WO2021213111A1 - Snail抑制剂及其衍生物，制备方法、药物组合物和应用 - Google Patents

Snail抑制剂及其衍生物，制备方法、药物组合物和应用 Download PDF

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WO2021213111A1
WO2021213111A1 PCT/CN2021/082215 CN2021082215W WO2021213111A1 WO 2021213111 A1 WO2021213111 A1 WO 2021213111A1 CN 2021082215 W CN2021082215 W CN 2021082215W WO 2021213111 A1 WO2021213111 A1 WO 2021213111A1
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amino
methyl
benzamide
pyrimidin
sulfanyl
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French (fr)
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陆涛
崔昊
陈亚东
朱雍
吴照球
李红玫
陈泉威
魏然
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中国药科大学
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to a Snail inhibitor and its derivatives, preparation methods, pharmaceutical compositions and applications, in particular to a Snail inhibitor and its derivatives which can be prepared as drugs for the treatment and/or prevention of diseases related to Snail inhibition.
  • a Snail inhibitor and its derivatives which can be prepared as drugs for the treatment and/or prevention of diseases related to Snail inhibition.
  • Snail is a zinc finger transcription factor, which combines the zinc finger structure in the protein structure with the downstream target gene promoter with E-box (CAGGTG) as the core, participates in downstream gene transcription, inhibits the formation of chromatin structure and other processes to maintain the body Normal biological function. Under normal physiological conditions, the content of Snail protein in cells is very limited and maintained at an inactive low level.
  • Snail mRNA When cells are stimulated by oxidative stress, the translation speed of Snail mRNA increases and the ability to enter the nucleus is enhanced; Snail mRNA accumulates in the nucleus to increase protein stability, thereby enhancing the transcriptional activity of downstream target genes and inhibiting the cell cycle. Multiple processes such as stagnation, apoptosis resistance, invasion and metastasis, and immune regulation have an impact. Therefore, ensuring that Snail's timely and appropriate regulation is necessary to ensure its normal function of transcription.
  • Snail's transcription abnormality can be detected in many types of tumors, such as breast cancer, colon cancer, and lung cancer, and indicates a poor prognosis of the tumor.
  • Snail can inhibit the transcription of cell cycle D2 (Cyclin D2), increase the expression of p21Cip1/WAF1, and promote the growth of tumor cells; it can also activate the p53-mediated apoptosis resistance pathway to inhibit tumor cell apoptosis.
  • Snail as a key regulator of EMT (Mesenchymal Transformation), can accelerate tumor progression; it can also promote the expression of immunosuppressive factors, so that tumor cells can produce immune resistance. Therefore, Snail plays a central role in tumor progression.
  • the first object of the present invention is to provide a Snail inhibitor and its derivatives
  • the second object is to provide a method for preparing the Snail inhibitor and its derivatives
  • the third object is to provide a Snail inhibitor and its derivatives.
  • the fourth purpose of the pharmaceutical composition of the inhibitor and its derivatives is to provide the application of the Snail inhibitor and its derivatives in the preparation of drugs for the treatment and/or prevention of diseases related to Snail inhibition.
  • the Snail inhibitor and its derivatives of the present invention have a structure of formula (I), and the derivatives are isomers, diastereomers, enantiomers, and mutual isomers of the Snail inhibitor.
  • R 1 , R 2 or R 3 is R or -TWR 6 , or R 1 , R 2 or R 3 and the atoms between them together form a fused 5-8 membered unsaturated or partially unsaturated ring, and the ring Has 0-3 nitrogen, oxygen or sulfur ring heteroatoms; any substitutable ring carbon on the fused ring formed by R 2 and R 3 is halogen, oxo, -CN, -NO 2 , R 7 or -VR 6 substitution, any substitutable ring nitrogen on the fused ring formed by R 1 , R 2 or R 3 is substituted by R 4 ;
  • Q is an aryl group, a heteroaryl group or a heterocyclic group, and the aryl group or heteroaryl group is substituted by one or more R 4 , wherein the aryl group is a 6-10 membered aryl group; the heteroaryl group is a five-membered group Or a six-membered heteroaryl group, and the ring has 1-4 nitrogen, oxygen or sulfur ring heteroatoms; the heterocyclic group is a 5-10 membered heterocyclic group, and the ring has 1-4 nitrogen, oxygen or Sulfur ring heteroatom;
  • X is -O-, -S-, -SO-, -SO 2 -, -N(R 6 )SO 2 -, -SO 2 N(R 6 )-, -N(R 6 )-, -CO- , -CO 2 -, -N(R 6 )CO-, -N(R 6 )CO 2 -, -N(R 6 )CON(R 6 )-, -N(R 6 )SO 2 N(R 6 )-, -N(R 6 )N(R 6 )-, -CON(R 6 )-, -OCON(R 6 )-, -C(R 6 ) 2 O-, -C(R 6 ) 2 S -, -C(R 6 ) 2 SO-, -C(R 6 ) 2 SO 2 -, -C(R 6 ) 2 SO 2 N(R 6 )-, -C(R 6 ) 2 N(R 6 )-
  • G is D-L-Z
  • D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring
  • the 5-7 membered monocyclic ring or 8-10 membered bicyclic ring is an aryl, heteroaryl, heterocyclic or carbocyclic group, wherein The heteroaryl or heterocyclic group has 1-4 nitrogen, oxygen or sulfur ring heteroatoms; any substitutable ring carbon on the ring is substituted by oxo, TR 5 or VWR 5 ; any one of the ring can be substituted
  • the ring nitrogen of is replaced by R 7;
  • L is a chemical bond, -O-, -S-, -SO-, -SO 2 -, -N(R 6 )SO 2 -, -SO 2 N(R 6 )-, -N(R 6 )-,- CO-, -CO 2 -, -N(R 6 )CO-, -N(R 6 )CO 2 -, -N(R 6 )CON(R 6 )-, -N(R 6 )SO 2 N( R 6 )-, -N(R 6 )N(R 6 )-, -CON(R 6 )-, -OCON(R 6 )-, -C(R 6 ) 2 O-, -C(R 6 ) 2 S-, -C(R 6 ) 2 SO-, -C(R 6 ) 2 SO 2 -, -C(R 6 ) 2 SO 2 N(R 6 )-, -C(R 6 ) 2 N( R 6 )
  • Z is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring, and the 5-7 membered monocyclic ring or 8-10 membered bicyclic ring is an aryl, heteroaryl, heterocyclic or carbocyclic group, wherein The heteroaryl or heterocyclic group has 1-4 nitrogen, oxygen or sulfur ring heteroatoms; any substitutable ring carbon on the ring is substituted by oxo, -TR 5 or -VWR 5 ; any one of the ring can be substituted by oxo, -TR 5 or -VWR 5 The substituted ring nitrogen is replaced by R 7;
  • R is hydrogen or an optionally substituted group, and the optionally substituted group is a C 1 -C 6 aliphatic group, a C 1 -C 10 aryl group, and a 5-10 membered heteroaryl ring Or 5-10 membered heterocyclic ring;
  • T is a chemical bond or a C 1-4 alkylene chain
  • R 4 is hydrogen, C 1 -C 6 alkyl, cyano, halogen, halogenated C 1 -C 6 alkyl, hydroxyl, mercapto, C 1 -C 6 alkoxy, R 7 , -COR 7 , -CO 2 (substituted C 1 -C 6 aliphatic group), -CON(R 7 ) 2 or -SO 2 R 7 ;
  • V is -O-, -S-, -SO-, -SO 2 -, -N(R 6 )SO 2 -, -SO 2 N(R 6 )-, -N(R 6 )-, -CO- , -CO 2 -, -N(R 6 )CO-, -N(R 6 )CO 2 -, -N(R 6 )CON(R 6 )-, -N(R 6 )SO 2 N(R 6 )-, -N(R 6 )N(R 6 )-, -C(O)N(R 6 )-, -OC(O)N(R 6 )-, -C(R 6) 2 O-, -C(R 6 ) 2 S-, -C(R 6 ) 2 SO-, -C(R 6 ) 2 SO 2 -, -C(R 6 ) 2 SO 2 N(R 6 )-, -C( R 6 ) 2 N(R
  • R 6 is hydrogen or a substituted C 1 -C 4 aliphatic group, or two R 6 on the same nitrogen atom and the connected nitrogen atom form a 5-6 membered heterocyclic ring or heteroaromatic ring;
  • R 7 is hydrogen or a substituted C 1 -C 6 aliphatic group, or two R 7 on the same nitrogen atom and the connected nitrogen atom form a 5-8 membered heterocyclic ring or heteroaromatic ring.
  • Q is an aryl group, a heteroaryl group or a heterocyclic group, and the aryl group or heteroaryl group is substituted by one or more R 4 , wherein the aryl group is a phenyl group; the heteroaryl group is a pyrrolyl group or a pyrazolyl group , Imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; the heterocyclic group is piperidinyl, Morpholinyl or piperazinyl;
  • G is DLZ, where L is a chemical bond, -NH- or -N(CH 3 )-.
  • Q is an aryl group, a heteroaryl group, or a heterocyclic group, and the aryl group or heteroaryl group is substituted by one or more R 4 , wherein the aryl group is a phenyl group; the heteroaryl group is a pyridyl group;
  • G is DLZ, where L is a chemical bond, -NH- or -N(CH 3 )-; Z is phenyl, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl , Triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, piperazinyl, piperidinyl or 1,4-oxazin-4-yl, the substituent R 7 is methyl Group, ethyl, tert-butyl, 1-2 halogens, trifluoromethyl, methoxy, tert-butoxycarbonyl, cyano, cyclopropyl or phenyl.
  • the Snail inhibitor is any of the following compounds:
  • the pharmaceutically acceptable salt is a salt formed by the Snail inhibitor with an acid or a base
  • the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid , Naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid, the alkali contains alkaline metal cations, alkaline earth Inorganic base of metal cation or ammonium cation salt.
  • the preparation method of the Snail inhibitor and its derivatives of the present invention is any one of the following methods:
  • the corresponding acid or base solution is added to the solution of the compound having the structure of formula (I) prepared by any of the above methods, and the solvent is removed under reduced pressure after the salt is formed, to obtain the pharmaceutically acceptable salt of the Snail inhibitor .
  • the pharmaceutical composition of the present invention comprises the Snail inhibitor and/or its derivative and a pharmaceutically acceptable carrier.
  • the Snail inhibitor and its derivatives can be added with pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, injections, and can be added with flavors, sweeteners, liquid or solid fillers Or diluents and other commonly used pharmaceutical excipients.
  • Snail inhibitor and its derivatives of the present invention in the preparation of drugs for treating and/or preventing diseases related to Snail inhibition.
  • composition of the present invention in the preparation of drugs for treating and/or preventing diseases related to Snail inhibition.
  • the diseases related to Snail inhibition are lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, rectal cancer, colon cancer, ovarian cancer, testicular cancer, breast cancer, Bladder cancer, gallbladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, schwannoma, mesothelioma, non-insulin-dependent Diabetes or autoimmune disease.
  • This type of inhibitors and their derivatives and pharmaceutical compositions have a strong affinity with Snail protein. At nanomolar concentrations, they have a good affinity with Snail protein, which can effectively inhibit the activity of Snail and affect cells. It also has a good inhibitory effect. When the concentration is 1 ⁇ M, the cell inhibition rate can reach 99% or more;
  • the prepared drugs have a wide range of targets, which can be used to treat and/or prevent a variety of diseases related to the inhibition of Snail activity;
  • Figure 1 is a 1 H NMR spectrum of compound 1-1;
  • Figure 2 is a mass spectrum of compound I-1.
  • Formic acid and p-fluoroo-phenylenediamine come from Shanghai Bi De Pharmaceutical Technology Co., Ltd., Titan Technology Co., Ltd., and Saen Chemical Technology Co., Ltd.
  • the HCT-116 colon cancer cell line was derived from Nanjing Anakang Biotechnology Co., Ltd.
  • MST Microscale Thermophoresis
  • compounds I-1, I-24 and I-42 all have affinity for Snail protein.
  • the affinity is at the micromolar or even nanomolar concentration level, and the affinity is obvious, which is beneficial to Play an inhibitory role.
  • Example 4 Determination of the anti-tumor activity of the compound in vitro
  • the CCK-8 method was used to determine the inhibitory effect on the HCT-116 colon cancer cell line.
  • the CCK-8 method uses a new water-soluble tetrazolium salt 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4- Disulfobenzene)-2H-tetrazole monosodium salt is a colorimetric detection product for rapid and highly sensitive detection of bacterial activity.
  • This tetrazolium salt can be reduced to orange-yellow water-soluble by bacterial dehydrogenase in the presence of electronic carriers Formazan, the amount of formazan produced is directly proportional to the activity of the bacteria. The stronger the bacterial activity, the darker the color; the weaker the bacterial activity, the lighter the color. For the same bacteria, the intensity of the color is linearly related to the activity of the bacteria.
  • Compound HCT-116 inhibition rate (%) Compound HCT-116 inhibition rate (%) I-1 99.7 I-26 99.8 I-5 83.5 I-27 90.8 I-6 70.9 I-28 85.8 I-8 64.3 I-29 90.9 I-12 99.6 I-30 99.8 I-13 99.7 I-31 98.8 I-15 99.8 I-35 99.7 I-18 86.2 I-37 99.7 I-24 98.9 I-38 82.6 I-25 99.1 I-41 83.4

Abstract

本发明公开了一种Snail抑制剂及其衍生物，制备方法、药物组合物和应用。该Snail抑制剂的化合物结构如式(I)，该Snail抑制剂衍生物涉及所述化合物的异构体、非对映异构体、对映异构体、互变异构体、溶剂化物、药学上可接受的盐、前体药物或它们的混合物，该化合物及其衍生物可以抑制Snail活性和细胞活性，可用于制备治疗和/或预防与Snail抑制有关疾病的药物，并且该类化合物制备方法简便，且产率较高，易于工艺放大。

Description

Snail抑制剂及其衍生物，制备方法、药物组合物和应用 技术领域
本发明涉及一种Snail抑制剂及其衍生物，制备方法、药物组合物和应用，尤其涉及一种可制备为治疗和/或预防与Snail抑制有关疾病药物的Snail抑制剂及其衍生物，制备方法、药物组合物和应用。
背景技术
真核生物基因的转录因子存在广泛，可调控多种靶基因，与肿瘤细胞的生长、增殖、凋亡、浸润转移及血管生成等各个环节密切相关。Snail为锌指转录因子，其通过蛋白结构中的锌指结构与以E-box(CAGGTG)为核心的下游靶基因启动子结合，参与下游基因转录、抑制染色质结构形成等过程，使机体维持正常生物学功能。在正常生理条件下，细胞内Snail蛋白含量非常有限，维持在无活性的低水平状态。当细胞受到氧化应激等刺激后，Snail mRNA的翻译速度加快、入核能力增强；Snail mRNA聚集于细胞核，使蛋白稳定性增加，从而增强了调控下游目的基因的转录活性，并对细胞周期阻滞、凋亡抵抗、侵袭与转移、免疫调节等多个过程产生影响。因此，保证Snail适时、适度的调控是确保其正常行使转录功能的必要条件。
Snail的转录异常在乳腺癌、结肠癌、肺癌等多种类型的肿瘤中均可检测到，并预示着肿瘤的不良预后。Snail可以抑制细胞周期D2(Cyclin D2)的转录，增加p21Cip1/WAF1表达，促进肿瘤细胞生长；也可以激活p53介导的凋亡抵抗通路，抑制肿瘤细胞凋亡。Snail作为EMT(间质上皮转化)的关键调控因子，可以使肿瘤进程加快；还可以促进免疫抑制因子表达，从而使肿瘤细胞产生免疫抵抗。因此，Snail在肿瘤恶化进程中起着核心节点性作用。
发明内容
发明目的：本发明的第一目的是提供一种Snail抑制剂及其衍生物，第二目的是提供所述Snail抑制剂及其衍生物的制备方法，第三目的是提供一种包含所述Snail抑制剂及其衍生物的药物组合物，第四目的是提供所述Snail抑制剂及其衍生物在制备治疗和/或预防与Snail抑制有关疾病药物中的应用。
技术方案：本发明的Snail抑制剂及其衍生物具有式(I)的结构，所述衍生物为所述Snail抑制剂的异构体、非对映异构体、对映异构体、互变异构体、溶剂化物、药学上可接受的盐、前体药物或它们的混合物：
Figure PCTCN2021082215-appb-000001
其中：
R 1、R 2或R 3为R或-T-W-R 6，或者R 1、R 2或R 3与它们之间的原子一起构成稠合的5-8元不饱和或部分不饱和环，且环上具有0-3个氮、氧或硫环杂原子；由R 2和R 3构成的所述稠合环上任一可取代的环碳被卤素、氧代、-CN、-NO 2、R 7或-V-R 6取代，由R 1、R 2或R 3构成的所述稠合环上任一可取代的环氮被R 4取代；
Q为芳基、杂芳基或杂环基，且芳基或杂芳基被一个或多个R 4取代，其中所述芳基为6-10元芳基；所述杂芳基为五元或六元杂芳基，且环上具有1-4个氮、氧或硫环杂原子；所述杂环基为5-10元杂环基，且环上具有1-4个氮、氧或硫环杂原子；
X为-O-、-S-、-SO-、-SO 2-、-N(R 6)SO 2-、-SO 2N(R 6)-、-N(R 6)-、-CO-、-CO 2-、-N(R 6)CO-、-N(R 6)CO 2-、-N(R 6)CON(R 6)-、-N(R 6)SO 2N(R 6)-、-N(R 6)N(R 6)-、-CON(R 6)-、-OCON(R 6)-、-C(R 6) 2O-、-C(R 6) 2S-、-C(R 6) 2SO-、-C(R 6) 2SO 2-、-C(R 6) 2SO 2N(R 6)-、-C(R 6) 2N(R 6)-、-C(R 6) 2N(R 6)CO-、-C(R 6) 2N(R 6)CO 2-、-C(R 6)＝NN(R 6)-、-C(R 6)＝N-O-、-C(R 6) 2N(R 6)N(R 6)-、-C(R 6) 2N(R 6)SO 2N(R 6)-或-C(R 6) 2N(R 6)CON(R 6)-；
G为D-L-Z；
其中D为5-7元单环或8-10元二环，所述5-7元单环或8-10元二环为芳基、杂芳基、杂环基或碳环基，其中所述杂芳基或杂环基具有1-4个氮、氧或硫环杂原子；所述环上任一可取代的环碳被氧代、T-R 5或V-W-R 5取代；所述环上任一可取代的环氮被R 7取代；
L为化学键、-O-、-S-、-SO-、-SO 2-、-N(R 6)SO 2-、-SO 2N(R 6)-、-N(R 6)-、-CO-、-CO 2-、-N(R 6)CO-、-N(R 6)CO 2-、-N(R 6)CON(R 6)-、-N(R 6)SO 2N(R 6)-、-N(R 6)N(R 6)-、-CON(R 6)-、-OCON(R 6)-、-C(R 6) 2O-、-C(R 6) 2S-、-C(R 6) 2SO-、-C(R 6) 2SO 2-、-C(R 6) 2SO 2N(R 6)-、-C(R 6) 2N(R 6)-、-C(R 6) 2N(R 6)CO-、-C(R 6) 2N(R 6)CO 2-、-C(R 6)＝NN(R 6)-、-C(R 6)＝N-O-、-C(R 6) 2N(R 6)N(R 6)-、-C(R 6) 2N(R 6)SO 2N(R 6)-或-C(R 6) 2N(R 6)CON(R 6)-；
Z为5-7元单环或8-10元二环，所述5-7元单环或8-10元二环为芳基、杂 芳基、杂环基或碳环基，其中所述杂芳基或杂环基具有1-4个氮、氧或硫环杂原子；所述环上任一可取代的环碳被氧代、-T-R 5或-V-W-R 5取代；所述环上任一可取代的环氮被R 7取代；
R为氢或可选择性被取代的基团，所述可选择性被取代的基团为C 1-C 6脂族基团、C 1-C 10芳基、5-10元杂芳基环或5-10元杂环基环；
T为化学键或C 1-4亚烷基链；
R 4为氢、C 1-C 6烷基、氰基、卤素、卤代C 1-C 6烷基、羟基、巯基、C 1-C 6烷氧基、R 7、-COR 7、-CO 2(取代的C 1-C 6脂族基团)、-CON(R 7) 2或-SO 2R 7；
R 5为R、卤素、-OR、-COR、-CO 2R、-COCOR、-NO 2、-CN、-SOR、-SO 2R、-SR、-N(R 4) 2、-CON(R 4) 2、-SO 2N(R 4) 2、-OCOR、-N(R 4)COR、-N(R 4)CO(取代的C 1-C 6脂族基团)、-N(R 4)N(R 4) 2、-C＝NN(R 4) 2、-C＝N、-OR、-N(R 4)CON(R 4) 2、-N(R 4)SO 2N(R 4) 2、-N(R 4)SO 2R或-OCON(R 4) 2；
V为-O-、-S-、-SO-、-SO 2-、-N(R 6)SO 2-、-SO 2N(R 6)-、-N(R 6)-、-CO-、-CO 2-、-N(R 6)CO-、-N(R 6)CO 2-、-N(R 6)CON(R 6)-、-N(R 6)SO 2N(R 6)-、-N(R 6)N(R 6)-、-C(O)N(R 6)-、-OC(O)N(R 6)-、-C(R 6) 2O-、-C(R 6) 2S-、-C(R 6) 2SO-、-C(R 6) 2SO 2-、-C(R 6) 2SO 2N(R 6)-、-C(R 6) 2N(R 6)-、-C(R 6) 2N(R 6)CO-、-C(R 6) 2N(R 6)CO 2-、-C(R 6)＝NN(R 6)-、-C(R 6)＝N-O-、-C(R 6) 2N(R 6)N(R 6)-、-C(R 6) 2N(R 6)SO 2N(R 6)-或-C(R 6) 2N(R 6)CON(R 6)-；
W为-C(R 6) 2O-、-C(R 6) 2S-、-C(R 6) 2SO-、-C(R 6) 2SO 2-、-C(R 6) 2SO 2N(R 6)-、-C(R 6) 2N(R 6)-、-CO-、-CO 2-、-C(R 6)OCO-、-C(R 6)OCON(R 6)-、-C(R 6) 2N(R 6)CO-、-C(R 6) 2N(R 6)C(O)O-、-C(R 6)＝NN(R 6)-、-C(R 6)＝N-O-、-C(R 6) 2N(R 6)N(R 6)-、-C(R 6) 2N(R 6)SO 2N(R 6)-、-C(R 6) 2N(R 6)CON(R 6)-或-CON(R 6)-；
R 6为氢或取代的C 1-C 4脂族基团，或者同一氮原子上的两个R 6与所连接的氮原子构成5-6元杂环或杂芳环；
R 7为氢或取代的C 1-C 6脂族基团，或者同一氮原子上的两个R 7与所连接的氮原子构成5-8元杂环或杂芳环。
优选，所述Snail抑制剂及其衍生物结构中：
Q为芳基、杂芳基或杂环基，且芳基或杂芳基被一个或多个R 4取代，其中所述芳基为苯基；所述杂芳基为吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；所述杂环基为哌啶基、吗啉基或哌嗪基；
X为-O-、-S-、-SO-、-SO 2-、-NH-、-N(CH 3)-、-C＝、化学键或亚甲基单位；
G为D-L-Z，其中L为化学键、-NH-或-N(CH 3)-。
优选，所述Snail抑制剂及其衍生物结构中：
Q为芳基、杂芳基或杂环基，且芳基或杂芳基被一个或多个R 4取代，其中所述芳基为苯基；所述杂芳基为吡啶基；
X为-O-、-S-、-SO-、-SO 2-、-NH-、-C＝、化学键或亚甲基单位；
G为D-L-Z，其中L为化学键、-NH-或-N(CH 3)-；Z为苯基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基、三氮唑基、四氮唑基、吡啶基、吡嗪基、嘧啶基、吗啉基、哌嗪基、哌啶基或1,4-恶嗪-4-基，取代基R 7为甲基、乙基、叔丁基、1-2个卤素、三氟甲基、甲氧基、叔丁氧羰基、氰基、环丙基或苯基。
优选，所述Snail抑制剂为以下任一化合物：
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺的制备(I-1)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-氯-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺的制备(I-2)，
N-(2-氨基-4-氟苯基)-4-[[[[4-[(5-甲基-1H-1,2,4-***-3-基)氨基]嘧啶-2-基]硫基]甲基苯甲酰胺(I-3)，
N-(2-氨基-4-氟苯基)-4-[[[[4-[(2-甲基-2H-四唑-5-基)氨基]嘧啶-2-基]硫基]甲基苯甲酰胺(I-4)，
N-(2-氨基苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺的制备(I-5)，
N-(2-(甲基氨基)苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺的制备(I-6)，
N-(1H-吲哚-7-基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-7)，
N-(5-氟-2-吲哚酮-7-基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-8)，
N-(2-氨基-4-氟-6-甲基苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-9)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]亚磺酰基]甲基]苯甲酰胺(I-10)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]磺酰基] 甲基]苯甲酰胺(I-11)，
N-(2-氨基-4-氟苯基)-4-[[(4-[(5-甲基异噁唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-12)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(1,5-二甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-13)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(1,5-二甲基-1H-吡唑-3-基)(甲基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-14)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-环丙基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-15)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-环丙基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-16)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-叔丁基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-17)，
N-(2-氨基-4-氟苯基)-4-[[(4-吗啉代吡啶-2-基)硫基]甲基]苯甲酰胺(I-18)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(4-氟苄基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-19)，
N-(2-氨基苯基)-4-[[[4-[(4-三氟甲基苄基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-20)，
N-(2-氨基苯基)-4-[[[4-[(4-甲氧基苄基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-21)，
N-(2-氨基苯基)-4-[[[4-[(3,4-二甲氧基苄基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-22)，
N-(2-氨基苯基)-4-[[[4-[(2,4-二甲氧基苄基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-23)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-24)，
N-(2-氨基-4-氟苯基)-4-[[(4-苯基氨基)嘧啶-2-基]硫基]甲基]苯甲酰胺(I-25)，
N-(2-氨基-4苯基)-4-[[[4-[(3-甲基吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-26)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(4-甲基吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-27)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯 甲酰胺(I-28)，
N-(2-氨基-4-氟苯基)-4-[[[4-[[3-(三氟甲基)吡啶-2-基]氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-29)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(3-氟吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-30)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(3-甲氧基吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-31)，
N-(2-氨基-4-氟-6-吗啉代苯基)-4-[[[4-[(3-甲基吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-32)，
N-(2-氨基苯基)-4-[[[4-[(N-Boc哌啶-4-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-33)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(哌啶-4-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-34)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]氨基]甲基]苯甲酰胺(I-35)，
N-(2-氨基-4-氟苯基)-4-[[甲基[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]氨基]甲基]苯甲酰胺(I-36)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]氧基]甲基]苯甲酰胺(I-37)，
N-(2-氨基-4-氟苯基)-5-[[[4-[(5-甲基异噁唑-3-基)氨基]嘧啶-2-基]硫基]甲基]吡啶酰胺的制备(I-38)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]吡啶-2-基]氨基]甲基]苯甲酰胺(I-39)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]吡啶-2-基]氨基]甲基]苯甲酰胺(I-40)，
N-(2-氨基-4-氟苯基)-4-[[[3-[(5-甲基-1H-吡唑-3-基)氨基]苯基]硫基]氨基]甲基]苯甲酰胺(I-41)，
N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]喹唑啉-2-基]硫基]甲基]苯甲酰胺(I-42)，
N-(2-氨基-4-氟苯基)-4-[[[4-(二甲基氨基)-6-[[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-43)，
N-(2-氨基-4-氟苯基)-4-[[[[4-[(5-甲基-1H-吡唑-3-基)氨基]-6-(4-甲基哌嗪-1- 基)嘧啶-2-基]硫基]甲基]苯甲酰胺(I-44)，
N-(2-氨基-4-氟苯基)-4-[[[6-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-4-基]硫基]甲基]苯甲酰胺(I-45)。
优选，所述药学上可接受的盐为所述Snail抑制剂与酸或碱形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、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、苯基乙酸或杏仁酸，所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱。
本发明的Snail抑制剂及其衍生物的制备方法为以下任一方法：
方法一：
化合物1经烷基化反应引入Q得到化合物2，化合物2经氯代和烷基化反应引入Z、L得到化合物4，化合物4经水解反应得到化合物5，化合物5再与化合物6发生酰化反应得到化合物I；
Figure PCTCN2021082215-appb-000002
方法二：
化合物5经不同程度的氧化反应分别得到化合物7、化合物8，化合物7、化合物8再分别与化合物6发生酰化反应得到化合物I；
Figure PCTCN2021082215-appb-000003
其中，Q、Z、L、R、R 1、R 2和R 3的定义如权利要求1～3任一所述；
将相应的酸或碱的溶液加入到以上任一方法制备的具有式(I)结构的化合物的溶液中，成盐完全后减压除去溶剂，即得所述Snail抑制剂药学上可接受的盐。
本发明的药物组合物包含所述Snail抑制剂和/或其衍生物以及药学上可接受的载体。
所述Snail抑制剂及其衍生物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂、注射剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明的Snail抑制剂及其衍生物在制备治疗和/或预防与Snail抑制有关疾病药物中的应用。
本发明的药物组合物在制备治疗和/或预防与Snail抑制有关疾病药物中的应用。
优选，所述与Snail抑制有关的疾病为肺癌、黑色素瘤、肝癌、肾癌、白血病、***癌、甲状腺癌、皮肤癌、胰腺癌、直肠癌、结肠癌、卵巢癌、睾丸癌、乳腺癌、膀胱癌、胆囊癌、骨髓增生异常综合症、淋巴瘤、食管癌、胃肠道癌、星形细胞瘤、神经母细胞瘤、神经胶质瘤、神经鞘瘤、间皮瘤、非胰岛素依赖型糖尿病或自身免疫性疾病。
有益效果：与现有技术相比，本发明具有如下显著优点：
(1)该类抑制剂及其衍生物和药物组合物与Snail蛋白的亲和力强，在纳摩尔浓度级时，便与Snail蛋白具有很好的亲和作用，可有效抑制Snail活性，并对细胞也具有较好的抑制作用，给药浓度为1μM时细胞抑制率最高可达到99％以上；
(2)所制备的药物作用靶点广泛，可用于治疗和/或预防多种与Snail活性抑制有关的疾病；
(3)制备方法简便，且产率较高，易于工艺放大。
附图说明
图1为化合物1-1的 1H NMR谱图；
图2为化合物I-1的质谱图。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
试剂与材料：
2-硫脲嘧啶、4-溴甲基苯甲酸甲酯、三氯氧磷、5-甲基-3-氨基吡唑、N,N-二 异丙基乙胺、HATU、间氯过氧苯甲酸、对氟邻苯二胺来源于上海毕得医药科技有限公司、泰坦科技有限公司、萨恩化学技术有限公司。
HCT-116结肠癌细胞株来源于南京安纳康生物科技有限公司。
仪器：
1H NMR采用BRUKER AVANCE-300型核磁共振仪(瑞士Brucker公司)测定，以TMS为内标，位移值(δ)单位为ppm；低分辨质谱采用expression紧凑型傅里叶变换质谱仪测定。
实施例1：N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(化合物I-1)的合成
Figure PCTCN2021082215-appb-000004
(1)4-[[(4-羟基嘧啶-2-基)硫基]甲基]苯甲酸甲酯(化合物2-1)的合成
将2-硫脲嘧啶(2g，15.61mmol)溶于甲醇(20mL)，加入N,N-二异丙基乙胺(2.58g，15.61mmol)搅拌约5min，再加入4-溴甲基苯甲酸甲酯(3.93g，17.17mmol)，室温反应3h后，TLC显示反应结束，过滤得到白色滤饼3.98g，产率：92.34％。ESI-MS m/z:277.3[M+H] +。
(2)4-[[(4-氯嘧啶-2-基)硫基]甲基]苯甲酸甲酯(化合物3-1)的合成
将化合物2-1(3.93g，17.17mmol)溶于三氯氧磷(15mL)中，加入N,N-二乙基苯胺(11.01g，73.78mmol)，氮气保护，加热回流10h后TLC显示反应结束。减压蒸除大部分三氯氧磷，真空冷却至室温后，将反应物倒入冰水(400mL)中，乙酸乙酯萃取(60mL×3)，合并有机层，饱和食盐水(60mL)洗涤后加无水硫酸钠干燥，静置，过滤，减压蒸除溶剂，硅胶柱层析分离(石油醚：乙酸乙酯＝50：1)，得黄色固体3.87g，产率：91.06％。ESI-MS m/z:295.2[M+H] +。
(3)4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酸甲酯(化 合物4-1)的合成
将化合物3-1(1g，3.39mmol)溶于N,N-二甲基甲酰胺(20mL)，加入碘化钾(1.91g，11.50mmol)70℃搅拌5分钟。再加入N,N-二异丙基乙胺(1.32g，10.18mmol)和5-甲基-3-氨基吡唑(659mg，6.79mmol)，80℃下反应36h，TLC检测反应完全。反应液中加水(80mL)，乙酸乙酯萃取(30mL×3)，合并有机层，饱和食盐水(50mL)洗涤后加无水硫酸钠干燥，静置，过滤，减压蒸除溶剂，硅胶柱层析分离(石油醚：乙酸乙酯＝1：3)，得白色固体790mg，产率：65.29％。ESI-MS m/z:356.4[M+H] +。
(4)4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酸化合物(5-1)的合成
将化合物4-1(790mg，2.22mmol)和氢氧化钠(178mg，4.45mmol)，加入水(10mL)和甲醇(20mL)，60℃下反应12h，TLC检测反应完全。减压蒸除溶剂，加水(5mL)，冰浴下用冰醋酸溶液调节pH至6-7，冰箱中冷冻静置2h，抽滤，滤饼真空干燥，得白色固体708mg，产率：93.25％。ESI-MS m/z:342.3[M+H] +。
(5)N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(化合物I-1)的合成
将化合物5-1(120mg，0.35mmol)、HATU(191mg，0.39mmol)，加入N,N-二甲基甲酰胺(10mL)，再加入N,N-二异丙基乙胺(136mg，1.05mmol)，常温搅拌30min，再加入对氟邻苯二胺(49mg，0.39mmol)，继续常温搅拌过夜，TLC检测反应完全。反应液中加水(80mL)，乙酸乙酯萃取(30mL×3)，合并有机层，饱和食盐水(50mL)洗涤后加无水硫酸钠干燥，静置，过滤，减压蒸除溶剂，硅胶柱层析分离(石油醚：乙酸乙酯＝1：3)，得白色固体120mg，产率：75.95％。ESI-MS m/z:450.0[M+H] +。 1H NMR(300MHz,DMSO-d 6)δ12.05(d,J＝5.9Hz,1H),9.88(s,1H),9.53(s,1H),8.11(s,1H),7.92(d,J＝8.7Hz,2H),7.55(s,2H),7.10(s,1H),6.89(s,1H),6.52(d,J＝10.3Hz,1H),6.35(s,1H),6.08(s,1H),5.21(d,J＝5.6Hz,2H),4.44(d,J＝5.6Hz,2H),2.20(t,J＝4.7Hz,3H)。
用与实施例1相似的操作，制得下列化合物：
Figure PCTCN2021082215-appb-000005
Figure PCTCN2021082215-appb-000006
Figure PCTCN2021082215-appb-000007
Figure PCTCN2021082215-appb-000008
Figure PCTCN2021082215-appb-000009
Figure PCTCN2021082215-appb-000010
Figure PCTCN2021082215-appb-000011
Figure PCTCN2021082215-appb-000012
Figure PCTCN2021082215-appb-000013
实施例2：N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]亚磺酰基]甲基]苯甲酰胺(化合物I-10)的合成
Figure PCTCN2021082215-appb-000014
(1)4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]亚磺酰基]甲基]苯甲酸(化合物7-1)的合成
将化合物4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酸(1.00g，2.93mmol)溶于分析纯二氯甲烷(30mL)，加入间氯过氧苯甲酸(505mg，2.93mmol)常温反应3h后，用水和饱和氯化铵溶液(50mL)萃取洗涤后加无水硫酸钠干燥静置，过滤，减压蒸除溶剂，硅胶柱层析分离(二氯甲烷：甲醇＝10：1)，得白色固体441mg，产率：42.03％。ESI-MS m/z:358.1[M+H] +。
(2)N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]亚磺酰基]甲基]苯甲酰胺(化合物I-10)的合成
向25mL茄型瓶中加入化合物7-1(200mg，0.56mmol)、TBTU(234mg，0.62mmol)，加入N,N-二甲基甲酰胺(10mL)，再加入N,N-二异丙基乙胺(217mg，1.68mmol)，常温搅拌1h，再加入对氟邻苯二胺(85mg，0.68mmol)，继续常温搅拌4h后，TLC检测反应完全。反应液中加水(80mL)，乙酸乙酯萃取(30mL×3)，合并有机层，饱和食盐水(50mL)洗涤后加无水硫酸钠干燥，静置，过滤，减压蒸除溶剂，硅胶柱层析分离(石油醚：乙酸乙酯＝1：1)，得白色固体107mg，产率：41.11％。ESI-MS m/z:465.3[M+H] +。1H NMR(300MHz,DMSO-d6)δ12.03(s,1H),9.51(s,1H),8.53(d,J＝5.6Hz,1H),7.83–7.73(m,3H),7.54–7.42(m,3H),6.86(s,1H),6.75(d,J＝8.0,2.3Hz,1H),6.38(t,J＝8.2,2.3Hz,1H),6.13(s,1H),4.45(t,J＝1.0Hz,2H),4.15(s,2H),2.38(s,3H)。
用与实施例2相似的操作，制得下列化合物：
Figure PCTCN2021082215-appb-000015
实施例3：化合物对Snail蛋白亲和力测试(MST分子相互作用)
1、准备耗材：毛细管，GFP标记的蛋白或者重组蛋白，0.2mL，1.5mL，10mL，50mL tube，PBS，DMSO，移液枪，枪头，1.5mL板，50mL板。
2、实验原理：微量热泳动技术(Microscale Thermophoresis，MST)通过测量微观温度梯度场中的分子移动来分析生物分子间的相互作用。该技术能够测量出分子大小、电荷以及水化层变化引起的移动速度的改变，具有极高的灵敏度。
3、实验步骤和方法：将化合物配成2.5mM的DMSO母液，取4μL加入至100μL PBS，观察其溶解情况，必须保证在最高浓度可溶解；配制4％DMSO的PBS溶液，将化合物母液逐级稀释，混匀；加入同等体积的蛋白离心，静置10min；上机操作，连续测定2次，结果见表1。
表1化合物对Snail蛋白亲和力
Figure PCTCN2021082215-appb-000016
如表1所示，化合物I-1、I-24和I-42对Snail蛋白均具有亲和作用，亲和能力在微摩尔浓度级别，甚至是纳摩尔浓度级别，亲和作用明显，有利于发挥抑制作用。
实施例4：化合物对体外抗肿瘤活性测定
用CCK-8法测定对HCT-116结肠癌细胞株的抑制作用。
1、实验原理：CCK-8法应用新型的水溶性四唑盐2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑单钠盐快速高灵敏检测细菌活性的比色检测产品，本四唑盐在电子载体存在的情况下能够被细菌的脱氢酶还原成橙黄色的水溶性的甲臜，生成的甲臜量与细菌的活性成正比。细菌活性越强，则颜色越深；细菌活性越弱，则颜色越浅。对于同样的细菌，颜色的深浅和细菌活性呈线性关 系。
2、实验步骤和方法：制备适当浓度微生物细胞悬液，在96孔板内每孔接种190μL悬液；每孔加入10μL的染色溶液；将培养板在培养箱中培养(37℃或合适的温度)；用酶标仪测定在450nm处的吸光度；细胞活力计算：各重复孔的OD值取平均数，抑制率(％)＝(测试孔OD-空白OD)/(对照孔OD-空白OD)×100％。
表2 1μM浓度下化合物对HCT-116细胞株的抑制率(％)
化合物 HCT-116抑制率(％) 化合物 HCT-116抑制率(％)
I-1 99.7 I-26 99.8
I-5 83.5 I-27 90.8
I-6 70.9 I-28 85.8
I-8 64.3 I-29 90.9
I-12 99.6 I-30 99.8
I-13 99.7 I-31 98.8
I-15 99.8 I-35 99.7
I-18 86.2 I-37 99.7
I-24 98.9 I-38 82.6
I-25 99.1 I-41 83.4
如表2所示，在1μM浓度下，化合物I-1、I-5、I-6、I-8、I-12、I-13、I-15、I-18、I-24、I-25、I-26、I-27、I-28、I-29、I-30、I-31、I-35、I-37、I-38和I-41对HCT-116细胞株均有抑制作用，抑制率在60％以上，甚至可以达到99％以上，抑制效果明显。

Claims (10)

  1. 一种Snail抑制剂及其衍生物，其特征在于，所述Snail抑制剂及其衍生物具有式(I)的结构，所述衍生物为所述Snail抑制剂的异构体、非对映异构体、对映异构体、互变异构体、溶剂化物、药学上可接受的盐、前体药物或它们的混合物：
    Figure PCTCN2021082215-appb-100001
    其中：
    R 1、R 2或R 3为R或-T-W-R 6，或者R 1、R 2或R 3与它们之间的原子一起构成稠合的5-8元不饱和或部分不饱和环，且环上具有0-3个氮、氧或硫环杂原子；由R 2和R 3构成的所述稠合环上任一可取代的环碳被卤素、氧代、-CN、-NO 2、R 7或-V-R 6取代，由R 1、R 2或R 3构成的所述稠合环上任一可取代的环氮被R 4取代；
    Q为芳基、杂芳基或杂环基，且芳基或杂芳基被一个或多个R 4取代，其中所述芳基为6-10元芳基；所述杂芳基为五元或六元杂芳基，且环上具有1-4个氮、氧或硫环杂原子；所述杂环基为5-10元杂环基，且环上具有1-4个氮、氧或硫环杂原子；
    X为-O-、-S-、-SO-、-SO 2-、-N(R 6)SO 2-、-SO 2N(R 6)-、-N(R 6)-、-CO-、-CO 2-、-N(R 6)CO-、-N(R 6)CO 2-、-N(R 6)CON(R 6)-、-N(R 6)SO 2N(R 6)-、-N(R 6)N(R 6)-、-CON(R 6)-、-OCON(R 6)-、-C(R 6) 2O-、-C(R 6) 2S-、-C(R 6) 2SO-、-C(R 6) 2SO 2-、-C(R 6) 2SO 2N(R 6)-、-C(R 6) 2N(R 6)-、-C(R 6) 2N(R 6)CO-、-C(R 6) 2N(R 6)CO 2-、-C(R 6)＝NN(R 6)-、-C(R 6)＝N-O-、-C(R 6) 2N(R 6)N(R 6)-、-C(R 6) 2N(R 6)SO 2N(R 6)-或-C(R 6) 2N(R 6)CON(R 6)-；
    G为D-L-Z；
    其中D为5-7元单环或8-10元二环，所述5-7元单环或8-10元二环为芳基、杂芳基、杂环基或碳环基，其中所述杂芳基或杂环基具有1-4个氮、氧或硫环杂原子；所述环上任一可取代的环碳被氧代、-T-R 5或-V-W-R 5取代；所述环上任一可取代的环氮被R 7取代；
    L为化学键、-O-、-S-、-SO-、-SO 2-、-N(R 6)SO 2-、-SO 2N(R 6)-、-N(R 6)-、-CO-、-CO 2-、-N(R 6)CO-、-N(R 6)CO 2-、-N(R 6)CON(R 6)-、-N(R 6)SO 2N(R 6)-、-N(R 6)N(R 6)-、-CON(R 6)-、-OCON(R 6)-、-C(R 6) 2O-、-C(R 6) 2S-、-C(R 6) 2SO-、-C(R 6) 2SO 2-、-C(R 6) 2SO 2N(R 6)-、-C(R 6) 2N(R 6)-、-C(R 6) 2N(R 6)CO-、-C(R 6) 2N(R 6)CO 2-、 -C(R 6)＝NN(R 6)-、-C(R 6)＝N-O-、-C(R 6) 2N(R 6)N(R 6)-、-C(R 6) 2N(R 6)SO 2N(R 6)-或-C(R 6) 2N(R 6)CON(R 6)-；
    Z为5-7元单环或8-10元二环，所述5-7元单环或8-10元二环为芳基、杂芳基、杂环基或碳环基，其中所述杂芳基或杂环基具有1-4个氮、氧或硫环杂原子；所述环上任一可取代的环碳被氧代、-T-R 5或-V-W-R 5取代；所述环上任一可取代的环氮被R 7取代；
    R为氢或可选择性被取代的基团，所述可选择性被取代的基团为C 1-C 6脂族基团、C 1-C 10芳基、5-10元杂芳基环或5-10元杂环基环；
    T为化学键或C 1-4亚烷基链；
    R 4为氢、C 1-C 6烷基、氰基、卤素、卤代C 1-C 6烷基、羟基、巯基、C 1-C 6烷氧基、R 7、-COR 7、-CO 2(取代的C 1-C 6脂族基团)、-CON(R 7) 2或-SO 2R 7；
    R 5为R、卤素、-OR、-COR、-CO 2R、-COCOR、-NO 2、-CN、-SOR、-SO 2R、-SR、-N(R 4) 2、-CON(R 4) 2、-SO 2N(R 4) 2、-OCOR、-N(R 4)COR、-N(R 4)CO(取代的C 1-C 6脂族基团)、-N(R 4)N(R 4) 2、-C＝NN(R 4) 2、-C＝N、-OR、-N(R 4)CON(R 4) 2、-N(R 4)SO 2N(R 4) 2、-N(R 4)SO 2R或-OCON(R 4) 2；
    V为-O-、-S-、-SO-、-SO 2-、-N(R 6)SO 2-、-SO 2N(R 6)-、-N(R 6)-、-CO-、-CO 2-、-N(R 6)CO-、-N(R 6)CO 2-、-N(R 6)CON(R 6)-、-N(R 6)SO 2N(R 6)-、-N(R 6)N(R 6)-、-CON(R 6)-、-OC(O)N(R 6)-、-C(R 6) 2O-、-C(R 6) 2S-、-C(R 6) 2SO-、-C(R 6) 2SO 2-、-C(R 6) 2SO 2N(R 6)-、-C(R 6) 2N(R 6)-、-C(R 6) 2N(R 6)CO-、-C(R 6) 2N(R 6)CO 2-、-C(R 6)＝NN(R 6)-、-C(R 6)＝N-O-、-C(R 6) 2N(R 6)N(R 6)-、-C(R 6) 2N(R 6)SO 2N(R 6)-或-C(R 6) 2N(R 6)CON(R 6)-；
    W为-C(R 6) 2O-、-C(R 6) 2S-、-C(R 6) 2SO-、-C(R 6) 2SO 2-、-C(R 6) 2SO 2N(R 6)-、-C(R 6) 2N(R 6)-、-CO-、-CO 2-、-C(R 6)OCO-、-C(R 6)OCON(R 6)-、-C(R 6) 2N(R 6)CO-、-C(R 6) 2N(R 6)C(O)O-、-C(R 6)＝NN(R 6)-、-C(R 6)＝N-O-、-C(R 6) 2N(R 6)N(R 6)-、-C(R 6) 2N(R 6)SO 2N(R 6)-、-C(R 6) 2N(R 6)CON(R 6)-或-CON(R 6)-；
    R 6为氢或取代的C 1-C 4脂族基团，或者同一氮原子上的两个R 6与所连接的氮原子构成5-6元杂环或杂芳环；
    R 7为氢或取代的C 1-C 6脂族基团，或者同一氮原子上的两个R 7与所连接的氮原子构成5-8元杂环或杂芳环。
  2. 根据权利要求1所述的Snail抑制剂及其衍生物，其特征在于，所述Snail抑制剂及其衍生物结构中：
    Q为芳基、杂芳基或杂环基，且芳基或杂芳基被一个或多个R 4取代，其中 所述芳基为苯基；所述杂芳基为吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；所述杂环基为哌啶基、吗啉基或哌嗪基；
    X为-O-、-S-、-SO-、-SO 2-、-NH-、-N(CH 3)-、-C＝、化学键或亚甲基单位；
    G为D-L-Z，其中L为化学键、-NH-或-N(CH 3)-。
  3. 根据权利要求1所述的Snail抑制剂及其衍生物，其特征在于，所述Snail抑制剂及其衍生物结构中：
    Q为芳基、杂芳基或杂环基，且芳基或杂芳基被一个或多个R 4取代，其中所述芳基为苯基；所述杂芳基为吡啶基；
    X为-O-、-S-、-SO-、-SO 2-、-NH-、-C＝、化学键或亚甲基单位；
    G为D-L-Z，其中L为化学键、-NH-或-N(CH 3)-；Z为苯基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基、三氮唑基、四氮唑基、吡啶基、吡嗪基、嘧啶基、吗啉基、哌嗪基、哌啶基或1,4-恶嗪-4-基，取代基R 7为甲基、乙基、叔丁基、1-2个卤素、三氟甲基、甲氧基、叔丁氧羰基、氰基、环丙基或苯基。
  4. 根据权利要求1所述的Snail抑制剂及其衍生物，其特征在于，所述Snail抑制剂为以下任一化合物：
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺的制备(I-1)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-氯-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺的制备(I-2)，
    N-(2-氨基-4-氟苯基)-4-[[[[4-[(5-甲基-1H-1,2,4-***-3-基)氨基]嘧啶-2-基]硫基]甲基苯甲酰胺(I-3)，
    N-(2-氨基-4-氟苯基)-4-[[[[4-[(2-甲基-2H-四唑-5-基)氨基]嘧啶-2-基]硫基]甲基苯甲酰胺(I-4)，
    N-(2-氨基苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺的制备(I-5)，
    N-(2-(甲基氨基)苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺的制备(I-6)，
    N-(1H-吲哚-7-基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-7)，
    N-(5-氟-2-吲哚酮-7-基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基] 甲基]苯甲酰胺(I-8)，
    N-(2-氨基-4-氟-6-甲基苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-9)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]亚磺酰基]甲基]苯甲酰胺(I-10)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]磺酰基]甲基]苯甲酰胺(I-11)，
    N-(2-氨基-4-氟苯基)-4-[[(4-[(5-甲基异噁唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-12)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(1,5-二甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-13)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(1,5-二甲基-1H-吡唑-3-基)(甲基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-14)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-环丙基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-15)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-环丙基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-16)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-叔丁基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-17)，
    N-(2-氨基-4-氟苯基)-4-[[(4-吗啉代吡啶-2-基)硫基]甲基]苯甲酰胺(I-18)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(4-氟苄基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-19)，
    N-(2-氨基苯基)-4-[[[4-[(4-三氟甲基苄基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-20)，
    N-(2-氨基苯基)-4-[[[4-[(4-甲氧基苄基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-21)，
    N-(2-氨基苯基)-4-[[[4-[(3,4-二甲氧基苄基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-22)，
    N-(2-氨基苯基)-4-[[[4-[(2,4-二甲氧基苄基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-23)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-24)，
    N-(2-氨基-4-氟苯基)-4-[[(4-苯基氨基)嘧啶-2-基]硫基]甲基]苯甲酰胺(I-25)，
    N-(2-氨基-4苯基)-4-[[[4-[(3-甲基吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-26)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(4-甲基吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-27)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-28)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[[3-(三氟甲基)吡啶-2-基]氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-29)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(3-氟吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-30)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(3-甲氧基吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-31)，
    N-(2-氨基-4-氟-6-吗啉代苯基)-4-[[[4-[(3-甲基吡啶-2-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-32)，
    N-(2-氨基苯基)-4-[[[4-[(N-Boc哌啶-4-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-33)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(哌啶-4-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-34)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]氨基]甲基]苯甲酰胺(I-35)，
    N-(2-氨基-4-氟苯基)-4-[[甲基[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]氨基]甲基]苯甲酰胺(I-36)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]氧基]甲基]苯甲酰胺(I-37)，
    N-(2-氨基-4-氟苯基)-5-[[[4-[(5-甲基异噁唑-3-基)氨基]嘧啶-2-基]硫基]甲基]吡啶酰胺的制备(I-38)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]吡啶-2-基]氨基]甲基]苯甲酰胺(I-39)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]吡啶-2-基]氨基]甲基]苯甲酰胺(I-40)，
    N-(2-氨基-4-氟苯基)-4-[[[3-[(5-甲基-1H-吡唑-3-基)氨基]苯基]硫基]氨基]甲 基]苯甲酰胺(I-41)，
    N-(2-氨基-4-氟苯基)-4-[[[4-[(5-甲基-1H-吡唑-3-基)氨基]喹唑啉-2-基]硫基]甲基]苯甲酰胺(I-42)，
    N-(2-氨基-4-氟苯基)-4-[[[4-(二甲基氨基)-6-[[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-2-基]硫基]甲基]苯甲酰胺(I-43)，
    N-(2-氨基-4-氟苯基)-4-[[[[4-[(5-甲基-1H-吡唑-3-基)氨基]-6-(4-甲基哌嗪-1-基)嘧啶-2-基]硫基]甲基]苯甲酰胺(I-44)，
    N-(2-氨基-4-氟苯基)-4-[[[6-[(5-甲基-1H-吡唑-3-基)氨基]嘧啶-4-基]硫基]甲基]苯甲酰胺(I-45)。
  5. 根据权利要求1～4任一所述的Snail抑制剂及其衍生物，其特征在于，所述药学上可接受的盐为所述Snail抑制剂与酸或碱形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、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、苯基乙酸或杏仁酸，所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱。
  6. 一种权利要求1～5任一所述的Snail抑制剂及其衍生物的制备方法，其特征在于，所述制备方法为以下任一方法：
    方法一：
    化合物1经烷基化反应引入Q得到化合物2，化合物2经氯代和烷基化反应引入Z、L得到化合物4，化合物4经水解反应得到化合物5，化合物5再与化合物6发生酰化反应得到化合物I；
    Figure PCTCN2021082215-appb-100002
    方法二：
    化合物5经不同程度的氧化反应分别得到化合物7、化合物8，化合物7、化合物8再分别与化合物6发生酰化反应得到化合物I；
    Figure PCTCN2021082215-appb-100003
    其中，Q、Z、L、R、R 1、R 2和R 3的定义如权利要求1～3任一所述；
    将相应的酸或碱的溶液加入到以上任一方法制备的化合物(I)的溶液中，成盐完全后减压除去溶剂，即得所述Snail抑制剂药学上可接受的盐。
  7. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1～6任一所述Snail抑制剂和/或其衍生物以及药学上可接受的载体。
  8. 一种权利要求1～6任一所述的Snail抑制剂及其衍生物在制备治疗和/或预防与Snail抑制有关疾病药物中的应用。
  9. 一种权利要求7所述的药物组合物在制备治疗和/或预防与Snail抑制有关疾病药物中的应用。
  10. 根据权利要求8或9所述的应用，其特征在于，所述与Snail抑制有关的疾病为肺癌、黑色素瘤、肝癌、肾癌、白血病、***癌、甲状腺癌、皮肤癌、胰腺癌、直肠癌、结肠癌、卵巢癌、睾丸癌、乳腺癌、膀胱癌、胆囊癌、骨髓增生异常综合症、淋巴瘤、食管癌、胃肠道癌、星形细胞瘤、神经母细胞瘤、神经胶质瘤、神经鞘瘤、间皮瘤、非胰岛素依赖型糖尿病或自身免疫性疾病。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1578663A (zh) * 2001-09-14 2005-02-09 梅特希尔基因公司 组蛋白脱乙酰化酶抑制剂
CN1997649A (zh) * 2004-03-26 2007-07-11 梅特希尔基因公司 组蛋白脱乙酰基酶的抑制剂
WO2009063054A1 (en) * 2007-11-16 2009-05-22 4Sc Ag Novel bifunctional compounds which inhibit protein kinases and histone deacetylases
CN109593065A (zh) * 2018-12-03 2019-04-09 重庆医科大学 一类hdac/alk双靶点抑制剂及其制备方法与应用
CN111187268A (zh) * 2020-01-16 2020-05-22 中国药科大学 作为Snail抑制剂的化合物CYD19或可药用的盐及其制备方法、药物组合物和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009036057A1 (en) * 2007-09-10 2009-03-19 Curis, Inc. Antiproliferative agents containing a zinc binding moiety

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1578663A (zh) * 2001-09-14 2005-02-09 梅特希尔基因公司 组蛋白脱乙酰化酶抑制剂
CN1997649A (zh) * 2004-03-26 2007-07-11 梅特希尔基因公司 组蛋白脱乙酰基酶的抑制剂
WO2009063054A1 (en) * 2007-11-16 2009-05-22 4Sc Ag Novel bifunctional compounds which inhibit protein kinases and histone deacetylases
CN109593065A (zh) * 2018-12-03 2019-04-09 重庆医科大学 一类hdac/alk双靶点抑制剂及其制备方法与应用
CN111187268A (zh) * 2020-01-16 2020-05-22 中国药科大学 作为Snail抑制剂的化合物CYD19或可药用的盐及其制备方法、药物组合物和用途

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