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 PDFInfo
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- 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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- 0 C**N(C)CCN(C)C Chemical compound C**N(C)CCN(C)C 0.000 description 4
- ANUGDUQKNJRYSS-UHFFFAOYSA-N CCC(C)N(C)CCN(CCOC1)C1=O Chemical compound CCC(C)N(C)CCN(CCOC1)C1=O ANUGDUQKNJRYSS-UHFFFAOYSA-N 0.000 description 1
- QIWOPTPFRIJINT-UHFFFAOYSA-N CN(C)CCN1CCCC1 Chemical compound CN(C)CCN1CCCC1 QIWOPTPFRIJINT-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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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
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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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1832929A (en) * | 2003-08-15 | 2006-09-13 | 诺瓦提斯公司 | 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
WO2011140338A1 (en) * | 2010-05-05 | 2011-11-10 | Gatekeeper Pharmaceuticals, Inc. | Compounds that modulate egfr activity and methods for treating or preventing conditions therewith |
WO2013169401A1 (en) * | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
CN103501612A (en) * | 2011-05-04 | 2014-01-08 | 阿里亚德医药股份有限公司 | Compounds for inhibiting cell proliferation in EGFR-driven cancers |
WO2015003658A1 (en) * | 2013-07-11 | 2015-01-15 | Betta Pharmaceuticals Co., Ltd | Protein tyrosine kinase modulators and methods of use |
-
2016
- 2016-05-13 CN CN201610318055.6A patent/CN106187915A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1832929A (en) * | 2003-08-15 | 2006-09-13 | 诺瓦提斯公司 | 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
WO2011140338A1 (en) * | 2010-05-05 | 2011-11-10 | Gatekeeper Pharmaceuticals, Inc. | Compounds that modulate egfr activity and methods for treating or preventing conditions therewith |
CN103501612A (en) * | 2011-05-04 | 2014-01-08 | 阿里亚德医药股份有限公司 | Compounds for inhibiting cell proliferation in EGFR-driven cancers |
WO2013169401A1 (en) * | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
WO2015003658A1 (en) * | 2013-07-11 | 2015-01-15 | Betta Pharmaceuticals Co., Ltd | Protein tyrosine kinase modulators and methods of use |
Cited By (19)
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---|---|---|---|---|
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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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