CN106478700A - The phenyl aminess kinases inhibitor that boryl replaces - Google Patents
The phenyl aminess kinases inhibitor that boryl replaces Download PDFInfo
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Abstract
The invention discloses a kind of scalable protein kinase activity and the compound for treatment or prevention and protein kinase related disorder.Specifically, the present invention relates to the phenyl aminess kinases inhibitor that a kind of boryl replaces, belong to the compound adjusting anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) activity, and provide the preparation method of such compound, and such compound is used for treatment or the pharmaceutical applications of the prevention disease related to ALK.
Description
Technical field
The present invention relates to regulatory protein kinase activity and the compound for treatment or prevention and protein kinase related disorder.Specifically, the present invention relates to the phenyl aminess kinases inhibitor that a kind of boryl replaces, belong to the compound adjusting anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) activity, and provide the preparation method of such compound, and such compound is used for treatment or the pharmaceutical applications of the prevention disease related to ALK.
Background technology
Malignant tumor is a kind of serious commonly encountered diseases threatening human health and frequently-occurring disease, is characterized in cell or mutant abnormality proliferation.The propagation of tumor cell, apoptosis, transfer etc. and certain link in a series of signal pathway of intraor extracellular occur abnormal closely related.In these signal transduction paths, the important molecule of a class is exactly protein kinase, and the exception of protein kinase is closely related with the generation of tumor, development and prognosis and outcome, is also the main cause leading to a series of other human diseasess relevant with inflammation or breeder reaction；The medicine of exploitation target protein kinase is the Main Means of therapy-related disease, the existing granted listing of a lot of medicines, and this kind of medicine has the characteristics that target spot is clear, clear curative effect, safe, the accreditation therefore increasingly put into practice by clinical treatment 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 that overexpression, mutation and the fusion protein of ALK are directly related with kinds of tumors, including but not limited to neuroblastoma, primary cutaneous type (ALCL), nonsmall-cell lung cancer (NSCLC) and inflammatory myofibroblastic tumor (IMT) etc..First generation medicine gram azoles for ALK fusion gene replaces Buddhist nun (Crizotinib) and second filial generation medicine Ceritinib (Ceritinib) to list respectively at 2011 and 2014, treatment for ALK positive lung cancer patient obtains significant Progression free survival and objective effective percentage it was confirmed the clear and definite clinical value of this target spot.Although drug effect is notable, due to the adaptation to ambient pressure of Tumor Heterogeneity feature and tumor cell, increasing research report is had to show, tumor drug resistance, progressive disease almost remain the inevitable destiny of such patient；Additionally, the problems such as the serious adverse reaction of existing medicine, as too high in side effect of digestive tract incidence rate, hepatotoxicity and QT interval prolongation, also limit the application of such medicine.In view of this, continue to develop the noval chemical compound with good ALK inhibitory activity and safety and developed listing, to tackle the problems referred to above, there is important social benefit and value.
Content of the invention
Present invention aim at providing a kind of structure phenyl aminess kinases inhibitor that novel boryl replaces, being modified by the replacement of group, synthesizing and filter out a series of compounds with anti-tumor activity.
For achieving the above object, this invention takes technical scheme below：
The phenyl aminess kinases inhibitor that a kind of boryl replaces, for having compound and its pharmaceutically acceptable salt of following general structure I：Wherein, R1It is selected from Q is-O- ,-S- or-NR13-；R2、R3、R4、R5、R6It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, cyano group or amino；R7Selected from hydroxyl or C1-6Alkoxyl；R0、R8、R9、R13It is each independently selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6One or more of alkynyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, aryl, heterocyclic radical；R10Selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, cyano group, aryl, heterocyclic radical ,-(CH2)wOR11、 -(CH2)wNR11R12、-CO2R11、-CONR11R12One or more of；R11、R12It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl or heterocyclic radical；Heterocyclic radical is selected from N, O heteroatomic 3-12 circle heterocycles；And n is selected from any integer value in 1～3, L, p are selected from any integer value in 0～6, and k is selected from any integer value in 2～6, and m, w are each independently selected from any integer value in 0～3.
Preferably, in general structure I, R1It is selected from Q is-O- ,-S- or-NR13-；R2、R3、R4、R5、R6It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkoxyl, cyano group or amino；R7Selected from hydroxyl or C1-6Alkoxyl；R0、R8、R9、R13It is each independently selected from hydrogen, C1-6Alkyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, phenyl or heterocyclic radical；R10Selected from hydrogen, C1-6Alkyl, cyano group, phenyl, heterocyclic radical ,-(CH2)wOR11、-(CH2)wNR11R12、-CO2R11Or-CONR11R12；R11、R12It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, phenyl or heterocyclic radical；Heterocyclic radical is selected from N, O heteroatomic 3-6 circle heterocycles；And n is selected from any integer value in 1～3, L, p are selected from any integer value in 0～6, and k is selected from any integer value in 2～6, and m, w are each independently selected from any integer value in 0～3.
The phenyl aminess kinases inhibitor that a kind of boryl replaces, also includes the compound for having following general formula II and its pharmaceutically acceptable salt：Wherein, R1It is selected from Q is-O- ,-S- or-NR13-；R2、R3、R4、R5、R6It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, cyano group or amino；R7、R14It is each independently selected from hydroxyl, C1-6Alkoxyl or R7、R14The cycloalkyloxy being formed；R0、R8、R9、R13It is each independently selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6One or more of alkynyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, aryl, heterocyclic radical；R10Selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, cyano group, aryl, heterocyclic radical ,-(CH2)wOR11、-(CH2)wNR11R12、-CO2R11、-CONR11R12One or more of；R11、R12It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl or heterocyclic radical；Heterocyclic radical is selected from N, O heteroatomic 3-12 circle heterocycles；N is selected from any integer value in 0～3, and L, p are selected from any integer value in 0～6, and k is selected from any integer value in 2～6, and m, w are each independently selected from any integer value in 0～3.
Preferably, in general formula II, R1It is selected from Q is-O- ,-S- or-NR13-；R2、R3、R4、R5、R6It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkoxyl, cyano group or amino；R7、R14It is each independently selected from hydroxyl, C1-6Alkoxyl or R7、R14The cycloalkyloxy being formed；R0、R8、R9、R13It is each independently selected from hydrogen, C1-6Alkyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, phenyl or heterocyclic radical；R10Selected from hydrogen, C1-6Alkyl, cyano group, phenyl, heterocyclic radical ,-(CH2)wOR11、-(CH2)wNR11R12、-CO2R11Or-CONR11R12；R11、R12It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, phenyl or heterocyclic radical；Heterocyclic radical is selected from N, O heteroatomic 3-6 circle heterocycles；N is selected from any integer value in 0～3, and L, p are selected from any integer value in 0～6, and k is selected from any integer value in 2～6, and m, w are each independently selected from any integer value in 0～3.
Preferably, aryl is phenyl, naphthyl or anthryl；Described heterocyclic radical is morpholinyl, piperidyl, pyranose, furyl, pyridine radicals or pyrimidine radicals.
Preferably, halogen is one or more of fluorine, chlorine, bromine, iodine.
The phenyl aminess kinases inhibitor that a kind of boryl replaces, the following characteristic compounds being REX-C1～REX-C23 selected from numbering：
REX-C1：7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C2：4- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C3：7- ((5- trifluoromethoxy -2- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C4：7- ((the chloro- 2- of 5- ((2- trifluoromethoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C5：7- ((the chloro- 2- of 5- ((the chloro- 4- of 2- isopropoxy -5- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C6：7- ((the fluoro- 2- of 5- ((the fluoro- 4- of 2- isopropoxy -5- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C7：7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- methyl piperidine base) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C8：7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (1- (4- THP trtrahydropyranyl) -4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C9：7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (1- (morpholinyl methyl) cyclopropyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C10：(2- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) phenyl) boric acid；
REX-C11：(2- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzyl) boric acid；
REX-C12：8- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amino) -4- pyrimidine radicals) amine) -3, double hydrogen-benzo [c] [1,2] oxo 1 (3H) boric acid of 4-；
REX-C13：7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- (1- methyl piperidine base)) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C14：7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- (1- acetamido piperidyl)) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C15：7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- (1- ethanol phenylpiperidines base)) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C16：7- ((the chloro- 2- of 5- ((2- isopropoxy -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C17：7- ((5- methyl -2- ((2- isopropoxy -5- methyl -4- (4- (1- methyl piperidine base)) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C18：7- ((5- trifluoromethyl -2- ((2- isopropoxy -5- methyl -4- (4- (1- methyl piperidine base)) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
REX-C19：The chloro- N of 5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-N4- (2- ((4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) methyl) phenyl) -2,4- di-amino-pyrimidine；
REX-C20：(2- ((the chloro- 2- of 5- ((4- (1- (ethoxyl methyl) cyclopropyl) -2- isopropoxy -5- aminomethyl phenyl) amino) 4- pyrimidine radicals) amine) benzyl) boric acid；
REX-C21：7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (1- (4- THP trtrahydropyranyl) -4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzyl) boric acid；
REX-C22：The chloro- N of 5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-N4- (4- ((4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) methyl) phenyl) -2,4- di-amino-pyrimidine；
REX-C23：(4- ((the chloro- 2- of 5- ((4- (1- (ethoxyl methyl) cyclopropyl) -2- isopropoxy -5- aminomethyl phenyl) amino) 4- pyrimidine radicals) amine) benzyl) boric acid.
Aforementioned numbering is the compound of REX-C1～REX-C23, and structural formula sees below：
Present invention also offers a kind of compound is foregoing formula I and the synthetic method of formula II, overall reaction route is as follows：
Formula I：
Formula II：
Based on above-mentioned overall reaction route, including following synthetic schemes：
(1) synthetic schemes 1：The synthesis of compound 1-3
Step 1：Compound 1-1 is dissolved in organic solvent, is slowly added to catalyst, nitrogen displacement, logical hydrogen, reacting by heating N hour；After reaction terminates, filter and remove unnecessary catalyst, organic solvent is dried, reduce pressure, be dried, obtain compound 1-2.
Step 2：Compound 1-3 is dissolved in organic solvent, is slowly added to sodium hydride and 2,4,5- trichloropyrimidines, nitrogen displacement, reacting by heating N hour；After reaction terminates, plus a small amount of frozen water destroys unnecessary sodium hydride, plus extractant, extracts, is dried, reduces pressure, being spin-dried for, obtains compound 1-3.
In synthetic schemes 1, organic solvent is selected from one or more of DMF, oxolane, methanol, dioxane；Extractant is selected from one or more of pure water, dichloromethane, ethyl acetate；Catalyst is selected from one or more of palladium charcoal, tetrakis triphenylphosphine palladium, platinum dioxide.
In synthetic schemes 1, the temperature of reacting by heating is 60～120 DEG C, preferably 60 DEG C, 120 DEG C；Response time is 10～14 hours, preferably 10 hours, 14 hours.
(2) synthetic schemes 2：The synthesis of compound 2-3
Step 1：Will(i.e. compound 2-1) andIt is dissolved in the mixed liquor of the organic solvent configuring in proportion and water, be slowly added to potassium phosphate and catalyst, nitrogen displacement, reacting by heating N hour；After reaction terminates, plus extractant, extract, be dried, reduce pressure, being spin-dried for, obtain compound 2-2.
Step 2：Compound 2-2 is dissolved in organic solvent, adds catalyst, nitrogen displacement, logical hydrogen, reacting by heating N hour；After reaction terminates, filtration under diminished pressure removes unnecessary catalyst, reduces pressure, is spin-dried for, obtains compound 2-3.
In synthetic schemes 2, organic solvent is selected from one or more of DMF, methanol, isopropanol, dioxane；Extractant is selected from one or more of pure water, dichloromethane, ethyl acetate；Catalyst is selected from one or more of palladium charcoal, tetrakis triphenylphosphine palladium, platinum dioxide.
In synthetic schemes 2, the temperature of reacting by heating is 100～120 DEG C, preferably 100 DEG C；Response time is 12～16 hours, preferably 12 hours, 16 hours.
(3) synthetic schemes 3：The synthesis of target compound
Step 1：The compound 2-3 that the prepared compound 1-4 of synthetic schemes 1, synthetic schemes 2 are obtained is dissolved in organic solvent, continuously adds cesium carbonate and catalyst, nitrogen displacement, microwave heating reaction N hour；After reaction terminates, filtration under diminished pressure removes unnecessary catalyst, crosses column chromatography, obtains target compound (i.e. the compound of formula I or formula II).
In synthetic schemes 3, organic solvent is selected from one or more of DMF, oxolane, methanol, dioxane；Catalyst is selected from one or more of palladium charcoal, tetrakis triphenylphosphine palladium, platinum dioxide, palladium, the double diphenylphosphine -9,9- dimethyl xanthene of 4,5-.
In synthetic schemes 3, the response time is 0.5～1 hour, preferably 0.5 hour.
In foregoing synthetic schemes 1, synthetic schemes 2, synthetic schemes 3, R1It is selected from Q is-O- ,-S- or-NR13-；R2、R3、R4、R5、R6It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, cyano group or amino；R7Selected from hydrogen, C1-6One or more of alkyl, amide groups, hydroxyl, aryl, heterocyclic radical；R0、R8、R9、R13It is each independently selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6One or more of alkynyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, aryl, heterocyclic radical；R10Selected from hydrogen, halogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, cyano group, aryl, heterocyclic radical ,-(CH2)wOR11、-(CH2)wNR11R12、-CO2R11、-CONR11R12One or more of；R11、R12It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, aryl or heterocyclic radical；Heterocyclic radical is selected from N, O heteroatomic 3-12 circle heterocycles；And n is selected from any integer value in 1～6, L, p are selected from any integer value in 0～6, and k is selected from any integer value in 2～6, and m, w are each independently selected from any integer value in 0～3.
" compound " of the present invention, including all stereoisomers, geometric isomer, tautomer and isotope.
" compound " of the present invention, can be asymmetric, for example, have one or more stereoisomers.Unless otherwise stated, all stereoisomers all include, such as enantiomer and diastereomer.Compound containing asymmetric carbon atom in the present invention, can be separated with the pure form of optical activity or racemic form.The pure form of optical activity from racemic mixture, or can synthesize by using chiral raw material or chiral reagent.
" compound " of the present invention, also includes tautomeric forms.Tautomeric forms derive from singly-bound and adjacent double bond exchanges and together with a proton migration.
Present invention additionally comprises all isotopic atoms, either in intermediate or last compound.Isotopic atom includes having identical atomic number but different quality number.For example, the isotope of hydrogen includes deuterium and tritium.
Compound containing aforementioned formula structure, term used herein has 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 " alkyl ", refers to the saturated hydrocarbons group of straight or branched being made up of carbon atom and hydrogen atom, such 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 (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2- methylhexyl etc..Described alkyl can be non-substituted or be replaced by one or more substituent groups, and substituent group includes but is not limited to alkyl, alkoxyl, cyano group, hydroxyl, carbonyl, carboxyl, 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.The version of-NH (alkyl) isSpecific example includes but is not limited to-NHCH3、-NHCH(CH3)2、-NHC2H5Deng；- N (alkyl)2Version beSpecific example includes but is not limited to-N (CH3)2、-N(CH3)C2H5Deng.
Term " aryl ", refer to have the pi-electron system of total conjugated full carbon is monocyclic or fused rings, generally there is 6-14 carbon atom, preferably there is 6-12 carbon atom, most preferably there are 6 carbon atoms.Aryl can be non-substituted or be replaced by one or more substituent groups, and substituent group includes but is not limited to alkyl, alkoxyl, cyano group, hydroxyl, carbonyl, carboxyl, aryl, aralkyl, amino, halogen, sulfonyl, sulfinyl, phosphoryl.The example of non-substituted aryl includes but is not limited to phenyl, naphthyl and anthryl.
Term " heterocyclic radical ", refers to the monocyclic or fused rings with 3-12 (integer) annular atom, wherein has 1,2 or 3 annular atoms to be selected from one or more of N, O, remaining annular atom is C, and has the π-electron system of total conjugated.Heterocyclic radical can be non-substituted or be replaced by one or more substituent groups, and substituent group includes but is not limited to alkyl, alkoxyl, cyano group, hydroxyl, carbonyl, carboxyl, aryl, aralkyl, amino, halogen, sulfonyl, sulfinyl, phosphoryl.The example of non-substituted heterocyclic radical includes but is not limited to pyrrole radicals, indyl, pyrrolidinyl, imidazole radicals, pyrazolyl, tetrazole radical, pyridine radicals, quinolyl, isoquinolyl, piperidyl, pyrimidine radicals, pyrazinyl, piperazinyl, furyl, pyranose, morpholinyl.
Formula I in the present invention,
Present invention also offers a kind of pharmaceutical composition, comprise foregoing compound or its pharmaceutically acceptable salt as active ingredient, and one or more pharmaceutically acceptable carrier.
" pharmaceutical composition " of the present invention, refers to the compound or its salt of one or more present invention and the preparation of the carrier for bioactive compound is delivered to organism (such as people) generally accepting in the art.The purpose of pharmaceutical composition is advantageous for being administered conveying to organism.
Term " pharmaceutically acceptable carrier ", refer to and material that is active ingredient co-administered and being conducive to active ingredient administration, including but not limited to acceptable any fluidizer for human or animal (such as domestic animal) of State Food and Drug Administration's license, sweetener, diluent, preservative, dyestuff/coloring agent, taste masking reinforcing agent, surfactant, wetting agent, dispersant, disintegrating agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent.For example include but is not limited to Calcium Carbonate, calcium phosphate, various sugared and each kind of starch, cellulose derivative, gelatin, vegetable oil and Polyethylene Glycol.
Pharmaceutical composition of the present invention, solid-state, semisolid, liquid or gaseous state preparation can be configured to, such 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 adopt method manufacture well known in the art, such as the mixing method of routine, dissolution method, granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc..
Compound of the present invention or the route of administration of its pharmaceutically acceptable salt or its pharmaceutical composition, including but not limited to oral, rectum, saturating mucosa, through enteral administration, or local, percutaneous, suction, parenteral, Sublingual, intravaginal, intranasal, ophthalmic, intraperitoneal, intramuscular, subcutaneous, intravenous administration.Preferably route of administration is oral administration.
For oral administration, this pharmaceutical composition can be prepared by mixing reactive compound with pharmaceutically acceptable carrier well known in the art.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 the oral administration to patient.For example, for the pharmaceutical composition of oral administration, tablet can be obtained in the following way：Active component is merged with one or more solid carrier, if necessary by gained granulating mixture, and adds a small amount of excipient to process resulting mixture or granule, to form tablet or label if necessary.Label can be combined with the coating material of optionally suitable enteric, is processed into the coated preparation form being more beneficial for that organism (such as people) absorbs.
Present invention also offers a kind of foregoing compound or its pharmaceutically acceptable salt purposes in the medicine that preparation is used for treatment or prevents the disease related to protein kinase.
A kind of foregoing compound or its pharmaceutically acceptable salt purposes in the medicine that preparation is used for treatment or prevents the disease related to anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK kinases).
Preferably, the aforementioned disease related to ALK kinases is selected from cell proliferation disorders, preferably tumor.
Preferably, aforementioned cells proliferative disease 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, body tissue's cellular proliferative disorder and neuroblastoma.
In the present invention, the amino benzenes compounds that inventor replaces to a series of boryl that synthesis obtains, carry out the combination rate determination experiment of ALK kinase inhibiting activity and ALK relevant mutational site, find that part of compounds shows higher inhibitory activity to ALK, preferable combination rate is shown to ALK mutational site (as L1196M, F1174L, C1156Y), to ROS1, also there is significant inhibitory activity；Additionally, also having carried out cell proliferation experiment and the experiment of Brachydanio rerio phenotypic screen of lung cancer cell line, find that part of compounds anti-tumor activity in vivo is notable.
Compared with prior art, the phenyl aminess kinases inhibitor that the boryl that the present invention provides replaces, based on the Rational drug design of target, is modified by the replacement of group, obtains a series of novel compound of structures；And combining kinase activity experiment, cell proliferation experiment, the experiment of Brachydanio rerio phenotypic screen, optimal screening goes out a series of compounds with anti-tumor activity.Therefore, can be used for developing into the kinases inhibitor of a new generation, for targeted therapy or prevention, great clinical value is had by the disease that ALK mediates, market potential is considerable.
Brief description
Fig. 1 is scattergram on back for the Albino Brachydanio rerio iris pigment cell
The dose-effect relationship figure (mean ± sem) that Fig. 2 affects on Brachydanio rerio iris pigment cell for REX-C1/REX-C3
Fig. 3 is the impact figure to Brachydanio rerio iris pigment cell for the REX-C1/REX-C3
Specific embodiment
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 substitute are included within protection scope of the present invention.
In the target compound preparation method that the present invention provides, liquid chromatograph adopts WatersSymmetry C18 chromatographic column.Thin layer chromatography adopts GF254 (0.25 millimeter).Nuclear magnetic resonance, NMR chromatograph (NMR) uses Bruker-400 nmr determination；Liquid matter is used in conjunction (LC/MS) and uses Waters ZQ mass detector (pillar：WatersSymmetryC18, millimeter, 5 microns, 35 DEG C), using ESI (+) ion mode.
Additionally, all operations of all raw materials being related to oxidizable or facile hydrolysiss are all carried out under nitrogen protection.Unless otherwise stated, the raw material that the present invention uses is all marketable material, need not be further purified and can directly use.
Embodiment 1 7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid【Numbering is REX-C1】Preparation
Synthetic route is as follows：
Synthetic schemes 1：The synthesis of intermediate 7- ((2,5- dichloro pyrimidine base) amino) benzo [c] [1,2] oxo 1 (3H) boric acid (i.e. compound 1-5)
Step 1：The preparation of 3- nitro -2- (4,4,5,5- tetramethyl -1,3,2- dioxo boryl) benzylacetic acid (i.e. compound 1-2)
Bromo- for raw material 2- 3- nitrobenzyl acetic acid (i.e. compound 1-1,11.3g, 40.0mmol) is dissolved in 1, in 4 dioxane (150.0mL), it is slowly added to potassium acetate (13.7g, 140.0mmol), 1, the double Diphenyl phosphino ferrocene palladium chloride (2.6g of 1'-, 3.0mmol), double (pinacol conjunction) two boron (15.2g, 60.0mmol), nitrogen displacement, maintains the temperature at 90～95 DEG C and reacts 16 hours；Reaction is poured in 500.0mL water after terminating, and is extracted with ethyl acetate, and is dried, concentrates, silica gel column chromatography separates, and obtains compound 1-2 (13.0g), yield：98.0%.
MSm/z[ESI]：322.1[M+1].
Step 2：The preparation of intermediate 7- nitro benzo [c] [1,2] oxo 1 (3H) boric acid (i.e. compound 1-3)
Compound 1-2 (6.4g, 20.0mmol) is dissolved in methanol (200.0mL), the sodium hydroxide solution (8.0mL, 40.0mmol) of Deca 5.0mol/L, maintains the temperature at 60～70 DEG C and react 24 minutes；React room temperature of rising again after terminating, add 3.0mol/L hydrochloric acid water destruct, extracted with water and ethyl acetate, organic faciess sodium bicarbonate washs secondary, anhydrous sodium sulfate drying, is concentrated to give compound 1-3 (2.2g), yield：63.0%.
MSm/z[ESI]：179.2[M+1].
Step 3：The preparation of intermediate 7- amino benzo [c] [1,2] oxo 1 (3H) boric acid (i.e. compound 1-4)
Compound 1-3 (2.2g, 12.0mmol) and 10% palladium charcoal (i.e. Pd/C, 0.5g) are added in dry methanol (25.0mL), nitrogen displacement, logical hydrogen, react 12 hours in 25 DEG C；Filtered, separated, anhydrous sodium sulfate drying, concentration with kieselguhr after cooling, obtain compound 1-4 (1.1g), yield：58.0%.
MSm/z[ESI]：150.2[M+1].
Step 4：The preparation of 7- ((2,5- dichloro pyrimidine base) amino) benzo [c] [1,2] oxo 1 (3H) boric acid (i.e. compound 1-5)
Under the conditions of ice-water bath, by compound 1-4 (1.1g, 7.0mmol) it is dissolved in DMF (30.0mL), it is slowly added to sodium hydride (0.18g in reaction system, 7.0mmol) and stir 15 minutes in 0 DEG C, then by 2,4,5- trichloropyrimidine (1.2g, 6.0mmol) is added drop-wise in reaction system and is stirred overnight in 25 DEG C；It is poured into after cooling in 50.0mL water, is extracted with ethyl acetate, be dried, concentrate, silica gel column chromatography separates, and obtains compound 1-5 (1.0g), yield：53.0%.
MSm/z[ESI]：296.2[M+1].1H-NMR(400MHz,DMSO-d6)：H NMR(400MHz,DMSO-d6):δ=9.531 (s, 1H), 8.940 (s, 1H), 8.462 (s, 1H), 8.021 (d, 1H, J=8.4Hz), 7.554-7.548 (m, 1H), 7.218-7.199 (d, 1H, J=7.6Hz), 5.040 (s, 2H).
Synthetic schemes 2：The synthesis of intermediate 4- (4- amino 5- isopropoxy -2- aminomethyl phenyl) piperidines -1- tertiary fourth oxygen carbonic ester (i.e. compound 2-4)
Step 1：The preparation of intermediate 1- chloro- 5- isopropoxy -2- methyl -4- Nitrobenzol (i.e. compound 2-2)
Fluoro- for chloro- for raw material 2- 4- 5- Methylnitrobenzene (i.e. compound 2-1,14.2g, 74.9mmol) is dissolved in isopropanol (100.0mL), adds cesium carbonate (122.0g, 374.4mmol), finish, react overnight at 60 DEG C；After reaction terminates, concentrate, remove isopropanol, be poured in 500.0mL water, extracted with ethyl acetate, organic faciess anhydrous sodium sulfate drying, concentrate, obtain compound 2-2 (14.3g), yield：82.0%.
MSm/z[ESI]：230.6[M+1].1H-NMR(400MHz,CDCl3)：δ=7.880 (s, 1H), 7.498 (s, 1H), 4.871-4.795 (m, 1H), 2.294 (s, 1H), 1.281-1.266 (d, J=6.0Hz, 6H).
Step 2：The preparation of intermediate 4- (5- isopropoxy -2- methyl -4- nitro-phenyl)-pyridine (i.e. compound 2-3)
4- pyridine boronic acid (14.7g, 120.0mmol) is dissolved in mixed liquor (both volume ratios v/v=2 of dioxane and water:1), nitrogen displacement, stirring 5 minutes.By three (1; 3- dibenzalacetone) close two palladium (10.0g; 10.9mmol), 2- dicyclohexyl phosphine -2', 6'- dimethoxy -1; 1'- biphenyl (11.2g; 27.2mmol), compound 2-2 (25.0g, 109.0mmol) and potassium phosphate (46.2g; 218.0mmol) sequentially add under nitrogen protection, reaction backflow is overnight.Reaction is cooled to room temperature after terminating, the saturation NaOH washing of 1.0mol is secondary, is extracted with ethyl acetate.Organic faciess anhydrous sodium sulfate drying, concentrates, silica gel column chromatography separates, and obtains compound 2-3 (20.0g), yield：67.4%.
MSm/z[ESI]：272.6[M+1].1H-NMR(400MHz,DMSO-d6)：δ=8.698-8.683 (dd, J1=1.6Hz, J2=4.4Hz 1H), 7.831 (s, 1H), 7.474-7.459 (dd, J1=2.0Hz, J2=4.8Hz1H), 7.230 (s, 1H), 4.912-4.822 (m, 1H), 2.196 (s, 1H), 1.285-1.270 (d, J=6.0Hz, 6H).
Step 3：The preparation of intermediate 4- (4- amino 5- isopropoxy -2- aminomethyl phenyl) piperidines -1- tertiary fourth oxygen carbonic ester (i.e. compound 2-4)
By compound 2-3 (43.8g, 161.0mmol) it is dissolved in acetic acid (400.0mL) and the mixed liquor of trifluoroacetic acid (25.0mL), add the platinum dioxide (17.6g) of platinum containing amount 40%, nitrogen displacement, logical hydrogen, stirring 5 minutes, it is pressurized to 1 atmospheric pressure, react 36 hours.Reaction is cooled to room temperature after terminating, and filters, removes platinum dioxide, adds the dilution of 100.0mL water, is extracted with ethyl acetate；Organic faciess saturation NaOH of 1.0mol washs secondary, anhydrous sodium sulfate drying, concentration, silica gel column chromatography separation, obtains compound 2-4 (34.0g), yield：60.6%.
MSm/z[ESI]：348.2[M+1].1H-NMR(400MHz,DMSO-d6)：δ=6.575 (s, 1H), 6.432 (s, 1H), 4.439-4.345 (m, 2H), 4.083-4.063 (m, 2H), 2.818-2.81 (m, 2H), 2.122 (s, 3H), 1.620-1.590 (m, 2H), 1.423 (s, 9H), 1.401-1.388 (m, 2H), 1.231-1.216 (m, 6H).
Synthetic schemes 3：The synthesis of target compound 7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid (i.e. REX-C1)
Step 1：Intermediate 4- (4- ((1- hydroxyl -1,3 benzos [c] [1,2] oxo 1 (3H) boronate) -2- pyrimdinyl-amino) -5- isopropoxy -2- tolyl) and the piperidines -1- hydroxy acid tert-butyl ester (i.e. compound 3-1) preparation
By compound 2-4 (0.9g, 2.7mmol), compound 1-5 (0.8g, 2.7mmol), double (diphenylphosphine) -9,9- dimethyl xanthene (0.3g of 4,5-, 0.5mmol), palladium (63.0mg, 0.3mmol) it is dissolved in dioxane (50.0mL) with cesium carbonate (2.7g, 8.1mmol), and add in tube sealing, nitrogen displacement, reacts 18 hours in 95 DEG C.After reaction terminates, it is spin-dried for solvent, adds ethyl acetate and water, extraction, organic faciess are dried, cross silica gel chromatography, obtain compound 3-1 (0.2g), yield：16.0%.
MSm/z[ESI]：608.1[M+1].
Step 2：The preparation of target compound (i.e. REX-C1)
Under stirring condition, compound 3-1 (0.2g, 0.4mmol) is added in dichloromethane (10.0mL), Deca trifluoroacetic acid (2mL), it is stirred overnight under room temperature.First it is adjusted to pH ＞ 10.0 with 5.0% sodium bicarbonate aqueous solution, then is extracted with ethyl acetate, is dried, is spin-dried for, obtain target compound REX-C1 (80.0mg), yield：34.0%.
MSm/z[ESI]：508.1[M+1].1H-NMR(400MHz,DMSO-d6)：δ=8.444 (s, 1H), 8.176 (m, 2H), 7.976 (s, 1H), 7.600 (s, 1H), 7.320-7.315 (m, 1H), (7.086-7.066 m, 1H), 6.835 (s, 1H), 5.007 (s, 2H), (4.540-4.445 m, 1H), 3.060-3.055 (m, 2H), 2.740-2.735 (m, 1H), (2.630-2.628 m, 2H), 2.095 (s, 3H), 1.650-1.550 (m, 4H), (1.250-1.235 d, 6H, J=6Hz).
Embodiment 2 4- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid【Numbering is REX-C2】Preparation
Synthetic route is as follows：
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-5 ", step 1 raw material 2- bromo- 6- nitrobenzyl acetic acid replaces the 2- bromo- 3- nitrobenzyl acetic acid of embodiment 1 to be reacted, remaining synthetic method is with the synthetic schemes 1 of embodiment 1, compound 1-5, yield is obtained final product after multistep reaction：28.0%.
MSm/z[ESI]：296.4[M+1].
In synthetic schemes 2 " synthesis of compound 2-4 ", the chloro- 4- of raw material 2- fluoro- 5- Methylnitrobenzene (i.e. compound 2-1), remaining synthetic method all with the synthetic schemes 2 of embodiment 1, obtain final product compound 2-4, yield：62.8%.
MSm/z[ESI]：348.2[M+1].
In synthetic schemes 3 " synthesis of target compound REX-C2 ", the compound 1-5 that be obtained the present embodiment and compound 2-4, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound REX-C2, yield：9.0%.
MSm/z[ESI]：508.1[M+1].1H-NMR(400MHz,DMSO-d6)：δ=9.478 (s,1H),8.725-8.690(d,1H,J=14Hz),8.499-8.463(m,1H),8.236(s,1H),8.188(s,1H),7.716-7.699(d,1H,J=6.8Hz),7.475-7.741(m,2H),7.314(s,1H),6.699(s,1H),4.916(s,2H),4.514(m,1H),3.339-3.335(m,2H),3.020-3.015(m,2H),2.873-2.870(m,1H),1.850(s,3H),1.754-1.740(m,4H),1.257-1.242(d,6H,J=6Hz).
Embodiment 3 7- ((5- trifluoromethoxy -2- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid【Numbering is REX-C3】Preparation
Synthetic route is as follows：
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-5 ", step 4 raw material 2, the chloro- 5- trifluoromethyl pyrimidine of 4- bis- replaces the 2 of embodiment 1,4,6- trichloropyrimidines are reacted, and remaining synthetic method is with the synthetic schemes 1 of embodiment 1, compound 1-5, yield is obtained final product after multistep reaction：31.0%.
MSm/z[ESI]：296.4[M+1].
In synthetic schemes 2 " synthesis of compound 2-4 ", the chloro- 4- of raw material 2- fluoro- 5- Methylnitrobenzene (i.e. compound 2-1), remaining synthetic method all with the synthetic schemes 2 of embodiment 1, obtain final product compound 2-4, yield：62.8%.
MSm/z[ESI]：348.2[M+1].
In synthetic schemes 3 " synthesis of target compound REX-C3 ", the compound 1-5 that be obtained the present embodiment and compound 2-4, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound REX-C3, yield：18.0%.
MSm/z[ESI]：542.1[M+1].1H-NMR(400MHz,DMSO-d6)：δ=9.404-9.554 (m, 2H), 8.613 (s, 1H), 7.751-7.902 (br s, 1H), (7.341-7.385 m, 2H), 7.203-7.261 (m, 1H), 6.851 (s, 1H), (4.995 s, 2H), 4.503-4.574 (m, 1H), 3.311-3.392 (m, 2H), (2.962-3.093 m, 2H), 2.083 (s, 3H), 1.932-1.993 (m, 2H), (1.771-1.862 m, 2H), 1.241-1.262 (d, J=6Hz, 6H).
Embodiment 4 7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (1- (morpholinyl methyl) cyclopropyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo 1 (3H) boric acid【Numbering is REX-C9】Preparation
Synthetic route is as follows：
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-5 ", raw material 2- bromo- 3- nitrobenzyl acetic acid (i.e. compound 2-1), remaining synthetic method all with the synthetic schemes 1 of embodiment 1, obtain final product compound 1-5, yield：28.0%.
MSm/z[ESI]：296.4[M+1].
Synthetic schemes 2：The synthesis of intermediate 2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) aniline (i.e. compound 2-5)
Step 1：The preparation of intermediate 1- (2- methyl -4- nitro -5- isopropoxy) cyclopropyl-phenyl acetic acid (i.e. compound 2-2)
By raw material 1- (2- methyl -4- nitro -5- hydroxyl) cyclopropyl-phenyl methyl acetate (i.e. compound 2-1,1g, 3.4mmol) with Lithium hydrate (571mg, 13.6mmol) it is dissolved in methanol (50ml) and water (10ml), reaction is heated to 80 DEG C and stirs 60 minutes.After reaction terminates, the hydrochloric acid of the 1N that adds water adjusts pH=4, filters, obtains compound 2-2 (750mg), yield：79%.
MSm/z[ESI]：280.2[M+1].
Step 2：The preparation of intermediate (1- (5- isopropoxy -2- methyl -4- nitro) cyclopropyl) phenylacetic acid morpholine (i.e. compound 2-3)
By compound 2-2 (600mg, 2.15mmol), triethylamine (653mg, 6.45mmol), HATU (1.064g, 2.8mmol), morpholine (281mg, 3.23mmol) it is dissolved in DMF (50ml), room temperature reaction 3 hours.After reaction terminates, the ethyl acetate that adds water extracts, and drying is spin-dried for, and obtains compound 2-3 (673mg), yield：90%.
MSm/z[ESI]：347.4[M+1].
Step 3：The preparation of intermediate 2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) Nitrobenzol (i.e. compound 2-4)
Compound 2-3 (673mg, 1.93mmol) is dissolved in oxolane (50ml), room temperature Deca boron trifluoride (14.4ml, 14.4mmol, 1M in THF).After reaction terminates, the ethyl acetate that adds water extracts, and is dried, is spin-dried for, obtains compound 2-4 (450mg), yield：69%.
MSm/z[ESI]：333.4[M+1].
Step 4：The preparation of intermediate 2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) aniline (i.e. compound 2-5)
By compound 2-4 (450mg, 1.35mmol), Pd/C (238mg, 58.8%in H2O) it is dissolved in methanol (25ml), hydrogen exchange, ambient temperature overnight.After reaction terminates, filter and remove palladium removing charcoal, be dried, be spin-dried for, obtain compound 2-5 (400mg), yield：97%.
MSm/z[ESI]：305.4[M+1].
In synthetic schemes 3 " synthesis of target compound REX-C9 ", the compound 1-5 that be obtained the present embodiment and compound 2-5, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound REX-C9, yield：20.0%.
MSm/z[ESI]：564.1[M+1].1H-NMR(400MHz,DMSO-d6)：δ=8.382-8.360 (d,J=8.8Hz,1H),8.299(s,1H),8.061(s,1H),8.012(s,1H),7.460(s,1H),7.402-7.360(t,J=8.4Hz,1H),6.881-6.862(d,J=7.6Hz,1H),6.805(s,1H),4.999(s,2H),4.607-4.547(m,1H),3.721-3.698(t,J=4.6Hz,4H),2.594(m,6H),2.478(s,3H),2.044-2.027(m,1H),1.442-1.427(d,J=6Hz,6H),0.886(m,2H),0.811(m,2H).
Embodiment 5 ALK kinase inhibiting activity and the mensure of relevant mutational site combination rate
Compound R EX-C1, REX-C2, REX-C3 and REX-C9 that above-described embodiment 1～4 is obtained, adopts(FRET) measuring aforesaid compound to ALK kinase inhibiting activity, this inhibitory activity adopts IC to method50This index representing, IC50The i.e. concentration of the compound during activity inhibited 50% of ALK kinases.
Adopt simultaneouslyThe compound that Eu Kinase Binging Assay (TR-FRET) determines the present invention measures to the combination rate of ALK relevant mutational site such as ALK L1196M, is also adopted by IC50This index is representing.LanthaScreen Eu kinases Binding experiment passes through to add Eu traget antibody or anti-tag antibody detects that Alexa Fluor conjugate or kinases " tracer " combine.The combination of tracer and antibody and kinases leads to the FRET of height, otherwise replaces tracer that FRET can be caused to lose using kinase inhibitor.
The present invention is measured using the kinase assay platform of Life technology company, and measurement result is shown in Table one.Result shows, the compound that the present invention provides has preferable ALK inhibitory activity, and also there is preferable combination rate in the mutational site (as ALK L1196M) to ALK.
The ALK inhibitory activity of table one embodiment compound and ALK L1196M combination rate measure
| ALK IC50(nM) | ALK F1196M IC50(nM) | |
| REX-C1 | 80.9 | 92.3 |
| REX-C2 | 31.5 | 51.3 |
| REX-C3 | 32.6 | 17.6 |
| REX-C9 | 1070 | 1040 |
Further, the present invention selects and selects compound R EX-C1, and using kinase assay platform assay aforesaid compound determination of activity to associated kinase under 100nM concentration of Life technology company, measurement result is shown in Table two.Result shows, compound R EX-B2, REX-B3 and REX-B4 that the present invention provides show preferable combination rate to ALK F1174L, ALK C1156Y, and LTK, ROS1 are shown with higher inhibitory activity simultaneously.
Table two embodiment compound determination of activity to associated kinase under 100nM concentration
Embodiment 6 cell proliferation experiment (detection of Cell Titer GLO method)
Testing compound：Compound R EX-C1, REX-C2, REX-C3 and REX-C9 that the embodiment of the present invention 1～4 is obtained.
Cell strain：People primary cutaneous type cell strain Karpas-299, non-small cell lung cancer cell strain NCI-H3122, purchased from bio tech ltd of Nanjing section one hundred.
Method：Collect exponential phase cell, count, with complete medium Eddy diffusion cell, adjust cell concentration to suitable concn (determining according to cell density optimization result of the test), inoculate 96 orifice plates, every hole adds 100 μ l cell suspension.Cell at 37 DEG C, 100% relative humidity, 5%CO2It is incubated 24 hours in incubator.With culture medium, testing compound is diluted to set respective action concentration, adds cell by 25 μ l/ holes.Compound effects final concentration from the beginning of 10 μM, 3 times of gradient dilutions, totally 10 concentration point.Cell is placed in 37 DEG C, 100% relative humidity, 5%CO2It is incubated 72 hours in incubator.Incubation requires according to Cell Titer Glo reagent description after terminating, and adds, in cell version, the reagent preparing, and after fully mixing, room temperature lucifuge is incubated 10 minutes.Cell plates are put into plate reader be analyzed, set and read chemiluminescence record data.Calculate suppression ratio.According to the suppression ratio to each cell growth for each compound variable concentrations, calculate IC on each cell for each compound with graphad 6.050Value.
Computing formula is：
Result：It is shown in Table three.
Table three Cell Titer GLO method detects the cell proliferation IC to Karpas-299/NCI-H3122 cell strain for the embodiment compound50Value
| IC50(μM) | Karpas-299 | NCI-H3122 |
| REX-C1 | <1 | <0.2 |
| REX-C2 | <1 | <1 |
| REX-C3 | <0.3 | <0.05 |
| REX-C9 | <0.5 | <0.5 |
Embodiment 8 Brachydanio rerio phenotypic screen is tested
Brachydanio rerio is a kind of vertebratess, is up to 85% with human gene's homology, and its signal transduction pathway is substantially approximate with the mankind, and biological structure and physiological function are highly similar to mammal；Its small volume, blastoprolepsis, embryo are transparent, egg laying amount is high, and these unique advantages make Brachydanio rerio become one of optimal mode organism of human diseasess research and live body high-flux medicaments sifting.Wherein, anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase ALK (Anaplastic lymphoma kinase) genetic homology in the mankind with Brachydanio rerio reaches 76%.Leukocyte tyrosine kinase ltk (leukocyte tyrosine kinase) of Brachydanio rerio regulates and controls the generation (Lopes of Brachydanio rerio iris pigment cell, S.S., Yang, X., et al. (2008) .Leukocyte tyrosine kinase functions in pigment cell development.PLoS Genet, 4.), iris pigment cell shows as a kind of silver color corpusculum in Brachydanio rerio, it is distributed in head, eyes, outside spinal column (viewed in reflected light), Albino Brachydanio rerio using melanin disappearance, it is observed that silver color corpusculum is black in saturating coloured light, see Fig. 1.ALK and LTK is sister kinase, researcher finds that the ALK plasmid of injection of exogenous equally can adjust the generation of iris pigment cell, experimental result also indicates that ALK inhibitor has LTK activity mostly, generation (the Rodrigues of iris pigment cell can be suppressed, F.S., Yang, X., Nikaido, M., Liu, Q. ， ＆Kelsh, R.N. (2012) .A simple, highly visual in vivo screen for anaplastic lymphoma kinase inhibitors.ACS Chem Biol, 7,1968-1974.).
Therefore, using this principle, we investigate the impact to normal Brachydanio rerio iris pigment cell for the compound, to inquire into the compound active power of anti-ALK in vivo.
The experiment impact to normal Brachydanio rerio iris pigment cell for (one) compound
Scheme：Choose the fish roe of 6hpf (hours post fertilization), random packet, it is subsequently adding the test medicine of each concentration, carry out image acquisition during to 3dpf (days post fertilization), then utilize ImageJ software analysis cloacal aperture to IOD (the integrated option density) value of tail fin position Brachydanio rerio back side iris pigment cell, Dunnett ' s T- inspection is carried out using Graphpad prism6.0 and carries out statistical analysis, p<0.05 shows that, with significant difference, iris pigment suppression ratio computing formula is as follows：
Result of calculation is shown in Table four, table five, and compound R EX-C1/REX-C3 is shown in Fig. 2 to the dose-effect relationship figure (mean ± sem) that Brachydanio rerio iris pigment cell affects, and the impact figure to Brachydanio rerio iris pigment cell for the compound R EX-C1/REX-C3 is shown in Fig. 3.
The impact (mean ± sem) to Brachydanio rerio iris pigment cell for the table four compound R EX-C1
compared with control,*,p<0.05；**,p<0.01
The impact (mean ± sem) to Brachydanio rerio iris pigment cell for the table five compound R EX-C3
compared with control,*,p<0.05；**,p<0.01 .
Claims (12)
1. the phenyl aminess kinases inhibitor that a kind of boryl replaces, for having the chemical combination of following general structure I
Thing and its pharmaceutically acceptable salt：
Wherein, R1It is selected from
Q is-O- ,-S- or-NR13-；
R2、R3、R4、R5、R6It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl,
C1-6Alkoxyl, halo C1-6Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, cyano group or amino；
R7Selected from hydroxyl or C1-6Alkoxyl；
R0、R8、R9、R13It is each independently selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, acyl
One or more of base, amide groups, sulfo group, sulfophenyl, hydroxyl, aryl, heterocyclic radical；
R10Selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, cyano group, aryl, heterocyclic radical ,-(CH2)wOR11、
-(CH2)wNR11R12、-CO2R11、-CONR11R12One or more of；
R11、R12It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl,
Aryl or heterocyclic radical；
Described heterocyclic radical is selected from N, O heteroatomic 3-12 circle heterocycles；
And n is selected from any integer value in 1～3, L, p are selected from any integer value in 0～6, and k is selected from 2～6
In any integer value, m, w are each independently selected from any integer value in 0～3.
2. boryl according to claim 1 replaces phenyl aminess kinases inhibitor it is characterised in that：
In described general structure I,
R1It is selected from
Q is-O- ,-S- or-NR13-；
R2、R3、R4、R5、R6It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl,
C1-6Alkoxyl, halo C1-6Alkoxyl, cyano group or amino；
R7Selected from hydroxyl or C1-6Alkoxyl；
R0、R8、R9、R13It is each independently selected from hydrogen, C1-6Alkyl, acyl group, amide groups, sulfo group, sulphur
Amido, hydroxyl, phenyl or heterocyclic radical；
R10Selected from hydrogen, C1-6Alkyl, cyano group, phenyl, heterocyclic radical ,-(CH2)wOR11、-(CH2)wNR11R12、
-CO2R11Or-CONR11R12；
R11、R12It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, phenyl or heterocyclic radical；
Described heterocyclic radical is selected from N, O heteroatomic 3-6 circle heterocycles；
And n is selected from any integer value in 1～3, L, p are selected from any integer value in 0～6, and k is selected from 2～6
In any integer value, m, w are each independently selected from any integer value in 0～3.
3. the phenyl aminess kinases inhibitor that a kind of boryl replaces, for having the chemical combination of following general formula II
Thing and its pharmaceutically acceptable salt：
Wherein, R1It is selected from
Q is-O- ,-S- or-NR13-；
R2、R3、R4、R5、R6It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl,
C1-6Alkoxyl, halo C1-6Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, cyano group or amino；
R7、R14It is each independently selected from hydroxyl, C1-6Alkoxyl or R7、R14The cycloalkyloxy being formed；
R0、R8、R9、R13It is each independently selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, acyl
One or more of base, amide groups, sulfo group, sulfophenyl, hydroxyl, aryl, heterocyclic radical；
R10Selected from hydrogen, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, cyano group, aryl, heterocyclic radical ,-(CH2)wOR11、
-(CH2)wNR11R12、-CO2R11、-CONR11R12One or more of；
R11、R12It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl,
Aryl or heterocyclic radical；
Described heterocyclic radical is selected from N, O heteroatomic 3-12 circle heterocycles；
N is selected from any integer value in 0～3, and L, p are selected from any integer value in 0～6, and k is selected from 2～6
In any integer value, m, w are each independently selected from any integer value in 0～3.
4. boryl according to claim 3 replaces phenyl aminess kinases inhibitor it is characterised in that：
In described general formula II,
R1It is selected from
Q is-O- ,-S- or-NR13-；
R2、R3、R4、R5、R6It is each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl,
C1-6Alkoxyl, halo C1-6Alkoxyl, cyano group or amino；
R7、R14It is each independently selected from hydroxyl, C1-6Alkoxyl or R7、R14The cycloalkyloxy being formed；
R0、R8、R9、R13It is each independently selected from hydrogen, C1-6Alkyl, acyl group, amide groups, sulfo group, sulphur
Amido, hydroxyl, phenyl or heterocyclic radical；
R10Selected from hydrogen, C1-6Alkyl, cyano group, phenyl, heterocyclic radical ,-(CH2)wOR11、-(CH2)wNR11R12、
-CO2R11Or-CONR11R12；
R11、R12It is each independently selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, phenyl or heterocyclic radical；
Described heterocyclic radical is selected from N, O heteroatomic 3-6 circle heterocycles；
N is selected from any integer value in 0～3, and L, p are selected from any integer value in 0～6, and k is selected from 2～6
In any integer value, m, w are each independently selected from any integer value in 0～3.
5. the phenyl aminess kinases inhibitor that the boryl according to any one of Claims 1 to 4 replaces, its
It is characterised by：Described aryl is phenyl, naphthyl or anthryl；Described heterocyclic radical be morpholinyl, piperidyl,
Pyranose, furyl, pyridine radicals or pyrimidine radicals.
6. the phenyl aminess kinases inhibitor that the boryl according to any one of Claims 1 to 4 replaces, its
It is characterised by：Described halogen is one or more of fluorine, chlorine, bromine, iodine.
7. the phenyl aminess kinases inhibitor that a kind of boryl replaces, selected from following characteristic compounds：
7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo
[c] [1,2] oxo 1 (3H) boric acid；
4- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo
[c] [1,2] oxo 1 (3H) boric acid；
7- ((5- trifluoromethoxy -2- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine)
Benzo [c] [1,2] oxo 1 (3H) boric acid；
7- ((the chloro- 2- of 5- ((2- trifluoromethoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo
[c] [1,2] oxo 1 (3H) boric acid；
7- ((the chloro- 2- of 5- ((the chloro- 4- of 2- isopropoxy -5- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2]
Oxo 1 (3H) boric acid；
7- ((the fluoro- 2- of 5- ((the fluoro- 4- of 2- isopropoxy -5- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2]
Oxo 1 (3H) boric acid；
7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- methyl piperidine base) phenyl) amine) 4- pyrimidine radicals) amine) benzo
[c] [1,2] oxo 1 (3H) boric acid；
((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (1- (4- THP trtrahydropyranyl) -4- piperidyl) phenyl) amine) 4- is phonetic for 7-
Piperidinyl) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (1- (morpholinyl methyl) cyclopropyl) phenyl) amine) 4- pyrimidine radicals)
Amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
(2- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) phenyl) boron
Acid；
(2- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzyl) boron
Acid；
8- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amino) -4- pyrimidine radicals) amine) -3,4- is double
Hydrogen-benzo [c] [1,2] oxo 1 (3H) boric acid；
7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- (1- methyl piperidine base)) phenyl) amine) 4- pyrimidine radicals) amine)
Benzo [c] [1,2] oxo 1 (3H) boric acid；
7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- (1- acetamido piperidyl)) phenyl) amine) 4- pyrimidine radicals)
Amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
7- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- (1- ethanol phenylpiperidines base)) phenyl) amine) 4- pyrimidine radicals) amine)
Benzo [c] [1,2] oxo 1 (3H) boric acid；
7- ((the chloro- 2- of 5- ((2- isopropoxy -4- (4- piperidyl) phenyl) amine) 4- pyrimidine radicals) amine) benzo [c] [1,2] oxo
1 (3H) boric acid；
7- ((5- methyl -2- ((2- isopropoxy -5- methyl -4- (4- (1- methyl piperidine base)) phenyl) amine) 4- pyrimidine radicals) amine)
Benzo [c] [1,2] oxo 1 (3H) boric acid；
7- ((5- trifluoromethyl -2- ((2- isopropoxy -5- methyl -4- (4- (1- methyl piperidine base)) phenyl) amine) 4- pyrimidine
Base) amine) benzo [c] [1,2] oxo 1 (3H) boric acid；
The chloro- N of 5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-N4- (2- ((4,4,5,5- tetramethyl -1,3,2-
Dioxaborolan -2- base) methyl) phenyl) -2,4- di-amino-pyrimidine；
(((the chloro- 2- of 5- ((4- (1- (ethoxyl methyl) cyclopropyl) -2- isopropoxy -5- aminomethyl phenyl) amino) 4- is phonetic for 2-
Piperidinyl) amine) benzyl) boric acid；
((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (1- (4- THP trtrahydropyranyl) -4- piperidyl) phenyl) amine) 4- is phonetic for 7-
Piperidinyl) amine) benzyl) boric acid；
The chloro- N of 5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-N4- (4- ((4,4,5,5- tetramethyl -1,3,2-
Dioxaborolan -2- base) methyl) phenyl) -2,4- di-amino-pyrimidine；
(((the chloro- 2- of 5- ((4- (1- (ethoxyl methyl) cyclopropyl) -2- isopropoxy -5- aminomethyl phenyl) amino) 4- is phonetic for 4-
Piperidinyl) amine) benzyl) boric acid.
8. a kind of 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 carrier.
9. a kind of compound such as defined in claim 1 or its pharmaceutically acceptable salt are used for treating in preparation
Or prevent the purposes in the medicine of disease related to protein kinase.
10. a kind of compound such as defined in claim 1 or its pharmaceutically acceptable salt are used for controlling in preparation
Treat or prevent the purposes in the medicine of disease related to anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase.
11. purposes as described in claim 9 or 10 it is characterised in that：Described disease is selected from cell and increases
Growing property disease, preferably tumor.
12. purposes as claimed in claim 11 it is characterised in that：Described cell proliferation disorders include
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 histocytosises and neuroblastoma.
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| CN108341835A (en) * | 2017-01-22 | 2018-07-31 | 正大天晴药业集团股份有限公司 | Boron-containing compound as tyrosine kinase inhibitor |
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