定义，
所述碱优选地是NaH，和/或所述酸优选地是浓盐酸。
在第三个方面中，本发明提供一种药物组合物，其包含本发明前述的喹啉衍生物以及可药用载体。
在第四个方面中，本发明还提供所述喹啉衍生物用于制备治疗增生性疾病的药物中的用途。
在一个实施方案中，所述增生性疾病是恶性肿瘤。具体地，所述增生性疾病可以选自白血病、结直肠癌、肝癌、非小细胞肺癌、卵巢癌、***和胃癌。
与以上第四个方面相似，本发明还提供治疗增生性疾病的方法，其包括向有此需要的对象施用有效量的本发明喹啉衍生物。
发明人意外地发现，本发明的喹啉衍生物具有优异的抗肿瘤活性，能够用于有效治疗增生性疾病，尤其是恶性肿瘤。
具体实施方式
本申请中所用术语具有相关领域中常规解释。特别地，下面给出一些术语在本申请中的具体含义。当这些术语在相关领域有不同解释时，以本申请中的定义为准。
术语“烷基”在本申请中表示直链或支链的饱和烃基，通常所述烷基具有1个或更多个碳原子，例如C1-C12烷基表示具有1-12个碳原子的烷基。类似地，所述烷基还可以是C2-C12烷基、C2-C11烷基、C2-C10烷基、C2-C9烷基、C2-C8烷基、C2-C7烷基、C2-C6烷基、C2-C5烷基、C2-C4烷基，例如是C2烷基(即乙基)、C3烷基(包括正丙基、异丙基)、C4烷基(包括正丁基、异丁基)、C5烷基(包括正戊基、异戊基、新戊基)、C6烷基(包括正己基、各种支链己基)、C7烷基(庚基)、C8烷基(辛基)、C9烷基(壬基)、C10烷基(癸基)、C11烷基(十一烷基)、C12烷基(十二烷基)。此外，在本申请中，当在其他基团中提到烷基时，例如烷氧基、烷酰基、烷氧羰基，其中的烷基具有此处烷基的定义，只不过有些基团(如烷酰基)在计算碳原子数时还包括烷基以外结构上的碳原子。
术语“烯基”在本申请中表示具有一个或更多个碳碳双键的直链或支链烃基。例如C2-C12烯基、C3-C12烯基、C3-C11烯基、C3-C10烯基、C3-C9烯基、C3-C8烯基、C3-C7烯基、C3-C6烯基、C3-C5烯基、C3-C4烯基、C4-C12烯基、C4-C11烯基、C4-C10烯基、C4-C9烯基、C4-C8烯基、C4-C7烯基、C4-C6烯基、C4-C5烯基。具体地，所述烯基可以是C3烯基(如烯丙基)、C4烯基(如1,3-丁二烯基)、C5烯基、C6烯基、C7烯基、C8烯基、C9烯基、C10烯基、C11烯基、C12烯基。
类似地，术语“炔基”在本申请中表示具有一个或更多个碳碳三键的直链或支链烃基。例如C2-C12炔基、C3-C12炔基、C3-C11炔基、C3-C10炔基、C3-C9炔基、C3-C8炔基、C3-C7炔基、C3-C6炔基、C3-C5炔基、C3-C4炔基、C4-C12炔基、C4-C11炔基、C4-C10炔基、C4-C9炔基、C4-C8炔基、C4-C7炔基、C4-C6炔基、C4-C5炔基。具体地，所述炔基可以是C3炔基(如炔丙基)、C4炔基(如1,3-丁二炔基)、C5炔基、C6炔基、C7炔基、C8炔基、C9炔基、C10炔基、C11炔基、C12炔基。
术语“芳基”在本申请中表示具有环状共轭结构的碳环基团。所述芳基可以具有6个或更多个碳原子，例如C6-C14芳基、C6-C12芳基、C6-C10芳基。具体地所述芳基可以是苯基、萘基、蒽基、菲基。
术语“杂芳基”在本申请中表示在环状共轭结构中具有选自N、O和S的一个或更多个杂原子的环状基团。杂芳基中环原子数可以是5、6、7、8、9、10、11、12、13、14个或更多个。具体地，所述杂芳基可以是吡啶基、噻吩基、吡唑基、嘧啶基、吲哚基、嘌呤基、噻唑基、吗啉基。
术语“杂环基”在本申请中表示具有选自N、O和S的一个或更多个杂原子的环状基团，例如哌啶基、哌嗪基、吡咯烷基、吡喃基、氧杂环戊基、二氧六环基。
术语“卤素”在本申请中表示氟、氯、溴、碘。
术语“治疗”在本申请中表示使待治疗对象的健康状况得以从疾病状态中缓解、改善、恢复、消除以及预防患病风险和改善疾病预后的任何处理。所述治疗包括但不限于药物治疗、放射治疗、化学治疗、手术治疗和疫苗接种。
本发明将参考以下实施例进一步解释说明。必须指出的是，这些实施例仅是为了方便技术人员理解本发明的精神和实质，本发明保护范围并不限于这些实施例，而应以所附权利要求书为准。
实施例
本发明将参考以下实施例进一步解释说明。必须指出的是，这些实施例仅是为了方便技术人员理解本发明的精神和实质，本发明保护范围并不限于这些实施例，而应以所附权利要求书为准。
以下是本发明所述喹啉衍生物的一般性合成路线图。化合物6a-6e的合成根据现有技术公开的方案(中国专利申请公开CN103864680A，对应申请CN201310652191.5)进行。
Figure PCTCN2017084929-appb-000005
制备实施例1
化合物7a-d的通用合成工艺
将相应的7-取代-4-喹诺酮6(30mmol)和POCl3(45mL)混合加热回流2h。将反应液冷却至室温后，逐滴滴加到冰水中，再滴加浓NaOH溶液调节pH至6.0～7.0，析出大量固体，过滤，水洗，干燥，可得较纯的7a-d。
制备实施例1.1：4-氯-7-氟喹啉(7a)
以7-氟-4-喹诺酮6a(30mmol)为原料，得白色固体(4.20g，77.1％)。1H NMR(400MHz,CDCl3)δ8.79(d,J＝4.8Hz,1H),8.26(m,1H),7.77(d,J＝9.6Hz,1H),7.48(d,J＝4.8Hz,1H),7.44(d,J＝8.4Hz,1H).13C NMR(100MHz,CDCl3)δ164.7,162.2,151.0,150.03(d,J＝12.8Hz),142.6,126.49(d,J＝10.0Hz),123.4,120.61(d,J＝1.9Hz),118.2,117.9,113.5,113.3.
制备实施例1.2：4,7-二氯喹啉(7b)
以7-氯-4-喹诺酮6b(30mmol)为原料，得白色固体(5.02g，85.0％)。ESI-MS m/z 197[M]+.1H NMR(300MHz,CDCl3):δ8.74(1H,d,J＝4.8Hz),8.09–8.15(2H,m),7.54–7.58(1H,m),7.45(1H,d,J＝4.8Hz).13C NMR(75MHz,CDCl3)δ151.0,149.4,142.8,136.7,128.8(2C),125.7,125.1,121.6.
制备实施例1.3：4-氯-7-溴喹啉(7c)
以7-溴-4-喹诺酮6c(30mmol)为原料，得白色固体(4.35g，90.3％)。1H NMR(400MHz,CDCl3)δ8.79(d,J＝4.4Hz,1H),8.32(s,1H),8.11(d,J＝8.8Hz,1H),7.74(d,J＝9.2Hz,1H),7.51(d,J＝4.4Hz,1H).13C NMR(100MHz,CDCl3)δ150.9,149.5,142.7,132.0,131.1,125.5,125.2,124.8,121.6.
制备实施例1.4：4-氯-7-甲氧基喹啉(7d)
以7-甲氧基-4-喹诺酮6d(30mmol)为原料，得橙色固体(4.19g，67.8％)。
ESI-MS m/z 194[M+H]+.1H NMR(300MHz,CDCl3):δ8.67(1H,d,J＝4.8Hz),8.09(1H,d,J＝9.0Hz),7.42(1H,d,J＝2.4Hz),7.33(1H,d,J＝4.8Hz),7.28(1H,dd,J＝9.0Hz,J＝2.4Hz),3.97(3H,s).13CNMR(75MHz,CDCl3)δ161.3,151.0,150.2,142.4,125.3,121.7,120.8,119.3,107.7,55.9.
制备实施例2
化合物7e-l的通用合成工艺
在250ml的圆底烧瓶中加入4-氯-7-羟基喹啉6e(15mmol)，DMF(70ml)和60％NaH(45mmol)，室温搅拌15min，加入相应的卤代烷烃继续反应，TLC跟踪监测至反应完毕。将反应混合液倒入冰水中停止反应，乙酸乙酯萃取3次，合并有机相，再分别水洗，饱和食盐水洗，无水硫酸钠干燥。过滤，减压浓缩至干，柱层析除去反应杂质，用流动相二氯甲烷:甲醇＝200:1、二氯甲烷:甲醇＝100:1洗脱，收集目标产物，减压浓缩至干。
制备实施例2.1：4-氯-7-乙氧基喹啉(7e)
以4-氯-7-羟基喹啉6e(15mmol)和1-溴乙烷(30mmol)为原料，得浅黄色固体(2.11g，68.0％)。Mp 70-71℃.MS(ESI):m/z(M+H)+207.8.1H NMR(300MHz,CDCl3)δ8.66(1H,d,J＝4.7Hz),8.09(1H,d,J＝9.2Hz),7.39(1H,d,J＝1.8Hz),7.32(1H,d,J＝4.7Hz),7.29–7.20(1H,m),4.19(2H,q,J＝6.9Hz),1.50(3H,t,J＝7.0Hz).13C NMR(75MHz,CDCl3)δ160.3,150.6,149.8,142.0,124.9,121.2,120.7,118.8,107.8,63.7,14.6.HRMS(ESI)calcd for C11H11ClNO[M+H]+208.0524,found 208.0515.
制备实施例2.2：4-氯-7-异丙氧基喹啉(7f)
以4-氯-7-羟基喹啉6e(15mmol)和2-溴丙烷(30mmol)为原料，得浅黄色固体(2.08g，62.6％)。Mp 65-66℃.MS(ESI):m/z(M+H)+221.8.1H NMR(300MHz,CDCl3)δ8.65(1H,d,J＝4.7Hz),8.08(1H,d,J＝9.2Hz),7.39(1H,s),7.30(1H,d,J＝4.7Hz),7.27–7.20(1H,m),4.82–4.67(1H,m),1.43(6H,d,J＝6.0Hz).13C NMR(75MHz,CDCl3)δ159.3,150.5,149.7,142.1,125.0,121.5,121.0,118.7,108.8,70.2,21.7.HRMS(ESI)calcd for C12H13ClNO[M+H]+222.0680,found 222.0676.
制备实施例2.3：4-氯-7-烯丙氧基喹啉(7g)
以4-氯-7-羟基喹啉6e(15mmol)和烯丙基溴(30mmol)为原料，得浅黄色固体(2.40g，72.8％)。Mp 36-37℃.MS(ESI):m/z(M+H)+219.8.1H NMR(300MHz,CDCl3)δ8.66(1H,d,J＝4.6Hz),8.09(1H,d,J＝9.1Hz),7.41(1H,s),7.29(2H,dd,J＝15.9Hz,J＝6.2Hz),6.10(1H,m),5.48(1H,d,J＝17.2Hz),5.34(1H,d,J＝10.4Hz),4.69(2H,d,J＝4.8Hz).13C NMR(75MHz,CDCl3)δ159.9,150.5,149.9,142.1,132.2,125.1,121.4,120.8,119.0,118.1,108.4,68.9
制备实施例2.4：4-氯-7-正丁氧基喹啉(7h)
以4-氯-7-羟基喹啉6e(15mmol)和1-溴丁烷(30mmol)为原料，得白色固体(2.22g,63.0％)。Mp37-38℃.MS(ESI):m/z(M+H)+236.1.1H NMR(300MHz,CDCl3)δ8.65(1H,d,J＝4.8Hz),8.08(1H,d,J＝9.2Hz),7.39(1H,d,J＝1.9Hz),7.31(1H,d,J＝4.8Hz),7.29–7.23(1H,m),4.12(2H,t,J＝6.5Hz),1.92–1.79(2H,m),1.62–1.47(2H,m),1.00(3H,t,J＝7.3Hz).13C NMR(75MHz,CDCl3)δ160.5,150.7,149.8,142.0,124.9,121.2,120.8,118.8,108.0,68.0,31.0,19.2,13.8
制备实施例2.5：4-氯-7-正辛氧基喹啉(7i)
以4-氯-7-羟基喹啉6e(15mmol)和1-碘代辛烷(45mmol)为原料，得淡黄色固体(2.51g，57.4％)。1H NMR(400MHz,CDCl3)δ8.68(1H,d,J＝4.8Hz),8.11(1H,d,J＝9.2Hz),7.41(1H,s),7.33(1H,d,J＝4.8Hz),7.27(1H,d,J＝4.8Hz),4.12(2H,t,J＝6.4Hz),1.92–1.81(2H,m),1.55–1.45(2H,m),1.42–1.22(8H,m),0.89(3H,t,J＝6.4Hz).
制备实施例2.6：4-氯-7-苄氧基喹啉(7j)
以4-氯-7-羟基喹啉6e(15mmol)和溴化苄(30mmol)为原料，得白色固体(2.11g，52.2％)。Mp 87-88℃.MS(ESI):m/z(M+H)+269.8.1H NMR(300MHz,CDCl3)δ8.67(1H,d,J＝4.7Hz),8.12(1H,d,J＝9.2Hz),7.52–7.30(8H,m),5.21(2H,s).13C NMR(75MHz,CDCl3)δ160.2,150.7,150.0,142.2,135.9,128.5,128.1,127.5,125.2,121.6,120.9,119.2,108.7,70.3.HRMS(ESI)calcd for C16H13ClNO[M+H]+270.0680,found 270.0678.
制备实施例2.7：4-氯-7-((4’-氟苄基)氧基)喹啉(7k)
以4-氯-7-羟基喹啉6e(15mmol)和4-氟溴化苄(30mmol)为原料，得黄色固体(2.80g,65.1％)。Mp 98-99℃.MS(ESI):m/z(M+H)+287.9.1H NMR(300MHz,CDCl3)δ8.67(1H,d,J＝4.8Hz),8.12(1H,d,J＝9.2Hz),7.49–7.42(3H,m),7.36–7.30(2H,m),7.08(2H,t,J＝8.7Hz),5.17(2H,s).13C NMR(75MHz,CDCl3)δ162.4(d,J＝246.4Hz),159.9,150.6,150.0,142.2,131.7(d,J＝2.2Hz),129.4(d,J＝8.1Hz),125.2,121.6,120.8,119.2,115.44(d,J＝21.5Hz),108.6,69.5.HRMS(ESI)calcd for C16H12ClFNO[M+H]+288.0586,found 288.0587.
制备实施例2.8：4-氯-7-((3’-苯丙基)氧基)喹啉(7l)
以4-氯-7-羟基喹啉6e(15mmol)和1-溴-3-苯基丙烷(45mmol)为原料，得浅黄色固体(2.22g，49.8％)。Mp 84-85℃.MS(ESI):m/z(M+H)+283.8.1H NMR(300MHz,CDCl3)δ8.64(1H,d,J＝4.0Hz),8.07(1H,d,J＝9.1Hz),7.40(1H,s),7.36–7.19(7H,m),4.34(2H,t,J＝6.7Hz),3.18(2H,t,J＝6.7Hz).13CNMR(75MHz,CDCl3)δ160.1150.6,149.8,142.0,137.7,128.7,128.3,126.4,124.9,121.3,120.7,118.9,108.1,68.7,35.4.
制备实施例3
化合物8-51的通用合成工艺
在100ml的圆底烧瓶中加入4-氯-7-取代喹啉7(2mmol)，丙酮(20ml)和相应的芳香胺(8mmol)，室温搅拌下滴加浓盐酸(15滴)，加热回流反应12h，TLC跟踪监测至反应完毕，将反应液冷却至室温，倒入冰水中，氢氧化钠溶液调节pH至9，乙酸乙酯萃取3次，合并有机相，分别水洗，饱和食盐水洗各一次，有机相用无水硫酸钠干燥，过滤，减压浓缩至干，柱层析除去反应杂质，用流动相PE：EA＝4：1、PE：EA＝3：1、PE：EA＝2：1洗脱，收集目标产物，减压浓缩至干，即得目标产物8-51。其中
制备实施例3.1：4-((3’-氟苯基)氨基)-7-氟喹啉(化合物8)的合成
以4-氯-7-氟喹啉7a(1.5mmol)和间氟苯胺(8mmol)为原料，得白色固体(0.37g,96.3％)。Mp191.1-191.7℃.1H NMR(400MHz,CDCl3)δ8.61(1H,d,J＝5.2Hz),7.95–7.72(1H,m),7.69(1H,d,J＝10.4Hz),7.40–7.30(2H,m),7.07–7.01(3H,m),6.89(1H,t,J＝8.0Hz),6.64(1H,s).13C NMR(100MHz,DMSO-d6)δ164.0,163.7,161.6,161.2,151.9,150.23(d,J＝12.5Hz),147.2,142.65(d,J＝10.3Hz),130.88(d,J＝9.7Hz),125.15(d,J＝10.1Hz),117.40(d,J＝2.3Hz),117.2,114.7,114.5,112.38(d,J＝19.4Hz),110.0,109.8,108.5,108.2,102.4.
制备实施例3.2：4-((3’-氯苯基)氨基)-7-氟喹啉(化合物9)的合成
以4-氯-7-氟喹啉7a(1.5mmol)和间氯苯胺(8mmol)为原料，得白色固体(0.31g,76.0％)。Mp223.0-223.4℃.1H NMR(400MHz,CDCl3)δ8.61(1H,d,J＝5.6Hz),7.94–7.91(1H,m),7.71–7.68(1H,m),7.37–7.29(3H,m),7.17(2H,d,J＝8.0Hz),7.01(1H,d,J＝5.2Hz),6.61(1H,s).13C NMR(100MHz,DMSO-d6)δ163.7,161.2,151.9,150.20(d,J＝12.5Hz),147.2,142.3,133.7,130.9,125.09(d,J＝10.1Hz),123.1,121.3,120.0,117.1,114.8,114.64(d,J＝24.7Hz),112.39(d,J＝19.5Hz),102.2.
制备实施例3.3：4-((3’-溴苯基)氨基)-7-氟喹啉(化合物10)的合成
以4-氯-7-氟喹啉7a(1.5mmol)和间溴苯胺(8mmol)为原料，得白色固体(0.22g,46.2％)。Mp234.5-235.0℃.1H NMR(400MHz,DMSO-d6)δ9.20(1H,s),8.54(1H,d,J＝5.2Hz),8.47–8.43(1H,m),7.65–7.62(1H,m),7.58–7.45(2H,m),7.44–7.27(3H,m),7.02(1H,d,J＝5.2Hz).13C NMR(100MHz,DMSO-d6)δ163.7,161.2,151.9,150.17(d,J＝12.5Hz),147.2,142.4,131.2,126.0,125.09(d,J＝10.1Hz),124.2,122.1,120.4,117.1,114.8,114.5,112.37(d,J＝19.5Hz),102.2.
制备实施例3.4：4-((3’-硝基苯基)氨基)-7-氟喹啉(化合物11)的合成
以4-氯-7-氟喹啉7a(1.5mmol)和间硝基苯胺(8mmol)为原料，得黄色固体(0.29g,68.3％)。Mp231.9-232.5℃.1H NMR(400MHz,DMSO-d6)δ9.47(1H,s),8.59(1H,d,J＝5.2Hz),8.47–8.44(1H,m),8.16(1H,s),7.92(1H,d,J＝7.6Hz),7.83(1H,d,J＝7.6Hz),7.67(2H,t,J＝8.4Hz),7.56–7.52(1H,m),7.15(1H,d,J＝4.8Hz).13C NMR(100MHz,DMSO-d6)δ163.7,161.3,151.9,150.1,148.6,146.6,142.3,130.6,126.8,125.14(d,J＝10.1Hz),117.30(d,J＝7.7Hz),115.0,114.8,112.41(d,J＝19.0Hz),102.7.
制备实施例3.5：4-((3’-甲氧基苯基)氨基)-7-氟喹啉(化合物12)的合成
以4-氯-7-氟喹啉7a(1.5mmol)和间甲氧基苯胺(8mmol)为原料，得白色固体(0.35g,76.6％)。Mp213.9-214.7℃.1H NMR(400MHz,CDCl3)δ8.57(1H,d,J＝5.6Hz),7.95–7.92(1H,m),7.69–7.66(1H,m),7.35–7.29(2H,m),7.01(1H,d,J＝5.2Hz),6.88(1H,d,J＝8.0Hz),6.84(1H,s),6.77–6.74(1H,m),6.65(1H,s),3.83(3H,s).13C NMR(100MHz,DMSO-d6)δ163.6,161.2,160.2,151.9,150.23(d,J＝12.4Hz),147.9,141.6,130.1,125.10(d,J＝10.1Hz),116.9,114.48(d,J＝3.5Hz),114.2,112.33(d,J＝19.4Hz),109.5,108.1,101.7,55.1.
制备实施例3.6：4-((3’-甲氧基苯基)氨基)-7-氯喹啉(化合物13)的合成
以4-氯-7-氯喹啉7b(1.5mmol)和间甲氧基苯胺(8mmol)为原料，得白色固体(0.33g,产率77.3％)。Mp 213.7-214.1℃.1H NMR(400MHz,CDCl3)δ8.56(1H,d,J＝5.2Hz),8.04(1H,s),7.88(1H,d,J＝9.2Hz),7.45(1H,d,J＝8.8Hz),7.33(1H,t,J＝8.0Hz),7.02(1H,d,J＝5.6Hz),6.88(1H,d,J＝8.4Hz),6.85(1H,s),6.76(1H,d,J＝8.0Hz),6.70(1H,s),3.83(3H,s).13C NMR(101MHz,DMSO-d6)δ160.2,151.9,149.4,147.9,141.4,134.0,130.2,127.6,125.0,124.5,118.4,114.5,109.6,108.1,102.3,55.1.
制备实施例3.7：4-((3’-氟苯基)氨基)-7-氯喹啉(化合物14)的合成
以4-氯-7-氯喹啉7b(1.5mmol)和间氟苯胺(8mmol)为原料，得白色固体(0.40g,97.8％)。Mp209.3-209.6℃.1H NMR(400MHz,CDCl3)δ8.61(1H,d,J＝5.2Hz),8.05(1H,d,J＝1.6Hz),7.87(1H,d,J＝8.8Hz),7.47(1H,dd,J＝8.8,1.6Hz),7.40–7.34(1H,m),7.07–7.00(3H,m),6.91–6.85(1H,m),6.68(1H,s).13C NMR(100MHz,DMSO-d6)δ163.9,161.5,152.0,149.5,147.1,142.50(d,J＝10.4Hz),134.1,130.94(d,J＝9.7Hz),127.6,125.2,124.5,118.6,117.43(d,J＝2.3Hz),110.1,109.9,108.5,108.2,103.0.
制备实施例3.8：4-((3’-硝基苯基)氨基)-7-氯喹啉(化合物15)的合成
以4-氯-7-氯喹啉7b(1.5mmol)和间硝基苯胺(8mmol)为原料，得白色固体(0.28g,62.3％)。Mp234-237℃.1H NMR(400MHz,DMSO-d6)δ9.48(1H,s),8.59(1H,d,J＝5.2Hz),8.40(1H,d,J＝9.2Hz),8.16(1H,s),7.99–7.88(2H,m),7.83(1H,d,J＝8.0Hz),7.70–7.60(2H,m),7.18(1H,d,J＝4.8Hz).13CNMR(100MHz,DMSO-d6)δ151.9,149.5,148.6,146.6,142.2,134.3,130.7,127.7,126.8,125.5,124.5,118.8,117.4,115.1,103.3.
制备实施例3.9：4-((3’-氟苯基)氨基)-7-溴喹啉(化合物16)的合成
以4-氯-7-溴喹啉7c(2mmol)和间氟苯胺(8mmol)为原料，得白色固体(0.52g,82.3％)。Mp 212.5-214.0℃.1H NMR(400MHz,CDCl3)δ8.60(1H,d,J＝5.2Hz),8.23(1H,s),7.80(1H,d,J＝9.2Hz),7.60(1H,d,J＝8.8Hz),7.40–7.34(1H,dd,J＝14.8,7.9Hz),7.08–7.00(3H,m),6.91–6.87(1H,m),6.68(1H,s).13CNMR(101MHz,DMSO-d6)δ163.9,161.5,152.0,149.8,147.1,142.45(d,J＝10.6Hz),130.95(d,J＝9.5Hz),127.8,124.5,122.8,118.9,117.40(d,J＝2.3Hz),110.1,109.9,108.4,108.2,103.0.
制备实施例3.10：4-((3’-氯苯基)氨基)-7-溴喹啉(化合物17)的合成
以4-氯-7-溴喹啉7c(1.5mmol)和间氯苯胺(8mmol)为原料，得白色固体(0.34g,68.3％)。Mp229.0-229.7℃.1H NMR(400MHz,CDCl3)δ8.60(1H,d,J＝5.2Hz),8.24(1H,s),7.79(1H,d,J＝8.8Hz),7.63–7.58(1H,m),7.35(1H,t,J＝8.0Hz),7.30(1H,s),7.17(2H,d,J＝8.0Hz),7.04(1H,d,J＝5.2Hz),6.62(1H,s).13C NMR(100MHz,DMSO-d6)δ151.9,149.7,147.2,142.2,133.7,130.9,127.8,124.5,123.2,122.8,121.2,120.0,118.9,102.9.
制备实施例3.11：4-((3’-溴苯基)氨基)-7-溴喹啉(化合物18)的合成
以4-氯-7-溴喹啉7c(1.5mmol)和间溴苯胺(8mmol)为原料，得白色固体(0.39g,69.2％)。Mp238.5-239.9℃.1H NMR(400MHz,CDCl3)δ8.61(1H,d,J＝5.2Hz),8.24(1H,s),7.78(1H,d,J＝8.8Hz),7.62(1H,d,J＝8.0Hz),7.46(s,1H,),7.34–7.29(2H,m),7.22(1H,d,J＝7.6Hz),7.03(1H,d,J＝5.2Hz),6.57(1H,s).13C NMR(100MHz,DMSO-d6)δ151.7,149.6,147.3,142.3,131.2,130.8,127.8,126.2,124.5,124.2,122.9,122.1,120.5,118.8,102.8.
制备实施例3.12：4-((3’-硝基苯基)氨基)-7-溴喹啉(化合物19)的合成
以4-氯-7-溴喹啉7c(2mmol)和间硝基苯胺(8mmol)为原料，得黄色固体(0.74g,97.2％)。Mp222.0-223.4℃.1H NMR(400MHz,DMSO-d6)δ9.50(1H,s),8.58(1H,d,J＝4.8Hz),8.33(1H,d,J＝8.8Hz),8.14(2H,d,J＝11.2Hz),7.93(1H,d,J＝8.4Hz),7.83(1H,d,J＝8.0Hz),7.76(1H,d,J＝8.8Hz),7.67(1H,t,J＝8.0Hz),7.20(1H,d,J＝4.4Hz).13C NMR(101MHz,DMSO-d6)δ151.7,149.6,148.5,146.6,142.2,130.8,130.6,128.0,126.8,124.5,123.0,119.0,117.3,115.1,103.3.
制备实施例3.13：4-((3’-甲氧基苯基)氨基)-7-溴喹啉(化合物20)的合成
以4-氯-7-溴喹啉7c(2mmol)和间甲氧基苯胺(8mmol)为原料，得浅绿色固体(0.30g,63.3％)。Mp215.4-216.4℃.1H NMR(400MHz,CDCl3)δ8.56(1H,d,J＝5.2Hz),8.22(1H,s),7.80(1H,d,J＝8.8Hz), 7.58(1H,d,J＝8.8Hz),7.33(1H,t,J＝8.0Hz),7.04(1H,d,J＝5.2Hz),6.88(1H,d,J＝8.0Hz),6.84(1H,s),6.76(1H,d,J＝8.4Hz),6.65(1H,s),3.83(3H,s).13C NMR(100MHz,DMSO-d6)δ160.2,151.8,149.8,147.9,141.4,130.9,130.1,127.5,124.5,122.6,118.7,114.4,109.5,108.0,102.4,55.1.
制备实施例3.14：4-((3’-氟苯基)氨基)-7-甲氧基喹啉(化合物21)的合成
以4-氯-7-甲氧基喹啉7d(1mmol)和间氟苯胺(8mmol)为原料，得白色固体(0.12g,44.8％)。Mp238-239℃.1H NMR(400MHz,DMSO-d6)δ8.46(1H,d,J＝5.6Hz),8.33(1H,d,J＝8.8Hz),7.51–7.43(1H,m),7.30–7.19(4H,m),7.02–6.97(1H,m),6.94(1H,d,J＝6.0Hz),3.93(3H,s).13C NMR(100MHz,DMSO-d6)δ162.74(d,J＝241.0Hz),160.0,150.9(d,J＝4.7Hz),146.7,143.1(d,J＝10.3Hz),130.8(d,J＝9.7Hz),123.5,116.9(2C),114.7,109.4,109.2,107.8(d,J＝6.5Hz),107.6,101.7,55.3.
制备实施例3.15：4-((3’-溴苯基)氨基)-7-甲氧基喹啉(化合物22)的合成
以4-氯-7-甲氧基喹啉7d(1mmol)和间溴苯胺(8mmol)为原料，得白色固体(0.22g,67.1％)。Mp>250℃.1H NMR(400MHz,DMSO-d6)δ9.01(1H,s),8.46(1H,d,J＝5.2Hz),8.23(1H,d,J＝9.2Hz),7.51(1H,s),7.38–7.25(4H,m),7.22–7.19(1H,m),6.94(1H,d,J＝5.2Hz),3.91(3H,s).13C NMR(100MHz,DMSO-d6)δ160.0,151.0,146.6,142.9,131.2,125.4,123.6,123.5,122.0,119.9,117.0,114.7,107.8,101.5,55.3.
制备实施例3.16：4-((3’-硝基苯基)氨基)-7-甲氧基喹啉(化合物23)的合成
以4-氯-7-甲氧基喹啉7d(1mmol)和间硝基苯胺(8mmol)为原料，得黄色固体(0.12g,40.7％)。Mp200-201℃.1H NMR(400MHz,DMSO-d6)δ9.34(1H,s),8.51(1H,d,J＝4.8Hz),8.26(1H,d,J＝9.2Hz),8.13(1H,t,J＝2.0Hz),7.88(1H,dd,J＝8.0,2.4Hz),7.80(1H,dd,J＝8.0,1.6Hz),7.64(1H,t,J＝8.0Hz),7.33(1H,d,J＝2.4Hz),7.24(1H,dd,J＝9.2,2.8Hz),7.07(1H,d,J＝5.2Hz),3.93(3H,s).13C NMR(100MHz,DMSO-d6)δ160.2,150.9,148.6,146.1,142.8,130.6,126.3,123.6,117.3,116.7,114.9,114.4,107.8,102.1,55.4.
制备实施例3.17：4-((3’-羟基苯基)氨基)-7-甲氧基喹啉(化合物24)的合成
以4-氯-7-甲氧基喹啉7d(1mmol)和间羟基苯胺(8mmol)为原料，得白色固体(0.07g,26.3％)。Mp248-249℃.1H NMR(400MHz,DMSO-d6)δ9.50(1H,s),8.79(1H,s),8.38(1H,d,J＝5.2Hz),8.26(1H,d,J＝9.2Hz),7.25(1H,d,J＝2.4Hz),7.22–7.14(2H,m),6.85(1H,d,J＝5.2Hz),6.78–6.76(2H,m),6.54–6.52(1H,m),3.90(3H,s).13C NMR(100MHz,DMSO-d6)δ160.0,158.2,150.8,147.6,141.8,130.0,123.6,116.5,114.4,112.8,110.7,109.0,107.7,100.9,55.3.
制备实施例3.18：4-((3’-甲氧基苯基)氨基)-7-甲氧基喹啉(化合物25)的合成
以4-氯-7-甲氧基喹啉7d(1.5mmol)和间甲氧基苯胺(8mmol)为原料，得白色固体(0.34g,81.0％)。Mp 221.0-222.3℃.1H NMR(400MHz,CDCl3)δ8.50(1H,d,J＝5.2Hz),7.82(1H,d,J＝9.2Hz),7.38(1H,s),7.31(1H,t,J＝8.0Hz),7.15(1H,d,J＝9.2Hz),6.96(1H,d,J＝5.2Hz),6.88(1H,d,J＝8.0Hz),6.84(1H,s),6.72(1H,d,J＝8.0Hz),6.61(1H,s),3.95(3H,s),3.82(3H,s).13C NMR(100MHz,DMSO-d6)δ160.2,160.1,150.7,150.6,147.6,141.9,130.1,123.6,116.7,114.4,114.2,109.1,107.7,107.6,101.0,55.3,55.1.
制备实施例3.19：4-((3’,4’-二氯苯基)氨基)-7-甲氧基喹啉(化合物26)的合成
以4-氯-7-甲氧基喹啉7d(1mmol)和3,4-二氯苯胺(8mmol)为原料，得浅黄色固体(0.13g,40.9％)。Mp 216-218℃.1H NMR(400MHz,DMSO-d6)δ9.10(1H,s),8.48(1H,d,J＝5.2Hz),8.22(1H,d,J＝9.2 Hz),7.59(1H,d,J＝8.8Hz),7.54(1H,d,J＝2.4Hz),7.35–7.30(2H,m),7.22(1H,dd,J＝9.2,2.4Hz),6.97(1H,d,J＝5.2Hz),3.92(3H,s).13C NMR(100MHz,DMSO-d6)δ160.1,150.8,146.4,141.6,131.5,131.0,124.0,123.5,122.2,120.8,117.1,114.8,107.7,102.0,55.3.
制备实施例3.20：4-((3’-氟苯基)氨基)-7-乙氧基喹啉(化合物27)的合成
以4-氯-7-乙氧基喹啉7e(1.2mmol)和间氟苯胺(8mmol)为原料，得白色固体(0.24g,70.9％)。Mp223.2-224.4℃.1H NMR(400MHz,CDCl3)δ8.54(1H,d,J＝5.2Hz),7.82(1H,d,J＝9.2Hz),7.37–7.31(2H,m),7.15(1H,dd,J＝9.2,2.0Hz),7.05–6.97(3H,m),6.86–6.82(1H,m),6.71(1H,s),4.17(2H,q,J＝6.8Hz),1.49(3H,t,J＝6.8Hz).13C NMR(100MHz,DMSO-d6)δ163.9,161.5,159.3,150.87(d,J＝6.4Hz),146.6,143.09(d,J＝10.5Hz),130.82(d,J＝9.7Hz),123.5,117.2,116.84(d,J＝2.3Hz),114.6,109.4,109.2,108.3,107.8,107.6,101.7,63.3,14.5.
制备实施例3.21：4-((3’-甲氧基苯基)氨基)-7-乙氧基喹啉(化合物28)的合成
以4-氯-7-乙氧基喹啉7e(1.2mmol)和间甲氧基苯胺(8mmol)为原料，得白色固体(0.34g,96.3％)。Mp 176.4-177.9℃.1H NMR(400MHz,CDCl3)δ8.50(1H,d,J＝5.2Hz),7.81(1H,d,J＝9.2Hz),7.37–7.29(2H,m),7.15(1H,dd,J＝9.2,2.4Hz),6.96(1H,d,J＝5.2Hz),6.88–6.84(2H,m),6.72(1H,d,J＝6.8Hz),6.57(1H,s),4.19(2H,q,J＝6.8Hz),3.83(3H,s),1.50(3H,t,J＝6.8Hz).13C NMR(100MHz,CDCl3)δ160.8,160.1,151.1,151.0,147.7,141.6,130.5,121.5,118.4,114.7,114.6,109.8,108.7,108.2,101.8,63.8,55.5,14.8.
制备实施例3.22：4-((3’-硝基苯基)氨基)-7-乙氧基喹啉(化合物29)的合成
以4-氯-7-乙氧基喹啉7e(1.2mmol)和间硝基苯胺(8mmol)为原料，得黄色固体(0.22g,59.4％)。Mp 184.9-185.6℃.1H NMR(400MHz,CDCl3)δ8.59(1H,d,J＝5.2Hz),8.10(1H,s),7.95(1H,d,J＝7.6Hz),7.86(1H,d,J＝9.2Hz),7.60–7.52(2H,m),7.39(1H,s),7.22–7.15(1H,m),7.00(1H,d,J＝5.2Hz),6.88(1H,s),4.17(2H,q,J＝6.8Hz),1.49(3H,t,J＝6.8Hz).13C NMR(100MHz,DMSO-d6)δ159.4,150.8,148.6,146.1,142.8,130.6,126.2,123.5,117.5,116.7,114.8,114.4,108.3,102.1,63.3,14.5.
制备实施例3.23：4-((3’-氟苯基)氨基)-7-异丙氧基喹啉(化合物30)的合成
以4-氯-7-异丙氧基喹啉7f(1.5mmol)和间氟苯胺(8mmol)为原料，得白色固体(0.27g,61.4％)。Mp>250℃.1H NMR(400MHz,CDCl3)δ8.54(1H,d,J＝5.2Hz),7.81(1H,d,J＝9.2Hz),7.38–7.31(2H,m),7.13(1H,d,J＝9.2Hz),7.04–6.97(3H,m),6.84(1H,t,J＝8.0Hz),6.62(1H,s),4.77–4.71(1H,m),1.42(6H,d,J＝6.0Hz).13C NMR(100MHz,DMSO-d6)δ164.0,161.5,158.2,150.78(d,J＝10.7Hz),146.7,143.09(d,J＝10.6Hz),130.86(d,J＝9.8Hz),123.7,117.8,116.88(d,J＝2.1Hz),114.5,109.4,109.2,107.8,107.6,101.6,69.4,21.7.
制备实施例3.24：4-((3’-甲氧基)氨基)-7-异丙氧基喹啉(化合物31)的合成
以4-氯-7-异丙氧基喹啉7f(1.5mmol)和间甲氧基苯胺(8mmol)为原料，得淡黄色固体(0.34g,73.9％)。Mp 155.3-156.1℃.1H NMR(400MHz,CDCl3)δ8.49(d,J＝5.2Hz,1H,),7.82(d,J＝9.2Hz,1H,),7.37(s,1H,),7.30(t,J＝8.0Hz,1H,),7.12(dd,J＝9.2,2.0Hz,1H,),6.94(d,J＝5.2Hz,1H,),6.88–6.84(m,2H,),6.72(d,J＝8.4Hz,1H,),6.62(s,1H,NH),4.77–4.71(m,1H,OCH(CH3)2),3.82(s,3H,OCH3),1.42(d,J＝6.0Hz,6H,OCH(CH3)2).13C NMR(100MHz,CDCl3)δ160.8,159.0,151.12,151.0,147.6,141.6,130.5,121.5,119.2,114.7,114.4,109.8,109.7,108.2,101.7,70.1,55.5,22.0.
制备实施例3.25：4-((3’-硝基苯基)氨基)-7-异丙氧基喹啉(化合物32)的合成
以4-氯-7-异丙氧基喹啉7f(1.5mmol)和间硝基苯胺(8mmol)为原料，得黄色固体(0.20g,50.0％)。Mp 204.6-206.5℃.1H NMR(400MHz,CDCl3)δ8.56(1H,d,J＝5.2Hz),8.08(1H,s),7.99(1H,d,J＝9.2Hz),7.90(1H,d,J＝8.0Hz),7.60(1H,d,J＝8.0Hz),7.49(1H,t,J＝8.0Hz),7.31(1H,s),7.08(1H,d,J＝8.8Hz),6.99(1H,d,J＝4.8Hz),4.60–4.54(1H,m),1.32(6H,d,J＝6.0Hz).13C NMR(100MHz,CDCl3)δ159.3,151.2,151.0,149.3,146.6,142.5,130.4,126.8,122.1,119.81,118.0,115.6,115.0,109.6,102.7,70.2,21.9.
制备实施例3.26：4-((3’-氟苯基)氨基)-7-烯丙氧基喹啉(化合物33)的合成
以4-氯-7-烯丙氧基喹啉7g(1.5mmol)和间氟苯胺(8mmol)为原料，得白色固体(0.10g,22.7％)。Mp 206.2-207.3℃.1H NMR(400MHz,CDCl3)δ8.55(1H,d,J＝5.2Hz),7.83(1H,d,J＝9.2Hz),7.39–7.32(2H,m),7.19(1H,d,J＝9.2Hz),7.05–6.98(3H,m),6.85(1H,t,J＝8.0Hz),6.63(1H,s),6.17–6.08(1H,m),5.49(1H,d,J＝17.2Hz),5.35(1H,d,J＝10.8Hz),4.69(2H,d,J＝5.2Hz).13C NMR(100MHz,DMSO-d6)δ164.0,161.5,158.9,150.92(d,J＝22.2Hz),150.47–149.81(m),146.6,143.07(d,J＝10.1Hz),133.4,130.87(d,J＝9.7Hz),123.6,117.7,117.2,116.89(d,J＝2.3Hz),114.8,109.32(d,J＝21.1Hz),109.18–108.97(m),108.9,107.9,107.6,101.8,68.3.
制备实施例3.27：4-((3’-甲氧基苯基)氨基)-7-烯丙氧基喹啉(化合物34)的合成
以4-氯-7-烯丙氧基喹啉7g(1.5mmol)和间甲氧基苯胺(8mmol)为原料，得白色固体(0.10g,21.8％)。Mp 174.6-175.4℃.1H NMR(400MHz,CDCl3)δ8.47(1H,d,J＝5.6Hz),7.85(1H,d,J＝9.2Hz),7.37(1H,d,J＝2.4Hz),7.31(1H,t,J＝8.0Hz),7.18(1H,dd,J＝9.2,2.4Hz),6.95(1H,d,J＝5.2Hz),6.90–6.85(2H,m),6.74–6.71(1H,m),6.16–6.06(1H,m),5.48(1H,d,J＝17.2),5.34(1H,d,J＝10.4),4.66(2H,d,J＝5.2Hz),3.82(3H,s).13C NMR(100MHz,CDCl3)δ160.9,159.6,151.3,151.0,147.6,141.5,132.9,130.5,121.5,118.4,118.3,114.8,114.7,109.8,109.3,108.2,101.9,69.0,55.5.
制备实施例3.28：4-((3’-硝基苯基)氨基)-7-烯丙氧基喹啉(化合物35)的合成
以4-氯-7-烯丙氧基喹啉7g(1.5mmol)和间硝基苯胺(8mmol)为原料，得黄色固体(0.44g,92.1％)。Mp 159.8-161.4℃.1H NMR(400MHz,CDCl3)δ8.59(1H,d,J＝4.8Hz),8.10(1H,s),7.95(1H,d,J＝8.0Hz),7.89(1H,d,J＝5.2Hz),7.60–7.52(2H,m),7.39(1H,s),7.21(1H,d,J＝8.8Hz),7.01(1H,d,J＝5.1Hz),6.14–6.04(1H,m),5.47(1H,d,J＝17.2Hz),5.33(1H,d,J＝10.4Hz),4.64(2H,d,J＝5.2Hz).13CNMR(100MHz,DMSO-d6)δ159.0,151.0,148.6,146.1,142.8,133.4,130.6,126.2,123.6,117.7,117.5,116.7,115.0,114.4,108.9,102.2,68.4.
制备实施例3.29：4-((3’-氟苯基)氨基)-7-正丁氧基喹啉(化合物36)的合成
以4-氯-7-正丁氧基喹啉7h(1mmol)和间氟苯胺(8mmol)为原料，得淡黄色固体(0.11g,32.2％)。1HNMR(400MHz,DMSO-d6)δ9.05(1H,s),8.45(1H,d,J＝5.6Hz),8.24(1H,d,J＝9.2Hz),7.41(1H,dd,J＝15.2,8.0Hz),7.28(1H,d,J＝2.4Hz),7.21–7.13(3H,m),6.97(1H,d,J＝5.6Hz),6.92–6.87(1H,m),4.12(2H,t,J＝6.4Hz),1.82–1.73(2H,m),1.52–1.45(2H,m),0.97(3H,t,J＝7.2Hz).13C NMR(100MHz,DMSO-d6)δ162.7(d,J＝240.9Hz),159.4,150.8(d,J＝4.8Hz),146.6,143.1(d,J＝10.6Hz),130.8(d,J＝9.7Hz),123.5,117.2,116.8,114.6,109.4,109.3(d,J＝20.9Hz),108.3,107.7(d,J＝24.0Hz),101.7,67.3,30.6,18.8,13.7.
制备实施例3.30：4-((3’-溴苯基)氨基)-7-正丁氧基喹啉(化合物37)的合成
以4-氯-7-正丁氧基喹啉7h(1mmol)和间溴苯胺(8mmol)为原料，得白色固体(0.24g,64.7％)。1H NMR(400MHz,DMSO-d6)δ9.01(1H,s),8.45(1H,d,J＝5.2Hz),8.23(1H,d,J＝9.2Hz),7.50(1H,s),7.38– 7.31(2H,m),7.28–7.24(2H,m),7.19(1H,dd,J＝9.2,2.4Hz),6.93(1H,d,J＝5.2Hz),4.12(2H,t,J＝6.4Hz),1.81–1.74(2H,m),1.54–1.45(2H,m),0.97(3H,q,J＝7.2Hz).13C NMR(100MHz,DMSO-d6)δ159.4,150.9,146.6,142.9,131.1,125.3,123.5,122.0,119.8,117.2,114.6,108.4,101.5,67.3,30.6,18.8,13.7.制备实施例3.31：4-((3’-甲氧基苯基)氨基)-7-正丁氧基喹啉(化合物38)的合成
以4-氯-7-正丁氧基喹啉7h(1mmol)和间甲氧基苯胺(8mmol)为原料，得白色固体(0.31g,62.9％)。Mp 166.0-167.0℃.1H NMR(400MHz,CDCl3)δ8.49(1H,d,J＝5.2Hz),7.82(1H,d,J＝9.2Hz),7.36(1H,d,J＝2.0Hz),7.30(1H,t,J＝8.0Hz),7.15(1H,dd,J＝9.2,2.4Hz),6.95(1H,d,J＝5.6Hz),6.87(1H,d,J＝8.0Hz),6.84(1H,s),6.73–6.71(1H,m),6.64(1H,s),4.11(2H,t,J＝6.4Hz),3.82(3H,s),1.88–1.81(2H,m),1.58–1.49(2H,m),1.00(3H,t,J＝7.2Hz).13C NMR(100MHz,CDCl3)δ160.7,160.2,151.1,147.8,141.7,130.4,121.7,118.3,114.7,114.6,109.6,108.6,108.2,101.7,67.9,55.4,31.2,19.4,14.00.
制备实施例3.32：4-((3’-硝基苯基)氨基)-7-正丁氧基喹啉(化合物39)的合成
以4-氯-7-正丁氧基喹啉7h(1mmol)和间硝基苯胺(8mmol)为原料，得黄色固体(0.07g,20.8％)。Mp 70-71℃.1H NMR(400MHz,DMSO-d6)δ9.31(1H,s),8.50(1H,t,J＝5.2Hz),8.25(1H,d,J＝9.2Hz),8.13(1H,s),7.88–7.86(1H,m),7.80–7.78(1H,m),7.64(1H,t,J＝8.0Hz),7.31(1H,d,J＝2.4Hz),7.23(1H,dd,J＝9.2,2.4Hz),7.06(1H,d,J＝4.8Hz),4.13(2H,t,J＝6.4Hz),1.81–1.74(2H,m),1.54–1.45(2H,m),0.97(3H,t,J＝7.2Hz).13C NMR(100MHz,DMSO-d6)δ159.6,150.9,148.6,146.0,142.8,130.6,126.2,123.5,117.5,116.6,114.9,114.3,108.4,102.1,67.4,30.6,18.8,13.7.
制备实施例3.33：4-((3’-甲氧基苯基)氨基)-7-正辛氧基喹啉(化合物40)的合成
以4-氯-7-正辛氧基喹啉7i(1mmol)和间甲氧基苯胺(8mmol)为原料，得白色固体(0.26g,68.7％)。Mp 136.8-138.4℃.1H NMR(400MHz,CDCl3)δ8.49(1H,d,J＝5.2Hz),7.81(1H,d,J＝8.8Hz),7.36(1H,s),7.30(1H,t,J＝8.0Hz),7.15(1H,dd,J＝9.2,2.0Hz),6.95(1H,d,J＝5.2Hz),6.88–6.84(2H,m),6.72(1H,d,J＝8.4Hz),6.64(1H,s),4.10(2H,t,J＝6.4Hz),3.82(3H,s),1.89–1.82(2H,m),1.53–1.46(2H,m),1.34–1.26(8H,m),0.89(3H,t,J＝6.4Hz).13C NMR(100MHz,CDCl3)δ160.8,160.2,151.08,151.01,147.7,141.6,130.4,121.5,118.4,114.7,114.6,109.7,108.6,108.2,101.8,68.3,55.5,32.0,29.5,29.4,29.2,26.2,22.8,14.3.
制备实施例3.34：4-((3’-氟苯基)氨基)-7-正辛氧基喹啉(化合物41)的合成
以4-氯-7-正辛氧基喹啉7i(1mmol)和间氟苯胺(8mmol)为原料，得灰色固体(0.48g,87.4％)。Mp184.4-185.0℃.1H NMR(400MHz,CDCl3)δ8.53(1H,d,J＝5.2Hz),7.81(1H,d,J＝9.2Hz),7.37–7.31(2H,m),7.16(1H,d,J＝9.2Hz),7.05–6.97(3H,m),6.84(1H,t,J＝8.0Hz),6.67(1H,s),4.10(2H,t,J＝6.4Hz),1.89–1.82(2H,m),1.51–1.46(2H,m),1.39–1.30(8H,m),0.89(3H,t,J＝6.8Hz).13C NMR(100MHz,DMSO-d6)δ163.4,161.5,159.4,151.0,146.6,130.85(d,J＝9.8Hz),123.5,117.2,116.8,114.6,109.27(d,J＝21.1Hz),108.94–108.72(m),108.4,107.97–107.80(m),107.66(d,J＝24.1Hz),101.7,67.6,31.2,28.9,28.7,28.6,25.6,22.1,14.0.
制备实施例3.35：4-((3’-硝基苯基)氨基)-7-正辛氧基喹啉(化合物42)的合成
以4-氯-7-正辛氧基喹啉7i(1mmol)和间硝基苯胺(8mmol)为原料，得白色固体(0.11g,28.0％)。Mp 131.0-132.7℃.1H NMR(400MHz,CDCl3)δ8.59(1H,d,J＝4.8Hz),8.11(1H,s),7.95(1H,d,J＝8.0Hz),7.85(1H,d,J＝9.2Hz),7.60–7.52(2H,m),7.39(1H,s),7.19(1H,d,J＝9.2Hz),7.00(1H,d,J＝5.2Hz),4.10(2H,t,J＝6.8Hz),1.90–1.81(2H,m),1.53–1.46(2H,m),1.34–1.27(8H,m),0.89(3H,t,J＝5.6Hz).13C NMR(100MHz,DMSO-d6)δ159.6,150.9,148.6,146.1,142.8,130.6,126.2,123.5,117.5,116.6, 114.4,108.3,102.1,67.8,31.2,28.8,28.7,28.6,25.6,22.1,14.0.
制备实施例3.36：4-((3’-氟苯基)氨基)-7-苄氧基喹啉(化合物43)的合成
以4-氯-7-苄氧基喹啉7j(1.5mmol)和间氟苯胺(8mmol)为原料，得灰白色固体(0.43g,83.3％)。Mp 225.4-226.4℃.1H NMR(400MHz,CDCl3)δ8.55(1H,d,J＝5.2Hz),7.84(1H,d,J＝9.2Hz),7.50–7.47(3H,m),7.41(2H,t,J＝7.2Hz),7.37–7.30(2H,m),7.25–7.23(1H,m,),7.04–6.92(3H,m),6.87–6.83(1H,m),6.66(1H,s),5.20(2H,s).13C NMR(100MHz,DMSO-d6)δ163.9,161.5,159.0,151.0,150.8,146.59(s),143.04(d,J＝10.5Hz),136.8,130.83(d,J＝9.7Hz),128.4,127.82(d,J＝13.3Hz),123.6,117.3,116.84(d,J＝2.2Hz),114.8,109.4,109.2,107.8,107.6,101.8,69.4.
制备实施例3.37：4-((3’-甲氧基苯基)氨基)-7-苄氧基喹啉(化合物44)的合成
以4-氯-7-苄氧基喹啉7j(1.5mmol)和间甲氧基苯胺(8mmol)为原料，得白色固体(0.42g,78.6％)。Mp 200.4-201.6℃.1H NMR(400MHz,CDCl3)δ8.51(1H,d,J＝5.2Hz),7.84(1H,d,J＝9.2Hz),7.49(3H,t,J＝8.0Hz),7.41(2H,t,J＝7.6Hz),7.37–7.28(3H,m),7.24(1H,dd,J＝9.2,1.6Hz),6.96(1H,d,J＝5.2Hz),6.89–6.84(2H,m),6.72(1H,d,J＝6.8Hz),6.59(1H,s),5.21(2H,s),3.82(3H,s).13C NMR(100MHz,CDCl3)δ160.8,159.8,151.3,151.0,147.7,141.5,136.6,130.5,128.8,128.3,127.9,121.6,118.4,114.8,109.8,109.4,108.3,102.0,70.2,55.5.
制备实施例3.38：4-((3’-硝基苯基)氨基)-7-苄氧基喹啉(化合物45)的合成
以4-氯-7-苄氧基喹啉7j(1.2mmol)和间硝基苯胺(8mmol)为原料，得黄色固体(0.27g,60.5％)。Mp 192.0-193.4℃.1H NMR(400MHz,CDCl3)δ8.60(1H,d,J＝5.2Hz),8.10(1H,s),7.95(1H,d,J＝7.6Hz),7.88(1H,d,J＝9.2Hz),7.62–7.46(5H,m),7.40(2H,t,J＝6.8Hz),7.36–7.33(1H,m),7.28(1H,s),7.01(1H,d,J＝5.2Hz),6.88(1H,s),5.19(2H,s).13C NMR(100MHz,DMSO-d6)δ159.2,151.00,148.6,146.1,142.8,136.7,130.6,128.4,127.9,127.8,126.2,123.6,117.6,116.7,115.0,114.4,109.1,102.2,69.4.
制备实施例3.39：4-((3’-氟苯基)氨基)-7-((4’-氟苄基)氧基)喹啉(化合物46)的合成
以4-氯-7-((4’-氟苄基)氧基)喹啉7k(1mmol)和间氟苯胺(8mmol)为原料，得淡黄色固体(0.16g,44.2％)。Mp 232.4-233.1℃.1H NMR(400MHz,DMSO-d6)δ9.07(1H,s),8.46(1H,d,J＝4.8Hz),8.28(1H,d,J＝9.2Hz),7.66–7.52(2H,m),7.44–7.38(2H,m),7.29–7.14(5H,m),6.99(1H,d,J＝5.2Hz),6.90(1H,t,J＝8.0Hz),5.27(2H,s).13C NMR(100MHz,DMSO-d6)δ164.0,163.0,161.5,160.6,159.0,151.93–151.15(m),150.88(d,J＝24.8Hz),146.68(s),143.07(d,J＝10.2Hz),133.01(d,J＝2.9Hz),130.84(d,J＝9.7Hz),130.04(d,J＝8.3Hz),123.7,117.2,116.87(d,J＝2.1Hz),115.4,115.2,114.9,109.71–109.06(m),109.06–108.74(m),107.9,107.6,101.8,68.7.
制备实施例3.40：4-((3’-甲氧基苯基)氨基)-7-((4’-氟苄基)氧基)喹啉(化合物47)的合成
以4-氯-7-((4’-氟苄基)氧基)喹啉7k(1mmol)和间甲氧基苯胺(8mmol)为原料，得白色固体(0.22g,58.8％)。Mp206.4-206.9℃.1H NMR(400MHz,CDCl3)δ8.50(1H,d,J＝5.2Hz),7.86(1H,d,J＝9.2Hz),7.47–7.42(3H,m),7.30(1H,t,J＝8.0Hz),7.20(1H,dd,J＝8.8,2.4Hz),7.08(2H,t,J＝8.8Hz),6.97(1H,d,J＝5.2Hz),6.87(1H,d,J＝8.0Hz),6.84(1H,s),6.75–6.71(2H,m),5.13(2H,s),3.81(3H,s).13C NMR(100MHz,CDCl3)δ163.9,161.5,160.8,159.6,151.4,151.0,147.7,141.5,132.34(d,J＝3.1Hz),130.5,129.70(d,J＝8.2Hz),121.8,118.3,115.8,115.6,114.84(d,J＝15.2Hz),109.8,109.3,108.3,102.0,69.5,55.5.
制备实施例3.41：4-((3’-硝基苯基)氨基)-7-((4’-氟苄基)氧基)喹啉(化合物48)的合成
以4-氯-7-((4’-氟苄基)氧基)喹啉7k(1mmol)和间硝基苯胺(8mmol)为原料，得黄色固体(0.15g,38.5％)。Mp 187-188℃.1H NMR(400MHz,CDCl3)δ8.60(1H,d,J＝5.2Hz),8.12–8.11(1H,m),7.97(1H,d,J＝7.6Hz),7.88(1H,d,J＝9.2Hz),7.60–7.52(2H,m),7.49–7.46(3H,m),7.28(1H,s),7.10(2H,t,J＝8.4Hz),7.02(1H,d,J＝5.2Hz),5.17(2H,s).13C NMR(100MHz,DMSO-d6)δ161.8(d,J＝242.2Hz),159.1,150.9,148.6,146.2,142.8,133.0(d,J＝2.9Hz),130.6,130.1(d,J＝8.3Hz),126.3,123.7,117.6,116.8,115.3(d,J＝21.3Hz),115.0,114.5,109.0,102.2,68.7.
制备实施例3.42：4-((3’-氟苯基)氨基)-7-((3’-苯丙基)氧基)喹啉(化合物49)的合成
以4-氯-7-((3’-苯丙基)氧基)喹啉7l(1.5mmol)和间氟苯胺(8mmol)为原料，得白色固体(0.33g,59.1％)。Mp 190.1-192.1℃.1H NMR(400MHz,CDCl3)δ8.54(1H,d,J＝5.6Hz),7.81(1H,d,J＝9.2Hz),7.36–7.28(5H,m),7.24–7.18(3H,m),7.05–6.98(3H,m),6.85(1H,t,J＝8.0Hz),6.56(1H,s),4.13(2H,t,J＝6.4Hz),2.86(2H,t,J＝7.6Hz),2.23–2.16(2H,m).13C NMR(100MHz,CDCl3)δ164.9,162.5,159.8,151.17(d,J＝18.6Hz),147.0,142.25(d,J＝10.1Hz),132.8,131.00(d,J＝9.6Hz),128.6,121.5,118.8,118.4,117.34(d,J＝2.7Hz),115.0,111.0,110.8,109.3,109.0,108.8,102.4,69.1,32.4,30.9.
制备实施例3.43：4-((3’-甲氧基苯基)氨基)-7-((3’-苯丙基)氧基)喹啉(化合物50)的合成
以4-氯-7-((3’-苯丙基)氧基)喹啉7l(1.5mmol)和间甲氧基苯胺(8mmol)为原料，得棕色固体(0.30g,52.0％)。Mp 158.9-161.0℃.1H NMR(400MHz,CDCl3)δ8.44(d,J＝5.2Hz,1H,),7.85(d,J＝9.2Hz,1H,),7.34–7.28(m,5H,),7.24–7.15(m,3H,),6.92–6.86(m,3H,),6.73(d,J＝8.8Hz,1H,),4.11(t,J＝6.4Hz,2H,OCH2CH2CH2Ph),3.83(s,3H,OCH3),2.85(t,J＝7.6Hz,2H,OCH2CH2CH2Ph),2.21–2.14(m,2H,OCH2CH2CH2Ph).13C NMR(100MHz,CDCl3)δ160.9,160.2,151.3,151.1,147.4,141.6,141.5,130.6,128.7,128.6,126.2,121.2,118.5,114.7,114.6,109.9,109.0,108.2,101.9,67.4,55.6,32.4,30.9.
制备实施例3.44：4-((3’-硝基苯基)氨基)-7-((3’-苯丙基)氧基)喹啉(化合物51)的合成
以4-氯-7-((3’-苯丙基)氧基)喹啉7l(1.5mmol)和间硝基苯胺(8mmol)为原料，得黄色固体(0.26g,43.4％)。Mp 149.1-150.3℃.1H NMR(400MHz,CDCl3)δ8.60(1H,d,J＝5.2Hz),8.11(1H,s),7.96(1H,d,J＝8.0Hz),7.84(1H,d,J＝9.2Hz),7.59–7.52(2H,m),7.38(1H,s),7.33–7.27(2H,m),7.24–7.19(4H,m),7.01(1H,d,J＝5.2Hz),6.75(1H,s),4.12(2H,t,J＝6.4Hz),2.86(2H,t,J＝7.6Hz),2.24–2.14(2H,m).13C NMR(100MHz,DMSO-d6)δ159.5,151.0,148.6,146.0,142.8,141.4,130.6,128.4,126.2,125.9,123.6,117.5,116.7,115.0,114.4,108.5,102.2,67.0,31.5,30.3.
下表1示出了本发明化合物8-51编号与结构式和基本参数的对应关系。
表1.化合物8-51结构和基本参数
Figure PCTCN2017084929-appb-000006
Figure PCTCN2017084929-appb-000007
Figure PCTCN2017084929-appb-000008
Figure PCTCN2017084929-appb-000009
Figure PCTCN2017084929-appb-000010
Figure PCTCN2017084929-appb-000011
测试实施例1
体外抗肿瘤活性试验
本发明所述喹啉衍生物作为治疗癌症的药物的药理研究。所有测试的化合物在试验前均制备成盐酸盐形式，以临床上常用的抗肿瘤药物－顺铂和伯舒替尼作为阳性对照药物。
分别选用人直肠癌细胞系(HCT116)、人肝癌细胞系(HepG2)、人非小细胞肺癌细胞系(A549和NCI-H1650)、人卵巢癌细胞系(A2780)、人***细胞(Hela)、人胃癌细胞系(BGC-823)、等人肿瘤细胞系，采用MTT法进行测试。具体方法如下:按照标准培养方法培养各种细胞系，分别将生长状态良好、处于对数生长期的细胞系以5×104个/ml的浓度接种于96孔板，每孔接种160μl，随后将96孔板置于37℃、含5％CO2的培养箱中培养24小时，弃旧液，换新鲜培养液，加入灭菌处理的喹啉衍生物，继续培养48小时后，然后弃去培养液，每孔加20ul含5mg/ml MTT的RPMI-1640培养液，继续培养4小时，小心除去上清后，每孔加入200μl的DMSO，振荡约10min溶解沉淀，随后用酶标仪检测OD值，波长490nm。用下式求出每一样品浓度下的细胞存活率。
存活率％＝样品组平均OD值/对照组平均OD值×100％
以细胞存活率对药物浓度对数作图，按作图法求出每个样品的IC50值，结果见下表2。
表2.化合物8-51体外抗肿瘤活性评价结果(IC50,μM)
Figure PCTCN2017084929-appb-000012
Figure PCTCN2017084929-appb-000013
Figure PCTCN2017084929-appb-000014
制备实施例4：化合物9a-c的通用合成工艺
在100mL的圆底烧瓶中加入化合物6e(10mmol)和DMF(30ml)以及K2CO3(12mmol)，搅拌溶解，随后加入相应的卤化物(12mmol)，60℃搅拌2h，TLC跟踪至反应完毕。将反应混合液倒入冰水中，乙酸乙酯(EA)萃取3次，合并有机相，有机相水洗3次，饱和食盐水洗1次，无水硫酸钠干燥。过滤，减压浓缩至干，柱层析除去反应杂质，流动相分别为乙酸乙酯:石油醚＝8:1、乙酸乙酯:石油醚＝4:1，收集目标产物，减压浓缩至干，得化合物9a-c。
制备实施例4.1:4-氯-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉(9a)的合成
以4-氯-7-羟基喹啉6e(10mmol)和3,4,5-三甲氧基苄氯(12mmol)为原料，得白色固体(3.02g，产率:84.5％)。Mp:100.0-100.6℃.MS(ESI):m/z 359.90[M+H]+.1H NMR(400MHz,CDCl3)δ8.64(m,1H,ArH),8.13(m,1H,ArH),7.57(d,J＝4.8Hz,1H,ArH),7.54–7.46(m,1H,ArH),7.38(m,1H,ArH),6.72(s,2H,ArH),5.15(s,2H,PhCH2O-),3.89(s,6H,-OCH3),3.86(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ160.29,153.52,150.17,137.94,133.85,131.59,128.11,125.45,123.14,121.27,121.04,119.40,108.78,104.81(2C),70.67,60.86,56.18(2C).
制备实施例4.2：4-氯-7-((3’,4’-二甲氧基)苄氧基)喹啉(9b)的合成
以4-氯-7-羟基喹啉6e(10mmol)和3,4-二甲氧基苄氯(12mmol)为原料，得白色固体(2.53g，产率:77.8％)。Mp:124.5-125.8℃.MS(ESI):m/z 329.85[M+H]+.1H NMR(400MHz,CDCl3)δ8.64(dd,J＝18.0,9.2Hz,1H,ArH),8.12(dd,J＝18.0,9.2Hz,1H,ArH),7.56(d,J＝4.4Hz,1H,ArH),7.52(d,J＝7.2Hz,1H,ArH),7.39–7.35(m,1H,ArH),7.05(d,J＝8.4Hz,1H,ArH),7.02(s,1H,ArH),6.90(d,J＝8.0Hz,1H,ArH),5.15(s,2H,-OCH2Ph),3.92(s,3H,-OCH3),3.90(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ160.42,150.14,150.05,149.22,149.14,128.46,128.03,125.38,123.05,121.39,121.17,120.65,119.31,111.14,108.68,70.49,55.96,55.93.
制备实施例4.3：4-氯-7-((4-甲氧基)苄氧基)喹啉(9c)的合成
以4-氯-7-羟基喹啉6e(10mmol)和4-甲氧基苄氯(12mmol)为原料，得白色固体(2.59g，产率:86.6％)。Mp:120.8-122.2℃.MS(ESI):m/z 299.90[M+H]+.1H NMR(400MHz,CDCl3)δ8.63(dd,J＝18.4,9.2Hz,1H,ArH),8.10(dd,J＝18.4,9.2Hz,1H,ArH),7.54(d,J＝4.6Hz,1H,ArH),7.53-7.48(m,1H,ArH),7.42(d,J＝8.0Hz,2H,ArH),7.36–7.32(m,1H,ArH),6.94(d,J＝8.0Hz,2H,ArH),5.15(s,2H,-OCH2Ph),3.82(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ160.43,159.68,150.20,150.09,129.51(2C),128.11,127.99,125.33,123.01,121.40,121.17,119.26,114.12,108.70,70.18,55.32.
制备实施例5：化合物52-68的合成工艺
Figure PCTCN2017084929-appb-000015
制备实施例5.1：化合物52,53,56,57,58,62,63,66,68的通用合成工艺
在100mL的圆底烧瓶中加入4-氯-7-取代喹啉(1mmol)，丙酮(10mL)和相应的芳香胺(4mmol)，室温搅拌下滴加浓盐酸(15滴)，加热回流反应，TLC跟踪监测至反应完毕。反应液冷却至室温，转入500mL烧杯中，加入适量冰水，滴加氢氧化钠溶液调节pH至碱性，乙酸乙酯萃取3次，合并有机相，水及饱和食盐水洗各一次，无水硫酸钠干燥。过滤，减压浓缩至干，柱层析除去反应杂质，流动相PE：EA＝4：1、PE：EA＝3：1、PE：EA＝2：1洗脱，收集目标产物，减压浓缩至干。
制备实施例5.1.1：4-((3’-硝基苯基)氨基)-7-羟基喹啉(52)的合成
以4-氯-7-羟基喹啉6e(1mmol)与3-硝基苯胺(1.2mmol)为原料，得黄色固体(0.20g，产率:72.8％)。Mp:＞250℃.MS(ESI):m/z 281.90[M+H]+.1H NMR(400MHz,DMSO)δ10.18(s,1H,ArOH),9.29(s,1H,NH),8.43(d,J＝4.4Hz,1H,ArH),8.18(d,J＝8.8Hz,1H,ArH),8.11(s,1H,ArH),7.87(d,J＝8.0Hz,1H,ArH),7.78(d,J＝8.0Hz,1H,ArH),7.64(t,J＝8.0Hz,1H,ArH),7.19(s,1H,ArH),7.12(d,J＝9.2Hz,1H,ArH),6.99(s,1H,ArH).13C NMR(101MHz,DMSO)δ159.12,151.04,150.90,149.04,146.80,143.43,131.03,126.74,124.14,117.87,117.10,114.87,114.60,110.69,101.95.
制备实施例5.1.2：4-((3’-甲氧基苯基)氨基)-7-羟基喹啉(53)的合成
以4-氯-7-羟基喹啉6e(1mmol)与3-甲氧基苯胺(1.2mmol)为原料，得黄色固体(0.18g，产率:66.5％)。Mp:148.9-150.8℃.MS(ESI):m/z 266.95[M+H]+.1H NMR(400MHz,DMSO)δ9.08(s,1H,NH),8.33(d,J＝5.6Hz,1H,ArH),8.24(d,J＝8.8Hz,1H,ArH),7.32(t,J＝8.0Hz,1H,ArH),7.16(s,1H,ArH),7.09(d,J＝9.2Hz,1H,ArH),6.94(d,J＝8.0Hz,1H,ArH),6.90(s,1H,ArH),6.81(d,J＝5.6Hz,1H,ArH),6.73(d,J＝8.4Hz,1H,ArH),3.77(s,3H,-OCH3).13C NMR(101MHz,DMSO)δ160.58,159.47,149.89,149.83,148.87,142.08,130.55,124.29,117.59,114.92,113.65,109.80,109.69,108.47,100.57,55.55.
制备实施例5.1.3：4-((4’-硝基苯基)氨基)-7-((3’-苯基)丙氧基)喹啉(56)的合成
以4-氯-7-((3’-苯基)丙氧基)喹啉7l(1mmol)与4-硝基苯胺(1.2mmol)为原料，得黄色固体(0.23g，产率:58.3％)。Mp:131.6-133.5℃.MS(ESI):m/z 400.00[M+H]+.1H NMR(400MHz,CDCl3)δ8.64(d,J＝ 5.2Hz,1H,ArH),8.24(d,J＝8.8Hz,2H,ArH),7.87(d,J＝9.2Hz,1H,ArH),7.39(d,J＝2.0Hz,1H,ArH),7.33-7.28(m,4H,ArH),7.25–7.18(m,4H,ArH),7.17(d,J＝5.2Hz,1H,ArH),4.11(t,J＝6.4Hz,2H,-OCH2CH2CH2Ph),2.85(t,J＝7.6Hz,2H,-OCH2CH2CH2Ph),2.26–2.13(m,2H,-OCH2CH2CH2Ph).13C NMR(101MHz,DMSO)δ160.23,150.94,149.43,145.59,141.78,140.77,128.81(4C),126.32(2C),126.06(2C),124.78,118.51,118.12(2C),116.40,108.36,106.32,67
制备实施例5.1.4：4-((4’-三氟甲基苯基)氨基)-7-((3’–苯基)丙氧基)喹啉(57)的合成
以4-氯-7-((3’–苯基)丙氧基)喹啉7l(1mmol)与4-三氟甲基苯胺(1.2mmol)为原料，得白色固体(0.31g，产率:73.8％)。Mp:170.0-171.9℃.MS(ESI):m/z 423.00[M+H]+.1H NMR(400MHz,CDCl3)δ8.58(d,J＝5.2Hz,1H,ArH),7.84(d,J＝9.2Hz,1H,ArH),7.63(d,J＝8.4Hz,2H,ArH),7.39–7.27(m,5H,ArH),7.26–7.15(m,4H,ArH),7.06(d,J＝5.2Hz,1H,ArH),6.69(s,1H,NH),4.12(t,J＝6.2Hz,2H,-OCH2CH2CH2Ph),2.86(t,J＝7.6Hz,2H,-OCH2CH2CH2Ph),2.26–2.13(m,2H,-OCH2CH2CH2Ph).13C NMR(101MHz,CDCl3)δ160.21(s),151.14,151.01,146.06,144.00,141.31,128.48(2C),128.47(2C),127.34–126.71(m),126.01,125.54,125.22,124.90,121.40,120.13(2C),118.86,115.16,108.78,103.20,67.21,32.19,30.63.
制备实施例5.1.5：4-((3’-三氟甲基苯基)氨基)-7-((3’–苯基)丙氧基)喹啉(58)的合成
以4-氯-7-((3’–苯基)丙氧基)喹啉7l(1mmol)与3-三氟甲基苯胺(1.2mmol)为原料，得白色固体(0.34g，产率:80.4％)。Mp:162.5-164.9℃.MS(ESI):m/z 423.00[M+H]+.1H NMR(400MHz,CDCl3)δ8.54(d,J＝5.2Hz,1H,ArH),7.88(d,J＝9.2Hz,1H,ArH),7.57–7.45(m,3H,ArH),7.40(d,J＝7.2Hz,1H,ArH),7.36(d,J＝2.4Hz,1H,ArH),7.33–7.28(m,2H,ArH),7.27–7.14(m,4H,ArH),6.94(d,J＝5.6Hz,1H,ArH),4.09(t,J＝6.4Hz,2H,-OCH2CH2CH2Ph),2.85(t,J＝7.6Hz,2H,-OCH2CH2CH2Ph),2.24–2.14(m,2H,-OCH2CH2CH2Ph).13C NMR(101MHz,CDCl3)δ160.23,150.84,146.81,141.32,141.03,132.64-131.68(m),130.19,128.49(2C),128.46(2C),126.01,124.69,121.28,120.50,120.47,118.73,118.33,118.29,114.63,108.66,101.98,67.21,32.20,30.64.
制备实施例5.1.6：4-((3’-硝基苯基)氨基)-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉(62)的合成
以4-氯-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉9a(1mmol)与3-硝基苯胺(1.2mmol)为原料，得黄色固体(0.30g，产率:65.0％)。Mp:66.1-68.0℃.MS(ESI):m/z 462.00[M+H]+.1H NMR(400MHz,CDCl3)δ8.60(d,J＝5.1Hz,1H,ArH),8.12(s,1H,ArH),7.97(d,J＝8.0Hz,1H,ArH),7.90(d,J＝9.2Hz,1H,ArH),7.62–7.49(m,3H,ArH),7.30(s,1H,ArH),7.01(d,J＝5.2Hz,1H,ArH),6.72(s,2H,ArH),5.13(s,2H,-OCH2Ph),3.89(s,6H,-OCH3),3.86(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ159.86,153.42(2C),150.96,150.91,149.17,146.62,142.27,137.73,131.88,130.25,126.66,122.08,118.75,117.92,115.57,115.34,108.95,104.85(2C),102.77,70.37,60.86,56.12(2C).
制备实施例5.1.7：4-((3’-三氟甲基苯基)氨基)-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉(63)的合成
以4-氯-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉9a(1mmol)与3-三氟甲基苯胺(1.2mmol)为原料，得黄色固体(0.22g，产率:45.0％)。Mp:158.8-159.7℃.MS(ESI):m/z 484.95[M+H]+.1H NMR(400MHz,CDCl3)δ8.55(d,J＝5.2Hz,1H,ArH),7.90(d,J＝9.2Hz,1H,ArH),7.55-7.50(m,2H,ArH),7.48(d,J＝3.2Hz,1H,ArH),7.46(d,J＝2.4Hz,1H,ArH),7.39(d,J＝7.2Hz,1H,ArH),7.24(dd,J＝9.2,2.4Hz,1H,ArH),6.95(d,J＝5.2Hz,1H,ArH),6.70(s,2H,ArH),5.08(s,2H,-OCH2Ph),3.88(s,6H,-OCH3),3.86(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ159.74,153.46,151.12,151.95,147.01,141.18,137.81,132.56-131.59(m),130.92,130.12,128.80,124.73,121.74,120.39,120.35,118.55,118.38,118.35,109.15,104.85(2C),102.12, 70.37,60.84,56.12(2C).
制备实施例5.1.8：4-((3’-硝基苯基)氨基)-7-((4’-甲氧基)苄氧基)喹啉(66)的合成
以4-氯-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉9a(1mmol)与3-三氟甲基苯胺(1.2mmol)为原料，得黄色固体(0.27g，产率:67.5％)。Mp:197.0-197.8℃.MS(ESI):m/z 401.95[M+H]+.1H NMR(400MHz,DMSO)δ9.33(s,1H,NH),8.50(d,J＝4.8Hz,1H,ArH),8.25(d,J＝9.2Hz,1H,ArH),8.12(s,1H,ArH),7.88(dd,J＝8.1,1.5Hz,1H,ArH),7.79(d,J＝7.6Hz,1H,ArH),7.64(t,J＝8.0Hz,1H,ArH),7.46(d,J＝8.8Hz,2H,ArH),7.41(d,J＝2.0Hz,1H,ArH),7.28(dd,J＝9.2,2.4Hz,1H,ArH),7.07(d,J＝4.4Hz,1H,ArH),6.98(d,J＝8.4Hz,2H,ArH),5.20(s,2H,-OCH2Ph),3.77(s,3H,-OCH3).13C NMR(101MHz,DMSO)δ159.70,159.53,151.35,151.22,149.05,146.60,143.28,131.03,130.05(2C),129.03,126.70,124.04,118.12,117.16,115.47,114.87,114.31(2C),109.52,102.63,69.70,55.55.
制备实施例5.1.9：4-((3’-三氟甲基苯基)氨基)-7-((4’-甲氧基)苄氧基)喹啉(68)的合成
以4-氯-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉9a(1mmol)与3-三氟甲基苯胺(1.2mmol)为原料，得黄色固体(0.20g，产率:47.1％)。Mp:196.8-197.7℃.MS(ESI):m/z 425.00[M+H]+.1H NMR(400MHz,CDCl3)δ8.54(d,J＝5.6Hz,1H,ArH),7.86(d,J＝9.2Hz,1H,ArH),7.56–7.45(m,4H,ArH),7.44-7.38(m,3H,ArH),7.22(dd,J＝8.8,2.4Hz,1H,ArH),6.99–6.89(m,3H,ArH),5.11(s,2H,-OCH2Ph),3.82(s,3H,-OCH3).13C NMR(101MHz,DMSO)δ159.64,159.53,151.41,151.24,147.02,142.55,130.90,130.78,130.46,130.04,129.07,(125.90,124.78,123.99,123.20),119.43,119.40,117.93,117.66,117.63,115.29,114.31(2C),109.55,102.02,69.67,55.54.
制备实施例5.2:化合物54,55,59,60,61,64,65,67的通用合成工艺
在100mL的圆底烧瓶中加入相应的4-氯-7-取代喹啉1mmol，乙二醇单甲醚10mL和相应的含取代基的苯胺1.2mmol，吡啶盐酸盐1.5mmol，加热回流反应2h，TLC跟踪监测至反应完毕。反应液冷却转入500mL烧杯中，加入150mL水，调PH至碱性，DCM萃取3次，合并有机相，水洗1次，饱和食盐水洗1次，无水硫酸钠干燥。过滤，减压浓缩至干，柱层析除去反应杂质，用流动相PE：EA＝10：1、PE：EA＝5：1、PE：EA＝2：1洗脱，收集目标产物。
制备实施例5.2.1：4-((2’-甲氧基-5’-硝基苯基)氨基)-7-((3’–苯基)丙氧基)喹啉(54)的合成
以4-氯-7-((3’–苯基)丙氧基)喹啉7l(1mmol)与2-甲氧基-5-硝基苯基苯胺(1.2mmol)为原料，得黄色固体(0.36g，产率:83.7％)。Mp:139.5-141.4℃.MS(ESI):m/z 430.00[M+H]+.1H NMR(400MHz,CDCl3)δ8.65(d,J＝5.1Hz,1H,ArH),8.35(d,J＝2.4Hz,1H,ArH),7.97(m,1H,ArH),7.87(d,J＝9.2Hz,1H,ArH),7.40(d,J＝2.0Hz,1H,ArH),7.29(m,2H,ArH),7.24(m,2H,ArH),7.22–7.18(m,2H,ArH),7.07–6.95(m,2H,ArH),4.14(t,J＝6.2Hz,2H,-OCH2CH2CH2-),4.07(s,3H,OCH3),2.87(t,J＝7.6Hz,2H,-OCH2CH2CH2-Ph),2.25–2.15(m,2H,-OCH2CH2CH2-Ph).13C NMR(101MHz,CDCl3)δ160.20,154.08,151.22(2C),144.85,141.66,141.32,130.82,128.50(2C),128.47(2C),126.01,121.16,119.01,118.52,115.48,112.55,110.02,109.04,103.16,67.26,56.57,32.22,30.66.
制备实施例5.2.2：4-((2’-甲氧基-4’-硝基苯基)氨基)-7-((3’–苯基)丙氧基)喹啉(55)
以4-氯-7-((3’-甲氧基)丙氧基)喹啉9c(1mmol)与2-甲氧基-4-硝基苯基苯胺(1.2mmol)为原料，得黄色固体(0.26g，产率:61.2％)。Mp:165.4-166.9℃.MS(ESI):m/z 430.00[M+H]+.1H NMR(400MHz,CDCl3):δ8.70(d,J＝4.8Hz,1H,NH),7.93(d,J＝8.8Hz,1H,ArH),7.88(d,J＝9.2Hz,1H,ArH),7.85(s, 1H,ArH),7.45–7.39(m,2H,ArH),7.29(d,J＝7.6Hz,4H,ArH),7.22(m,J＝6.8Hz,4H,ArH),4.14(t,J＝6.4Hz,2H,-OCH2CH2CH2-),4.08(s,3H,OCH3),2.87(t,J＝7.6Hz,2H,-OCH2CH2CH2-Ph),2.21(dt,J＝13.8,6.8Hz,2H,-OCH2CH2CH2-Ph).13C NMR(100MHz,CDCl3)δ159.24,150.19,149.80(2C),146.53,142.65,140.11,139.99,136.43,127.33(2C),124.88,120.44,118.40,116.98,115.23,112.49,107.74,104.98,104.90,66.17,55.27,31.04,29.47,28.54.
制备实施例5.2.3：4-((3’,5’-二三氟甲基苯基)氨基)-7-((3’–苯基)丙氧基)喹啉(59)的合成
以4-氯-7-((3’–苯基)丙氧基)喹啉7l(1mmol)与3,5-二三氟甲基苯胺(1.2mmol)为原料，得黄色固体(0.35g，产率:71.4％)。Mp:171.6-172.8℃.MS(ESI):m/z 491.00[M+H]+.1H NMR(400MHz,CDCl3)δ8.63(d,J＝4.8Hz,1H,ArH),7.84(d,J＝9.2Hz,1H,ArH),7.66(s,2H,ArH),7.58(s,1H,ArH),7.39(s,1H,ArH),7.30(t,J＝7.4Hz,2H,ArH),7.25-7.17(m,4H,ArH),7.01(d,J＝4.8Hz,1H,ArH),6.79(s,1H,NH),4.12(t,J＝6.0Hz,2H,-OCH2CH2CH2Ph),2.86(t,J＝7.6Hz,2H-OCH2CH2CH2Ph),2.26–2.13(m,2H,-OCH2CH2CH2Ph).13C NMR(101MHz,CDCl3)δ160.42,151.21,151.02,145.66,142.71,141.27,(133.58,133.25,132.92,132.58(-CF3)2C),128.46(4C),126.02(2C),124.42,121.71,121.45,119.93,119.24,116.29,115.24,108.73,103.30,67.24,32.17,30.59.
制备实施例5.2.4：4-((4’–氨基苯基)氨基)-7-((3’–苯基)丙氧基)喹啉(60)的合成
以4-氯-7-((3’–苯基)丙氧基)喹啉7l(1mmol)与对苯二胺(1.2mmol)为原料，得黄色固体(0.21g，产率:58.1％)。Mp:193.8-194.1℃.MS(ESI):m/z 370.00[M+H]+.1H NMR(400MHz,DMSO)δ8.60(s,1H,NH),8.27(d,J＝8.8Hz,1H,ArH),8.23(d,J＝5.2Hz,1H),7.34–7.24(m,4H),7.20(d,J＝7.2Hz,1H,ArH),7.16(s,1H,ArH),7.12(d,J＝9.2Hz,1H,ArH),6.98(d,J＝8.0Hz,2H,ArH),6.65(d,J＝8.0Hz,2H,ArH),6.35(d,J＝5.6Hz,1H,ArH),5.09(s,2H,NH),4.09(t,J＝6.0Hz,2H,-OCH2CH2CH2Ph),2.80(t,J＝7.6Hz,2H,-OCH2CH2CH2Ph),2.14-2.04(m,2H,-OCH2CH2CH2Ph).13C NMR(101MHz,DMSO)δ159.58,151.11,150.86,150.40,146.85,141.84,128.82(4C),128.52,126.72(2C),126.32,123.77,116.61,115.01(2C),113.90,108.68,99.26,67.23,31.98,30.77.
制备实施例5.2.5：4-((3’–甲氧基苯基)氨基)-7-((3’,4’,5’–三甲氧基)苄氧基)喹啉(61)的合成
以4-氯-7-((3’,4’,5’–三甲氧基)苄氧基)喹啉9a(1mmol)与3-甲氧基苯胺(1.2mmol)为原料，得黄色固体(0.22g，产率:50.8％)。Mp:180.1-180.6℃.MS(ESI):m/z 447.00[M+H]+.1H NMR(400MHz,CDCl3)δ8.50(d,J＝5.2Hz,1H,ArH),7.87(d,J＝9.2Hz,1H,ArH),7.46(s,1H,NH),7.31(t,J＝8.0Hz,1H,ArH),7.23(d,J＝9.2Hz,1H,ArH),6.97(d,J＝5.2Hz,1H,ArH),6.88(d,J＝8.0Hz,1H,ArH),6.85(s,1H,ArH),6.74(s,1H,ArH),6.72(s,3H,ArH),5.11(s,2H,-OCH2Ph),3.89(s,6H,-OCH3),3.86(s,3H,-OCH3),3.82(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ160.69,159.57,153.44(2C),151.13,150.77,147.54,141.29,137.75,131.98,130.37,121.48,118.21,114.70,114.59,109.69,109.15,108.14,104.80(2C),101.81,70.38,60.87,56.14(2C),55.35.
制备实施例5.2.6：4-((3’,5’–二三氟甲基苯基)氨基)-7-((3’,4’,5’–三甲氧基)苄氧基)喹啉(64)的合成
以4-氯-7-((3’,4’,5’–三甲氧基)苄氧基)喹啉9a(1mmol)与3’,5’–二三氟甲基苯胺(1.2mmol)为原料，得黄色固体(0.26g，产率:47.1％)。Mp:70.6-72.4℃.MS(ESI):m/z 553.05[M+H]+.1H NMR(400MHz,CDCl3)δ8.64(d,J＝5.2Hz,1H,ArH),7.87(d,J＝9.2Hz,1H,ArH),7.68(s,2H,ArH),7.58(s,1H,ArH),7.50(d,J＝2.0Hz,1H,ArH),7.29(d,J＝2.4Hz,1H,ArH),7.03(d,J＝5.2Hz,1H,ArH),6.72(s,2H,ArH),5.12(s,2H,-OCH2Ph),3.89(s,6H,-OCH3),3.86(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ159.97,153.46(2C),151.06(2C),145.86,142.74,137.79,(133.52,133.19,132.86,132.53(2C)),131.85,124.43,121.76(2C),120.04,119.12(2C),116.28,115.51,109.12,104.93(2C),103.38,70.46,60.87,56.12(2C).
制备实施例5.2.7：4-((3’–甲氧基苯基)氨基)-7-((3’,4’–二甲氧基)苄氧基)喹啉(65)的合成
以4-氯-7-((3’,4’–二甲氧基)苄氧基)喹啉(1mmol)9b与间甲氧基苯胺(1.2mmol)为原料，得黄色固体(0.30g，产率:71.1％)。Mp:172.1-174.0℃.MS(ESI):m/z 417.00[M+H]+.1H NMR(400MHz,CDCl3)δ8.47(d,J＝5.2Hz,1H,ArH),7.86(d,J＝9.2Hz,1H,ArH),7.50(s,1H,ArH),7.32(t,J＝8.0Hz,1H,ArH),7.22(d,J＝8.8Hz,1H,ArH),7.07-7.00(m,2H,ArH),6.95(d,J＝5.2Hz,1H,ArH),6.89(d,J＝8.0Hz,2H,ArH),6.86(s,1H,ArH),6.74(d,J＝8.0Hz,1H,ArH),5.13(s,2H,-OCH2Ph),3.92(s,3H,-OCH3),3.90(s,3H,-OCH3),3.83(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ160.73,159.79,150.71,150.46,149.19,149.06,147.65,141.21,130.38,128.82,121.39,120.64,118.41,114.61,114.52,111.21,111.17,109.82,108.97,108.18,101.72,70.24,55.95,55.92,55.36.
制备实施例5.2.8：4-((3’–甲氧基苯基)氨基)-7-((4’–甲氧基)苄氧基)喹啉(67)的合成
以4-氯-7-((3’–甲氧基)苄氧基)喹啉9c(1mmol)与间甲氧基苯胺(1.2mmol)为原料，得黄色固体(0.32g，产率:57.0％)。Mp:191.4-192.4℃.MS(ESI):m/z 386.95[M+H]+.1H NMR(400MHz,CDCl3)δ8.50(d,J＝5.2Hz,1H,ArH),7.84(d,J＝9.2Hz,1H,ArH),7.46(s,1H,NH),7.41(d,J＝8.4Hz,2H,ArH),7.30(t,J＝8.0Hz,1H,ArH),7.20(d,J＝8.8Hz,1H,ArH),7.02–6.90(m,3H,ArH),6.87(d,J＝8.0Hz,1H,ArH),6.84(s,1H,ArH),6.72(d,J＝8.4Hz,2H,ArH),5.11(s,2H,-OCH2Ph),3.82(s,6H,-OCH3).13C NMR(101MHz,DMSO)δ160.58,159.51,159.48,151.34,151.14,147.89,142.45,130.51,130.05(2C),129.11,123.99,117.49,114.96,114.51,114.31(2C),109.50,109.42,108.04,101.49,69.62,55.56,55.54.
Figure PCTCN2017084929-appb-000016
制备实施例6：化合物69-81的通用合成工艺
在100mL的圆底烧瓶中加入4-氯-7-取代喹啉1mmol，DMF(10mL)和相应的苯硫酚1mmol，密封，室温搅拌下反应，TLC跟踪监测至反应完毕。反应液冷却转入500mL烧杯中，加入150mL水，调PH至碱性，DCM萃取3次，合并有机相，水洗3-5次，饱和食盐水洗1次，无水硫酸钠干燥。过滤，减 压浓缩至干，柱层析除去反应杂质，用流动相PE：EA＝6：1、PE：EA＝3：1、PE：EA＝2：1洗脱，收集目标产物。
制备实施例6.1：4-苯硫基-7–甲氧基喹啉(69)的合成
以4-氯-7甲氧基喹啉7d(1mmol)与苯硫酚(1mmol)为原料，得白色固体(0.21g，产率:78.6％)。Mp:111.6-112.0℃.MS(ESI):m/z 267.85[M+H]+.1H NMR(400MHz,CDCl3)δ8.49(d,J＝4.8Hz,1Hc),8.11(d,J＝9.2Hz,1H,ArH),7.58(m,2H,ArH),7.47(m,3H,ArH),7.40(d,J＝2.4Hz,1H,ArH),7.24(dd,J＝9.2,2.8Hz,1H,ArH),6.65(d,J＝4.8Hz,1H,ArH),3.96(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ160.85,149.74,149.52,148.17,135.11(2C),129.95(2C),129.88,129.51,124.73,121.15,119.47,116.33,107.82,55.55.
制备实施例6.2：4-(2’-氨基苯硫基)-7–((3’-苯基)丙氧基)喹啉(70)的合成
以4-氯-7-((3’–苯基)丙氧基)喹啉7l(1mmol)与邻氨基苯硫酚(1mmol)为原料，得黄色固体(0.28g，产率:72.5％)。Mp:184.9-186.2℃.MS(ESI):m/z 386.95[M+H]+.1H NMR(400MHz,CDCl3)δ8.40(d,J＝5.2Hz,1H,ArH),7.62(d,J＝7.6Hz,1H,ArH),7.37–7.28(m,5H,ArH),7.25–7.20(m,3H,ArH),7.16(t,J＝7.6Hz,1H,ArH),7.05(d,J＝8.8Hz,1H,ArH),6.89(t,J＝7.6Hz,1H,ArH),6.83(d,J＝5.2Hz,1H,ArH),4.12(t,J＝6.4Hz,2H,-OCH2CH2CH2Ph),2.87(t,J＝7.6Hz,2H,-OCH2CH2CH2Ph),2.25–2.15(m,2H,-OCH2CH2CH2Ph).13C NMR(101MHz,CDCl3)δ160.04,150.93,150.84,145.35,142.07,141.33,136.56,131.22,128.53(2C),128.49(2C),126.09,126.03,123.28,121.08,119.48,118.70,115.23,108.73,102.37,67.22,32.23,30.67.
制备实施例6.3：4-(3’-氨基苯硫基)-7–((3’-苯基)丙氧基)喹啉(71)的合成
以4-氯-7-((3’–苯基)丙氧基)喹啉7l(1mmol)与间氨基苯硫酚(1mmol)为原料，得黄色固体(0.34g，产率:88.0％)。Mp:110.5-110.8℃.MS(ESI):m/z 386.95[M+H]+.1H NMR(400MHz,CDCl3)δ8.49(d,J＝4.8Hz,1H,ArH),8.09(d,J＝9.2Hz,1H,ArH),7.35(s,1H,ArH),7.30(d,J＝7.2Hz,1H,ArH),7.27–7.17(m,6H,ArH),6.95(d,J＝7.6Hz,1H,ArH),6.87(s,1H,ArH),6.76(d,J＝5.2Hz,2H,ArH),4.12(t,J＝6.2Hz,2H,-OCH2CH2CH2Ph),3.79(s,2H,NH),2.86(t,J＝7.8Hz,2H,-OCH2CH2CH2Ph),2.23–2.15(m,2H,-OCH2CH2CH2Ph).13C NMR(101MHz,CDCl3)δ160.23,149.70,149.41,148.37,147.81,141.35,130.67,130.46,128.53,128.51,128.48,126.02,124.78,124.75,121.15,120.85,119.64,116.40,116.11,108.42,67.23,32.22,30.67,29.73.
制备实施例6.4：4-(3’-甲氧基苯硫基)-7–((3’-苯基)丙氧基)喹啉(72)的合成
以4-氯-7-((3’–苯基)丙氧基)喹啉7l(1mmol)与间甲氧基苯硫酚(1mmol)为原料，得白色固体(0.34g，产率:84.7％)。Mp:73.1-75.0℃.MS(ESI):m/z 402.05[M+H]+.1H NMR(400MHz,CDCl3)δ8.50(d,J＝4.8Hz,1H,ArH),8.10(d,J＝9.2Hz,1H,ArH),7.37(t,J＝7.8Hz,2H,ArH),7.29(m,3H,ArH),7.21m,3H,ArH),7.15(d,J＝7.6Hz,1H,ArH),7.10(s,1H,ArH),7.00(d,J＝8.0Hz,1H,ArH),6.72(d,J＝4.8Hz,1H,ArH),4.12(t,J＝6.2Hz,2H,-OCH2CH2CH2Ph),3.81(s,3H,-OCH3),2.89–2.83(m,2H,-OCH2CH2CH2Ph),2.25–2.13(m,2H,-OCH2CH2CH2Ph).13C NMR(101MHz,CDCl3)δ160.49,160.26,149.77,149.56,147.82,141.33,131.04,130.70,128.53(2C),128.49(2C),127.08,126.03,124.73,121.18,119.83,119.76,116.54,115.50,108.53,67.23,55.45,32.23,30.67.
制备实施例6.5：4-(4’-氟基苯硫基)-7–((3’-苯基)丙氧基)喹啉(73)的合成
以4-氯-7-((3’–苯基)丙氧基)喹啉7l(1mmol)与对氟苯硫酚(1mmol)为原料，得白色固体(0.35g，产率:89.2％)。Mp:108.3-109.5℃.MS(ESI):m/z 389.95[M+H]+.1H NMR(400MHz,CDCl3)δ8.49(d,J＝4.8 Hz,1H,ArH),8.09(d,J＝9.2Hz,1H,ArH),7.58(dd,J＝8.2,5.4Hz,2H,ArH),7.38(s,1H,ArH),7.34–7.26(m,3H,ArH),7.21(dd,J＝5.6,2.8Hz,5H,ArH),6.58(d,J＝4.8Hz,1H,ArH),4.13(t,J＝6.4Hz,2H,-OCH2CH2CH2Ph),2.86(t,J＝7.6Hz,2H-OCH2CH2CH2Ph),2.26–2.13(m,2H,-OCH2CH2CH2Ph).13C NMR(101MHz,CDCl3)δ164.95,162.45,160.34,149.69,149.49,148.29,141.32,(137.61,137.52),128.54(2C),128.50,126.04,124.90,126.86,124.52,120.87,119.81,117.41,117.19,115.71,108.54,67.26,32.22,30.66.
制备实施例6.6：4-(3’-羟基苯硫基)-7–((3’-苯基)丙氧基)喹啉(74)的合成
以4-氯-7-((3’–苯基)丙氧基)喹啉7l(1mmol)与间羟基苯硫酚(1mmol)为原料，得白色固体(0.23g，产率:59.4％)。Mp:194.8-196.2℃.MS(ESI):m/z 387.95[M+H]+.1H NMR(400MHz,DMSO)δ9.92(s,1H,ArOH),8.57(d,J＝4.4Hz,1H,ArH),8.07(d,J＝9.2Hz,1H,ArH),7.49–7.23(m,7H,ArH),7.19(t,J＝6.8Hz,1H,ArH),7.01(d,J＝7.6Hz,1H,ArH),6.85-6.98(m,2H,ArH),6.77(d,J＝4.4Hz,1H,ArH),4.15(t,J＝6.0Hz,2H,-OCH2CH2CH2Ph),2.80(t,J＝7.6Hz,2H,-OCH2CH2CH2Ph),2.17–2.05(m,2H,-OCH2CH2CH2Ph).13C NMR(101MHz,DMSO)δ160.23,159.01,150.53,149.61,146.89,141.76,131.61,130.22,128.81(4C),126.32,125.26,125.03,121.16,120.76,120.05,117.36,116.98,109.08,67.60,31.95,30.68.
制备实施例6.7：4-(3’-羟基苯硫基)-7–((3’,4’,5’-三甲氧基)苄氧基)喹啉(75)的合成
以4-氯-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉9a(1mmol)与间羟基苯硫酚(1mmol)为原料，得白色固体(0.39g，产率:86.7％)。Mp:173.2-174.1℃.MS(ESI):m/z 449.95[M+H]+.1H NMR(400MHz,CDCl3)δ8.27(d,J＝4.8Hz,1H,ArH),8.04(d,J＝9.6Hz,1H,ArH),7.45(s,1H,ArH),7.36(t,J＝8.0Hz,1H,ArH),7.30(s,1H,ArH),7.11(d,J＝7.6Hz,1H,ArH),7.05(d,J＝8.0Hz,1H,ArH),6.86-6.81(m,2H,ArH),6.70(s,2H,ArH),5.08(s,2H,-OCH2Ph),3.87(s,6H,-OCH3),3.83(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ160.33,158.90,153.46(2C),150.07,148.13,147.87,137.83,131.55,131.15,129.77,125.30,124.96,121.35,121.06,120.21,118.18,116.09,107.43,104.91(2C),70.61,60.86,56.13(2C).
制备实施例6.8：4-(4’-氟苯硫基)-7–((3’,4’,5’-三甲氧基)苄氧基)喹啉(76)的合成
以4-氯-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉9a(1mmol)与对氟苯硫酚(1mmol)为原料，得黄色固体(0.41g，产率:90.9％)。Mp:120.7-121.1℃.MS(ESI):m/z 452.00[M+H]+.1H NMR(400MHz,CDCl3)δ8.50(d,J＝4.8Hz,1H,ArH),8.11(d,J＝9.2Hz,1H,ArH),7.61-7.55(m,2H,ArH),7.49(s,1H,ArH),7.33(dd,J＝9.2,1.2Hz,1H,ArH),7.18(t,J＝8.4Hz,2H,ArH),6.72(s,2H,ArH),6.59(d,J＝4.8Hz,1H,ArH),5.15(s,2H,-OCH2-),3.89(s,6H,-OCH3),3.86(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ164.94,162.44,159.88,153.49(2C),149.75,149.33,148.44,137.86,(137.62,137.54),131.81,124.69,124.64,121.04,119.76,117.42,117.20,115.81,109.08,104.79(2C),70.50,60.84,56.15(2C).
制备实施例6.9：4-(3’-甲氧基苯硫基)-7–((3’,4’,5’-三甲氧基)苄氧基)喹啉(77)的合成
以4-氯-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉9a(1mmol)与间甲氧基苯硫酚(1mmol)为原料，得黄色固体(0.44g，产率:95.6％)。Mp:106.7-108.2℃.MS(ESI):m/z 463.95[M+H]+.1H NMR(400MHz,CDCl3)δ8.52(d,J＝4.8Hz,1H,ArH),8.13(d,J＝9.2Hz,1H,ArH),7.49(d,J＝1.6Hz,1H,ArH),7.41–7.30(m,2H,ArH),7.15(d,J＝7.6Hz,1H,ArH),7.10(s,1H,ArH),7.01(d,J＝8.0Hz,1H,ArH),6.77–6.70(m,3H,ArH),5.14(s,2H,-OCH2-),3.89(s,6H,-OCH3),3.86(s,3H,-OCH3),3.81(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ160.51,159.86,153.50,149.77,149.35,148.12,137.86,131.83,130.82,130.74,127.12,124.88,121.36,119.91,119.77,116.64,115.54,109.03,104.79(3C),70.51,60.86,56.17(2C),55.45.
制备实施例6.10：4-(3’-氨基苯硫基)-7–((3’,4’,5’-三甲氧基)苄氧基)喹啉(78)的合成
以4-氯-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉9a(1mmol)与间氨基苯硫酚(1mmol)为原料，得黄色固体(0.29g，产率:64.6％)。Mp:60.1-61.8℃.MS(ESI):m/z 448.95[M+H]+.1H NMR(400MHz,CDCl3)δ8.51(d,J＝4.8Hz,1H,ArH),8.12(d,J＝9.2Hz,1H,ArH),7.48(d,J＝1.6Hz,1H,ArH),7.31(dd,J＝9.2,2.0Hz,1H,ArH),7.26-7.20(m,1H,ArH),6.95(d,J＝7.6Hz,1H,ArH),6.88(s,1H,ArH),6.81–6.75(m,2H,ArH),6.72(s,2H,ArH),5.14(s,2H,-OCH2-),3.89(s,6H,-OCH3),3.86(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ159.79,153.48(2C),149.75,149.26,148.59,147.89,137.82,131.89,130.69,130.24,124.89,124.74,121.33,120.85,119.62,116.50,116.16,108.97,104.80(2C),70.48,60.86,56.17(2C).
制备实施例6.11：4-(3’-甲氧基苯硫基)-7–((3’,4’–二甲氧基)苄氧基)喹啉(79)的合成
以4-氯-7-((3’,4’-二甲氧基)苄氧基)喹啉9b(1mmol)与间甲氧基苯硫酚(1mmol)为原料，得黄色固体(0.39g，产率:90.2％)。Mp:186.9-187.9℃.MS(ESI):m/z 433.95[M+H]+.1H NMR(400MHz,CDCl3)δ8.38-8.31(m,2H,ArH),8.23(d,J＝9.2Hz,1H,ArH),7.58–7.46(m,2H,ArH),7.23(d,J＝7.6Hz,1H,ArH),7.16(t,J＝10.0Hz,3H,ArH),7.06(s,1H,ArH),6.93(d,J＝8.4Hz,1H,ArH),6.82(d,J＝6.0Hz,1H,ArH),5.27(s,2H,-OCH2Ph),3.95(s,3H,-OCH3),3.90(s,3H,-OCH3),3.87(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ163.55,162.96,161.16,149.35,149.14,139.33,139.14,131.87,127.78,127.05,126.13,124.99,123.36,121.38,120.87,120.27,117.50,113.31,111.60,111.20,101.11,71.50,56.10,55.93,55.66.
制备实施例6.12：4-(3’-甲氧基苯硫基)-7–((4’–甲氧基)苄氧基)喹啉(80)的合成
以4-氯-7-((4’-甲氧基)苄氧基)喹啉9c(1mmol)与间甲氧基苯硫酚(1mmol)为原料，得白色固体(0.39g,产率:96.7％)。Mp:127.1-127.7℃.MS(ESI):m/z 403.9[M+H]+.1H NMR(400MHz,CDCl3)δ8.51(d,J＝4.8Hz,1H,ArH),8.11(d,J＝9.2Hz,1H,ArH),7.49(d,J＝1.6Hz,1H,ArH),7.42(d,J＝8.4Hz,2H,ArH),7.37(t,J＝8.0Hz,1H,ArH),7.29(dd,J＝9.2,2.0Hz,1H,ArH),7.15(d,J＝7.6Hz,1H,ArH),7.10(s,1H,ArH),7.00(d,J＝8.4Hz,1H,ArH),6.94(d,J＝8.4Hz,2H,ArH),6.73(d,J＝4.8Hz,1H,ArH),5.14(s,2H,-OCH2Ph),3.82(s,3H,-OCH3),3.81(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ160.49,160.00,159.63,149.79,149.49,147.86,130.99,130.70,129.50(2C),128.35,127.08,124.80,121.29,119.89,119.84,116.63,115.49,114.10(2C),109.05,70.03,55.43,55.31.
制备实施例6.13：4-(3’-氨基苯硫基)-7–((4’–甲氧基)苄氧基)喹啉(81)的合成
以4-氯-7-((4’-甲氧基)苄氧基)喹啉9c(1mmol)与间氨基苯硫酚(1mmol)为原料，得黄色固体(0.32g,产率:82.3％)。Mp:186.9-188.7℃.MS(ESI):m/z 388.9[M+H]+.1H NMR(400MHz,DMSO)δ8.74(d,J＝6.4Hz,1H,ArH),8.32(d,J＝9.2Hz,1H,ArH),7.67(s,1H,ArH),7.62(d,J＝9.2Hz,1H,ArH),7.49(d,J＝8.4Hz,2H,ArH),7.33(t,J＝7.8Hz,1H,ArH),6.99(d,J＝8.0Hz,2H,ArH),6.95-6.85(m,4H,ArH),5.29(s,2H,-OCH2Ph),3.77(s,3H,-OCH3).13C NMR(101MHz,DMSO)δ162.85,160.66,159.82,149.58,143.39,140.11,131.85,130.54(2C),127.79,126.20,125.94,123.63,122.32,120.97,119.98,117.99,114.65,114.41(2C),102.65,70.66,55.62.
Figure PCTCN2017084929-appb-000017
制备实施例7：化合物82-87的通用合成工艺
在100mL的圆底烧瓶中加入4-氯-7-取代喹啉1mmol，二甲苯10mL和相应的含取代基的苯酚1.2mmol，4-二甲氨基吡啶0.25mmol(DMAP)，搅拌回流反应2h，TLC跟踪监测至反应完毕。反应液冷却转入500mL烧杯中，加入150mL水，调PH至碱性，DCM萃取3次，合并有机相，水洗3-5次，饱和食盐水洗1次，无水硫酸钠干燥。过滤，减压浓缩至干，柱层析除去反应杂质，用流动相PE：EA＝6：1、PE：EA＝3：1、PE：EA＝2：1洗脱，收集目标产物。
制备实施例7.1：4-(4’-硝基苯氧基)-7–正丁氧基喹啉(82)的合成
以4-氯-7–正丁氧基喹啉7h(1mmol)和对硝基苯酚(1.2mmol)为原料，得白色固体(0.28g,产率:82.8％)。Mp:99.8-101.8℃.MS(ESI):m/z 338.95[M+H]+.1H NMR(400MHz,CDCl3)δ8.72(d,J＝5.2Hz,1H,ArH),8.31(d,J＝9.1Hz,2H,ArH),8.06(d,J＝9.2Hz,1H,ArH),7.46(d,J＝1.9Hz,1H,ArH),7.26(s,1H,ArH),7.23(dd,J＝5.6,2.4Hz,2H,ArH),6.67(d,J＝5.1Hz,1H,ArH),4.15(t,J＝6.8Hz,2H,-OCH2CH2-),1.90–1.82(m,2H,-CH2CH2CH2-),1.55(m,2H,CH3CH2CH2-),1.01(t,J＝7.2Hz,3H,CH3CH2-).13C NMR(101MHz,CDCl3)δ161.14,160.64,159.46,152.21,151.35,144.29,126.16(2C),122.57,120.35,119.71(2C),116.28,107.98,105.54,68.09,31.04,19.27,13.83.
制备实施例7.2：4-(3’-硝基苯氧基)-7–((3’-苯基)丙氧基)喹啉(83)的合成
以4-氯-7-((3’–苯基)丙氧基)喹啉7l(1mmol)与间硝基苯酚(1.2mmol)为原料，得白色固体(0.28g，产率:63.4％)。Mx:61.2-62.4℃.MS(ESI):m/z 400.90[M+H]+.1H NMR(400MHz,CDCl3)δ8.66(d,J＝5.2Hz,1H,ArH),8.19–8.11(m,2H,ArH),8.03(t,J＝2.2Hz,1H,ArH),7.63(t,J＝8.2Hz,1H,ArH),7.54–7.49(m,1H,ArH),7.41(d,J＝2.0Hz,1H,ArH),7.33–7.28(m,2H,ArH),7.26(d,J＝1.7Hz,1H,ArH),7.25(d,J＝1.6Hz,1H,ArH),7.23(s,1H,ArH),7.22–7.15(m,1H,ArH),6.52(d,J＝5.2Hz,1H,ArH),4.14(t,J＝6.4Hz,2H,-OCH2CH2CH2Ph),2.87(t,J＝7.6Hz,2H,-OCH2CH2CH2Ph),2.25–2.17(m,2H,-OCH2CH2CH2Ph).13C NMR(101MHz,CDCl3)δ160.97,160.38,155.57,152.03,151.37,149.49,141.28,130.91,128.51(2C),128.48(2C),126.57,126.04,122.66,120.02(2C),116.07,115.78,108.04,103.97,67.31,32.21,30.63.
制备实施例7.3：4-(3’-甲氧基苯氧基)-7–((3’,4’,5’-三甲氧基)苄氧基)喹啉(84)的合成
以4-氯-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉9a(1mmol)与间甲氧基苯酚(1.2mmol)为原料，得粉色固体(0.20g，产率:44.7％)。Mp:144.7-146.2℃.MS(ESI):m/z 447.95[M+H]+.1H NMR(400MHz,CDCl3)δ 8.61(d,J＝5.2Hz,1H,ArH),8.26(d,J＝9.2Hz,1H,ArH),7.51(s,1H,ArH),7.38–7.29(m,2H,ArH),6.84(d,J＝8.0Hz,1H,ArH),6.80–6.71(m,4H,ArH),6.52(d,J＝5.2Hz,1H,ArH),5.16(s,2H,-OCH2-),3.90(s,6H,,-OCH3),3.86(s,3H,-OCH3),3.82(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ161.69,161.22,160.23,155.45,153.49,151.57,137.82,131.92,130.63,123.20,119.31,116.41,112.99,111.26,108.37,106.91,104.76(4C),103.33,70.45,60.86,56.16(2C),55.49.
制备实施例7.4：4-(4’-硝基基苯氧基)-7–((3’,4’,5’-三甲氧基)苄氧基)喹啉(85)的合成
以4-氯-7-((3’,4’,5’-三甲氧基)苄氧基)喹啉9a(1mmol)与对硝基苯酚(1.2mmol)为原料，得粉色固体(0.26g，产率:56.2％)。Mp:70.8-78.9℃.MS(ESI):m/z 462.95[M+H]+.1H NMR(400MHz,DMSO)δ8.77-8.67(m,1H,ArH),8.35(d,J＝9.0Hz,2H,ArH),8.12-8.00(m,1H,ArH),7.58(s,1H,ArH),7.51–7.37(m,3H,ArH),6.90–6.86(m,2H,ArH),5.23(s,2H,-OCH2-),3.80(s,6H,-OCH3),3.67(s,3H,-OCH3).13C NMR(101MHz,DMSO)δ160.68,160.38,159.18,153.43,152.47,151.97,144.37,137.63,132.51,126.77(2C),123.16,120.60,120.48(2C),120.33,116.25,109.25,106.61,105.80(2C),70.34,60.47,56.36(2C).
制备实施例7.5：4-(3’-硝基苯氧基)-7–((3’,4’–二甲氧基)苄氧基)喹啉(86)的合成
以4-氯-7-((3’,4’–二甲氧基)苄氧基)喹啉9b(1mmol)与间硝基苯酚(1.2mmol)为原料，得粉色固体(0.30g，产率:69.4％)。Mp:143.7-144.5℃.MS(ESI):m/z 432.95[M+H]+.1H NMR(400MHz,CDCl3)δ8.69(d,J＝5.2Hz,1H,ArH),8.18(d,J＝9.6Hz,1H,ArH),8.15(d,J＝8.4Hz,1H,ArH),8.04(s,1H,ArH),7.64(t,J＝8.2Hz,1H,ArH),7.58–7.49(m,2H,ArH),7.32(d,J＝8.8Hz,1H,ArH),7.10–7.02(m,2H,ArH),6.90(d,J＝8.0Hz,1H,ArH),6.54(d,J＝5.2Hz,1H,ArH),5.17(s,2H,-OCH2Ph),3.93(s,3H,-OCH3),3.90(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ160.67,160.43,155.51,151.91,151.42,149.48,149.23,149.13,130.95,128.62,126.62,122.79,120.65,120.14,120.07,116.24,115.80,111.18(2C),108.53,104.06,70.38,55.97,55.94.
制备实施例7.6：4-(3’-硝基苯氧基)-7–((4’-三甲氧基)苄氧基)喹啉(87)的合成
以4-氯-7-((4’–甲氧基)苄氧基)喹啉9c(1mmol)与间硝基苯酚(1.2mmol)为原料，得粉色固体(0.25g，产率:62.5％)。Mp:℃.MS(ESI):m/z 402.90[M+H]+.1H NMR(400MHz,CDCl3)δ8.68(d,J＝5.2Hz,1H,ArH),8.15(t,J＝9.2Hz,2H,ArH),8.03(s,1H,ArH),7.63(t,J＝8.2Hz,1H,ArH),7.57–7.49(m,2H,ArH),7.43(d,J＝8.4Hz,2H,ArH),7.30(d,J＝8.8Hz,1H,ArH),6.95(d,J＝8.0Hz,2H,ArH),6.53(d,J＝5.2Hz,1H,ArH),5.17(s,2H,-OCH2Ph),3.83(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ160.67,160.37,159.65,155.49,151.94,151.42,149.44,130.93,129.49(2C),128.21,126.61,122.75,120.13,120.03,116.18,115.78,114.10(2C),108.53,104.02,70.07,55.31.
Figure PCTCN2017084929-appb-000018
制备实施例8：化合物88的通用合成工艺
在100mL的圆底烧瓶中加入四氢呋喃10mL、3,4,5-三甲氧基苄醇(4mmol,0.79g)、60％的NaH粉末(5mmol,0.2g)，室温下搅拌30min，再加入碘化钾(1.5mmol,0.25g)、7-((3’,4’,5’-三甲氧基)苄氧基)-4氯喹啉9a(1mmol,0.36g)，搅拌回流反应4h，TLC跟踪监测至反应完毕。反应液冷却转入500mL烧杯中，加入150mL水，乙酸乙酯萃取3次，合并有机相，水洗3-5次，饱和食盐水洗1次，无水硫酸钠干燥。过滤，减压浓缩至干，柱层析除去反应杂质，用流动相PE：EA＝6：1、PE：EA＝3：1、PE：EA＝2：1洗脱，收集目标产物，得0.25g白色固体，产率49.9％。
制备实施例8.1：4,7-二((3’,4’,5’-三甲氧基)苄氧基)喹啉(88)的合成
以7–((3’,4’,5’-三甲氧基)苄氧基)喹啉(1mmol)与3,4,5-三甲氧基苯甲醇(4mmol)为原料，得粉色固体(0.25g，产率:49.9％)。Mp:44.2-44.6℃.MS(ESI):m/z 522.05[M+H]+.1H NMR(400MHz,CDCl3)δ8.72(d,J＝5.2Hz,1H,ArH),8.21(d,J＝9.2Hz,1H,ArH),7.50(s,1H,ArH),7.30(d,J＝6.0Hz,1H,ArH),6.75(s,5H,ArH),5.23(s,2H,-OCH2Ph),5.17(s,2H,-OCH2Ph),3.92(s,15H,-OCH3),3.89(s,3H,-OCH3).13C NMR(101MHz,CDCl3)δ161.37,160.00,153.52(2C),153.44(2C),151.78,151.03,138.01,137.76,131.96,131.31,123.29,118.68,116.24,108.36,104.76(4C),100.02,70.57,70.39,60.88,60.83,56.19(2C),56.13(2C).
测试实施例2
体外抗肿瘤活性试验
本测试实施例中，所有测试的化合物在试验前均制备成盐酸盐形式，以临床上常用的抗肿瘤药物－顺铂和伯舒替尼作为阳性对照药物。
分别选用人直肠癌细胞系(HCT116)、人肝癌细胞系(HepG2)、人非小细胞肺癌细胞系(A549)、人卵巢癌细胞系(A2780)、人胃癌细胞系(BGC-823)、等人肿瘤细胞系，采用MTT法进行测试。具体方法如下:按照标准培养方法培养各种细胞系，分别将生长状态良好、处于对数生长期的细胞系以5×104个/ml的浓度接种于96孔板，每孔接种160μl，随后将96孔板置于37℃、含5％CO2的培养箱中培养24小时，弃旧液，换新鲜培养液，加入灭菌处理的喹啉衍生物，继续培养48小时后，然后弃去培养液，每孔加20ul含5mg/ml MTT的RPMI-1640培养液，继续培养4小时，小心除去上清后，每孔加入200μl的DMSO，振荡约10min溶解沉淀，随后用酶标仪检测OD值，波长490nm。用下式求出每一样品浓度下的细胞存活率。
存活率％＝样品组平均OD值/对照组平均OD值×100％
以细胞存活率对药物浓度对数作图，按作图法求出每个样品的IC50值，结果见下表3。
表3.化合物9a-9c和52-88体外抗肿瘤活性评价结果(IC50,μM)
Figure PCTCN2017084929-appb-000019
Figure PCTCN2017084929-appb-000020

Claims (10)

  1. 一种喹啉衍生物，其是式I化合物：
    Figure PCTCN2017084929-appb-100001
    或其可药用盐，其中
    R是一个、两个或三个各自独立地选自以下的基团：任选取代的氢、卤素、羟基、氨基、烷基、烷氧基、烷酰基氧基、烷基硫基、烷基氨基、氰基、硝基、羧基、磺酰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、酰氨基、烷氧基羰基或烷基酰基，
    R1是任选取代的烷基、烯基或炔基，
    当存在时所述任选的取代基各自独立地选自芳基、杂芳基、杂环基、烷基芳基、烷基杂芳基、烷基杂环基、氨基、烷基氨基、酰胺基、烷基酰基氨基、羟基、烷氧基、烷基酰基、烷基酰基氧基、巯基、烷基硫基，所述任选的取代基可进一步被取代；和
    W选自NH、O或S。
  2. 前述任一项权利要求的喹啉衍生物，其中至少一个所述R选自：任选取代的卤素、烷氧基、烷酰基氧基、烷基硫基、烷基氨基、氰基、硝基、羧基、磺酰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、酰氨基、烷氧基羰基或烷基酰基，优选地，至少一个所述R选自：任选取代的氰基、硝基、羧基、磺酰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、酰氨基、烷氧基羰基或烷基酰基。
  3. 前述任一项权利要求的喹啉衍生物，其中至少一个所述R是硝基、甲氧基、氟、氯或溴。
  4. 前述任一项权利要求的喹啉衍生物，其中所述R1是任选取代的C2-C12烷基、C3-C12烯基或C3-C12炔基，例如是乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、烯丙基、烯丁基、炔丙基、或炔丁基。
  5. 前述任一项权利要求的喹啉衍生物，其中所述R1是任选取代的芳烷基或杂芳基烷基，优选地是芳基甲基、芳基乙基、芳基丙基，例如是苯甲基、苯乙基、苯基丙基、苯基丁基；所述芳基烷基或杂芳基烷基任选地被一个或更多个卤素如氟、氯或溴、烷基、烷氧基、卤代烷基或卤代烷氧基所取代，例如所述R1可以是氟代苯甲基、氟代苯乙基、氟代苯丙基。
  6. 前述任一项权利要求的喹啉衍生物，其中所述化合物选自
    Figure PCTCN2017084929-appb-100002
    Figure PCTCN2017084929-appb-100003
    Figure PCTCN2017084929-appb-100004
    Figure PCTCN2017084929-appb-100005
    Figure PCTCN2017084929-appb-100006
    Figure PCTCN2017084929-appb-100007
    Figure PCTCN2017084929-appb-100008
  7. 制备权利要求1-6中任一项所述喹啉衍生物的方法，其包括：
    1)使式II化合物在碱存在下与R1X接触，
    Figure PCTCN2017084929-appb-100009
    获得式III化合物，和
    Figure PCTCN2017084929-appb-100010
    2)使式III化合物在酸存在下与R取代苯胺接触，获得式I化合物，
    Figure PCTCN2017084929-appb-100011
    其中，X各自独立地是卤素，R、R1和W如权利要求1-6中所定义，
    所述碱优选地是NaH，和/或所述酸优选地是浓盐酸。
  8. 一种药物组合物，其包含权利要求1-6中任一项所述喹啉衍生物以及可药用载体。
  9. 权利要求1-6任一项所述喹啉衍生物用于制备治疗增生性疾病的药物中的用途。
  10. 权利要求9的用途，其中所述增生性疾病是恶性肿瘤，优选地所述增生性疾病选自白血病、结直肠癌、肝癌、非小细胞肺癌、卵巢癌、***和胃癌。
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