CN106336382A - 4-Saturated cyclosubstituted aniline protein kinase inhibitor - Google Patents

4-Saturated cyclosubstituted aniline protein kinase inhibitor Download PDF

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CN106336382A
CN106336382A CN201610541082.XA CN201610541082A CN106336382A CN 106336382 A CN106336382 A CN 106336382A CN 201610541082 A CN201610541082 A CN 201610541082A CN 106336382 A CN106336382 A CN 106336382A
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phenyl
methyl
amino
cyclopropyl
pyrimidine
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CN106336382B (en
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王永辉
高羽军
周娟
朱研
刘万登
王栋
沈锡明
吴耀东
李春启
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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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention discloses a compound being able to adjust the activity of protein kinase and used for treating or preventing protein kinase related diseases, concretely relates to a 4-saturated cyclosubstituted aniline protein kinase inhibitor belonging to a compound for adjusting the activity of anaplastic lymphoma kinase (ALK), and provides a preparation method of the compound and a pharmaceutical use of the compound in treatment or prevention of ALK related diseases.

Description

The phenyl aminess kinases inhibitor that 4- saturation ring group replaces
Technical field
The present invention relates to regulatory protein kinase activity and the chemical combination for treatment or prevention and protein kinase related disorder Thing.Specifically, the present invention relates to a kind of phenyl aminess kinases inhibitor of 4- saturation ring group replacement, belong to degeneration between regulation The compound of lymphom kinase (alk) activity, and provide the preparation method of such compound, and such compound is used for treating Or prevent the pharmaceutical applications of the 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. are gone out with certain link in a series of signal pathway of intraor extracellular Now abnormal closely related.In these signal transduction paths, the important molecule of a class is exactly protein kinase, the exception of protein kinase Generation with tumor, development and prognosis and outcome are closely related, are also to lead to a series of other relevant with inflammation or breeder reaction The main cause of human diseasess；The medicine of exploitation target protein kinase is the Main Means of therapy-related disease, existing a lot of medicines The granted listing of thing, this kind of medicine has the characteristics that target spot is clear, clear curative effect, safe, is therefore increasingly cured by clinic Treat accreditation and the support of practice.
Anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (alk) is the important member of protein kinase family, now there are some researches show the excessive table of alk Reach, be mutated and fusion protein is directly related with kinds of tumors, including but not limited to neuroblastoma, Anaplastic large cell lymph Tumor (alcl), nonsmall-cell lung cancer (nsclc) and inflammatory myofibroblastic tumor (imt) etc..For alk fusion gene Generation medicine gram azoles replace Buddhist nun (crizotinib) and second filial generation medicine Ceritinib (ceritinib) respectively at 2011 and Listing in 2014, the treatment for alk positive lung cancer patient obtains significant Progression free survival and objective effective percentage it was confirmed being somebody's turn to do The clear and definite clinical value of 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；This Outward, the serious adverse reaction of existing medicine, as too high in side effect of digestive tract incidence rate, hepatotoxicity and qt interval prolongation etc. are asked Topic, also limit the application of such medicine.In view of this, continue to develop newization with good alk inhibitory activity and safety Compound 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 4- saturation ring group replaces, Modified by the replacement of group, synthesize 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 4- saturation ring group replaces, for having the compound of following general structure And its pharmaceutically acceptable salt:Wherein, r1Selected from hydrogen, halogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, cyano group, aryl, heterocyclic radical ,-(ch2)wor10、-(ch2)wnr10r11、-co2r10、-conr10r11、-(ch2)wso2r10、-(ch2)wso2nr2r10One or more of；r2、r3、r4、r5、r6It is each independently selected from hydrogen, halogen, c1-6Alkane Base, halo c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkoxyl, c2-6Thiazolinyl, c2-6Alkynyl, cyano group or amino；r7Selected from hydrogen, halogen Element, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-6Alkoxyl, halo c1-6Alkoxyl ,-nr2cor8、-nr2conr2r8、- nr2so2r8、-cor8、-conr2r8、-so2r8、-so2nr2r8、-por8r9、r8、r9, each From being independently selected from hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6One or more of alkynyl, hydroxyl, aryl；r10、r11Independently of one another Selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, aryl or heterocyclic radical；Heterocyclic radical is selected from n, o hetero atom 3-12 circle heterocycles；And n is selected from any integer value in 1～6, w is selected from any integer value in 0～3.
Preferably, in said structure formula, r1Selected from hydrogen, halogen, c1-6Alkyl, cyano group, phenyl, heterocyclic radical ,- co2r10、-(ch2)wor10、-(ch2)wnr10r11、-conr10r11、-(ch2)wso2r10Or-(ch2)wso2nr2r10；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 hydrogen, c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkoxyl ,-so2r8、-por8r9、-so2nr8r9、-conr8r9、r8、r9It is each independently selected from hydrogen, halogen, c1-6One of alkyl, hydroxyl, phenyl Or it is several；r10、r11It is each independently selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, phenyl or heterocyclic radical；Heterocyclic radical be selected from n, O heteroatomic 3-6 circle heterocycles；And n is selected from any integer value in 1～6, w is selected from any integer value in 0～3.
The phenyl aminess kinases inhibitor that a kind of 4- saturation ring group replaces, is also included for having following general structure Compound and its pharmaceutically acceptable salt:Wherein, r1Selected from hydrogen, halogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, cyano group, aryl, heterocyclic radical ,-co2r10、-(ch2)wor10、-(ch2)wnr10r11、-conr10r11、- (ch2)wso2r10、-(ch2)wso2nr2r10One or more of；r2、r3、r4、r5、r6Be each independently selected from hydrogen, halogen, c1-6Alkyl, halo c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkoxyl, c2-6Thiazolinyl, c2-6Alkynyl, cyano group or amino；r7It is selected from Hydrogen, halogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-6Alkoxyl, halo c1-6Alkoxyl ,-nr2cor8、-nr2conr2r8、- nr2so2r8、-cor8、-conr2r8、-so2r8、-so2nr2r8、-por8r9、r8、r9, each From being independently selected from hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6One or more of alkynyl, hydroxyl, aryl；r10、r11Independently of one another Selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, aryl or heterocyclic radical；Q is-o- ,-s- or-nr0-；r0Choosing From hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6One or more of alkynyl, amide groups, hydroxyl, aryl, heterocyclic radical；Heterocyclic radical is choosing From n, o heteroatomic 3-12 circle heterocycles；M, n are each independently selected from any integer value in 0～6, and m, are 0 when n is different.
Preferably, in said structure formula, r1Selected from hydrogen, halogen, c1-6Alkyl, cyano group, phenyl, heterocyclic radical ,- co2r10、-(ch2)wor10、-(ch2)wnr10r11、-conr10r11、-(ch2)wso2r10Or-(ch2)wso2nr2r10；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 hydrogen, c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkoxyl ,-so2r8、-por8r9、-so2nr8r9、-conr8r9、r8、r9It is each independently selected from hydrogen, halogen, c1-6One of alkyl, hydroxyl, phenyl Or it is several；r10、r11It is each independently selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, phenyl or heterocyclic radical；Q be-o- ,-s- or- nr0-；r0Selected from hydrogen, c1-6One or more of alkyl, amide groups, hydroxyl, phenyl, heterocyclic radical；Heterocyclic radical is miscellaneous selected from n, o The 3-6 circle heterocycles of atom；M, n are each independently selected from any integer value in 0～6, and m, are 0 when n is different.
Preferably, aryl is phenyl, naphthyl or anthryl；Heterocyclic radical is morpholinyl, piperidyl, piperazinyl, pyrrolidinyl, miscellaneous Azo-cycle butane group, 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 4- saturation ring group replaces, is rex-b1～rex-b28's selected from numbering Following characteristic compounds:
The chloro- n of rex-b1:5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b2:5-2- (4- (1- ((dimethylamino) methyl) cyclopropyl) -2- isopropoxy -5- methylbenzene)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b3:5-2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo-piperidine base) methyl) cyclopropyl) benzene Base)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b4:5-2- (2- isopropoxy -5- methyl -4- (1- (ketone base piperazinyl) cyclopropyl) phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b5:5-2- (2- isopropoxy -5- methyl -4- (1- (methylene piperazinyl) cyclopropyl) phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b6:5-2- (2- isopropoxy -5- methyl -4- (1- (methylenepiperidines base) cyclopropyl) phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b7:5-2- (2- isopropoxy -5- methyl -4- (1- (methylene pyrrole alkyl) cyclopropyl) phenyl) - n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b8:5-2- (2- isopropoxy -5- methyl -4- (1- (methylene heterocyclic butane group) cyclopropyl) benzene Base)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b9:5-2- (2- isopropoxy -5- methyl -4- (1- (((4- THP trtrahydropyranyl) amino) methyl) ring third Base) phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b10:5-2- (2- isopropoxy -5- methyl -4- (1- (morpholino cyclopropyl) phenyl)-n4- (2- is (different Sulfonyl propyl base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b11:5-2- (2- isopropoxy -5- methyl -4- (1- ((4- THP trtrahydropyranyl) amino) cyclopropyl) benzene Base)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b12:5-2- (2- isopropoxy -5- methyl -4- (1- (oxo -4- tetrahydrochysene piperidyl) cyclopropyl) benzene Base)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b13:5-2- (2- isopropoxy -5- methyl -4- (2- (4- piperidyl is for cyclopropyl)) phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b14:5-2- (2- trifluoromethoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl) - n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b15:5-2- (the chloro- 4- of 2- isopropoxy -5- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
Rex-b16:5- trifluoromethyl-n2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) benzene Base)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b17:5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (dimethyl oxygen phosphorio) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b18:5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b19:5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (n- isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b20:5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (ethoxy sulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b21:5-2- (2- isopropoxy -5- methyl -4- (1- ((mesyl) methyl) cyclopropyl) phenyl) - n4- (2- (n- isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b22:5-2- (2- isopropoxy -5- methyl -4- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n4- (2- (n- isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b23:5-2- (2- isopropoxy -5- methyl -4- (1- ((trifluoromethoxy) methyl) cyclopropyl) benzene Base)-n4- (2- (n- isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b24:5-2- (2- isopropoxy -5- methyl -4- (1- (carboxyl) cyclopropyl) phenyl)-n4- ((n- is different for 2- Sulfonyl propyl base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b25:5-2- (2- isopropoxy -5- methyl -4- (1- (aminomethyl) cyclopropyl) phenyl)-n4-(2-(n- Isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b26:5-2- (2- isopropoxy -5- methyl -4- (1- (4- oxo Pentamethylene oxide .) methyl) cyclopropyl) Phenyl)-n4- (2- (n- isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b27:5-2- (2- isopropoxy -5- methyl -4- (1- ((methylamino) methyl) cyclopropyl) phenyl)-n4- (2- (n- isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b28:5-2- (2- isopropoxy -5- methyl -4- (1- (Methanamide) cyclopropyl) phenyl)-n4-(2-(n- Isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b29:5-2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo-pyrrolidine base) methyl) cyclopropyl) Phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-b30:5-2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo hydroxy azetidine base) first Base) cyclopropyl) phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
Rex-b31:5- trifluoromethyl-n2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo-piperidine base) methyl) ring Propyl group) phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine.
Aforementioned numbering is the compound of rex-b1～rex-b31, and structural formula sees below:
Present invention also offers a kind of compound is the synthetic method of foregoing formula and formula, overall reaction road Line is as follows: formula:
Formula:
Based on above-mentioned overall reaction route, including following synthetic schemes:
(1) synthetic schemes 1: the synthesis of compound 1-3
Step 1: will(i.e. compound 1-1) andIt is dissolved in organic solvent, slowly Add sodium hydride, after normal-temperature reaction n hour, plus extractant, extract, be dried, reduce pressure, being spin-dried for, obtain compound 1-2.
Step 2: compound 1-2 is dissolved in organic solvent, is slowly added to catalyst, nitrogen displacement, logical hydrogen, room temperature is anti- After answering n hour, plus extractant, extract, be dried, reduce pressure, being spin-dried for, obtain compound 1-3.
In synthetic schemes 1, organic solvent is selected from dichloromethane, n, in n- dimethylformamide, methanol, dioxane Plant or several；Extractant is selected from one or more of dichloromethane, pure water, ethyl acetate；Catalyst is double selected from palladium charcoal, 4,5- One or more of (diphenylphosphine) -9,9- dimethyl xanthene, palladium.
In synthetic schemes 1, the temperature of normal-temperature reaction is 20～30 DEG C, and response time n is 3～10 hours.
(2) synthetic schemes 2: the synthesis of compound 2-2
Step 1: will(i.e. compound 2-1) andIt is dissolved in organic solvent, be slowly added to sodium hydride and phonetic Pyridine class compound, after nitrogen displacement, reacting by heating n hour, plus a small amount of frozen water destroys unnecessary sodium hydride, plus extractant, extracts, does Dry, reduce pressure, be spin-dried for, obtain compound 2-2.
In synthetic schemes 2, organic solvent is selected from dichloromethane, n, in n- dimethylformamide, methanol, dioxane Plant or several；Extractant is selected from one or more of dichloromethane, pure water, ethyl acetate；Catalyst is double selected from palladium charcoal, 4,5- One or more of (diphenylphosphine) -9,9- dimethyl xanthene, palladium.
In synthetic schemes 2, the temperature of reacting by heating is 60～120 DEG C, and response time n is 12～16 hours.
(3) synthetic schemes 3: the synthesis of target compound
Step 1: the compound 2-2 that the prepared compound 1-3 of synthetic schemes 1, synthetic schemes 2 are obtained is dissolved in organic molten Agent, 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 or formula).
In synthetic schemes 3, organic solvent is selected from dichloromethane, n, in n dimethylformamide, methanol, dioxane Plant or several；Catalyst is selected from palladium charcoal, 4,5- double one of (diphenylphosphine) -9,9- dimethyl xanthene, palladium or several Kind.
In synthetic schemes 3, the response time is 10～20 hours, preferably 16 hours.
In foregoing synthetic schemes 1, synthetic schemes 2, synthetic schemes 3, r1Selected from hydrogen, halogen, c1-6Alkyl, c2-6 Thiazolinyl, c2-6Alkynyl, cyano group, aryl, heterocyclic radical ,-(ch2)wor10、-(ch2)wnr10r11、-co2r10、-conr10r11、-(ch2)wso2r10、-(ch2)wso2nr2r10One or more of；r2、r3、r4、r5、r6It is each independently selected from hydrogen, halogen, c1-6Alkane Base, halo c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkoxyl, c2-6Thiazolinyl, c2-6Alkynyl, cyano group or amino；r7Selected from hydrogen, halogen Element, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-6Alkoxyl, halo c1-6Alkoxyl ,-nr2cor8、-nr2conr2r8、- nr2so2r8、-cor8、-conr2r8、-so2r8、-so2nr2r8、-por8r9、r8、r9, each From being independently selected from hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6One or more of alkynyl, hydroxyl, aryl；r10、r11Independently of one another Selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, aryl or heterocyclic radical；Q is-o- ,-s- or-nr0-；r0Choosing From hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6One or more of alkynyl, amide groups, hydroxyl, aryl, heterocyclic radical；Heterocyclic radical is choosing From n, o heteroatomic 3-12 circle heterocycles；M, n are each independently selected from any integer value in 0～6, and m, are 0 when n is different.
" compound " of the present invention, including all stereoisomers, geometric isomer, tautomer and same position Element.
" compound " of the present invention, can be asymmetric, for example, have one or more stereoisomers.Remove Non- be otherwise noted, all stereoisomers all include, such as enantiomer and diastereomer.Contain asymmetric in the present invention The compound of carbon atom, can be separated with the pure form of optical activity or racemic form.The pure form of optical activity can With from racemic mixture, or by using chiral raw material or chiral reagent synthesis.
" compound " of the present invention, also includes tautomeric forms.Tautomeric forms derive from a list Key and adjacent double bond exchange and together with a proton migration.
Present invention additionally comprises all isotopic atoms, either in intermediate or last compound.Isotopic former Attached bag includes has 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 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 " alkyl ", refers to the saturated hydrocarbons group of straight or branched being made up of carbon atom and hydrogen atom, such as c1-20Alkyl, It is preferably c1-6Alkyl, such as methyl, ethyl, propyl group (include n-pro-pyl and isopropyl), butyl (include 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 Replace to be non-substituted or by one or more substituent groups, substituent group include 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.- nh's (alkyl) Version isSpecific example includes but is not limited to-nhch3、-nhch(ch3)2、-nhc2h5Deng；- n (alkyl)2Knot Configuration formula isSpecific 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 has 6-12 carbon atom, most preferably has 6 carbon atoms.Aryl can be non-substituted or by one or Multiple substituent groups are replaced, and substituent group includes but is not limited to alkyl, alkoxyl, cyano group, hydroxyl, carbonyl, carboxyl, aryl, aralkyl Base, amino, halogen, sulfonyl, sulfinyl, phosphoryl.The example of non-substituted aryl include 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 rings Atom is selected from one or more of n, o, and remaining annular atom is c, and has the π-electron system of total conjugated.Heterocyclic radical is permissible It is non-substituted or is replaced by one or more substituent groups, substituent group includes but is not limited to alkyl, alkoxyl, cyano group, hydroxyl Base, carbonyl, carboxyl, aryl, aralkyl, amino, halogen, sulfonyl, sulfinyl, phosphoryl.The reality of non-substituted heterocyclic radical Example includes but is not limited to pyrrole radicals, indyl, pyrrolidinyl, imidazole radicals, pyrazolyl, tetrazole radical, pyridine radicals, quinolyl, isoquinoline Quinoline base, piperidyl, pyrimidine radicals, pyrazinyl, piperazinyl, furyl, pyranose, morpholinyl.
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, refer to the compound or its salt of one or more present invention with the art The preparation of the carrier for bioactive compound being delivered to organism (such as people) generally accepting.The mesh of pharmaceutical composition Be advantageous for organism be administered conveying.
Term " pharmaceutically acceptable carrier ", refer to active ingredient co-administered and be conducive to active ingredient be administered Material, including but not limited to State Food and Drug Administration license acceptable for human or animal (such as domestic animal) Any fluidizer, sweetener, diluent, preservative, dyestuff/coloring agent, taste masking reinforcing agent, surfactant, wetting agent, point Powder, 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, can be configured to solid-state, semisolid, liquid or gaseous state preparation, such as tablet, ball Agent, 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 conventional mixing method, molten Solution, 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 Be not limited to be administered orally, rectum, saturating mucosa, through enteral administration, or local, percutaneous, suction, parenteral, Sublingual, intravaginal, intranasal, eye Interior, intraperitoneal, intramuscular, subcutaneous, intravenous administration.Preferably route of administration is oral administration.
For oral administration, can be by reactive compound be mixed with pharmaceutically acceptable carrier well known in the art Close, to prepare 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 the oral administration to patient.For example, for oral administration Pharmaceutical composition, tablet can be obtained in the following way: active component is merged with one or more solid carrier, if need By gained granulating mixture, and a small amount of excipient is added to process resulting mixture or granule, to form tablet if necessary Or label.Label can be combined with the coating material of optionally suitable enteric, be processed into and be more beneficial for what organism (such as people) absorbed Coated preparation form.
Present invention also offers a kind of foregoing compound or its pharmaceutically acceptable salt are used for treating in preparation Or prevent the purposes in the medicine of disease related to protein kinase.
A kind of foregoing compound or its pharmaceutically acceptable salt or prevent and a degeneration for treatment in preparation Purposes in the related medicine of disease of lymphom 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 flesh fibre Dimension blastoma, nasopharyngeal carcinoma, breast carcinoma, colorectal cancer, diffuse big 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 4- saturation ring group that synthesis obtains, carry out The combination rate determination experiment of alk kinase inhibiting activity and alk relevant mutational site, finds that part of compounds shows relatively to alk High inhibitory activity, shows preferable combination rate to alk mutational site (as l1196m, f1174l, c1156y), to ltk, Ros1 also has significant inhibitory activity；Additionally, also having carried out cell proliferation experiment and the Brachydanio rerio phenotype sieve of lung cancer cell line Choosing experiment, finds that part of compounds anti-tumor activity in vivo is notable.
Compared with prior art, the phenyl aminess kinases inhibitor that the 4- saturation ring group that the present invention provides replaces, is based on The Rational drug design of target, is modified by the replacement of group, obtains a series of novel compound of structures；And combine kinases Activity experiment, cell proliferation experiment, the experiment of Brachydanio rerio phenotypic screen, optimal screening goes out a series of chemical combination with anti-tumor activity Thing.Therefore, can be used for developing into the kinases inhibitor of a new generation, the disease that targeted therapy or prevention are mediated by alk There is great clinical value, 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 that Fig. 2 affects on Brachydanio rerio iris pigment cell for rex-b1/rex-b2
Fig. 3 is the impact figure to Brachydanio rerio iris pigment cell for the rex-b1/rex-b2
Specific embodiment
The following is the specific embodiment of the present invention, technical scheme is further described, but the present invention Protection domain be not limited to these embodiments.Every change without departing substantially from present inventive concept or equivalent substitute are included in this Within bright protection domain.
In the target compound preparation method that the present invention provides, liquid chromatograph adopts waterssymmetry c18 chromatograph Post.Thin layer chromatography adopts 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), 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 Illustrate, the raw material that the present invention uses is all marketable material, need not be further purified and can directly use.
The chloro- n of embodiment 1 5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- The preparation of (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-b1]
Synthetic route is as follows:
Synthetic schemes 1: intermediate 2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) aniline (is changed Compound 1-12) synthesis
Step 1: the preparation of intermediate 2- methyl-5-nitro-phenylacetic acid (i.e. compound 1-2)
Raw material 2- methyl-benzeneacetic acid (200.0g, 1.33mol) is dissolved in dichloromethane (700ml), less than 0 DEG C is delayed Slow add concentrated sulphuric acid (584ml), continue reaction 0.5 hour, then Deca concentrated nitric acid (30ml) after adding, maintain the temperature at -2～ 3 DEG C are reacted 16 hours；After reaction terminates, it is poured in 500ml water, with dichloromethane extraction, be dried, concentrate, obtain compound 1-2 (90.0g), yield: 34.6%.
Msm/z [esi]: 196.1 [m+1].
Step 2: the preparation of intermediate 2- methyl-5-nitro-methyl phenylacetate (i.e. compound 1-3)
Compound 1-2 (20.0g, 102mmol) is dissolved in methanol (250ml), less than 0～5 DEG C is slowly added to dichloro Sulfoxide (27.5g, 204mmol), maintains the temperature at 75～85 DEG C and reacts 3 hours；Reaction cools to room temperature after terminating, and add water second Acetoacetic ester extracts, and organic faciess sodium bicarbonate washs secondary, anhydrous sodium sulfate drying, concentration, obtains compound 1-3 (21.0g), Yield: 98.0%.
Msm/z [esi]: 201.2 [m+1].
Step 3: the preparation of intermediate 1- (2- methyl-5-nitro) cyclopropyl-phenyl methyl acetate (i.e. compound 1-4)
Under the conditions of ice-water bath, compound 1-3 (10.0g, 47.8mmol) is dissolved in n, n- dimethylformamide is (i.e. Dmf, 100ml) in, sodium hydride (3.8g, 95.6mmol) is slowly added in reaction system 0 DEG C and stirs 15 minutes；1,2- dibromo Ethane (26.0g, 143.4mmol) is added drop-wise in reaction system, is heated to 45 DEG C and reacts 3 hours；It is poured into after cooling in 50ml water, Extracted with ethyl acetate, be dried, concentrate, silica gel column chromatography separates, and obtains compound 1-4 (2.0g), yield: 17.8%.
Msm/z [esi]: 236.5 [m+1].1h-nmr(400mhz,cdcl3): δ=8.12 (s, 1h), 8.07-8.05 (d, 1h, j=8.4hz), 7.35-7.33 (d, 1h, j=8.4hz), 3.65 (s, 3h), 2.44 (s, 3h), 1.794-1.787 (t, 2h, J=2.8hz), 1.233-1.226 (t, 2h, j=2.8hz).
Step 4: the preparation of intermediate 1- (2- methyl -5- amino) cyclopropyl-phenyl methyl acetate (i.e. compound 1-5)
Compound 1-4 (2.0g, 8.5mmol) and 10% palladium charcoal (i.e. pd/c, 0.4g) are added to dry methanol (50ml) In, nitrogen displacement, logical hydrogen, 25 DEG C are reacted 12 hours；Kieselguhr filtration separation after cooling, anhydrous sodium sulfate drying, concentration, obtain To compound 1-5 (1.5g), yield: 86.0%.
Msm/z [esi]: 206.2 [m+1].
Step 5: the preparation of intermediate 1- (2- methyl -5- hydroxyl) cyclopropyl-phenyl methyl acetate (i.e. compound 1-6)
Under the conditions of ice-water bath, by compound 1-5 (7.1g, 34.89mmol) be dissolved in sulphuric acid (aq, 6.25%, 240ml), sodium nitrite (2.8g, 41.87mmol) is slowly added in reaction system, and 0 DEG C is stirred 15 minutes；By copper sulfate (1mol/l, 150ml) is added drop-wise in reaction system, and 65 DEG C are reacted 2 hours；It is poured into after cooling in 500ml water, carried with ethyl acetate Take, be dried, concentrate, silica gel column chromatography separates, and obtains compound 1-6 (4.3g), yield: 57.6%.
Msm/z [esi]: 207.2 [m+1].1h-nmr(400mhz,dmso-d6): δ=7.039-7.019 (d, 1h, j= 8hz), 6.754-6.747 (s, 1h), 6.692-6.665 (d, 1h, j=10.8hz), 5.317 (s, 1h), 3.66 (s, 3h), 2.252 (s, 3h), 1.703-1.687 (t, 2h, j=3.2hz), 1.187-1.161 (t, 2h, j=3.6hz).
Step 6: the system of intermediate 1- (2- methyl -4- nitro -5- hydroxyl) cyclopropyl-phenyl methyl acetate (i.e. compound 1-7) Standby
Under the conditions of ice-water bath, compound 1-7 (4.3g, 20.85mmol) is dissolved in dichloromethane (100ml), nitric acid (10.4ml, 20.8mmol, 2mol/l) is slowly added in reaction system, and 0 DEG C is stirred 15 minutes, with little after 65 DEG C of reactions 2 When；Reaction terminates, and is poured in 100ml water after cooling, is extracted with ethyl acetate, is dried, concentrates, silica gel column chromatography separates, obtaining Compound 1-7:(2.5g), yield: 47.3%.
Msm/z [esi]: 252.2 [m+1].
Step 7: intermediate 1- (2- methyl -4- nitro -5- isopropoxy) cyclopropyl-phenyl methyl acetate (i.e. compound 1-8) Preparation
Compound 1-7 (2.5g, 9.87mmol) and potassium carbonate (4.1g, 29.61mmol) are dissolved in dichloromethane (60ml), isopropyl iodide (5.1g, 29.61mmol) is slowly added in reaction system, and 0 DEG C is stirred 15 minutes, with after 25 DEG C Reaction 2 hours；After reaction terminates, plus pure water and dichloromethane extraction, it is dried, concentrates, silica gel column chromatography separates, and obtains compound 1-8 (2.8g), yield: 100.0%.
Msm/z [esi]: 294.2 [m+1].1h-nmr(400mhz,cdcl3)=δ 7.602 (s, 1h), 6.969 (s, 1h), 4.629 (m, 1h), 3.652 (s, 3h), 2.287 (s, 3h), 1.75-1.743 (t, 2h, j=2.8hz), 1.39-1.375 (d, 6h, j=6hz), 1.172-1.165 (t, 2h, j=2.8hz).
Step 8: the system of intermediate 1- (2- methyl -4- nitro -5- isopropoxy) cyclopropyl-phenyl acetic acid (i.e. compound 1-9) Standby
Compound 1-8 (1.0g, 3.4mmol) and Lithium hydrate (571.0mg, 13.6mmol) are dissolved in methanol (50ml) In the mixed liquor of pure water (10ml), reaction is heated to 80 DEG C and stirs 1 hour；After reaction terminates, plus the hydrochloric acid of 1mol/l is adjusted Save to ph=4, filter, obtain compound 1-9 (750.0mg), yield: 79.0%.
Msm/z [esi]: 280.2 [m+1].
Step 9: intermediate (1- (5- isopropoxy -2- methyl -4- nitro) cyclopropyl) phenylacetic acid morpholine (i.e. compound 1- 10) preparation
By compound 1-9 (600.0mg, 2.15mmol), triethylamine (653.0mg, 6.45mmol), 2- (7- azo benzo Triazole)-n, n, n', n'- tetramethylurea hexafluorophosphoric acid ester (1.1g, 2.8mmol), morpholine (281.0mg, 3.23mmol) dissolves In n, n- dimethylformamide (50ml), room temperature reaction 3 hours；After reaction terminates, with pure water and ethyl acetate extraction, do Dry, be spin-dried for, obtain compound 1-10 (673.0mg), yield: 90.0%.
Msm/z [esi]: 347.4 [m+1].
Step 10: intermediate 2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) Nitrobenzol (is changed Compound 1-11) preparation
Compound 1-10 (673.0mg, 1.93mmol) is dissolved in oxolane (50ml), Deca borine tetrahydrochysene under room temperature Tetrahydrofuran solution (14.4ml, 14.4mmol, 1mol/l)；After reaction terminates, with pure water and ethyl acetate extraction, it is dried, is spin-dried for, obtain To compound 1-11 (450.0mg), yield: 69.0%.
Msm/z [esi]: 333.4 [m+1].
Step 11: intermediate 2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) aniline (i.e. chemical combination Thing 1-12) preparation
By compound 1-11 (450.0mg, 1.35mmol), palladium charcoal (238.0mg) is dissolved in methanol (25ml), and hydrogen is put Change, ambient temperature overnight；After reaction terminates, filter and remove palladium removing charcoal, be dried, be spin-dried for, obtain compound 1-12 (400.0mg), yield: 97.0%.
Msm/z [esi]: 305.4 [m+1].
Synthetic schemes 2: the chloro- n- of intermediate 2,5- bis- [2- [(1- Methylethyl) sulphonyl] phenyl] -4- aminopyrimidine (is changed Compound 2-5) synthesis
Step 1: the preparation of intermediate 2- (isopropyl thioether group) Nitrobenzol (i.e. compound 2-2)
By raw material 2- fluoronitrobenzene (i.e. compound 2-1,10.0g, 70.0mmol), isopropyl mercaptan (5.4g, 70.0mmol) It is added to dry n with potassium carbonate (25.0g, 177.0mmol), in n- dimethylformamide (100ml), nitrogen displacement, in 100～ 110 DEG C are stirred overnight；After reaction terminates, it is cooled to room temperature, extracted with pure water and ethyl acetate, organic faciess are done with anhydrous sodium sulfate Dry, concentration, obtains compound 2-2 (10.0g), yield: 72.0%.
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) (i.e. compound 2-3)
In dichloromethane (100ml) solution of compound 2-2 (13g, 65.9mmol), between adding while stirring in 0 DEG C Chloroperoxybenzoic acid (25.6g, 149.4mmol), finishes, and reacts 16 hours in 0 DEG C；After reaction terminates, use saturated sodium bicarbonate Solution washs, and is dried, concentrates, silica gel column chromatography separates, and obtains compound 2-3 (10.6g), yield: 70.0%.
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 (20.0g, 87.3mmol) and 10% palladium charcoal (2.0g) are added in dry methanol (250ml), nitrogen Gas displacement, logical hydrogen, react 2 hours in 60 DEG C；After reaction terminates, cooling, use kieselguhr filtration separation, anhydrous sodium sulfate is done Dry, concentration, obtains compound 2-4 (17.3g), yield: 95.0%.
Msm/z [esi]: 200.2 [m+1].1h-nmr(400mhz,dmso-d6): 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 (i.e. compound Preparation 2-5)
Under the conditions of ice-water bath, compound 2-4 (30.0g, 150mmol) is dissolved in n, n- dimethylformamide (300ml) in, sodium hydride (7.3g, 300mmol) is slowly added in reaction system, stirs 15 minutes in 0 DEG C；Again by 2,4,5- Trichloropyrimidine (33.1g, 180mmol) is added drop-wise in reaction system, and room temperature reaction is simultaneously stirred overnight；Reaction terminates, and cools down hypsokinesis Enter in 500ml water, extracted with ethyl acetate, be dried, concentrate, silica gel column chromatography separates, and obtains compound 2-5 (17.3g), receiving Rate: 32.0%.
Msm/z [esi]: 370.2 [m+1].1h-nmr(400mhz,dmso-d6): 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: the chloro- n of target compound 5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) ring Propyl group) phenyl)-n4The synthesis of-(2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine (i.e. rex-b1)
Step 1: the preparation of target compound (i.e. rex-b1)
By compound 1-12 (400.0mg, 1.31mmol), compound 2-5 (1029.0mg, 2.97mmol), cesium carbonate Double (diphenylphosphine) -9,9- dimethyl xanthene (232.0mg, 0.4mmol) of (2.6g, 8mmol), catalyst 4,5- and palladium (44.0mg, 0.2mmol), is dissolved in dioxane (15ml) and adds in tube sealing, nitrogen displacement, reacts 18 hours in 95 DEG C； After reaction terminates, it is spin-dried for solvent, with pure water and ethyl acetate extraction, organic faciess are dried, concentrate, silica gel chromatography, obtain Compound rex-b1 (200mg), yield: 24.8%.
Msm/z [esi]: 615.1 [m+1].1hnmr(400mhz,cdcl3): δ=9.995 (s, 1h), 9.152 (s, 1h), 8.493-8.471 (d, 1h, j=8.8hz), 8.106 (s, 1h), 7.974-7.954 (d, 1h, j=8hz), 7.818 (s, 1h), 7.563-7.519 (t, 1h, j=8.8hz), 7.359-7.321 (t, 1h, j=8hz), 7.216 (s, 1h), 4.723-4.684 (m, 1h), 3.886-3.880 (m, 6h), 2.725-2.718 (m, 5h), 2.305-2.300 (s, 3h), 1.361-1.266 (m, 16h).
The chloro- n of embodiment 2 5-2- (4- (1- ((dimethylamino) methyl) cyclopropyl) -2- isopropoxy -5- methylbenzene)-n4- The preparation of (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-b2]
Synthetic route is as follows:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-12 ", in step 9 The morpholine replacing embodiment 1 with dimethylamine is reacted, and remaining synthetic method, with the synthetic schemes 1 of embodiment 1, obtains final product compound 1-12, yield: 22.0%.
Msm/z [esi]: 263.4 [m+1].
In synthetic schemes 2 " synthesis of compound 2-5 ", raw material 2- fluoro nitrotoluene (i.e. compound 2-1), remaining synthesis Method all with the synthetic schemes 2 of embodiment 1, obtains final product compound 2-5, yield: 33%.
Msm/z [esi]: 370.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-b2 ", by the prepared compound 1-12 of the present embodiment and change Compound 2-5, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-b2, yield: 16%.
Msm/z [esi]: 573.1 [m+1].1h-nmr(400mhz,dmso-d6): δ=9.484 (s, 1h), 9.106 (s, 1h), 8.430-8.409 (d, 1h, j=8.4hz), 8.3 (s, 1h), 8.052 (s, 1h), 7.903-7.883 (d, 1h, j= 8hz), 7.71 (s, 1h), 7.452-7.414 (t, 1h, j=7.6hz), 7.02 (s, 1h), 4.654 (m, 1h), 3.456 (q, 1h), 3.085 (s, 1h), 2.327 (s, 1h), 2.215 (s, 3h), 1.284-1.076 (m, 18h).
The chloro- n of embodiment 3 5-2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo-piperidine base) methyl) cyclopropyl) benzene Base)-n4The preparation of-(2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-b3]
Synthetic route is as follows:
The present embodiment provide synthetic route as described in, in synthetic schemes 1, due to the present embodiment " step 1 is to step 7 " raw material, synthetic method, all identical with " step 1 to step 7 " of embodiment 1 synthetic schemes 1, therefore can direct Example Compound 1-8 obtained by 1 synthetic schemes 1, by the route synthesis of step 8 to step 11, obtains midbody compound 1-12, system Standby process is specific as follows:
Step 8: the system of intermediate 1- (2- methyl -4- nitro -5- isopropoxy) cyclopropyl-phenyl ethanol (i.e. compound 1-9) Standby
Compound 1-8 (500mg, 1.7mmol) is dissolved in oxolane (50ml), 0 DEG C is dividedly in some parts lithium aluminium hydride reduction (128mg, 3.37mmol), reaction is heated to 25 DEG C and stirs 14 hours；After reaction terminates, extracted with pure water and ethyl acetate, Filter, concentrate, obtain compound 1-9 (300mg), yield: 66.67%.
Msm/z [esi]: 266.2 [m+1].
Step 9: intermediate 1- (1- (bromomethyl) cyclopropyl) -5- isopropoxy -2- methyl -4- Nitrobenzol (i.e. compound Preparation 1-10)
By compound 1-9 (240.0mg, 0.9mmol), triphenylphosphine (260.0mg, 0.99mmol), n- bromo succinyl Imines (260.0mg, 0.99mmol) is dissolved in dichloromethane (50ml), room temperature reaction 3 hours；After reaction terminates, with pure water and Ethyl acetate extracts, and is dried, is spin-dried for, column chromatography, obtains compound 1-10 (238.0mg), yield: 80.6%.
Msm/z [esi]: 329.4 [m+1].
Step 10: intermediate 4- ((1- (5- isopropoxy -2- methyl -4- nitrobenzophenone) cyclopropyl) oxomethyl) piperazine The preparation of pyridine -1- t-butyl carbonate (i.e. compound 1-11)
By compound 1-10 (238.0mg, 0.73mmol), 1- tertbutyloxycarbonyl -4- hydroxy piperidine (177.0mg, 0.88mmol) it is dissolved in n, n- dimethylformamide (50ml), add sodium hydride (47.0mg, 1.17mmol) at 0 DEG C, room temperature is anti- Answer 3 hours；After reaction terminates, with pure water and ethyl acetate extraction, it is dried, is spin-dried for, obtain compound 1-11 (140.0mg), receive Rate: 42.8%.
Msm/z [esi]: 449.5 [m+1].
Step 11: intermediate 4- ((1- (5- isopropoxy -2- methyl -4- anilino-) cyclopropyl) oxomethyl) piperidines - The preparation of 1- t-butyl carbonate (i.e. compound 1-12)
Take compound 1-11, with reference to the step 11 method preparation of embodiment 1 synthetic schemes 1, obtain final product compound 1-12, receive Rate: 85.0%.
Msm/z [esi]: 419.5 [m+1].
In synthetic schemes 2 " synthesis of compound 2-5 ", raw material 2- fluoronitrobenzene (i.e. compound 2-1), remaining synthesis side Method all with the synthetic schemes 2 of embodiment 1, obtains final product compound 2-5, yield: 33%.
Msm/z [esi]: 370.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-b3 ", by the prepared compound 1-12 of the present embodiment and change Compound 2-5, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-b3, yield: 16.0%.
Msm/z [esi]: 629.2 [m+1].1H-nmr (400mhz, dmso-d6): δ=10.028 (s, 1h), 9.016- 8.864 (m, 3h), 8.485 (s, 1h), 8.172-8.128 (d, 1h, j=17.6hz), 7.951-7.936 (d, 1h, j=6hz), 7.775-7.735 (t, 1h, j=9.2hz), 7.568-7.531 (t, 1h, j=7.6hz), 7.357 (s, 1h), 6.887 (s, 1h), 4.568-4.560 (m, 1h), 3.492-3.339 (m, 2h), 2.97-2.879 (m, 4h), 2.099 (s, 3h), 1.828 (m, 2h), 1.568 (m, 2h), 1.263-1.248 (d, 6h, j=6hz), 1.144-1.128 (d, 6h, j=6.4hz), 0.876- 0.852 (t, 2h, j=5.2hz), 0.714-0.689 (t, 2h, j=5.2hz).
The chloro- n of embodiment 4 5-2- (2- isopropoxy -5- methyl -4- (1- (ketone base piperazinyl) cyclopropyl) phenyl)-n4- The preparation of (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-b4]
Synthetic route is as follows:
The present embodiment provide synthetic route as described in, in synthetic schemes 1, due to the present embodiment " step 1 is to step 8 " raw material, synthetic method, all identical with " step 1 to step 8 " of embodiment 1 synthetic schemes 1, therefore can directly press embodiment The method of 1 synthetic schemes 1 is obtained compound 1-9；Step 9, is reacted with the morpholine that n-boc- piperazine replaces embodiment 1, is obtained To compound 1-10；Step 10, compound 1-10 is reacted according to the step 11 of the synthetic schemes 1 of embodiment 1, in obtaining final product Intermediate compounds therefor 1-11, yield: 90.0%.
Msm/z [esi]: 418.5 [m+1].
In synthetic schemes 2 " synthesis of compound 2-5 ", raw material 2- fluoronitrobenzene (i.e. compound 2-1), remaining synthesis side Method all with the synthetic schemes 2 of embodiment 1, obtains final product compound 2-5, yield: 33.0%.
Msm/z [esi]: 370.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-b4 ", by the prepared compound 1-11 of the present embodiment and change Compound 2-5, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-b4, yield: 25.0%.
Msm/z [esi]: 628.2 [m+1].1h-nmr(400mhz,dmso-d6): δ=9.965 (s, 1h), 9.305- 9.300 (m, 2h), 8.897 (s, 1h), 8.474 (s, 1h), 8.147-8.128 (d, 1h, j=7.6hz), 7.959-7.937 (d, 1h, j=7.6hz), 7.781-7.743 (t, 1h, j=7.6hz), 7.578-7.540 (t, 1h, j=8hz), 7.44 (s, 1h), 7.059 (s, 1h), 4.722-4.720 (m, 1h), 3.651 (s, 4h), 3.471-3.470 (m, 1h), 2.834-2.828 (m, 4h), 1.963 (s, 3h), 1.374 (s, 2h), 1.255-1.241 (d, 6h, j=5.6hz), 1.139-1.123 (d, 6h, j= 6.4hz), 1.037 (s, 2h).
The chloro- n of embodiment 5 5-2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo-pyrrolidine base) methyl) cyclopropyl) Phenyl)-n4The preparation of-(2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-b29]
Synthetic route is as follows:
The present embodiment provide synthetic route as described in, in synthetic schemes 1, due to the present embodiment " step 1 is to step 9 " raw material, synthetic method, all identical with " step 1 to step 9 " of embodiment 3 synthetic schemes 1, therefore can directly press embodiment The method of 3 synthetic schemes 1 is obtained compound 1-10；Step 10, replaces the n-boc- of embodiment 3 with 1-boc-3- hydroxyl pyrrolidine 4- hydroxy piperidine is reacted, and obtains compound 1-11；Step 11, by compound 1-11 according to the synthetic schemes 1 of embodiment 3 Step 11 is reacted, and obtains final product midbody compound 1-12, yield: 70.0%.
Msm/z [esi]: 405.5 [m+1].
In synthetic schemes 2 " synthesis of compound 2-5 ", raw material 2- fluoronitrobenzene (i.e. compound 2-1), remaining synthesis side Method all with the synthetic schemes 2 of embodiment 1, obtains final product compound 2-5, yield: 33.0%.
Msm/z [esi]: 370.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-b29 ", by the prepared compound 1-12 of the present embodiment and change Compound 2-5, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-b29, yield: 23.0%.
Msm/z [esi]: 615.2 [m+1].
The chloro- n of embodiment 6 5-2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo hydroxy azetidine base) first Base) cyclopropyl) phenyl)-n4The preparation of-(2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-b30]
Synthetic route is as follows:
The present embodiment provide synthetic route as described in, in synthetic schemes 1, due to the present embodiment " step 1 is to step 9 " raw material, synthetic method, all identical with " step 1 to step 9 " of embodiment 3 synthetic schemes 1, therefore can directly press embodiment The method of 3 synthetic schemes 1 is obtained compound 1-10；Step 10, replaces the n- of embodiment 3 with n-boc-3- hydroxy azetidine Boc-4- hydroxy piperidine is reacted, and obtains compound 1-11；In step 11, by compound 1-11 according to embodiment 3 synthesis The step 11 of scheme 1 is reacted, and obtains final product midbody compound 1-12, yield: 50.0%.
Msm/z [esi]: 392.5 [m+1].
In synthetic schemes 2 " synthesis of compound 2-5 ", raw material 2- fluoronitrobenzene (i.e. compound 2-1), remaining synthesis side Method all with the synthetic schemes 2 of embodiment 1, obtains final product compound 2-5, yield: 33.0%.
Msm/z [esi]: 370.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-b30 ", by the prepared compound 1-12 of the present embodiment and change Compound 2-5, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-b30, yield: 12.0%.
Msm/z [esi]: 601.2 [m+1].
Embodiment 7 5- trifluoromethyl-n2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo-piperidine base) methyl) ring Propyl group) phenyl)-n4The preparation synthesis of-(2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-b31] 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- benzene Acetic acid (i.e. compound 1-1), remaining synthetic method all with the synthetic schemes 1 of embodiment 3, obtain final product compound 1-12, yield: 30.0%.
Msm/z [esi]: 419.5 [m+1].
In synthetic schemes 2, due to raw material, the synthetic method of " step 1 to step 3 " of the present embodiment, all with embodiment 3 " step 1 to step 3 " of synthetic schemes 2 is identical, compound 2-4 that therefore can directly obtained by Example 3 synthetic schemes 2, Step 4 uses the chloro- 5- trifluoromethyl pyrimidine of 2,4- bis- to replace 2,4,5- trichloropyrimidines of embodiment 3 to be reacted, and obtains compound 2-5；Yield: 60.0%.
Msm/z [esi]: 370.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-b31 ", by the prepared compound 1-12 of the present embodiment and change Compound 2-5, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-b30, yield: 12.0%.
Msm/z [esi]: 663.2 [m+1].1hnmr(400mhz,dmso),δ:9.523(s,1h),9.279-9.228(m, 2h), 8.456 (s, 1h), 8.222 (m, 2h), 7.821-7.801 (d, 1h, j=8), 7.628 (s, 1h), 7.559-7.524 (t, 1h, j=7), 7.360-7.322 (t, 1h, j=7.6), 6.946 (s, 1h), 4.580-4.523 (m, 1h), 3.477-3.429 (m,3h),2.960-2.860(m,4h),2.227(s,3h),1.846(m,2h),1.608(m,2h),1.191-1.176(d, 6h, j=6), 1.147-1.131 (d, 6h, j=6.4), 0.892 (s, 2h), 0.732 (s, 2h).
Embodiment 8alk kinase inhibiting activity and the mensure of relevant mutational site combination rate
Compound rex-b1～rex-b4 that above-described embodiment 1～4 is obtained, adopts(fret) method is come Measure aforesaid compound to alk kinase inhibiting activity, this inhibitory activity adopts ic50This index representing, ic50I.e. alk kinases Activity inhibited 50% when compound concentration.
Adopt simultaneouslyEu kinase binging assay (tr-fret) determines the change of the present invention Compound 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 is even Connection thing or kinases " tracer " combine.The combination of tracer and antibody and kinases leads to the fret of height, otherwise is pressed down using kinases The factor processed replaces tracer that fret can be caused to lose.
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 a preferable alk inhibitory activity, and to the mutational site of alk (as alk L1196m) also there is preferable combination rate.
The alk inhibitory activity of table one embodiment compound and alk l1196m combination rate measure
alk ic50(nm) alk f1196m ic50(nm)
rex-b1 143 121
rex-b2 <30 <30
rex-b3 <30 <30
rex-b4 <100 <30
Further, the present invention selects and selects compound rex-b1, rex-b2, rex-b3 and rex-b4, using life The kinase assay platform assay of technology company aforesaid compound activity to associated kinase under 100nm concentration Measure, measurement result is shown in Table two.Result shows, compound rex-b2, rex-b3 and rex-b4 that the present invention provides are to alk F1174l, alk c1156y shows preferable combination rate, and ltk, ros1 are shown with higher inhibitory activity simultaneously.
Table two embodiment compound determination of activity to associated kinase under 100nm concentration
Embodiment 9 cell proliferation experiment (detection of mtt method)
Testing compound: compound rex-b2, rex-b3 and rex-b4 that the embodiment of the present invention 2～4 is obtained.
Cell strain: lung cancer cell line nci-h2228, nci-h3122, purchased from bio tech ltd of Nanjing section one hundred.
Method: cell strain nci-h2228, nci-h3122 are placed in 20%fbs (hyclone) (gibco)+1640+1% Dual anti-cultivated.Then take nci-h2228, nci-h3122 cell that growth conditions are good, 5000/hole is inoculated in respectively 96 porocyte plates, are placed in 37 DEG C, contain 5%co2Incubator in incubation 24h make cell attachment complete.Discard old culture fluid, every hole Sequentially add the culture that 100 μ l contain 0.3,1,3,10,30,100,300,1000,3000 and 10000nmol/l testing compound Liquid, the every hole of solvent control group adds the culture fluid that 100 μ l contain 0.1%dmso, every group of 3 multiple holes, discards old culture fluid after 72h, Under the conditions of lucifuge, every hole adds 100 μ l ml containing 0.5mg-1The culture fluid of mtt, is placed in cell culture incubator and continues incubation 4h, abandon Remove supernatant, every hole adds 100 μ l dmso, vibration, measures each hole absorbance with microplate reader under 490nm wavelength.According to eachization The suppression ratio to each cell growth for the compound variable concentrations, calculates ic on each cell for each compound with graphad 6.050Value.
Computing formula is:
Result: be shown in Table three.
Table three mtt method detects the cell proliferation ic to lung cancer cell line for the embodiment compound50Value
ic50(μm) nci-h2228 nci-h3122
rex-b2 <1 <1
rex-b3 <1 <1
rex-b4 <1 <1
Embodiment 10 cell proliferation experiment (detection of ckk-8 method)
Testing compound: compound rex-b1, rex-b2 that the embodiment of the present invention 1～2 is obtained.
Cell strain: people primary cutaneous type cell strain karpas-299, limited purchased from Nanjing section one hundred biotechnology Company.
Method: collect exponential phase cell, count, with complete medium Eddy diffusion cell, adjust cell concentration extremely Suitable concn (determines according to cell density optimization result of the test), inoculates 96 orifice plates, every hole adds 100 μ l cell suspension.Cell exists 37 DEG C, 100% relative humidity, it is incubated 24 hours in 5%co2 incubator.With culture medium, testing compound is diluted to set Respective action concentration, by 25 μ l/ holes add cells.Compound effects final concentration from the beginning of 10 μm, 3 times of gradient dilutions, totally 10 Individual concentration point.Cell is placed in 37 DEG C, 100% relative humidity, 5%co2It is incubated 72 hours in incubator.It is directly added into 1/10 volume Cck-8 solution, mix, be placed in 37 DEG C of incubators incubation 1-4 hour.In spectramax after gently shaking Absorbance at 450nm wavelength is measured on m5microplate reader, absorbance, as reference, calculates suppression using at 650nm Rate.According to the suppression ratio to each cell growth for each compound variable concentrations, calculate each compound in each cell with graphad 6.0 On ic50Value.
Computing formula is:
Result: be shown in Table four.
Table four ckk-8 method detects the cell proliferation ic to karpas-299 cell strain for the embodiment compound50Value
ic50(μm) karpas-299
rex-b1 <1
rex-b2 <0.05
Embodiment 11 Brachydanio rerio phenotypic screen is tested
Brachydanio rerio is a kind of vertebratess, is up to 85% with human gene's homology, its signal transduction pathway and mankind's base This is approximate, and biological structure and physiological function are highly similar to mammal；Its small volume, blastoprolepsis, embryo are transparent, egg laying amount Height, these unique advantages make Brachydanio rerio become the optimal mode organism of human diseasess research and live body high-flux medicaments sifting One of.Wherein, anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase alk (anaplastic lymphoma kinase) gene in the mankind with Brachydanio rerio Homology reaches 76%.Leukocyte tyrosine kinase ltk (leukocyte tyrosine kinase) the regulation and control Brachydanio rerio of Brachydanio rerio Generation (lopes, s.s., yang, x., et al. (2008) the .leukocyte tyrosine kinase of iris pigment cell Functions in pigment cell development.plos genet, 4.), iris pigment cell table in Brachydanio rerio Be now a kind of silver color corpusculum, be distributed in head, eyes, outside spinal column (viewed in reflected light), using the albino of melanin disappearance Brachydanio rerio, it is observed that silver color corpusculum is black in saturating coloured light, sees Fig. 1.Alk and ltk is sister kinase, research Person finds that the alk plasmid of injection of exogenous equally can adjust the generation of iris pigment cell, and experimental result also indicates that alk suppresses Agent mostly have ltk activity, can suppress iris pigment cell generation (rodrigues, 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, be subsequently adding each concentration Test medicine, carry out image acquisition during to 3dpf (days post fertilization), then divided using imagej software Analyse 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 with statistics Difference, the computing formula of iris pigment suppression ratio is as follows:
Result of calculation is shown in Table five, the dose-effect relationship that compound rex-b1/rex-b2 affects on Brachydanio rerio iris pigment cell Figure is shown in Fig. 2, and the impact figure to Brachydanio rerio iris pigment cell for the compound rex-b1/rex-b2 is shown in Fig. 3.
The impact (mean ± sem) to Brachydanio rerio iris pigment cell for table five compound
compared with control,*,p<0.05；**,p<0.01.

Claims (12)

1. the phenyl aminess kinases inhibitor that a kind of 4- saturation ring group replaces, for have following general structure compound and Its pharmaceutically acceptable salt:
Wherein, r1Selected from hydrogen, halogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, cyano group, aryl, heterocyclic radical ,-(ch2)wor10、- (ch2)wnr10r11、-co2r10、-conr10r11、-(ch2)wso2r8、-(ch2)wso2nr2r8One or more of；
r2、r3、r4、r5、r6It is each independently selected from hydrogen, halogen, c1-6Alkyl, halo c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkane Epoxide, c2-6Thiazolinyl, c2-6Alkynyl, cyano group or amino；
r7Selected from hydrogen, halogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-6Alkoxyl, halo c1-6Alkoxyl ,-nr2cor8、- nr2conr2r8、-nr2so2r8、-cor8、-conr2r8、-so2r8、-so2nr2r8、-por8r9、
r8、r9, be each independently selected from hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6One or more of alkynyl, hydroxyl, aryl；
r10、r11It 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 1～6, w is selected from any integer value in 0～3.
2. 4- saturation ring group according to claim 1 replaces phenyl aminess kinases inhibitor it is characterised in that: described General structure in,
r1Selected from hydrogen, halogen, c1-6Alkyl, cyano group, phenyl, heterocyclic radical ,-co2r10、-(ch2)wor10、-(ch2)wnr10r11、- conr10r11、-(ch2)wso2r10Or-(ch2)wso2nr2r10；
r2、r3、r4、r5、r6It is each independently selected from hydrogen, halogen, c1-6Alkyl, halo c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkane Epoxide, cyano group or amino；
r7Selected from hydrogen, c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkoxyl ,-so2r8、-por8r9、-so2nr8r9、-conr8r9、
r8、r9It is each independently selected from hydrogen, halogen, c1-6One or more of alkyl, hydroxyl, phenyl；
r10、r11It 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 1～6, w is selected from any integer value in 0～3.
3. the phenyl aminess kinases inhibitor that a kind of 4- saturation ring group replaces, for have following general structure compound and Its pharmaceutically acceptable salt:
Wherein, r1Selected from hydrogen, halogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, cyano group, aryl, heterocyclic radical ,-co2r10、-(ch2)wor10、-(ch2)wnr10r11、-conr10r11、-(ch2)wso2r10、-(ch2)wso2nr2r10One or more of；
r2、r3、r4、r5、r6It is each independently selected from hydrogen, halogen, c1-6Alkyl, halo c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkane Epoxide, c2-6Thiazolinyl, c2-6Alkynyl, cyano group or amino；
r7Selected from hydrogen, halogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, c1-6Alkoxyl, halo c1-6Alkoxyl ,-nr2cor8、- nr2conr2r8、-nr2so2r8、-cor8、-conr2r8、-so2r8、-so2nr2r8、-por8r9、
r8、r9, be each independently selected from hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6One or more of alkynyl, hydroxyl, aryl；
r10、r11It is each independently selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, aryl or heterocyclic radical；
Q is-o- ,-s- or-nr0-；
r0Selected from hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6One or more of alkynyl, amide groups, hydroxyl, aryl, heterocyclic radical；
Described heterocyclic radical is selected from n, o heteroatomic 3-12 circle heterocycles；
M, n are each independently selected from any integer value in 0～6, and m, are 0 when n is different.
4. 4- saturation ring group according to claim 3 replaces phenyl aminess kinases inhibitor it is characterised in that: described General structure in,
r1Selected from hydrogen, halogen, c1-6Alkyl, cyano group, phenyl, heterocyclic radical ,-co2r10、-(ch2)wor10、-(ch2)wnr10r11、- conr10r11、-(ch2)wso2r10Or-(ch2)wso2nr2r10；
r2、r3、r4、r5、r6It is each independently selected from hydrogen, halogen, c1-6Alkyl, halo c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkane Epoxide, cyano group or amino；
r7Selected from hydrogen, c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkoxyl ,-so2r8、-por8r9、-so2nr8r9、-conr8r9、
r8、r9It is each independently selected from hydrogen, halogen, c1-6One or more of alkyl, hydroxyl, phenyl；
r10、r11It is each independently selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, phenyl or heterocyclic radical；
Q is-o- ,-s- or-nr0-；
r0Selected from hydrogen, c1-6One or more of alkyl, amide groups, hydroxyl, phenyl, heterocyclic radical；
Described heterocyclic radical is selected from n, o heteroatomic 3-6 circle heterocycles；
M, n are each independently selected from any integer value in 0～6, and m, are 0 when n is different.
5. the phenyl aminess kinases inhibitor that the 4- saturation ring group according to any one of Claims 1 to 4 replaces, its feature It is: described aryl is phenyl, naphthyl or anthryl；Described heterocyclic radical be morpholinyl, piperidyl, piperazinyl, pyrrolidinyl, Heterocyclic butane group, pyranose, furyl, pyridine radicals or pyrimidine radicals.
6. the phenyl aminess kinases inhibitor that the 4- saturation ring group according to any one of Claims 1 to 4 replaces, its feature It is: described halogen is one or more of fluorine, chlorine, bromine, iodine.
7. the phenyl aminess kinases inhibitor that a kind of 4- saturation ring group replaces, selected from following characteristic compounds:
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (isopropyl sulphur Acyl group) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (4- (1- ((dimethylamino) methyl) cyclopropyl) -2- isopropoxy -5- methylbenzene)-n4- (2- (isopropyl sulphur Acyl group) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo-piperidine base) methyl) cyclopropyl) phenyl)-n4- (2- is (different Sulfonyl propyl base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (ketone base piperazinyl) cyclopropyl) phenyl)-n4- (2- (isopropyl sulphur Acyl group) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (methylene piperazinyl) cyclopropyl) phenyl)-n4- (2- (isopropyl sulphur Acyl group) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (methylenepiperidines base) cyclopropyl) phenyl)-n4- (2- (isopropyl sulphur Acyl group) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (methylene pyrrole alkyl) cyclopropyl) phenyl)-n4- (2- (isopropyl Sulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (methylene heterocyclic butane group) cyclopropyl) phenyl)-n4- (2- is (different Sulfonyl propyl base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (((4- THP trtrahydropyranyl) amino) methyl) cyclopropyl) phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (morpholino cyclopropyl) phenyl)-n4- (2- (isopropelsulfonyl) benzene Base) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- ((4- THP trtrahydropyranyl) amino) cyclopropyl) phenyl)-n4- (2- is (different Sulfonyl propyl base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (oxo -4- tetrahydrochysene piperidyl) cyclopropyl) phenyl)-n4- (2- is (different Sulfonyl propyl base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (2- (4- piperidyl is for cyclopropyl)) phenyl)-n4- (2- (isopropyl sulphonyl Base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- trifluoromethoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (isopropyl Sulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (the chloro- 4- of 2- isopropoxy -5- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (isopropyl sulphonyl Base) phenyl) -2,4- di-amino-pyrimidine；
5- trifluoromethyl-n2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- is (different Sulfonyl propyl base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (dimethyl oxygen Phosphorio) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (1- (ethoxy Ylmethyl) cyclopropyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (n- isopropyl Sulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (methylene morpholinyl) cyclopropyl) phenyl)-n4- (2- (ethoxy sulphur Acyl group) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- ((mesyl) methyl) cyclopropyl) phenyl)-n4- (2- (n- isopropyl Base sulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n4- (2- (n- isopropyl sulphur Acyl group) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- ((trifluoromethoxy) methyl) cyclopropyl) phenyl)-n4- ((n- is different for 2- Sulfonyl propyl base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (carboxyl) cyclopropyl) phenyl)-n4- (2- (n- isopropelsulfonyl) Phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (aminomethyl) cyclopropyl) phenyl)-n4- (2- (n- isopropyl sulphonyl Base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (4- oxo Pentamethylene oxide .) methyl) cyclopropyl) phenyl)-n4-(2- (n- isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- ((methylamino) methyl) cyclopropyl) phenyl)-n4- (2- (n- isopropyl Sulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- (Methanamide) cyclopropyl) phenyl)-n4- (2- (n- isopropyl sulphonyl Base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo-pyrrolidine base) methyl) cyclopropyl) phenyl)-n4-(2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo hydroxy azetidine base) methyl) cyclopropyl) benzene Base)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine；
5- trifluoromethyl-n2- (2- isopropoxy -5- methyl -4- (1- ((4- oxo-piperidine base) methyl) cyclopropyl) phenyl)-n4- (2- (isopropelsulfonyl) phenyl) -2,4- di-amino-pyrimidine.
8. a kind of pharmaceutical composition, comprises the compound as the definition of any one of Claims 1 to 4 or its pharmaceutically acceptable salt As active ingredient, and one or more pharmaceutically acceptable carrier.
9. a kind of compound as the definition of any one of Claims 1 to 4 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 as the definition of any one of Claims 1 to 4 or its pharmaceutically acceptable salt are used for treating in preparation Or prevent the purposes in the medicine of disease related to anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase.
11. purposes as claimed in claim 10 it is characterised in that: described disease be selected from cell proliferation disorders, preferably swollen Tumor.
12. purposes as claimed in claim 11 it is characterised in that: described cell proliferation disorders include non-small cell lung Cancer, primary cutaneous type, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast carcinoma, colorectal cancer, diffuse big b cell and drench Bar tumor, hepatocarcinoma, gastric cancer, esophageal carcinoma, cancer of pancreas, ovarian cancer, body tissue's cellular proliferative disorder and neuroblastoma.
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CN109422733A (en) * 2017-09-03 2019-03-05 上海美志医药科技有限公司 One kind inhibits and the compound for the tyrosine protein kinase ALK that degrades
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CN109627263B (en) * 2017-12-21 2022-05-20 深圳市塔吉瑞生物医药有限公司 Diphenylaminopyrimidine compounds for inhibiting kinase activity
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WO2021173677A1 (en) * 2020-02-25 2021-09-02 Dana-Farber Cancer Institute, Inc. Potent and selective degraders of alk

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