CN106187915A - There is inhibitor of ALK Yu EGFR double activity and its preparation method and application - Google Patents

There is inhibitor of ALK Yu EGFR double activity and its preparation method and application Download PDF

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Publication number
CN106187915A
CN106187915A CN201610318055.6A CN201610318055A CN106187915A CN 106187915 A CN106187915 A CN 106187915A CN 201610318055 A CN201610318055 A CN 201610318055A CN 106187915 A CN106187915 A CN 106187915A
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amino
phenyl
base
pyrimidine
alkyl
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仝朝龙
崔媛媛
危明松
包如迪
喻红平
徐耀昌
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansen Biological Medicine Technology Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansen Biological Medicine Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Abstract

The invention discloses the inhibitor with ALK Yu EGFR double activity and its preparation method and application.It relates to having formula (I) compound N (3 ((4 ((2 (isopropyl sulphonyl) phenyl) amino) pyrimidine 2 base) amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts.This series compound has suppression EGF-R ELISA (EGFR) L858R EGFR mutant, T790MEGFR mutant and exons 19 and lacks the activity of activated mutant body；This series compound has ALK inhibitory activity simultaneously.Therefore this series compound can be used to treat individually or partly disease mediated by EGFR mutant and ALK activity, as being widely used with the tool in treatment cancer especially non-small cell lung cancer drug in prevention, it is expected to develop into EGFR of new generation or/and ALK inhibitor.

Description

There is inhibitor of ALK Yu EGFR double activity and its preparation method and application
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to a kind of there is ALK Yu EGFR double activity inhibitor, its system Preparation Method and application.
Background technology
EGFR (Epidermal Growth Factor Receptor) is transmembrane protein tyrosine kinases erbB receptor man A member of race.By the combination with its part-such as epidermal growth factor (EGF), EGFR can form homology on cell membrane Dimer, or with family in other receptor (such as erbB2, erbB3, or erbB4) formed heterodimer.These dimerization The formation of body, can cause the tyrosine residue phosphorylation of the intracellular key of EGFR, thus the signal in multiple downstreams in active cell Path.These intracellular signaling pathway play an important role in cell proliferation, existence and anti-apoptotic.EGFR signal transduction pathway loses Adjust, increase including the expression of part and receptor, EGFR gene amplification and sudden change etc., can promote cell to vicious transformation, and The propagation of tumor cell, attack, shift and vascularization plays an important role.Therefore, EGFR is the conjunction of cancer therapy drug exploitation Reason target spot.
First generation small molecule EGFR inhibitor, including gefitinib (IressaTM) and Erlotinib (ErlotinibTM), at lung Cancer treatment demonstrates preferable curative effect, as first-line drug for treating the nonsmall-cell lung cancer with EGFR activated mutant 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 (includes L858R and exons 19 deletion mutation DelE746_A750) adenosine triphosphate (ATP) affinity is declined, and the affinity of micromolecular inhibitor is increased, thus lead Cause tumor cell the sensitivity of first generation EGFR inhibitor such as gefitinib or Erlotinib is increased, reach targeted therapy Purpose (Science [2004] the 304th phase, 1497-500；New England Journalof medicine [2004] the 350th Phase, 2129-39).
But, after the first generation small molecule EGFR inhibitor treatment 10-12 month, almost all of NSCLC patient all produces Drug resistance to 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 to guard the gate the secondary mutation of gene residue T790M due to EGFR, thus reduce medicine and target spot affinity and Develop immunity to drugs, cause recurrence or the disease progression of tumor.
In view of this sudden change produces importance and the universality of drug resistance, many medicament research and development in pulmonary carcinoma EGFR targeted therapy Company (Pfizer, BI, AZ etc.) attempts to develop second filial generation small molecule EGFR inhibitor, is reached by suppression EGFR T790M mutant To the patients with lung cancer of this type of drug resistance for the treatment of, but all end in failure because of poor selectivity.Even if afatinib is used by FDA approval In the treatment of pulmonary carcinoma, but it is only used for the first-line treatment with EGFR activated mutant patient；And suffer from EGFR T790M sudden change Person, owing to afatinib has higher inhibitory action to Wild type EGFR, causes serious skin and gastrointestinal toxicity to limit Make dosage, do not demonstrate therapeutic effect.
Therefore, it is necessary to exploitation third generation small molecule EGFR inhibitor, the high Selective depression EGFR T790M mutant of energy, And Wild type EGFR is not had or low activity.Due to this high selectivity, can be substantially reduced because Wild type EGFR suppression is drawn The skin risen and gastrointestinal damage, to reach to treat the tumor of EGFR T790M secondary mutation drug resistance.It addition, retain EGFR The inhibitory activity of activated mutant body (including L858R EGFR, exons 19 deletion mutation delE746_A750), the most highly significant. Due to more weak to Wild type EGFR suppression, third generation EGFR inhibitor has more more preferable safety than first generation EGFR inhibitor, It is expected to treat as First Line, the NSCLC for the treatment of adjoint EGFR activated mutant while, it is possible to removing initial therapy patient may The a small amount of EGFRT790T mutant existed, to delay the generation of drug resistance.
Anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) is a kind of receptor tyrosine protein kinase, is to drench at Anaplastic large cell the earliest One hypotype of bar tumor (ALCL) is found, therefore names as anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (anaplasticlymphoma Kinase, ALK) (Morris, S.W.et al., Science, 1994,263,1281-1284；Shiota,M.et al, Oncogene,1994,9,1567-1574).Alk protein contains 1620 aminoacid, and molecular weight is 177 kilodaltons (kDa), 254 kinase amino acid domains are made up of 1123 to 1376 amino acids residues, are one before this and are made up of aminoacid Short cross-film district.Expression-form in Mice Body point out its maincenter and and the growth of peripheral nervous system in work； Finding in fruit bat with the form that part combines, ALK promotes that intestinal tube muscular tissue is formed, mammalian ligands not yet determines；The mankind Retina detects alk protein matter.Bearing Mice Life cycle and the vital movement that ALK gene knocks out show no obvious abnormalities (Webb, T.R.et al., Expert Rev.Anti-cancer Ther., 2009,9,331-356), imply that ALK suppression will not be right Body causes serious injury.
2007 Nian Liangge independent studies groups identify ALK gene in nonsmall-cell lung cancer respectively and reset.One of which Research worker develops retrovirus cDNA expression library for screening new oncogene.They have transfected and have extracted from one and sieve in advance Choosing shows the cDNA library of 62 years old Japanese male smoker's adenocarcinoma of lung of KRAS and EGFR sudden change feminine gender, and design generates and turns base Because of mice, specific expressed EML4-ALK in alveolar cell, thus generate many adenocarcinoma of lung tuberositys.Use ALK inhibitor Treating these transgenic mices causes tumor load to reduce compared to untreated mice.Major part mice is quickly in 1 month Dead.Identical ALK inhibitor for treating is used to cause lungs without EML4-ALK/3T3 cellular infiltration and life span extension.This research has Power confirms that EML4-ALK is uniquely to drive sudden change in nonsmall-cell lung cancer, and suppression EML4-ALK activity can be led in vivo Cause pulmonary carcinoma load and reduce (Soda, M., Choi, Y.L., Enomoto, M., et al., Nature, 2007:448).EML4-ALK Merge in the nonsmall-cell lung cancer occurring in about 3-5%, specifically because of the crowd studied and the difference of the ALK detection method of use And difference, it is that nonsmall-cell lung cancer uniquely drives mutant gene.
Experimental data shows, suppression ALK gene can effectively stop lymphoma cell that ALK is positive and lung carcinoma cell Growth, demonstrate ALK inhibitor have in this kind of oncotherapy important value (Piva, R.et al., Blood, 2006, 107,689-697；Galkin,A.V.et al.,Proc.Natl.Acad.Sci.USA,2007,104,270-275； Koivunen,J.P.et al.,Clin.Cancer Res.,2008,14,4275-4238))。
Summary of the invention
Inventor finds that in research process a class has formula (I) structure N-(3-((4-((2-(isopropyl sulphonyl) phenyl) Amino) pyrimidine-2-base) amino) phenyl) acryloyl group amide analogue have suppression L858R EGFR mutant, T790M EGFR mutant and exons 19 lack the activity of activated mutant body, and this series compound also has ALK inhibitory activity simultaneously.Cause This this series compound can be used to treat individually or partly disease mediated by EGFR mutant and ALK activity, such as, exist Prevent to be widely used with the tool in treatment cancer especially non-small cell lung cancer drug.
One aspect of the present invention provides one to have such as following formula (I) compound N-(3-((4-((2-(isopropyl sulphonyl) phenyl) Amino) pyrimidine-2-base) amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts:
Wherein,
R1Selected from C1-8Alkyl, C3-8Cycloalkyl, the most further by one or more selected from fluorine, chlorine, bromine, iodine, hydroxyl, C1-8Alkyl, C1-8Alkoxyl, halogen replace C1-8Alkoxyl, C3-8Cycloalkyl or C3-8The substituent group of cycloalkyloxy is replaced；
R2Selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro, C1-8Alkoxyl, trifluoromethyl, trifluoromethoxy, C (O) R5、C(O)OR5Or P (O) R6R7；
R3Selected from following structure:
R4Selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-8Alkyl, C3-8Cycloalkyl, halogen replace C1-8Alkyl, C1-8Alkoxyl, C3-8Ring Alkoxyl, halogen replace C1-8Alkoxyl, phenyl or p-methylphenyl；
R5、R6、R7It is independently selected from C1-8Alkyl, C3-8Cycloalkyl, halogen replace C1-8Alkyl, C1-8Alkoxyl, amino or Two C1-8Alkyl amino.
As preferred scheme, described N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) ammonia Base) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, C1-8Alkyl is selected from C1-6Alkyl, Preferably C1-3Alkyl；Halogen replaces C1-8Alkyl replaces C selected from halogen1-6Alkyl, preferably halogen replace C1-3Alkyl；C1-8Alkoxyl is selected from C1-6 Alkoxyl, preferably C1-3Alkoxyl；Halogen replaces C1-8Alkoxyl replaces C selected from halogen1-6Alkoxyl, preferably halogen replace C1-3Alkoxyl； C3-8Cycloalkyl is selected from C3-6Cycloalkyl.
As further preferred scheme, described N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2- Base) amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, R3It is selected from:R1、R2、R4、R5、R6、R7As formula (I) compound defines.
As further preferably scheme, described N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine- 2-yl) amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, R1Selected from C1-4Alkane Base, C3-6Cycloalkyl, the most further by one or more selected from fluorine, chlorine, bromine, iodine, hydroxyl, C1-8Alkyl, C1-8Alkoxyl, halogen Replace C1-8Alkoxyl, C3-8Cycloalkyl or C3-8The substituent group of cycloalkyloxy is replaced；R2、R3、R4、R5、R6、R7Such as formula (I) chemical combination Thing is defined.
As further preferably scheme, described N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine- 2-yl) amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, R1Selected from methyl, Ethyl, isopropyl, trifluoromethyl, difluoromethyl；R2、R3、R4、R5、R6、R7As formula (I) compound defines.
As further preferably scheme, described N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine- 2-yl) amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, R2Selected from hydrogen, fluorine, Chlorine, cyano group, C1-3Alkoxyl, trifluoromethyl or trifluoromethoxy.
As further preferably scheme, (((4-((2-(isopropyl sulphonyl) phenyl) amino) is phonetic for 3-for described N- Pyridine-2-base) amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, R4Selected from hydrogen, Fluorine, chlorine, C1-3Alkyl, C1-3Alkoxyl, trifluoromethyl, trifluoromethoxy or difluoro-methoxy.
As most preferred scheme, described N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) Amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, selected from following compound:
Another aspect of the present invention provides aforementioned N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) Amino) phenyl) acryloyl group amide analogue, its stereoisomer or the preparation method of its pharmaceutically-acceptable salts, including such as Lower step:
Wherein, X1、X2Selected from fluorine, chlorine, bromine or iodine；R1、R2、R3、R4、R5、R6、R7As formula (I) compound defines.
Further aspect of the present invention provides a kind of pharmaceutical composition, it aforementioned N-(3-((4-including treating effective dose ((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) phenyl) acryloyl group amide analogue, its stereoisomer Or its pharmaceutically-acceptable salts and pharmaceutically useful carrier.
Further aspect of the present invention provide a kind of aforementioned N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine- 2-yl) amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, or foregoing pharmaceutical group Compound lacks activated mutant body activity in preparation for treatment and is situated between and ALK leads the treatment of disease EGFR mutant, exons 19 Application in medicine.
As further preferred scheme, aforementioned N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2- Base) amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, or foregoing pharmaceutical combination Thing preparation for treat individually or partly by the disease mediated medicine of EGFR mutant activity and ALK should With.
As further preferably scheme, described EFGR mutant is selected from L858R EGFR mutant or T790MEGFR Mutant.
As further preferably scheme, aforementioned N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2- Base) amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, or foregoing pharmaceutical combination Thing is used for treating the application in cancer drug in preparation.
As further preferably scheme, described cancer selected from ovarian, cervical cancer, colorectal carcinoma, breast carcinoma, pancreas Adenocarcinoma, glioma, glioblastoma multiforme, melanoma, carcinoma of prostate, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, Pulmonary carcinoma, hepatocarcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid carcinoma, cancer of biliary duct, carcinoma of endometrium, renal carcinoma, anaplastic Large celllymphoma, acute myelocytic leukemia (AML), multiple myeloma, melanoma or mesothelioma；Preferably be selected from non-little carefully Born of the same parents' pulmonary carcinoma.
Detailed description of the invention
Describing in detail: unless stated to the contrary, following have following containing with term in the specification and in the claims Justice.
“C1-8Alkyl " refer to include the straight chained alkyl of 1 to 8 carbon atom and containg branched alkyl radical, alkyl refers to saturated aliphatic hydrocarbon Group, such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1-diformazan Base propyl group, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 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 group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, 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-ethyl pentyl group, 2-methyl-3-ethyl pentyl group or it is each Plant branched chain isomer etc..
" cycloalkyl " refers to the unsaturated monocycle of saturated or part or multi-ring cyclic hydrocarbon substituent, " C3-8Cycloalkyl " refer to include 3 to The cycloalkyl of 8 carbon atoms, such as:
The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, ring Hexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc..
Polycyclic naphthene base includes the cycloalkyl of volution, condensed ring and bridged ring." spiro cycloalkyl group " refers to share between monocycle a carbon The polycyclic moiety of atom (title spiro-atom), these can contain one or more double bonds, but neither one ring has total conjugated Pi-electron system.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spiro cycloalkyl group by the number according to spiro-atom shared between ring and ring Base or many spiro cycloalkyl group, the non-limiting example of spiro cycloalkyl group comprises:
" cycloalkyl " refers to that each ring in system and other rings in system share the full carbon of a pair carbon atom adjoined Polycyclic moiety, wherein one or more rings can contain one or more double bonds, but neither one ring has the π electricity of total conjugated Subsystem.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl, cycloalkyl unrestricted Property embodiment comprises:
" bridge ring alkyl " refers to that any two ring shares the full carbon polycyclic moiety of two carbon atoms not being directly connected to, and these can With containing one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Number according to makeup ring is permissible Being divided into dicyclo, three rings, Fourth Ring or multi-ring bridge ring alkyl, the non-limiting example of bridge ring alkyl comprises:
Described cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, is wherein connected to precursor structure Ring together is cycloalkyl, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..
" alkoxyl " refers to-O-(alkyl), and wherein alkyl is as defined above.“C1-8Alkoxyl " refer to the alkane containing 1-8 carbon Base epoxide, non-limiting example comprises methoxyl group, ethyoxyl, propoxyl group, butoxy etc..
" cycloalkyloxy " refers to and-O-(unsubstituted cycloalkyl), and wherein cycloalkyl is as defined above.“C3-8Cycloalkanes oxygen Base " refer to the cycloalkyl oxy containing 3-8 carbon, non-limiting example comprises ring propoxyl group, cyclobutoxy group, cyclopentyloxy, hexamethylene Epoxide etc..
" the substituted C of halogen1-8Alkyl " refer to 1-8 the carbon alkyl replaced by fluorine, chlorine, bromine, atomic iodine that the hydrogen on alkyl is optional Group, such as difluoromethyl, dichloromethyl, two bromomethyls, trifluoromethyl, trichloromethyl, trisbromomethyl etc..
“C(O)R5" refer to R5Substituted carbonyl.
“P(O)R6R7" refer to R6、R7Substituted phosphoryl, R6、R7The most identical or different substituent group.
" two C1-8Alkyl amino " refer to two C1-8The substituted amino group of alkyl.
" THF " refers to oxolane.
" DCM " refers to dichloromethane.
" DMF " refers to N, dinethylformamide.
" DIPEA " refers to diisopropylethylamine.
" optionally " or " optionally " mean ground described later event or environment can but need not occur, this explanation includes This event or environment occur or not spot occasion.Such as, " heterocyclic group optionally replaced by alkyl " means that alkyl is permissible But necessarily existing, this explanation includes situation that heterocyclic group replaced by alkyl and the situation that heterocyclic group is not replaced by alkyl.
" substituted " refers to that the one or more hydrogen atoms in group are replaced by the substituent group of respective number independently of one another.No Saying and explain, substituent group is only in their possible chemical position, and those skilled in the art can not pay too much effort In the case of determine (by experiment or theoretical) may or impossible replacement.Such as, there is the amino of free hydrogen or hydroxyl and tool The carbon atom having unsaturation (such as olefinic) key is probably instability when combining.
" pharmaceutical composition " represent containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or The mixture of prodrug and other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.Medicine The purpose of compositions is to promote the absorption of the administration to organism, beneficially active component and then play biological activity.
Below in conjunction with embodiment, the present invention is described in further detail and completely, but limits by no means the present invention, the present invention Also the content of embodiment it is not intended to be limited to.
The compound structure of the present invention is or/and LC-MS chromatograph (LC-MS) determines by nuclear magnetic resonance, NMR (NMR) 's.Nmr chemical displacement (δ) is given with the unit of 1/1000000th (ppm).The mensuration of NMR is with Bruker AVANCE-400 core Magnetic instrument, measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3And deuterochloroform (CDCl OD)3It is designated as in) Tetramethylsilane (TMS).
The mensuration of LC-MS chromatograph LC-MS Agilent 1200Infinity Series mass spectrograph.The mensuration of HPLC Use Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 × 4.6mm chromatographic column) and Waters 2695- 2996 high pressure liquid chromatographs (Gimini C18 150 × 4.6mm chromatographic column).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that TLC uses is 0.15mm～0.20mm, the specification that the isolated and purified product of thin layer chromatography uses is 0.4mm～0.5mm.Column chromatography generally uses cigarette Platform Huanghai Sea silica gel 200～300 mesh silica gel is carrier.
Initiation material in the embodiment of the present invention is known and can be commercially available, or can use or press Synthesize according to methods known in the art.
In the case of without specified otherwise, the present invention is responded all under continuous print magnetic agitation, at drying nitrogen Or carry out under argon atmospher, solvent is for being dried solvent.
The preparation of embodiment compound
Embodiment one: N-(5-((4-((the chloro-2-of 5-(isopropyl sulphonyl) phenyl) amino)-5-(trifluoromethyl) pyrimidine-2- Base) amino)-2-((2-(dimethylamino) ethyl) (methyl) amino)-4-anisyl) preparation of acryloyl group amide
The preparation of the first step: 4-chloro-2-(isopropylthio) aniline
By 5-chloro-2-aminothiophenol (500mg, 3.13mmol), potassium carbonate (973mg, 7.04mmol) is placed in 50mL circle In end bottle, add 15ml DMF, under agitation add isopropyl bromide (0.5mL), mixture is stirred at room temperature overnight, add 50 milliliters of water, ethyl acetate extracts, and anhydrous sodium sulfate is dried, and filters, steams solvent, and residue obtains pale yellow through silica gel column chromatography Color oily thick liquid (0.520g).
The preparation of the chloro-2-of second step: 4-(isopropyl sulphonyl) aniline
By chloro-for 4-2-(isopropylthio) aniline (520mg, 3.33mmol) and metachloroperbenzoic acid (mCPBA) (85%, 1.33g) is placed in 100mL round-bottomed bottle, adds 15ml dichloromethane, is stirred at room temperature by mixture 5 hours, adds 10 milliliters of saturated sodium bisulfite solution stir 10 minutes, add 20 milliliters of saturated sodium bicarbonate solutions and stir 10 minutes, dichloromethane Alkane extracts, and anhydrous sodium sulfate is dried, and filters, steams solvent, and residue obtains the chloro-2-of product 4-(isopropyl sulphonyl) through column chromatography again Aniline (320mg).
The preparation of the 3rd chloro-N-of step: 2-(the chloro-2-of 5-(isopropyl sulphonyl) phenyl)-5-(trifluoromethyl) pyrimidine-4-amine
Chloro-for 4-2-(isopropyl sulphonyl) aniline (710mg, 3.04mmol) is dissolved in dry DMF, at 0 DEG C, adds hydrogenation Sodium (243mg, 6.08mmol), stirs half an hour at 0 DEG C, is added drop-wise to by this suspended matter dissolved with 2,4-bis-chloro-5-trifluoromethyl In 5 milliliters of DMF solution of pyrimidine (988mg, 4.56mmol), it is slowly increased to room temperature, is stirred overnight.The cancellation that adds water is reacted, and is evaporated off Solvent, the inverted column chromatographic isolation and purification of residue (water: acetonitrile=40:60) obtains light yellow solid (200mg).
LC-MS:tR=3.18min, 414.1 ([M+H]+)。
4th step: N-4-(the chloro-2-of 5-(isopropyl sulphonyl) phenyl)-N-2-(4-fluoro-2-methoxyl group-5-nitrobenzophenone)- The preparation of 5-(trifluoromethyl) pyrimidine-2,4-diamidogen
By chloro-for 2-N-(the chloro-2-of 5-(isopropyl sulphonyl) phenyl)-5-(trifluoromethyl) pyrimidine-4-amine (200mg, 0.483mmol) it is dissolved in 1,4-dioxane (15ml) with 4-fluoro-2-methoxyl group-5-nitroaniline (135mg, 0.724mmol) In, add p-methyl benzenesulfonic acid (166mg, 0.966mmol), be heated to 140 DEG C and react three hours, be cooled to room temperature, solvent is evaporated off, The inverted column chromatographic isolation and purification of residue obtain N-4-(the chloro-2-of 5-(isopropyl sulphonyl) phenyl)-N-2-(4-fluoro-2-methoxyl group- 5-nitrobenzophenone)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen (150mg).
LC-MS:tR=3.24min, 564.1 ([M+H]+)。
5th step: N-4-(the chloro-2-of 5-(isopropyl sulphonyl) phenyl)-N2-(4-((2-(dimethylamino) ethyl) (methyl) Amino)-2-methoxyl group-5-nitrobenzophenone) preparation of-5-(trifluoromethyl) pyrimidine-2,4-diamidogen
By N-4-(the chloro-2-of 5-(isopropyl sulphonyl) phenyl)-N-2-(4-fluoro-2-methoxyl group-5-nitrobenzophenone)-5-(three Methyl fluoride) pyrimidine-2,4-diamidogen (150mg) is dissolved in DMF (5ml), adds 0.2mL trimethyl ethylenediamine, is heated to 125 DEG C instead Answer 2 hours, solvent is evaporated off, obtain thick product (120mg).
6th step: N-4-(4-((the chloro-2-of 5-(isopropyl sulphonyl) phenyl) amino)-5-(trifluoromethyl) pyrimidine-2-base)- The preparation of N1-(2-(dimethylamino) ethyl)-5-methoxyl group-N1-methylbenzene-1,2,4-triamine
The thick product (120mg) that previous step reaction obtains is dissolved in ethanol, adds ammonium chloride (100mg), iron powder (80mg), heating reflux reaction 2 hours, reacts complete, is cooled to room temperature, filter, collect filtrate, filtrate solvent is evaporated off, strengthen Amount water dilution residue, isopropanol-dichloromethane mixed solvent (1:3) aqueous phase extracted three times, merge organic facies, organic facies is evaporated off Solvent, obtains thick product (60mg).
LC-MS:tR=2.48min, 616.3 ([M+H]+)。
7th step: N-(5-((4-((the chloro-2-of 5-(isopropyl sulphonyl) phenyl) amino)-5-(trifluoromethyl) pyrimidine-2- Base) amino)-2-((2-(dimethylamino) ethyl) (methyl) amino)-4-anisyl) preparation of acryloyl group amide
The thick product (60mg, 0.097mmol) that previous step reaction obtains is dissolved in 5 milliliters of anhydrous tetrahydro furans, 0 DEG C Under, nitrogen protect, add 0.1mL diisopropyl ethyl amine, 1M acryloyl chloride tetrahydrofuran solution (0.15mL) be slowly added dropwise into In above-mentioned solution, react half an hour at 0 DEG C, add 2 milliliters of saturated sodium bicarbonate aqueous solution cancellation reactions, oxolane is evaporated off, The inverted column chromatographic isolation and purification of residue obtains final products (25.6mg).
LC-MS:tR=2.50min, 670.3 ([M+H]+)；
1HNMR(CD3OD,
400MHz)δ:8.47(s,1H),8.27(br,1H),8.09(s,1H),7.85(d,1H),7.35(d,1H),6.98 (s,1H),6.56(m,1H),6.33(m,1H),5.83(d,1H),3.96(s,3H),3.46(m,2H),3.37(m,1H),3.31 (m,2H),2.91(s,6H),2.70(s,3H),1.29(d,6H)；
F-NMR:-62.49。
Embodiment two: N-(2-((2-(dimethylamino) ethyl) (methyl) amino)-5-((4-((2-(isopropyl sulphonyl)- 5-(trifluoromethyl) phenyl) amino)-5-(trifluoromethyl) pyrimidine-2-base) amino)-4-anisyl) acryloyl group amide Preparation
The first step: the preparation of isopropyl (2-nitro-4-(trifluoromethyl) phenyl) sulfane
Take 100mL single port bottle, add 1-fluoro-2-nitro-4-(trifluoromethyl) benzene (1g) and 15mL DMF, potassium carbonate (3.3g) being separately added in above-mentioned solution with isopropyl mercaptan (0.72g), 50 DEG C are stirred 3 hours, are cooled to 0 DEG C, add 2ml NaOH (1M) aqueous solution, ethyl acetate extracts, and is dried, and concentrates, obtains white solid (2.5g).
1H NMR (400MHz, CDCl3) δ 8.44 (s, 1H), 7.76 (d, J=8.5Hz, 1H), 7.76 (d, J=8.5Hz, 1H), 7.58 (d, J=8.5Hz, 1H), 7.58 (d, J=8.5Hz, 1H), 3.62 (dt, J=13.3,6.7Hz, 1H), 3.62 (dt, J=13.3,6.7Hz, 1H), 1.44 (d, J=6.7Hz, 6H).
The preparation of second step: 1-(isopropyl sulphonyl)-2-nitro-4-(trifluoromethyl) benzene
Take 50mL single port bottle, be sequentially added into isopropyl (2-nitro-4-(trifluoromethyl) phenyl) sulfane (2,5g), m-chloro mistake Oxybenzoic acid (4g), 50ml dichloromethane, this mixture is stirred at room temperature 5 hours, addition saturated sodium bicarbonate aqueous solution, and two Chloromethanes extracts, and is concentrated to give white solid (2g).
The preparation of the 3rd step: 1-(isopropyl sulphonyl)-2-amino-4-(trifluoromethyl) benzene
Take 100mL single port bottle, be sequentially added into 1-(isopropyl sulphonyl)-2-nitro-4-(trifluoromethyl) benzene (900mg), ferrum Powder (1.7g), ammonium chloride (3.27g), 50ml ethanol and 2ml water.Stirring 1 hour at 70 DEG C, filter, filtrate concentrates, ethyl acetate Extraction, obtains yellow solid (840mg).
The 4th chloro-N-of step: 2-(2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl)-5-(trifluoromethyl) pyrimidine-4-amine Preparation
1-(isopropyl sulphonyl)-2-amino-4-(trifluoromethyl) benzene (800mg, 2.993mmol) is dissolved in dry DMF (10mL) in, under ice bath, it is dividedly in some parts NaH (359mg, 8.979mmol), after stirring 20 minutes, gained suspension is added 2, In the DMF (5mL) of 4-bis-chloro-5-trifluoromethyl pyrimidine (714mg, 3.292mmol), reaction is stirred 2 hours under ice bath, LCMS Display reaction is completely.The saturated NH of reactant liquor4Cl (3mL) cancellation, concentrates after doing, with dichloromethane (20mL), water (20mL) point Layer, organic facies dry filter concentrates, and residue obtains the chloro-N-of 2-(2-(isopropyl sulphonyl)-5-(trifluoro by rapid column chromatography Methyl) phenyl)-5-(trifluoromethyl) pyrimidine-4-amine (130mg, 9.7%).
5th step: N-2-(4-fluoro-2-methoxyl group-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-(fluoroform Base) phenyl) preparation of-5-(trifluoromethyl) pyrimidine-2,4-diamidogen
By chloro-for 2-N-(2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl)-5-(trifluoromethyl) pyrimidine-4-amine (130mg, 0.29mmol), 4-fluoro-2-methoxyl group-5-nitroaniline (54mg, 0.29mmol), p-methyl benzenesulfonic acid (55mg, 0.29mmol) it is dissolved in 2-amylalcohol (10mL).Reaction is heated to 120 DEG C, stirs 3 hours, and completely, reactant liquor is dense in LCMS display reaction Contracting, residue adds water (10mL), methanol (5mL), after mixture stirs 10 minutes, filters, and filter cake methyl tertiary butyl ether(MTBE) is washed After obtain crude product (170mg).
6th step: N-2-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxyl group-5-nitrobenzophenone)-N- The preparation of 4-(2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen
The thick product (170mg, 0.285mmol) that previous step reaction is obtained, triethylamine (86mg, 0.854mmol), N, N, N-trimethyl ethylenediamine (87mg, 0.854mmol) is dissolved in DMF (5mL), and reaction is heated to 120 DEG C and stirs 1 hour, and LCMS shows Showing that reaction, reaction concentrate dry, residue obtains N-2-(4-((2-(dimethylamino) ethyl) (methyl) ammonia by rapid column chromatography Base)-2-methoxyl group-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl)-5-(trifluoromethyl) is phonetic Pyridine-2,4-diamidogen (110mg, 57%).
7th step: N-1-(2-(dimethylamino) ethyl)-N-4-(4-((2-(isopropyl sulphonyl)-5-(trifluoromethyl) benzene Base) amino)-5-(trifluoromethyl) pyrimidine-2-base) preparation of-5-methoxyl group-N1-methylbenzene-1,2,4-triamine
N-2-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxyl group-5-nitrobenzophenone)-N-4-(2- (isopropyl sulphonyl)-5-(trifluoromethyl) phenyl)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen (110mg, 0.162mmol) is dissolved in Methanol (20mL), adds Pd/C (20mg).Reaction stirs 10min, LCMS display reaction completely under hydrogen, reacting liquid filtering, Filtrate is spin-dried for, and residue obtains N-1-(2-(dimethylamino) ethyl)-N-4-(4-((2-(isopropyl sulphur by reversed-phase column purification Acyl)-5-(trifluoromethyl) phenyl) amino)-5-(trifluoromethyl) pyrimidine-2-base)-5-methoxyl group-N1-methylbenzene-1,2,4-three Amine (80mg, 76.2%).
8th step: N-(2-((2-(dimethylamino) ethyl) (methyl) amino)-5-((4-((2-(isopropyl sulphonyl)-5- (trifluoromethyl) phenyl) amino)-5-(trifluoromethyl) pyrimidine-2-base) amino)-4-anisyl) system of acryloyl group amide Standby
By N-1-(2-(dimethylamino) ethyl)-N-4-(4-((2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl) ammonia Base)-5-(trifluoromethyl) pyrimidine-2-base)-5-methoxyl group-N1-methylbenzene-1,2,4-triamines (80mg, 0.123mmol), three second Amine (37mg, 0.369mmol) is dissolved in oxolane (30mL), and reactant liquor is cooled to-30 DEG C.Under nitrogen protection, it is slowly added to third Alkene acyl chlorides (0.37mL, 1.0M in THF).Reaction is stirred 30 minutes at-30 DEG C, and reaction terminates, and adds methanol (5mL) and continues Stirring 10 minutes, reactant liquor concentrates dry, and residue first passes through prepares the most inverted column purification after plate separates, and obtains final products (35mg, 40.4%).
m/z:704.5；
1H NMR (400MHz, MeOD) δ: 8.51 (s, 2H), 8.20 (s, 1H), 8.08 (d, J=8.2Hz, 1H), 7.65 (d, J=7.9Hz, 1H), 6.96 (s, 1H), 6.57 (dd, J=16.9,10.2Hz, 1H), 6.28 (d, J=17.1Hz, 1H), 5.80 (d, J=11.2Hz, 1H), 3.94 (s, 3H), 3.49 (dd, J=11.6,4.9Hz, 1H), 3.43 (t, J=7.7Hz, 2H), 3.29 (t, J=5.7Hz, 2H), 2.88 (s, 6H), 2.67 (s, 3H), 1.34 (d, J=6.8Hz, 6H).
Embodiment three: N-(2-((2-(dimethylamino) ethyl) (methyl) amino)-5-((4-((2-(isopropyl sulphonyl)- 5-aminomethyl phenyl) amino)-5-(trifluoromethyl) pyrimidine-2-base) amino)-4-anisyl) preparation of acryloyl group amide
The preparation of the first step: 1-(isopropyl sulphonyl)-4-methyl-2-Nitrobenzol
Fluoro-for 2-5 methyl Nitrobenzol (3.0g, 19.355mmol) are dissolved in DMF (50mL), add isopropyl mercaptan (2.95g, 38.71mmol) and potassium carbonate (8.01g, 58.065mmol).Reacting 60 degree to stir 2 hours, LCMS display has been reacted Entirely.Reactant liquor is dissolved in dichloromethane, washing, and saturated sodium-chloride is washed, and organic facies dry filter concentrates, and residue is dissolved in DCM (100mL), in, it is dividedly in some parts metachloroperbenzoic acid (8.35g, 48.387mmol).Stirring 16 hours, LCMS display has been reacted Entirely, reactant liquor saturated sodium sulfite (20mL) cancellation, organic facies saturated sodium bicarbonate aqueous solution (3X15mL) is washed, organic relevant Dry filtration, concentrate, residue by Flash silica column purification obtain 1-(isopropyl sulphonyl)-4-methyl-2-Nitrobenzol (4.2g, 91.3%).
The preparation of second step: 2-(isopropyl sulphonyl)-5-monomethylaniline.
By 1-(isopropyl sulphonyl)-4-methyl-2-Nitrobenzol (4.2g, 17.263mmol), ammonium chloride (9.236g, 172.6mmol) it is dissolved in ethanol (90mL), water (30mL), adds reduced iron powder (9.667g, 172.6mmol), be heated to reflux 3 little Time, completely, reacting liquid filtering, filtrate concentrates, and residue aqueous phase DCM (3X10mL) extracts, organic relevant in LCMS display reaction Dry filtration, concentrates, obtains 2-(isopropyl sulphonyl)-5-monomethylaniline. (3g, 81.5%) by Flash silica column purification.
The preparation of the 3rd chloro-N-of step: 2-(2-(isopropyl sulphonyl)-5-aminomethyl phenyl)-5-(trifluoromethyl) pyrimidine-4-amine
2-(isopropyl sulphonyl)-5-monomethylaniline. (875mg, 4.102mmol) is dissolved in dry DMF (15mL), at ice It is dividedly in some parts NaH (492mg, 12.307mmol) under bath, after stirring 20 minutes, gained suspension is added 2, the chloro-5-of 4-bis-tri- In the DMF (10mL) of l (979mg, 4.512mmol), reaction is stirred 2 hours under ice bath, and LCMS display has been reacted Entirely.The saturated NH of reactant liquor4Cl (3mL) cancellation, concentrates after doing, and with dichloromethane (20mL), water (20mL) is layered, organic relevant Dry filtering and concentrating, residue obtains the chloro-N-of 2-(2-(isopropyl sulphonyl)-5-aminomethyl phenyl)-5-(trifluoro by rapid column chromatography Methyl) pyrimidine-4-amine (211mg, 13.1%).
4th step: N-2-(4-fluoro-2-methoxyl group-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-methylbenzene Base) preparation of-5-(trifluoromethyl) pyrimidine-2,4-diamidogen
By chloro-for 2-N-(2-(isopropyl sulphonyl)-5-aminomethyl phenyl)-5-(trifluoromethyl) pyrimidine-4-amine (211mg, 0.536mmol), 4-fluoro-2-methoxyl group-5-nitroaniline (99.7mg, 0.536mmol), p-methyl benzenesulfonic acid (102mg, 0.536mmol) it is dissolved in 2-amylalcohol (10mL).Reaction is heated to 120 DEG C, stirs 3 hours, and LCMS display reaction is complete, reactant liquor Concentrating, residue adds water (10mL), methanol (5mL), after mixture stirs 10 minutes, filters, filter cake methyl tertiary butyl ether(MTBE) Crude product (291mg) is obtained after washing.
5th step: N-2-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxyl group-5-nitrobenzophenone)-N- The preparation of 4-(2-(isopropyl sulphonyl)-5-aminomethyl phenyl)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen
The crude product (291mg, 0.535mmol) that previous step reaction is obtained, triethylamine (163mg, 1.606mmol), N, N, N-trimethyl ethylenediamine (164mg, 1.606mmol) is dissolved in DMF (5mL), and reaction is heated to 120 DEG C and stirs 1 hour, and LCMS shows Showing that reaction, reaction concentrate dry, residue obtains N-2-(4-((2-(dimethylamino) ethyl) (methyl) ammonia by rapid column chromatography Base)-2-methoxyl group-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-aminomethyl phenyl)-5-(trifluoromethyl) pyrimidine-2, 4-diamidogen (78mg, 23.3%).
6th step: N-1-(2-(dimethylamino) ethyl)-N-4-(4-((2-(isopropyl sulphonyl)-5-aminomethyl phenyl) ammonia Base)-5-(trifluoromethyl) pyrimidine-2-base) preparation of-5-methoxyl group-N1-methylbenzene-1,2,4-triamine
N-2-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxyl group-5-nitrobenzophenone)-N-4-(2- (isopropyl sulphonyl)-5-aminomethyl phenyl)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen (78mg, 0.125mmol) is dissolved in methanol (20mL), Pd/C (20mg) is added.Reaction stirs 10min, LCMS display reaction completely under hydrogen, reacting liquid filtering, filtrate Be spin-dried for, residue by reversed-phase column purification obtain N-1-(2-(dimethylamino) ethyl)-N-4-(4-((2-(isopropyl sulphonyl)- 5-aminomethyl phenyl) amino)-5-(trifluoromethyl) pyrimidine-2-base)-5-methoxyl group-N1-methylbenzene-1,2,4-triamine (65mg, 87.8%).
7th step: N-(2-((2-(dimethylamino) ethyl) (methyl) amino)-5-((4-((2-(isopropyl sulphonyl)-5- Aminomethyl phenyl) amino)-5-(trifluoromethyl) pyrimidine-2-base) amino)-4-anisyl) preparation of acryloyl group amide
By N-1-(2-(dimethylamino) ethyl)-N-4-(4-((2-(isopropyl sulphonyl)-5-aminomethyl phenyl) amino)-5- (trifluoromethyl) pyrimidine-2-base)-5-methoxyl group-N1-methylbenzene-1,2,4-triamines (65mg, 0.109mmol), triethylamine (33mg, 0.327mmol) is dissolved in oxolane (30mL), and reactant liquor is cooled to-30 DEG C.Under nitrogen protection, it is slowly added to propylene Acyl chlorides (0.33mL, 1M in THF).Reaction is stirred 30 minutes at-30 DEG C, and reaction terminates, and adds methanol (5mL) and continues stirring 10 minutes, reactant liquor concentrated dry, and residue first passes through to prepare crosses column purification inverted after plate separates, and obtains final products (5mg, 7.04%).
m/z:650.5；
1H NMR (400MHz, MeOD) δ: 8.44 (s, 1H), 7.92 (d, J=16.2Hz, 2H), 7.78 (d, J=8.1Hz, 1H), 7.21 (d, J=7.9Hz, 1H), 6.95 (s, 1H), 6.46 (ddd, J=18.8,16.9,5.9Hz, 2H), 5.89 (dd, J =9.9,1.9Hz, 1H), 3.96 (s, 3H), 3.45 (t, J=5.7Hz, 2H), 3.34 3.32 (m, 4H), 3.28 (dd, J= 11.1,5.2Hz, 2H), 2.87 (s, 6H), 2.69 (s, 3H), 2.35 (s, 3H), 1.28 (d, J=6.8Hz, 6H).
Embodiment four: N-(2-((2-(dimethylamino) ethyl) (methyl) amino)-5-((4-((2-(isopropyl sulphonyl)- 5-anisyl) amino)-5-(trifluoromethyl) pyrimidine-2-base) amino)-4-anisyl) preparation of acryloyl group amide
The preparation of the first step: 1-(isopropyl sulphonyl)-4-methoxyl group-2-Nitrobenzol
Isopropyl (4-methoxyl group-2-nitrobenzophenone) sulfane (2.0g, 8.8mmol) is dissolved in DCM (20mL), adds in batches Enter metachloroperbenzoic acid (3.8g, 22.0mmol).Stirring 16 hours, LCMS display reaction is complete, the saturated sulfurous acid of reactant liquor Sodium (20mL) cancellation, organic facies saturated sodium bicarbonate aqueous solution (3X15mL) washes, organic facies dry filter, concentrates, residue Yellow solid (1.8g, 78%) is obtained by Flash silica column purification.
The preparation of second step: 1-(isopropyl sulphonyl)-4-methoxyl group-2-aniline
By 1-(isopropyl sulphonyl)-4-methoxyl group-2-Nitrobenzol (1.8g, 6.94mmol), ammonium chloride (3.8g, 69.4mmol) it is dissolved in methanol (10mL), THF (10mL), water (10), adds reduced iron powder (3.7g, 69.4mmol), be heated to reflux 3 hours, completely, reacting liquid filtering, filtrate concentrates removed methanol and THF, residue aqueous phase DCM in LCMS display reaction (3X10mL) extraction, organic facies dry filter, concentrate, obtain light yellow solid (1.5g, 85%) by Flash silica column purification.
The preparation of the 3rd chloro-N-of step: 2-(2-(isopropyl sulphonyl)-5-anisyl)-5-(trifluoromethyl) pyrimidine-4-amine
1-(isopropyl sulphonyl)-4-methoxyl group-2-aniline (400mg, 1.74mmol) is dissolved in dry DMF (10mL), Under ice bath, it is dividedly in some parts NaH (140mg, 3.48mmol), after stirring 20 minutes, gained suspension is added 2, the chloro-5-of 4-bis- In the DMF (10mL) of methylpyrimidine (570mg, 2.62mmol), reaction is stirred 2 hours under ice bath, and LCMS display reaction is completely. The saturated NH of reactant liquor4Cl (3mL) cancellation, concentrates after doing, with dichloromethane (20mL), water (20mL), organic facies dry filter Concentrating, residue obtains the chloro-N-of 2-(2-(isopropyl sulphonyl)-5-anisyl)-5-(trifluoromethyl) by rapid column chromatography Pyrimidine-4-amine (400mg, 55%).
4th step: N-2-(4-fluoro-2-methoxyl group-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-methoxy benzene Base) preparation of-5-(trifluoromethyl) pyrimidine-2,4-diamidogen
By chloro-for 2-N-(2-(isopropyl sulphonyl)-5-anisyl)-5-(trifluoromethyl) pyrimidine-4-amine (300mg, 0.73mmol), 4-fluoro-2-methoxyl group-5-nitroaniline (162mg, 0.88mmol), p-methyl benzenesulfonic acid (210mg, 1.1mmol) It is dissolved in 1,4-dioxane (20mL).Reaction is heated to 110 DEG C, stirs 16 hours, and completely, reactant liquor is dense in LCMS display reaction Contracting, residue adds water (10mL), methanol (5mL), after mixture stirs 10 minutes, filters, and filter cake methyl tertiary butyl ether(MTBE) is washed After obtain crude product (400mg).
5th step: N-2-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxyl group-5-nitrobenzophenone)-N- The preparation of 4-(2-(isopropyl sulphonyl)-5-anisyl)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen
By N-2-(4-fluoro-2-methoxyl group-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-anisyl)-5- (trifluoromethyl) pyrimidine-2,4-diamidogen (400mg, 0.71mmol), triethylamine (0.5mL), N, N, N-trimethyl ethylenediamine (150mg, 1.42mmol) is dissolved in DMF (10mL), and reaction is heated to 110 DEG C and stirs 2 hours, and LCMS shows reaction, reacts dense Contracting is dry, and residue dichloromethane (20mL), water (20mL) are layered, and are filtered by insoluble matter, and organic facies is dried, and filters, and concentrates, surplus Excess obtains yellow solid (200mg, 50%) by rapid column chromatography.
6th step: N-1-(2-(dimethylamino) ethyl)-N-4-(4-((2-(isopropyl sulphonyl)-5-anisyl) ammonia Base)-5-(trifluoromethyl) pyrimidine-2-base) preparation of-5-methoxyl group-N1-methylbenzene-1,2,4-triamine
N-2-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxyl group-5-nitrobenzophenone)-N-4-(2- (isopropyl sulphonyl)-5-anisyl)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen (200mg, 0.31mmol) is dissolved in methanol (20mL), Pd/C (20mg) is added.Reaction stirs 10min, LCMS display reaction completely under hydrogen, reacting liquid filtering, filtrate Be spin-dried for, residue by reversed-phase column purification obtain N-1-(2-(dimethylamino) ethyl)-N-4-(4-((2-(isopropyl sulphonyl)- 5-anisyl) amino)-5-(trifluoromethyl) pyrimidine-2-base)-5-methoxyl group-N1-methylbenzene-1,2,4-triamine (150mg, 75%).
7th step: N-(2-((2-(dimethylamino) ethyl) (methyl) amino)-5-((4-((2-(isopropyl sulphonyl)-5- Anisyl) amino)-5-(trifluoromethyl) pyrimidine-2-base) amino)-4-anisyl) preparation of acryloyl group amide
By N-1-(2-(dimethylamino) ethyl)-N-4-(4-((2-(isopropyl sulphonyl)-5-anisyl) amino)-5- (trifluoromethyl) pyrimidine-2-base)-5-methoxyl group-N1-methylbenzene-1,2,4-triamines (150mg, 0.24mmol), triethylamine (0.3mL) being dissolved in oxolane (20mL), reactant liquor is cooled to-10 to-5 DEG C.Under nitrogen protection, it is slowly added to acryloyl chloride (0.36mL,1M in THF).Reaction is stirred 30 minutes at-10 to-5 DEG C, and reaction terminates, and adds methanol (3mL) and continues stirring 10 minutes, reactant liquor concentrated dry, and residue first passes through prepares the most inverted column purification after plate separates, obtain final products (15mg, 10%).
m/z:666.3；
1H NMR (400MHz, MeOD) δ: 8.46 (s, 1H), 8.03 (s, 1H), 7.80 (d, J=8.9Hz, 1H), 7.74 (s, 1H), 6.96 (s, 1H), 6.90 (dd, J=8.9,2.1Hz, 1H), 6.63 6.29 (m, 2H), 5.87 (dd, J=9.9, 1.8Hz, 1H), 3.96 (s, 3H), 3.73 (s, 3H), 3.47 (t, J=5.6Hz, 2H), 3.28 (t, J=6.4Hz, 3H), 2.88 (s, 6H), 2.70 (s, 3H), 1.28 (d, J=6.8Hz, 6H).
Embodiment five: N-(5-((the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-anisyl) amino) pyrimidine-2-base) ammonia Base)-2-((2-(dimethylamino) ethyl) (methyl) amino)-4-anisyl) preparation of acryloyl group amide
The preparation of the chloro-N-of the first step: 2,5-bis-(2-(isopropyl sulphonyl)-5-anisyl) pyrimidine-4-amine
1-(isopropyl sulphonyl)-4-methoxyl group-2-aniline (350mg, 1.52mmol) is dissolved in dry DMF (10mL), Under ice bath, it is dividedly in some parts NaH (120mg, 3.0mmol), after stirring 20 minutes, gained suspension is added 2,4-bis-chloro-5-first In the DMF (10mL) of yl pyrimidines (420mg, 2.28mmol), reaction is stirred 2 hours under ice bath, and LCMS display reaction is completely.Instead Answering liquid saturated NH4Cl (3mL) cancellation, concentrate after doing, with dichloromethane (20mL), water (20mL), organic facies dry filter is dense Contracting, residue obtains product (300mg, 52%) by rapid column chromatography.
The chloro-N-2-of second step: 5-(4-fluoro-2-methoxyl group-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-methoxy Phenyl) preparation of pyrimidine-2,4-diamidogen
By chloro-for 2,5-bis-N-(2-(isopropyl sulphonyl)-5-anisyl) pyrimidine-4-amine (300mg, 0.79mmol), 4- Fluoro-2-methoxyl group-5-nitroaniline (180mg, 0.96mmol), p-methyl benzenesulfonic acid (225mg, 1.2mmol) is dissolved in 1,4-dioxy Six rings (20mL).Reaction is heated to 120 DEG C, stirs 16 hours, and completely, reactant liquor concentrates, and residue adds in LCMS display reaction Water (10mL), methanol (5mL), after mixture stirs 10 minutes, filter, filter cake methyl tertiary butyl ether(MTBE) obtains crude product after washing (400mg)。
The 3rd chloro-N-2-of step: 5-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxyl group-5-Nitrobenzol Base) preparation of-N-4-(2-(isopropyl sulphonyl)-5-anisyl) pyrimidine-2,4-diamidogen
By chloro-for 5-N-2-(4-fluoro-2-methoxyl group-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-anisyl) Pyrimidine-2,4-diamidogen (400mg, 0.70mmol), triethylamine (1mL), N, N, N-trimethyl ethylenediamine (140mg, 1.4mmol) are molten In DMF (10mL), reaction is heated to 110 DEG C and stirs 2 hours, and LCMS shows that reaction, reaction concentrate dry, residue dichloromethane Alkane (20mL), water (20mL) is layered, and is filtered by insoluble matter, and organic facies is dried, and filters, and concentrates, and residue passes through rapid column chromatography Obtain product (150mg, 34%).
4th step: N-4-(the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-anisyl) amino) pyrimidine-2-base)-N-1- The preparation of (2-(dimethylamino) ethyl)-5-methoxyl group-N1-methylbenzene-1,2,4-triamine
Chloro-for 5-N-2-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxyl group-5-nitrobenzophenone)-N- 4-(2-(isopropyl sulphonyl)-5-anisyl) pyrimidine-2,4-diamidogen (100mg, 0.16mmol) is dissolved in methanol (5mL), adds Pd/C(20mg).Reaction stirs 10min, LCMS display reaction completely under hydrogen, and reacting liquid filtering, filtrate is spin-dried for, residue Product (80mg, 80%) is obtained by reversed-phase column purification.
5th step: N-(5-((the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-anisyl) amino) pyrimidine-2-base) ammonia Base)-2-((2-(dimethylamino) ethyl) (methyl) amino)-4-anisyl) preparation of acryloyl group amide
By N-4-(the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-anisyl) amino) pyrimidine-2-base)-N-1-(2-(two Methylamino) ethyl)-5-methoxyl group-N1-methylbenzene-1,2,4-triamines (80mg, 0.12mmol), triethylamine (0.5mL) is dissolved in four Hydrogen furan (20mL), reactant liquor is cooled to-10 to-5 DEG C.Under nitrogen protection, it is slowly added to acryloyl chloride (0.3mL, 1M in THF).Reaction is stirred 30 minutes at-10 to-5 DEG C, and reaction terminates, and adds methanol (3mL) and continues stirring 10 minutes, reactant liquor Concentrating dry, residue first passes through to prepare crosses column purification inverted after plate separates, and obtains final products (15mg, 15%).
m/z:632.2；
1H NMR (400MHz, MeOD) δ: 8.11 (s, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.70 (d, J= 8.9Hz, 1H), 6.85 (s, 1H), 6.79 (dd, J=8.9,2.5Hz, 1H), 6.41 (dd, J=16.9,10.1Hz, 1H), 6.27 (dd, J=16.9,1.8Hz, 1H), 5.73 (dd, J=10.1,1.8Hz, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 3.35 (t, J=5.8Hz, 2H), 3.22 3.13 (m, 3H), 2.77 (s, 6H), 2.59 (s, 3H), 1.16 (d, J=6.8Hz, 6H).
Embodiment six: N-(5-((the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl) amino) pyrimidine-2- Base) amino)-2-((2-(dimethylamino) ethyl) (methyl) amino)-4-anisyl) preparation of acryloyl group amide
The preparation of the chloro-N-of the first step: 2,5-bis-(2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl) pyrimidine-4-amine
Take 50mL single port bottle, be sequentially added into 1-(isopropyl sulphonyl)-2-amino-4-(trifluoromethyl) benzene (270mg), 2,4, 5-trichloropyrimidine (220mg), sodium hydride (36mg), DMF (15mL).React one hour under 0 DEG C of zero degree, add 100 milliliters Water is in reactant liquor, and dichloromethane extracts, and silica gel column chromatography (20%EA/PE) obtains white solid (380mg).
The chloro-N-2-of second step: 5-(4-fluoro-2-methoxyl group-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-(three Methyl fluoride) phenyl) preparation of pyrimidine-2,4-diamidogen
Take 100mL single port bottle, add 2, the chloro-N-of 5-bis-(2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl) pyrimidine-4- Amine (380mg), 4-fluoro-2-methoxyl group-5-nitroaniline (170mg) and p-methyl benzenesulfonic acid (158mg), be dissolved in 2-amylalcohol (20mL), react 3 hours at 120 DEG C.NaHCO is added after cooling3Aqueous solution, stirs 30 minutes, filters, and collects solid and obtains Huang Color solid (400mg).
The 3rd chloro-N-2-of step: 5-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxyl group-5-Nitrobenzol Base) preparation of-N-4-(2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl) pyrimidine-2,4-diamidogen
Taking 100mL single port bottle, (2-is (different for-N-4-to be separately added into the chloro-N-2-of 5-(4-fluoro-2-methoxyl group-5-nitrobenzophenone) Sulfonyl propyl)-5-(trifluoromethyl) phenyl) pyrimidine-2,4-diamidogen (400mg), N, N, N ,-3-Methylethyl-diamidogen (108mg), DIPEA (183mg) and 5ml DMF, react 1 hour at 100 DEG C, concentrate, dichloromethane extracts, and obtains thick product (400mg)。
4th step: N-4-(the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl) amino) pyrimidine-2-base)- The preparation of N-1-(2-(dimethylamino) ethyl)-5-methoxyl group-N-1-methylbenzene-1,2,4-triamine
Take 100mL single port bottle, be separately added into the chloro-N-2-of 5-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-first Epoxide-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl) pyrimidine-2,4-diamidogen (400mg), ferrum Powder (347mg), ammonium chloride (670mg) and 20mL ethanol and 7mL water.Reacting 3 hours at 70 DEG C, 100mL ethanol adds reactant liquor, Filter, concentrate, extract with dichloromethane, obtain thick product (380mg).
5th step: N-(5-((the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl) amino) pyrimidine-2- Base) amino)-2-((2-(dimethylamino) ethyl) (methyl) amino)-4-anisyl) preparation of acryloyl group amide
Take 100mL single port bottle, add N-4-(the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-(trifluoromethyl) phenyl) amino) Pyrimidine-2-base)-N-1-(2-(dimethylamino) ethyl)-5-methoxyl group-N-1-methylbenzene-1,2,4-triamines (380mg), DIPEA (221mg) with 100mL THF, it is cooled to-10 DEG C, then dropping 0.5ml acryloyl chloride (1M tetrahydrofuran solution), continues stirring 2 hours, methanol cancellation, concentrate, residue reversed phase column chromatography unexpectedly obtains final products (180mg).
m/z:670.2；
1H NMR (400MHz, MeOD) δ: 8.60 (s, 1H), 8.27 (s, 1H), 8.19 8.00 (m, 2H), 7.66 (d, J= 8.0Hz, 1H), 6.96 (s, 1H), 6.68 6.49 (m, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.2Hz, 1H), 3.90 (s, 3H), 3.51 3.27 (m, 5H), 2.87 (s, 6H), 2.67 (s, 3H), 1.31 (d, J=6.7Hz, 6H).
Embodiment seven: N-(5-((the chloro-4-of 5-((2-(isopropyl sulphonyl) the chloro-phenyl of-5-) amino) pyrimidine-2-base) ammonia Base)-2-((2-(dimethylamino) ethyl) (methyl) amino)-4-anisyl) preparation of acryloyl group amide
The preparation of the chloro-N-of the first step: 2-(the chloro-2-of 5-(isopropyl sulphonyl) phenyl)-5-chloropyrimide-4-amine
Chloro-for 4-2-(isopropyl sulphonyl) aniline (700mg, 3.00mmol) is dissolved in dry DMF, at 0 DEG C, adds hydrogenation Sodium (243mg, 6.08mmol), stirs half an hour, at 0 DEG C, is added drop-wise to by this suspended matter dissolved with 2,4,5-trichloropyrimidines (600mg, In 3.29mmol), it is slowly increased to room temperature, is stirred overnight.The cancellation that adds water is reacted, and solvent is evaporated off, and the inverted column chromatography of residue divides Product (600mg) is obtained from purification (water: acetonitrile=40:60).
LC-MS:tR=3.18min, 380.0 ([M+H]+).
The chloro-N-4-of second step: 5-(the chloro-2-of 5-(isopropyl sulphonyl) phenyl)-N-2-(4-fluoro-2-methoxyl group-5-Nitrobenzol Base) preparation of pyrimidine-2,4-diamidogen
By chloro-for 2-N-(the chloro-2-of 5-(isopropyl sulphonyl) phenyl)-5-chloropyrimide-4-amine (600mg, 1.58mmol) and 4- Fluoro-2-methoxyl group-5-nitroaniline (350mg, 1.89mmol) is dissolved in 2-amylalcohol, addition p-methyl benzenesulfonic acid (410mg, 2.36mmol), being heated to 140 DEG C and react three hours, be cooled to room temperature, solvent is evaporated off, residue reversed phase column chromatography is isolated and purified Obtain product (400mg).
LC-MS:tR=3.24min, 530.0 ([M+H]+).
The 3rd chloro-N4-of step: 5-(the chloro-2-of 5-(isopropyl sulphonyl) phenyl)-N2-(4-((2-(dimethylamino) ethyl) (first Base) amino)-2-methoxyl group-5-nitrobenzophenone) preparation of pyrimidine-2,4-diamidogen
By phonetic for chloro-for 5-N-4-(the chloro-2-of 5-(isopropyl sulphonyl) phenyl)-N-2-(4-fluoro-2-methoxyl group-5-nitrobenzophenone) Pyridine-2,4-diamidogen (400mg) is dissolved in DMF, adds 0.5mL trimethyl ethylenediamine, is heated to 125 DEG C of reactions, after 2 hours, instead Should be complete.Solvent is evaporated off, obtains thick product, the most purified be directly used in the next step.
LC-MS:tR=2.54min, 612.1 ([M+H]+).
4th step: N-4-(the chloro-4-of 5-((the chloro-2-of 5-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base)-N-1-(2- (dimethylamino) ethyl) preparation of-5-methoxyl group-N-1-methylbenzene-1,2,4-triamine
The crude product (300mg) that previous step reaction obtains is dissolved in ethanol, adds ammonium chloride (300mg), iron powder (200mg), heating reflux reaction 2 hours, reacts complete.It is cooled to room temperature, filters, collect filtrate, solvent is evaporated off, adds a large amount of water Dilution residue, isopropanol-dichloromethane mixed solvent (1:3) aqueous phase extracted three times, merge organic facies, organic mix is evaporated off Agent, obtains thick product (150mg), the most purified direct plunges into next step.
LC-MS:tR=2.37min, 582.1 ([M+H]+).
5th step: N-(5-((the chloro-4-of 5-((the chloro-2-of 5-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino)- 2-((2-(dimethylamino) ethyl) (methyl) amino)-4-anisyl) preparation of acryloyl group amide
Being dissolved in anhydrous tetrahydro furan by the crude product (150mg, 0.26mmol) that previous step reaction obtains, at 0 DEG C, nitrogen is protected Protecting, add 0.3mL diisopropyl ethyl amine, 1M acryloyl chloride tetrahydrofuran solution (0.4mL) is slowly added dropwise in above-mentioned solution, Reacting half an hour at 0 DEG C, oxolane is evaporated off, residue reversed phase column chromatography is isolated and purified obtains final products (52mg).
LC-MS:tR=2.38min, 636.1 ([M+H]+)；
1HNMR(400MHz,CD3OD) δ:
8.45(s,1H),8.26(br,1H),8.09(s,1H),7.86(d,1H),7.37(dd,1H),7.00(s,1H), 6.60(m,1H),6.32(d,1H),5.79(d,1H),3.95(s,3H),3.46(m,2H),3.39(m,1H),3.33(m,2H), 2.89(s,6H),2.71(s,3H),1.29(d,6H)。
Embodiment eight: N-(5-((5-methyl-4-((2-(isopropyl sulphonyl) the chloro-phenyl of-5-) amino) pyrimidine-2-base) ammonia Base)-2-((2-(dimethylamino) ethyl) (methyl) amino)-4-anisyl) preparation of acryloyl group amide
The preparation of the chloro-N-of the first step: 2,5-bis-(2-(isopropyl sulphonyl)-5-aminomethyl phenyl) pyrimidine-4-amine
2-(isopropyl sulphonyl)-5-monomethylaniline. (800mg, 3.751mmol) is dissolved in dry DMF (15mL), at ice It is dividedly in some parts NaH (450mg, 11.252mmol) under bath, after stirring 20 minutes, gained suspension is added 2,4,5-trichloropyrimidines In the DMF (5mL) of (757mg, 4.126mmol), reaction is stirred 1 hour under ice bath, and LCMS display reaction is completely.Reactant liquor is used Saturated NH4Cl (3mL) cancellation, concentrates after doing, and with dichloromethane (20mL), water (20mL) is layered, and organic facies dry filter concentrates, Residue obtains the chloro-N-of 2,5-bis-(2-(isopropyl sulphonyl)-5-aminomethyl phenyl) pyrimidine-4-amine by rapid column chromatography (470mg, 34.8%).
The chloro-N-2-of second step: 5-(4-fluoro-2-methoxyl group-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-methyl Phenyl) preparation of pyrimidine-2,4-diamidogen
By chloro-for 2,5-bis-N-(2-(isopropyl sulphonyl)-5-aminomethyl phenyl) pyrimidine-4-amine (470mg, 1.309mmol), 4- Fluoro-2-methoxyl group-5-nitroaniline (243mg, 1.309mmol), p-methyl benzenesulfonic acid (243mg, 1.309mmol) is dissolved in 2-amylalcohol (10mL).Reaction is heated to 120 DEG C, stirs 3 hours, and completely, reactant liquor concentrates, and residue adds water in LCMS display reaction (10mL), methanol (5mL), after mixture stirs 10 minutes, filter, filter cake methyl tertiary butyl ether(MTBE) obtains crude product after washing (530mg)。
The 3rd chloro-N-2-of step: 5-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxyl group-5-Nitrobenzol Base) preparation of-N-4-(2-(isopropyl sulphonyl)-5-aminomethyl phenyl) pyrimidine-2,4-diamidogen
The crude product (530mg, 1.039mmol) that previous step reaction is obtained, triethylamine (317mg, 3.118mmol), N, N, N-trimethyl ethylenediamine (318mg, 3.118mmol) is dissolved in DMF (10mL), and reaction is heated to 120 DEG C and stirs 1 hour, LCMS Display reaction, reaction concentrates dry, and residue obtains the chloro-N-2-of 5-(4-((2-(dimethylamino) ethyl) by rapid column chromatography (methyl) amino)-2-methoxyl group-5-nitrobenzophenone)-N-4-(2-(isopropyl sulphonyl)-5-aminomethyl phenyl) pyrimidine-2,4-diamidogen (365mg, 59.3%).
4th step: N-4-(the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-aminomethyl phenyl) amino) pyrimidine-2-base)-N-1- The preparation of (2-(dimethylamino) ethyl)-5-methoxyl group-N-1-methylbenzene-1,2,4-triamine
Chloro-for 5-N-2-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxyl group-5-nitrobenzophenone)-N- 4-(2-(isopropyl sulphonyl)-5-aminomethyl phenyl) pyrimidine-2,4-diamidogen (365mg, 0.616mmol) is dissolved in methanol (20mL), adds Enter Pd/C (40mg).Reaction stirs 10min, LCMS display reaction completely under hydrogen, reacting liquid filtering, and filtrate is spin-dried for, residue Thing by reversed-phase column purification obtain N-4-(the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-aminomethyl phenyl) amino) pyrimidine-2-base)- N-1-(2-(dimethylamino) ethyl)-5-methoxyl group-N-1-methylbenzene-1,2,4-triamine (150mg, 43.4%).
5th step: N-(5-((the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-aminomethyl phenyl) amino) pyrimidine-2-base) ammonia Base)-2-((2-(dimethylamino) ethyl) (methyl) amino)-4-anisyl) preparation of acryloyl group amide
By N-4-(the chloro-4-of 5-((2-(isopropyl sulphonyl)-5-aminomethyl phenyl) amino) pyrimidine-2-base)-N-1-(2-(two Methylamino) ethyl)-5-methoxyl group-N-1-methylbenzene-1,2,4-triamines (150mg, 0.267mmol), triethylamine (81mg, 0.801mmol) being dissolved in oxolane (50mL), reactant liquor is cooled to-30 DEG C.Under nitrogen protection, it is slowly added to acryloyl chloride (0.8mL,1M in THF).Reaction is stirred 30 minutes at-30 DEG C, and reaction terminates, and adds methanol (10mL) and continues stirring 10 points Clock, reactant liquor concentrates dry, residue first pass through prepare after plate separates the most inverted cross column purification obtain final products (24mg, 14.6%).
m/z:617.1；
1H NMR (400MHz, MeOD) δ: 8.23 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.80 (d, J= 8.1Hz, 1H), 7.25 (d, J=7.9Hz, 1H), 6.99 (s, 1H), 6.59 (dd, J=16.9,10.2Hz, 1H), 6.38 (dd, J =16.9,1.6Hz, 1H), 5.85 (dd, J=10.2,1.6Hz, 1H), 3.94 (s, 3H), 3.46 (t, J=5.8Hz, 2H), 3.37 (dd, J=13.6,6.8Hz, 1H), 3.33 3.29 (m, 2H), 2.88 (s, 6H), 2.70 (s, 3H), 2.37 (s, 3H), 1.28 (d, J=6.8Hz, 6H).
Test evaluation biology (one)
1.EGFR T790M saltant type zymetology is tested
This experiment uses the method test compound of FRET (fluorescence resonance energy transfer) (TR-FRET) to dash forward exon 20T790M The inhibitory action of modification EGFR enzyme, and draw the compound half-inhibition concentration IC to this enzymatic activity50。
1) in 384 orifice plates, 1～5ul EGFR T790M enzymatic solution, enzyme final concentration of 0.1～1nM are added.
2) compound solution that 1～5ul gradient dilution is good is added.
3) incubated at room 10 minutes.
4) add 1～5ul Substrate cocktail and comprise substrate polypeptide final concentration 5～50nM and ATP final concentration 1～10uM.
5) incubated at room 0.5～2 hours.
6) add 5ul EDTA stop buffer and terminate reaction 5 minutes.
7) 5ul detection liquid containing traget antibody, incubated at room 1 hour are added.
8) microplate reader measures the 665nm fluorescence signal value of each plate.
9) suppression ratio is calculated by fluorescence signal value.
10) drawn the IC of compound by curve matching according to the suppression ratio of variable concentrations50。
2.EGFR wild type (WT) zymetology is tested
This experiment uses pressing down of the method test compounds against wild type EGFR enzyme of FRET (fluorescence resonance energy transfer) (TR-FRET) Make use, and draw the compound half-inhibition concentration IC to this enzymatic activity50。
1) in 384 orifice plates, 1～5ul EGFR wild-type enzyme solution, enzyme final concentration of 0.1～1nM are added.
2) compound solution that 1～5ul gradient dilution is good is added.
3) incubated at room 10 minutes.
4) add 1～5ul Substrate cocktail and comprise substrate polypeptide final concentration 5～50nM and ATP final concentration 0.1～5uM.
5) incubated at room 0.5～2 hours.
6) add 5ul EDTA stop buffer and terminate reaction 5 minutes.
7) 5ul detection liquid containing traget antibody, incubated at room 1 hour are added.
8) microplate reader measures the 665nm fluorescence signal value of each plate.
9) suppression ratio is calculated by fluorescence signal value.
10) drawn the IC of compound by curve matching according to the suppression ratio of variable concentrations50。
The biochemical activity of the compounds of this invention is measured by above test, the IC recorded50Value see table.
Conclusion: the embodiment of the present invention has the strongest inhibitory activity, simultaneously to wild type kinase to EGFR saltant type kinases There is more weak inhibitory activity, demonstrate good selectivity；And EGFR is dashed forward by reference compound crizotinib and LDK378 Modification kinases does not has inhibitory activity substantially.
3.NCI-H1975 cell growth inhibition assay
This experiment uses the method test compound inhibitory action to NCI-H1975 cell proliferation of CellTiter-Glo, And draw the half-inhibition concentration IC of compound suppression cell-proliferation activity50。
1) inoculating the H1975 cell suspension of 90 μ L in 96 porocyte culture plates, density is 1～5*103Cell/ml, will Culture plate in incubator cultivate 16～24 hours (37 DEG C, 5%CO2)。
2) in culture plate cell, add the testing compound solution of the variable concentrations of gradient dilution, culture plate is being cultivated Case hatch 72 hours (37 DEG C, 5%CO2)。
3) every hole adds 50～100 μ L CellTiter-Glo reagent, and vibrates 10 minutes, and room temperature stands 10 minutes.
4) microplate reader measures the chemiluminescence signal value of each plate.
5) suppression ratio is calculated by chemiluminescence signal value.
6) drawn the IC of compound by curve matching according to the suppression ratio of variable concentrations50。
4.A431 cell growth inhibition assay
This experiment uses the method test compound inhibitory action to A431 cell proliferation of CellTiter-Glo, and obtains Go out the half-inhibition concentration IC of compound suppression cell-proliferation activity50。
1) inoculating the A431 cell suspension of 90 μ L in 96 porocyte culture plates, density is 1～5*103Cell/ml, will training Support plate in incubator cultivate 16～24 hours (37 DEG C, 5%CO2)。
2) in culture plate cell, add the testing compound solution of the variable concentrations of gradient dilution, culture plate is being cultivated Case hatch 72 hours (37 DEG C, 5%CO2)。
3) every hole adds 50～100 μ L CellTiter-Glo reagent, and vibrates 10 minutes, and room temperature stands 10 minutes.
4) microplate reader measures the chemiluminescence signal value of each plate.
5) suppression ratio is calculated by chemiluminescence signal value.
6) drawn the IC of compound by curve matching according to the suppression ratio of variable concentrations50。
The biochemical activity of the compounds of this invention is measured by above test, the IC recorded50Value see table.
Conclusion: the embodiment of the present invention has the strongest inhibitory activity to the propagation of EGFR mutant cell H1975, and to open country The propagation of raw type A431 cell has relatively low suppression, and embodiment has good selectivity to wild type/mutant cell；And Reference compound crizotinib and LDK378 does not has inhibitory activity substantially to the propagation of EGFR mutant cell H1975.
Test evaluation biology (two)
Experimental example 1, ALK gene fused cell Proliferation Ability are tested
It is thin for the human lymphoma of ALK gene fusion high expressed that following in vitro tests can be used to measure the compounds of this invention The proliferation inhibition activity of born of the same parents Karpas 299.
The cell assay in vitro of the following stated can measure the increasing to human lymphoma cell Karpas 299 of test-compound Grow inhibitory activity, the available IC of its activity50Value represents.The general approach of this type of test is as follows: first select human lymphoma cell Karpas 299, is seeded in 96 well culture plates with suitable cell concentration (e.g.6000 cell/well100uL medium) On, the test-compound with a series of gradient concentrations (general 6 to 10 concentration) of backward each hole addition culture medium dilution is molten Liquid, cultivates 72 hours continuously.After 72 hours, available CellTiter-Luminescent Cell Viability Assay kit (is purchased from Promega).Method measures the activity of compound suppression cell proliferation.IC50Value can be a series of by measuring Under variable concentrations, the suppression numerical value of test-compound cell proliferation calculates.
The biochemical activity of the compounds of this invention is measured by above test, the IC recorded50Value see table.
Compound IC50(nM)
Crizotinib 38.5
LDK378 32
Embodiment one 24
Embodiment two 290
Embodiment three 99
Embodiment four 530
Embodiment five 360
Embodiment six 230
Embodiment seven 20
Embodiment eight 74
Conclusion: embodiment of the present invention compound as reference compound Crizotinib and LDK378 to Karpas 299 Cell all has proliferation inhibition activity significantly；The especially inhibitory activity of embodiment one and embodiment seven compound has the biggest Improve.
Experimental example 2, ALK kinase inhibition are tested
Following in vitro tests can be used to measure the compounds of this invention and for ALK kinases and produces the ALKL1196M made a variation Kinase inhibiting activity, the available IC of its activity50Value represents.The half-inhibition concentration IC of compound50(certain density enzyme is lived Property suppression to compound concentration required when 50%) be by treating a certain amount of kinases and specific substrate and variable concentrations After surveying compound hybrid reaction, measure and calculation goes out.ALK kinases behaviour source recombiant protein used by this experiment, this enzyme is containing 50mM HEPES (pH7.5), 10mM MgCl2, in the buffer solution of 2M DTT (1000x) and the reaction system of 30 μMs of ATP with The test-compound of peptide substrate and variable concentrations carries out reacting (25 DEG C, 45min) jointly, and FAM traget antibody is the end of to subsequently Thing is marked, and finally quantitative determines ALK kinase activity in time-resolved fluorescence mode.
The biochemical activity of the compounds of this invention is measured by above test, the IC recorded50Value see table.
Conclusion: embodiment of the present invention compound as reference compound Crizotinib and LDK378 to ALK and ALKL1196M kinase activity all has inhibitory action significantly.

Claims (15)

1. N-shown in formula (I) (3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) phenyl) acryloyl Base amide analogue, its stereoisomer or its pharmaceutically-acceptable salts:
Wherein,
R1Selected from C1-8Alkyl, C3-8Cycloalkyl, the most further by one or more selected from fluorine, chlorine, bromine, iodine, hydroxyl, C1-8Alkane Base, C1-8Alkoxyl, halogen replace C1-8Alkoxyl, C3-8Cycloalkyl or C3-8The substituent group of cycloalkyloxy is replaced；
R2Selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro, C1-8Alkoxyl, trifluoromethyl, trifluoromethoxy, C (O) R5、C (O)OR5Or P (O) R6R7；
R3Selected from following structure:
R4Selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-8Alkyl, C3-8Cycloalkyl, halogen replace C1-8Alkyl, C1-8Alkoxyl, C3-8Cycloalkanes oxygen Base, halogen replace C1-8Alkoxyl, phenyl or p-methylphenyl；
R5、R6、R7It is independently selected from C1-8Alkyl, C3-8Cycloalkyl, halogen replace C1-8Alkyl, C1-8Alkoxyl, amino or two C1-8Alkyl amino.
N-the most according to claim 1 (3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) benzene Base) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, it is characterised in that C1-8Alkyl is selected from C1-6Alkyl, preferably C1-3Alkyl；Halogen replaces C1-8Alkyl replaces C selected from halogen1-6Alkyl, preferably halogen replace C1-3Alkyl；C1-8Alcoxyl Base is selected from C1-6Alkoxyl, preferably C1-3Alkoxyl；Halogen replaces C1-8Alkoxyl replaces C selected from halogen1-6Alkoxyl, preferably halogen replace C1-3Alkoxyl；C3-8Cycloalkyl is selected from C3-6Cycloalkyl.
N-the most according to claim 1 (3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) benzene Base) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, it is characterised in that R3It is selected from:R1、R2、R4、R5、R6、R7As defined in claim 1.
N-the most according to claim 1 (3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) benzene Base) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, it is characterised in that R1Selected from C1-4Alkane Base, C3-6Cycloalkyl, the most further by one or more selected from fluorine, chlorine, bromine, iodine, hydroxyl, C1-8Alkyl, C1-8Alkoxyl, halogen Replace C1-8Alkoxyl, C3-8Cycloalkyl or C3-8The substituent group of cycloalkyloxy is replaced；R2、R3、R4、R5、R6、R7Such as claim 1 Defined.
N-the most according to claim 1 (3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) benzene Base) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, it is characterised in that R1Selected from methyl, second Base, isopropyl, trifluoromethyl, difluoromethyl；R2、R3、R4、R5、R6、R7As defined in claim 1.
N-the most according to claim 1 (3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) benzene Base) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, it is characterised in that R2Selected from hydrogen, fluorine, Chlorine, cyano group, C1-3Alkoxyl, trifluoromethyl or trifluoromethoxy.
N-the most according to claim 1 (3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) benzene Base) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, it is characterised in that R4Selected from hydrogen, fluorine, Chlorine, C1-3Alkyl, C1-3Alkoxyl, trifluoromethyl, trifluoromethoxy or difluoro-methoxy.
N-the most according to claim 1 (3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) benzene Base) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, it is characterised in that selected from following chemical combination Thing:
9. according to N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-described in any one of claim 1-8 Base) amino) phenyl) acryloyl group amide analogue, its stereoisomer or the preparation method of its pharmaceutically-acceptable salts, including Following steps:
Wherein, X1、X2Selected from fluorine, chlorine, bromine or iodine；R1、R2、R3、R4、R5、R6、R7As defined in claim 1.
10. a pharmaceutical composition, it include treat effective dose according to the N-(3-described in any one of claim 1-8 ((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) phenyl) acryloyl group amide analogue, its solid be different Structure body or its pharmaceutically-acceptable salts and pharmaceutically useful carrier.
11. according to N-(3-((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-described in any one of claim 1-8 Base) amino) phenyl) acryloyl group amide analogue, its stereoisomer or its pharmaceutically-acceptable salts, or claim 10 institute The pharmaceutical composition stated lacks activated mutant body activity in preparation for treatment and is situated between or ALK leads EGFR mutant, exons 19 Application in the medicine of disease.
12. application according to claim 11, it is characterised in that according to the N-(3-described in any one of claim 1-8 ((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) phenyl) acryloyl group amide analogue, its solid be different Structure body or its pharmaceutically-acceptable salts, or the pharmaceutical composition described in claim 10 is used for treating individually or partly in preparation By EGFR mutant activity or and the disease mediated medicine of ALK in application.
13. application according to claim 11, it is characterised in that described EFGR mutant is selected from L858R EGFR mutant Or T790MEGFR mutant.
14. application according to claim 11, it is characterised in that according to the N-(3-described in any one of claim 1-8 ((4-((2-(isopropyl sulphonyl) phenyl) amino) pyrimidine-2-base) amino) phenyl) acryloyl group amide analogue, its solid be different Structure body or its pharmaceutically-acceptable salts, or the pharmaceutical composition described in claim 10 in preparation for treating in cancer drug Application.
15. application according to claim 11, it is characterised in that described cancer selected from ovarian, cervical cancer, colorectum Cancer, breast carcinoma, cancer of pancreas, glioma, glioblastoma multiforme, melanoma, carcinoma of prostate, leukemia, lymphoma, non-Hodgkin′s Lymphoma, gastric cancer, pulmonary carcinoma, hepatocarcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid carcinoma, cancer of biliary duct, carcinoma of endometrium, Renal carcinoma, primary cutaneous type, acute myelocytic leukemia (AML), multiple myeloma, melanoma or mesothelioma； Preferably nonsmall-cell lung cancer.
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CN114008028A (en) * 2019-06-20 2022-02-01 昂科比克斯有限公司 Pyrimidine derivative for inhibiting growth of cancer cells and medical application thereof
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CN114539269A (en) * 2020-11-19 2022-05-27 上海医药工业研究院 Nitrogen-containing macrocyclic compound, preparation method and application thereof
CN114539269B (en) * 2020-11-19 2023-04-28 上海医药工业研究院有限公司 Nitrogen-containing macrocyclic compound, preparation method and application thereof
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