WO2022174779A1 - Nucleotide derivative having anti-tumor activity, pharmaceutical composition and use thereof - Google Patents

Nucleotide derivative having anti-tumor activity, pharmaceutical composition and use thereof Download PDF

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WO2022174779A1
WO2022174779A1 PCT/CN2022/076591 CN2022076591W WO2022174779A1 WO 2022174779 A1 WO2022174779 A1 WO 2022174779A1 CN 2022076591 W CN2022076591 W CN 2022076591W WO 2022174779 A1 WO2022174779 A1 WO 2022174779A1
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compound
dsc33
formula
groups
alkyl
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PCT/CN2022/076591
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French (fr)
Chinese (zh)
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张哲峰
刘骏
李向阳
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南京赛弗斯医药科技有限公司
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Priority to CN202280010088.8A priority Critical patent/CN117157081A/en
Publication of WO2022174779A1 publication Critical patent/WO2022174779A1/en

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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to, but is not limited to, the technical field of medicinal chemistry, especially nucleotide derivatives and their pharmaceutical compositions and anti-tumor uses.
  • Such compounds can be used in various dosage forms such as injection, inhalation, liposome and oral preparation.
  • CVD cardiovascular diseases
  • Nucleotide substances participate in the molecular mechanism of gene information retention, replication and transcription in organisms, and play an important role in the regulation of cell structure, metabolism, energy and function, and are used to supplement endogenous substances or antagonize Enzymes in vivo, such as citicoline sodium, adenosine triphosphate disodium, cyclic adenosine monophosphate, riboflavin sodium phosphate, sodium phosphate creatine, etc., have good clinical effects. These endogenous substances or their structural analogs can enhance myocardial contractility, causing increased blood pressure and increased cardiac output. And can relax smooth muscle, dilate coronary blood vessels, promote the activity of respiratory chain oxidase and improve myocardial hypoxia.
  • nucleotides and their analogs have strong water solubility and polarity, not only low bioavailability, but also poor cell membrane penetration, difficulty in entering cells, and inability to exert their effects through the blood-brain barrier.
  • Nucleotides and their analogs contain multiple active groups in their molecules, which can be modified in various ways to improve their pharmacokinetic characteristics and even biological activities, so as to exert better or even various clinical therapeutic effects . Therefore, there remains a need in the art for nucleotide analogs of novel structures.
  • the inventors have developed a new class of nucleotide derivatives. During the research process, it was completely beyond the expectation of those skilled in the art that such derivatives have good anti-tumor activity, which is similar to the existing anti-tumor nucleosides. Compared with other compounds, the series of compounds of the present invention have a new base structure and better anti-tumor activity; on the whole, the nucleoside analogs of this class have good anti-tumor prospects, especially liver cancer. Nasal cancer, respiratory cancer, etc. also have better results.
  • One aspect of the present invention provides a nucleotide derivative, tautomer, stereoisomer, solvate, or a pharmaceutically acceptable salt thereof as shown in (I):
  • Y 0 is selected from -O-, -N(R a )-, -S- or -(C R b1 R b2 ) n1 -;
  • n 1 is selected from 1, 2, or 3;
  • R a , R b1 and R b2 are each independently selected from hydrogen, or C1-C8 alkyl;
  • Y 1 and Y 2 are each independently -O-, -N(H)- or -S-;
  • R 1 is selected from hydrogen, C6-C20 aryl or aryl derivatives substituted or unsubstituted with one or more groups A, C1-C8 alkyl substituted or unsubstituted with one or more groups A, or R 2 ;
  • R 2 is selected from in,
  • n 2 is selected from 1, 2, 3, or 4;
  • Y 3 is -O-, or -S-;
  • R 7 , R 8 , R c1 and R c2 are each independently hydrogen, or are selected from the following groups substituted or unsubstituted with one or more groups A: C1-C8 alkyl, benzyl;
  • R 9 is selected from the following groups substituted or unsubstituted by one or more groups A: C9-C20 alkyl, C9-C20 alkenyl, C9-C20 alkynyl, in,
  • R d1 and R d2 are each independently selected from the following groups, substituted or unsubstituted with one or more groups A: C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 Aryl, C5-C20 heteroaryl;
  • R 10 is the following groups substituted or unsubstituted by one or more groups A: C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C6-C20 aryl or C5-C20 heteroaryl base;
  • R 5 and R 6 are each independently hydrogen or selected from the following groups substituted or unsubstituted with one or more groups A: C1-C8 alkyl, benzyl;
  • the group A is one or more of the following groups: C1-C8 alkyl, C1-C8 alkoxy, aryloxy, alkylthio, alkylamino, trifluoromethyl, halogen, amino , mercapto, hydroxyl, carboxyl, cyano and nitro.
  • nucleotide derivatives provided by the present invention are shown in formula (II):
  • nucleotide derivatives provided by the present invention are shown in formula (III):
  • nucleotide derivatives provided by the present invention are shown in formula (IV):
  • nucleotide derivatives provided by the present invention are shown in formula (V):
  • alkyl refers to a saturated aliphatic hydrocarbon group consisting of carbon atoms, including straight-chain, branched or cyclic alkanes, as well as cycloalkyl-substituted alkanes and alkyl-substituted alkanes
  • the cycloalkane; the C1-C20 alkyl group represents a saturated aliphatic hydrocarbon group of 1-20 carbon atoms, such as but not limited to: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl , tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl base, tetradecyl
  • the C1-C8 alkyl group represents a saturated aliphatic hydrocarbon group of 1-8 carbon atoms, such as but not limited to: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, Pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • C9-C20 alkyl group represents the saturated aliphatic hydrocarbon group of 9-20 carbon atoms, for example including but not limited to: nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl Alkyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, 2-butyl-hexane, 3,5-dimethylcyclohexylmethyl.
  • the "alkynyl” refers to an aliphatic hydrocarbon group consisting of carbon atoms and containing at least one unsaturated carbon-carbon triple bond, including straight-chain, branched-chain or cyclic alkynes, as well as cyclic Alkynyl-substituted hydrocarbyl and hydrocarbyl-substituted cycloalkynes, wherein the alkynyl can be in the middle of a carbon chain or carbocyclic ring, or at the end;
  • the "C6-C20 aryl group” includes but is not limited to benzene, naphthalene, anthracene, or biphenyl; the “C6-C20 aryl derivative” refers to a The aryl group substituted by or multiple substituents also includes 5,6,7,8-tetrahydronaphthyl and the like.
  • the substituents include: alkyl, cycloalkyl, alkoxy, aryloxy, alkylthio, alkylamino, alkylcarbonyl, aminoalkyl, hydroxyalkyl, aminoalkylcarbonyl, heterocycloalkyl, Heterocycloalkylmethylene, monoalkylaminomethylene, bisalkylaminomethylene, halogen, amino, mercapto, hydroxyl, carboxyl, cyano and nitro.
  • the "C5-C20 heteroaryl” may be selected from thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, Triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thitriazolyl, oxtriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, Purinyl, benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl and indolyl.
  • the "alkoxy group” refers to an alkyl group connected to an oxygen atom, wherein the alkyl group is as described above;
  • the alkylthio group refers to an alkyl group connected to a sulfur atom, wherein the alkyl group The group is the same as above;
  • the alkylamino group means that the alkyl group is connected to a nitrogen atom, wherein the alkyl group is the same as the above.
  • aryloxy refers to an aryl group connected to an oxygen atom, wherein the aryl group includes substituted or unsubstituted aryl groups, and also includes aryl derivatives and heteroaryl groups.
  • the alkyl group, alkoxy group, alkylthio group, and alkyl group in the alkylamino group in the group A can be C1-C8 alkyl groups, examples include but are not limited to: methyl, ethyl propyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or 2,2-diethylethyl and the like.
  • the alkylamino group in the group A may be a monoalkylamino group or a dialkylamino group, wherein the alkyl group is as defined above.
  • the halogen in the group A is fluorine, chlorine, bromine or iodine.
  • the pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts, such as hydrochloride, sulfate, or phosphate; organic acid salts, such as methanesulfonate, ethanesulfonate, besylate, besylate, citrate, or acetate, etc.
  • Y 0 is selected from -O-, -N(R a )-, or -C(R b1 R b2 ) n1 - ;in,
  • n 1 is selected from 1, 2, or 3, preferably, n 1 is selected from 1 or 2;
  • R a is selected from hydrogen, or C1-C8 alkyl, preferably, R a is hydrogen;
  • R b1 and R b2 are each independently selected from hydrogen, or C1-C8 alkyl, preferably, one of R b1 and R b2 is hydrogen, and the other is C1-C8 alkyl, more preferably, R b1 and Both R b2 are hydrogen;
  • Y 0 is -C(R b1 R b2 ) n1 -; wherein, R b1 and R b2 are as described above Defined;
  • Y 0 is -O-.
  • Y 1 is -O-;
  • Y 1 is -N(H)-.
  • Y 2 is -O-;
  • Y 2 is -N(H)-.
  • R 1 is selected from C6-C20 aryl or aryl derivatives substituted or unsubstituted by one or more groups A, preferably, R 1 is selected from phenyl, naphthyl, 5,6,7,8-tetrahydronaphthyl substituted or unsubstituted by one or more groups A;
  • R 1 is selected from C1-C8 alkyl substituted or unsubstituted by one or more groups A, preferably, R 1 is selected from ethyl, Propyl, butyl, isobutyl, p-amyl;
  • R 1 and R 2 are the same group
  • R 1 is hydrogen
  • R 2 is in
  • R 7 and R 8 are the same, selected from hydrogen or substituted by one or more groups A Or unsubstituted following groups: C1-C8 alkyl, benzyl;
  • R 7 and R 8 are different, each independently hydrogen or selected from the group consisting of one or more groups A substituted or unsubstituted following groups: C1-C8 alkyl, benzyl;
  • R 7 is a C1-C8 alkyl or benzyl group, and R 8 is hydrogen;
  • the above Y 3 is selected from -O-, or -S-;
  • the above Y 3 is -O-;
  • the above R 9 is a C9-C20 alkyl group substituted or unsubstituted by one or more groups A;
  • the above R 9 is a C9-C20 alkenyl substituted or unsubstituted by one or more groups A;
  • the above R 9 is a C9-C20 alkynyl group substituted or unsubstituted by one or more groups A;
  • R d1 and R d2 are the same, and both are selected from the following groups: hydrogen, substituted or unsubstituted by one or more groups A: C1-C8 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C5-C20 heteroaryl;
  • the above R d1 and R d2 are different and are independently selected from the following groups: hydrogen, substituted or unsubstituted by one or more groups A: C1 -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C5-C20 heteroaryl;
  • the above R d1 and R d2 are independently selected from the following groups substituted or unsubstituted by one or more groups A: C1- C8 alkyl, C6-C20 aryl;
  • R d1 and R d2 are as defined above.
  • R 2 is in
  • R c1 and R c2 are the same, selected from hydrogen or selected from substituted or unsubstituted by one or more groups A The following groups: C1-C8 alkyl, benzyl;
  • R c1 and R c2 are different, each independently hydrogen or selected from substituted with one or more groups A or not Substituted the following groups: C1-C8 alkyl, benzyl;
  • R c1 is a C1-C8 alkyl or benzyl group, and R c2 is hydrogen;
  • Y 3 and R 9 are as defined above.
  • R 5 and R 6 are the same, and both are selected from hydrogen, or selected from the following groups substituted or unsubstituted by one or more groups A: C1-C8 alkyl, benzyl, preferably, R 5 and R 6 are both selected from hydrogen, methyl, cyclopropyl or benzyl, more preferably, R 5 and R 6 are both selected from hydrogen;
  • R 5 and R 6 are different, each independently selected from hydrogen, or selected from the following groups substituted or unsubstituted by one or more groups A Group: C1-C8 alkyl, benzyl, preferably, R 5 and R 6 are each independently selected from hydrogen, methyl, cyclopropyl or benzyl.
  • nucleotide derivatives provided by the present invention are selected from the following compounds:
  • nucleotide derivatives provided by the present invention are selected from the following compounds:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned nucleotide derivatives, tautomers, stereoisomers, solvates or pharmaceutically acceptable salts thereof.
  • the present invention discloses a pharmaceutical composition, which uses the compounds, tautomers, stereoisomers, solvates or pharmaceutically acceptable salts thereof described in the present invention as active ingredients or main active ingredients, supplemented by pharmaceutical on an acceptable carrier.
  • the present invention provides the use of the above-mentioned nucleotide derivatives, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof as antitumor drugs, for the treatment of tumors, especially liver cancer, by inhalation or inhalation. It also has good effects on lung cancer and respiratory tract cancer when it is administered in the nasal cavity.
  • the tumor especially refers to liver cancer, lung cancer, nasal cancer, respiratory tract cancer and the like.
  • nucleotide derivatives of the present invention can be formulated into pharmaceutical compositions and administered to a patient according to a variety of suitably selected modes of administration, including systemic such as oral, inhalation, nasal or parenteral, intravenous, intramuscular , transdermal or subcutaneous, etc.
  • the nucleotide derivatives of the present invention lactose and calcium stearate are mixed, pulverized, granulated and dried to prepare granules of appropriate size. Next, calcium stearate was added, and compression molding was performed to obtain a tablet.
  • the nucleotide derivatives of the present invention, lactose and microcrystalline cellulose are mixed, granulated and then compressed to form an orally disintegrating tablet.
  • the nucleotide derivatives of the present invention are mixed with a phosphate buffer to prepare an injection.
  • the nucleotide derivatives of the present invention and lactose are mixed and pulverized to form an inhalant.
  • a solution for inhalation is prepared by co-dissolving the nucleotide derivatives of the present invention, an appropriate amount of surfactant and an osmotic pressure regulator.
  • Methyltriphenylphosphonium bromide (35.7 g, 100 mmol) was added to dry toluene (500 mL) at room temperature, then potassium tert-butoxide (13.5 g, 120 mmol) was slowly added to the above system in four portions. The mixture was refluxed under an argon atmosphere for 1 hour and then cooled to room temperature. 5-Nonanone (10.9 g, 76.9 mmol) in anhydrous toluene (50 mL) was added dropwise, and the addition was complete, followed by stirring for 30 minutes.
  • compound DSC33-0401 (5.0 g, 7.23 mmol) and 80% formic acid (30 mL) were added to the reaction flask, the system was heated to 40° C. and stirred for 20 hours, the system was concentrated to dryness, water and ethyl acetate were added for extraction, and saturated common salt was added. After washing with water, the organic phase was concentrated, and the residue was separated by column chromatography to obtain compound DSC33-04 (2.41 g) with a yield of 51.2%.
  • ESI-MS(-): m/z 650.38.
  • isobutyric acid (1.76 g, 20 mmol) and N,N-carbonyldiimidazole (CDI, 3.24 g, 20 mmol) were added to tetrahydrofuran (50 mL), and the system was stirred at room temperature for 2 hours, then heated to 40 °C and stirred at After 1 hour, the temperature was raised to 80°C, and DSC33-0905 (3.64 g, 10 mmol), 4-dimethylaminopyridine (2.44 g, 20 mmol) and triethylamine (2.02 g, 20 mmol) were added to the system. The reaction was maintained at this temperature for 3 hours.
  • Step 5-Step 7 Preparation of target compound DSC33-09
  • step 5 Referring to the synthesis procedures of step 5, step 6 and step 8 in Example 2, compound DSC33-09 (54 mg) was prepared, with a total yield of 10.1%.
  • ESI-MS(-): m/z 721.32.
  • compound DSC33-1203 (3.82 g, 20 mmol) and dichloromethane (50 mL) were added to the reaction flask, the system was cooled to below -5°C, and the dichloromethane solution of compound DSC33-0205 (4.59 g, 20 mmol) was added dropwise. (15 mL), after the dripping was completed, triethylamine (2.02 g, 2 mmol) was added dropwise, the internal temperature was controlled not to be higher than 10° C., the dripping was completed, and the system was reacted for 2 hours.
  • mice with successful modeling were randomly divided into 4 groups. Negative control group: given the same volume of normal saline according to the administration volume of group D; positive control injection group: gemcitabine 5mg/ml (70umol/kg); DSC33-02iso injection group: 70umol/kg; DSC33-05iso injection group: 70umol/kg kg.
  • the first administration was recorded as the first day, once every three days for a total of three administrations, the mice were weighed every day, and the tumor volume was measured.
  • tumor inhibition rate (%) (average tumor weight of control group-average tumor weight of experimental group)/average tumor weight of control group ⁇ 100%.

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Abstract

Disclosed are a nucleotide derivative as shown in formula (I), and a pharmaceutical composition and a use thereof. The compound has good anti-tumor activity and good pharmacokinetic features, and can be used for the treatment of tumors, particularly liver cancer. Administration by inhalation or through the nasal cavity also has a good effect against lung cancer, nasal cancer, and respiratory tract cancer.

Description

一种具有抗肿瘤活性的核苷酸衍生物及其药物组合物和用途A kind of nucleotide derivative with antitumor activity and its pharmaceutical composition and use 技术领域technical field
本发明涉及但不限于药物化学技术领域，尤指核苷酸衍生物及其药物组合物和抗肿瘤用途。该类化合物可用于注射剂、吸入剂、脂质体、口服制剂等多种剂型。The present invention relates to, but is not limited to, the technical field of medicinal chemistry, especially nucleotide derivatives and their pharmaceutical compositions and anti-tumor uses. Such compounds can be used in various dosage forms such as injection, inhalation, liposome and oral preparation.
背景技术Background technique
随着社会经济水平的提高，全球化和城镇化程度的加深，人们饮食习惯等生活方式发生了重大转变。同时随着全球老龄化程度加剧，越来越多证据表明非传染性疾病，特别是心血管病(cardiovasculardisease，CVD)已经成为全球疾病负担的主要原因。2019年全球疾病、伤害和风险因素负担研究(Global Burden of Disease，GBD)显示，2019年CVD在全球共造成1856.21万死亡，已经成为全球第一大死因。With the improvement of social and economic level, the deepening of globalization and urbanization, people's eating habits and other lifestyles have undergone major changes. At the same time, with the aging of the world, more and more evidence shows that non-communicable diseases, especially cardiovascular diseases (CVD), have become the main cause of the global disease burden. According to the 2019 Global Burden of Disease, Injury and Risk Factors Study (GBD), CVD caused a total of 18.5621 million deaths worldwide in 2019, and has become the world's leading cause of death.
2019年，中国CVD患病人数为1.20亿，新发病例数1234.11万，死亡458.43万；病率、发病率和死亡率从1990年的4235.43/10万、447.81/10万和204.75/10万，分别升至2019年的8460.08/10万、867.65/10万和322.30/10万。患病率、发病率和死亡率均随年龄呈上升趋势。未来，由于高血压、饮食因素、空气污染和烟草等原因，加上人口老龄化迅速，中国CVD疾病负担仍然十分严峻。In 2019, the number of CVD patients in China was 120 million, the number of new cases was 12.3411 million, and the number of deaths was 4.5843 million; They rose to 84.608/100,000, 8.6765/100,000 and 3.2230/100,000 respectively in 2019. Prevalence, morbidity, and mortality all tend to increase with age. In the future, due to high blood pressure, dietary factors, air pollution, and tobacco, coupled with the rapid aging of the population, the burden of CVD in China will remain severe.
核苷酸类物质参与生物体中基因信息的保留、复制和转录的分子机制，在细胞的结构、代谢、能量和功能的调节等方面起着十分重要作用，用于补充内源性物质或拮抗生物体内的酶，如胞磷胆碱钠、三磷酸腺苷二钠、环磷腺苷、核黄素磷酸钠、磷酸肌酸钠等具有很好的临床效果。这些内源性物质或其结构类似物能使心肌收缩力增强，引起血压升高，心输出量增高。并能舒张平滑肌、扩张冠状动脉血管、促进呼吸链氧化酶的活性及改善心肌缺氧 等。Nucleotide substances participate in the molecular mechanism of gene information retention, replication and transcription in organisms, and play an important role in the regulation of cell structure, metabolism, energy and function, and are used to supplement endogenous substances or antagonize Enzymes in vivo, such as citicoline sodium, adenosine triphosphate disodium, cyclic adenosine monophosphate, riboflavin sodium phosphate, sodium phosphate creatine, etc., have good clinical effects. These endogenous substances or their structural analogs can enhance myocardial contractility, causing increased blood pressure and increased cardiac output. And can relax smooth muscle, dilate coronary blood vessels, promote the activity of respiratory chain oxidase and improve myocardial hypoxia.
然而，很多核苷酸及其类似物水溶性和极性较强，不仅生物利用度低，而且细胞膜穿透性差、难以进入细胞内以及通过血脑屏障而不能发挥其作用。核苷酸及其类似物的化合物分子中含多个活泼基团，可进行多种方式的修饰以改善其药代动力学特征甚至生物活性，从而发挥更好的甚至各种不同的临床治疗效果。因此，本领域仍需要新型结构的核苷酸类似物。However, many nucleotides and their analogs have strong water solubility and polarity, not only low bioavailability, but also poor cell membrane penetration, difficulty in entering cells, and inability to exert their effects through the blood-brain barrier. Nucleotides and their analogs contain multiple active groups in their molecules, which can be modified in various ways to improve their pharmacokinetic characteristics and even biological activities, so as to exert better or even various clinical therapeutic effects . Therefore, there remains a need in the art for nucleotide analogs of novel structures.
发明内容SUMMARY OF THE INVENTION
本发明人开发了一类新的核苷酸衍生物，在研究过程中，完全出乎本领域技术人员预料的发现，这类衍生物具有良好的抗肿瘤活性，与现有抗肿瘤核苷类似物相比，本发明系列化合物具有新的碱基结构和更好的抗肿瘤活性；其整体上，本类核苷类似物具有良好的抗肿瘤尤其肝癌前景，吸入或鼻腔给药时对肺癌、鼻癌、呼吸道癌等同样有较好效果。The inventors have developed a new class of nucleotide derivatives. During the research process, it was completely beyond the expectation of those skilled in the art that such derivatives have good anti-tumor activity, which is similar to the existing anti-tumor nucleosides. Compared with other compounds, the series of compounds of the present invention have a new base structure and better anti-tumor activity; on the whole, the nucleoside analogs of this class have good anti-tumor prospects, especially liver cancer. Nasal cancer, respiratory cancer, etc. also have better results.
本发明一方面提供一种如(I)所示的核苷酸衍生物、互变异构体、立体异构体、溶剂化物、或其药学上可接受盐：One aspect of the present invention provides a nucleotide derivative, tautomer, stereoisomer, solvate, or a pharmaceutically acceptable salt thereof as shown in (I):
Figure PCTCN2022076591-appb-000001
Figure PCTCN2022076591-appb-000001
式(I)中，In formula (I),
Y 0选自-O-、-N(R a)-、-S-或-(C R b1R b2) n1-；其中， Y 0 is selected from -O-, -N(R a )-, -S- or -(C R b1 R b2 ) n1 -; wherein,
n 1选自1、2、或3； n 1 is selected from 1, 2, or 3;
R a、R b1和R b2分别独立地选自氢、或C1-C8的烷基； R a , R b1 and R b2 are each independently selected from hydrogen, or C1-C8 alkyl;
Y 1和Y 2各自独立地为-O-、-N(H)-或-S-； Y 1 and Y 2 are each independently -O-, -N(H)- or -S-;
R 1选自氢、被一个或者多个基团A取代或未取代的C6-C20的芳基或芳 基衍生物、被一个或者多个基团A取代或未取代的C1-C8烷基、或R 2； R 1 is selected from hydrogen, C6-C20 aryl or aryl derivatives substituted or unsubstituted with one or more groups A, C1-C8 alkyl substituted or unsubstituted with one or more groups A, or R 2 ;
R 2选自
Figure PCTCN2022076591-appb-000002
其中， R 2 is selected from
Figure PCTCN2022076591-appb-000002
in,
n 2选自1、2、3、或4； n 2 is selected from 1, 2, 3, or 4;
Y 3为-O-、或-S-； Y 3 is -O-, or -S-;
R 7、R 8、R c1和R c2各自独立地为氢、或选自被一个或者多个基团A取代或未取代的下列基团：C1-C8的烷基、苄基； R 7 , R 8 , R c1 and R c2 are each independently hydrogen, or are selected from the following groups substituted or unsubstituted with one or more groups A: C1-C8 alkyl, benzyl;
R 9选自被一个或者多个基团A取代或未取代的下列基团：C9-C20的烷基、C9-C20的烯基、C9-C20的炔基、
Figure PCTCN2022076591-appb-000003
其中， R 9 is selected from the following groups substituted or unsubstituted by one or more groups A: C9-C20 alkyl, C9-C20 alkenyl, C9-C20 alkynyl,
Figure PCTCN2022076591-appb-000003
in,
R d1和R d2各自独立地选自氢、被一个或者多个基团A取代或未取代的下列基团：C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C20芳基、C5-C20杂芳基； R d1 and R d2 are each independently selected from the following groups, substituted or unsubstituted with one or more groups A: C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 Aryl, C5-C20 heteroaryl;
R 3和R 4各自独立地为H、或下列基团：-C(＝O)-R 10、-C(＝O)-O-R 10；其中， R 3 and R 4 are each independently H, or the following groups: -C(=O)-R 10 , -C(=O)-OR 10 ; wherein,
上述R 10为被一个或者多个基团A取代或未取代的下列基团：C1-C20烷基、C2-C20烯烃基、C2-C20炔烃基、C6-C20芳基或C5-C20杂芳基； The above R 10 is the following groups substituted or unsubstituted by one or more groups A: C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C6-C20 aryl or C5-C20 heteroaryl base;
R 5和R 6各自独立地为氢或选自被一个或者多个基团A取代或未取代的下列基团：C1-C8的烷基、苄基； R 5 and R 6 are each independently hydrogen or selected from the following groups substituted or unsubstituted with one or more groups A: C1-C8 alkyl, benzyl;
所述基团A为下列基团中一种或多种：C1-C8的烷基、C1-C8的烷氧基、芳氧基、烷硫基、烷氨基、三氟甲基、卤素、氨基、巯基、羟基、羧基、氰基和硝基。The group A is one or more of the following groups: C1-C8 alkyl, C1-C8 alkoxy, aryloxy, alkylthio, alkylamino, trifluoromethyl, halogen, amino , mercapto, hydroxyl, carboxyl, cyano and nitro.
在本发明的实施方案中，本发明提供的核苷酸衍生物，如式(II)所示：In an embodiment of the present invention, the nucleotide derivatives provided by the present invention are shown in formula (II):
Figure PCTCN2022076591-appb-000004
Figure PCTCN2022076591-appb-000004
式(II)中取代基的定义如式(I)所定义的。Substituents in formula (II) are defined as in formula (I).
在本发明的实施方案中，本发明提供的核苷酸衍生物，如式(III)所示：In an embodiment of the present invention, the nucleotide derivatives provided by the present invention are shown in formula (III):
Figure PCTCN2022076591-appb-000005
Figure PCTCN2022076591-appb-000005
式(III)中其它取代基的定义如式(I)所定义的。The other substituents in formula (III) are as defined in formula (I).
在本发明的实施方案中，本发明提供的核苷酸衍生物，如式(IV)所示：In an embodiment of the present invention, the nucleotide derivatives provided by the present invention are shown in formula (IV):
Figure PCTCN2022076591-appb-000006
Figure PCTCN2022076591-appb-000006
式(IV)中取代基的定义如式(I)所定义的。Substituents in formula (IV) are defined as in formula (I).
在本发明的实施方案中，本发明提供的核苷酸衍生物，如式(Ⅴ)所 示：In an embodiment of the present invention, the nucleotide derivatives provided by the present invention are shown in formula (V):
Figure PCTCN2022076591-appb-000007
Figure PCTCN2022076591-appb-000007
式(Ⅴ)中取代基的定义如式(I)所定义的。Substituents in formula (V) are defined as in formula (I).
在本申请的实施方案中，所述的“烷基”是指由碳原子组成的饱和的脂肪烃基，包括直链、支链或环状烷烃，也包括环烷基取代的烷烃和烷基取代的环烷烃；所述的C1-C20烷基表示1-20个碳原子的饱和的脂烃基，例如包括但不限于：甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、己基、环丙基、环丁基、环戊基、环己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基。所述C1-C8烷基表示1-8个碳原子的饱和的脂烃基，例如包括但不限于：甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、己基、环丙基、环丁基、环戊基、环己基。所述的C9-C20烷基表示9-20个碳原子的饱和的脂烃基，例如包括但不限于：壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、2-丁基-己烷基、3，5-二甲基环己基甲基。In the embodiments of the present application, the "alkyl" refers to a saturated aliphatic hydrocarbon group consisting of carbon atoms, including straight-chain, branched or cyclic alkanes, as well as cycloalkyl-substituted alkanes and alkyl-substituted alkanes The cycloalkane; the C1-C20 alkyl group represents a saturated aliphatic hydrocarbon group of 1-20 carbon atoms, such as but not limited to: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl , tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl base, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl. The C1-C8 alkyl group represents a saturated aliphatic hydrocarbon group of 1-8 carbon atoms, such as but not limited to: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, Pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Described C9-C20 alkyl group represents the saturated aliphatic hydrocarbon group of 9-20 carbon atoms, for example including but not limited to: nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl Alkyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, 2-butyl-hexane, 3,5-dimethylcyclohexylmethyl.
在本申请的实施方案中，所述的“烯基”是指由碳原子组成的含至少一个不饱和碳碳双键的脂肪烃基，包括直链、支链或环状烯烃，也包括环烯烃基取代的烃基和烃基取代的环烯烃，其中烯基可以碳链或碳环中间，也可以在末端；所述C2-C20烯烃基指含有2～20个碳原子及至少一个碳-碳双键的非芳香烃基，例如包括但不限于烯丙基、2-丁烯基(-CH 2-CH＝CH-CH 3)、3-丁烯基(-CH 2-CH 2-CH＝CH 2)、4-戊烯基(-CH 2-CH 2-CH 2-CH＝CH 2)、2-甲基-2-戊烯基(-CH 2-C(CH 3)＝CH-CH 2-CH 3)、5-己烯基(-CH 2CH 2CH 2CH＝CH 2)、2-壬烯基、2-癸烯基、2-丁基-2-己烯基、3，5-二甲基-1-环己烯基甲基、2-十二碳烯、2-十四碳烯、2-十六碳烯；所述C9-C20烯 烃基指含有9～20个碳原子及至少一个碳-碳双键的非芳香烃基，例如包括但不限于2-壬烯基、2-癸烯基、2-丁基-2-己烯基、3，5-二甲基-1-环己烯基甲基、2-十二碳烯基、2-十四碳烯基、2-十六碳烯基。 In the embodiments of this application, the "alkenyl" refers to an aliphatic hydrocarbon group consisting of carbon atoms and containing at least one unsaturated carbon-carbon double bond, including straight-chain, branched-chain or cyclic olefins, as well as cyclic olefins Hydrocarbyl-substituted hydrocarbyl and hydrocarbyl-substituted cycloalkenes, wherein the alkenyl group can be in the middle of a carbon chain or carbocyclic ring, or at the end; the C2-C20 alkene group refers to containing 2 to 20 carbon atoms and at least one carbon-carbon double bond non-aromatic hydrocarbon groups such as but not limited to allyl, 2-butenyl (-CH 2 -CH=CH-CH 3 ), 3-butenyl (-CH 2 -CH 2 -CH=CH 2 ) , 4-pentenyl (-CH 2 -CH 2 -CH 2 -CH=CH 2 ), 2-methyl-2-pentenyl (-CH 2 -C(CH 3 )=CH-CH 2 -CH 3 ), 5-hexenyl (-CH 2 CH 2 CH 2 CH=CH 2 ), 2-nonenyl, 2-decenyl, 2-butyl-2-hexenyl, 3,5-di Methyl-1-cyclohexenylmethyl, 2-dodecene, 2-tetradecene, 2-hexadecene; the C9-C20 alkenyl refers to containing 9 to 20 carbon atoms and at least A non-aromatic hydrocarbon group with a carbon-carbon double bond, such as, but not limited to, 2-nonenyl, 2-decenyl, 2-butyl-2-hexenyl, 3,5-dimethyl-1-ring Hexenylmethyl, 2-dodecenyl, 2-tetradecenyl, 2-hexadecenyl.
在本申请的实施方案中，所述的“炔基”是指由碳原子组成的含至少一个不饱和碳碳三键的脂肪烃基，包括直链、支链或环状炔烃，也包括环炔烃基取代的烃基和烃基取代的环炔烃，其中炔基可以碳链或碳环中间，也可以在末端；所述C2-C20炔烃基包括但不限于乙炔基、1-丁炔-4-基、2-丁炔基(-CH 2-C＝C-CH 3)、2-壬炔基、2-癸炔基、2-丁基-3-己炔基、2-十二碳炔基、2-十四碳炔基、2-十六碳炔基；所述C9-C20炔烃基包括但不限于2-壬炔基、2-癸炔基、2-丁基-3-己炔基、2-十二碳炔基、2-十四碳炔基、2-十六碳炔基。 In the embodiments of the present application, the "alkynyl" refers to an aliphatic hydrocarbon group consisting of carbon atoms and containing at least one unsaturated carbon-carbon triple bond, including straight-chain, branched-chain or cyclic alkynes, as well as cyclic Alkynyl-substituted hydrocarbyl and hydrocarbyl-substituted cycloalkynes, wherein the alkynyl can be in the middle of a carbon chain or carbocyclic ring, or at the end; the C2-C20 alkynyl groups include but are not limited to ethynyl, 1-butyne-4- base, 2-butynyl (-CH 2 -C=C-CH 3 ), 2-nonynyl, 2-decynyl, 2-butyl-3-hexynyl, 2-dodecynyl , 2-tetradecynyl, 2-hexadecynyl; the C9-C20 alkynyl groups include but are not limited to 2-nonynyl, 2-decynyl, 2-butyl-3-hexynyl , 2-dodecynyl, 2-tetradecynyl, 2-hexadecynyl.
在本申请的实施方案中，所述的“C6-C20的芳基”包括但不限于苯、萘、蒽、或联苯；所述的“C6-C20的芳基衍生物”是指被一个或多个取代基所取代的芳基，也包括5,6,7,8-四氢萘基等。所述取代基包含：烷基、环烷基、烷氧基、芳氧基、烷硫基、烷氨基、烷基羰基、氨基烷基、羟基烷基、氨基烷基羰基、杂环烷基、杂环烷基亚甲基、单烷胺基亚甲基、双烷胺基亚甲基、卤素、氨基、巯基、羟基、羧基、氰基和硝基。In the embodiments of the present application, the "C6-C20 aryl group" includes but is not limited to benzene, naphthalene, anthracene, or biphenyl; the "C6-C20 aryl derivative" refers to a The aryl group substituted by or multiple substituents also includes 5,6,7,8-tetrahydronaphthyl and the like. The substituents include: alkyl, cycloalkyl, alkoxy, aryloxy, alkylthio, alkylamino, alkylcarbonyl, aminoalkyl, hydroxyalkyl, aminoalkylcarbonyl, heterocycloalkyl, Heterocycloalkylmethylene, monoalkylaminomethylene, bisalkylaminomethylene, halogen, amino, mercapto, hydroxyl, carboxyl, cyano and nitro.
在本申请的实施方案中，所述“C5-C20杂芳基”可以选自噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基、噁二唑基、四唑基、噻三唑基、噁三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、四嗪基、嘌呤基、苯并噁唑基、苯并呋喃基、苯并噻唑基、苯并噻二唑基、苯并三唑基、苯并咪唑基和吲哚基。In the embodiments of the present application, the "C5-C20 heteroaryl" may be selected from thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, Triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thitriazolyl, oxtriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, Purinyl, benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl and indolyl.
在本申请的实施方案中，所述的“烷氧基”是指烷基与氧原子相连，其中的烷基同上所述；所述烷硫基是指烷基与硫原子相连，其中的烷基同上所述；所述烷氨基是指烷基与氮原子相连，其中的烷基同上所述。In the embodiments of the present application, the "alkoxy group" refers to an alkyl group connected to an oxygen atom, wherein the alkyl group is as described above; the alkylthio group refers to an alkyl group connected to a sulfur atom, wherein the alkyl group The group is the same as above; the alkylamino group means that the alkyl group is connected to a nitrogen atom, wherein the alkyl group is the same as the above.
在本申请的实施方案中，所述的“芳氧基”是指芳基与氧原子相连，其中的芳基包括取代或未取代的芳基，也包括芳基衍生物和杂芳基。In the embodiments of the present application, the "aryloxy" refers to an aryl group connected to an oxygen atom, wherein the aryl group includes substituted or unsubstituted aryl groups, and also includes aryl derivatives and heteroaryl groups.
在本申请的实施方案中，所述基团A中的烷基、烷氧基、烷硫基、烷氨基中的烷基可以是C1-C8烷基，示例包括但不限于：甲基、乙基、正丙基、 异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、新戊基、正己基或2,2-二乙基乙基等。In the embodiments of the present application, the alkyl group, alkoxy group, alkylthio group, and alkyl group in the alkylamino group in the group A can be C1-C8 alkyl groups, examples include but are not limited to: methyl, ethyl propyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or 2,2-diethylethyl and the like.
在本申请的实施方案中，所述基团A中的烷胺基可以是单烷基氨基或二烷基氨基，其中的烷基定义如上所述。In the embodiments of the present application, the alkylamino group in the group A may be a monoalkylamino group or a dialkylamino group, wherein the alkyl group is as defined above.
在本申请的实施方案中，所述基团A中的卤素为氟、氯、溴或碘。In an embodiment of the present application, the halogen in the group A is fluorine, chlorine, bromine or iodine.
在本申请的实施方案中，所述的药学上可接受的盐，包括但不限于，无机酸盐，例如盐酸盐、硫酸盐、或磷酸盐等；有机酸盐，例如甲磺酸盐、乙磺酸盐、苯磺酸盐、苯甲磺酸盐、枸橼酸盐、或乙酸盐等。In the embodiments of the present application, the pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts, such as hydrochloride, sulfate, or phosphate; organic acid salts, such as methanesulfonate, ethanesulfonate, besylate, besylate, citrate, or acetate, etc.
在一些实施方案中，上述式(I)-(Ⅱ)和/或(Ⅴ)中，Y 0选自-O-、-N(R a)-、或-C(R b1R b2) n1-；其中， In some embodiments, in the above formulas (I)-(II) and/or (V), Y 0 is selected from -O-, -N(R a )-, or -C(R b1 R b2 ) n1 - ;in,
上述n 1选自1、2、或3，优选地，n 1选自1或2； The above n 1 is selected from 1, 2, or 3, preferably, n 1 is selected from 1 or 2;
R a选自氢、或C1-C8的烷基，优选地，R a为氢； R a is selected from hydrogen, or C1-C8 alkyl, preferably, R a is hydrogen;
R b1和R b2分别独立地选自氢、或C1-C8的烷基，优选地，R b1和R b2一个为氢，另一个为C1-C8的烷基，更有选地，R b1和R b2均为氢； R b1 and R b2 are each independently selected from hydrogen, or C1-C8 alkyl, preferably, one of R b1 and R b2 is hydrogen, and the other is C1-C8 alkyl, more preferably, R b1 and Both R b2 are hydrogen;
在一些更具体的实施方案中，上述式(I)-(Ⅲ)和/或(Ⅴ)中，Y 0为-C(R b1R b2) n1-；其中，R b1和R b2如上述所定义的； In some more specific embodiments, in the above formulas (I)-(III) and/or (V), Y 0 is -C(R b1 R b2 ) n1 -; wherein, R b1 and R b2 are as described above Defined;
在一些更具体的实施方案中，上述式(I)-(Ⅱ)和/或(Ⅳ)-(Ⅴ)中，Y 0为-O-。 In some more specific embodiments, in the above formulae (I)-(II) and/or (IV)-(V), Y 0 is -O-.
在一些实施方案中，上述式(I)-(Ⅴ)中，Y 1为-O-； In some embodiments, in the above formulas (I)-(V), Y 1 is -O-;
在一些实施方案中，上述式(I)-(Ⅴ)中，Y 1为-N(H)-。 In some embodiments, in the above formulas (I)-(V), Y 1 is -N(H)-.
在一些实施方案中，上述式(I)-(Ⅴ)中，Y 2为-O-； In some embodiments, in the above formulas (I)-(V), Y 2 is -O-;
在一些实施方案中，上述式(I)-(Ⅴ)中，Y 2为-N(H)-。 In some embodiments, in the above formulas (I)-(V), Y 2 is -N(H)-.
在一些实施方案中，上述式(I)-(Ⅳ)中，R 1选自被一个或者多个基团A取代或未取代的C6-C20的芳基或芳基衍生物，优选地，R 1选自被一个或者多个基团A取代或未取代的苯基、萘基、5,6,7,8-四氢萘基； In some embodiments, in the above formulas (I)-(IV), R 1 is selected from C6-C20 aryl or aryl derivatives substituted or unsubstituted by one or more groups A, preferably, R 1 is selected from phenyl, naphthyl, 5,6,7,8-tetrahydronaphthyl substituted or unsubstituted by one or more groups A;
在一些实施方案中，上述式(I)-(Ⅳ)中，R 1选自被一个或者多个基团A取代或未取代的C1-C8烷基，优选地，R 1选自乙基、丙基、丁基、异丁基、特戊基； In some embodiments, in the above formulas (I)-(IV), R 1 is selected from C1-C8 alkyl substituted or unsubstituted by one or more groups A, preferably, R 1 is selected from ethyl, Propyl, butyl, isobutyl, p-amyl;
在一些实施方案中，上述式(I)-(Ⅳ)中，在一些实施方案中，R 1和R 2为相同基团； In some embodiments, in the above formulas (I)-(IV), in some embodiments, R 1 and R 2 are the same group;
在一些更具体的实施方案中，上述式(I)-(Ⅴ)中，R 1为氢。 In some more specific embodiments, in the above formulae (I)-(V), R 1 is hydrogen.
在一些实施方案中，上述式(I)-(Ⅱ)和/或(Ⅳ)-(Ⅴ)中，R 2为
Figure PCTCN2022076591-appb-000008
其中， In some embodiments, in the above formulas (I)-(II) and/or (IV)-(V), R 2 is
Figure PCTCN2022076591-appb-000008
in,
在一些实施方案中，上述式(I)-(Ⅱ)和/或(Ⅳ)-(Ⅴ)中，上述R 7和R 8相同，选自氢或选自被一个或者多个基团A取代或未取代的下列基团：C1-C8的烷基、苄基； In some embodiments, in the above formulae (I)-(II) and/or (IV)-(V), the above R 7 and R 8 are the same, selected from hydrogen or substituted by one or more groups A Or unsubstituted following groups: C1-C8 alkyl, benzyl;
在一些实施方案中，上述式(I)-(Ⅱ)和/或(Ⅳ)-(Ⅴ)中，上述R 7和R 8不同，各自独立地为氢或选自被一个或者多个基团A取代或未取代的下列基团：C1-C8的烷基、苄基； In some embodiments, in the above formulae (I)-(II) and/or (IV)-(V), the above R 7 and R 8 are different, each independently hydrogen or selected from the group consisting of one or more groups A substituted or unsubstituted following groups: C1-C8 alkyl, benzyl;
在一些实施方案中，上述式(I)-(Ⅱ)和/或(Ⅳ)-(Ⅴ)中，上述R 7为C1-C8的烷基或苄基，R 8为氢； In some embodiments, in the above formulas (I)-(II) and/or (IV)-(V), the above R 7 is a C1-C8 alkyl or benzyl group, and R 8 is hydrogen;
在一些实施方案中，上述式(I)-(Ⅱ)和/或(Ⅳ)-(Ⅴ)中，上述Y 3选自-O-、或-S-； In some embodiments, in the above formulas (I)-(II) and/or (IV)-(V), the above Y 3 is selected from -O-, or -S-;
优选地，在一些更进一步的实施方案中，上述式(I)-(Ⅱ)和/或(Ⅳ)-(Ⅴ)中，上述Y 3为-O-； Preferably, in some further embodiments, in the above formulas (I)-(II) and/or (IV)-(V), the above Y 3 is -O-;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 9为被一个或者多个基团A取代或未取代的C9-C20的烷基； In some embodiments, in the above formulas (I)-(V), the above R 9 is a C9-C20 alkyl group substituted or unsubstituted by one or more groups A;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 9为被一个或者多个基团A取代或未取代的C9-C20的烯基； In some embodiments, in the above formulas (I)-(V), the above R 9 is a C9-C20 alkenyl substituted or unsubstituted by one or more groups A;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 9为被一个或者多个 基团A取代或未取代的C9-C20的炔基； In some embodiments, in the above formulas (I)-(V), the above R 9 is a C9-C20 alkynyl group substituted or unsubstituted by one or more groups A;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 9为
Figure PCTCN2022076591-appb-000009
其中， In some embodiments, in the above formulas (I)-(V), the above R 9 is
Figure PCTCN2022076591-appb-000009
in,
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R d1和R d2相同，均选自氢、被一个或者多个基团A取代或未取代的下列基团：C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C20芳基、C5-C20杂芳基； In some embodiments, in the above formulas (I)-(V), the above R d1 and R d2 are the same, and both are selected from the following groups: hydrogen, substituted or unsubstituted by one or more groups A: C1-C8 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C5-C20 heteroaryl;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R d1和R d2不同，分别独立地选自氢、被一个或者多个基团A取代或未取代的下列基团：C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C20芳基、C5-C20杂芳基； In some embodiments, in the above formulae (I)-(V), the above R d1 and R d2 are different and are independently selected from the following groups: hydrogen, substituted or unsubstituted by one or more groups A: C1 -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 aryl, C5-C20 heteroaryl;
在一些更具体的实施方案中，上述式(I)-(Ⅴ)中，上述R d1和R d2分别独立地选自被一个或者多个基团A取代或未取代的下列基团：C1-C8烷基、C6-C20芳基； In some more specific embodiments, in the above formulas (I)-(V), the above R d1 and R d2 are independently selected from the following groups substituted or unsubstituted by one or more groups A: C1- C8 alkyl, C6-C20 aryl;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 9为
Figure PCTCN2022076591-appb-000010
其中， In some embodiments, in the above formulas (I)-(V), the above R 9 is
Figure PCTCN2022076591-appb-000010
in,
R d1和R d2如上述所定义的。 R d1 and R d2 are as defined above.
在一些实施方案中，上述式(I)-(Ⅲ)和/或(Ⅴ)中，R 2为
Figure PCTCN2022076591-appb-000011
其中， In some embodiments, in the above formulas (I)-(III) and/or (V), R 2 is
Figure PCTCN2022076591-appb-000011
in,
在一些实施方案中，上述式(I)-(Ⅲ)和/或(Ⅴ)中，上述R c1和R c2相同，选自氢或选自被一个或者多个基团A取代或未取代的下列基团：C1-C8的烷基、苄基； In some embodiments, in the above formulae (I)-(III) and/or (V), the above R c1 and R c2 are the same, selected from hydrogen or selected from substituted or unsubstituted by one or more groups A The following groups: C1-C8 alkyl, benzyl;
在一些实施方案中，上述式(I)-(Ⅲ)和/或(Ⅴ)中，上述R c1和R c2不同，各自独立地为氢或选自被一个或者多个基团A取代或未取代的下列基团：C1-C8的烷基、苄基； In some embodiments, in the above formulae (I)-(III) and/or (V), the above R c1 and R c2 are different, each independently hydrogen or selected from substituted with one or more groups A or not Substituted the following groups: C1-C8 alkyl, benzyl;
在一些实施方案中，上述式(I)-(Ⅲ)和/或(Ⅴ)中，上述R c1为C1-C8的烷基或苄基，R c2为氢； In some embodiments, in the above formulas (I)-(III) and/or (V), the above R c1 is a C1-C8 alkyl or benzyl group, and R c2 is hydrogen;
Y 3和R 9如上述所定义的。 Y 3 and R 9 are as defined above.
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 3和R 4各自独立地为H、或下列基团：-C(＝O)-R 10、-C(＝O)-O-R 10；其中，上述R 10选自被一个或者多个基团A取代或未取代的下列基团：C1-C20烷基、C2-C20烯烃基、C2-C20炔烃基、C6-C20芳基或C5-C20杂芳基； In some embodiments, in the above formulae (I)-(V), the above R 3 and R 4 are each independently H, or the following groups: -C(=O)-R 10 , -C(=O) -OR 10 ; wherein, the above R 10 is selected from the following groups substituted or unsubstituted by one or more groups A: C1-C20 alkyl group, C2-C20 alkenyl group, C2-C20 alkynyl group, C6-C20 aryl group base or C5-C20 heteroaryl;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 3和R 4均为H； In some embodiments, in the above formulas (I)-(V), the above R 3 and R 4 are both H;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 3和R 4均为-C(＝O)-R 10； In some embodiments, in the above formulas (I)-(V), the above R 3 and R 4 are both -C(=O)-R 10 ;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 3和R 4均为-C(＝O)-O-R 10； In some embodiments, in the above formulas (I)-(V), the above R 3 and R 4 are both -C(=O)-OR 10 ;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 3和R 4其中一个为H，另一个为-C(＝O)-R 10； In some embodiments, in the above formulas (I)-(V), one of the above R 3 and R 4 is H, and the other is -C(=O)-R 10 ;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 3和R 4其中一个为H，另一个为-C(＝O)-O-R 10。 In some embodiments, in the above formulae (I)-(V), one of the above R 3 and R 4 is H, and the other is -C(=O)-OR 10 .
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 5和R 6相同，均选自氢、或选自被一个或者多个基团A取代或未取代的下列基团：C1-C8的烷基、苄基，优选地，R 5和R 6均选自氢、甲基、环丙基或苄基，更优选地，R 5和R 6均选自氢； In some embodiments, in the above formulae (I)-(V), the above R 5 and R 6 are the same, and both are selected from hydrogen, or selected from the following groups substituted or unsubstituted by one or more groups A: C1-C8 alkyl, benzyl, preferably, R 5 and R 6 are both selected from hydrogen, methyl, cyclopropyl or benzyl, more preferably, R 5 and R 6 are both selected from hydrogen;
在一些实施方案中，上述式(I)-(Ⅴ)中，上述R 5和R 6不同，分别独立地选自氢、或选自被一个或者多个基团A取代或未取代的下列基团：C1-C8的烷基、苄基，优选地，R 5和R 6分别独立地选自氢、甲基、环丙基或苄基。 In some embodiments, in the above formulae (I)-(V), the above R 5 and R 6 are different, each independently selected from hydrogen, or selected from the following groups substituted or unsubstituted by one or more groups A Group: C1-C8 alkyl, benzyl, preferably, R 5 and R 6 are each independently selected from hydrogen, methyl, cyclopropyl or benzyl.
在一些实施方案中，本发明提供的上述核苷酸衍生物，选自下列化合物：In some embodiments, the above-mentioned nucleotide derivatives provided by the present invention are selected from the following compounds:
Figure PCTCN2022076591-appb-000012
Figure PCTCN2022076591-appb-000012
Figure PCTCN2022076591-appb-000013
Figure PCTCN2022076591-appb-000013
或者上述化合物的药学上可接受盐。Or a pharmaceutically acceptable salt of the above compound.
在一些更具体地实施方案中，本发明提供的上述核苷酸衍生物，选自下列化合物：In some more specific embodiments, the above-mentioned nucleotide derivatives provided by the present invention are selected from the following compounds:
Figure PCTCN2022076591-appb-000014
Figure PCTCN2022076591-appb-000014
Figure PCTCN2022076591-appb-000015
Figure PCTCN2022076591-appb-000015
或者上述化合物的药学上可接受盐。Or a pharmaceutically acceptable salt of the above compound.
另一方面，本发明提供了包含上述核苷酸衍生物、互变异构体、立体异构体、溶剂化物或其药学上可接受盐的药物组合物。In another aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned nucleotide derivatives, tautomers, stereoisomers, solvates or pharmaceutically acceptable salts thereof.
本发明公开了一种药物组合物，其以本发明所述的化合物、互变异构 体、立体异构体、溶剂化物或其药学上可接受盐为活性成分或主要活性成分，辅以药学上可接受的载体组成。The present invention discloses a pharmaceutical composition, which uses the compounds, tautomers, stereoisomers, solvates or pharmaceutically acceptable salts thereof described in the present invention as active ingredients or main active ingredients, supplemented by pharmaceutical on an acceptable carrier.
第三方面，本发明提供了上述核苷酸衍生物、互变异构体、立体异构体、及其药学上可接受的盐作为抗肿瘤药物的应用，用于治疗肿瘤尤其肝癌，吸入或鼻腔给药时对肺癌、呼吸道癌同样有较好效果。这里，所述的肿瘤尤其指肝癌、肺癌、鼻癌、呼吸道癌等。In a third aspect, the present invention provides the use of the above-mentioned nucleotide derivatives, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof as antitumor drugs, for the treatment of tumors, especially liver cancer, by inhalation or inhalation. It also has good effects on lung cancer and respiratory tract cancer when it is administered in the nasal cavity. Here, the tumor especially refers to liver cancer, lung cancer, nasal cancer, respiratory tract cancer and the like.
本发明所述核苷酸衍生物可以被配制为药用组合物，按照多种合适选择的给予方式给患者用药，这些途径包括全身例如口服、吸入、鼻腔或胃肠外，通过静脉内、肌肉、透皮或皮下等。The nucleotide derivatives of the present invention can be formulated into pharmaceutical compositions and administered to a patient according to a variety of suitably selected modes of administration, including systemic such as oral, inhalation, nasal or parenteral, intravenous, intramuscular , transdermal or subcutaneous, etc.
在本发明的一些实例中，将本发明核苷酸衍生物、乳糖及硬脂酸钙进行混合，进行粉碎制粒并进行干燥，制成适当尺寸的颗粒剂。接着添加硬脂酸钙，进行压缩成形而制成片剂。In some embodiments of the present invention, the nucleotide derivatives of the present invention, lactose and calcium stearate are mixed, pulverized, granulated and dried to prepare granules of appropriate size. Next, calcium stearate was added, and compression molding was performed to obtain a tablet.
在本发明的一些实例中，将本发明核苷酸衍生物、乳糖及微晶纤维素进行混合，造粒后进行压片而制成口腔崩解片。In some embodiments of the present invention, the nucleotide derivatives of the present invention, lactose and microcrystalline cellulose are mixed, granulated and then compressed to form an orally disintegrating tablet.
在本发明的一些实例中，将本发明核苷酸衍生物以及磷酸盐缓冲液进行混合而制成注射剂。In some embodiments of the present invention, the nucleotide derivatives of the present invention are mixed with a phosphate buffer to prepare an injection.
在本发明的一些实例中，将本发明核苷酸衍生物及乳糖进行混合并进行粉碎，由此制成吸入剂。In some embodiments of the present invention, the nucleotide derivatives of the present invention and lactose are mixed and pulverized to form an inhalant.
在本发明的一些实例中，将本发明核苷酸衍生物及适量表面活性剂和渗透压调节剂共同溶解后，制成吸入用溶液剂。In some embodiments of the present invention, a solution for inhalation is prepared by co-dissolving the nucleotide derivatives of the present invention, an appropriate amount of surfactant and an osmotic pressure regulator.
具体实施方式Detailed ways
以下实施例可以使本领域技术人员更全面地理解本发明，但不以任何方式限制本发明，所有化合物的结构均经MS确定。The following examples may enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way, and the structures of all compounds are confirmed by MS.
实施例1：化合物ZJT1的合成Example 1: Synthesis of compound ZJT1
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000016
Figure PCTCN2022076591-appb-000016
制备方法：Preparation:
在0℃，向化合物SM1(5.8g,20mmoL)的丙酮(150mL)溶液中缓慢加入2,2-二甲氧基丙烷(12mL,95.0mmol)，再缓慢加入浓硫酸(1.4mL,26.0mmol)，加热至45℃，反应3.5小时，TLC检测反应完全，冷却至0℃，用饱和碳酸氢钠溶液淬灭反应，减压除去丙酮，加入乙酸乙酯，分层，水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，柱层析得化合物ZJT1(6.20g)，收率93.9％。ESI-MS(+):m/z＝332.13。To a solution of compound SM1 (5.8 g, 20 mmol) in acetone (150 mL) was slowly added 2,2-dimethoxypropane (12 mL, 95.0 mmol) at 0°C, and then concentrated sulfuric acid (1.4 mL, 26.0 mmol) was slowly added , heated to 45°C, reacted for 3.5 hours, TLC detected the reaction was complete, cooled to 0°C, quenched the reaction with saturated sodium bicarbonate solution, removed acetone under reduced pressure, added ethyl acetate, separated the layers, and the aqueous phase was extracted with ethyl acetate , the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain compound ZJT1 (6.20 g) with a yield of 93.9%. ESI-MS(+): m/z=332.13.
实施例2：化合物DSC33-02的合成Example 2: Synthesis of compound DSC33-02
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000017
Figure PCTCN2022076591-appb-000017
制备方法：Preparation:
步骤1：化合物DSC33-0207的合成Step 1: Synthesis of compound DSC33-0207
在室温下，将甲基三苯基溴化磷(35.7g，100mmol)加入到无水甲苯(500mL)中，然后将叔丁醇钾(13.5g，120mmol)分四批缓慢加入到上述体系。混合物在氩气气氛下回流1小时，然后冷却至室温。滴加溶有5-壬酮(10.9g，76.9mmol)的无水甲苯溶有(50mL)，加入完毕，然后搅拌30分钟。将饱和氯化铵水溶液(300mL)加入到反应混合物中，分液，水相用正己烷萃取3次。合并有机相，用饱和食盐水洗涤2次，分出有机相，无水硫酸钠干燥，过滤，浓缩，剩余物过柱纯化，得化合物DSC33-0207(6.63g)，收率61.4％。ESI-MS(+):m/z＝141.16。Methyltriphenylphosphonium bromide (35.7 g, 100 mmol) was added to dry toluene (500 mL) at room temperature, then potassium tert-butoxide (13.5 g, 120 mmol) was slowly added to the above system in four portions. The mixture was refluxed under an argon atmosphere for 1 hour and then cooled to room temperature. 5-Nonanone (10.9 g, 76.9 mmol) in anhydrous toluene (50 mL) was added dropwise, and the addition was complete, followed by stirring for 30 minutes. A saturated aqueous ammonium chloride solution (300 mL) was added to the reaction mixture, the layers were separated, and the aqueous phase was extracted three times with n-hexane. The organic phases were combined, washed twice with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column to obtain compound DSC33-0207 (6.63 g) with a yield of 61.4%. ESI-MS(+): m/z=141.16.
步骤2：化合物DSC33-0206的合成Step 2: Synthesis of compound DSC33-0206
将化合物DSC33-0207(6.5g，46.34mmol)溶于无水四氢呋喃(500mL)中，降温至0℃，滴加2.0M的硼烷无水甲苯溶液(15mL，30.0mmol)，加入完毕，在0℃下搅拌2小时后，将反应混合物升温至室温，再搅拌2.5小时，冷却至0℃，加入乙醇(100mL)、3.0M的氢氧化钠(550mL)和35％的过氧化氢水溶液(550mL)，搅拌30分钟后，升温至室温并搅拌过夜。碱性体系用3M的盐酸水溶液调至中性，分离有机层，水层用正己烷萃取3次，合并有机相，饱和食盐水洗涤3次，分出有机相，无水硫酸钠干燥，过滤，浓缩，剩余物硅胶柱纯化，得化合物DSC33-0206(4.39g)，收率59.8％。ESI-MS(+):m/z＝159.17。Compound DSC33-0207 (6.5 g, 46.34 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL), cooled to 0 °C, 2.0 M borane anhydrous toluene solution (15 mL, 30.0 mmol) was added dropwise, the addition was completed, and the solution was heated to 0 °C. After stirring at °C for 2 hours, the reaction mixture was warmed to room temperature, stirred for another 2.5 hours, cooled to 0 °C, and ethanol (100 mL), 3.0 M sodium hydroxide (550 mL) and 35% aqueous hydrogen peroxide (550 mL) were added. , after stirring for 30 minutes, it was warmed to room temperature and stirred overnight. The alkaline system was adjusted to neutrality with 3M aqueous hydrochloric acid solution, the organic layer was separated, the aqueous layer was extracted three times with n-hexane, the organic phases were combined, washed three times with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, After concentration, the residue was purified by silica gel column to obtain compound DSC33-0206 (4.39 g) with a yield of 59.8%. ESI-MS(+): m/z=159.17.
步骤3：化合物DSC33-0205的合成Step 3: Synthesis of Compound DSC33-0205
在室温条件下，向反应瓶中依次加入化合物DSC33-0206(7.3g,46.2mmoL)，L-丙氨酸(3.3g，37.0mmoL)，对甲苯磺酸一水合物(8.1g,42.5mmoL)，安装分水器，回流反应8小时，TLC检测反应完全，冷却至室温，加入乙酸乙酯，萃取分层，有机相用饱和碳酸氢钠洗，无水硫酸钠干燥，过滤，浓缩，柱层析得化合物DSC33-0205(7.0g，82％)。ESI-MS(+):m/z＝230.20。At room temperature, compound DSC33-0206 (7.3g, 46.2mmoL), L-alanine (3.3g, 37.0mmoL), p-toluenesulfonic acid monohydrate (8.1g, 42.5mmoL) were sequentially added to the reaction flask , installed a water separator, refluxed for 8 hours, TLC detected that the reaction was complete, cooled to room temperature, added ethyl acetate, extracted and separated, the organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, concentrated, and the column layer The compound DSC33-0205 (7.0 g, 82%) was isolated. ESI-MS(+): m/z=230.20.
步骤4：化合物DSC33-0204的合成Step 4: Synthesis of Compound DSC33-0204
在氩气保护，-78℃下，向三氯氧(2.43mL，26.1mmoL)的无水二氯甲烷(25mL)溶液中缓慢滴加化合物DSC33-0205(6.0g，26.1mmoL)，三乙胺(3.63mL，26.1mmoL)的无水二氯甲烷(50mL)溶液，升温至0℃，TLC检测反应完全，冷却至-78摄氏度，向其中滴加硝基苯酚(7.26g,52.2mmoL)，三乙胺(7.26mL,52.2mmoL)的无水DCM(50mL)溶液，升温至室温反应3小时，TLC检测反应完全，饱和氯化铵淬灭反应，分层，二氯甲烷萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，柱层析得化合物DSC33-0204(10.0g)，收率69.5％。ESI-MS(+):m/z＝552.20。Under argon protection, at -78°C, compound DSC33-0205 (6.0 g, 26.1 mmol), triethylamine was slowly added dropwise to a solution of oxychloroform (2.43 mL, 26.1 mmol) in anhydrous dichloromethane (25 mL) (3.63mL, 26.1mmoL) solution in anhydrous dichloromethane (50mL), warmed to 0°C, TLC detected that the reaction was complete, cooled to -78°C, nitrophenol (7.26g, 52.2mmol) was added dropwise to it, three A solution of ethylamine (7.26 mL, 52.2 mmol) in anhydrous DCM (50 mL) was warmed to room temperature and reacted for 3 hours. TLC detected that the reaction was complete, saturated ammonium chloride was used to quench the reaction, the layers were separated, extracted with dichloromethane, and the organic phases were combined, Washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain compound DSC33-0204 (10.0 g) with a yield of 69.5%. ESI-MS(+): m/z=552.20.
步骤5：化合物DSC33-0203的合成Step 5: Synthesis of Compound DSC33-0203
在氩气保护，室温下，向化合物DSC33-0204(6.4g，11.6mmoL)、化合 物ZJT1(1.92g，5.8mmoL)和无水氯化镁(0.552g，5.8mmoL)的乙腈(100mL)溶液中滴加N,N-二异丙基乙基胺(1.87g，15.5mmoL)，升温至35℃反应2小时，TLC检测反应完全，冷却至0℃，饱和氯化铵淬灭反应，减压浓缩除去乙腈，柱层析得化合物DSC33-0203(2.2g)，收率51.0％。ESI-MS(+):m/z＝744.30。Under argon protection at room temperature, a solution of compound DSC33-0204 (6.4g, 11.6mmoL), compound ZJT1 (1.92g, 5.8mmoL) and anhydrous magnesium chloride (0.552g, 5.8mmoL) in acetonitrile (100mL) was added dropwise N,N-Diisopropylethylamine (1.87g, 15.5mmol), warmed up to 35°C and reacted for 2 hours, TLC detected the reaction was complete, cooled to 0°C, quenched the reaction with saturated ammonium chloride, concentrated under reduced pressure to remove acetonitrile , the compound DSC33-0203 (2.2g) was obtained by column chromatography, and the yield was 51.0%. ESI-MS(+): m/z=744.30.
步骤6：化合物DSC33-0202的合成Step 6: Synthesis of Compound DSC33-0202
在氩气保护，室温下，向2-(三甲基硅基)乙醇(0.32g，2.68mmoL)的四氢呋喃(20mL)溶液中加入1N叔丁基氯化镁的四氢呋喃溶液(3.48mL，3.48mmoL)，搅拌30分钟，加入化合物DSC33-0203(2.0g，2.68mmoL)的四氢呋喃(20mL)溶液，反应10小时，TLC检测反应完全，饱和氯化铵淬灭反应，减压浓缩除去四氢呋喃，柱层析得化合物DSC33-0202(1.62g)，收率83.6％。ESI-MS(+):m/z＝723.36。To a solution of 2-(trimethylsilyl)ethanol (0.32 g, 2.68 mmol) in tetrahydrofuran (20 mL) was added 1N tert-butylmagnesium chloride in tetrahydrofuran (3.48 mL, 3.48 mmol) under argon at room temperature, Stir for 30 minutes, add a solution of compound DSC33-0203 (2.0 g, 2.68 mmol) in tetrahydrofuran (20 mL), react for 10 hours, TLC detects that the reaction is complete, saturated ammonium chloride quenches the reaction, and concentrates under reduced pressure to remove tetrahydrofuran. Compound DSC33-0202 (1.62 g), yield 83.6%. ESI-MS(+): m/z=723.36.
步骤7：化合物DSC33-0201的合成Step 7: Synthesis of Compound DSC33-0201
在0℃下，向化合物DSC33-0202(1.6g，2.21mmoL)的THF(40mL)溶液中缓慢滴加3N稀盐酸(7.0mL)，30℃反应10小时，TLC检测反应完全，冷却至0℃，用饱和碳酸氢钠溶液调节PH至8，减压浓缩除去THF，柱层析得化合物DSC33-0201(0.46g)，收率30.5％。ESI-MS(+):m/z＝683.33。3N dilute hydrochloric acid (7.0 mL) was slowly added dropwise to a solution of compound DSC33-0202 (1.6 g, 2.21 mmol) in THF (40 mL) at 0 °C, and the reaction was carried out at 30 °C for 10 hours. TLC detected that the reaction was complete, and cooled to 0 °C. , adjusted PH to 8 with saturated sodium bicarbonate solution, concentrated under reduced pressure to remove THF, and obtained compound DSC33-0201 (0.46 g) by column chromatography with a yield of 30.5%. ESI-MS(+): m/z=683.33.
步骤8：化合物DSC33-02的合成Step 8: Synthesis of Compound DSC33-02
在氩气保护，室温下，向化合物DSC33-0201(0.42g，0.62mmoL)的THF(20mL)溶液中加入四丁基氟化铵(1.01mL,1moL/L)，反应3小时，TLC检测反应完全，减压浓缩除去四氢呋喃，甲醇(30mL)复溶加入DOWEX50WX8离子交换树脂(1.0g)，搅拌2小时，过滤，减压浓缩除去甲醇，柱层析得化合物DSC33-02(70mg)，收率25.3％。ESI-MS(+):m/z＝583.5。 1H-NMR(300MHz,MEOD)δ：8.03(1H,s)，7.22-7.20(1H,d,J6.0)，7.10-7.08(1H,d,J6.0)，4.80-4.78(1H,d,J6.0)，4.40-4.36(1H,q)，4.27-3.85(6H,m)，1.38-1.24(15H,m),0.94-0.86(6H,t)。 Under argon protection, at room temperature, tetrabutylammonium fluoride (1.01 mL, 1 moL/L) was added to a solution of compound DSC33-0201 (0.42 g, 0.62 mmoL) in THF (20 mL), and the reaction was carried out for 3 hours, and the reaction was detected by TLC. Complete, concentrated under reduced pressure to remove tetrahydrofuran, redissolved in methanol (30 mL), added DOWEX50WX8 ion exchange resin (1.0 g), stirred for 2 hours, filtered, concentrated under reduced pressure to remove methanol, and obtained compound DSC33-02 (70 mg) by column chromatography. The yield 25.3%. ESI-MS(+): m/z=583.5. 1 H-NMR (300MHz, MEOD) δ: 8.03 (1H, s), 7.22-7.20 (1H, d, J6.0), 7.10-7.08 (1H, d, J6.0), 4.80-4.78 (1H, d, J6.0), 4.40-4.36(1H,q), 4.27-3.85(6H,m), 1.38-1.24(15H,m), 0.94-0.86(6H,t).
实施例3：化合物DSC33-02iso的合成Example 3: Synthesis of compound DSC33-02iso
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000018
Figure PCTCN2022076591-appb-000018
制备方法：Preparation:
化合物DSC33-02(1.0g)采用手性制备液相分离，得化合物DSC33-02iso()，收率45.2％。ESI-MS(+):m/z＝583.3。Compound DSC33-02 (1.0 g) was separated by chiral preparative liquid phase to obtain compound DSC33-02iso() with a yield of 45.2%. ESI-MS(+): m/z=583.3.
实施例4：化合物ZJT2的合成Example 4: Synthesis of compound ZJT2
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000019
Figure PCTCN2022076591-appb-000019
制备方法：Preparation:
步骤1：化合物ZJT2-04的制备Step 1: Preparation of compound ZJT2-04
氮气保护下，反应瓶中依次加入化合物ZJT1(3.0g，9.1mmol)、二氯甲烷(20mL)，吡啶(2.15g，27.2mmol)、硝酸银(6.15g，36.2mmol)和4-甲氧基三苯基氯甲烷(MMTrCl，5.6g，18.1mmol)，体系室温下搅拌16小时。体系过滤、加饱和食盐水搅拌分液，分出有机相，浓缩至干，柱层析分离纯化得化 合物ZJT2-04(4.8g)，收率87.3％，ESI-MS(+):m/z＝604.25。Under nitrogen protection, compound ZJT1 (3.0 g, 9.1 mmol), dichloromethane (20 mL), pyridine (2.15 g, 27.2 mmol), silver nitrate (6.15 g, 36.2 mmol) and 4-methoxyl group were sequentially added to the reaction flask Triphenylchloromethane (MMTrCl, 5.6 g, 18.1 mmol), and the system was stirred at room temperature for 16 hours. The system was filtered, added with saturated brine and stirred for separation, the organic phase was separated, concentrated to dryness, and separated and purified by column chromatography to obtain compound ZJT2-04 (4.8g), yield 87.3%, ESI-MS(+): m/z = 604.25.
步骤2：化合物ZJT2-03的制备Step 2: Preparation of compound ZJT2-03
在氮气保护下，将化合物ZJT2-04(3.0g，5.0mmol)的二氯甲烷溶液(30mL)降温至0℃，体系加入戴斯-马丁试剂(3.74g，8.8mmol)。室温下搅拌6小时，加入二氯甲烷稀释(50mL)，用饱和硫代硫酸钠溶液和碳酸氢钠溶液洗涤，有机相浓缩至干，柱层析分离得2.6g化合物ZJT2-03(2.60g)，收率86.7％。ESI-MS(+):m/z＝602.23。Under nitrogen protection, the dichloromethane solution (30 mL) of compound ZJT2-04 (3.0 g, 5.0 mmol) was cooled to 0°C, and Dess-Martin reagent (3.74 g, 8.8 mmol) was added to the system. The mixture was stirred at room temperature for 6 hours, diluted with dichloromethane (50 mL), washed with saturated sodium thiosulfate solution and sodium bicarbonate solution, the organic phase was concentrated to dryness, and 2.6 g of compound ZJT2-03 (2.60 g) was obtained by column chromatography. , the yield is 86.7%. ESI-MS(+): m/z=602.23.
步骤3：化合物ZJT2-02的制备Step 3: Preparation of compound ZJT2-02
在氮气保护下,亚甲基二磷酸四甲酯(0.97g，4.2mmol)溶于无水四氢呋喃(25mL)中，降温至0℃，体系加入氢化钠(0.20g，8.4mmol)，0℃下搅拌0.5小时，滴加溶有化合物ZJT2-03(2.1g，3.5mmol)的四氢呋喃溶液(15mL)。体系在室温下继续反应3小时，加入饱和氯化铵水溶液淬灭反应。体系浓缩至干，加入乙酸乙酯稀释，用饱和食盐水洗涤。有机相浓缩至干，柱层析分离得到2.0g化合物ZJT2-02(2.0g)，收率80.7％。ESI-MS(+):m/z＝708.25。Under nitrogen protection, tetramethyl methylene diphosphate (0.97g, 4.2mmol) was dissolved in anhydrous tetrahydrofuran (25mL), cooled to 0°C, sodium hydride (0.20g, 8.4mmol) was added to the system, and the temperature was lowered to 0°C. After stirring for 0.5 hours, a solution of compound ZJT2-03 (2.1 g, 3.5 mmol) in tetrahydrofuran (15 mL) was added dropwise. The system continued to react for 3 hours at room temperature, and was quenched by adding saturated aqueous ammonium chloride solution. The system was concentrated to dryness, diluted with ethyl acetate, and washed with saturated brine. The organic phase was concentrated to dryness and separated by column chromatography to obtain 2.0 g of compound ZJT2-02 (2.0 g) with a yield of 80.7%. ESI-MS(+): m/z=708.25.
步骤4：化合物ZJT2-01的制备Step 4: Preparation of compound ZJT2-01
室温下，反应瓶中加入化合物ZJT2-02(2.0g，2.8mmol)和5％钯炭(0.67g，33.5％)，加入甲醇(50mL)，体系通入一个大气压的氢气搅拌过夜。体系用硅藻土过滤，浓缩至干，柱层析分离得化合物ZJT2-01(1.03g)，收率82.5％。ESI-MS(+):m/z＝438.15。At room temperature, compound ZJT2-02 (2.0 g, 2.8 mmol) and 5% palladium on carbon (0.67 g, 33.5%) were added to the reaction flask, methanol (50 mL) was added, and the system was stirred overnight under one atmosphere of hydrogen. The system was filtered through celite, concentrated to dryness, and separated by column chromatography to obtain compound ZJT2-01 (1.03 g) with a yield of 82.5%. ESI-MS(+): m/z=438.15.
步骤4：化合物ZJT2的制备Step 4: Preparation of compound ZJT2
在氮气保护下，将化合物ZJT2-01(0.8g，1.84mmol)的无水乙腈溶液(15mL)降温至0℃，体系加入三甲基溴硅烷(2.8g，18.30mmol)。体系在室温下反应3小时，体系浓缩除去过量的三甲基溴硅烷，加水淬灭，得到大量固体，体系过滤，加入二氯甲烷打浆得到化合物ZJT2(0.57g)，收率75.7％。ESI-MS(-):m/z＝408.12。Under nitrogen protection, a solution of compound ZJT2-01 (0.8 g, 1.84 mmol) in anhydrous acetonitrile (15 mL) was cooled to 0 °C, and trimethylsilyl bromide (2.8 g, 18.30 mmol) was added to the system. The system was reacted at room temperature for 3 hours, the system was concentrated to remove excess trimethylbromosilane, quenched with water to obtain a large amount of solid, the system was filtered, and dichloromethane was added to make a slurry to obtain compound ZJT2 (0.57g), yield 75.7%. ESI-MS(-): m/z=408.12.
实施例5：化合物DSC33-04的制备Example 5: Preparation of compound DSC33-04
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000020
Figure PCTCN2022076591-appb-000020
制备方法：Preparation:
步骤1：3-十六烷氧基-1丙醇的制备Step 1: Preparation of 3-hexadecyloxy-1 propanol
向反应瓶中依次加入1,3-丙二醇(9.13g，0.12mol)、叔丁醇钾(6.8g，0.061mo1)和叔戊醇(50mL)，回流状态下,慢慢滴加溴代十六烷(12.17g，0.04mol)和四氢呋喃(50mL)的混合液，3小时滴完。再回流搅拌46小时后，冷至室温，将反应液倾入水中，搅拌，用10％的盐酸调节PH＝7，加入正己烷，分出有机相，水相用正己烷萃取，合并有机相，有机相干燥，过滤，浓缩，剩余物用正戊烷重结晶得3-十六烷氧基-1丙醇(7.3g)，收率：60.6％。Add 1,3-propanediol (9.13g, 0.12mol), potassium tert-butoxide (6.8g, 0.061mol) and tert-amyl alcohol (50mL) to the reaction flask in turn, and slowly add bromohexadecanol dropwise under reflux. A mixture of alkane (12.17 g, 0.04 mol) and tetrahydrofuran (50 mL) was added dropwise in 3 hours. After refluxing and stirring for 46 hours, cooled to room temperature, the reaction solution was poured into water, stirred, adjusted to pH=7 with 10% hydrochloric acid, n-hexane was added, the organic phase was separated, the aqueous phase was extracted with n-hexane, and the organic phases were combined, The organic phase was dried, filtered, concentrated, and the residue was recrystallized from n-pentane to obtain 3-hexadecyloxy-1-propanol (7.3 g), yield: 60.6%.
步骤2：化合物DSC33-0401的制备Step 2: Preparation of compound DSC33-0401
在反应瓶中依次加入ZJT2(10.2g，25mmo1)、3-十六烷氧基-1丙醇(7.5g，25mmo1)混合溶于N-甲基吡咯烷酮(65mL)中，加热到85℃搅拌30分钟后，慢慢滴加三乙胺(16.0g，158mmol)，然后升温至100℃，滴加二环己基碳二亚胺(DCC，11.0g，53.3mmol)的N-甲基吡咯烷酮溶液(16mL)。滴加完毕，在100℃下搅拌反应10小时后，冷却至50℃，旋干，加入二氯甲烷:甲醇＝1:1的混合溶剂(500mL)，搅拌1小时后抽滤，多次冲洗滤饼,合并滤液后干燥浓缩，剩余物硅胶柱层析,得到化合物DSC33-0401(6.15g)，收率35.5％。ESI-MS(-):m/z＝690.41。ZJT2 (10.2 g, 25 mmol), 3-hexadecyloxy-1 propanol (7.5 g, 25 mmol) were added to the reaction flask in turn, mixed and dissolved in N-methylpyrrolidone (65 mL), heated to 85 °C and stirred for 30 After minutes, triethylamine (16.0 g, 158 mmol) was slowly added dropwise, then the temperature was raised to 100 °C, and a solution of dicyclohexylcarbodiimide (DCC, 11.0 g, 53.3 mmol) in N-methylpyrrolidone (16 mL) was added dropwise. ). After the dropwise addition was completed, the reaction was stirred at 100 ° C for 10 hours, cooled to 50 ° C, spin-dried, and a mixed solvent (500 mL) of dichloromethane: methanol = 1: 1 was added, stirred for 1 hour, filtered with suction, and rinsed for several times. The filtrate was combined, dried and concentrated, and the residue was subjected to silica gel column chromatography to obtain compound DSC33-0401 (6.15 g) with a yield of 35.5%. ESI-MS(-): m/z=690.41.
步骤3：化合物DSC33-04的制备Step 3: Preparation of compound DSC33-04
室温下，反应瓶中加入化合物DSC33-0401(5.0g，7.23mmol)和80％的甲酸(30mL)，体系加热至40℃搅拌20小时，体系浓缩至干，加水和乙酸乙酯萃取，饱和食盐水洗涤，有机相浓缩，剩余物柱层析分离得化合物DSC33-04(2.41g)，收率51.2％。ESI-MS(-):m/z＝650.38。At room temperature, compound DSC33-0401 (5.0 g, 7.23 mmol) and 80% formic acid (30 mL) were added to the reaction flask, the system was heated to 40° C. and stirred for 20 hours, the system was concentrated to dryness, water and ethyl acetate were added for extraction, and saturated common salt was added. After washing with water, the organic phase was concentrated, and the residue was separated by column chromatography to obtain compound DSC33-04 (2.41 g) with a yield of 51.2%. ESI-MS(-): m/z=650.38.
实施例6：化合物DSC33-04iso的制备Example 6: Preparation of compound DSC33-04iso
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000021
Figure PCTCN2022076591-appb-000021
制备方法：Preparation:
化合物DSC33-04(0.63g)采用手性制备液相分离，得化合物DSC33-04iso(0.13g)，收率20.6％。ESI-MS(-):m/z＝650.36。Compound DSC33-04 (0.63 g) was separated by chiral preparative liquid phase to obtain compound DSC33-04iso (0.13 g) with a yield of 20.6%. ESI-MS(-): m/z=650.36.
实施例7：化合物ZJT3的制备Example 7: Preparation of compound ZJT3
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000022
Figure PCTCN2022076591-appb-000022
制备方法：Preparation:
步骤1：化合物ZJT3-02的制备Step 1: Preparation of compound ZJT3-02
氮气保护下将对溴三氟甲苯(22.5g，0.1mol)加入无水四氢呋喃(350mL)中，依次加入镁粉(4.8g，0.2mol)和碘粒(0.9g，3.5mmol)，室温搅拌直至反应 完全，向其中加入5-甲氧基戊醛(11.6g，0.1mol)的四氢呋喃溶液(50mL)，继续搅拌反应13小时，冰浴下加入氯化铵溶液淬灭，用0.01M盐酸调节pH值至5～6，浓缩，所得残留物加入水和乙酸乙酯，振摇，分出有机相，用饱和食盐水洗涤，分出有机相，无水硫酸钠干燥，过滤，有机相浓缩，柱层析分离得化合物ZJT3-02(11.9g)，收率45.7％。ESI-MS(+):m/z＝261.10。Under nitrogen protection, p-bromotrifluorotoluene (22.5 g, 0.1 mol) was added to anhydrous tetrahydrofuran (350 mL), followed by magnesium powder (4.8 g, 0.2 mol) and iodine particles (0.9 g, 3.5 mmol), and stirred at room temperature until The reaction was complete, 5-methoxypentanal (11.6 g, 0.1 mol) in tetrahydrofuran solution (50 mL) was added thereto, the reaction was continued to stir for 13 hours, quenched by adding ammonium chloride solution under ice bath, and pH was adjusted with 0.01 M hydrochloric acid The obtained residue was added with water and ethyl acetate, shaken, the organic phase was separated, washed with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated, and the column The compound ZJT3-02 (11.9 g) was isolated by chromatography with a yield of 45.7%. ESI-MS(+): m/z=261.10.
步骤2：化合物ZJT3-01的制备Step 2: Preparation of compound ZJT3-01
将化合物ZJT3-02(13.0g，50mmol)加入无水四氢呋喃(150mL)中，加入乙酸(15mL)，SM2(8.8g，50mmol)，40℃下搅拌直至反应完全，向其中加入浓盐酸(7.5mL)，60℃下搅拌直至反应完全，减压浓缩，剩余物加入无水乙酸乙酯(100mL)和三乙胺(50mL)，再次浓缩，所得残留物柱层析分离得化合物ZJT3-01(7.6g)，收率47.8％。ESI-MS(+):m/z＝319.16。Compound ZJT3-02 (13.0 g, 50 mmol) was added to anhydrous tetrahydrofuran (150 mL), acetic acid (15 mL), SM2 (8.8 g, 50 mmol) were added, and stirred at 40°C until the reaction was complete, and concentrated hydrochloric acid (7.5 mL) was added thereto. ), stirred at 60°C until the reaction was complete, concentrated under reduced pressure, added anhydrous ethyl acetate (100 mL) and triethylamine (50 mL) to the residue, concentrated again, and the obtained residue was separated by column chromatography to obtain compound ZJT3-01 (7.6 g), yield 47.8%. ESI-MS(+): m/z=319.16.
步骤3：化合物ZJT3的制备Step 3: Preparation of Compound ZJT3
参考实施例2步骤4的合成工序，制备得化合物ZJT3(9.5g)，收率52.1％。ESI-MS(+):m/z＝641.16。Referring to the synthesis procedure of step 4 of Example 2, compound ZJT3 (9.5 g) was prepared with a yield of 52.1%. ESI-MS(+): m/z=641.16.
实施例8：化合物DSC33-05的制备Example 8: Preparation of compound DSC33-05
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000023
Figure PCTCN2022076591-appb-000023
制备方法：Preparation:
参考实施例2步骤5-步骤8的合成工序，制备得化合物DSC33-05(0.12g)，总收率3.1％。ESI-MS(+):m/z＝670.19Referring to the synthesis procedures from Step 5 to Step 8 in Example 2, compound DSC33-05 (0.12 g) was prepared, with a total yield of 3.1%. ESI-MS(+): m/z=670.19
实施例9：化合物DSC33-05iso的制备Example 9: Preparation of compound DSC33-05iso
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000024
Figure PCTCN2022076591-appb-000024
制备方法：Preparation:
化合物DSC33-05(1.0g)采用手性制备液相分离，得化合物DSC33-05iso(0.22g)，收率22.0％。ESI-MS(+):m/z＝748.27。Compound DSC33-05 (1.0 g) was separated by chiral preparative liquid phase to obtain compound DSC33-05iso (0.22 g) with a yield of 22.0%. ESI-MS(+): m/z=748.27.
实施例10：化合物DSC33-06的制备Example 10: Preparation of compound DSC33-06
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000025
Figure PCTCN2022076591-appb-000025
制备方法：Preparation:
步骤1：化合物DSC33-0604的制备Step 1: Preparation of compound DSC33-0604
参考实施例4步骤1的操作工序，制备得化合物DSC33-0604(2.11g)，收率67.3％。ESI-MS(+):m/z＝346.17。Referring to the operation procedure of step 1 in Example 4, compound DSC33-0604 (2.11 g) was prepared with a yield of 67.3%. ESI-MS(+): m/z=346.17.
步骤2-步骤5分别参考实施例2步骤5-步骤8的操作工序，制备得化合物DSC33-06(58mg)，总收率2.4％。ESI-MS(-):m/z＝595.23。Step 2-Step 5 Referring to the operation procedures of Step 5-Step 8 in Example 2, respectively, compound DSC33-06 (58 mg) was prepared, and the total yield was 2.4%. ESI-MS(-): m/z=595.23.
实施例11：化合物DSC33-14的制备Example 11: Preparation of compound DSC33-14
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000026
Figure PCTCN2022076591-appb-000026
制备方法：Preparation:
化合物DSC33-06(0.3g)采用手性制备液相分离，得化合物DSC33-06iso(42mg)，收率14.0％。ESI-MS(-):m/z＝595.25。Compound DSC33-06 (0.3 g) was separated by chiral preparative liquid phase to obtain compound DSC33-06iso (42 mg) with a yield of 14.0%. ESI-MS(-): m/z=595.25.
实施例12：化合物DSC33-09的制备Example 12: Preparation of compound DSC33-09
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000027
Figure PCTCN2022076591-appb-000027
制备方法：Preparation:
步骤1：化合物DSC33-0906的制备Step 1: Preparation of compound DSC33-0906
氮气保护下，将化合物ZJT1(6.62g，20mmol)和2，6-二甲基吡啶(4.3g，40mmol)溶液N,N-二甲基甲酰胺(50mL)中，体系降温至0℃，滴加三甲基氯硅烷(TMSCl，2.83g，26mmol)，滴加完毕，体系自然升温至20℃反应2小时。反应结束后，体系加水析晶，得到化合物DSC33-0906(6.91g)，收率85.6％。ESI-MS(+):m/z＝404.18。Under nitrogen protection, a solution of compound ZJT1 (6.62 g, 20 mmol) and 2,6-lutidine (4.3 g, 40 mmol) in N,N-dimethylformamide (50 mL) was cooled to 0 °C, dropwise added. Trimethylchlorosilane (TMSCl, 2.83 g, 26 mmol) was added, and the dropwise addition was completed, and the system was naturally heated to 20° C. to react for 2 hours. After the reaction, water was added to the system for crystallization to obtain compound DSC33-0906 (6.91 g) with a yield of 85.6%. ESI-MS(+): m/z=404.18.
步骤2：化合物DSC33-0905的制备Step 2: Preparation of compound DSC33-0905
将化合物DSC33-0906(6.5g，16.1mmol)加入三氟乙酸和水的混合溶液(8：2，15mL)中，控温至30℃搅拌1小时。体系浓缩至干，用乙酸乙酯萃取，分出有机相浓缩至干，过硅胶柱纯化得到化合物DSC33-0905(4.93g)，收率84.3％，ESI-MS(+):m/z＝364.18。Compound DSC33-0906 (6.5 g, 16.1 mmol) was added to a mixed solution of trifluoroacetic acid and water (8:2, 15 mL), and the temperature was controlled to 30° C. and stirred for 1 hour. The system was concentrated to dryness, extracted with ethyl acetate, the organic phase was separated and concentrated to dryness, and purified by silica gel column to obtain compound DSC33-0905 (4.93g), yield 84.3%, ESI-MS(+): m/z=364.18 .
步骤3：化合物DSC33-0904的制备Step 3: Preparation of compound DSC33-0904
室温下，将异丁酸(1.76g，20mmol)和N,N-羰基二咪唑(CDI，3.24g，20mmol)加入到四氢呋喃(50mL)中，体系室温下搅拌2小时，升温到40℃下搅拌1小时，然后升温至80℃，体系中加入DSC33-0905(3.64g，10mmol)和4-二甲氨基吡啶(2.44g，20mmol)和三乙胺(2.02g，20mmol)。维持该温度反应3小时。体系降温浓缩，加入甲基叔丁基醚和水，分出有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，剩余物过柱纯化得到化合物DSC33-0904(3.28g)，收率65.1％。ESI-MS(+):m/z＝504.20。At room temperature, isobutyric acid (1.76 g, 20 mmol) and N,N-carbonyldiimidazole (CDI, 3.24 g, 20 mmol) were added to tetrahydrofuran (50 mL), and the system was stirred at room temperature for 2 hours, then heated to 40 °C and stirred at After 1 hour, the temperature was raised to 80°C, and DSC33-0905 (3.64 g, 10 mmol), 4-dimethylaminopyridine (2.44 g, 20 mmol) and triethylamine (2.02 g, 20 mmol) were added to the system. The reaction was maintained at this temperature for 3 hours. The system was cooled and concentrated, methyl tert-butyl ether and water were added, the organic phase was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column to obtain compound DSC33-0904 (3.28 g ), the yield was 65.1%. ESI-MS(+): m/z=504.20.
步骤4：化合物DSC33-0903的制备Step 4: Preparation of compound DSC33-0903
反应瓶中，将化合物DSC33-0904(3.2g，6.32mmol)和四丁基氟化胺(1.65g，6.32mmol)溶液甲醇(50mL)，体系30℃反应5小时。体系浓缩至干。体系用乙酸乙酯和水萃取多次，分出有机相浓缩至干，过硅胶柱纯化得到化合物DSC33-0903(1.70g)，收率62.3％。ESI-MS(+):m/z＝432.20。In the reaction flask, compound DSC33-0904 (3.2 g, 6.32 mmol) and tetrabutylamine fluoride (1.65 g, 6.32 mmol) solution in methanol (50 mL) were reacted at 30° C. for 5 hours. The system was concentrated to dryness. The system was extracted with ethyl acetate and water for several times, the organic phase was separated and concentrated to dryness, and purified by silica gel column to obtain compound DSC33-0903 (1.70 g) with a yield of 62.3%. ESI-MS(+): m/z=432.20.
步骤5-步骤7：目标化合物DSC33-09的制备Step 5-Step 7: Preparation of target compound DSC33-09
分别参考实施例2步骤5、步骤6和步骤8的合成工序，制备得化合物DSC33-09(54mg)，总收率10.1％。ESI-MS(-):m/z＝721.32。Referring to the synthesis procedures of step 5, step 6 and step 8 in Example 2, compound DSC33-09 (54 mg) was prepared, with a total yield of 10.1%. ESI-MS(-): m/z=721.32.
实施例13：化合物DSC33-09iso的制备Example 13: Preparation of compound DSC33-09iso
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000028
Figure PCTCN2022076591-appb-000028
制备方法：Preparation:
化合物DSC33-09(0.43g)采用手性制备液相分离，得化合物DSC33-09iso(67mg)，收率15.6％。ESI-MS(-):m/z＝721.36。Compound DSC33-09 (0.43 g) was separated by chiral preparative liquid phase to obtain compound DSC33-09iso (67 mg) with a yield of 15.6%. ESI-MS(-): m/z=721.36.
实施例14：化合物DSC33-12的制备Example 14: Preparation of compound DSC33-12
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000029
Figure PCTCN2022076591-appb-000029
制备方法：Preparation:
步骤1：化合物DSC33-1203的制备Step 1: Preparation of compound DSC33-1203
向将异丁醇(7.41g，100.0mmol)溶于二氯甲烷(100mL)中，然后加入三乙胺(10.1g，100.0mmol)，冷却至0℃，缓慢加入三氯氧磷(15.3g，100mmol)，并在0℃下搅拌混合物1小时。体系过滤，滤液减压蒸干，得化合物DSC33-1203(18.3g)，收率95.8％。To isobutanol (7.41 g, 100.0 mmol) was dissolved in dichloromethane (100 mL), then triethylamine (10.1 g, 100.0 mmol) was added, cooled to 0 °C, and phosphorus oxychloride (15.3 g, 100.0 mmol) was added slowly. 100 mmol), and the mixture was stirred at 0 °C for 1 h. The system was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain compound DSC33-1203 (18.3 g) with a yield of 95.8%.
步骤2：化合物DSC33-1202的制备Step 2: Preparation of compound DSC33-1202
氮气保护下，反应瓶中加入化合物DSC33-1203(3.82g，20mmol)和二氯甲烷(50mL)，体系降温至-5℃以下，滴加化合物DSC33-0205(4.59克20mmol)的二氯甲烷溶液(15mL)，滴毕，滴加三乙胺(2.02g，2mmol)，控制内温不高于10℃，滴毕，体系反应2小时。滴加五氟苯酚(3.68g，20mmol)的二氯甲烷溶液(15mL)，控制内温不高于10℃，滴毕，再次滴加三乙胺(2.02g，19mmol)。滴毕，体系升温室温反应。反应结束后，加入硫酸氢钠的水溶液，搅拌30分钟，分出有机相，有机相水洗后浓缩至干，过柱纯化，得化合物DSC33-1202(6.75g)，收率63.5％。ESI-MS(+):m/z＝532.21。Under nitrogen protection, compound DSC33-1203 (3.82 g, 20 mmol) and dichloromethane (50 mL) were added to the reaction flask, the system was cooled to below -5°C, and the dichloromethane solution of compound DSC33-0205 (4.59 g, 20 mmol) was added dropwise. (15 mL), after the dripping was completed, triethylamine (2.02 g, 2 mmol) was added dropwise, the internal temperature was controlled not to be higher than 10° C., the dripping was completed, and the system was reacted for 2 hours. A solution of pentafluorophenol (3.68 g, 20 mmol) in dichloromethane (15 mL) was added dropwise, and the internal temperature was controlled not to be higher than 10 °C. After the dropping was completed, triethylamine (2.02 g, 19 mmol) was added dropwise again. After dripping, the system was heated to room temperature for reaction. After the reaction, an aqueous solution of sodium bisulfate was added, stirred for 30 minutes, the organic phase was separated, the organic phase was washed with water, concentrated to dryness, and purified by column to obtain compound DSC33-1202 (6.75 g) with a yield of 63.5%. ESI-MS(+): m/z=532.21.
步骤3：化合物DSC33-1201的制备Step 3: Preparation of compound DSC33-1201
氮气保护下，反应瓶中加入化合物DSC33-12022(1.93g，3.63mmol)和化合物ZJT1(1.0g，3.0mmol)，无水乙腈(20mL)，无水氯化镁(0.58g，6.0mmol)，体系加热至50℃，加入二异丙基乙胺(1.0g，7.74mmol)，反应体系在50℃继续反应。反应结束后，体系减压蒸馏浓缩至干，加入二氯甲烷和水，分出有机相浓缩至干，过硅胶柱纯化得到化合物DSC3301(1.05g)，收率51.6％。ESI-MS(+):m/z＝679.33。Under nitrogen protection, compound DSC33-12022 (1.93g, 3.63mmol) and compound ZJT1 (1.0g, 3.0mmol), anhydrous acetonitrile (20mL), anhydrous magnesium chloride (0.58g, 6.0mmol) were added to the reaction flask, and the system was heated To 50°C, diisopropylethylamine (1.0 g, 7.74 mmol) was added, and the reaction system continued to react at 50°C. After the reaction, the system was concentrated to dryness by distillation under reduced pressure, dichloromethane and water were added, the organic phase was separated and concentrated to dryness, and purified by silica gel column to obtain compound DSC3301 (1.05g), yield 51.6%. ESI-MS(+): m/z=679.33.
步骤4：化合物DSC33-12的制备Step 4: Preparation of compound DSC33-12
参考实施例2步骤7的操作工序，制备得化合物DSC33-12(0.23g)，收率31.1％。ESI-MS(+):m/z＝639.33。Referring to the operation procedure of step 7 of Example 2, the compound DSC33-12 (0.23 g) was prepared with a yield of 31.1%. ESI-MS(+): m/z=639.33.
化合物DSC33-12ios的制备Preparation of compound DSC33-12ios
反应式：Reaction formula:
Figure PCTCN2022076591-appb-000030
Figure PCTCN2022076591-appb-000030
制备方法：Preparation:
化合物DSC33-12(1.0g)采用手性制备液相分离，得化合物DSC33-12iso(0.342g)，收率34.2％。ESI-MS(+):m/z＝638.34。Compound DSC33-12 (1.0 g) was separated by chiral preparative liquid phase to obtain compound DSC33-12iso (0.342 g) with a yield of 34.2%. ESI-MS(+): m/z=638.34.
按照与上述实施例相似的方法，使用市售化合物或由市售化合物适当合成的中间体化合物，合成了下列实施例化合物。The following example compounds were synthesized in a similar manner to the above examples, using commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.
Figure PCTCN2022076591-appb-000031
Figure PCTCN2022076591-appb-000031
Figure PCTCN2022076591-appb-000032
Figure PCTCN2022076591-appb-000032
Figure PCTCN2022076591-appb-000033
Figure PCTCN2022076591-appb-000033
Figure PCTCN2022076591-appb-000034
Figure PCTCN2022076591-appb-000034
本申请描述了多个实施例，但是该描述是示例性的，而不是限制性的，并且对于本领域的普通技术人员来说显而易见的是，在本申请所描述的实施例包含的范围内可以有更多的实施例和实现方案。This application describes a number of embodiments, but the description is exemplary rather than restrictive, and it will be apparent to those of ordinary skill in the art that within the scope of the embodiments described in this application can be There are many more examples and implementations.
实施例6：DSC3311动物模型抗肿瘤药效学评价Example 6: Antitumor pharmacodynamic evaluation of DSC3311 animal model
取昆明小鼠(雄性)，将肝癌细胞(鼠源)H22注射到腹腔内，培养至腹腔长满腹水，抽取小鼠腹水，离心，取上层液稀释成浓度约为2×10 7个细胞/ml的悬液。左前侧腋下接种0.2ml。至第3天，挑选肿瘤大小相近的荷瘤小鼠，注射给药。 Take Kunming mice (male), inject liver cancer cells (mouse source) H22 into the abdominal cavity, culture until the abdominal cavity is full of ascites, extract the mouse ascites, centrifuge, and take the supernatant and dilute it to a concentration of about 2 × 10 7 cells/ ml of suspension. Inoculate 0.2ml in the left anterior axilla. On the third day, tumor-bearing mice with similar tumor sizes were selected and administered by injection.
取建模成功小鼠，随机分成4组。阴性对照组∶按D组给药体积量给予等体积生理盐水；阳性对照注射组∶吉西他滨5mg/ml(70umol/kg)；DSC33-02iso注射组：70umol/kg；DSC33-05iso注射组：70umol/kg。第一次给药记作第一天，每三天给药一次，共给药三次，每天称量小鼠体重，测肿瘤体积。The mice with successful modeling were randomly divided into 4 groups. Negative control group: given the same volume of normal saline according to the administration volume of group D; positive control injection group: gemcitabine 5mg/ml (70umol/kg); DSC33-02iso injection group: 70umol/kg; DSC33-05iso injection group: 70umol/kg kg. The first administration was recorded as the first day, once every three days for a total of three administrations, the mice were weighed every day, and the tumor volume was measured.
药效评价：抑瘤率(％)＝(对照组平均瘤重-实验组平均瘤重)/对照组平均瘤重×100％。Efficacy evaluation: tumor inhibition rate (%)=(average tumor weight of control group-average tumor weight of experimental group)/average tumor weight of control group×100%.
// 阴性对照组negative control group 阳性对照组positive control group DSC33-02iso组DSC33-02iso group DSC33-05iso组DSC33-05iso group
平均瘤重(g)Average tumor weight (g) 3.12±0.323.12±0.32 0.88±0.170.88±0.17 0.83±0.240.83±0.24 0.58±0.110.58±0.11
平均抑瘤率(％)Average tumor inhibition rate (%) ---- 69.369.3 73.473.4 78.678.6
该结果表明DSC33-02iso和DSC33-05iso均具有明显抗肝癌活性。The results indicated that both DSC33-02iso and DSC33-05iso had significant anti-cancer activity.
本申请描述了多个实施例，但是该描述是示例性的，而不是限制性的，并且对于本领域的普通技术人员来说显而易见的是，在本申请所描述的实施例包含的范围内可以有更多的实施例和实现方案。This application describes a number of embodiments, but the description is exemplary rather than restrictive, and it will be apparent to those of ordinary skill in the art that within the scope of the embodiments described in this application can be There are many more examples and implementations.

Claims (9)

  1. 一种如(I)所示的核苷酸衍生物、互变异构体、立体异构体、溶剂化物、或其药学上可接受盐：A nucleotide derivative, tautomer, stereoisomer, solvate, or a pharmaceutically acceptable salt thereof as shown in (I):
    Figure PCTCN2022076591-appb-100001
    Figure PCTCN2022076591-appb-100001
    式(I)中，In formula (I),
    Y 0选自-O-、-N(R a)-、-S-或-(C R b1R b2n) 1-；其中， Y 0 is selected from -O-, -N(R a )-, -S- or -(C R b1 R b2n ) 1 -; wherein,
    n 1选自1、2、或3； n 1 is selected from 1, 2, or 3;
    R a、R b1和R b2分别独立地选自氢、或C1-C8的烷基； R a , R b1 and R b2 are each independently selected from hydrogen, or C1-C8 alkyl;
    Y 1和Y 2各自独立地为-O-、-N(H)-或-S-； Y 1 and Y 2 are each independently -O-, -N(H)- or -S-;
    R 1选自氢、被一个或者多个基团A取代或未取代的C6-C20的芳基或芳基衍生物、被一个或者多个基团A取代或未取代的C1-C8烷基、或R 2； R 1 is selected from hydrogen, C6-C20 aryl or aryl derivatives substituted or unsubstituted with one or more groups A, C1-C8 alkyl substituted or unsubstituted with one or more groups A, or R 2 ;
    R 2选自
    Figure PCTCN2022076591-appb-100002
    其中，     R 2 is selected from
    Figure PCTCN2022076591-appb-100002
    in,
    n 2选自1、2、3、或4； n 2 is selected from 1, 2, 3, or 4;
    Y 3为-O-、或-S-； Y 3 is -O-, or -S-;
    R 7、R 8、R c1和R c2各自独立地选自氢、或选自被一个或者多个基团A取代或未取代的下列基团：C1-C8的烷基、苄基； R 7 , R 8 , R c1 and R c2 are each independently selected from hydrogen, or from the following groups substituted or unsubstituted with one or more groups A: C1-C8 alkyl, benzyl;
    R 9选自被一个或者多个基团A取代或未取代的下列基团：C9-C20的烷基、C9-C20的烯基、C9-C20的炔基、
    Figure PCTCN2022076591-appb-100003
    其中，     R 9 is selected from the following groups substituted or unsubstituted by one or more groups A: C9-C20 alkyl, C9-C20 alkenyl, C9-C20 alkynyl,
    Figure PCTCN2022076591-appb-100003
    in,
    R d1和R d2各自独立地选自氢、被一个或者多个基团A取代或未取代的 下列基团：C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C20芳基、C5-C20杂芳基； R d1 and R d2 are each independently selected from the following groups, substituted or unsubstituted with one or more groups A: C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C20 Aryl, C5-C20 heteroaryl;
    R 3和R 4各自独立地为H、或下列基团：-C(＝O)-R 10、-C(＝O)-O-R 10；其中， R 3 and R 4 are each independently H, or the following groups: -C(=O)-R 10 , -C(=O)-OR 10 ; wherein,
    上述R 10为被一个或者多个基团A取代或未取代的下列基团：C1-C20烷基、C2-C20烯烃基、C2-C20炔烃基、C6-C20芳基或C5-C20杂芳基； The above R 10 is the following groups substituted or unsubstituted by one or more groups A: C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C6-C20 aryl or C5-C20 heteroaryl base;
    R 5和R 6各自独立地为氢或选自被一个或者多个基团A取代或未取代的下列基团：C1-C8的烷基、苄基； R 5 and R 6 are each independently hydrogen or selected from the following groups substituted or unsubstituted with one or more groups A: C1-C8 alkyl, benzyl;
    所述基团A为下列基团中一种或多种：C1-C8的烷基、C1-C8的烷氧基、芳氧基、烷硫基、烷氨基、三氟甲基、卤素、氨基、巯基、羟基、羧基、氰基和硝基。The group A is one or more of the following groups: C1-C8 alkyl, C1-C8 alkoxy, aryloxy, alkylthio, alkylamino, trifluoromethyl, halogen, amino , mercapto, hydroxyl, carboxyl, cyano and nitro.
  2. 如权利要求1所述核苷酸衍生物，如式(II)所示：Nucleotide derivatives as claimed in claim 1, as shown in formula (II):
    Figure PCTCN2022076591-appb-100004
    Figure PCTCN2022076591-appb-100004
    式(II)中其它取代基的定义如权利要求1式(I)所定义的。The definitions of other substituents in formula (II) are as defined in claim 1 for formula (I).
  3. 如权利要求1至2所述核苷酸衍生物，如式(III)所示：Nucleotide derivatives as claimed in claims 1 to 2, as shown in formula (III):
    Figure PCTCN2022076591-appb-100005
    Figure PCTCN2022076591-appb-100005
    式(III)中其它取代基的定义如权利要求1式(I)所定义的。The definitions of other substituents in formula (III) are as defined in claim 1 for formula (I).
  4. 如权利要求1至2所述核苷酸衍生物，如式(IV)所示：Nucleotide derivatives as claimed in claims 1 to 2, as shown in formula (IV):
    Figure PCTCN2022076591-appb-100006
    Figure PCTCN2022076591-appb-100006
    式(IV)中取代基的定义如权利要求1式(I)所定义的。Substituents in formula (IV) are defined as in claim 1 for formula (I).
  5. 如权利要求1至2所述核苷酸衍生物，如式(Ⅴ)所示：Nucleotide derivatives as claimed in claims 1 to 2, represented by formula (V):
    Figure PCTCN2022076591-appb-100007
    Figure PCTCN2022076591-appb-100007
    式(Ⅴ)中取代基的定义如权利要求1式(I)所定义的。Substituents in formula (V) are defined as in claim 1 for formula (I).
  6. 如权利要求1至5所述的核苷酸衍生物，选自下列化合物：The nucleotide derivatives of claims 1 to 5 are selected from the group consisting of the following compounds:
    Figure PCTCN2022076591-appb-100008
    Figure PCTCN2022076591-appb-100008
    Figure PCTCN2022076591-appb-100009
    Figure PCTCN2022076591-appb-100009
    或者上述化合物的药学上可接受盐。Or a pharmaceutically acceptable salt of the above compound.
  7. 如权利要求1至5所述的核苷酸衍生物，选自下列化合物：The nucleotide derivatives of claims 1 to 5 are selected from the group consisting of the following compounds:
    Figure PCTCN2022076591-appb-100010
    Figure PCTCN2022076591-appb-100010
    Figure PCTCN2022076591-appb-100011
    Figure PCTCN2022076591-appb-100011
  8. 包含如权利要求1～7中任一项所述的核苷酸衍生物、互变异构体、立体异构体、溶剂化物、或其药学上可接受盐的药物组合物。A pharmaceutical composition comprising the nucleotide derivative, tautomer, stereoisomer, solvate, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.
  9. 权利要求1～7中任一项所述的核苷酸衍生物、互变异构体、立体异 构体、溶剂化物、或其药学上可接受盐，或者权利要求8所述的药物组合物在制备抗肿瘤药物中的应用。The nucleotide derivative, tautomer, stereoisomer, solvate, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 8 Application in the preparation of antitumor drugs.
PCT/CN2022/076591 2021-02-19 2022-02-17 Nucleotide derivative having anti-tumor activity, pharmaceutical composition and use thereof WO2022174779A1 (en)

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