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CN113372267B - C-Met kinase inhibitor - Google Patents

C-Met kinase inhibitor Download PDF

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Publication number
CN113372267B
CN113372267B CN202010160921.XA CN202010160921A CN113372267B CN 113372267 B CN113372267 B CN 113372267B CN 202010160921 A CN202010160921 A CN 202010160921A CN 113372267 B CN113372267 B CN 113372267B
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compound
formula
acid
pharmaceutically acceptable
alkyl
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CN113372267A (en
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张贵民
张君香
白文钦
刘忠
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical Kinetics & Catalysis (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a sulfonylamidine compound with a novel structure as well as a preparation method and application thereof. The sulfonylamidine compound is a compound shown in a formula (I), or polymorphs, prodrugs, solvates, hydrates, co-crystals, pharmaceutically acceptable salts and the like thereof. The sulfonylamidine compound provided by the invention has a good proliferation inhibition effect on various cancer cells, has a low tumor cell inhibition concentration, remarkably improves the activity of the compound, has a good selectivity on tumor cells, and is expected to be a specific antitumor drug targeting c-Met kinase.

Description

C-Met kinase inhibitor
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a c-Met kinase inhibitor.
Background
The c-Met or HGFR is a protein product encoded by the c-Met protooncogene, is a receptor tyrosine kinase with high affinity, and is the only known high affinity receptor for Hepatocyte Growth Factor (HGF). Activation of the HGF/c-Met signaling pathway plays a very important role in cell proliferation, motility, migration and survival. However, in many common malignant tumors, abnormally high expression of c-Met and HGF results in abnormal activation of HGF/c-Met signaling pathway, which is in close and indiscriminate association with proliferation, metastasis, invasion, anti-apoptosis and tumor angiogenesis of tumor cells. Therefore, c-Met kinase and related signal pathways have become an important target for anti-tumor drug research. Of the many c-Met kinase inhibitors, the most prominent is the research directed to small molecule inhibitors. The structure-activity relationship shows that the inhibitor mainly consists of three parts, namely a framework which is easy to form hydrogen bonds with c-Met kinase, an aryl fragment which can be extended into a hydrophobic capsule and an intermediate bridging chain part, and the influence of the intermediate bridging chain part on the activity of the inhibitor is particularly remarkable. However, with the use of c-Met kinase inhibitors in large quantities, secondary gene mutations or subcloning of tumor cells in the body result in the generation and expansion of drug-resistant tumor cells containing the new mutated genes, ultimately leading to the generation of drug resistance of this class of drugs. Thus, there is an urgent need to study and develop c-Met kinase inhibitors having novel structures in order to find therapeutic methods for solving drug resistance.
The sulfonylamidine fragment is an important pharmacophore, can form hydrogen bond interaction with a drug target, and is widely applied to the design of anticancer drugs. Based on the application of the segment in the design of antitumor drugs, the study tries to take the sulfonylamidine segment as the intermediate bridge chain part of the c-Met inhibitor so as to obtain the lead compound with better antitumor activity.
The following compounds are part of the reported compounds:
Disclosure of Invention
In view of the deficiencies of the prior art, one aspect of the present application is to provide a c-Met kinase inhibitor.
Specifically, the invention provides a compound represented by the general formula I or a polymorph, prodrug, solvate, hydrate, co-crystal or pharmaceutically acceptable salt thereof:
wherein,
R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, aryl, azaaryl, which are optionally substituted with: alkoxy, halogen, alkyl and haloalkyl, wherein the hetero element in the heterocycloalkyl of the C 3-6 is O, N, S;
R 2 is aryl, azaaryl, cycloalkyl of C 3-6, heterocycloalkyl of C 3-6, said aryl and azaaryl optionally being substituted with: alkoxy, halogen, alkyl, haloalkyl and nitro, wherein the hetero element in the heterocycloalkyl of the C 3-6 is O, N, S;
R 3 is aryl, heteroaryl, het selected from the group consisting of piperidinyl, pyrrolyl, pyrazolyl, piperidinyl, imidazolyl, furanyl, morpholinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, piperazinyl, substituted piperazinyl, pyrazinyl, and pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, thiophen [3,2-B ] pyridinyl, 7H-pyrrolo [2,3-d ] pyrimidinyl, benzothienyl, 2, 3-dihydrobenzo [ B ] [1,4] dioxanyl, or benzo [ d ] [1,3] dioxolyl; each of said monocyclic or bicyclic heterocycles being optionally substituted with 1,2 or 3 substituents, each substituent being independently selected from halogen, haloalkyl, alkyl or alkoxy, or from an aliphatic carbocycle of C 3-C8, or from an aliphatic heterocycle of the following formula: tetrahydropyrrolyl, morpholinyl, alkoxymorpholinyl, piperazinyl, piperidinyl, alkylamino piperidinyl; piperidine substituted alkyl, piperazine substituted alkyl; each monocyclic or bicyclic heterocycle is optionally substituted by 1,2 or 3 substituents, and the hetero element in the heteroaryl, the monocyclic heterocycle, the aliphatic heterocycle and the bicyclic heterocycle is O, N, S;
x is hydrogen or halogen, and halogen is selected from one of fluorine, chlorine and bromine.
Preferably, R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, aryl, azaaryl, which may be optionally substituted with: c 1-3 alkoxy, halogen, C 1-3 alkyl and haloalkyl, wherein the hetero element in the heterocycloalkyl of the C 3-6 is O, N, S;
R 2 is aryl, azaaryl, which may be optionally substituted with: alkoxy, halogen, alkyl, haloalkyl, nitro;
R 3 is quinolinyl, thienyl [3,2-B ] pyridinyl, 7H-pyrrolo [2,3-d ] pyrimidinyl, quinolinyl, thienyl [3,2-B ] pyridinyl, and 7H-pyrrolo [2,3-d ] pyrimidinyl optionally substituted with 1,2, or 3 substituents, each substituent independently selected from halogen, haloalkyl, alkyl, or alkoxy; piperidine substituted alkyl, piperazine substituted alkyl;
x is halogen, and halogen is selected from one of fluorine, chlorine and bromine.
Further preferably, R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, pyridinyl, which are optionally substituted with 0, 1, 2 groups: c 1-3 alkoxy, halogen, C 1-3 alkyl, haloalkyl;
R 2 is phenyl, pyridinyl, which are optionally substituted with 0,1 or 2 groups: alkoxy of C 1-6, halogen, alkyl of C 1-6, haloalkyl, nitro;
R 3 is quinolinyl, quinolinyl optionally substituted with 1,2, or 3 substituents, each substituent independently selected from halogen, haloalkyl, C 1-5 alkyl, or C 1-5 alkoxy; 2- (1-piperidine) -ethyl, 2- (1-piperazine) -ethyl;
x is fluorine.
More preferably, the compound is selected from the following compounds:
in a second aspect the present invention provides a process for the preparation of a compound of formula I, the process comprising the step of reacting a compound of formula IV, a compound of formula III and a compound of formula II to obtain a compound of formula I:
Wherein X, R 1、R2 and R 3 are as defined above.
Preferably, the synthesis method specifically comprises the following steps: the compound of the formula IV is dissolved in an organic solvent, organic alkali is added, stirring and inert gas protection are carried out, and the compound of the formula III, the compound of the formula II and a catalyst are added for reaction to obtain the compound of the formula I.
Further preferably, the organic base is selected from one of triethylamine, pyridine, triethanolamine, 3-methylpyridine, DMAP and triisooctylamine; the organic solvent is selected from one or more of dichloromethane, 1, 4-dioxane, meCN, THF, DMF and toluene; the inert gas is argon or nitrogen; the catalyst is CuX, and X is selected from one of Cl, I and Br.
The method further comprises the step of reducing the nitro group of the compound of formula V to provide the compound of formula IV:
Wherein R 3 is as defined above.
Preferably, the reducing agent used for reducing the compound of formula V is selected from iron powder or zinc powder.
The process further comprises the step of reacting a compound of formula VII with a compound of formula VI to obtain a compound of formula V:
wherein X, R 3 is as defined above.
Preferably, the molar ratio of the compound of formula VII to the compound of formula VI in the present reaction is from 1:1.0 to 1.5.
The process further comprises reacting the compound of formula VIII with a chlorinating agent to obtain a compound of formula VI:
R3-OH
VIII，
Wherein R 3 is as defined above.
The following further details the preparation of the compounds of formula I of the present invention:
At room temperature, dissolving the compound of the formula IV in an organic solvent, adding an organic base, stirring, protecting by inert gas, adding the compound of the formula III, the compound of the formula II and a catalyst to react at room temperature, adding dichloromethane and saturated NH 4 Cl aqueous solution into the reaction solution, continuously stirring, separating liquid, extracting the aqueous phase with dichloromethane, merging the organic phases, drying, filtering, concentrating under reduced pressure, and performing column chromatography to obtain the compound of the formula I.
Preferably, the catalyst is selected from one of cuprous iodide, cuprous bromide and cuprous chloride.
Preferably, the organic base is selected from one of triethylamine, DMAP and pyridine.
Preferably, the molar ratio of the compound of formula IV to the organic base is 1:2 to 3; the molar ratio of the compound of the formula IV to the compound of the formula III is 1:1.0-1.1; the molar ratio of the compound of the formula IV to the compound of the formula II is 1:1.1-1.3.
In one embodiment, the molar ratio of the compound of formula IV to the organic base is 1:2.4; the molar ratio of the compound of formula IV to the compound of formula III is 1:1; the molar ratio of the compound of formula IV to the compound of formula II is 1:1.2.
The preparation of the compound of formula IV comprises the steps of: and (3) dissolving the compound shown in the formula V in a proton solvent, heating, adding a saturated NH 4 Cl solution and a reducing agent, and heating and refluxing for reaction.
Preferably, the protic solvent is selected from ethanol, water or a mixed solvent of both; the reducing agent is selected from iron powder or zinc powder.
In one embodiment, the volume ratio of ethanol to water is 9:1; the reducing agent is iron powder.
The preparation of the compound of formula V comprises the steps of: and dissolving the compound of the formula VI and the compound of the formula VII in an organic solvent, heating and refluxing, and reacting for 15-32 hours.
Preferably, the organic solvent is selected from one of chlorobenzene, ethylene glycol dimethyl ether, paraxylene, diphenyl ether, 1, 4-dioxane, pyridine/1, 4-dioxane mixed solvent, NMP/1, 4-dioxane mixed solvent, DMF/pyridine mixed solvent.
Preferably, the molar ratio of the compound of formula VII to the compound of formula VI is from 1:1.0 to 1.5; the reaction time is 28 to 32 hours.
In one embodiment, the molar ratio of the compound of formula VII to the compound of formula VI is 1:1.2; the reaction time was 30 hours.
The preparation of the compound of formula VI comprises the steps of: the compound of formula VIII and the chloro reagent are dissolved in the reaction solvent and heated to reflux for reaction.
Preferably, the reaction solvent is POCl 3 or acetonitrile.
Preferably, the molar ratio of the compound of formula VIII to the chlorinating agent is from 1:15 to 28.
Further preferably, the chlorinating agent is selected from one of phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride.
In one embodiment, the molar ratio of the compound of formula VIII to the chlorinating agent is 1:21.5; the chlorinating agent is phosphorus oxychloride.
In a preferred embodiment, the process for the preparation of the compounds of formula I comprises the steps of: the hydroxyl on the compound of the formula VIII is chlorinated and then reacts with the compound of the formula VII to obtain the compound of the formula V; reducing the nitro group on the compound of formula V to provide a compound of formula IV; finally, the compound of formula IV, the compound of formula III and the compound of formula II react to obtain the compound of formula I.
The synthetic route is as follows:
the compound of the invention can be prepared by the preparation method or the preparation method similar to the preparation method, and corresponding raw materials are selected according to different substituents and different substituent positions.
The synthetic route of the compound I-1 in the invention is as follows:
In a third aspect the present invention provides a pharmaceutical composition comprising a compound of formula I or a polymorph, prodrug, solvate, hydrate, co-crystal, pharmaceutically acceptable salt and other pharmaceutically acceptable ingredients thereof.
The compositions of the present invention refer to pharmaceutical products comprising a therapeutically effective amount of the specified ingredients, as well as any products that result directly or indirectly from the combination of the specified ingredients in the specified amounts.
The compositions of the present invention are particularly pharmaceutical compositions which are generally safe, non-toxic and biologically desirable, and therefore, the pharmaceutically acceptable carriers or excipients of the present invention are non-toxic and safe, and their combination with the compounds of the present invention are also non-toxic and safe. Pharmaceutically acceptable carriers and excipients as described herein are generally well known to those skilled in the art or can be determined by those skilled in the art depending on the actual situation. Examples of suitable carriers and excipients include dextrose, water, glycerol, ethanol, propylene glycol, corn starch, gelatin, lactose, sucrose, alginic acid, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, croscarmellose sodium, sodium starch glycolate, polysorbate 80, polyethylene glycol 300, polyethylene glycol 400, cyclodextrins or derivatives thereof, such as ((2-hydroxypropyl) -cyclodextrin) and (2-hydroxyethyl) -cyclodextrin, also known as HPCD, pegylated castor oil, poloxamers (such as poloxamer 407 or 188); hydrophilic carriers, hydrophobic carriers, combinations thereof, or the like. Hydrophobic carriers include, for example, fat emulsions, lipids, pegylated phospholipids, biocompatible polymers, lipid globules, liposomes, vesicles, polymeric matrices, particles, and the like.
The carrier may be present in the pharmaceutical composition in an amount of 1% to 98% by weight, typically about 80% by weight.
The composition of the present invention may be administered in any manner selected from the group consisting of: oral, spray inhalation, rectal, nasal, vaginal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, with oral, intramuscular, intraperitoneal or intravenous modes of administration being preferred.
The compounds of the present invention or compositions or pharmaceutical preparations containing the same may be administered in unit dosage form. The administration dosage form may be liquid dosage form or solid dosage form. The liquid dosage form can be true solution, colloid, microparticle, emulsion, and mixed rotation. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, landfill, patch, liniment, etc.
In a fourth aspect, the invention provides the use of a compound of formula I or a polymorph, prodrug, solvate, hydrate, co-crystal or pharmaceutically acceptable salt thereof in the preparation of an anti-tumour medicament.
Preferably, the tumor is selected from: non-small cell lung cancer, liver cancer, papillary renal cell carcinoma, gastric cancer, esophageal cancer, glioblastoma, head and neck squamous cell, renal cancer, acute leukemia, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, mesothelioma, or the like.
Interpretation of the terms
The following sets forth definitions of various terms used to describe the application. These definitions apply to the terms used throughout the specification and claims unless otherwise limited in specific instances, either alone or as part of a larger group.
The term "alkyl" in the present invention refers to saturated straight or branched chain hydrocarbon groups, in certain embodiments containing 1 to 6 or 1 to 3 carbon atoms, respectively, examples of C 1-6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, or the like, and examples of C 1-3 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, or the like.
The term "halo" as used herein refers to a group formed by substitution of a halogen atom for a hydrogen atom on a carbon atom, wherein the halogen atom includes, but is not limited to F, cl, br, I.
The term "alkoxy" in the present invention refers to-O-alkyl, wherein the alkyl includes, but is not limited to, C 1-3 alkyl, C 1-6 alkyl, and C 3-6 cycloalkyl, and specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and halogenated versions thereof.
The term "aryl" in the present invention refers to a mono-or polycyclic carbocyclic ring system having one or more aromatic rings, either fused or unfused, including but not limited to phenyl, naphthyl, tetrahydronaphthyl, and the like, and which ring carbon hydrogen atoms may also be substituted with one or more substituents including but not limited to alkyl, alkoxy, halo, haloalkoxy.
The term "heterocycloalkyl" according to the present invention refers to a mono-or polycyclic non-aromatic ring system containing 2 to 6 ring carbon atoms and 1 to 3 ring heteroatoms, wherein the heteroatoms are selected from N, O, S.
The term "cycloalkyl" as used herein refers to a monovalent radical of a monocyclic or polycyclic saturated or partially unsaturated carbocyclic compound, C 3-6 cycloalkyl including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and the hydrogen atoms on its ring carbon may also be substituted with one or more substituents including, but not limited to, alkyl, alkoxy, halo.
The term "heteroaryl" according to the invention refers to an aromatic ring system containing 1 to 6 carbons and at least one heteroatom selected from N, S, O; and the hydrogen atoms on the ring carbons thereof may also be substituted with one or more substituents including, but not limited to, alkyl, alkoxy, halo, nitro.
The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the present invention prepared from the compounds of the present invention having the specified substituents found herein and relatively non-toxic acids or bases. The relatively basic functional groups of the present invention may be present in pure solution or in a suitable inert solvent to obtain acid addition salts, including inorganic and organic acid salts, by contacting the neutral form of such compounds with a sufficient amount of the acid. The inorganic acid salts include, but are not limited to, hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, lactic, pyruvic, acetic, maleic or succinic acid, fumaric, salicylic, phenylacetic, mandelic, sulfamic, acetylsalicylic acid, and also include the acid salts of inorganic bases and the like.
The "solvate" as used herein refers to a form containing a stoichiometric or non-stoichiometric addition of a solvent selected from methanol, ethanol, acetone, DMF, DMSO, and the like.
As used herein, "hydrate" refers to a form containing water addition in either a stoichiometric or non-stoichiometric amount.
"Prodrug" as used herein refers to a compound that is metabolically convertible in vivo to provide any compound described by the formulas of the present application, and various forms of drugs are known in the art.
An "effective amount" as used herein refers to a dosage that achieves the desired therapeutic effect in the desired subject without undue adverse effects, as may be generally determined by one of skill in the art as desired.
The term "treatment" as used herein refers to a method of alleviating or moderating a disease or its complications; by prevention is meant reducing or eliminating the onset of symptoms or complications of a disease, condition or disorder.
It should be understood that other terms not explained hereinabove but appearing in the present invention should be defined as commonly understood by one of ordinary skill in the art.
It is to be understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (including embodiments) may be combined with each other to constitute new or preferred technical solutions.
Compared with the prior art, the invention has the main advantages that:
(1) Compared with the existing compounds, the sulfonyl amidine compound has lower tumor cell inhibition concentration and obviously enhanced anti-tumor activity.
(2) Compared with the known similar compounds, the sulfonyl amidine compound of the formula I provided by the invention has the advantages of shorter synthetic route, simpler operation and suitability for industrial scale-up production.
Detailed Description
The advantages of the invention will now be further described by the following examples, which are given for illustrative purposes only and do not limit the scope of the invention, while variations and modifications apparent to those skilled in the art in light of the present disclosure are included within the scope of the invention.
The synthetic route of the compound of the formula I-1 is as follows:
example 1: preparation of Compounds of formula VI
4-Hydroxy-6, 7-dimethoxyquinoline (VIII) (4.10 g,20.0 mmol) and POCl 3 (40 mL) were placed in a reaction flask and the flask was placed in an oil bath under reflux for 6h. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the resulting residue was poured ice water (100 mL) and vigorously stirred, and the pH was adjusted to 8 with concentrated NH 4 OH, controlling the temperature to within 20 ℃. The mixture was extracted twice with dichloromethane (320 mL. Times.2). The combined organic phases were washed successively with saturated aqueous NaCl and water, dried over anhydrous Na 2SO4, filtered and concentrated to give a white solid, the compound of formula VI, yield 68.3% and HPLC purity 98.11%. m.p.134-136 ℃; ESI-HRMS (m/z): 246.0413[ M+Na ] +.
Example 2: preparation of Compounds of formula VI
4-Hydroxy-6, 7-dimethoxyquinoline (VIII) (4.10 g,20.0 mmol) and PCl 3 (40 ml,0.458 mol) were dissolved in dry acetonitrile (40 ml) and the reaction flask was placed in an oil bath and heated under reflux for 5h. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the resulting residue was poured ice water (100 ml) and vigorously stirred, and the pH was adjusted to 8 with concentrated NH 4 OH at a temperature of within 20 ℃. The mixture was extracted twice with dichloromethane (320 ml. Times.2). The combined organic phases were washed successively with saturated aqueous NaCl and water, dried over anhydrous Na 2SO4, filtered and concentrated to a white solid, yield: 66.2%, HPLC purity: 98.06%. m.p.134-136 ℃; ESI-HRMS (m/z): 246.0415[ M+Na ] +.
Example 3: preparation of Compounds of formula VI
4-Hydroxy-6, 7-dimethoxyquinoline (VIII) (4.10 g,20.0 mmol) and PCl 5 (40 ml,0.307 mol) were dissolved in dry acetonitrile (40 ml) and the reaction flask was placed in an oil bath and heated under reflux for 7h. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the resulting residue was poured ice water (100 ml) and vigorously stirred, and the pH was adjusted to 8 with concentrated NH 4 OH at a temperature of within 20 ℃. The mixture was extracted twice with dichloromethane (320 ml. Times.2). The combined organic phases were washed successively with saturated aqueous NaCl and water, dried over anhydrous Na 2SO4, filtered and concentrated to a white solid, yield: 65.1%, HPLC purity: 98.97%. m.p.134-136 ℃; ESI-HRMS (m/z): 246.0412[ M+Na ] +.
Example 4: preparation of Compounds of formula V
The compound of formula VI (4.46 g,20.0 mmol) and 2-fluoro-4-nitrophenol (VII) (4.78 g,24.1 mmol) were dissolved in chlorobenzene (40 mL) and the mixture was heated to reflux for 20h. The reaction is stopped when the residual amount of the compound of formula VI is less than 5%. And (5) cooling to room temperature, and distilling under reduced pressure. The residue was dissolved in dichloromethane (80 mL), washed twice with saturated K 2CO3 (20 mL. Times.2) aqueous solution and once with water (20 mL). The organic phase is dried by anhydrous Na 2SO4, filtered, and the solid obtained by concentration is recrystallized by absolute ethyl alcohol to obtain light yellow solid, and the yield is: 80.4% of HPLC purity 98.90%. m.p.161-163 ℃; ESI-HRMS (m/z): 367.0809[ M+Na ] +.
Example 5: preparation of Compounds of formula V
The compound of formula VI (4.46 g,20.0 mmol) and 2-fluoro-4-nitrophenol (compound of formula VII) (3.14 g,20.0 mmol) were dissolved in paraxylene (40 ml) and the mixture was heated to reflux for 32h. The reaction is stopped when the residual amount of the compound of formula VI is less than 5%. And (5) cooling to room temperature, and distilling under reduced pressure. The residue was dissolved in dichloromethane (80 ml), washed twice with saturated K 2CO3 solution (20 ml. Times.2) and once with water (20 ml). The organic phase was dried over anhydrous Na 2SO4, filtered and the solid obtained by concentration was recrystallized from anhydrous ethanol to give a pale yellow solid with a yield of 78.9% and an HPLC purity of 98.09%. m.p.161-163 ℃; ESI-HRMS (m/z): 367.0811[ M+Na ] +.
Example 6: preparation of Compounds of formula V
The compound of formula VI (4.46 g,20.0 mmol) and 2-fluoro-4-nitrophenol (compound of formula VI) (4.71 g,30.0 mmol) were dissolved in ethylene glycol dimethyl ether (40 ml) and the mixture was heated to reflux for 28h. The reaction is stopped when the residual amount of the compound of formula VI is less than 5%. And (5) cooling to room temperature, and distilling under reduced pressure. The residue was dissolved in dichloromethane (80 ml), washed twice with saturated K 2CO3 solution (20 ml. Times.2) and once with water (20 ml). The organic phase was dried over anhydrous Na 2SO4, filtered and the solid obtained by concentration was recrystallized from anhydrous ethanol to give a pale yellow solid with a yield of 77.2% and an HPLC purity of 98.79%. m.p.161-163 ℃; ESI-HRMS (m/z): 367.0808[ M+Na ] +.
Example 7: preparation of Compounds of formula IV
The compound of formula V (6.88 g,20.0 mmol) was dissolved in ethanol/water (90 mL,9:1 v/v) and saturated NH 4 Cl solution (90 mL) and iron powder (11.17 g,0.2 mol) were added to the mixture at reflux for 5h when the oil bath temperature was raised to 78deg.C. The reaction was detected by TLC and immediately filtered, the filter cake was rinsed with ethanol, and the filtrate was concentrated under reduced pressure to give a white solid in 90.6% yield and 99.06% purity by HPLC. m.p.193-195 ℃; ESI-HRMS (m/z): 337.1105[ M+Na ] +.
Example 8: preparation of Compounds of formula IV
The compound of formula V (6.88 g,20.0 mmol) was dissolved in ethanol (90 ml), and when the oil bath temperature was raised to 78 ℃, saturated NH 4 Cl solution (90 ml) and Fe powder (11.17 g,0.2 mol) were added, and the mixture was refluxed for 4h. The reaction is immediately filtered after TLC detection is complete, filter cakes are leached by ethanol, filtrate is decompressed and concentrated to obtain white solid, and the yield is: 88.2%, HPLC purity: 99.05%. m.p.193-195 ℃; ESI-HRMS (m/z): 337.1108[ M+Na ] +.
Example 9: preparation of Compounds of formula IV
The compound of formula V (6.88 g,20.0 mmol) was dissolved in ethanol/water (90 ml,9:1 v/v) and saturated NH 4 Cl solution (90 ml) and Zn powder (13.08 g,0.2 mol) were added to the mixture at reflux for 6h when the oil bath temperature was raised to 78 ℃. The reaction is immediately filtered after TLC detection is complete, filter cakes are leached by ethanol, filtrate is decompressed and concentrated to obtain white solid, and the yield is: 89.6%, HPLC purity: 99.16%. m.p.193-195 ℃; ESI-HRMS (m/z): 337.1109[ M+Na ] +.
Example 10: preparation of Compound I-1
Triethylamine (2.42 g,24.0 mmol) was slowly added dropwise to a dichloromethane solution (400 mL) of the compound of formula IV (3.14 g,10.0 mmol) at room temperature, stirred for 10min, after which cyclopropylacetylene (III) (0.66 g,10.0 mmol), benzenesulfonyl azide (II) (2.20 g,12.0 mmol) and iodoketone (190.45 mg,1.0 mmol) were added to the reaction flask under N 2 protection. The mixture was reacted at room temperature for 2 to 6 hours, after completion of the TLC detection reaction, it was diluted with DCM (45 mL) and saturated aqueous NH 4 Cl (66 mL), stirring was continued for 30min to separate layers, and the aqueous phase was extracted three times with DCM (40 mL. Times.3). The combined organic phases were dried over anhydrous Na 2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE: ea=10:1) to give the desired compound I-1. White solid, yield 82.1%, HPLC purity: 98.87%, melting point 189-191℃,1H NMR(400Hz,CDCl3)δ:9.89(s,1H,-NH-),9.03(d,J＝8.1Hz,1H,-N＝CH-CH＝),7.80-7.59(m,6H,Ph-H,-N＝CH-CH＝),7.30(s,1H,quinoline-H),7.07(s,1H,quinoline-H),6.55-6.53(m,3H,Ph-H),3.92(s,3H,-OCH3),3.83(s,3H,-OCH3),2.20(d,J＝6.3Hz,2H,-CH2-cyclopropare),1.02(m,1H,cyclopropare-H),0.40(m,4H,cyclopropare-H);13C NMR(100MHz,CDCl3)δ:157.7,156.7,151.3,150.9,150.6,146.2,145.2,144.1,136.0,133.7,129.7(2C),125.5(2C),120.0(2C),117.3(2C),114.5,107.9,106.2,100.7,56.1(2C),42.6,6.1(2C),1.2.ESI-HRMS(m/z):558.1577[M+Na]+
Example 11: preparation of Compound I-1
DMAP (2.93 g,24.0 mmol) was slowly added dropwise to a solution of the compound of formula IV (3.14 g,10.0 mmol) in acetonitrile (400 mL) at room temperature, stirred for 10min, after which cyclopropylacetylene (III) (0.66 g,10.0 mmol), benzenesulfonyl azide (II) (2.20 g,12.0 mmol) and bromoketone (143.45 mg,1.0 mmol) were added to the reaction flask under argon. The mixture was reacted at room temperature for 2 to 6 hours, after completion of the TLC detection reaction, it was diluted with DCM (45 mL) and saturated aqueous NH 4 Cl (66 mL), stirring was continued for 30min to separate layers, and the aqueous phase was extracted three times with DCM (40 mL. Times.3). The combined organic phases were dried over anhydrous Na 2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE: ea=10:1) to give the desired compound I-1, yield: 83.25%, HPLC purity: 99.13%.
Example 12: preparation of Compound I-1
Pyridine (1.90 g,24.0 mmol) was slowly added dropwise to a THF solution (400 mL) of the compound of formula IV (3.14 g,10.0 mmol) at room temperature, stirred for 10min, after which cyclopropylacetylene (III) (0.66g, 10.0 mmol), benzenesulfonyl azide (II) (2.20 g,12.0 mmol) and chloroketone (99.0 mg,1.0 mmol) were added to the reaction flask under N 2 protection. The mixture was reacted at room temperature for 2 to 6 hours, after completion of the TLC detection reaction, it was diluted with DCM (45 mL) and saturated aqueous NH 4 Cl (66 mL), stirring was continued for 30min to separate layers, and the aqueous phase was extracted three times with DCM (40 mL. Times.3). The combined organic phases were dried over anhydrous Na 2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE: ea=10:1) to give the desired compound I-1, yield: 82.03%, HPLC purity: 99.00%.
Example 13: preparation of Compound I-2
The synthesis method is the same as that of I-1, white solid, yield 81.6% and HPLC purity: 99.07%, melting point 177-179℃.1H NMR(400Hz,CDCl3)δ:9.87(s,1H,-NH-),9.22(d,J＝8.3Hz,1H,-N＝CH-CH＝),8.11-7.97(m,3H,quinoline-H),7.80(d,J＝5.1Hz,1H,quinoline-H),7.48(dd,J＝0.6Hz,8.1Hz,2H,Ph-H),7.24(dd,J＝1.3Hz,12.0Hz,2H,Ph-H),6.73(t,J＝4.5Hz,1H,Ph-H),6.64(t,J＝6.0Hz,1H,Ph-H),6.20(d,J＝4.3Hz,1H,Ph-H),2.43(s,3H,-Ph-CH3),2.20(s,2H,-CH2-cyclopropare),1.02(m,1H,cyclopropare-H),0.40-0.15(m,4H,cyclopropare-H);13C NMR(100MHz,CDCl3)δ:159.8,158.1,156.7,152.6,148.6,141.9,141.1,139.4,132.6,132.0,131.3,130.0,128.2(2C),125.5(2C),123.7,119.2,118.5,112.9,110.7,105.8,42.6,6.1(2C),1.2.ESI-HRMS(m/z):546.1133[M+Na]+.
Example 14: preparation of Compound I-3
The synthesis method is the same as that of I-1, white solid, yield 80.1% and HPLC purity: 98.76%, melting point 193-195℃.1H NMR(400Hz,CDCl3)δ:10.01(s,1H,-NH-),9.03(d,J＝7.0Hz,1H,-N＝CH-CH＝),7.80-7.59(m,6H,Ph-H,-N＝CH-CH＝),7.30(s,1H,quinoline-H),7.08(s,1H,quinoline-H),6.55-6.53(m,3H,Ph-H),3.92(s,3H,-OCH3),3.83(s,3H,-OCH3),3.81(s,3H,-OCH3),2.20(d,J＝8.1Hz,2H,-CH2-cyclopropare),1.02(m,1H,cyclopropare-H),0.40(m,4H,cyclopropare-H);13C NMR(100MHz,CDCl3)δ:157.7,156.1,151.3,150.7,150.4,146.2,145.2,144.1,136.0,133.7,129.7(2C),125.5(2C),120.0(2C),117.3(2C),114.5,107.9,106.2,100.7,56.1(2C),55.8,42.6,6.1(2C),1.2.ESI-HRMS(m/z):588.1683[M+Na]+.
Example 15: preparation of Compound I-4
The synthesis method is the same as that of I-1. White solid, yield 81.2%, HPLC purity: 98.75%, melting point 179-181℃.1H NMR(400Hz,CDCl3)δ:9.88(s,1H,-NH-),9.03(d,J＝8.4Hz,1H,-N＝CH-CH＝),7.78(m,2H,Ph-H),7.59-7.50(m,2H,Ph-H,-N＝CH-CH＝),7.31(s,1H,quinoline-H),7.05(s,1H,quinoline-H),6.73(t,J＝6.0Hz,1H,Ph-H),6.64(t,J＝8.1Hz,1H,Ph-H),6.20(t,J＝4.5Hz,1H,Ph-H),3.92(s,3H,-OCH3),3.83(s,3H,-OCH3),2.20(d,J＝5.3Hz,2H,-CH2-cyclopropare),1.02(m,1H,cyclopropare-H),0.40-0.15(m,4H,cyclopropare-H);13C NMR(100MHz,CDCl3)δ:167.9,159.9,157.7,156.5,151.3,150.7,150.6,146.2,141.9,139.7,131.3,129.9(2C),123.7,116.5(2C),114.5,112.0,107.9,106.2,105.8,100.7,56.1(2C),42.6,6.1(2C),1.2.ESI-HRMS(m/z):576.1483[M+Na]+.
Example 16: preparation of Compound I-5
The synthesis method is the same as that of I-1. White solid, yield 82.4%, HPLC purity: 98.89%, melting point 148-150℃.1H NMR(400Hz,CDCl3)δ:9.86(s,1H,-NH-),9.04(d,J＝8.1Hz,1H,-N＝CH-CH＝),7.80(d,J＝7.0Hz,2H,Ph-H),7.59(d,J＝8.6Hz,1H,quinoline-H),7.59(d,J＝4.7Hz,1H,quinoline-H),7.32(s,1H,quinoline-H),7.12(t,J＝12.1Hz,2H,Ph-H),7.06(s,1H,quinoline-H),6.73(d,J＝3.8Hz,1H,Ph-H),6.64(d,J＝4.3Hz,1H,Ph-H),6.21(d,J＝6.5Hz,1H,Ph-H),3.92(s,3H,-OCH3),3.84(s,3H,-OCH3),2.14(s,2H,-CH2-C(CH3)3),0.94(s,9H,-C(CH3)3);13C NMR(100MHz,CDCl3)δ:159.9,157.7,156.9,152.9,151.3,150.7,150.5,146.2,141.9,136.4,131.3,128.6,129.3(2C),123.7,115.3(2C),114.5,113.2,107.9,106.3,105.8,100.7,56.2(2C),45.1,32.9,29.6(3C).ESI-HRMS(m/z):658.1713[M+Na]+.
Example 17: preparation of Compound I-6
The synthesis method is the same as that of I-1. White solid, yield 82.7%, HPLC purity: 99.20%, melting point 149-151℃.1H NMR(400Hz,CDCl3)δ:9.85(s,1H,-NH-),9.14(d,J＝8.2Hz,1H,-N＝CH-CH＝),8.48(d,J＝7.1Hz,2H,Ph-H),8.10(s,1H,quinoline-H),8.06(d,J＝6.4Hz,2H,Ph-H),7.70(d,J＝8.5Hz,1H,quinoline-H),7.37(s,1H,quinoline-H),6.73(d,J＝4.2Hz,1H,Ph-H),6.64(d,J＝5.0Hz,1H,Ph-H),6.29(d,J＝5.8Hz,1H,Ph-H),2.63(t,J＝8.0Hz,4H,CH3-CH2-CH2-),2.14(s,2H,-CH2-(CH3)3),2.14(s,2H,-CH2-C(CH3)3),1.64(m,4H,CH3-CH2-CH2-),0.94(t,15H,-CH2-CH2-CH3,-CH2-(CH3)3);13C NMR(100MHz,CDCl3)δ:159.8,158.1,156.7,152.9,151.1,150.8,145.6,141.9,141.0,137.9,131.3,129.2(2C),127.6,124.9(2C),123.7,119.2,115.7,112.9,108.3,105.8,45.1,36.1,35.7,29.6(3C),26.7,24.4(2C),13.7(2C).ESI-HRMS(m/z):643.2469[M+Na]+.
Example 18: preparation of Compound I-7
The synthesis method is the same as that of I-1. White solid, 86.3% yield, HPLC purity: 98.88%, melting point 198-200℃.1H NMR(400Hz,CDCl3)δ:9.91(s,1H,-NH-),9.01(d,J＝8.5Hz,1H,-N＝CH-CH＝),8.14(d,J＝7.0Hz,1H,Pyridine-H),8.35(dd,J＝1.3Hz,8.3Hz,1H,Pyridine-H),7.80(d,J＝4.7Hz,2H,Pyridine-H,Ph-H),7.75(t,J＝6.0Hz,1H,Ph-H),7.68(t,J＝4.1Hz,2H,Ph-H),7.67(t,J＝5.0Hz,1H,Ph-H),7.68(t,J＝3.3Hz,2H,Ph-H),7.59(d,J＝6.4Hz,1H,Pyridine-H),7.30(s,1H,quinoline-H),7.24(t,J＝5.7Hz,1H,Pyridine-H),7.08(s,1H,quinoline-H),6.73(d,J＝12.0Hz,1H,Ph-H),6.64(t,J＝4.1Hz,1H,Ph-H),6.30(d,J＝8.0Hz,1H,Ph-H),3.92(s,3H,-OCH3),3.92(s,3H,-OCH3),3.83(s,2H,Ph-CH2-),3.58(s,2H,Pyridine-CH2-);13C NMR(100MHz,CDCl3)δ:157.9,157.0,151.5,150.7,150.3,146.0,145.2,143.9,136.3,135.6,134.0,129.7(2C),129.0(2C),125.7,125.5(2C),120.0(2C),117.3(2C),114.5,107.9,106.2,100.7,56.1(2C),39.5.ESI-HRMS(m/z):595.1530[M+Na]+.
Example 19: preparation of Compound I-8
The synthesis method is the same as that of I-1. White solid, yield 84.1%, HPLC purity: 98.96%, melting point 190-192℃.1H NMR(400Hz,CDCl3)δ:9.87(s,1H,-NH-),9.17(d,J＝8.3Hz,1H,-N＝CH-CH＝),8.55(d,J＝7.0Hz,2H,Pyridine-H),7.89(d,J＝4.4Hz,1H,quinoline-H),7.73(d,J＝4.7Hz,2H,Ph-H),7.69(d,J＝6.3Hz,1H,quinoline-H),7.63(s,H,quinoline-H),7.56(t,J＝5.0Hz,2H,Ph-H),7.45(d,J＝8.6Hz,1H,quinoline-H),7.22(dd,J＝1.9Hz,8.5Hz,2H,Pyridine-H),6.73(d,J＝12.0Hz,1H,Ph-H),6.64(t,J＝7.1Hz,1H,Ph-H),6.30(d,J＝8.4Hz,1H,Ph-H),4.46(s,2H,-OCH2-CF3),4.36(s,2H,Pyridine-CH2-);13C NMR(100MHz,CDCl3)δ:160.0,158.0,157.5,156.7,150.2,149.8(2C),146.5,143.8,142.2,141.9,139.3,131.3,130.0,129.8(2C),127.7(2C),124.2(2C),123.7,122.8,122.4,118.8,112.9,110.1,105.7,99.2,82.5,39.5.ESI-HRMS(m/z):667.0908[M+Na]+.
Example 20: preparation of Compound I-9
The synthesis method is the same as that of I-1. White solid, yield 78.1%, HPLC purity: 98.37%, melting point 203-205℃.1H NMR(400Hz,CDCl3)δ:9.84(s,1H,-NH-),9.18(d,J＝8.5Hz,1H,-N＝CH-CH＝),8.33(d,J＝7.0Hz,1H,quinoline-H),7.77(d,J＝6.1Hz,1H,quinoline-H),7.52(t,J＝3.9Hz,1H,quinoline-H),7.49(d,J＝9.0Hz,1H,quinoline-H),7.46(m,2H,Ph-H),7.24(m,2H,Ph-H),7.14(m,2H,Ph-H),6.73-6.64(m,4H,Ph-H),6.30(t,J＝5.6Hz,1H,Ph-H),4.64(s,2H,Cl-CH2-),3.81(s,3H,Ph-OCH3),3.58(s,2H,Ph-CH2-),2.43(s,1H,Ph-CH3);13C NMR(100MHz,CDCl3)δ:159.7,158.6,157.6,156.9,152.2,147.6,141.9,141.1,139.4,139.0,131.3,130.0(2C),128.8,128.4,128.2(2C),127.7,125.5(2C),123.7,120.9,115.8,114.2(2C),112.9,108.5,105.8,55.8,46.2,39.5,21.3.ESI-HRMS(m/z):626.1395[M+Na]+.
Example 21: preparation of Compound I-10
The synthesis method is the same as that of I-1. White solid, yield 78.4%, HPLC purity: 98.73%, melting point 201-203℃.1H NMR(400Hz,CDCl3)δ:9.82(s,1H,-NH-),9.05(d,J＝8.1Hz,1H,-N＝CH-CH＝),7.59(d,J＝7.0Hz,1H,quinoline-H),7.46(dd,J＝1.7Hz,6.4Hz,2H,Ph-H),7.34(s,1H,quinoline-H),7.24(dd,J＝2.9Hz,8.6Hz,2H,Cl-Ph-H),7.14(m,2H,Ph-H),7.09(s,1H,quinoline-H),6.72(dd,J＝2.2Hz,7.4Hz,2H,Ph-H),6.55-6.53(m,4H,Ph-H),3.92(s,3H,-OCH3),3.83(s,3H,-OCH3),3.81(s,3H,Ph-OCH3),3.58(s,2H,Ph-CH2-),2.43(s,1H,Ph-CH3);13C NMR(100MHz,CDCl3)δ:157.8,157.1,156.6,150.9,150.7,150.4,147.4,145.7,145.2,136.4(2C),129.8(2C),128.5(2C),127.8(2C),127.6,124.1,120.6(2C),116.9(2C),114.5,114.2(2C),108.3,106.6,100.5,55.9(2C),55.7,39.8.ESI-HRMS(m/z):692.1557[M+Na]+.
Example 22: preparation of Compound I-11
The synthesis method is the same as that of I-1. White solid, yield 78.5%, HPLC purity: 98.54%, melting point 212-213℃.1H NMR(400Hz,CDCl3)δ:9.84(s,1H,-NH-),9.19(d,J＝8.4Hz,1H,-N＝CH-CH＝),8.37(d,J＝7.0Hz,1H,quinoline-H),7.78(d,J＝5.3Hz,1H,quinoline-H),7.60(t,J＝4.2Hz,2H,Ph-H),7.55(dd,J＝2.7Hz,6.4Hz,2H,Ph-H),7.52(t,J＝5.7Hz,1H,quinoline-H),7.51(d,J＝3.9Hz,1H,quinoline-H),6.73(d,J＝6.1Hz,1H,Ph-H),6.64(d,J＝6.0Hz,1H,Ph-H),2.72(m,2H,-CH2-CH3),2.69(t,J＝8.2Hz,2H,Piperidine-CH2-CH2-),2.67(t,J＝7.6Hz,2H,Piperidine-CH2-CH2-),2.42(m,4H,Piperidine-H),2.20(d,J＝4.8Hz,2H,Cyclohexane-H),1.53-1.37(m,17H,Piperidine-H,Cyclohexane-H),1.18(t,J＝4.6Hz,3H,-CH2-CH3);13C NMR(100MHz,CDCl3)δ:159.5,158.8,156.9,152.2,149.3,147.6,141.9,141.3,139.0,131.3,128.8,128.7(2C),128.4,128.2(2C),123.7,120.9,115.8,112.9,108.5,105.8,60.7,57.1(2C),37.9,33.4(2C),28.2,26.4,26.0,25.9(2C),25.5(2C),24.5,14.5.ESI-HRMS(m/z):679.3196[M+Na]+.
Example 23: preparation of Compound I-12
The synthesis method is the same as that of I-1. White solid, yield 82.1%, HPLC purity: 98.85%, melting point 186-188℃.1H NMR(400Hz,CDCl3)δ:9.93(s,1H,-NH-),9.13(d,J＝8.3Hz,1H,-N＝CH-CH＝),8.91(d,J＝4.9Hz,1H,Pyridine-H),8.89(t,J＝6.0Hz,1H,Pyridine-H),8.43(t,J＝7.5Hz,1H,Pyridine-H),8.37(t,J＝5.5Hz,1H,quinoline-H),7.78(d,J＝7.1Hz,1H,quinoline-H),7.69(m,1H,Pyridine-H),7.52(t,J＝8.3Hz,1H,quinoline-H),7.51(s,1H,quinoline-H),6.73(d,J＝4.6Hz,1H,Ph-H),6.64(d,J＝6.0Hz,1H,Ph-H),6.20(t,J＝4.4Hz,1H,Ph-H),2.69-2.65(m,8H,Piperazine-H,-CH2-CH2-),2.34(m,4H,Piperazine-H),2.20(d,J＝8.7Hz,2H,-CH2-cyclopropare),1.07(s,1H,-NH-),1.02(m,1H,cyclopropare-H),0.40-0.15(m,4H,cyclopropare-H);13C NMR(100MHz,CDCl3)δ:159.7,158.7,156.7,154.6,152.2,147.8,147.6,141.9,139.0,133.7,133.6,131.3,128.8,128.4,124.8,123.7,120.9,115.8,114.2,108.5,105.8,60.4,57.6(2C),46.2(2C),42.6,33.4,6.3(2C),1.4.ESI-HRMS(m/z):611.2319[M+Na]+.
Biological Activity Studies
1. In vitro tumor cell proliferation inhibition experiment
In order to study the capability of the synthesized target compound to inhibit the proliferation of tumor cells in the experiment, the in vitro cytotoxicity of the compound to four tumor cells, namely human colon cancer cells (HT-29), human non-small cell lung cancer cells (A549), human large cell lung cancer cells (H460) and human gastric cancer cells (MKN-45), is measured, and Foretinib is used as a positive control. The assay used was the standard MTT assay.
The experimental method specifically comprises the following steps:
The cell cryopreservation tube was removed from liquid nitrogen, rapidly thawed at 39 ℃ and transferred to a 15mL centrifuge tube, 10mL of 10% fbs-containing medium was added, centrifuged for 5min (1000 rpm), the medium was removed, 10% fbs-containing medium and diabody-containing medium was added again, and transferred to a flask for culturing. Taking cells in logarithmic growth phase, removing culture solution in a culture flask, washing the cells once by PBS, carrying out pancreatin digestion and centrifugation collection, re-suspending the cells by using a culture medium containing 10% fetal bovine serum, counting and adjusting the cells to a proper concentration (the cell density is 5 multiplied by 104/mL, the cell activity is more than 90%), and adding the cell suspension into a 96-micro-well plate with 100 mu L per well. The target compounds were diluted with DMSO to 20. Mu.L solution, and the test target compounds were diluted with DMSO in a 3-fold gradient. 5. Mu.L of the diluted compound solution was added to 495. Mu.L of a medium containing 10% FBS, respectively, to prepare test compounds. 100. Mu.L of the solution containing the compound to be tested was added to the corresponding wells of a 96-well plate and cultured in a carbon dioxide cell incubator for 72 hours. The medium was removed, and 150. Mu.L of 0.3 mg/mL -1 MTT working solution (0.00265 mg/mL -1 PMS) was added to each well, followed by placing the mixture in a carbon dioxide incubator for 2 hours. The 96-well plate was shaken in an oscillator for 5min, and the absorbance A450 (450 nm) was read with an ELISA reader. All experiments were performed in 3 parallel groups or in triplicate. Finally, the median inhibitory concentration (IC 50) of the test compound is calculated. The test results are the mean ± Standard Deviation (SD) of three experiments.
The results of in vitro toxicity tests of the compounds I-1 to 12 on proliferation inhibition of four cancer cells, namely human colon cancer cells (HT 29), human non-small cell lung cancer cells (A549), human large cell lung cancer cells (H460) and human gastric cancer cells (MKN-45), are shown in Table 1.
TABLE 1
Note that: (1) screening method: MTT method; (2) action time: 72 hours. (3) P < 0.05.
In vitro experiments show that the compound I-1-12 has stronger inhibition activity on four cancer cells, namely human colon cancer cells (HT 29), human non-small cell lung cancer cells (A549), human large cell lung cancer cells (H460), and human gastric cancer cells (MKN-45), and most of the compound activities are equivalent to clinical medicines Foretinib, wherein the inhibition activity of the compound I-8 on the human non-small cell lung cancer cells (A549) and the human large cell lung cancer cells (H460) is obviously better than that of a control medicine, and the inhibition activity of the compound I-11 on the human colon cancer cells (HT 29), the human large cell lung cancer cells (H460) and the human gastric cancer cells (MKN-45) is obviously better than that of the control medicine, so that the compound I-8 has a good application prospect.
2. In vitro cytotoxicity assay on Normal cells
The invention selects the compounds I-8 and I-11 with better antiproliferative activity on tumor cells, tests the inhibition effect on human umbilical mesenchymal stem cells (normal cells), discovers that the cell survival rate of the compounds is 76.2% and 84.5% respectively at the concentration of 100uM, and shows that the compounds have no obvious toxicity on the normal cells and have certain cell selectivity on the tumor cells.
In general, the series of compounds of the invention have stronger proliferation inhibition capability on tumor cells HT29, A549, H460 and MKN-45, and the activity of part of the compounds is better than that of a positive control drug Foretinib, and the compounds have no toxic effect on normal cells, thus the compounds have very good development prospect.

Claims (8)

1. A compound or pharmaceutically acceptable salt represented by formula I:
，
wherein,
R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, pyridyl, said phenyl and pyridyl optionally substituted with 0, 1,2 groups: c 1-3 alkoxy, halogen, C 1-3 alkyl;
R 2 is phenyl, pyridinyl, which are optionally substituted with 0,1 or 2 groups: alkoxy of C 1-6, halogen, alkyl of C 1-6, nitro;
R 3 is quinolinyl, quinolinyl optionally substituted with 1,2, or 3 substituents, each substituent independently selected from halogen, C 1-5 alkyl, C 1-5 alkoxy, 2- (1-piperidine) -ethyl, 2- (1-piperazine) -ethyl;
x is hydrogen or halogen, and halogen is selected from one of fluorine, chlorine and bromine.
2. The compound of claim 1, wherein the compound is the following:
。
3. The compound or pharmaceutically acceptable salt of claim 1, wherein the pharmaceutically acceptable salt comprises an acid addition salt of a compound of formula I with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, sulfamic acid or acetylsalicylic acid.
4. A process for the preparation of a compound as claimed in claim 1, comprising the steps of: dissolving a compound of a formula IV in an organic solvent, adding an organic base, stirring, protecting by inert gas, and adding a compound of a formula III, a compound of a formula II and a catalyst to react to obtain a compound of a formula I;
，
Wherein X, R 1、R2 and R 3 are as defined in claim 1;
the organic base is selected from one of triethylamine, pyridine, triethanolamine, 3-picoline, DMAP and triisooctyl amine; the organic solvent is selected from one or more of dichloromethane, 1, 4-dioxane, meCN, THF, DMF and toluene; the inert gas is argon or nitrogen; the catalyst is one selected from CuCl, cuI and CuBr.
5. The method of claim 4, comprising the step of reducing the nitro group of the compound of formula V to provide the compound of formula IV:
，
Wherein X, R 3 is as defined in claim 1;
the reducing agent used for reducing the compound of the formula V is selected from iron powder or zinc powder.
6. The method of claim 5, comprising the step of reacting a compound of formula VII with a compound of formula VI to provide a compound of formula V:
，
Wherein X, R 3 is as defined in claim 1;
The mol ratio of the compound of the formula VII to the compound of the formula VI is 1:1.0-1.5.
7. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 1 and other pharmaceutically acceptable ingredients.
8. Use of a compound or pharmaceutically acceptable salt according to claim 1 for the manufacture of an anti-tumor medicament, said tumor being selected from the group consisting of non-small cell lung cancer, stomach cancer, colon cancer.
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