CN106336398A - 2-Saturated cyclosubstituted aniline protein kinase inhibitor - Google Patents
2-Saturated cyclosubstituted aniline protein kinase inhibitor Download PDFInfo
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- CN106336398A CN106336398A CN201610540835.5A CN201610540835A CN106336398A CN 106336398 A CN106336398 A CN 106336398A CN 201610540835 A CN201610540835 A CN 201610540835A CN 106336398 A CN106336398 A CN 106336398A
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- 0 **C1(**C1)c(cccc1)c1Nc1nc(Nc(c(*)c2*)c(*)c(*)c2I)ncc1* Chemical compound **C1(**C1)c(cccc1)c1Nc1nc(Nc(c(*)c2*)c(*)c(*)c2I)ncc1* 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The invention discloses a compound being able to adjust the activity of protein kinase and used for treating or preventing protein kinase related diseases, concretely relates to a 2-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
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 2- 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 2- 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 2- saturation ring group replaces, for having the compound of following general structure
And its pharmaceutically acceptable salt:Wherein, r1It is selected from 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, cyano group, aryl, heterocyclic radical ,-co2r10、-(ch2)wor10、-(ch2)wnr10r11、-conr10r11、-(ch2)wso2r10、-(ch2)wso2nr2r10One or more of；r0、r8、r9Select independently of one another
From hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6One of alkynyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, aryl, heterocyclic radical
Or it is several；r10、r11It is each independently selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, aryl or heterocycle
Base；Described heterocyclic radical is selected from n, o, s heteroatomic 3-12 circle heterocycles；N be selected from 1～6 in any integer value, p be selected from 0～
Any integer value in 6, 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 said structure formula, r1It is selected from r2、r3、r4、r5、r6Be each independently selected from hydrogen, halogen,
c1-6Alkyl, halo c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkoxyl, cyano group or amino；r7Selected from hydrogen, halogen, c1-6Alkyl,
Cyano group, phenyl, heterocyclic radical ,-co2r10、-(ch2)wor10、-(ch2)wnr10r11、-conr10r11、-(ch2)wso2r10Or-(ch2)wso2nr2r10；r0、r8、r9It is each independently selected from hydrogen, c1-6Alkyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, phenyl or
Heterocyclic radical；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；N is selected from any integer value in 1～6, and p is selected from any integer value in 0～6, and k selects
Any integer value from 2～6, m, w are each independently selected from any integer value in 0～3.
The phenyl aminess kinases inhibitor that a kind of 2- saturation ring group replaces, is also included for having following general structure
Compound and its pharmaceutically acceptable salt:Wherein, q is-o- ,-s- or-nr12-；r1
It is selected from r2、r3、r4、r5、r6Respectively
From independently selected from hydrogen, halogen, c1-6Alkyl, halo c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkoxyl, c2-6Thiazolinyl, c2-6Alkynes
Base, cyano group or amino；r7Selected 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；r0、
r8、r9It is each independently selected from hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, virtue
One or more of base, heterocyclic radical；r10、r11、r12It is each independently selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, c2-6Alkene
Base, c2-6Alkynyl, aryl or heterocyclic radical；Described heterocyclic radical is selected from n, o, s heteroatomic 3-12 circle heterocycles；L, n, p are each only
On the spot it is selected from any integer value in 0～6, k is selected from any integer value in 2～6, and m, w are each independently selected from 0～3
Any integer value, and be 0 when l, n are different.
Preferably, in said structure formula, q is-o- ,-s- or-nr12-；r1It is selected from r2、r3、r4、r5、r6Be each independently selected from hydrogen, halogen,
c1-6Alkyl, halo c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkoxyl, cyano group or amino；r7Selected from hydrogen, halogen, c1-6Alkyl,
Cyano group, phenyl, heterocyclic radical ,-co2r10、-(ch2)wor10、-(ch2)wnr10r11、-conr10r11、-(ch2)wso2r10Or-(ch2)wso2nr2r10；r0、r8、r9It is each independently selected from hydrogen, c1-6Alkyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, phenyl or
Heterocyclic radical；r10、r11、r12It is each independently selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, phenyl or heterocyclic radical；Described heterocycle
Base is selected from n, o heteroatomic 3-6 circle heterocycles；L, n, p are each independently selected from any integer value in 0～6, and k is selected from 2～6
In any integer value, m, w be each independently selected from any integer value in 0～3, and is 0 when l, n are different.
Preferably, aryl is phenyl, naphthyl or anthryl；Heterocyclic radical is morpholinyl, pyranose, pyridine radicals, piperidyl, pyrimidine
Base or furyl.
Preferably, halogen is one or more of fluorine, chlorine, bromine, iodine.
The phenyl aminess kinases inhibitor that a kind of 2- saturation ring group replaces, is rex-a1～rex-a33's selected from numbering
Following characteristic compounds:
Rex-a1:1- (2- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) -4- pyrimidine)
Amine) phenyl)-n- cyclopropyl-acetamide；
The chloro- n of rex-a2:5-4- (2- (1- ((diethylin) methylene) cyclopropyl) phenyl)-n2- (2- isopropoxy -5-
Methyl -4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
Rex-a3:1- (2- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine)
Amine) phenyl) cyclopropyl) morpholinyl ketone；
The chloro- n of rex-a4:5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- (methylene
Quinoline base) cyclopropyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a5:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4-
(4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a6:5-4- (2- (1- (ethoxyl methyl) cyclobutyl) phenyl)-n2- (2- isopropoxy -5- methyl -4-
(4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a7:5-4- (2- (1- (ethoxyl methyl) -3- oxo Tetramethylene. base) phenyl)-n2- (2- isopropoxy-
5- methyl -4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a8:5-4- (2- (1- (ethoxyl methyl) -4- oxo thiacyclohexane base) phenyl)-n2- (2- isopropoxy-
5- methyl -4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a9:5-4- (2- (1- (ethoxy cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4- piperazine
Piperidinyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a10:5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- ((fluoroform
Base) methyl) cyclopropyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a11:5-4- (2- (1- ((difluoro-methoxy) methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5-
Methyl -4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
Rex-a12:n4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4-
Piperidyl) phenyl) -5- trifluoromethyl -2,4- di-amino-pyrimidine；
The chloro- n of rex-a13:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- methoxyl group -5- methyl -4-
(4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a14:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (5- methyl -4- (4- piperidines
Base) -2- (trifluoromethoxy) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a15:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (the fluoro- 4- of 5- (4- piperidyl)-
2- (trifluoromethoxy) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a16:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (the chloro- 4- of 5- (4- piperidyl)-
2- (trifluoromethoxy) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a17:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- methoxyl group -4- (4- piperidines
Base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a18:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (5- fluoro- 2- isopropoxy -4-
(4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a19:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (5- chloro- 2- isopropoxy -4-
(4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a20:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -
4- (methylene -4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
Rex-a21:2- (4- (4- (the chloro- 4- of 5- ((2- (1- (ethoxyl methyl) cyclopropyl) phenyl) -2- amine pyrimidine) -
5- isopropoxy -2- tolyl) -1- piperidines) acetamide；
Rex-a22:2- (4- (4- (the chloro- 4- of 5- ((2- (1- (ethoxyl methyl) cyclopropyl) phenyl) -2- amine pyrimidine) -
5- isopropoxy -2- tolyl) -1- piperidines) ethanol；
The chloro- n of rex-a23:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (4- (1- ethyl piperidine) -2- is different
Propoxyl group -5- methylbenzene) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a24:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -
4- (1- (4-2h- pyrans) piperidines) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a25:5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -
4- (4-2h- pyrans) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a26:5-4- (2- (1- (methylol) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4-
Piperidyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a27:5-2- (4- ((2- (dimethylamino) ethyl) methylamine) -2- isopropoxy -5- aminomethyl phenyl)-n4-
(2- (1- (ethoxyl methyl) cyclopropyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a28:5-4- (2- (1- ((lignocaine) methyl) cyclopropyl) phenyl)-n2- (4- (2- (dimethylamino)
Ethyl) -2- isopropoxy -5- aminomethyl phenyl) 2,4- di-amino-pyrimidine；
The chloro- n of rex-a29:5-2- (4- (2- ethoxy ethoxy) -2- isopropoxy -5- aminomethyl phenyl)-n4-(2-(1-
(ethoxyl methyl)) cyclopropyl) phenyl) 2,4- di-amino-pyrimidine；
The chloro- n of rex-a30:5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- (methylsulfonyl
Base) methyl) cyclopropyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a31:5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- aminomethyl)
Cyclopropyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a32:5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- carboxyl) ring
Propyl group) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of rex-a33:5-2- (2- difluoro-methoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- (ethoxy
Ylmethyl) methyl) cyclopropyl) phenyl) -2,4- di-amino-pyrimidine；
Rex-a34:5- trifluoromethyl-n4- (2- (1- (methylol) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- first
Base -4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
Rex-a35:5- trifluoromethyl-n4- (2- (1- tert-butyl alcohol base) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4-
Piperidyl) phenyl) -2,4- di-amino-pyrimidine；
Rex-a36:5- trifluoromethyl-n4- (2- (1- (methylol) cyclobutyl) phenyl)-n2- (2- isopropoxy -5- first
Base -4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine.
Aforementioned numbering is the compound of rex-a1～rex-a36, 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
Enter sodium hydride, react in 0～25 DEG C；After reaction terminates, plus extractant, extraction, dry, column chromatography, obtain compound 1-2.
Step 2: compound 1-2 is dissolved in organic solvent, is slowly added to catalyst, nitrogen displacement, logical hydrogen, heating is anti-
Answer n hour；After reaction terminates, filter and remove unnecessary catalyst, organic solvent is dried, reduce pressure, be dried, obtain compound 1-3.
Step 3: compound 1-3 is dissolved in organic solvent, is slowly added to sodium hydride and 2,4,5- trichloropyrimidines, nitrogen is put
Change, reacting by heating n hour；React after terminating, plus a small amount of frozen water destroys unnecessary sodium hydride, plus extractant, extract, be dried, reducing pressure,
It is spin-dried for, obtain compound 1-4.
In synthetic schemes 1, organic solvent is selected from n, in n dimethylformamide, oxolane, methanol, dioxane
Plant or several；Extractant is selected from one or more of pure water, dichloromethane, ethyl acetate；Catalyst be selected from palladium charcoal, four (three
Phenylphosphine) palladium, one or more of 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
Hour, 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 organic solvent configuring in proportion and water
Mixed liquor, is slowly added to potassium phosphate and catalyst, nitrogen displacement, reacting by heating n hour；After reaction terminates, plus extractant, extraction
Take, be dried, reduce pressure, be spin-dried for, obtain compound 2-2.
Step 2: compound 2-2 is dissolved in organic solvent, adds catalyst, nitrogen displacement, logical hydrogen, 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 n, one of n dimethylformamide, methanol, isopropanol, dioxane
Or it is several；Extractant is selected from one or more of pure water, dichloromethane, ethyl acetate；Catalyst is selected from palladium charcoal, four (triphens
Base phosphine) palladium, one or more of platinum dioxide.
In synthetic schemes 2, the temperature of reacting by heating is 100～120 DEG C, preferably 100 DEG C；Response time is little for 12～16
When, 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 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 n, in n dimethylformamide, oxolane, methanol, dioxane
Plant or several；Catalyst is selected from palladium charcoal, tetrakis triphenylphosphine palladium, platinum dioxide, palladium, the double diphenylphosphine -9,9- two of 4,5-
One or more of methyl xanthene.
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, q is-o- ,-s- or-nr12-；r1It is selected from r2、r3、r4、r5、r6Respectively
From independently selected from hydrogen, halogen, c1-6Alkyl, halo c1-6Alkyl, c1-6Alkoxyl, halo c1-6Alkoxyl, c2-6Thiazolinyl, c2-6Alkynes
Base, cyano group or amino；r7Selected 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；r0、
r8、r9It is each independently selected from hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, virtue
One or more of base, heterocyclic radical；r10、r11、r12It is each independently selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, c2-6Alkene
Base, c2-6Alkynyl, aryl or heterocyclic radical；Described heterocyclic radical is selected from n, o, s heteroatomic 3-12 circle heterocycles；L, n, p are each only
On the spot it is selected from any integer value in 0～6, k is selected from any integer value in 2～6, and m, w are each independently selected from 0～3
Any integer value, and be 0 when l, n are 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 2- 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 2- 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-a5
Fig. 3 is the impact figure to Brachydanio rerio iris pigment cell for the rex-a5
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 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -
4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-a5] preparation
Synthetic route is as follows:
Synthetic schemes 1:
Synthetic schemes 2:
Synthetic schemes 3:
Synthetic schemes 1: the chloro- n- of intermediate 2,5- bis- (2- (1- ethoxy cyclopropyl) phenyl) -4- aminopyrimidine (i.e. chemical combination
Thing 1-6) synthesis
Step 1: the preparation of intermediate 1- (2- Nitrobenzol) ethylene-acetic acid methyl ester (i.e. compound 1-2)
Raw material 4- nitrophenyl-acetic acid methyl ester (i.e. compound 1-1,20.0g, 102.0mmol) is dissolved in n, n dimethyl methyl
In amide (200.0ml), at 0 DEG C, it is slowly added to sodium hydride (3.6g, 153.0mmol), continue reaction 0.5 hour after adding, so
Deca glycol dibromide (28.6g, 153.0mmol) afterwards, maintains the temperature at 20～25 DEG C and reacts 16 hours；Reaction terminates hypsokinesis
Enter in 500.0ml water, be extracted with ethyl acetate, be dried, concentrate, silica gel column chromatography separates, and obtains compound 1-2 (5.2g),
Yield: 23.3%.
Msm/z [esi]: 222.1 [m+1].
Step 2: the preparation of intermediate 1- (2- Nitrobenzol) cyclopropyl-carbinol (i.e. compound 1-3)
Compound 1-2 (2.0g, 9.0mmol) is dissolved in oxolane (50.0ml), is slowly added to aluminum hydride in 0～5 DEG C
Lithium (0.3g, 9.0mmol), maintains the temperature at 0～5 DEG C and reacts 60 minutes；React room temperature of rising again after terminating, add 3.0mol/l
Hydrochloric acid water destruct, is extracted with water and ethyl acetate, organic faciess sodium bicarbonate washs secondary, anhydrous sodium sulfate drying, is concentrated to give
To compound 1-3 (1.0g), yield: 58.0%.
Msm/z [esi]: 194.2 [m+1].
Step 3: the preparation of intermediate 1- (1- (ethoxyl methyl) cyclopropyl) -2- Nitrobenzol (i.e. compound 1-4)
Under the conditions of ice-water bath, compound 1-3 (1.0g, 5.2mmol) is dissolved in n, n dimethylformamide (i.e. dmf,
Similarly hereinafter, 20.0ml) in, sodium hydride (0.3g, 6.7mmol) is slowly added in reaction system simultaneously, stirs 15 points in 0 DEG C
Clock；Again iodoethane (1.0g, 6.4mmol) is added drop-wise in reaction system, is heated to 45 DEG C and reacts 3 hours；It is poured into after cooling
In 50.0ml water, it is extracted with ethyl acetate, be dried, concentrate, silica gel column chromatography separates, and obtains compound 1-4 (0.8g), yield:
70.0%.
Msm/z [esi]: 222.2 [m+1].1h-nmr(400mhz,cdcl3): δ=7.754-7.750 (m, 1h), 7.652-
7.650 (m, 1h), 7.519-7.515 (m, 1h), 7.375-7.370 (m, 1h), 3.618 (s, 1h), 3.437-3.432 (m,
2h), 1.113-1.110 (m, 3h), 0.969-0.965 (m, 2h), 0.769-0.765 (m, 2h).
Step 4: the preparation of intermediate 1- (1- (ethoxyl methyl) cyclopropyl) -2- aniline (i.e. compound 1-5)
Compound 1-4 (0.8g, 3.6mmol) and 10% palladium charcoal (i.e. pd/c, 0.2g) are added to dry methanol
(25.0ml) in, nitrogen displacement, logical hydrogen, react 12 hours in 25 DEG C；Filtered, separated, anhydrous slufuric acid with kieselguhr after cooling
Sodium is dried, concentrates, and obtains compound 1-5 (0.7g), yield: 95.0%.
Msm/z [esi]: 192.2 [m+1].
Step 5: the chloro- n- of intermediate 2,5- bis- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl) -4- aminopyrimidine (is changed
Compound 1-6) preparation
Under the conditions of ice-water bath, compound 1-5 (1.2g, 6.3mmol) is dissolved in dmf (30.0ml), reaction system
In be slowly added to sodium hydride (0.2g, 7.6mmol) and in 0 DEG C stir 15 minutes, then by 2,4,5- trichloropyrimidines (1.2g,
6.3mmol) it is added drop-wise in reaction system and be stirred overnight in 25 DEG C；It is poured into after cooling in 50.0ml water, be extracted with ethyl acetate,
It is dried, concentrates, silica gel column chromatography separates, and obtains compound 1-6 (0.8g), yield: 70.0%.
Msm/z [esi]: 339.2 [m+1].1h-nmr(400mhz,dmso-d6): δ=9.464 (s, 1h), 7.955-
7.950 (m, 2h), 7.412-7.410 (m, 2h), 3.479-3.475 (m, 4h), 1.291-1.288 (m, 3h), 0.958-0.955
(m, 2h), 0.786-0.784 (m, 2h).
Synthetic schemes 2: piperidines -1- tertiary fourth oxygen carbonic ester is (i.e. for intermediate 4- (4- amino 5- isopropoxy -2- aminomethyl phenyl)
Compound 2-4) synthesis
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), add 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, changed
Compound 2-2 (14.4g), 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 (7.4g, 60.0mmol) is dissolved in mixed liquor (both volume ratios v/v=of dioxane and water
2:1), nitrogen displacement, stirring 5 minutes.Three (1,3- dibenzalacetone) is closed two palladiums (5.0g, 5.6mmol), 2- dicyclohexyl
Phosphine -2', 6'- dimethoxy -1,1'- biphenyl (5.6g, 14.1mmol), compound 2-2 (12.5g, 54.0mmol) and phosphoric acid
Potassium (23.0g, 109.0mmol) sequentially adds under nitrogen protection, and reaction backflow is overnight.Reaction is cooled to room temperature after terminating,
The saturation naoh washing of 1mol/l is secondary, is extracted with ethyl acetate.Organic faciess anhydrous sodium sulfate drying, concentration, silicagel column color
Spectrum separates, and obtains compound 2-3 (10.0g), 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=4.8hz 1h), 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: intermediate 4- (4- amino 5- isopropoxy -2- aminomethyl phenyl) piperidines -1- tertiary fourth oxygen carbonic ester (i.e. chemical combination
Thing 2-4) preparation
Compound 2-3 (43.8g, 161.0mmol) is dissolved in the mixed of acetic acid (400.0ml) and trifluoroacetic acid (25.0ml)
Close liquid, add the platinum dioxide (17.6g) of platinum containing amount 40%, nitrogen displacement, logical hydrogen, stirring 5 minutes, it is pressurized to 1 air
Pressure, reacts 36 hours.Reaction is cooled to room temperature after terminating, and filters, removes platinum dioxide, adds the dilution of 100ml water, uses acetic acid second
Ester extracts；Organic faciess saturation naoh of 1mol/l washs secondary, anhydrous sodium sulfate drying, concentration, silica gel column chromatography separation, obtains
To 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 chloro- n of target compound 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropyl
Epoxide -5- methyl -4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine (i.e. rex-a5) synthesis
Step 1: intermediate 4- (4- ((the chloro- 4- of 5- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl) amino) -2- pyrimidine
Amino) -5- isopropoxy -2- tolyl) piperidines -1- hydroxy acid tert-butyl ester (i.e. compound 3-1) preparation
By compound 2-4 (0.2g, 0.6mmol), double (diphenylphosphine) -9 of compound 1-6 (0.2g, 0.6mmol), 4,5-,
9- dimethyl xanthene (68.0mg, 0.1mmol), palladium (14.0mg, 0.01mmol) and cesium carbonate (0.6g, 1.8mmol)
It is dissolved in dioxane (5.0ml), and add in tube sealing, nitrogen displacement, react 18 hours in 95 DEG C.After reaction terminates, it is spin-dried for
Solvent, adds ethyl acetate and water, and extraction, organic faciess are dried, cross silica gel chromatography, obtain compound 3-1
(120.0mg), yield: 30.0%.
Msm/z [esi]: 651.1 [m+1].
Step 2: the preparation of target compound (i.e. rex-a5)
Under stirring condition, compound 3-1 (120.mg, 0.2mmol) is added in dichloromethane (5.0ml), Deca trifluoro
Acetic acid (2.0ml), is stirred overnight under room temperature.First it is adjusted to ph ＞ 10 with 5% sodium bicarbonate aqueous solution, then be extracted with ethyl acetate,
It is dried, is spin-dried for, obtain target compound rex-a5 (75.0mg), yield: 75.0%.
Msm/z [esi]: 551.1 [m+1].1h-nmr(400mhz,dmso-d6): δ=9.772 (s, 1h), 9.278-
9.275 (m, 1h), 8.849-8.848 (m, 2h), 8.486-8.484 (m, 1h), 7.744-7.740 (m, 1h), 7.464-7.460
(m, 2h), 7.264-7.260 (m, 2h), 6.842 (s, 1h), 4.557-4.555 (m, 1h), 3.429-3.425 (m, 7h),
3.075-3.070 (m, 3h), 2.080 (s, 3h), 1.888-1.885 (m, 4h), 1.258-1.255 (m, 6h), 1.090-1.088
(m, 3h), 0.558-0.555 (m, 2h).
(((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) -4- is phonetic for 2- for embodiment 2 1-
Pyridine) amine) phenyl) and-n- cyclopropyl-acetamide [numbering is rex-a1] preparation
Synthetic route is as follows:
Synthetic schemes 1:
Synthetic schemes 2:
Synthetic schemes 3:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-6 ", step 2 hydrogen
Lithium oxide replaces the lithium aluminium hydride reduction of embodiment 1 to be reacted, and step 3 ethamine replaces iodoethane to be reacted, remaining synthesis side
Method, with the synthetic schemes 1 of embodiment 1, obtains final product compound 1-6, yield: 18.0% after multistep reaction.
Msm/z [esi]: 332.4 [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, obtains final product compound 2-4, yield: 62.8%.
Msm/z [esi]: 348.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-a1 ", by the prepared compound 1-6 of the present embodiment and chemical combination
Thing 2-4, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-a1, yield: 25%.
Msm/z [esi]: 564.1 [m+1].1h-nmr(400mhz,dmso-d6): δ=10.644 (s, 1h), 8.376 (s,
1h), 9.263-9.260 (m, 3h), 8.527 (s, 1h), 7.761-7.742 (d, j=7.6hz, 1h), 7.445-7.440 (m,
5h), 6.823 (s, 1h), 4.563-4.560 (m, 1h), 3.378-3.378 (m, 2h), 2.927-2.925 (m, 4h), 2.037
(s, 3h), 1.755-1.750 (m, 6h), 1.270-1.265 (m, 2h), 1.112-1.110 (m, 6h), 0.997-0.994 (m,
2h), 0.832-0.830 (m, 2h).
The chloro- n of embodiment 3 5-4- (2- (1- ((diethylin) methylene) cyclopropyl) phenyl)-n2- (2- isopropoxy -5-
Methyl -4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-a2] preparation
Synthetic route is as follows:
Synthetic schemes 1:
Synthetic schemes 2:
Synthetic schemes 3:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-6 ", step 3 uses two
Ethamine replaces iodoethane to be reacted, and remaining synthetic method, with the synthetic schemes 1 of embodiment 1, obtains final product compound after multistep reaction
1-6, yield: 14.0%.
Msm/z [esi]: 345.4 [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, obtains final product compound 2-4, yield: 65.2%.
Msm/z [esi]: 348.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-a2 ", by the prepared compound 1-6 of the present embodiment and chemical combination
Thing 2-4, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-a2, yield: 18%.
Msm/z [esi]: 578.1 [m+1].1h-nmr(400mhz,dmso-d6): δ=10.153 (s, 1h), 8.376 (s,
1h), 9.973-9.970 (m, 1h), 9.548-9.545 (m, 1h), 9.317-9.315 (m, 2h), 8.639-8.635 (m, 1h),
7.784-7.780 (m, 1h), 7.506-7.503 (m, 3h), 7.188-7.185 (m, 1h), 6.784-6.780 (m, 1h),
4.518-4.515 (m, 1h), 3.034-3.030 (m, 1h), 2.985-2.980 (m, 4h), 2.717-2.710 (m, 4h), 1.941
(s, 3h), 1.846-1.845 (m, 2h), 1.293-1.290 (m, 6h), 1.091-1.088 (m, 4h), 0.849-0.845 (m,
4h).
Embodiment 4 1- (2- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine)
Amine) phenyl) cyclopropyl) and morpholinyl ketone [numbering is rex-a3] preparation
Synthetic route is as follows:
Synthetic schemes 1:
Synthetic schemes 2:
Synthetic schemes 3:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-6 ", step 2 hydrogen
Lithium oxide replaces the lithium aluminium hydride reduction of embodiment 1 to be reacted, and step 3 is reacted for iodoethane with morpholino, remaining synthesis side
Method, with the synthetic schemes 1 of embodiment 1, obtains final product compound 1-6, yield: 12.0% after multistep reaction.
Msm/z [esi]: 374.4 [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, obtains final product compound 2-4, yield: 63.4%.
Msm/z [esi]: 348.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-a3 ", by the prepared compound 1-6 of the present embodiment and chemical combination
Thing 2-4, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-a3, yield: 25%.
Msm/z [esi]: 606.1 [m+1].1h-nmr(400mhz,dmso-d6): δ=9.812 (s, 1h), 8.693 (m,
1h), 8.451-8.450 (m, 1h), 8.229-8.225 (m, 2h), 7.846-7.825 (d, j=8.4hz, 1h), 7.536 (s,
1h), 7.534-7.513 (d, j=8.4hz, 1h), 7.228-7.225 (m, 1h), 7.177-7.175 (m, 1h), 6.784 (s,
1h), 4.528-4.525 (m, 1h), 3.401-3.400 (m, 4h), 3.036-3.035 (m, 4h), 2.505 (s, 3h), 1.794-
1.790 (m, 4h), 1.313-1.310 (m, 6h), 1.125-1.120 (m, 4h), 1.085-1.080 (m, 4h).
The chloro- n of embodiment 5 5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- (methylene
Morpholinyl) cyclopropyl) phenyl) and -2,4- di-amino-pyrimidine [numbering is rex-a4] preparation
Synthetic route is as follows:
Synthetic schemes 1:
Synthetic schemes 2:
Synthetic schemes 3:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-6 ", step 3 is used
Quinoline replaces iodoethane to be reacted, and remaining synthetic method, with the synthetic schemes 1 of embodiment 1, obtains final product compound 1- after multistep reaction
6, yield: 28.0%.
Msm/z [esi]: 360.8 [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, obtains final product compound 2-4, yield: 61.5%.
Msm/z [esi]: 348.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-a4 ", by the prepared compound 1-6 of the present embodiment and chemical combination
Thing 2-4, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-a4, yield: 10%.
Msm/z [esi]: 578.1 [m+1].1h-nmr(400mhz,dmso-d6): δ=10.950 (s, 1h), 10.134 (s,
1h), 9.473-9.470 (m, 1h), 9.123-9.120 (m, 2h), 8.646-8.640 (m, 1h), 7.812-7.792 (d, j=
8.0hz, 1h), 7.508-7.505 (m, 3h), 7.183 (s, 1h), 6.773 (s, 1h), 4.596-4.595 (m, 1h), 3.282-
3.280 (m, 4h), 2.986-2.980 (m, 4h), 2.676-2.675 (m, 2h), 1.808 (s, 3h), 1.688-1.685 (m,
6h), 1.299-1.295 (m, 6h), 1.094-1.090 (m, 4h).
The chloro- n of embodiment 6 5-4- (2- (1- (ethoxyl methyl) cyclobutyl) phenyl)-n2- (2- isopropoxy -5- methyl -
4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-a6] preparation
Synthetic route is as follows:
Synthetic schemes 1:
Synthetic schemes 2:
Synthetic schemes 3:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-6 ", step 1 uses 1,
3- dibromopropane replaces glycol dibromide to be reacted, and remaining synthetic method is with the synthetic schemes 1 of embodiment 1, multistep reaction
After obtain final product compound 1-6, yield: 25.0%.
Msm/z [esi]: 333.8 [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, obtains final product compound 2-4, yield: 64.2%.
Msm/z [esi]: 348.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-a6 ", by the prepared compound 1-6 of the present embodiment and chemical combination
Thing 2-4, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-a6, yield: 15%.
Msm/z [esi]: 565.4 [m+1].1h-nmr(400mhz,dmso-d6): δ=8.837 (s, 1h), 8.690-
8.688 (m, 1h), 8.440-8.438 (m, 1h), 8.228-8.225 (m, 1h), 8.121-8.120 (m, 1h), 7.662 (s,
1h), 7.594-7.590 (m, 1h), 7.276-7.275 (m, 2h), 7.121 (s, 1h), 6.741 (s, 1h), 4.452-4.450
(m, 1h), 3.747 (s, 2h), 3.504-3.500 (m, 2h), 3.359-3.355 (m, 2h), 3.033-3.030 (m, 4h),
2.232-2.230 (m, 6h), 2.086 (s, 3h), 1.779-1.775 (m, 4h), 1.280-1.278 (m, 6h), 1.146-1.144
(m,4h).
The chloro- n of embodiment 7 5-4- (2- (1- (methylol) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4-
Piperidyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-a26] preparation
Synthetic route is as follows:
Synthetic schemes 1:
Synthetic schemes 2:
Synthetic schemes 3:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-6 ", step 3 uses two
Fluorine iodomethane replaces iodoethane to be reacted, and remaining synthetic method is with the synthetic schemes 1 of embodiment 1, obtaining final product after multistep reaction
Compound 1-6, yield: 18.0%.
Msm/z [esi]: 360.4 [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, obtains final product compound 2-4, yield: 65.2%.
Msm/z [esi]: 348.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-a26 ", by the prepared compound 1-6 of the present embodiment and change
Compound 2-4, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-a26, yield: 17%.
Msm/z [esi]: 523.1 [m+1].1h-nmr(400mhz,dmso-d6): δ=9.772 (s, 1h), 9.278-
9.275 (m, 1h), 8.849-8.848 (m, 2h), 8.486-8.484 (m, 1h), 7.744-7.740 (m, 1h), 7.464-7.460
(m, 2h), 7.264-7.260 (m, 2h), 6.842 (s, 1h), 4.557-4.555 (m, 1h), 3.429-3.425 (m, 7h),
3.075-3.070 (m, 3h), 2.080 (s, 3h), 1.888-1.885 (m, 2h), 1.258-1.255 (m, 6h), 0.558-0.555
(m,2h).
Embodiment 8 5- trifluoromethyl-n4- (2- (1- (methylol) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- first
Base -4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-a34] preparation
Synthetic route is as follows:
Synthetic schemes 1:
Synthetic schemes 2:
Synthetic schemes 3:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-6 ", step 5 uses 2,
The chloro- 5- trifluoromethyl pyrimidine of 4- bis- replaces 2,4,5- trichloropyrimidines to be reacted, and remaining synthetic method is with the synthesis side of embodiment 1
Case 1, obtains final product compound 1-6, yield: 10.0% after multistep reaction.
Msm/z [esi]: 344.4 [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, obtains final product compound 2-4, yield: 65.2%.
Msm/z [esi]: 348.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-a34 ", by the prepared compound 1-6 of the present embodiment and change
Compound 2-4, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-a34, yield: 15%.
Msm/z [esi]: 556.1 [m+1].1h-nmr(400mhz,dmso-d6): δ: 9.365 (s, 1h), 8.333 (s, 1h)
8.026(s,1h),7.680-7.720(m,1h),7.523(s,1h),7.350-7.390(m,1h),7.117-7.238(m,
2h), 6.749 (s, 1h), 5.759 (s, 1h), 4.455-4.570 (m, 1h), 3.445 (s, 2h), 3.255 (d, 2h, j=
12.4hz), 2.822-2.938 (m, 3h), 2.037 (s, 3h), 1.675-1.817 (m, 4h), 1.244 (d, 6h, j=6hz),
0.818 (t, 2h, j=4.8hz), 0.590 (t, 2h, j=4.8hz).
Embodiment 9 5- trifluoromethyl-n4- (2- (1- tert-butyl alcohol base) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4-
Piperidyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-a35] preparation
Synthetic route is as follows:
Synthetic schemes 1:
Synthetic schemes 2:
Synthetic schemes 3:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-6 ", step 1 iodine
Methane replaces glycol dibromide to be reacted, and step 5 uses the chloro- 5- trifluoromethyl pyrimidine of 2,4- bis- to replace 2,4,5- trichloropyrimidines
Reacted, remaining synthetic method, with the synthetic schemes 1 of embodiment 1, obtains final product compound 1-6, yield after multistep reaction:
15.0%.
Msm/z [esi]: 357.4 [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, obtains final product compound 2-4, yield: 65.2%.
Msm/z [esi]: 348.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-a35 ", by the prepared compound 1-6 of the present embodiment and change
Compound 2-4, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-a35, yield: 15%.
Msm/z [esi]: 558.1 [m+1].1h-nmr(400mhz,dmso-d6): δ: 10.416 (s, 1h), 8.940-
8.549(m,4h),7.482-7.437(m,3h),7.275-7.252(m,2h),6.750(s,1h),4.260(s,1h),
3.000-2.812(m,3h),2.000-1.760(m,8h).
Embodiment 10 5- trifluoromethyl-n4- (2- (1- (methylol) cyclobutyl) phenyl)-n2- (2- isopropoxy -5- first
Base -4- (4- piperidyl) phenyl) -2,4- di-amino-pyrimidine [numbering is rex-a36] preparation
Synthetic route is as follows:
Synthetic schemes 1:
Synthetic schemes 2:
Synthetic schemes 3:
As described in the synthetic route that the present embodiment provides, in synthetic schemes 1 " synthesis of compound 1-6 ", step 1 uses 1,
3- dibromopropane replaces glycol dibromide to be reacted, and step 5 uses the chloro- 5- trifluoromethyl pyrimidine of 2,4- bis- to replace 2,4,5- tri-
Chloropyrimide is reacted, and remaining synthetic method, with the synthetic schemes 1 of embodiment 1, obtains final product compound 1-6, yield after multistep reaction:
12.0%.
Msm/z [esi]: 360.4 [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, obtains final product compound 2-4, yield: 65.2%.
Msm/z [esi]: 348.2 [m+1].
In synthetic schemes 3 " synthesis of target compound rex-a34 ", by the prepared compound 1-6 of the present embodiment and change
Compound 2-4, prepared by the synthetic schemes 3 according to embodiment 1, obtain final product target compound rex-a34, yield: 15%.
Msm/z [esi]: 571.1 [m+1].1h-nmr(400mhz,dmso-d6)δ:9.73(s,1h),8.914-8.859
(m,2h),8.747-8.688(m,1h),8.522(s,1h),7.559(s,1h),7.516-7.494(m,1h),7.252-
7.230(m,2h),7.111-7.089(m,1h),6.783(s,1h),4.590-4.532(m,1h),3.753(s,2h),3.647
(m,1h),3.047-2.917(m,3h),2.204-2.063(m,5h),2.01(s,3h),1.911(s,1h),1.868-1.709
(m, 6h), 1.284-1.269 (d, 6h, j=6hz).
Embodiment 11 alk kinase inhibiting activity and the mensure of relevant mutational site combination rate
The compound rex-a1 that above-described embodiment 1～7 is obtained～rex-a6, rex-a26, 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 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 l1196m ic50(nm) | |
| rex-a1 | <50 | <50 |
| rex-a2 | <50 | <50 |
| rex-a3 | 104 | 86.3 |
| rex-a4 | 298 | 163 |
| rex-a5 | <50 | <100 |
| rex-a6 | 226 | 880 |
| rex-a26 | <10 | <5 |
| rex-a34 | <20 | <5 |
| rex-a35 | <100 | <100 |
| rex-a36 | 16.9 | 24.2 |
Further, the present invention selects and selects compound rex-a1, rex-a2 and rex-a5, public using life technology
Kinase assay platform assay aforesaid compound determination of activity to associated kinase under 100nm concentration of department, measures knot
Fruit is shown in Table two.Result shows, compound rex-a1, rex-a2 that the present invention provides shows to alk f1174l, alk c1156y
Go out preferable combination rate, rex-a5, rex-a1, rex-a2 show higher inhibitory activity to ltk, ros1.
Table two embodiment compound determination of activity to associated kinase under 100nm concentration
Embodiment 12 cell proliferation experiment (detection of mtt method)
Testing compound: compound rex-a5, rex-a1, rex-a2 and rex- that the embodiment of the present invention 1,2,3 and 7 is obtained
a26.
Cell strain: lung cancer cell line nci-h2228 and nci-h3122, purchased from bio tech ltd of Nanjing section one hundred.
Method: cell strain nci-h2228 and nci-h3122 is placed in 20%fbs (hyclone) (gibco)+1640+
1% dual anti-is cultivated.Then take the nci-h2228 cell that growth conditions are good, 5000/hole is inoculated in 96 hole cells respectively
Plate, is placed in 37 DEG C, contains 5%co2Incubator in incubation 24h make cell attachment complete.Discard old culture fluid, every hole sequentially adds
100 μ l contain the culture fluid of 0.3,1,3,10,30,100,300,1000,3000 and 10000nmol/l testing compound, solvent pair
According to organizing the culture fluid that every hole adds 100 μ l to contain 0.1%dmso, every group of 3 multiple holes, discard 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, supernatant discarded, every hole
Add 100 μ l dmso, vibration, measure each hole absorbance under 490nm wavelength with microplate reader.Dense according to each compound difference
The suppression ratio to each cell growth for the degree, 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-a1 | <1 | nd |
| rex-a2 | <1 | <3 |
| rex-a5 | <2 | <3 |
| rex-a26 | <1 | <0.15 |
Embodiment 13 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 (rex-a5), carry out image acquisition during to 3dpf (days post fertilization), then utilize
Imagej software analysis cloacal aperture to tail fin position Brachydanio rerio back side iris pigment cell iod (integrated option
Density) value, carries out dunnett ' s t- inspection using graphpad prism6.0 and carries out statistical analysis, p < 0.05 shows
There is significant difference, iris pigment suppression ratio computing formula is as follows:
Result of calculation is shown in Table four, and the dose-effect relationship figure that compound rex-a5 affects on Brachydanio rerio iris pigment cell is shown in Fig. 2,
The impact figure to Brachydanio rerio iris pigment cell for the compound rex-a5 is shown in Fig. 3.
The impact (mean ± sem) to Brachydanio rerio iris pigment cell for table four compound
compared with control,*,p<0.05；**,p<0.01.
Claims (12)
1. the phenyl aminess kinases inhibitor that a kind of 2- saturation ring group replaces, for have following general structure compound and
Its pharmaceutically acceptable salt:
Wherein, r1It is selected from
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, cyano group, aryl, heterocyclic radical ,-co2r10、-(ch2)wor10、-
(ch2)wnr10r11、-conr10r11、-(ch2)wso2r10、-(ch2)wso2nr2r10One or more of；
r0、r8、r9It is each independently selected from hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, acyl group, amide groups, sulfo group, sulfophenyl,
One or more of hydroxyl, aryl, heterocyclic radical；
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, s heteroatomic 3-12 circle heterocycles；
N is selected from any integer value in 1～6, and p is selected from any integer value in 0～6, and k is selected from any integer value in 2～6,
M, w are each independently selected from any integer value in 0～3.
2. 2- saturated cyclic alkyls phenyl aminess kinases inhibitor according to claim 1 it is characterised in that: described knot
In structure formula,
r1It is selected from
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, halogen, c1-6Alkyl, cyano group, phenyl, heterocyclic radical ,-co2r10、-(ch2)wor10、-(ch2)wnr10r11、-
conr10r11、-(ch2)wso2r10Or-(ch2)wso2nr2r10；
r0、r8、r9It is each independently selected from hydrogen, c1-6Alkyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, phenyl or heterocycle
Base；
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；
N is selected from any integer value in 1～6, and p is selected from any integer value in 0～6, and k is selected from any integer value in 2～6,
M, w are each independently selected from any integer value in 0～3.
3. the phenyl aminess kinases inhibitor that a kind of 2- saturation ring group replaces, for have following general structure compound and
Its pharmaceutically acceptable salt:
Wherein, q is-o- ,-s- or-nr12-；
r1It is selected from
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, cyano group, aryl, heterocyclic radical ,-co2r10、-(ch2)wor10、-
(ch2)wnr10r11、-conr10r11、-(ch2)wso2r10、-(ch2)wso2nr2r10One or more of；
r0、r8、r9It is each independently selected from hydrogen, c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, acyl group, amide groups, sulfo group, sulfophenyl,
One or more of hydroxyl, aryl, heterocyclic radical；
r10、r11、r12It is each independently selected from hydrogen, c1-6Alkyl, halo c1-6Alkyl, c2-6Thiazolinyl, c2-6Alkynyl, aryl or heterocycle
Base；
Described heterocyclic radical is selected from n, o, s heteroatomic 3-12 circle heterocycles；
L, n, p are each independently selected from any integer value in 0～6, and k is selected from any integer value in 2～6, and m, w are each independent
Any integer value in 0～3 for the ground, and be 0 when l, n are different.
4. 2- saturation ring group according to claim 3 replaces phenyl aminess kinases inhibitor it is characterised in that: described
General structure in, q be-o- ,-s- or-nr12-；
r1It is selected from
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, halogen, c1-6Alkyl, cyano group, phenyl, heterocyclic radical ,-co2r10、-(ch2)wor10、-(ch2)wnr10r11、-
conr10r11、-(ch2)wso2r10Or-(ch2)wso2nr2r10；
r0、r8、r9It is each independently selected from hydrogen, c1-6Alkyl, acyl group, amide groups, sulfo group, sulfophenyl, hydroxyl, phenyl or heterocycle
Base；
r10、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；
L, n, p are each independently selected from any integer value in 0～6, and k is selected from any integer value in 2～6, and m, w are each independent
Any integer value in 0～3 for the ground, and be 0 when l, n are different.
5. the phenyl aminess kinases inhibitor that the 2- 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 is morpholinyl, pyranose, pyridine radicals, piperidyl, phonetic
Piperidinyl or furyl.
6. the phenyl aminess kinases inhibitor that the 2- 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 2- saturation ring group replaces, selected from following characteristic compounds:
1- (2- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) -4- pyrimidine) amine) phenyl)-n-
Cyclopropyl-acetamide；
The chloro- n of 5-4- (2- (1- ((diethylin) methylene) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4- piperazine
Piperidinyl) phenyl) -2,4- di-amino-pyrimidine；
1- (2- ((the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) amine) 4- pyrimidine) amine) phenyl) ring third
Base) morpholinyl ketone；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- (methylene morpholinyl) ring third
Base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4- piperidyl)
Phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclobutyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4- piperidyl)
Phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) -3- oxo Tetramethylene. base) phenyl)-n2- (2- isopropoxy -5- methyl -4-
(4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) -4- oxo thiacyclohexane base) phenyl)-n2- (2- isopropoxy -5- methyl -4-
(4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxy cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) -
2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- ((trifluoromethyl) methyl) ring third
Base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- ((difluoro-methoxy) methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4- piperazine
Piperidinyl) phenyl) -2,4- di-amino-pyrimidine；
n4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl) -
5- trifluoromethyl -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- methoxyl group -5- methyl -4- (4- piperidyl) benzene
Base) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (5- methyl -4- (4- piperidyl) -2- (trifluoro methoxy
Base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (the fluoro- 4- of 5- (4- piperidyl) -2- (trifluoro methoxy
Base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (the chloro- 4- of 5- (4- piperidyl) -2- (trifluoro methoxy
Base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- methoxyl group -4- (4- piperidyl) phenyl) -2,4-
Di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (5- fluoro- 2- isopropoxy -4- (4- piperidyl) benzene
Base) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (5- chloro- 2- isopropoxy -4- (4- piperidyl) benzene
Base) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (methylene -4-
Piperidyl) phenyl) -2,4- di-amino-pyrimidine；
2- (4- (4- (the chloro- 4- of 5- ((2- (1- (ethoxyl methyl) cyclopropyl) phenyl) -2- amine pyrimidine) -5- isopropoxy -2-
Tolyl) -1- piperidines) acetamide；
2- (4- (4- (the chloro- 4- of 5- ((2- (1- (ethoxyl methyl) cyclopropyl) phenyl) -2- amine pyrimidine) -5- isopropoxy -2-
Tolyl) -1- piperidines) ethanol；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (4- (1- ethyl piperidine) -2- isopropoxy -5- first
Base benzene) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (1- (4-2h- pyrrole
Mutter) piperidines) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (ethoxyl methyl) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4-2h- pyrans)
Phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- (methylol) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4- piperidyl) benzene
Base) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (4- ((2- (dimethylamino) ethyl) methylamine) -2- isopropoxy -5- aminomethyl phenyl)-n4- (2- (1- (ethoxy
Ylmethyl) cyclopropyl) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-4- (2- (1- ((lignocaine) methyl) cyclopropyl) phenyl)-n2- (4- (2- (dimethylamino) ethyl) -2- isopropyl
Epoxide -5- aminomethyl phenyl) 2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (4- (2- ethoxy ethoxy) -2- isopropoxy -5- aminomethyl phenyl)-n4- (2- (1- (ethoxyl methyl))
Cyclopropyl) phenyl) 2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- (mesyl) methyl) ring third
Base) phenyl) -2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- aminomethyl) cyclopropyl) phenyl)-
2,4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- isopropoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- carboxyl) cyclopropyl) phenyl) -2,
4- di-amino-pyrimidine；
The chloro- n of 5-2- (2- difluoro-methoxy -5- methyl -4- (4- piperidyl) phenyl)-n4- (2- (1- (ethoxyl methyl) methyl)
Cyclopropyl) phenyl) -2,4- di-amino-pyrimidine；
Rex-a34:5- trifluoromethyl-n4- (2- (1- (methylol) cyclopropyl) phenyl)-n2- (2- isopropoxy -5- methyl -4-
(4- piperidyl) phenyl) -2,4- di-amino-pyrimidine；
Rex-a35:5- trifluoromethyl-n4- (2- (1- tert-butyl alcohol base) phenyl)-n2- (2- isopropoxy -5- methyl -4- (4- piperidines
Base) phenyl) -2,4- di-amino-pyrimidine；
Rex-a36:5- trifluoromethyl-n4- (2- (1- (methylol) cyclobutyl) phenyl)-n2- (2- isopropoxy -5- methyl -4-
(4- piperidyl) 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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|---|---|---|---|
| CN201510399861 | 2015-07-06 | ||
| CN2015103998616 | 2015-07-06 |
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| Publication Number | Publication Date |
|---|---|
| CN106336398A true CN106336398A (en) | 2017-01-18 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11529350B2 (en) | 2019-07-03 | 2022-12-20 | Sumitomo Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1852900A (en) * | 2003-09-18 | 2006-10-25 | 诺瓦提斯公司 | 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders |
| CN102105150A (en) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | Phosphorous derivatives as kinase inhibitors |
| US20140066406A1 (en) * | 2008-05-21 | 2014-03-06 | Ariad Pharmaceuticals, Inc. | Phosphorus Derivatives as Kinase Inhibitors |
-
2016
- 2016-07-06 CN CN201610540835.5A patent/CN106336398A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1852900A (en) * | 2003-09-18 | 2006-10-25 | 诺瓦提斯公司 | 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders |
| CN102105150A (en) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | Phosphorous derivatives as kinase inhibitors |
| US20140066406A1 (en) * | 2008-05-21 | 2014-03-06 | Ariad Pharmaceuticals, Inc. | Phosphorus Derivatives as Kinase Inhibitors |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11529350B2 (en) | 2019-07-03 | 2022-12-20 | Sumitomo Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof |
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