CN105503827B - EGFR inhibitor and its preparation method and application - Google Patents
EGFR inhibitor and its preparation method and application Download PDFInfo
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- CN105503827B CN105503827B CN201510626680.2A CN201510626680A CN105503827B CN 105503827 B CN105503827 B CN 105503827B CN 201510626680 A CN201510626680 A CN 201510626680A CN 105503827 B CN105503827 B CN 105503827B
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- 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
Abstract
The invention discloses EGFR inhibitors and its preparation method and application.Specifically; the present invention relates to one kind to have formula (I) compound N-(5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, and wherein each substituent group in formula (I) is identical as the definition in specification.The series compound has the activity for inhibiting L858R EGFR mutant, T790MEGFR mutant and exons 19 to lack activated mutant body, it can be used to treat individually or partly disease mediated by EGFR mutant activity, such as having in prevention and treatment cancer especially non-small cell lung cancer drug is widely applied, and is expected to exploitation into EGFR inhibitor of new generation.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of EGFR inhibitor, that is, N- (5- ((4- ((2- (alkyl substitution
Sulfonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino)-phenyl) allyl amide analogue and its preparation and application.
Background technique
EGFR (Epidermal Growth Factor Receptor) is transmembrane protein tyrosine kinases erbB receptor man
A member of race.By and its ligand-such as epidermal growth factor (EGF) combination, EGFR can form homologous on cell membrane
Dimer, or heterodimer is formed with receptors (such as erbB2, erbB3 or erbB4) other in family.These dimerization
The formation of body can cause the tyrosine residue phosphorylation that EGFR is intracellular crucial, thus in active cell multiple downstreams signal
Access.These intracellular signaling pathway play an important role in cell Proliferation, existence and anti-apoptotic.EGFR signal transduction pathway loses
It adjusts, the expression including ligand and receptor is increased, EGFR gene is expanded and is mutated etc., it can promote cell to vicious transformation, and
It plays an important role in the proliferation of tumour cell, invasion, transfer and vascularization.Therefore, EGFR is the conjunction of anticancer drug exploitation
Manage target spot.
First generation small molecule EGFR inhibitor, including Gefitinib (IressaTM) and Tarceva (ErlotinibTM), in lung
Preferable curative effect is shown in cancer treatment, is used to treat the non-small cell lung cancer with EGFR activated mutant as first-line drug
NSCLC (New England Journal of Medicine (2008) Vol.358,1160-74, Biochemical and
Biophysical Research Communications(2004)Vol.319,1-11)。
For wild type (WT) EGFR, activated mutant type EGFR (including 9 deletion mutation of L858R and exons 1
DelE746_A750) atriphos (ATP) affinity is declined, and the affinity of micromolecular inhibitor is increased, to lead
It causes tumour cell to increase the sensibility of first generation EGFR inhibitor such as Gefitinib or Tarceva, reaches targeted therapy
Purpose (the 304th phase of Science [2004], 1497-500；New England Journalof medicine [2004] the 350th
Phase, 2129-39).
However, almost all of NSCLC patient generates after first generation small molecule EGFR inhibitor treats the 10-12 month
To the drug resistance of this type small molecular inhibitor.Its resistance mechanism includes EGFR secondary mutation, bypass activation etc..Wherein half is suffered from
The drug resistance of person is the secondary mutation of gene residue T790M of being guarded the gate due to EGFR, thus reduce the affinity of drug and target spot and
It develops drug resistance, causes recurrence or the disease progression of tumour.
Drug resistant importance and generality, more medicament research and developments are generated in lung cancer EGFR targeted therapy in view of this mutation
Company (Pfizer, BI, AZ etc.) attempts to develop second generation small molecule EGFR inhibitor, is reached by inhibiting EGFR T790M mutant strain
To the such drug resistant patients with lung cancer for the treatment of, but end in failure because of poor selectivity.Even if afatinib is ratified to use by FDA
In the treatment of lung cancer, but it is only used for the first-line treatment with EGFR activated mutant patient；And suffer to being mutated with EGFR T790M
Person causes serious skin and gastrointestinal toxicity and limits since afatinib has stronger inhibiting effect to Wild type EGFR
Dosage has been made, has not shown therapeutic effect.
Therefore, it is necessary to third generation small molecule EGFR inhibitor is developed, the highly selective inhibition EGFR T790M mutant of energy,
And it is no or low active to Wild type EGFR.Since this is highly selective, can substantially reduce because Wild type EGFR inhibition is drawn
The damage of the skin and gastrointestinal tract that rise, to reach the treatment drug resistant tumour of EGFR T790M secondary mutation.In addition, retaining to EGFR
The inhibitory activity of activated mutant body (including L858R EGFR, 9 deletion mutation delE746_A750 of exons 1), it is also meaningful.
Due to inhibiting weaker to Wild type EGFR, third generation EGFR inhibitor has safety more better than first generation EGFR inhibitor,
Be expected to treat as First Line, treat with EGFR activated mutant NSCLC simultaneously, can also remove initial treatment patient may
Existing a small amount of EGFRT790T mutant strain, to delay drug resistant generation.
Lung cancer is to threaten the major disease of human health, and lung cancer death has accounted for the first place of all malignant tumours.In China, lung
Cancer morbidity rises year by year, annual new cases nearly 700,000.In America and Europe, accounted for the cases of lung cancer that EGFR activity is mutated all
NSCLC about 10%；And in China, this ratio is up to 30%.Therefore, for EGFR target spot, China has bigger market.
Summary of the invention
Inventor has found a kind of with formula (I) structure N- (5- ((4- ((2- (alkyl substituted sulphonyl) in the course of the research
Pyridin-3-yl) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue is with EGFR mutant is inhibited, especially
That L858R EGFR mutant, T790MEGFR and exons 19 lack the activity of activated mutant body, can be used to treat individually or
It is partly disease mediated by EGFR mutant activity, such as in prevention and treatment cancer especially non-small cell lung cancer drug
With extensive use.
One aspect of the present invention provides a kind of with such as following formula (I) compound N-(5- ((4- ((2- (alkyl substituted sulphonyl)
Pyridin-3-yl) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically
Acceptable salt:
Wherein,
X, Y is independently selected from CH or N, and X, Y be not identical；
R1Selected from C1-8Alkyl, C3-8Naphthenic base, optionally further by one or more selected from fluorine, chlorine, bromine, iodine, hydroxyl,
C1-8Alkyl, C1-8Alkoxy, halogen replace C1-8Alkoxy, C3-8Naphthenic base or C3-8Replaced the substituent group of cycloalkyloxy；
R2Selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-8Alkoxy, trifluoromethyl, trifluoromethoxy, SO2R5、
C(O)OR5、C(O)R6Or P (O) R7R8；
R3Selected from such as flowering structure:
R4Selected from C1-8Alkyl, C3-8Naphthenic base；
R5Selected from C1-8Alkyl, C3-8Naphthenic base, halogen replace C1-8Alkyl, phenyl or p-methylphenyl；
R6、R7、R8It is independently selected from C1-8Alkyl, C3-8Naphthenic base, halogen replace C1-8Alkyl, C1-8Alkoxy, amino or
Two C1-8Alkyl amino.
As scheme still more preferably, the N- (5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl)
Amino) pyrimidine -2-base) amino)-phenyl) allyl amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, R3Choosing
From:X、Y、R1、R2、R4、R5、R6、R7、R8As formula (I) compound defines.
As scheme still more preferably, the N- (5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl)
Amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts,
R1Selected from C1-4Alkyl, C3-6Naphthenic base is optionally further selected from fluorine, chlorine, bromine, iodine, hydroxyl, C by one or more1-8Alkyl,
C1-8Alkoxy, halogen replace C1-8Alkoxy, C3-8Naphthenic base or C3-8Replaced the substituent group of cycloalkyloxy；X,Y,R2、R3、R4、
R5、R6、R7、R8As formula (I) compound defines.
As scheme still more preferably, the N- (5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl)
Amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts,
R1Selected from C1-4Alkyl, C3-6Naphthenic base, optionally further by one or more substituent group institutes for being selected from fluorine, chlorine, bromine, iodine or hydroxyl
Replace；X,Y,R2、R3、R4、R5、R6、R7、R8As formula (I) compound defines.
As scheme still more preferably, the N- (5- ((4- ((2- (alkane substituted sulphonyl) pyridin-3-yl) ammonia
Base) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, R1
Selected from C1-4Alkyl, optionally further replaced one or more substituent groups selected from fluorine or hydroxyl；X,Y,R2、R3、R4、R5、
R6、R7、R8As formula (I) compound defines.
As scheme still more preferably, the N- (5- ((4- ((2- (alkane substituted sulphonyl) pyridin-3-yl) ammonia
Base) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, R1
Selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl；X,Y,R2、R3、R4、R5、R6、R7、R8Such as formula (I) compound institute
Definition.
As scheme still more preferably, N- (5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl) above-mentioned
Amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts,
R2Selected from hydrogen, fluorine, chlorine, cyano, C1-8Alkoxy, difluoromethyl, trifluoromethyl or trifluoromethoxy；R4Selected from isopropyl or cyclopropyl
Base；X,Y,R2、R3、R5、R6、R7、R8As formula (I) compound defines.
As most preferred scheme, (((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl) amino) is phonetic by 5- by the N-
Pyridine -2- base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, selected from as follows
Compound:
Another aspect of the present invention provides aforementioned N- (5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl) amino)
Pyrimidine -2-base) amino)-phenyl) and acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts preparation
Method includes the following steps:
Wherein, X1、X2Selected from fluorine, chlorine, bromine or iodine；X,Y,R1、R2、R3、R4、R5、R6、R7、R8As formula (I) compound is determined
Justice.
Further aspect of the present invention provides a kind of pharmaceutical composition comprising aforementioned N- (the 5- ((4- for the treatment of effective dose
((2- (alkyl substituted sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its
Stereoisomer or its pharmaceutically-acceptable salts and pharmaceutical carrier.
Further aspect of the present invention provides a kind of aforementioned N- (5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl) ammonia
Base) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, or
Foregoing pharmaceutical composition lacks L858R EGFR mutant, T790M EGFR mutant and exons 19 for treating in preparation
Application in the disease mediated therapeutic agent of activated mutant body activity.
As further preferred scheme, aforementioned N- (5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl) amino)
Pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts or aforementioned
Pharmaceutical composition is in preparation for treating individually or partly by answering in the disease mediated therapeutic agent of EGFR mutant activity
With.
As scheme still more preferably, aforementioned N- (5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl) ammonia
Base) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, or
Foregoing pharmaceutical composition is in preparation for the application in treating cancer drug.
As scheme still more preferably, the cancer is selected from oophoroma, cervical carcinoma, colorectal cancer, breast cancer, pancreas
Gland cancer, glioma, glioblastoma, melanoma, prostate cancer, leukaemia, lymthoma, non-Hodgkin lymphoma, gastric cancer,
Lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, denaturation
Large celllymphoma, acute myelocytic leukemia (AML), Huppert's disease, melanoma or celiothelioma；It preferably is selected from non-small thin
Born of the same parents' lung cancer.
Specific embodiment
It is described in detail: unless stated to the contrary, following that there is following contain with term in the specification and in the claims
Justice.
“C1-8Alkyl " refers to that straight chained alkyl and containg branched alkyl radical including 1 to 8 carbon atom, alkyl refer to the aliphatic hydrocarbon of saturation
Group, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- diformazan
Base propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl,
1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethyl butyrate
Base, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl,
N-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethyl amyl group, 2,4- dimethyl
Amyl, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2,3- dimethyl oneself
Base, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- dimethyl oneself
Base, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl or it is each
Kind branched isomer etc..
" naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, " C3-8Naphthenic base " refer to including 3 to
The naphthenic base of 8 carbon atoms, such as:
The non-limiting embodiment of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, ring
Hexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc..
Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring." spiro cycloalkyl group ", which refers to, shares a carbon between monocycle
The polycyclic moiety of atom (claiming spiro-atom), these can be containing one or more double bonds, but none ring has total conjugated
Pi-electron system.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spiro cycloalkyl groups according to the number for sharing spiro-atom between ring and ring
Base or more spiro cycloalkyl groups, the non-limiting embodiment of spiro cycloalkyl group includes:
" cycloalkyl " refers to the full carbon of each ring in system and shared a pair of of the carbon atom adjoined of other rings in system
Polycyclic moiety, wherein one or more rings can be containing one or more double bonds, but none ring has the π electricity of total conjugated
Subsystem.Bicyclic, tricyclic, Fourth Ring or polycyclic fused ring alkyl can be divided into according to a group cyclic number, cycloalkyl it is unrestricted
Property embodiment includes:
" bridge ring alkyl " refers to that any two ring shares the full carbon polycyclic moiety of two carbon atoms being not directly connected, these can
To contain one or more double bonds, but none ring has the pi-electron system of total conjugated.It can be with according to group cyclic number
It is divided into bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl, the non-limiting embodiment of bridge ring alkyl includes:
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure
Ring together is naphthenic base, and non-limiting embodiment includes indanyl, tetralyl, benzocyclohepta alkyl etc..
" alkoxy " refers to-O- (alkyl), and wherein alkyl is as defined above."C1-8Alkoxy " refers to the alkane containing 1-8 carbon
Base oxygroup, non-limiting embodiment include methoxyl group, ethyoxyl, propoxyl group, butoxy etc..
" cycloalkyloxy " refers to and-O- (unsubstituted naphthenic base), and wherein naphthenic base is as defined above."C3-8Cycloalkanes oxygen
Base " refers to the cycloalkyl oxy containing 3-8 carbon, and non-limiting embodiment includes cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, hexamethylene
Oxygroup etc..
" the C that halogen replaces1-8Alkyl " refers to the optional 1-8 carbon alkyl replaced by fluorine, chlorine, bromine, iodine atom of the hydrogen on alkyl
Group, such as difluoromethyl, dichloromethyl, two bromomethyls, trifluoromethyl, trichloromethyl, trisbromomethyl etc..
“C(O)R6" refer to R5Substituted carbonyl.
“P(O)R7R8" refer to R7、R8Substituted phosphoryl, R7、R8Optionally identical or different substituent group.
" two C1-8Alkyl amino " refers to two C1-8Alkyl-substituted amino group.
" THF " refers to tetrahydrofuran.
" DCM " refers to methylene chloride.
" DMF " refers to N, dinethylformamide.
" DIPEA " refers to diisopropylethylamine.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes
The event or environment generation or not spot occasion.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group "
But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to that one or more hydrogen atoms in group are replaced by the substituent group of respective number independently of one another.No
Speech and explain, substituent group is only in their possible chemistry position, and those skilled in the art can excessively make great efforts not paying
In the case of determine (pass through experiment or theoretical) may or impossible substitution.For example, amino or hydroxyl and tool with free hydrogen
Having the carbon atom of unsaturated (such as olefinic) key may be unstable when combining.
" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically/pharmaceutical salt or
The mixture and other components such as physiology/pharmaceutical carrier and excipient of pro-drug and other chemical constituents.Medicine
The purpose of compositions is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
Below with reference to embodiment, the present invention is described in further detail and completely, but the limitation present invention by no means, the present invention
Also it is not intended to be limited to the content of embodiment.
The compound of the present invention structure is determined by nuclear magnetic resonance (NMR) or/and LC-MS chromatography (LC-MS)
's.Nmr chemical displacement (δ) is provided with the unit of hundred a ten thousandths (ppm).The measurement of NMR is with Bruker AVANCE-400 core
Magnetic instrument, measurement solvent are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3) and deuterated chloroform (CDCl OD3) in be designated as
Tetramethylsilane (TMS).
The measurement of LC-MS chromatography LC-MS Agilent 1200Infinity Series mass spectrograph.The measurement of HPLC
Use Agilent 1200DAD high pressure liquid chromatograph (Sunfire 150 × 4.6mm of C18 chromatographic column) and Waters 2695-
2996 high pressure liquid chromatographs (Gimini 150 × 4.6mm of C18 chromatographic column).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that TLC is used is
0.15mm~0.20mm, the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.Column chromatography generally uses cigarette
200~300 mesh silica gel of platform Huanghai Sea silica gel is carrier.
Starting material in the embodiment of the present invention is known and can be commercially available, or can use or press
It is synthesized according to methods known in the art.
In the case where no specified otherwise, all reactions of the invention are under continuous magnetic agitation, in drying nitrogen
Or carried out under argon atmospher, solvent is dry solvent.
The preparation of intermediate
1, the preparation of the fluoro- 2- methoxyl group -5- nitroaniline of intermediate 1:4-
The fluoro- 2- methoxy nitrobenzene (10g, 58.44mmol) of 4- is dissolved in methanol, and 1g palladium/carbon is added, and hydrogen is replaced,
It is reacted three days under hydrogen environment.Filtering collects filtrate, methanol is evaporated off, obtains oily crude product.It is added in this crude product at 0 DEG C dense
Sulfuric acid dissolves solid in mixed liquor all, potassium nitrate (5.91g) is added in batches.Reaction solution is to slowly warm up to room temperature, stirring
Overnight.This reaction solution pours into ice water, and NaHCO is added3, adjust pH 6.0-8.0.Three times, collection has methylene chloride aqueous phase extracted
Machine phase, it is dry.Organic solvent is evaporated off, residue obtains the fluoro- 2- methoxyl group -5- nitroaniline of 4- through column chromatographic isolation and purification
(4.0g)。
2, the preparation of the fluoro- 2- isopropoxy -5- nitroaniline of intermediate 2:4-
Preparation of the preparation method of the fluoro- 2- isopropoxy -5- nitroaniline of 4- with intermediate 1.
3, the preparation of the fluoro- 2- ethyoxyl -5- nitroaniline of intermediate 3:4-
Preparation of the preparation method of the fluoro- 2- ethyoxyl -5- nitroaniline of 4- with intermediate 1.
4, the preparation of intermediate 4:2- (difluoro-methoxy) -4- fluoronitrobenzene
By the fluoro- 2- nitrophenol (3.0g, 19.1mmol) of 5-, potassium carbonate (5.28g, 38.2mmol) is dissolved in DMF, is added
One chlorine, two sodium fluoroethanoate (4.37g, 28.6mmol), reaction are heated to 100 DEG C under nitrogen protection, stir 16 hours, will react
H2O (50mL) and methyl tertiary butyl ether(MTBE) (50mL) is added in liquid concentration, residue, extracts liquid separation, and organic phase is washed three times afterwards through sulphur
Sour magnesium dries, filters rear filtrate concentration, and residue obtains 2- (difluoro-methoxy) -4- fluorine nitre by Flash silica column chromatographic purifying
Base benzene (3.0g, 75%).
5, the preparation of the fluoro- 5- nitroaniline of intermediate 5:2- (difluoro-methoxy) -4-
2- (difluoro-methoxy) -4- fluoronitrobenzene (3.0g, 14.5mmol) is dissolved in methanol (30mL), Pd/C is added
(500mg) reacts 2 hours, contact plate fully reacting at room temperature in nitrogen atmosphere, and reaction solution is filtered by diatomite, and filtrate is concentrated to give
To crude product (1.7g, 66%).This crude product is carefully dissolved in the concentrated sulfuric acid (5mL) under ice bath, is stirred to clarify under ice bath
Afterwards, it is slowly added in batches potassium nitrate (1.1g, 9.5mmol), reaction continues stirring 3 hours under ice bath, and LCMS display has been reacted
Entirely, reaction solution is slowly quenched in saturated aqueous sodium carbonate (100mL).After being quenched completely, water phase methyl tertiary butyl ether(MTBE)
(3X20mL) extraction is filtered after organic phase magnesium sulfate drying, and filtrate concentration, residue obtains 2- by Flash silica column purification
The fluoro- 5- nitroaniline (2.0g 90%) of (difluoro-methoxy) -4-.
6, the preparation of fluoro- 1- nitro -2- (trifluoromethoxy) benzene of intermediate 6:4-
The fluoro- trifluomethoxybenzene of 3- (20g) is dissolved in 40 milliliters of concentrated sulfuric acids under ice water is cooling, is quickly added portionwise under stirring
Potassium nitrate (28g) is stirred 3 hours at 0 DEG C, is stirred overnight at room temperature, and reaction solution carefully please to entering on 1 kilogram of trash ice, stirs
It 30 minutes, is extracted with ethyl acetate, sodium sulphate dries, filters, and steams filtrate, and residue column chromatographic purifying obtains 12 grams of light yellow liquids
Body.
7, the preparation of the fluoro- 2- of intermediate 7:4- (trifluoromethoxy) aniline
Previous step is prepared into fluoro- 1- nitro -2- (trifluoromethoxy) the benzene crude product (12g) of 6 4- of intermediate and is dissolved in 100 milliliters
Dehydrated alcohol, the cooling lower addition two hydrated stannous chlorides (25g) of ice water, reaction solution are stirred overnight at room temperature.1N sodium hydroxide is added
Aqueous solution adjusts pH value to 12 or so, and filtering, filtrate is extracted with ethyl acetate, and extract liquor is dried over sodium sulfate, and filtering steams molten
Agent, residue obtain pale yellow oily liquid 4- fluoro- 2- (trifluoromethoxy) aniline (4.78g) through column chromatographic purifying.
1H NMR(400MHz,CDCl3) δ 6.94 (d, J=8.8Hz, 1H), 6.83 (m, 1H), 6.76 (dd, J=5.4,
8.8Hz,1H),3.87-3.59(2H)。
8, the preparation of fluoro- 5- nitro -2- (trifluoromethoxy) aniline of intermediate 8:4-
4- fluoro- 2- (trifluoromethoxy) aniline (2.5g) is dissolved in the cooling concentrated sulfuric acid (10ml) of ice water, nitric acid is added
Potassium (3g) is stirred at room temperature 3 hours, and reaction solution adds 3N sodium hydrate aqueous solution to adjust pH value to 10 or so, second please to entering in ice water
Acetoacetic ester extraction, steams solvent, residue obtains the fluoro- 5- nitro -2- of 4- through column chromatographic purifying after being dried, filtered with anhydrous sodium sulfate
(trifluoromethoxy) aniline (1.79g).
9, intermediate 9: the preparation of cyclopropyl sulfinic acid sodium
By sodium sulfite (1.32g, 1.1mmol), sodium bicarbonate (1.6g, 20.0mmol) is dissolved in pure water (15mL), reaction
It stirs after ten minutes, is slowly added dropwise cyclopropyl sulfonic acid chloride (1.4g, 10.0mmol) at 55 DEG C, react after 60 DEG C are stirred 3 hours,
Water is directly concentrated and is done, cyclopropyl sulfinic acid sodium (4g) is obtained.
The preparation of embodiment compound
Embodiment 1:N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino)-
2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- anisyl) acryloyl group amide preparation
Step 1: the preparation of 2- isopropyl sulfydryl -3- nitropyridine
By the fluoro- 3- nitropyridine (500mg, 3.52mmol) of 2-, potassium carbonate (973mg, 7.04mmol) is placed in 100mL round bottom
In bottle, 15ml DMF is added, isopropyl mercaptan (0.36mL, 3.87mmol) is added under stiring, mixture is reacted 1 at room temperature
Hour, end of reaction back spin dereaction solvent, through washing, ethyl acetate extraction is concentrated, then column chromatographs gained crude product after dry
Product 2- isopropyl sulfydryl -3- nitropyridine (660mg, yield 95%).
LC-MS:t=4.31min, 198.9 (M+H+)；
1H NMR(400MHz,CDCl3) δ 8.61 (dd, J=4.8,1.6Hz, 1H), 8.40 (dd, J=8.4,1.6Hz,
1H), 7.10 (dd, J=8.4,4.8Hz, 1H), 4.13-4.06 (m, 1H), 1.35 (d, J=6.8Hz, 6H).
Step 2: the preparation of 2- isopropyl sulfuryl -3- nitropyridine
By 2- isopropyl sulfydryl -3- nitropyridine (660mg, 3.33mmol) and metachloroperbenzoic acid (mCPBA)
(85%, 2.2g, 9.99mmol) is placed in 100mL round-bottomed bottle, and 15ml methylene chloride is added, mixture was stirred at room temperature
Night, end of reaction back spin dereaction solvent, gained crude product successively use saturated sodium bisulfite solution, unsaturated carbonate potassium solution, saturation
Salt washing, methylene chloride extraction is dry, is spin-dried for, then chromatograph to obtain product 2- isopropyl sulfuryl -3- nitropyridine through column
(700mg, yield 91%).
LC-MS:t=3.39min, 230.2 (M+H+)；
1H NMR(400MHz,CDCl3) δ 8.84 (dd, J=4.4,1.6Hz, 1H), 8.06 (dd, J=8.4,1.6Hz,
1H), 7.68 (dd, J=8.0,4.4Hz, 1H), 4.03-3.96 (m, 1H), 1.36 (d, J=6.8Hz, 6H).
Step 3: the preparation of 2- isopropyl sulfuryl -3- aminopyridine
2- isopropyl sulfuryl -3- nitropyridine (700mg, 2.18mmol) is placed in 100mL hydrogenation bottle, 15ml first is added
100mg palladium/charcoal (10%) is added in bottle after nitrogen displacement, is stirred overnight after being replaced with hydrogen balloon by alcohol, after completion of the reaction will
Solution filtering, filtrate decompression are spin-dried for up to product (600mg, yield 90%).LC-MS:t=2.85min, 201.0 (M+H+)。
Step 4: the preparation of the chloro- N- of 2,5- bis- (2- (isopropyl sulphonyl) pyridin-3-yl) pyrimidine -4- amine
2- isopropyl sulfuryl -3- aminopyridine (200mg, 1.0mmol) is dissolved in DMF (6mL), is slowly added at 0 DEG C
Enter NaH (44mg, 1.1mmol), add the continuation of rear reaction solution and stirred half an hour at 0 DEG C, then by 2,5,6- trichloropyrimidine
(201mg, 1.1mmol) instills reaction solution at 0 DEG C, and drop finishes, and mixture is warmed to room temperature naturally and is stirred overnight.After be added
200mL water is simultaneously extracted with ethyl acetate (30mL*3), merges drying after organic phase, revolves dereaction solvent, gained crude product is through column layer
Analyse to obtain product (90mg, yield 26%).
LC-MS:t=3.95min, 346.9 (M+H+)；
1H NMR(400MHz,CDCl3) δ 10.48 (s, 1H), 9.17 (dd, J=8.4,1.6Hz, 1H), 8.38 (dd, J=
4.4,2.8Hz, 1H), 8.26 (s, 1H), 7.55 (dd, J=8.8,3.2Hz, 1H), 3.90-3.87 (m, 1H), 1.31 (d, J=
6.8Hz,6H)。
Step 5: the chloro- N of 5-2(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N4(2- (isopropyl sulphonyl) pyridin-3-yl)
The preparation of pyrimidine -2,4- diamines
By the preparation (130mg, 0.37mmol) of the chloro- N- of 2,5- bis- (2- (isopropyl sulphonyl) pyridin-3-yl) pyrimidine -4- amine
It is dissolved in 2- amylalcohol (10mL) with the fluoro- 2- methoxyl group -5- nitroaniline (70mg, 0.37mmol) of 4-, p-methyl benzenesulfonic acid is added
(129mg, 0.75mmol) is heated to 120 DEG C of reactions overnight.It is cooled to room temperature, solvent, residue methylene chloride is evaporated off
(30mL) dissolution, organic phase is washed twice, dry.Organic phase solvent is evaporated off and obtains the chloro- N of crude product 5-2(the fluoro- 2- methoxyl group-of 4-
5- nitrobenzophenone)-N4(2- (isopropyl sulphonyl) pyridin-3-yl) pyrimidine -2,4- diamines (100mg) is directly thrown without further purification
Enter and uses in next step.
LC-MS:tR=3.01min, 497.0 ([M+H]+)。
Step 6: the chloro- N of 5-2(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzene
Base)-N4The preparation of (2- (isopropyl sulphonyl) pyridin-3-yl) pyrimidine -2,4- diamines
By the chloro- N of 5-2(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N4(2- (isopropyl sulphonyl) pyridin-3-yl) pyrimidine-
2,4- diamines (100mg, 0.2mmol) are dissolved in 5ml n,N-dimethylacetamide, are added trimethyl ethylenediamine (204mg), micro-
Wave reacts 1 hour.It is cooled to room temperature.Solvent is evaporated off, residue obtains the chloro- N of 5- through silica gel column chromatography separating purification2-(4-((2-
(dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N4(2- (isopropyl sulphonyl) pyridin-3-yl)
Pyrimidine -2,4- diamines (70mg).LC-MS:tR=2.30min, 579.1 ([M+H]+)。
Step 7: N4(the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base)-N1(2- (two
Methylamino) ethyl) -5- methoxyl group-N1Methylbenzene -1,2,4- triamine
By the chloro- N of 5-2(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N4-
(2- (isopropyl sulphonyl) pyridin-3-yl) pyrimidine -2,4- diamines (70mg) is dissolved in 6mL ethanol-water mixed solvent (5:1), adds
Enter 65mg iron powder, 50mg ammonium chloride is heated to back flow reaction 2 hours.It is cooled to room temperature, filters, collect filtrate.It is evaporated off in filtrate
Ethyl alcohol, 5ml water and 5ml methylene chloride-methanol (20:1) is added.Organic phase is separated, it is dry.Organic solvent, residue is evaporated off
It is prepared thin-layer chromatography and separates to obtain N4(the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base)-N1-
(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methylbenzene -1,2,4- triamine (40mg).LC-MS:tR=2.08min, 549.3
([M+H]+)。
Step 8: N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino)-
2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- anisyl) acryloyl group amide preparation
By N4(the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base)-N1(2- (diformazan ammonia
Base) ethyl) -5- methoxyl group-N1Methylbenzene -1,2,4- triamine (40mg) are dissolved in 3ml anhydrous tetrahydro furan, and nitrogen displacement is protected
It protects, DIPEA (0.1mL) is added at 0 DEG C, be added dropwise 1M acryloyl chloride tetrahydrofuran solution (0.3mL).It is stirred 1 hour at 0 DEG C.Instead
It answers and 5ml water and 5ml methylene chloride is added in liquid, separate water phase and organic phase, water phase is again respectively with 3ml methylene chloride extraction three
It is secondary, merge organic phase, it is dry, solvent is evaporated off, residue is prepared thin-layer chromatography and separates to obtain crude product, and crude product uses reversed-phase column again
Chromatographic purifying (water: methanol=25:75) obtains N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine-
2- yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- anisyl) acryloyl group amide (6mg).
LC-MS:tR=2.19min, 603.3 ([M+H]+)；
1H NMR(400MHz,CDCl3) δ 10.01 (s, 2H), 9.14 (m, 2H), 8.28 (d, 1H), 8.22 (s, 1H), 7.34
(m, 2H), 6.79 (s, 1H), 6.30 (m, 2H), 5.68 (d, 1H), 3.88 (s, 3H), 3.80 (m, 1H), 2.93 (br, 2H),
2.73 (s, 3H), 2.36 (m, 8H), 1.43 (d, 6H).
Embodiment 2:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyrrole
Pyridine -3- base) amino) pyrimidine -2-base) amino) -4- anisyl) and acryloyl group amide preparation
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl)
Amino) pyrimidine -2-base) amino) -4- anisyl) acryloyl group amide the four~eight step that the preparation method is the same as that of Example 1.
LC-MS:tR=2.02min, 569.3 ([M+H]+)；
1H NMR(400MHz,CDCl3) δ 9.81 (s, 2H), 9.01 (m, 2H), 8.57 (d, 1H), 8.02 (s, 1H), 7.24-
7.35 (m, 3H), 6.79 (s, 1H), 6.10 (m, 2H), 5.48 (d, 1H), 3.88 (s, 3H), 3.80 (m, 1H), 2.93 (br,
2H), 2.73 (s, 3H), 2.36 (m, 8H), 1.43 (d, 6H).
Embodiment 3:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphur
Acyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -4- anisyl) acryloyl group amide preparation
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphonyl) pyridine -
3- yl) amino) pyrimidine -2-base) amino) -4- anisyl) the preparation method is the same as that of Example 1 the 4th for acryloyl group amide~
Eight steps, m/z 587.1.
Embodiment 4:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyrrole
Pyridine -3- base) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -4- anisyl) and acryloyl group amide preparation
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl)
Amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -4- anisyl) the preparation method is the same as that of Example 1 for acryloyl group amide
The four~eight step, m/z 636.7.
Embodiment 5:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyrrole
Pyridine -3- base) amino) -5- (trifluoromethoxy) pyrimidine -2-base) amino) -4- anisyl) and acryloyl group amide preparation
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl)
Amino) -5- (trifluoromethoxy) pyrimidine -2-base) amino) -4- anisyl) acryloyl group amide the same embodiment of preparation method
1 the four~eight step, m/z 653.1.
(((((2- is (different by 4- by -4- isopropoxy -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by embodiment 6:N-
Sulfonyl propyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) phenyl) acryloyl group amide preparation
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- isopropoxy -5- ((4- ((2- (isopropyl sulphonyl)
Pyridin-3-yl) amino) pyrimidine -2-base) amino) phenyl) the preparation method is the same as that of Example 1 the four~eight for acryloyl group amide
Step, m/z 597.3.
Embodiment 7:N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino)-
2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- isopropyl phenyl) acryloyl group amide preparation
N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -2- ((2-
(dimethylamino) ethyl) (methyl) amino) -4- isopropyl phenyl) the preparation method is the same as that of Example 1 for acryloyl group amide
Four~eight steps, m/z 632.2.
Embodiment 8:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphur
Acyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -4- isopropyl phenyl) acryloyl group amide preparation
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphonyl) pyridine -
3- yl) amino) pyrimidine -2-base) amino) -4- isopropyl phenyl) the preparation method is the same as that of Example 1 for acryloyl group amide
Four~eight steps, m/z 615.2.
Embodiment 9:N- (5- ((5- cyano -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- isopropyl phenyl) acryloyl group amide preparation
N- (5- ((5- cyano -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -2- ((2-
(dimethylamino) ethyl) (methyl) amino) -4- isopropyl phenyl) the preparation method is the same as that of Example 1 for acryloyl group amide
Four~eight steps, m/z 622.3.
(((((2- is (different by 4- by -4- isopropoxy -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by embodiment 10:N-
Sulfonyl propyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) acryloyl group amide preparation
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- isopropoxy -5- ((4- ((2- (isopropyl sulphonyl)
Pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) and acryloyl group amide preparation method with implement
Four~eight step of example 1, m/z 665.1.
Embodiment 11:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethyoxyl -5- ((fluoro- 4- ((2- of 5-
(isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) phenyl) and acryloyl group amide preparation
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethyoxyl -5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphur
Acyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) phenyl) the preparation method is the same as that of Example 1 the 4th for acryloyl group amide~
Eight steps, m/z 601.3.
Embodiment 12:N- (5- ((5- (t-butoxy) -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -
2- yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethoxyphenyl) and acryloyl group amide preparation
N- (5- ((5- (t-butoxy) -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethoxyphenyl) acryloyl group amide preparation side
Four~eight step of the method with embodiment 1, m/z 655.3.
Embodiment 13:N- (4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4-
((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) phenyl) and acryloyl group amide preparation
N- (4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl
Sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) phenyl) the preparation method is the same as that of Example 1 the 4th for acryloyl group amide
~eight steps, m/z 605.2.
Embodiment 14:N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acryloyl group amide preparation
N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -4- (difluoro
Methoxyl group) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) the preparation method is the same as that of Example 1 for acryloyl group amide
The four~eight step, m/z 639.6.
(((5- is fluoro- by -5- by 4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) by embodiment 15:N-
4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) phenyl) and acryloyl group amide preparation
(((((2- is (different by the fluoro- 4- of 5- by -5- by 4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) by N-
Sulfonyl propyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) phenyl) the preparation method is the same as that of Example 1 for acryloyl group amide
Four~eight step, m/z 622.7.
Embodiment 16:N- (4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4-
((2- (isopropyl sulphonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) acryloyl group amide
Preparation
N- (4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl
Sulphonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) acryloyl group amide preparation method it is same
Four~eight step of embodiment 1, m/z 673.1.
Embodiment 17:N- (5- ((5- cyano -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acryloyl group amide preparation
N- (5- ((5- cyano -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -4- (two
Fluorine methoxyl group) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acryloyl group amide the same embodiment of preparation method
1 the four~eight step, m/z 629.8.
(((5- is different by -5- by 4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) by embodiment 18:N-
Propoxyl group -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) phenyl) and acryloyl group amide system
It is standby
N- (4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((5- isopropoxy -4-
((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) phenyl) and acryloyl group amide preparation method with real
Apply the four~eight step of example 1, m/z 663.2.
Embodiment 19:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyrrole
Pyridine -3- base) amino) pyrimidine -2-base) amino) -4- (trifluoromethoxy) phenyl) and acryloyl group amide preparation
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl)
Amino) pyrimidine -2-base) amino) -4- (trifluoromethoxy) phenyl) the preparation method is the same as that of Example 1 the 4th for acryloyl group amide
~eight steps, m/z 622.7.
Embodiment 20:N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- (trifluoromethoxy) phenyl) acryloyl group amide preparation
N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -2- ((2-
(dimethylamino) ethyl) (methyl) amino) -4- (trifluoromethoxy) phenyl) the preparation method is the same as that of Example 1 for acryloyl group amide
The four~eight step, m/z 657.1.
Embodiment 21:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphur
Acyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -4- (trifluoromethoxy) phenyl) acryloyl group amide preparation
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphonyl) pyridine -
3- yl) amino) pyrimidine -2-base) amino) -4- (trifluoromethoxy) phenyl) the preparation method is the same as that of Example 1 for acryloyl group amide
The four~eight step, m/z 640.7.
Embodiment 22:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyrrole
Pyridine -3- base) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -4- (trifluoromethoxy) phenyl) and acryloyl group amide system
It is standby
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl)
Amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -4- (trifluoromethoxy) phenyl) acryloyl group amide preparation method it is same
Four~eight step of embodiment 1, m/z 690.7.
Embodiment 23:N- (5- ((5- (difluoromethyl) -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-
Base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- (trifluoromethoxy) phenyl) and acryloyl group amide system
It is standby
N- (5- ((5- (difluoromethyl) -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -
2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- (trifluoromethoxy) phenyl) acryloyl group amide preparation method it is same
Four~eight step of embodiment 1, m/z 672.7.
Embodiment 24:N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyrrole
Pyridine -3- base) amino) -5- (trifluoromethoxy) pyrimidine -2-base) amino) -4- (trifluoromethoxy) phenyl) acryloyl group amide
Preparation
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl)
Amino) -5- (trifluoromethoxy) pyrimidine -2-base) amino) -4- (trifluoromethoxy) phenyl) acryloyl group amide preparation method
With the four~eight step of embodiment 1, m/z 706.7.
Embodiment 25:N- (4- isopropoxy -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-
Base) amino) -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation
Step 1: N2(2- isopropoxy -4- (4- methylpiperazine-1-yl) -5- nitrobenzophenone)-N4(2- (isopropyl sulphur
Acyl) pyridin-3-yl) pyrimidine -2,4- diamines preparation
By N2(the fluoro- 2- isopropoxy -5- nitrobenzophenone of 4-)-N4(2- (isopropyl sulphonyl) pyridin-3-yl) pyrimidine -2,
4- diamines (98mg, 0.2mmol) is dissolved in 5ml n,N-dimethylacetamide, is added 1- methyl piperazine (20mg, 0.2mmol),
Microwave reaction 1 hour.It is cooled to room temperature.Solvent is evaporated off, residue obtains N through silica gel column chromatography separating purification2(2- isopropoxy-
4- (4- methylpiperazine-1-yl) -5- nitrobenzophenone)-N4(2- (isopropyl sulphonyl) pyridin-3-yl) pyrimidine -2,4- diamines
(72mg), m/z 570.7.
Step 2: N2(5- amino -2- isopropoxy -4- (4- methylpiperazine-1-yl) phenyl)-N4(2- (isopropyl sulphur
Acyl) pyridin-3-yl) pyrimidine -2,4- diamines preparation
By N2(2- isopropoxy -4- (4- methylpiperazine-1-yl) -5- nitrobenzophenone)-N4(2- (isopropyl sulphonyl) pyrrole
Pyridine -3- base) pyrimidine -2,4- diamines (72mg, 0.13mmol) is dissolved in 6mL ethanol-water mixed solvent (5:1), 70mg iron is added
Powder, 50mg ammonium chloride are heated to back flow reaction 2 hours.It is cooled to room temperature, filters, collect filtrate.The ethyl alcohol in filtrate is evaporated off,
5ml water and 5ml methylene chloride-methanol (20:1) is added.Organic phase is separated, it is dry.Organic solvent is evaporated off, residue is thin through preparing
Layer chromatography obtains N2(5- amino -2- isopropoxy -4- (4- methylpiperazine-1-yl) phenyl)-N4(2- (isopropyl sulphonyl)
Pyridin-3-yl) pyrimidine -2,4- diamines (41mg), m/z 540.7.
Step 3: N- (4- isopropoxy -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base)
Amino) -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation
By N2(5- amino -2- isopropoxy -4- (4- methylpiperazine-1-yl) phenyl)-N4(2- (isopropyl sulphonyl) pyrrole
Pyridine -3- base) pyrimidine -2,4- diamines (41mg, 0.076mmol) is dissolved in 3ml anhydrous tetrahydro furan, nitrogen displacement protection, at 0 DEG C
It is added DIPEA (0.1mL), is added dropwise 1M acryloyl chloride tetrahydrofuran solution (0.3mL).It is stirred 1 hour at 0 DEG C.Add in reaction solution
Enter 5ml water and 5ml methylene chloride, separate water phase and organic phase, water phase is extracted three times respectively with 3ml methylene chloride again, is associated with
Machine phase, it is dry, solvent is evaporated off, residue is prepared thin-layer chromatography and separates to obtain crude product, and crude product is purified with reversed phase column chromatography again
(water: methanol=25:75) obtains N- (4- isopropoxy -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-
Base) amino) -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide (8mg), m/z 594.7.
Embodiment 26:N- (5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -4- isopropoxy -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation
N- (5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -4- isopropyl oxygen
Base -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z 612.7.
Embodiment 27:N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -4- isopropoxy -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation
N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -4- isopropyl oxygen
Base -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z 628.7.
Embodiment 28:N- (4- isopropoxy -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) -5- (trifluoro
Methyl) pyrimidine -2-base) amino) -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation
N- (4- isopropoxy -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidine -
2- yl) amino) -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation method it is similar with embodiment 25, m/z
663.1。
Embodiment 29:N- (5- ((5- cyano -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -4- methoxyl group -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation
N- (5- ((5- cyano -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -4- methoxy
Base -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z 592.2.
Embodiment 30:N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -4- methoxyl group -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation
N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -4- methoxy
Base -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z 601.6.
Embodiment 31:N- (5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidine -2-
Base) amino) -4- methoxyl group -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation
N- (5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -
4- methoxyl group -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z
634.7。
Embodiment 32:N- (4- ethyoxyl -5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -
2- yl) amino) -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation
N- (4- ethyoxyl -5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z 598.7.
(((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) -5- methoxyl group is phonetic by 4- ethyoxyl -5- by embodiment 33:N-
Pyridine -2- base) amino) -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation
N- (4- ethyoxyl -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) -5- methoxy pyrimidine -2- base)
Amino) -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z 610.7.
Embodiment 34:N- (4- (difluoro-methoxy) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -
2- yl) amino) -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation
N- (4- (difluoro-methoxy) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z 602.7.
Embodiment 35:N- (4- (difluoro-methoxy) -5- ((fluoro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino)
Pyrimidine -2-base) amino) -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation
N- (4- (difluoro-methoxy) -5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-
Base) amino) -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation method it is similar with embodiment 25, m/z
620.7。
Embodiment 36:N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -4- (difluoro-methoxy) -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation
N- (5- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -4- (difluoro
Methoxyl group) -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z
637.6。
Embodiment 37:N- (5- ((5- cyano -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -4- (difluoro-methoxy) -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation
N- (5- ((5- cyano -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -4- (two
Fluorine methoxyl group) -2- (4- methylpiperazine-1-yl) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z
627.8。
Embodiment 38:N- (4- (difluoro-methoxy) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) -5- first
Oxygroup pyrimidine -2-base) amino) -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation
N- (4- (difluoro-methoxy) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) -5- methoxy pyrimidine -
2- yl) amino) -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation method it is similar with embodiment 25, m/z
632.8。
Embodiment 39:N- (4- (difluoro-methoxy) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) -5-
(trifluoromethyl) pyrimidine -2-base) amino) -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation
N- (4- (difluoro-methoxy) -5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) -5- (trifluoromethyl)
Pyrimidine -2-base) amino) -2- (4- methylpiperazine-1-yl) phenyl) and acryloyl group amide preparation method it is similar with embodiment 25,
m/z 670.8。
Embodiment 40:N- (5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -2-
(4- methylpiperazine-1-yl) -4- (trifluoromethoxy) phenyl) acryloyl group amide preparation
N- (5- ((4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -2- (4- methyl piperazine
Piperazine -1- base) -4- (trifluoromethoxy) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z 621.2.
Embodiment 41:N- (5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -2- (4- methylpiperazine-1-yl) -4- (trifluoromethoxy) phenyl) acryloyl group amide preparation
N- (5- ((the fluoro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -2- (4- first
Base piperazine -1- base) -4- (trifluoromethoxy) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z
638.6。
Embodiment 42:N- (5- ((5- cyano -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) ammonia
Base) -2- (4- methylpiperazine-1-yl) -4- (trifluoromethoxy) phenyl) acryloyl group amide preparation
N- (5- ((5- cyano -4- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -2- (4-
Methylpiperazine-1-yl) -4- (trifluoromethoxy) phenyl) acryloyl group amide preparation method it is similar with embodiment 25, m/z
645.7。
Embodiment 43:N- (5- ((4- ((3- (cyclopropyl sulfonyl) pyridine -2- base) amino) pyrimidine -2-base) amino) -2-
((2- (dimethylamino) ethyl) (methyl) amino) -4- anisyl) acryloyl group amide preparation
Step 1: the preparation of N- (3- bromopyridine -2- base) -2- chlorine pyrimidine -4- amine
3- bromopyridine -2- amine (680mg, 4.0mmol) is dissolved in anhydrous DMF (5mL), NaH is added portionwise under ice bath
After twenty minutes, the DMF of 2,4- dichloro pyrimidine (650mg, 4.4mmol) is added in gained suspension by (320mg, 8.0mmol), stirring
In (5mL), reaction is stirred 2 hours under ice bath, and LCMS shows fully reacting.Reaction solution saturation NH4Cl (3mL) is quenched, dense
After contracting is dry, with methylene chloride (20mL), water (20mL), organic phase dry filter is concentrated, and residue is obtained by rapid column chromatography
N- (3- bromopyridine -2- base) -2- chlorine pyrimidine -4- amine (850mg, yield 75%).
Step 2: N- (3- bromopyridine -2- base)-N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) pyrimidine -2,4- diamines
Preparation
By N- (3- bromopyridine -2- base) -2- chlorine pyrimidine -4- amine (850mg, 3.0mmol), the fluoro- 2- methoxyl group -5- nitro of 4-
Aniline (560mg, 3.0mmol), a water p-methyl benzenesulfonic acid (680mg, 3.6mmol) are dissolved in 1,4- dioxane (15mL).Reaction
120 DEG C are heated to, is stirred 16 hours, LCMS shows fully reacting, reaction solution concentration, and water (10mL) is added in residue, methanol
(5mL), mixture stir after ten minutes, and filtering, filter cake obtains N- (3- bromopyridine -2- base)-N- after being washed with methyl tertiary butyl ether(MTBE)
(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) pyrimidine -2,4- diamines (800mg, yield 60%).
Step 3: N- (3- bromopyridine -2- base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxy
Base -5- nitrobenzophenone) pyrimidine -2,4- diamines preparation
By N- (3- bromopyridine -2- base)-N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) pyrimidine -2,4- diamines (800mg,
1.84mmol), triethylamine (1mL), N, N, N- trimethyl ethylenediamine (280mg, 2.76mmol) are dissolved in DMF (10mL), reaction
It is heated to 110 DEG C to stir 2 hours, LCMS display reaction, reaction concentration is dry, residue methylene chloride (20mL), water (20mL)
Layering, insoluble matter is filtered, and organic phase dries, filters, and concentration, residue obtains N- (3- bromopyridine -2- by rapid column chromatography
Base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone) pyrimidine -2,4- diamines
(300mg, yield 32%).
Step 4: N- (3- (cyclopropyl sulfonyl) pyridine -2- base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -2- methoxyl group -5- nitrobenzophenone) pyrimidine -2,4- diamines preparation
By N- (3- bromopyridine -2- base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitre
Base phenyl) pyrimidine -2,4- diamines (70mg, 0.14mmol), cyclopropyl sulfinic acid sodium (86mg, 0.7mmol), CuI (27mg,
0.14mmol), Sodium proline (20mg, 0.14mmol) is dissolved in DMSO (5mL).Reaction solution is replaced three times with nitrogen, is heated to 120
DEG C, it reacts 2 hours.LCMS shows fully reacting, and methylene chloride (10mL) is added in reaction solution, water (10mL).Organic phase washing three
Secondary, magnesium sulfate dries, filters, and filtrate concentration, residue prepares plate with thickness and isolates and purifies to obtain N- (3- (cyclopropyl sulfonyl) pyrrole
Pyridine -2- base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone) pyrimidine -2,4- two
Amine (30mg, yield 40%).
Step 5: N- (4- ((3- (cyclopropyl sulfonyl) pyridine -2- base) amino) pyrimidine -2-base)-N- (2- (dimethylamino)
Ethyl) -5- methoxy-. N-methyl benzene -1,2,4- triamine preparation
N- (3- (cyclopropyl sulfonyl) pyridine -2- base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-
Methoxyl group -5- nitrobenzophenone) pyrimidine -2,4- diamines (30mg, 55.3umol) is dissolved in methanol (5mL), it is added Pd/C (10mg).Instead
It should be stirred at room temperature under a hydrogen atmosphere 10 minutes, LCMS shows fully reacting, reaction solution filtering, and filtrate is spin-dried for obtaining N4- (4- ((3-
(cyclopropyl sulfonyl) pyridine -2- base) amino) pyrimidine -2-base)-N1- (2- (dimethylamino) ethyl) -5- methoxyl group-N1- methyl
Benzene -1,2,4- triamine (20mg, yield 70%) do not make purifying and are directly used in reaction in next step.
Step 6: N- (5- ((4- ((3- (cyclopropyl sulfonyl) pyridine -2- base) amino) pyrimidine -2-base) amino) -2- ((2-
(dimethylamino) ethyl) (methyl) amino) -4- anisyl) and acryloyl group amide preparation
By N- (4- ((3- (cyclopropyl sulfonyl) pyridine -2- base) amino) pyrimidine -2-base)-N- (2- (dimethylamino) second
Base) -5- methoxy-. N-methyl benzene -1,2,4- triamine (20mg, 39.0umol), triethylamine (0.2mL) is dissolved in tetrahydrofuran
(10mL), reaction solution are cooled to -10~-5 DEG C.Under nitrogen protection, it is slowly added to acryloyl chloride (78ul, 1M in THF).Reaction
It is stirred 30 minutes at -10~-5 DEG C, reaction terminates, and methanol (3mL) is added and continues stirring 10 minutes, reaction solution concentration is dry, remains
Excess, which first passes through to prepare, crosses column purification inverted after plate separates, and obtains N- (5- ((4- ((3- (cyclopropyl sulfonyl) pyridine -2-
Base) amino) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- anisyl) acryloyl group
Amide (3.5mg, yield 16%).
1H NMR(400MHz,MeOD)δ8.78-8.67(m,1H),8.43-8.31(m,1H),8.19–8.13(m,1H),
7.92-7.84(m,1H),7.83-7.76(m,1H),7.54-7.42(m,1H),7.02(s,1H),6.66-6.55(m,1H),
6.52-6.44 (m, 1H), 5.98-5.86 (m, 1H), 3.98 (s, 3H), 3.59-3.47 (m, 2H), 3.33 (dt, J=3.3,
1.6Hz,2H),2.89(s,6H),2.76(s,3H),1.31(s,4H),1.17-1.11(m,1H).m/z 567.3。
Embodiment 44:N- (5- ((4- ((3- (cyclopropyl sulfonyl) pyridine -2- base) amino) -5- (trifluoromethyl) pyrimidine -2-
Base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- anisyl) and acryloyl group amide preparation
Step 1: the preparation of N- (3- bromopyridine -2- base) -2- chloro- 5- (trifluoromethyl) pyrimidine -4- amine
3- bromopyridine -2- amine (350mg, 2.0mmol) is dissolved in anhydrous DMF (5mL), NaH is added portionwise under ice bath
(160mg, 4.0mmol), stirring after twenty minutes, by gained suspension be added 2,4- bis- chloro- 5- (trifluoromethyl) pyrimidine (440mg,
In DMF (5mL) 2.0mmol), reaction is stirred 2 hours under ice bath, and LCMS shows fully reacting.Reaction solution saturation NH4Cl
(3mL) is quenched, and after concentration is dry, with methylene chloride (20mL), water (20mL), the concentration of organic phase dry filter, residue passes through fast
Fast column chromatographs to obtain N- (3- bromopyridine -2- base) -2- chloro- 5- (trifluoromethyl) pyrimidine -4- amine (500mg, yield 70%).
Step 2: N- (3- bromopyridine -2- base)-N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -5- (trifluoromethyl) is phonetic
The preparation of pyridine -2,4- diamines
By N- (3- bromopyridine -2- base) -2- chloro- 5- (trifluoromethyl) pyrimidine -4- amine (500mg, 1.41mmol), 4- is fluoro-
2- methoxyl group -5- nitroaniline (290mg, 1.56mmol), a water p-methyl benzenesulfonic acid (325mg, 1.7mmol) are dissolved in Isosorbide-5-Nitrae-dioxy
Six rings (30mL).Reaction is heated to 120 DEG C, stirs 16 hours, and LCMS shows fully reacting, reaction solution concentration, and residue is added
Water (10mL), methanol (5mL), mixture stir after ten minutes, and filtering, filter cake obtains N- (3- bromine after being washed with methyl tertiary butyl ether(MTBE)
Pyridine -2- base)-N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -5- (trifluoromethyl) pyrimidine -2,4- diamines (400mg), do not make
Purifying is directly used in reacts in next step.
Step 3: N- (3- bromopyridine -2- base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxy
Base -5- nitrobenzophenone) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By N- (3- bromopyridine -2- base)-N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -5- (trifluoromethyl) pyrimidine -2,
4- diamines (400mg, 0.79mmol), triethylamine (1mL), N, N, N- trimethyl ethylenediamine (120mg, 1.19mmol) are dissolved in DMF
In (10mL), reaction is heated to 110 DEG C and stirs 2 hours, and LCMS display reaction, reaction concentration is dry, residue methylene chloride
(20mL), water (20mL) layering, insoluble matter is filtered, and organic phase dries, filters, and concentration, residue is obtained by rapid column chromatography
To N- (3- bromopyridine -2- base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone) -
5- (trifluoromethyl) pyrimidine -2,4- diamines (270mg, yield 58%).
Step 4: N- (3- (cyclopropyl sulfonyl) pyridine -2- base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -2- methoxyl group -5- nitrobenzophenone) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By N- (3- bromopyridine -2- base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitre
Base phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (270mg, 0.46mmol), cyclopropyl sulfinic acid sodium (120mg,
0.92mmol), CuI (176mg, 0.92mmol), Sodium proline (126mg, 0.92mmol) are dissolved in DMSO (5mL).Reaction solution is used
Nitrogen is replaced three times, is heated to 120 DEG C, is reacted 2 hours.LCMS shows fully reacting, and methylene chloride (10mL) is added in reaction solution,
Water (10mL).Organic phase is washed three times, and magnesium sulfate dries, filters, and filtrate concentration, residue prepares plate with thickness and isolates and purifies to obtain
N- (3- (cyclopropyl sulfonyl) pyridine -2- base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitre
Base phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (50mg, yield 18%).
Step 5: N- (4- ((3- (cyclopropyl sulfonyl) pyridine -2- base) amino) -5- (trifluoromethyl) pyrimidine -2-base)-N-
The preparation of (2- (dimethylamino) ethyl) -5- methoxyl group-N1- methylbenzene -1,2,4- triamine
N- (3- (cyclopropyl sulfonyl) pyridine -2- base)-N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-
Methoxyl group -5- nitrobenzophenone) -5- (trifluoromethyl) pyrimidine -2,4- diamines (50mg, 81.8umol) is dissolved in methanol (5mL), water
(5mL) is added iron powder (50mg), ammonium chloride (50mg).Reaction is stirred at room temperature 2 hours, and LCMS shows fully reacting, reaction
Liquid filtering, filtrate are spin-dried for, and residue obtains N- (4- ((3- (cyclopropyl sulfonyl) pyridine -2- base) ammonia by Flash silica column purification
Base) -5- (trifluoromethyl) pyrimidine -2-base)-N- (2- (dimethylamino) ethyl) -5- methoxyl group-N1- methylbenzene -1,2,4- triamine
(30mg, yield 63%).
Step 6: N- (5- ((4- ((3- (cyclopropyl sulfonyl) pyridine -2- base) amino) -5- (trifluoromethyl) pyrimidine -2-
Base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- anisyl) and acryloyl group amide preparation
By N- (4- ((3- (cyclopropyl sulfonyl) pyridine -2- base) amino) -5- (trifluoromethyl) pyrimidine -2-base)-N- (2-
(dimethylamino) ethyl) -5- methoxy-. N-methyl benzene -1,2,4- triamine (30mg, 51.0umol), triethylamine (0.2mL) is dissolved in
Tetrahydrofuran (10mL), reaction solution are cooled to -10~-5 DEG C.Under nitrogen protection, it is slowly added to acryloyl chloride (78ul, 1M in
THF).Reaction is stirred 30 minutes at -10~-5 DEG C, and reaction terminates, and methanol (3mL) is added and continues stirring 10 minutes, reaction solution
Concentration is dry, and residue, which first passes through to prepare, crosses column purification inverted after plate separates, and obtains N- (5- ((4- ((3- (cyclopropyl sulfonyl)
Pyridine -2- base) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -
4- anisyl) acryloyl group amide (3.0mg, yield 10%).
1H NMR(400MHz,MeOD)δ8.70-8.62(m,1H),8.61-8.53(m,1H),8.50-8.42(m,1H),
8.09-7.93(m,1H),7.53-7.39(m,1H),7.09-7.00(m,1H),6.65-6.41(m,3H),5.97-5.85(m,
1H),3.97(s,3H),3.59-3.53(m,2H),3.32-3.27(m,2H),2.89(s,6H),2.78(s,3H),1.69-
1.57(m,1H),1.17-1.06(m,3H),1.00-0.84(m,1H).m/z 635.2。
Embodiment 45:N- (5- ((4- ((2- (cyclopropyl sulfonyl) pyridin-3-yl) amino) -5- methylpyrimidine -2- base) ammonia
Base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- anisyl) acryloyl group amide preparation
Step 1: the preparation of 2- (cyclopropyl sulfonyl) -3- nitropyridine
By the chloro- 3- nitropyridine (1.0g, 6.31mmol) of 2-, cyclopropyl sulfinic acid sodium (1.2g, 9.5mmol) is dissolved in DMSO
In (15mL), reaction is heated to 120 DEG C, stirs 8 hours, and LCMS shows fully reacting, reaction solution methylene chloride (30mL), water
(30mL) layering, organic phase dry filter, concentration, residue obtain 2- (cyclopropyl sulfonyl) -3- by Flash silica column purification
Nitropyridine (1.2g, yield 84%).
Step 2: the preparation of 2- (cyclopropyl sulfonyl) pyridine -3- amine
By 2- (cyclopropyl sulfonyl) -3- nitropyridine (1.2g, 5.26mmol), Pd/C (200mg) is dissolved in methanol
(20mL) is stirred at room temperature 30 minutes under nitrogen atmosphere, reaction solution filtering, filtrate concentration, and residue is obtained by Flash silica column purification
To 2- (cyclopropyl sulfonyl) pyridine -3- amine (800mg, yield 76%).
Step 3: the preparation of the chloro- N- of 2- (2- (cyclopropyl sulfonyl) pyridin-3-yl) -5- methylpyrimidine -4- amine
2- (cyclopropyl sulfonyl) pyridine -3- amine (400mg, 2.0mmol) is dissolved in anhydrous DMF (10mL), under ice bath
It is added portionwise NaH (160mg, 4.0mmol), the chloro- 5- methylpyrimidine of 2,4- bis- is added after twenty minutes, by gained suspension in stirring
In the DMF (10mL) of (400mg, 2.4mmol), reaction is stirred 2 hours under ice bath, and LCMS shows fully reacting.Reaction solution is used
It is saturated NH4Cl (3mL) is quenched, and after concentration is dry, with methylene chloride (20mL), water (20mL), the concentration of organic phase dry filter is remaining
Object obtains the chloro- N- of 2- (2- (cyclopropyl sulfonyl) pyridin-3-yl) -5- methylpyrimidine -4- amine (500mg, production by rapid column chromatography
Rate 75%).
Step 4: N- (2- (cyclopropyl sulfonyl) pyridin-3-yl)-N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -5- first
The preparation of yl pyrimidines -2,4- diamines
By the chloro- N- of 2- (2- (cyclopropyl sulfonyl) pyridin-3-yl) -5- methylpyrimidine -4- amine (500mg, 1.54mmol), 4-
Fluoro- 2- methoxyl group -5- nitroaniline (350mg, 1.85mmol), a water p-methyl benzenesulfonic acid (440mg, 2.31mmol) are dissolved in Isosorbide-5-Nitrae -
Dioxane (20mL).Reaction is heated to 120 DEG C, stirs 16 hours, and LCMS shows fully reacting, reaction solution concentration, residue
It is added water (10mL), methanol (5mL), mixture stirs after ten minutes, and filtering, filter cake obtains crude product after being washed with methyl tertiary butyl ether(MTBE)
N- (2- (cyclopropyl sulfonyl) pyridin-3-yl)-N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -5- methylpyrimidine -2,4- diamines
(600mg, yield 80%).
Step 5: N- (2- (cyclopropyl sulfonyl) pyridin-3-yl)-N- (4- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -2- methoxyl group -5- nitrobenzophenone) -5- methylpyrimidine -2,4- diamines preparation
N- (2- (cyclopropyl sulfonyl) pyridin-3-yl)-N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -5- methyl is phonetic
Pyridine -2,4- diamines (600mg, 1.26mmol), triethylamine (1mL), N, N, N- trimethyl ethylenediamine (200mg, 1.9mmol) are dissolved in
In DMF (10mL), reaction is heated to 110 DEG C and stirs 2 hours, and LCMS display reaction, reaction concentration is dry, residue methylene chloride
(20mL), water (20mL) layering, insoluble matter is filtered, and organic phase dries, filters, and concentration, residue is obtained by rapid column chromatography
To N4- (2- (cyclopropyl sulfonyl) pyridin-3-yl)-N2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -
5- nitrobenzophenone) -5- methylpyrimidine -2,4- diamines (600mg, yield 85%).
Step 6: N- (4- ((2- (cyclopropyl sulfonyl) pyridin-3-yl) amino) -5- methylpyrimidine -2- base)-N- (2- (two
Methylamino) ethyl) -5- methoxyl group-N1- methylbenzene -1,2,4- triamine preparation
N- (2- (cyclopropyl sulfonyl) pyridin-3-yl)-N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-
Methoxyl group -5- nitrobenzophenone) -5- methylpyrimidine -2,4- diamines (300mg, 0.54mmol) is dissolved in methanol (20mL), water
(10mL) is added iron powder (300mg), ammonium chloride (500mg).Reaction is stirred at room temperature 2 hours, and LCMS shows fully reacting,
Reaction solution filtering, filtrate are spin-dried for, and residue obtains N- (4- ((2- (cyclopropyl sulfonyl) pyridin-3-yl) ammonia by reverse phase column purification
Base) -5- methylpyrimidine -2- base)-N- (2- (dimethylamino) ethyl) -5- methoxy-. N-methyl benzene -1,2,4- triamine (250mg,
Yield 88%).
Step 7: N- (5- ((4- ((2- (cyclopropyl sulfonyl) pyridin-3-yl) amino) -5- methylpyrimidine -2- base) ammonia
Base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- anisyl) acryloyl group amide preparation
By N- (4- ((2- (cyclopropyl sulfonyl) pyridin-3-yl) amino) -5- methylpyrimidine -2- base)-N- (2- (diformazan ammonia
Base) ethyl) -5- methoxy-. N-methyl benzene -1,2,4- triamine (250mg, 0.47mmol), triethylamine (0.5mL) is dissolved in tetrahydro furan
Mutter (20mL), and reaction solution is cooled to -10~-5 DEG C.Under nitrogen protection, it is slowly added to acryloyl chloride (0.72mL, 1M in THF).
Reaction is stirred 30 minutes at -10~-5 DEG C, and reaction terminates, and methanol (3mL) is added and continues stirring 10 minutes, reaction solution concentration
Dry, residue, which first passes through to prepare, crosses column purification inverted after plate separates, and obtains N- (5- ((4- ((2- (cyclopropyl sulfonyl) pyrrole
Pyridine -3- base) amino) -5- methylpyrimidine -2- base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxy benzene
Base) acryloyl group amide (150mg, yield 54%).
1H NMR(400MHz,MeOD)δ8.68-8.59(m,1H),8.58-8.51(m,1H),7.95-7.80(m,1H),
7.66-7.60(m,1H),7.57(s,1H),7.00(s,1H),6.66-6.46(m,2H),6.03-5.88(m,1H),3.95(s,
3H),3.56-3.48(m,2H),3.32-3.27(m,2H),3.20-3.08(m,1H),2.90(s,6H),2.73(s,3H),
2.26 (d, J=0.8Hz, 3H), 1.34-1.24 (m, 2H), 1.21-1.11 (m, 2H) .m/z 581.3.
Biology test evaluation
The experiment of 1.EGFR T790M saltant type zymetology
This experiment is prominent to exon 20T790M using the method test compound of fluorescence resonance energy transfer (TR-FRET)
The inhibiting effect of modification EGFR enzyme, and obtain compound to the half-inhibitory concentration IC of the enzymatic activity50。
1) 1~5ul EGFR T790M enzyme solutions, the final concentration of 0.1~1nM of enzyme are added in 384 orifice plates.
2) the good compound solution of 1~5ul gradient dilution is added.
3) it is incubated at room temperature 10 minutes.
4) it includes 1~10uM of 5~50nM of substrate polypeptide final concentration and ATP final concentration that 1~5ul Substrate cocktail, which is added,.
5) it is incubated at room temperature 0.5~2 hour.
6) 5ul EDTA terminate liquid is added and terminates reaction 5 minutes.
7) detection liquid of the 5ul containing labelled antibody is added, is incubated at room temperature 1 hour.
8) microplate reader measures the 665nm fluorescence signal value of each plate.
9) inhibiting rate is calculated by fluorescence signal value.
10) IC of compound is obtained by curve matching according to the inhibiting rate of various concentration50。
The experiment of 2.EGFR wild type (WT) zymetology
The suppression of compounds against wild type EGFR enzyme is tested in this experiment using the method for fluorescence resonance energy transfer (TR-FRET)
Production is used, and obtains compound to the half-inhibitory concentration IC of the enzymatic activity50。
1) 1~5ul EGFR wild-type enzyme solution, the final concentration of 0.1~1nM of enzyme are added in 384 orifice plates.
2) the good compound solution of 1~5ul gradient dilution is added.
3) it is incubated at room temperature 10 minutes.
4) it includes 0.1~5uM of 5~50nM of substrate polypeptide final concentration and ATP final concentration that 1~5ul Substrate cocktail, which is added,.
5) it is incubated at room temperature 0.5~2 hour.
6) 5ul EDTA terminate liquid is added and terminates reaction 5 minutes.
7) detection liquid of the 5ul containing labelled antibody is added, is incubated at room temperature 1 hour.
8) microplate reader measures the 665nm fluorescence signal value of each plate.
9) inhibiting rate is calculated by fluorescence signal value.
10) IC of compound is obtained by curve matching according to the inhibiting rate of various concentration50。
The biochemical activity of the compounds of this invention is measured by above test, the IC measured50Value see the table below.
Wherein embodiment 6 arrives 45 compound EGFR IC of embodiment50Value is approximate with embodiment 1, shows good EGFR
Saltant type kinase inhibiting activity.
Conclusion: the embodiment of the present invention has very strong inhibitory activity to EGFR mutation type kinase, while to wild type kinase
With weaker inhibitory activity, good selectivity is shown.
3.NCI-H1975 cell growth inhibition assay
This experiment uses the method test compound of CellTiter-Glo to the inhibiting effect of NCI-H1975 cell Proliferation,
And show that compound inhibits the half-inhibitory concentration IC of cell-proliferation activity50。
1) the H1975 cell suspension of 90 μ L is inoculated in 96 porocyte culture plates, density is 1~5*103Cell/ml, will
Culture plate in incubator culture 16~24 hours (37 DEG C, 5%CO2)。
2) testing compound solution of the various concentration of gradient dilution is added into culture plate cell, culture plate is being cultivated
Case be incubated for 72 hours (37 DEG C, 5%CO2)。
3) 50~100 μ L CellTiter-Glo reagents are added in every hole, and vibrate 10 minutes, are stored at room temperature 10 minutes.
4) microplate reader measures the chemiluminescence signal value of each plate.
5) inhibiting rate is calculated by chemiluminescence signal value.
6) IC of compound is obtained by curve matching according to the inhibiting rate of various concentration50。
4.A431 cell growth inhibition assay
This experiment tests compound to the inhibiting effect of A431 cell Proliferation using the method for CellTiter-Glo, and
Compound inhibits the half-inhibitory concentration IC of cell-proliferation activity out50。
1) the A431 cell suspension of 90 μ L is inoculated in 96 porocyte culture plates, density is 1~5*103Cell/ml will be trained
Support plate in incubator culture 16~24 hours (37 DEG C, 5%CO2)。
2) testing compound solution of the various concentration of gradient dilution is added into culture plate cell, culture plate is being cultivated
Case be incubated for 72 hours (37 DEG C, 5%CO2)。
3) 50~100 μ L CellTiter-Glo reagents are added in every hole, and vibrate 10 minutes, are stored at room temperature 10 minutes.
4) microplate reader measures the chemiluminescence signal value of each plate.
5) inhibiting rate is calculated by chemiluminescence signal value.
6) IC of compound is obtained by curve matching according to the inhibiting rate of various concentration50。
The biochemical activity of the compounds of this invention is measured by above test, the IC measured50Value see the table below.
Wherein embodiment 3 arrives 45 compound EGFR IC of embodiment50To H1975 and A431 inhibitory activity and embodiment 1 in value
Approximation shows good inhibitory activity.
Conclusion: the embodiment of the present invention has very strong inhibitory activity to the proliferation of EGFR mutant cell H1975, and to open country
The proliferation of raw type A431 cell has lower inhibition, and embodiment has selectivity well to wild type/mutant cell.
Claims (14)
1. one kind has formula (I) compound N-(5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl) amino) pyrimidine -2-
Base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts:
Wherein,
X, Y is independently selected from CH or N, and X, Y be not identical；
R1Selected from C1-8Alkyl, C3-8Naphthenic base, optionally further by one or more substitutions for being selected from fluorine, chlorine, bromine, iodine or hydroxyl
Replaced base；
R2Selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-8Alkoxy, trifluoromethoxy；
R3Selected from such as flowering structure:
R4Selected from C1-8Alkyl, C3-8Naphthenic base.
2. according to claim 1 have formula (I) compound N-(5- ((4- ((2- (alkyl substituted sulphonyl) pyridine -3-
Base) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its is pharmaceutically acceptable
Salt, which is characterized in that R1Selected from C1-4Alkyl, C3-6Naphthenic base, optionally further by one or more selected from fluorine, chlorine, bromine, iodine or
Replaced the substituent group of hydroxyl；X,Y,R2、R3、R4As defined in claim 1.
3. according to claim 1 have formula (I) compound N-(5- ((4- ((2- (alkyl substituted sulphonyl) pyridine -3-
Base) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its is pharmaceutically acceptable
Salt, which is characterized in that R1Selected from C1-4Alkyl, optionally further replaced one or more substituent groups selected from fluorine or hydroxyl；
X、Y、R2、R3、R4As defined in claim 1.
4. according to claim 1 have formula (I) compound N-(5- ((4- ((2- (alkyl substituted sulphonyl) pyridine -3-
Base) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its is pharmaceutically acceptable
Salt, which is characterized in that R1Selected from methyl, ethyl, isopropyl, trifluoromethyl or difluoromethyl；X,Y,R2、R3、R4Such as claim
1 is defined.
5. according to claim 1 have formula (I) compound N-(5- ((4- ((2- (alkyl substituted sulphonyl) pyridine -3-
Base) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its is pharmaceutically acceptable
Salt, which is characterized in that R2Selected from hydrogen, fluorine, chlorine, cyano, C1-8Alkoxy or trifluoromethoxy；R4Selected from isopropyl or cyclopropyl；
X、Y、R3As defined in claim 1.
6. according to claim 1 have formula (I) compound N-(5- ((4- ((2- (alkyl substituted sulphonyl) pyridine -3-
Base) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its is pharmaceutically acceptable
Salt, which is characterized in that be selected from following compound:
7. according to claim 1 have formula (I) compound N-(5- ((4- ((2- (alkyl substituted sulphonyl) pyridine -3-
Base) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its is pharmaceutically acceptable
The preparation method of salt, includes the following steps:
Wherein, X1、X2It is each independently selected from fluorine, chlorine, bromine or iodine；X,Y,R1、R2、R3、R4As defined in claim 1.
8. pharmaceutical composition comprising there is the according to claim 1 to 6 for the treatment of effective dose formula (I) to change
Close object N- (5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group
Amide analogue, its stereoisomer or its pharmaceutically-acceptable salts and pharmaceutical carrier.
9. according to claim 1 to 6 have formula (I) compound N-(5- ((4- ((2- (alkyl substitution sulphonyl
Base) pyridin-3-yl) amino) pyrimidine -2-base) amino)-phenyl) acryloyl group amide analogue, its stereoisomer or its medicine
Acceptable salt or pharmaceutical composition according to any one of claims 8 are used to treat to EGFR mutant or exons 19 in preparation on
Lack the application in the disease mediated therapeutic agent of activated mutant body activity.
10. application according to claim 9, which is characterized in that the EFGR mutant be selected from L858REGFR mutant and
T790MEGFR mutant.
11. application according to claim 9, which is characterized in that according to claim 1 to 6 that there is formula
(I) compound N-(5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino)-phenyl) third
Enoyl- amide analogue, its stereoisomer or its pharmaceutically-acceptable salts or pharmaceutical composition according to any one of claims 8 exist
Preparation is for treating individually or partly by the application in the disease mediated therapeutic agent of EGFR mutant activity.
12. application according to claim 11, which is characterized in that according to claim 1 to 6 to have
Formula (I) compound N-(5- ((4- ((2- (alkyl substituted sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino)-phenyl)
Acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts or pharmaceutical composition according to any one of claims 8
In preparation for the application in treating cancer drug.
13. application according to claim 12, which is characterized in that the cancer is selected from oophoroma, cervical carcinoma, colorectum
Cancer, breast cancer, cancer of pancreas, glioma, glioblastoma, melanoma, prostate cancer, leukaemia, lymthoma, non-Hodgkin's
Lymthoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, denaturation
Large celllymphoma, acute myelocytic leukemia, Huppert's disease, melanoma or celiothelioma.
14. application according to claim 13, which is characterized in that the cancer is selected from non-small cell lung cancer.
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| WO2020001351A1 (en) * | 2018-06-27 | 2020-01-02 | 江苏威凯尔医药科技有限公司 | Egfr inhibitor, method for preparing the same, and uses thereof |
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| WO2020001350A1 (en) * | 2018-06-27 | 2020-01-02 | 江苏威凯尔医药科技有限公司 | Egfr inhibitor, method for preparing the same, and uses thereof |
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