CN106146468A - Pyridinone kinases inhibitor - Google Patents

Pyridinone kinases inhibitor Download PDF

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Publication number
CN106146468A
CN106146468A CN201510183879.2A CN201510183879A CN106146468A CN 106146468 A CN106146468 A CN 106146468A CN 201510183879 A CN201510183879 A CN 201510183879A CN 106146468 A CN106146468 A CN 106146468A
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hydrogen
pyrimidine
chloro
phenyl
amine
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CN106146468B (en
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王永辉
高羽军
周娟
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Hangzhou REX Pharmaceutical Co.,Ltd.
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HANGZHOU LEISUO PHARMACEUTICAL CO Ltd
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    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Abstract

The invention discloses a kind of scalable protein kinase activity and for treating or preventing the compound with protein kinase related disorder.Specifically, the present invention relates to a kind of pyridinone kinases inhibitor, belong to and regulate the compound that anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) is active, and provide the preparation method of this compounds, and this compounds is for treating or prevent the pharmaceutical applications of the disease relevant to ALK.

Description

Pyridinone kinases inhibitor
Technical field
The present invention relates to regulate protein kinase activity and for treating or preventing and protein kinase related disorder Compound.Specifically, the present invention relates to a kind of pyridinone kinases inhibitor, belong to and become between regulation Property lymphom kinase (ALK) activity compound, and provide the preparation method of this compounds, and should Compounds is for treating or prevent the pharmaceutical applications of the disease relevant to ALK.
Background technology
Malignant tumor is commonly encountered diseases and the frequently-occurring disease of a kind of serious threat human health, is characterized in cell or change Idioblas abnormality proliferation.The propagation of tumor cell, apoptosis, transfer etc. pass with a series of signal of intraor extracellular In guiding path, certain link occurs abnormal closely related.In these signal transduction paths, important the dividing of a class Son is exactly protein kinase, and the exception of protein kinase is closely related with the generation of tumor, development and prognosis and outcome, Also it is the main cause causing other human diseases relevant with inflammation or breeder reaction a series of；Exploitation targeting The medicine of protein kinase is the Main Means for the treatment of relevant disease, the existing granted listing of a lot of medicines, this kind of medicine The feature that thing has that target spot is clear, clear curative effect, safety are high, is the most increasingly put into practice by clinical treatment Accreditation and support.
Anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) is the important member of protein kinase family, now there are some researches show ALK Overexpression, sudden change and fusion protein directly related with kinds of tumors, include but not limited to neuroblast Tumor, primary cutaneous type (ALCL), nonsmall-cell lung cancer (NSCLC) and inflammatory muscle fiber are female Glucagonoma (IMT) etc..First generation medicine gram azoles for ALK fusion gene replaces Buddhist nun (Crizotinib) And second filial generation medicine Ceritinib (Ceritinib) is respectively at listing in 2011 and 2014, for ALK The treatment of positive lung cancer patient obtains significant Progression free survival and objective effective percentage it was confirmed this target spot is clear and definite Clinical value.Although drug effect is notable, owing to ambient pressure is fitted by Tumor Heterogeneity feature and tumor cell Should, there is increasing research report to show, tumor drug resistance, progressive disease almost remain this type of and suffer from The destiny that person is inevitable；Additionally, the serious adverse reaction of existing medicine, such as side effect of digestive tract incidence rate mistake The problems such as height, hepatotoxicity and QT interval prolongation, also limit the application of such medicine.In view of this, continue Continuous development have good ALK inhibitory activity and the noval chemical compound of safety and developed listing above-mentioned to tackle Problem has important social benefit and value.
Summary of the invention
Present invention aim at providing the pyridinone kinases inhibitor of a kind of novel structure, by pyrrole Replacement in pyridine ketone groups is modified, and synthesizes and filters out and a series of has anti-tumor activity (to EML4-ALK Positive and secondary mutation is inhibited) compound.
For achieving the above object, this invention takes techniques below scheme:
A kind of pyridinone kinases inhibitor, for having the compound and pharmaceutically of following general structure Acceptable salt:R1Selected from hydrogen, R0、R2、R3、R4、R11It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6 Alkoxyl, halo C1-6Alkoxyl, C1-6Cycloalkyl, halo C1-6Cycloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, Cyano group or amino；R5Selected from hydrogen, halogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Alkoxyl, halogen For C1-6Alkoxyl ,-NR2COR6、-NR2CONR2R6、-NR2SO2R6、-COR6、-CONR2R6、 -SO2R6、-SO2NR2R6、-POR8R9、R6Selected from hydrogen, halogen, C1-6Alkane Base, C2-6Thiazolinyl, C2-6One or more in alkynyl, hydroxyl, aryl, or beR7Selected from hydrogen, Halogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Alkoxyl, hydroxyl, aryl, miscellaneous selected from N, O One or more in the 3-12 unit heterocyclic radical of atom, or beR8、R9Be each independently selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6One or more in alkynyl, hydroxyl, aryl；R10Selected from hydrogen, C1-6 Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, amide groups, hydroxyl, aryl, selected from N, O heteroatomic 3-12 unit One or more in heterocyclic radical；And m, n, p are each independently selected from any integer value in 0～10.
Preferably, one or more during aryl is phenyl, naphthyl, anthryl；Described N, O hetero atom 3-12 unit heterocyclic radical be one or more in pyridine radicals, piperidyl, pyrimidine radicals, furyl, morpholinyl.
Preferably, one or more during halogen is fluorine, chlorine, bromine, iodine.
It is furthermore preferred that in foregoing general structure, R1It is selected from R0、R2、R3、R4、R11It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6 Alkoxyl, halo C1-6Alkoxyl, C1-6Cycloalkyl, halo C1-6Cycloalkyl, cyano group or amino；R5It is selected from Hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkoxyl, SO2R6、POR8R9、 R6Selected from hydrogen, C1-6Alkyl, C1-6Alkyl hydroxy orR7Selected from hydrogen, C1-6Alkoxyl, halo C1-6 Alkoxyl, selected from N, O heteroatomic 3-6 unit's heterocycle orR8、R9Be each independently selected from hydrogen or C1-6Alkyl；R10Selected from hydrogen, C1-6Alkyl, C1-6Alkylamidoalkyl, C1-6Alkyl hydroxy or selected from N, O Heteroatomic 3-6 unit heterocycle；And m, n, p are each independently selected from 0,1,2,3,4,5,6 Any value.
A kind of pyridinone kinases inhibitor, selected from the following characterization of numbered REX-1～REX-23 Compound:
REX-1:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) pyrrole Pyridine-2 (1 hydrogen)-one；
REX-2:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-methylene piperazine Piperidinyl) pyridine-2 (1 hydrogen)-one；
((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-5-methyl isophthalic acid-(4-is sub-for REX-3:4- Methyl piperidine base) pyridine-2 (1 hydrogen)-one；
REX-4:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-5-methyl isophthalic acid-(4-piperazine Piperidinyl) pyridine-2 (1 hydrogen)-one；
((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-6-methyl isophthalic acid-(4-is sub-for REX-5:4- Methyl piperidine base) pyridine-2 (1 hydrogen)-one；
REX-6:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-6-methyl isophthalic acid-(4-piperazine Piperidinyl) pyridine-2 (1 hydrogen)-one；
REX-7:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-5-fluoro-1-(4-piperidines Base) pyridine-2 (1 hydrogen)-one；
The chloro-4-of REX-8:5-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidines Base) pyridine-2 (1 hydrogen)-one；
REX-9:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl)-5- Trifluoromethyl pyridine-2 (1 hydrogen)-one；
REX-10:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidines Base)-5-trifluoro oxygen picoline-2 (1 hydrogen)-one；
REX-11:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-5-isopropoxy -1-(4-piperidyl) pyridine-2 (1 hydrogen)-one；
REX-12:2-(4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-2-1 (2H) Pyriconyl)-1-piperidines) acetamide；
REX-13:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(1-(2-hydroxyl second Base)-4-piperidyl) pyridine-2 (1 hydrogen)-one；
REX-14:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-(1-ethyl piperazine Piperidinyl)) pyridine-2 (1 hydrogen)-one；
REX 15:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-(1-2H-tetra- Hydrogen pyranose) piperidyl) pyridine-2 (1 hydrogen)-one；
REX-16:4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-2 hydrogen-pyrans Base) pyridine-2 (1 hydrogen)-one；
REX-17:4-((4-((2-(isopropelsulfonyl) phenyl) amine-5-trifluoromethyl) pyrimidine-2-amido)-1-(4- Piperidyl) pyridine-2 (1 hydrogen)-one；
REX-18:4-((the chloro-4-of 5-((2-(di(2-ethylhexyl)phosphate methyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) pyrrole Pyridine-2 (1 hydrogen)-one；
REX-19:4-((the chloro-4-of 5-((2-(N, N dimethyl sulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidines Base) pyridine-2 (1 hydrogen)-one；
REX-20:4-((the chloro-4-of 5-((2-(N-isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidines Base) pyridine-2 (1 hydrogen)-one；
REX-21:4-((the chloro-4-of 5-((2-(ethoxy sulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) Pyridine-2 (1 hydrogen)-one；
REX-22:4-((the chloro-4-of 5-((2-(1-(ethoxyl methyl) cyclopropyl) phenyl) amine) pyrimidine-2-amido)-1-(4- Piperidyl) pyridine-2 (1 hydrogen)-one；
REX-23:4-((the chloro-4-of 5-((2-methoxyphenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) pyridine-2 (1 Hydrogen)-one.
The compound of aforementioned numbered REX-1～REX-23, structural formula sees below:
Present invention also offers a kind of method preparing compound as previously mentioned, overall reaction route is as follows:
Based on above-mentioned overall reaction route, including following synthetic schemes:
(1) synthetic schemes 1: the synthesis of compound 1-3
Step 1: by R1-OH (i.e. compound 1-1) and triethylamine are dissolved in organic solvent, are slowly added dropwise first Base sulfonic acid chloride；After normal-temperature reaction N hour, add extractant, extract, be dried, reduce pressure, be spin-dried for, changed Compound 1-2.
Step 2: 4-amino-2 hydroxy pyrimidine compounds is dissolved in organic solvent, is slowly added to compound 1-2, after reacting by heating N hour, adds extractant, extracts, is dried, reduces pressure, is spin-dried for, and obtains compound 1-3.
In synthetic schemes 1, organic solvent is selected from dichloromethane, DMF, methanol, dioxy One or more in six rings, preferably dichloromethane, DMF or its mixing；Extractant selects One or more in dichloromethane, pure water, ethyl acetate, preferably dichloromethane, pure water or its mixing；
In synthetic schemes 1, the temperature of normal-temperature reaction is 20～30 DEG C, preferably 25 DEG C；The temperature of reacting by heating Being 70～90 DEG C, preferably 80 DEG C, response time N is 3～10 hours.
(2) synthetic schemes 2: the synthesis of compound 2-4
Step 1: fluoro-for 2-Nitrobenzol and R5-H are dissolved in organic solvent, is slowly added to potassium carbonate, and heating is anti- After answering N hour, add extractant, extract, be dried, reduce pressure, be spin-dried for, obtain compound 2-2.
Step 2: compound 2-2 is dissolved in organic solvent, adds catalyst, nitrogen displacement, logical hydrogen, adds After thermal response N hour, filtration under diminished pressure removes unnecessary catalyst, reduces pressure, is spin-dried for, obtains compound 2-3.
Step 3: compound 2-3 is dissolved in organic solvent, is slowly added to sodium hydride and 2,4,5-trichloropyrimidines, After nitrogen displacement, reacting by heating N hour, add a small amount of frozen water and destroy unnecessary sodium hydride, add extractant, extract, It is dried, reduces pressure, is spin-dried for, obtain compound 2-4.
In synthetic schemes 2, organic solvent is selected from dichloromethane, DMF, methanol, dioxy One or more in six rings, preferably DMF, methanol or its mixing；Extractant is selected from two One or more in chloromethanes, pure water, ethyl acetate, ethyl acetate, pure water or its mixing；Urge Agent selected from palladium charcoal, palladium, 4, double diphenylphosphine-9 of 5-, one or more in 9-dimethyl xanthene, excellent Select the palladium charcoal of 10%.
In synthetic schemes 2, the temperature of reacting by heating is 60～120 DEG C, preferably 60 DEG C, 100 DEG C or 120 DEG C； Response time N is 12～16 hours, preferably 12 hours, 14 hours or 16 hours.
(3) synthetic schemes 3: the synthesis of target compound
Step 1: the compound 2-4 prepared compound 1-3 of synthetic schemes 1, synthetic schemes 2 prepared is molten Solution, in organic solvent, continuously adds cesium carbonate and catalyst, after nitrogen displacement, microwave heating react N hour, Filtration under diminished pressure removes unnecessary catalyst, crosses column chromatography, obtains target compound.
In synthetic schemes 3, organic solvent is selected from dichloromethane, DMF, methanol, dioxy One or more in six rings, preferably dioxane；Catalyst is selected from palladium charcoal, palladium, the double diphenyl of 4,5- Phosphine-9, one or more in 9-dimethyl xanthene, preferably palladium and 4, double diphenylphosphine-9 of 5-, 9-dimethyl The mixing of xanthene.
In synthetic schemes 3, response time N is 0.5～1 hour, preferably 0.5 hour.
In foregoing synthetic schemes 1, synthetic schemes 2, synthetic schemes 3, R1Selected from hydrogen,R0、R2、R3、R4、R11It is each independently selected from hydrogen, halogen Element, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkoxyl, C1-6Cycloalkyl, halogen For C1-6Cycloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, cyano group or amino；R5Selected from hydrogen, halogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Alkoxyl, halo C1-6Alkoxyl ,-NR2COR6、-NR2CONR2R6、 -NR2SO2R6、-COR6、-CONR2R6、-SO2R6、-SO2NR2R6、-POR8R9、 R6Selected from hydrogen, halogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6One in alkynyl, hydroxyl, aryl Or several, or it isR7Selected from hydrogen, halogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6 Alkoxyl, hydroxyl, aryl, one or more in N, O heteroatomic 3-12 unit heterocyclic radical, or ForR8、R9It is each independently selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, hydroxyl, One or more in aryl；R10Selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, amide groups, hydroxyl Base, aryl, one or more in N, O heteroatomic 3-12 unit heterocyclic radical；And m, n, p are each From independently selected from any integer value in 0～10.
" compound " of the present invention, including all stereoisomers, geometric isomer, tautomer And isotope.
" compound " of the present invention, can be asymmetric, such as, has one or more solid different Structure body.Except as otherwise noted, all stereoisomers all include, such as enantiomer and diastereomer. Containing the compound of asymmetric carbon atom in the present invention, can be with the pure form of optical activity or racemic form quilt Separate.The pure form of optical activity can be from racemic mixture, or by using chiral raw material Or chiral reagent synthesis.
" compound " of the present invention, also includes tautomeric forms.Tautomeric forms derives from One singly-bound and the exchange of adjacent double bond and together with the migration of a proton.
Present invention additionally comprises all isotopic atoms, either at intermediate or last compound.Coordination The atom of element includes having identical atomic number but different quality number.Such as, the isotope of hydrogen includes deuterium And tritium.
Containing the compound of aforementioned formula structure, term used herein has a following implication:
Term " halogen ", refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Term " cyano group ", refers to-CN.
Term " hydroxyl ", refers to-OH.
Term " carbonyl ", refers to-CO.
Term " carboxyl ", refers to-COOH.
Term " alkyl ", refers to the saturated hydrocarbons group of the straight or branched being made up of carbon atom and hydrogen atom, as C1-20Alkyl, preferably C1-6Alkyl, such as methyl, ethyl, propyl group (including n-pro-pyl and isopropyl), Butyl (including normal-butyl, isobutyl group, sec-butyl or the tert-butyl group), amyl group (include n-pentyl, isopentyl, Neopentyl), n-hexyl, 2-methylhexyl etc..Described alkyl can be substituted with right and wrong or by one or many Individual substituent group is replaced, and substituent group includes but not limited to alkyl, alkoxyl, cyano group, hydroxyl, carbonyl, carboxylic Base, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl.
Term " amino ", refers to-NH2,-NH (alkyl) and-N (alkyl)2, the implication of alkyl is as previously mentioned.-NH (alkane Base) version beObject lesson includes but not limited to-NHCH3、-NHCH(CH3)2、 -NHC2H5Deng；-N (alkyl)2Version beObject lesson includes but not limited to-N (CH3)2、 -N(CH3)C2H5Deng.
Term " aryl ", refers to full carbon monocycle or the fused rings with the pi-electron system of total conjugated, generally has There is 6-14 carbon atom, preferably there is 6-12 carbon atom, most preferably there are 6 carbon atoms.Aryl is permissible Being non-substituted or replaced by one or more substituent groups, substituent group includes but not limited to alkyl, alcoxyl Base, cyano group, hydroxyl, carbonyl, carboxyl, aryl, aralkyl, amino, halogen, sulfonyl, sulfenyl Base, phosphoryl.The example of non-substituted aryl includes but not limited to phenyl, naphthyl and anthryl.
Term " heterocyclic radical ", refers to have monocycle or the fused rings of 3-12 (integer) annular atoms, wherein have 1, One or more in N, O of 2 or 3 annular atomses, remaining annular atoms is C, and has total conjugated π-electron system.Heterocyclic radical can be substituted with right and wrong or replaced by one or more substituent groups, replaces Base includes but not limited to alkyl, alkoxyl, cyano group, hydroxyl, carbonyl, carboxyl, aryl, aralkyl, ammonia Base, halogen, sulfonyl, sulfinyl, phosphoryl.The example of non-substituted heteroaryl includes but not limited to Pyrrole radicals, indyl, pyrrolidinyl, imidazole radicals, pyrazolyl, tetrazole radical, pyridine radicals, quinolyl, different Quinolyl, piperidyl, pyrimidine radicals, pyrazinyl, piperazinyl, furyl, morpholinyl.
Present invention also offers a kind of pharmaceutical composition, comprise foregoing compound or it pharmaceutically can connect The salt being subject to is as active ingredient, and one or more pharmaceutically acceptable carriers.
" pharmaceutical composition " of the present invention, refers to the compound or its salt of one or more present invention and at this The system of the carrier for bioactive compound being delivered to organism (such as people) generally accepted in field Agent.The purpose of pharmaceutical composition is advantageous for organism is administered conveying.
Term " pharmaceutically acceptable carrier ", refer to active ingredient co-administered and be conducive to activity become The material that part is administered, includes but not limited to that State Food and Drug Administration permits acceptable for people Or any fluidizer of animal (such as domestic animal), sweetener, diluent, preservative, dyestuff/coloring agent, rectify Taste reinforcing agent, surfactant, wetting agent, dispersant, disintegrating agent, suspending agent, stabilizer, isotonic agent, Solvent or emulsifying agent.Such as include but not limited to calcium carbonate, calcium phosphate, various sugared and each kind of starch, fiber Element derivant, gelatin, vegetable oil and Polyethylene Glycol.
Pharmaceutical composition of the present invention, can be configured to solid-state, semisolid, liquid or gaseous state preparation, as Tablet, pill, capsule, powder, granule, unguentum, Emulsion, suspending agent, solution, suppository, Injection, inhalant, gel, microsphere and aerosol etc..
Pharmaceutical composition of the present invention, can use method manufacture well known in the art, as conventional mixes Legal, dissolution method, granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc..
Compound of the present invention or its pharmaceutically acceptable salt or the route of administration of its pharmaceutical composition, Include but not limited to be administered orally, rectum, saturating mucosa, through enteral administration, or local, percutaneous, suction, the intestines and stomach Outward, Sublingual, intravaginal, intranasal, ophthalmic, intraperitoneal, intramuscular, subcutaneous, intravenous administration.Preferably Route of administration is oral administration.
For oral administration, can be by by reactive compound and pharmaceutically acceptable load well known in the art Body mixes, and prepares this pharmaceutical composition.These carriers can make the compound of the present invention be formulated into tablet, Pill, lozenge, sugar-coat agent, capsule, liquid, gel, slurry agent, suspending agent etc., for trouble The oral administration of person.Such as, for the pharmaceutical composition of oral administration, tablet can be obtained in the following way: Active component is merged with one or more solid carriers, if needed gained granulating mixture, and such as Fruit needs to add a small amount of excipient and is processed into mixture or granule, to form tablet or label.Label can be with The coating material being optionally suitable for enteric combines, and is processed into and is more beneficial for the coating that organism (such as people) absorbs Dosage form.
Present invention also offers a kind of foregoing compound or its pharmaceutically acceptable salt preparation for Purposes in the medicine for the treatment of or the prevention disease relevant to protein kinase.
A kind of foregoing compound or its pharmaceutically acceptable salt preparation for treatment or prevention and Purposes in the medicine of the disease that anaplastic lymphom kinase (ALK kinases) is relevant.
Preferably, the aforementioned disease relevant to ALK kinases is selected from cell proliferation disorders, preferably tumor.
Preferably, aforementioned cells proliferative disease include nonsmall-cell lung cancer, primary cutaneous type, Inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast carcinoma, colorectal cancer, Diffuse Large B-Cell Lymphoma, liver Cancer, gastric cancer, esophageal carcinoma, cancer of pancreas, ovarian cancer, body tissue's cellular proliferative disorder and neuroblastoma.
In the present invention, a series of pyridinone kinases inhibitor compound that synthesis is obtained by inventor, Carry out the active Inhibition test of ALK kinases and ALK relevant mutational site, find that part of compounds is to ALK The mutational site L1196M of kinases and ALK has significantly activity suppression；Additionally, also carried out lung The cell proliferation experiment of JEG-3, finds that part of compounds inhibition is notable.
Compared with prior art, the pyridinone kinases inhibitor that the present invention provides, conjunction based on target Reason drug design, by modifying the replacement on pyridone group, it is thus achieved that the chemical combination of a series of novel structures Thing；And optimal screening goes out, and a series of to have anti-tumor activity (especially positive to EML4-ALK and secondary prominent Become inhibited) compound.Therefore, can be used for developing into the kinases inhibitor of a new generation, The disease mediated by ALK for targeted therapy or prevention has great clinical value, and market potential can See.
Detailed description of the invention
The following is the specific embodiment of the present invention, technical scheme is further described, but Protection scope of the present invention is not limited to these embodiments.Every change without departing substantially from present inventive concept or equivalent Within replacement is included in protection scope of the present invention.
In the target compound preparation method that the present invention provides, liquid chromatograph uses WatersSymmetry C18 Chromatographic column.Thin layer chromatography uses GF254 (0.25 millimeter).Nuclear magnetic resonance, NMR chromatograph (NMR) uses Bruker-400 Nmr determination；Liquid matter be used in conjunction (LC/MS) use Waters ZQ mass detector (pillar: WatersSymmetryC18, millimeter, 5 microns, 35 DEG C), employing ESI (+) ion mode.
Additionally, all operations of all raw materials relating to oxidizable or facile hydrolysis is carried out the most under nitrogen protection.Remove Non-being otherwise noted, the raw material that the present invention uses is all marketable material, can directly use without being further purified.
Embodiment 1 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) The preparation of pyridine-2 (1 hydrogen)-one [numbered REX-1]
Synthetic route is as follows:
Synthetic schemes 1: intermediate 4-(4-amino-2-oxo pyridine-1 (2 hydrogen) base) piperidyl-1-carboxylic acid tert-butyl ester The synthesis of (i.e. compound 1-4)
Step 1: the preparation of intermediate N tertbutyloxycarbonyl-4-hydroxy piperidine (i.e. compound 1-2)
Raw material 4-hydroxy piperidine (i.e. compound 1-1,10g, 99.07mmol) is dissolved in dichloromethane (100mL), in, Bis(tert-butoxycarbonyl)oxide (21.7g, 99.1mmol) joins reactant liquor, is stirred at room temperature 2～4 hours.Reaction adds methyl tertiary butyl ether(MTBE) (200mL) and the hydrochloric acid (200mL) of 0.5N after terminating Extract.Organic facies anhydrous sodium sulfate is dried, and is concentrated to give compound 1-2 (15.0g), yield: 75.3%. MSm/z [ESI]: 202.1 [M+1].
Step 2: the preparation of intermediate 4-methanesulfonyloxy group piperidines-1-t-butyl formate (i.e. compound 1-3)
Compound 1-2 (15.0g, 74.6mmol) and triethylamine (21mL, 153mmol) are dissolved in two In chloromethanes (200mL), less than 5 DEG C are slowly added dropwise methylsufonyl chloride (6.0ml, 74.6mmol), keep Temperature is reacted 30 minutes at 5～15 DEG C.React room temperature of rising again after terminating, add the dilution of 400mL water, use Dichloromethane extraction.Organic facies sodium bicarbonate washs secondary, and anhydrous sodium sulfate is dried, and is concentrated to give chemical combination Thing 1-3 (13.0g), yield: 62.0%.MSm/z [ESI]: 280.1 [M+1].
Step 3: piperidyl-1-carboxylic acid tert-butyl ester is (i.e. for intermediate 4-(4-amino-2-oxo pyridine-1 (2 hydrogen) base) Compound 1-4) preparation
Under the conditions of ice-water bath, 4-amino-2 hydroxy pyrimidine (5.1g, 46.6mmol) is dissolved in DMF (80 ML), in, sodium hydride (2.0g, 51.3mmol) is slowly added in reaction system 0 DEG C and stirs 15 minutes. Again compound 1-3 (13.0g, 46.6mmol) is joined in reaction system, be heated to 45 DEG C and be stirred overnight. Being poured into after cooling in 500mL water, ethyl acetate is extracted, and is dried silica gel column chromatography after concentrating and separates, is changed Compound 1-4 (6.0g), yield: 43.9%.MSm/z [ESI]: 294.4 [M+1].1H-NMR (400MHz, DMSO6): δ=7.324-7.305 (d, J=7.6Hz, 1H), 5.963 (s, 2H), 5.694-5.669 (m, 1H), 5.246-5.240 (d, J=2.4Hz, 1H), 4.726 (s, 1H), 4.099-4.058 (m, 2H), 2.519-2.501 (m, 2H), 1.623-1.590 (m, 4H), 1.419-1.388 (s, 9H).
Synthetic schemes 2 :-4-aminopyrimidine is (i.e. for the chloro-N-of intermediate 2,5-bis-[2-[(1-Methylethyl) sulphonyl] phenyl] Compound 2-5) synthesis
Step 1: the preparation of intermediate 2-(iprotiazem ether) Nitrobenzol (i.e. compound 2-2)
By raw material 2-fluoronitrobenzene (i.e. compound 2-1,10g, 70mmol), isopropyl mercaptan (5.4g, 70 Mmol) being added in the DMF (100mL) being dried with potassium carbonate (25g, 177mmol), nitrogen is replaced, 100～110 DEG C are stirred overnight.Reactant mixture is cooled to room temperature, adds water (200mL), carries by ethyl acetate Take.Organic facies anhydrous sodium sulfate is dried, and is concentrated to give compound 2-2 (10g), yield: 72%. MSm/z [ESI]: 198.2 [M+1].1H-NMR (400MHz, CDCl3): δ=8.133-8.100 (dd, J1 =1.2Hz, J2=8.0Hz 1H), 7.579-7.485 (m, 2H), 7.286-7.245 (m, 1H), 3.640-3.547 (m, 1H), 1.412-1.396 (d, J1=6.4Hz 6H).
Step 2: the preparation of intermediate 1-(isopropelsulfonyl)-2-Nitrobenzol (i.e. compound 2-3)
0 DEG C, under stirring condition, the dichloromethane (100mL) of compound 2-2 (13g, 65.97mmol) In solution, it is dividedly in some parts m-CPBA (25.67g, 149.42mmol), finishes, at 0 DEG C, react 16 little Time.Add saturated sodium bicarbonate solution washing, be dried silica gel column chromatography after concentrating and separate, obtain compound 2-3 (10.66g), yield: 70%.MSm/z [ESI]: 230.2 [M+1].1H-NMR (400MHz, CDCl3): δ=8.115-8.071 (m, 1H), 8.042-8.003 (m, 1H), 7.974-7.932 (m, 1H), 3.825-3.757 (m, 1H), 1.285-1.268 (d, J=6.8Hz 6H).
Step 3: the preparation of intermediate 2-(isopropelsulfonyl) aniline (i.e. compound 2-4)
Compound 2-3 (20g, 87.3mmol) and 10% palladium charcoal (2.0g) are added to the methanol (250mL) being dried In, hydrogen exchange, 60 DEG C are reacted 2 hours.After cooling, kieselguhr filters and separates, and anhydrous sodium sulfate is dried dense Contracting, obtains compound 2-4 (17.3g), yield: 95%.MSm/z [ESI]: 200.2 [M+1]. 1H-NMR (400MHz, DMSO6): δ=7.457-7.434 (m, 1H), 7.373-7.300 (m, 1H), 6.888-6.868 (d, J=8.0Hz, 1H), 6.708-6.689 (d, J=7.6Hz, 1H), 6.088 (m, 2H), 3.370-3.304 (m, 1H), 1.176-1.159 (d, J=6.8Hz 6H).
Step 4: the chloro-N-of intermediate 2,5-bis-[2-[(1-Methylethyl) sulphonyl] phenyl]-4-aminopyrimidine (is i.e. changed Compound 2-5) preparation
Under the conditions of ice-water bath, compound 2-4 (30g, 150mmol) is dissolved in DMF (300mL) In, sodium hydride (7.23g, 300mmol) is slowly added in reaction system 0 DEG C and stirs 15 minutes.2,4,5- Trichloropyrimidine (33.1g, 180mmol) is added drop-wise in reaction system, reacts stirred overnight at room temperature.After cooling Being poured in 500mL water, ethyl acetate is extracted, and is dried silica gel column chromatography after concentrating and separates, obtains compound 2-5 (17.3g), yield: 32%.MSm/z [ESI]: 370.2 [M+1].1H-NMR (400MHz, DMSO6): δ=9.822 (s, 1H), 7.343-7.323 (d, J=8.0Hz, 1H), 7.911-7.839 (m, 2H), (3.585-3.484 m, 1H), 1.176-1.159 (d, J=6.8Hz, 6H).
Synthetic schemes 3: target compound 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amine Base) synthesis of-1-(4-piperidyl) pyridine-2 (1 hydrogen)-one (i.e. REX-1)
Step 1: intermediate 4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-2- Oxo pyridine-1 (2 hydrogen)-yl) preparation of the piperidines-1-hydroxy acid tert-butyl ester (i.e. compound 3-1)
By compound 1-4 (0.7g, 2.6mmol), compound 2-5 (0.91g, 2.38mmol), cesium carbonate Double (the diphenylphosphine)-9,9-dimethyl xanthene of (2.34g, 7.17mmol), catalyst 4,5-(0.3g, 0.5 And palladium (54mg, 0.24mmol) mmol), it is dissolved in dioxane (15mL) and adds in tube sealing, After nitrogen displaced air, react 18 hours at 95 DEG C.It is spin-dried for solvent, adds ethyl acetate and water, extraction Taking, organic facies is dried, silica gel chromatography, obtains compound 3-1 (0.7g), yield: 52%. MSm/z [ESI]: 603.1 [M+1].
Step 2: target compound 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amine Base) preparation of-1-(4-piperidyl) pyridine-2 (1 hydrogen)-one (i.e. REX-1)
Under agitation, compound 3-1 (0.5g, 8.3mmol) is added in dichloromethane (10mL), Dropping trifluoroacetic acid (5mL), is stirred overnight under room temperature.First it is adjusted to pH >=10 with 5% sodium bicarbonate aqueous solution, It is extracted with ethyl acetate again, is dried, is spin-dried for obtaining target compound REX-1, yield: 36%.MSm/z [ESI]: 504.1[M+1]。1H-NMR (400MHz, DMSO6): δ=9.741 (s, 1H), 8.575-8.555 (d, J =8Hz, 1H), 8.392 (s, 1H), 7.875-7.806 (m, 2H), 7.507-7.391 (m, 2H), 6.940-6.936 (d, J=1.6Hz, 1H), 6.493-6.469 (m, 1H), 4.667 (m, 1H), 3.572-3.441 (m, 1H), 3.059-3.028 (m, 2H), 2.599-2.583 (m, 2H), 1.648-1.601 (m, 4H), 1.231-1.116 (m, 6H)。
Embodiment 2 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-methylene Piperidyl) preparation of pyridine-2 (1 hydrogen)-one [numbered REX-2]
Synthetic route is as follows:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-4 ", Raw material 4-hydroxy piperidine (i.e. compound 1-1) in embodiment 1 is replaced with 4-hydroxymethyl piperidine, and remaining closes One-tenth method, with the synthetic schemes 1 of embodiment 1, obtains compound 1-4, yield: 43.0%.MSm/z [ESI]: 308.4[M+1]。
In synthetic schemes 2 " synthesis of compound 2-5 ", raw material 2-fluoronitrobenzene (i.e. compound 2-1), Remaining synthetic method all with the synthetic schemes 2 of embodiment 1, obtains compound 2-5, yield: 33%. MSm/z [ESI]: 370.2 [M+1].
In synthetic schemes 3 " synthesis of target compound REX-2 ", the compound that the present embodiment is prepared 1-4 and compound 2-5, prepares according to the synthetic schemes 3 of embodiment 1, obtains target compound REX-2, Yield: 36%.MSm/z [ESI]: 518.1 [M+1].1H-NMR (400MHz, DMSO6): δ=9.689 (s, 1H), 8.540-8.364 (m, 2H), 7.868-7.779 (m, 2H), 7.412 (m, 2H), 6.916 (m, 1H), 6.423 (m, 1H), 4.667 (m, 1H), 3.644-3.635 (m, 3H), 2.910 (m, 2H), 2.355 (m, 2H), 1.800 (m, 1H), 1.435 (m, 2H), 1.170-1.163 (m, 8H).
Embodiment 3 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-5-methyl isophthalic acid-(4- Methylenepiperidines base) preparation of pyridine-2 (1 hydrogen)-one [numbered REX-3]
Synthetic route is as follows:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-4 ", Raw material 4-hydroxy piperidine (i.e. compound 1-1) in embodiment 1 is replaced with 4-hydroxymethyl piperidine, embodiment In 1, the 4-amino-2 hydroxy pyrimidine of step 3 replaces with 4-amino-5-methyl-2 hydroxy pyrimidine, remaining synthesis side Method, with the synthetic schemes 1 of embodiment 1, obtains compound 1-4, yield: 38.0%.MSm/z [ESI]: 322.4 [M+1]。
In synthetic schemes 2 " synthesis of compound 2-5 ", raw material 2-fluoronitrobenzene (i.e. compound 2-1), Remaining synthetic method all with the synthetic schemes 2 of embodiment 1, obtains compound 2-5, yield: 34%. MSm/z [ESI]: 370.2 [M+1].
In synthetic schemes 3 " synthesis of target compound REX-3 ", the compound that the present embodiment is prepared 1-4 and compound 2-5, prepares according to the synthetic schemes 3 of embodiment 1, obtains target compound REX-3, Yield: 26%.MSm/z [ESI]: 532.1 [M+1].1H-NMR (400MHz, DMSO6): δ= 8.646-8.625 (d, J=8.4Hz, 1H), 8.625 (s, 1H), 8.371 (s, 1H), 7.845-7.824 (d, J =8.4Hz, 1H), 7.733 (m, 1H), 7.373 (m, 2H), 6.961 (s, 1H), 3.351-3.663 (d, J=7.2Hz, 2H), 3.535 (m, 3H), 2.976-2.943 (d, J=13.2Hz, 2H), 2.433 (m, 3H), 2.039 (s, 3H), 1.836 (m, 1H), 1.447 (m, 2H), 1.181 (m, 6H).
Embodiment 4 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-5-methyl isophthalic acid-(4- Piperidyl) preparation of pyridine-2 (1 hydrogen)-one [numbered REX-4]
Synthetic route is as follows:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-4 ", 4-amino-the 2 hydroxy pyrimidine of step 3 in embodiment 1 is replaced with 4-amino-5-methyl-2 hydroxy pyrimidine, its Remaining synthetic method, with the synthetic schemes 1 of embodiment 1, obtains compound 1-4, yield: 35.0%.MSm/z [ESI]: 307.4[M+1]。
In synthetic schemes 2 " synthesis of compound 2-5 ", raw material 2-fluoronitrobenzene (i.e. compound 2-1), Remaining synthetic method all with the synthetic schemes 2 of embodiment 1, obtains compound 2-5, yield: 31%. MSm/z [ESI]: 370.2 [M+1].
In synthetic schemes 3 " synthesis of target compound REX-4 ", the compound that the present embodiment is prepared 1-4 and compound 2-5, prepares according to the synthetic schemes 3 of embodiment 1, obtains target compound REX-4, Yield: 30%.MSm/z [ESI]: 516.1 [M+1].1H-NMR (400MHz, DMSO6): δ= 8.662-8.641 (d, J=8.4Hz, 1H), 8.447 (s, 1H), 8.386 (s, 1H), 7.851-7.831 (d, J =8.0Hz, 1H), 7.754 (m, 1H), 7.433 (s, 1H), 7.391 (m, 1H), 6.974 (s, 1H), 4.709 (m, 1H), 4.041 (m, 1H), 3.503 (m, 3H), 3.076 (m, 2H), 2.607 (m, 2H), 2.078 (s, 3H), 1.992 (m, 2H), 1.712 (m, 4H), 1.184 (m, 6H).
Embodiment 5 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-6-methyl isophthalic acid-(4- Piperidyl) preparation of pyridine-2 (1 hydrogen)-one [numbered REX-5]
Synthetic route is as follows:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-4 ", Raw material 4-hydroxy piperidine (i.e. compound 1-1) in embodiment 1 is replaced with 4-hydroxymethyl piperidine, embodiment In 1, the 4-amino-2 hydroxy pyrimidine of step 3 replaces with 4-amino-6-methyl-2 hydroxy pyrimidine, remaining synthesis side Method, with the synthetic schemes 1 of embodiment 1, obtains compound 1-4, yield: 45.0%.MSm/z [ESI]: 321.4 [M+1]。
In synthetic schemes 2 " synthesis of compound 2-5 ", raw material 2-fluoronitrobenzene (i.e. compound 2-1), Remaining synthetic method all with the synthetic schemes 2 of embodiment 1, obtains compound 2-5, yield: 38%. MSm/z [ESI]: 370.2 [M+1].
In synthetic schemes 3 " synthesis of target compound REX-5 ", the compound that the present embodiment is prepared 1-4 and compound 2-5, prepares according to the synthetic schemes 3 of embodiment 1, obtains target compound REX-5, Yield: 26%.MSm/z [ESI]: 531.1 [M+1].1H-NMR (400MHz, DMSO6): δ= 8.650-8.629 (d, J=8.4Hz, 1H), 8.620 (s, 1H), 8.370 (s, 1H), 7.835-7.814 (d, J =8.4Hz, 1H), 7.722 (m, 1H), 7.352 (m, 2H), 6.955 (s, 1H), 3.351-3.663 (d, J =7.2Hz, 2H), 3.535 (m, 3H), 2.976-2.944 (d, J=13.1Hz, 2H), 2.430 (m, 3H), 2.239 (s, 3H), 1.836 (m, 1H), 1.447 (m, 2H), 1.181 (m, 6H).
Embodiment 6 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-6-methyl isophthalic acid-(4- Piperidyl) preparation of pyridine-2 (1 hydrogen)-one [numbered REX-6]
Synthetic route is as follows:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-4 ", 4-amino-2 hydroxy pyrimidine in step 3 in embodiment 1 is replaced with 4-amino-6-methyl-2 hydroxy pyrimidine, Remaining synthetic method, with the synthetic schemes 1 of embodiment 1, obtains compound 1-4, yield: 36.0%. MSm/z [ESI]: 308.4 [M+1].
In synthetic schemes 2 " synthesis of compound 2-5 ", raw material 2-fluoronitrobenzene (i.e. compound 2-1), Remaining synthetic method all with the synthetic schemes 2 of embodiment 1, obtains compound 2-5, yield: 38%. MSm/z [ESI]: 370.2 [M+1].
In synthetic schemes 3 " synthesis of target compound REX-6 ", the compound that the present embodiment is prepared 1-4 and compound 2-5, prepares according to the synthetic schemes 3 of embodiment 1, obtains target compound REX-6, Yield: 33%.MSm/z [ESI]: 518.1 [M+1].1H-NMR (400MHz, DMSO6): δ= 8.660-8.639 (d, J=8.4Hz, 1H), 8.445 (s, 1H), 8.376 (s, 1H), 7.861-7.841 (d, J =8.0Hz, 1H), 7.750 (m, 1H), 7.436 (s, 1H), 7.390 (m, 1H), 6.975 (s, 1H), 4.708 (m, 1H), 4.041 (m, 1H), 3.503 (m, 3H), 3.073 (m, 2H), 2.607 (m, 2H), 2.070 (s, 3H), 1.997 (m, 2H), 1.711 (m, 4H), 1.180 (m, 6H).
Embodiment 7 2-(4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-2-1 (2H) Pyriconyl)-1-piperidines) preparation of acetamide [numbered REX-12]
Synthetic route is as follows:
Synthetic schemes 1: acetamide is (i.e. for intermediate 2-(4-(4-amino-2-oxo pyridine-1 (2 hydrogen) base) piperidyl) Compound 1-3) synthesis
Step 1: the preparation of intermediate 4-methanesulfonyloxy group piperidines-1-acetamide (i.e. compound 1-2)
By raw material N-acetamide-4-hydroxy piperidine (i.e. compound 1-1,10.0g, 63.2mmol) and triethylamine (17.5mL, 127mmol) is dissolved in dichloromethane (100mL), and less than 5 DEG C are slowly added dropwise methyl sulphur Acyl chlorides (5.1ml, 63.2mmol), maintains the temperature at 5～15 DEG C and reacts 30 minutes.Reaction is risen again after terminating Room temperature, adds the dilution of 200mL water, uses dichloromethane extraction.Organic facies sodium bicarbonate washs secondary, nothing Aqueous sodium persulfate is dried, and is concentrated to give compound 1-2 (8.0g), yield: 53.5%.MSm/z [ESI]: 237.3 [M+1]。
Step 2: intermediate 2-(4-(4-amino-2-oxo pyridine-1 (2 hydrogen) base) piperidyl) acetamide (i.e. chemical combination Thing 1-3) preparation
Under the conditions of ice-water bath, 4-amino-2 hydroxy pyrimidine (3.0g, 27.9mmol) is dissolved in DMF (50 ML), in, sodium hydride (1.2g, 30.8mmol) is slowly added in reaction system 0 DEG C and stirs 15 minutes. Again compound 1-2 (6.6g, 28.0mmol) is joined in reaction system, be heated to 45 DEG C and be stirred overnight. Being poured into after cooling in 400mL water, ethyl acetate is extracted, and is dried silica gel column chromatography after concentrating and separates, is changed Compound 1-3 (3.6g), yield: 51.6%.MSm/z [ESI]: 294.4 [M+1].
Synthetic schemes 2 :-4-aminopyrimidine is (i.e. for the chloro-N-of intermediate 2,5-bis-[2-[(1-Methylethyl) sulphonyl] phenyl] Compound 2-5) synthesis
Step 1: the preparation of intermediate 2-(iprotiazem ether) Nitrobenzol (i.e. compound 2-2)
By raw material 2-fluoronitrobenzene (i.e. compound 2-1,10g, 70mmol), isopropyl mercaptan (5.4g, 70 Mmol) being added in the DMF (100mL) being dried with potassium carbonate (25g, 177mmol), nitrogen is replaced, 100～110 DEG C are stirred overnight.Reactant mixture is cooled to room temperature, adds water (200mL), carries by ethyl acetate Take.Organic facies anhydrous sodium sulfate is dried, and is concentrated to give compound 2-2 (10g), yield: 72%. MSm/z [ESI]: 198.2 [M+1].1H-NMR (400MHz, CDCl3): δ=8.133-8.100 (dd, J1 =1.2Hz, J2=8.0Hz 1H), 7.579-7.485 (m, 2H), 7.286-7.245 (m, 1H), 3.640-3.547 (m, 1H), 1.412-1.396 (d, J1=6.4Hz 6H).
Step 2: the preparation of intermediate 1-(isopropelsulfonyl)-2-Nitrobenzol (i.e. compound 2-3)
0 DEG C, under stirring condition, the dichloromethane (100mL) of compound 2-2 (13g, 65.97mmol) In solution, it is dividedly in some parts m-CPBA (25.67g, 149.42mmol), finishes, at 0 DEG C, react 16 little Time.Add saturated sodium bicarbonate solution washing, be dried silica gel column chromatography after concentrating and separate, obtain compound 2-3 (10.66g), yield: 70%.MSm/z [ESI]: 230.2 [M+1].1H-NMR (400MHz, CDCl3): δ=8.115-8.071 (m, 1H), 8.042-8.003 (m, 1H), 7.974-7.932 (m, 1H), 3.825-3.757 (m, 1H), 1.285-1.268 (d, J=6.8Hz 6H).
Step 3: the preparation of intermediate 2-(isopropelsulfonyl) aniline (i.e. compound 2-4)
Compound 2-3 (20g, 87.3mmol) and 10% palladium charcoal (2.0g) are added to the methanol (250mL) being dried In, hydrogen exchange, 60 DEG C are reacted 2 hours.After cooling, kieselguhr filters and separates, and anhydrous sodium sulfate is dried dense Contracting, obtains compound 2-4 (17.3g), yield: 95%.MSm/z [ESI]: 200.2 [M+1]. 1H-NMR (400MHz, DMSO6): δ=7.457-7.434 (m, 1H), 7.373-7.300 (m, 1H), 6.888-6.868 (d, J=8.0Hz, 1H), 6.708-6.689 (d, J=7.6Hz, 1H), 6.088 (m, 2H), 3.370-3.304 (m, 1H), 1.176-1.159 (d, J=6.8Hz 6H).
Step 4: the chloro-N-of intermediate 2,5-bis-[2-[(1-Methylethyl) sulphonyl] phenyl]-4-aminopyrimidine (is i.e. changed Compound 2-5) preparation
Under the conditions of ice-water bath, compound 2-4 (30g, 150mmol) is dissolved in DMF (300mL) In, sodium hydride (7.23g, 300mmol) is slowly added in reaction system 0 DEG C and stirs 15 minutes.2,4,5- Trichloropyrimidine (33.1g, 180mmol) is added drop-wise in reaction system, reacts stirred overnight at room temperature.After cooling Being poured in 500mL water, ethyl acetate is extracted, and is dried silica gel column chromatography after concentrating and separates, obtains compound 2-5 (17.3g), yield: 32%.MSm/z [ESI]: 370.2 [M+1].1H-NMR (400MHz, DMSO6): δ=9.822 (s, 1H), 7.343-7.323 (d, J=8.0Hz, 1H), 7.911-7.839 (m, 2H), 3.585-3.484 (m, 1H), 1.176-1.159 (d, J=6.8Hz, 6H).
Synthetic schemes 3: target compound 2-(4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2- Amido)-2-1 (2H) pyriconyl)-1-piperidines) synthesis of acetamide (i.e. REX-12)
Step 1: by compound 1-3 (0.9g, 3.6mmol), compound 2-5 (1.4g, 3.6mmol), carbon Acid caesium (3.5g, 10.7mmol), double (the diphenylphosphine)-9,9-dimethyl xanthene of catalyst 4,5-(0.45g, 0.75 And palladium (81mg, 0.36mmol) mmol), it is dissolved in dioxane (20mL) and adds in tube sealing, After nitrogen displaced air, react 18 hours at 95 DEG C.It is spin-dried for solvent, adds ethyl acetate and water, extraction Taking, organic facies is dried, silica gel chromatography, obtains target compound REX-12 (0.75g), yield: 37%.MSm/z [ESI]: 561.1 [M+1].
Embodiment 8 ALK kinase inhibiting activity and the mensuration of relevant mutational site combination rate
Select compound R EX-1～REX-4 that anthology inventive embodiments 1～4 prepares, use(FRET) Method measures aforesaid compound to ALK kinase inhibiting activity, and this inhibitory activity uses IC50This index is come Represent, IC50The concentration of compound during the kinase whose activity inhibited 50% of i.e. ALK.
Use simultaneouslyEu Kinase Binging Assay (TR-FRET) determines the present invention Compound the combination rate of ALK relevant mutational site such as ALK L1196M is measured, be also adopted by IC50This Index represents.LanthaScreen Eu kinases Binding experiment resists by adding Eu traget antibody or anti-label Alexa Fluor conjugate is surveyed in health check-up or kinases " tracer " combines.Tracer and antibody and kinase whose combination Cause the FRET of height, otherwise use kinase inhibitor to replace tracer that FRET can be caused to lose.
The present invention utilizes the kinase assay platform of Life technology company to be measured, and measurement result is shown in Table one.Result shows, the compound that the present invention provides has preferable ALK inhibitory activity, and to ALK Mutational site (such as ALK L1196M) also have and preferably combine activity.
The ALK inhibitory activity of table one embodiment compound and ALK L1196M combination rate measure
ALK IC50(nM) ALK F1196M IC50(nM)
REX-1 <50 <50
REX-2 <50 <50
REX-3 <50 <50
REX-4 <50 <50
Embodiment 9 cell proliferation experiment
Testing compound: compound R EX-1, REX-2 that the embodiment of the present invention 1～2 prepares.
Cell strain: lung cancer cell line NCI-H2228, purchased from bio tech ltd of Nanjing section one hundred.
Method: cell strain NCI-H2228 is placed in 20%FBS (hyclone) (Gibco)+1640+1% Dual anti-cultivate.Then taking the NCI-H2228 cell that growth conditions is good, 5000/hole is inoculated in respectively 96 porocyte plates, are placed in 37 DEG C, containing 5%CO2Incubator in hatch 24h and make cell attachment complete.Abandon Old culture fluid, every hole is gone to be sequentially added into 100 μ L containing 0.3,1,3,10,30,100,300,1000,3000 With the culture fluid of 10000nmol/L testing compound, the every hole of solvent control group adds 100 μ L containing 0.1% The culture fluid of DMSO, often the multiple hole of group 3, discards old culture fluid after 72h, and under the conditions of lucifuge, every hole adds 100 μ L mL Han 0.5mg-1The culture fluid of MTT, is placed in cell culture incubator and continues to hatch 4h, discard Clearly, every hole adds 100 μ L DMSO, vibration, measures each hole absorbance by microplate reader under 490nm wavelength Value.The suppression ratio grown each cell according to each compound variable concentrations, calculates each chemical combination with graphad 6.0 Thing IC on each cell50Value.
Computing formula is:
Result: be shown in Table 2.
The table two embodiment compound cell proliferation IC to lung cancer cell line50Value
IC50(μM) NCI-H2228
REX-1 <1
REX-2 <10

Claims (10)

1. a pyridinone kinases inhibitor, for having compound and the pharmacy thereof of following general structure Upper acceptable salt:
Wherein, R1Selected from hydrogen,
R0、R2、R3、R4、R11It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkoxyl, C1-6Cycloalkyl, halo C1-6Cycloalkyl, C2-6Thiazolinyl, C2-6Alkynes Base, cyano group or amino；
R5Selected from hydrogen, halogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Alkoxyl, halo C1-6 Alkoxyl ,-NR2COR6、-NR2CONR2R6、-NR2SO2R6、-COR6、-CONR2R6、-SO2R6、 -SO2NR2R6、-POR8R9、
R6Selected from hydrogen, halogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6One in alkynyl, hydroxyl, aryl or Several, or be
R7Selected from hydrogen, halogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-6Alkoxyl, hydroxyl, virtue Base, one or more in N, O heteroatomic 3-12 unit heterocyclic radical, or be
R8、R9It is each independently selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6In alkynyl, hydroxyl, aryl One or more；
R10Selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, amide groups, hydroxyl, aryl, selected from N, One or more in O heteroatomic 3-12 unit heterocyclic radical；
And m, n, p are each independently selected from any integer value in 0～10.
Pyridinone kinases inhibitor the most according to claim 1, it is characterised in that: described Aryl is one or more in phenyl, naphthyl, anthryl；Described N, O heteroatomic 3-12 unit heterocycle Base is one or more in pyridine radicals, piperidyl, pyrimidine radicals, furyl, morpholinyl.
Pyridinone kinases inhibitor the most according to claim 1, it is characterised in that: described Halogen is one or more in fluorine, chlorine, bromine, iodine.
4. according to the arbitrary described pyridinone kinases inhibitor of claims 1 to 3, it is characterised in that: R in described general structure1It is selected from
R0、R2、R3、R4、R11It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkoxyl, C1-6Cycloalkyl, halo C1-6Cycloalkyl, cyano group or amino；
R5Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkoxyl, SO2R6、POR8R9、
R6Selected from hydrogen, C1-6Alkyl, C1-6Alkyl hydroxy or
R7Selected from hydrogen, C1-6Alkoxyl, halo C1-6Alkoxyl, selected from N, O heteroatomic 3-6 unit heterocycle Or
R8、R9It is each independently selected from hydrogen or C1-6Alkyl；
R10Selected from hydrogen, C1-6Alkyl, C1-6Alkylamidoalkyl, C1-6Alkyl hydroxy or selected from N, O hetero atom 3-6 unit heterocycle；
And m, n, p are each independently selected from any value in 0,1,2,3,4,5,6.
Pyridinone kinases inhibitor the most according to claim 1, it is characterised in that: selected from such as Lower characteristic compounds:
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) pyridine-2 (1 Hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-methylenepiperidines base) pyrrole Pyridine-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-5-methyl isophthalic acid-(4-methylene piperazine Piperidinyl) pyridine-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-5-methyl isophthalic acid-(4-piperidyl) pyrrole Pyridine-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-6-methyl isophthalic acid-(4-methylene piperazine Piperidinyl) pyridine-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-6-methyl isophthalic acid-(4-piperidyl) pyrrole Pyridine-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido) the fluoro-1-of-5-(4-piperidyl) pyridine -2 (1 hydrogen)-one；
The chloro-4-of 5-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) pyridine -2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl)-5-fluoroform Yl pyridines-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl)-5-trifluoro oxygen Picoline-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-5-isopropoxy-1-(4-piperidines Base) pyridine-2 (1 hydrogen)-one；
2-(4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-2-1 (2H) pyriconyl) -1-piperidines) acetamide；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(1-(2-ethoxy)-4-piperidines Base) pyridine-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-(1-ethyl piperidine base)) pyrrole Pyridine-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-(1-2H-THP trtrahydropyranyl) Piperidyl) pyridine-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-2 hydrogen-pyranose) pyridine -2 (1 hydrogen)-one；
4-((4-((2-(isopropelsulfonyl) phenyl) amine-5-trifluoromethyl) pyrimidine-2-amido)-1-(4-piperidyl) pyrrole Pyridine-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(di(2-ethylhexyl)phosphate methyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) pyridine-2 (1 hydrogen)- Ketone；
4-((the chloro-4-of 5-((2-(N, N dimethyl sulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) pyridine -2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(N-isopropelsulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) pyridine -2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-(ethoxy sulfonyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) pyridine-2 (1 Hydrogen)-one；
4-((the chloro-4-of 5-((2-(1-(ethoxyl methyl) cyclopropyl) phenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) pyrrole Pyridine-2 (1 hydrogen)-one；
4-((the chloro-4-of 5-((2-methoxyphenyl) amine) pyrimidine-2-amido)-1-(4-piperidyl) pyridine-2 (1 hydrogen)-one.
6. a pharmaceutical composition, comprises such as compound defined in claim 1 or it is pharmaceutically acceptable Salt is as active ingredient, and one or more pharmaceutically acceptable carriers.
7. one kind such as compound defined in claim 1 or its pharmaceutically acceptable salt is used for treating in preparation Or prevent the purposes in the medicine of the disease relevant to protein kinase.
8. one kind such as compound defined in claim 1 or its pharmaceutically acceptable salt is used for treating in preparation Or prevent the purposes in the medicine of the disease relevant to anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase.
9. purposes as claimed in claim 8, it is characterised in that: described disease is selected from cell proliferative disease Disease, preferably tumor.
10. purposes as claimed in claim 9, it is characterised in that: described cell proliferation disorders includes Nonsmall-cell lung cancer, primary cutaneous type, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast carcinoma, Colorectal cancer, Diffuse Large B-Cell Lymphoma, hepatocarcinoma, gastric cancer, esophageal carcinoma, cancer of pancreas, ovarian cancer, complete Body histocytosis and neuroblastoma.
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