CN106565782B - Phosphoryl pyrimidines, composition and purposes - Google Patents

Phosphoryl pyrimidines, composition and purposes Download PDF

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CN106565782B
CN106565782B CN201610884363.5A CN201610884363A CN106565782B CN 106565782 B CN106565782 B CN 106565782B CN 201610884363 A CN201610884363 A CN 201610884363A CN 106565782 B CN106565782 B CN 106565782B
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amine
phenyl
phosphoryl
chloro
acrylamide
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CN106565782A (en
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马晓东
葛阳
宋振东
黄珊珊
王长远
张建斌
唐泽耀
刘克辛
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Dalian Medical University
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Dalian Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Abstract

The present invention relates to phosphoryl pyrimidines, composition and purposes, the phosphoryl pyrimidines are specially the compound shown in formula (I), and each substituent of formula (I) is defined in the description.The invention further relates to the compound shown in the formula (I) or its pharmaceutically acceptable salt, or tumor disease is treated by suppressing bruton's EGFR-TK containing its pharmaceutical composition, particularly it is used for the purposes for treating Burkitt's lymphoma, diffusivity large B cell lymphoid tumor, follicular lymphoma or chronic lymphocytic leukemia；

Description

Phosphoryl pyrimidines, composition and purposes
Technical field
The present invention relates to phosphoryl pyrimidines, composition and purposes, belong to pharmaceutical technology field.
Background technology
Protein tyrosine kinase (protein tyrosine kinase, PTKs) is by controlling the signal transduction of cell to lead to Road adjusts a series of physiological and biochemical procedures such as the growth, differentiation, apoptosis of cell.Receptor type tyrosine kinase is one kind across cell The relatively large kinases of film, it has the ectodomain of ligand binding, membrane spaning domain and plays zymogenesis-in phosphorylation Specific tyrosine residue and the intracellular domain for thus influenceing cell propagation.(such as lung cancer, mammary gland in general human cancer Cancer, stomach cancer, oophoroma, lymthoma) have found the unconventionality expression of the kinases.Protein tyrosine kinase turns into antineoplastic One of important target spot of research and development.
BTK is one of non-receptor protein tyrosine kinase Tec family members, mainly expresses and (removes T cell in hematopoietic cell Outside), in BCR signal paths, with BCR activation, BTK relies on Syk, Lyn activation, and the BTK after activation can further phosphorus PLC γ 2 are acidified, and then cause the activation for including the downstream signals such as MAPK, NF κ B.BTK rises in the generating process of bone-marrow-derived lymphocyte Irreplaceable effect.BTK can control the hair of B cell by the active cell cycle positive regulation factor and differentiation factor Educate, break up, also can control the survival of B cell and propagation by adjusting the expression of rush apoptosis and anti-apoptotic proteins.BTK's continues Activation is a prerequisite of chronic lymphocytic leukemia (CLL) development, and the transmission of BCR-BTK signals can promote to diffuse extremely The survival of activating B cell hypotype in property large B cell lymphoid tumor (DLBCL).BTK micromolecular inhibitors swell for treatment haematological malignant Knurl and Autoimmune Disorders disease have good prospect.Ibrutinib (replacing Buddhist nun according to Shandong) is a kind of oral bruton's tyrosine Kinases (BTK) inhibitor, (US 7514444, CN101610676A) is developed by the Pharmacyclics companies of California, USA, Listing is approved by the FDA in the United States, for treating lymphoma mantle cell (MCL) and CLL.Other multiple compounds, such as CC-292 (AVL- 292) (US8563568, WO2014100748A1) be one by covalently bound, high selectivity BTK that can be oral suppresses Agent, its IC50Less than 0.5nmol/L, the selectivity that at least 1400 times of kinases is tested than other is illustrated, it is positive at present to carry out Phase I studies (Evans, E.K., et al.J.Pharmacol Exp.Ther., 2013,346,219-228.)；And for example ONO-4059 (Yasuhiro, T., et al.Blood, 2013,122,5151-5151.) is to replace Buddhist nun's analog according to Shandong, and high selectivity suppresses BTK, IC50For 23.9nmol/L, studied into PhaseI.In addition CNX-774 (Akinleye, A., et al.J.Hematol Oncol., a kind of 2013,6,59.) and orally active high selectivity BTK inhibitor, IC50Less than 1nmol/L, what is be related to is special Profit is such as：WO2010141406A2、US20140256759A1、CN102083800A.
In view for the treatment of cancer there is an urgent need to this area is necessary to develop the better medicine of new effect.
The content of the invention
An object of the present invention is to provide a kind of phosphoryl pyrimidines or its pharmaceutically acceptable salt, is somebody's turn to do Class compound has good antitumor activity.
Another object of the present invention is to provide to contain the phosphoryl pyrimidines or its pharmaceutically acceptable salt Pharmaceutical composition.
It is still another object of the present invention to provide the phosphoryl pyrimidines or its pharmaceutically acceptable salt, or The purposes of the composition.
Therefore, on the one hand, the present invention provides the compound or its pharmaceutically acceptable salt shown in a kind of formula (I), institute Stating the compound shown in formula (I) has following structure：
Wherein,
X is selected from chlorine or fluorine；
L is selected from-CH2- or-O (CH2)2CH2-；
R1Selected from hydrogen, methyl, methoxyl group or chlorine；
R2Selected from methoxyl group, ethyoxyl, butoxy, isopropoxy,
R3Selected from methoxyl group, ethyoxyl, butoxy or isopropoxy.
Preferably, the compound shown in formula (I) of the present invention has the structure shown in I-1~I-30：
Structural compounds as implied above are phosphoryl pyrimidines, and antitumor activity screening of the present invention is shown, big portion Divide such compound that there is stronger suppression lymphocytic leukemia cell (Ramos and Raji) multiplication capacity, part of compounds Show the anti-BTK activity more more excellent than Spebrutinib.The molecule novel as a class formation, the chemical combination in the present invention Thing have exploitation into new and effective BTK inhibitor potentiality, to treatment-related tumor disease especially Burkitt's lymphoma, Diffusivity large B cell lymphoid tumor, follicular lymphoma or chronic lymphocytic leukemia have larger application value.
Structure shown in foregoing I-1~I-30 has following title respectively：
(I-1) N- [3- [[the chloro- 2- of 5- [[4- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide；
(I-2) [[[the chloro- 2- of 5- [[3- methoxyl groups -4- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- is phonetic by 3- by N- Piperidinyl] amine] phenyl] acrylamide；
(I-3) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide；
(I-4) [[[the chloro- 2- of 5- [[4- [[(1- morpholines) ethyoxyl phosphoryl] propoxyl group]] phenyl] amine -4- is phonetic by 3- by N- Piperidinyl] amine] phenyl] acrylamide；
(I-5) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [[(1- morpholines) ethyoxyl phosphoryl] propoxyl group]] phenyl] Amine -4- pyrimidine radicals] amine] phenyl] acrylamide；
(I-6) N- [3- [[the chloro- 2- of 5- [[3- methoxyl groups -4- [[(1- morpholines) ethyoxyl phosphoryl] propoxyl group]] benzene Base] amine -4- pyrimidine radicals] amine] phenyl] acrylamide；
(I-7) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [[(1- morpholines) ethyoxyl phosphoryl] propoxyl group]] phenyl] amine- 4- pyrimidine radicals] amine] phenyl] acrylamide；
(I-8) N- [3- [[the chloro- 2- of 5- [[4- [[(1- methyl piperazines) ethyoxyl phosphoryl] propoxyl group]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide；
(I-9) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [[(1- methyl piperazines) ethyoxyl phosphoryl] propoxyl group]] phenyl] Amine -4- pyrimidine radicals] amine] phenyl] acrylamide；
(I-10) N- [3- [[the chloro- 2- of 5- [[4- [[(1- ethyl piperazidines) ethyoxyl phosphoryl] propoxyl group]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide；
(I-11) N- [3- [[the chloro- 2- of 5- [[4- [(diisopropoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide；
(I-12) N- [3- [[the chloro- 2- of 5- [[4- [(dimethoxyphosphoryl) propoxyl group]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide；
(I-13) N- [3- [[the chloro- 2- of 5- [[4- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide；
(I-14) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide；
(I-15) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide；
(I-16) N- [3- [[the chloro- 2- of 5- [[4- [[(1- morpholines) ethyoxyl phosphoryl] methyl]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide；
(I-17) N- [3- [[the chloro- 2- of 5- [[3- methoxyl groups -4- [[(1- morpholines) ethyoxyl phosphoryl] methyl]] phenyl] Amine -4- pyrimidine radicals] amine] phenyl] acrylamide；
(I-18) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [[(1- morpholines) ethyoxyl phosphoryl] methyl]] phenyl] amine- 4- pyrimidine radicals] amine] phenyl] acrylamide；
(I-19) [[[the chloro- 2- of 5- [[4- [[(1- methyl piperazines) ethyoxyl phosphoryl] methyl]] phenyl] amine -4- is phonetic by 3- by N- Piperidinyl] amine] phenyl] acrylamide；
(I-20) N- [3- [[the chloro- 2- of 5- [[4- [(diisopropoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide；
(I-21) N- [3- [[the chloro- 2- of 5- [[3- methoxyl groups -4- [[(1- methyl piperazines) ethyoxyl phosphoryl] methyl]] benzene Base] amine -4- pyrimidine radicals] amine] phenyl] acrylamide；
(I-22) [[[the chloro- 2- of 5- [[4- [[(1- methyl piperazines) ethyoxyl phosphoryl] methyl]] phenyl] amine -4- is phonetic by 3- by N- Piperidinyl] amine] phenyl] acrylamide；
(I-23) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [[(1- methyl piperazines) ethyoxyl phosphoryl] methyl]] phenyl] Amine -4- pyrimidine radicals] amine] phenyl] acrylamide；
(I-24) N- [3- [[the chloro- 2- of 5- [[4- [(dimethoxyphosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide；
(I-25) N- [3- [[the fluoro- 2- of 5- [[4- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide；
(I-26) N- [3- [[the fluoro- 2- of 5- [[the chloro- 4- of 3- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide；
(I-27) N- [3- [[the fluoro- 2- of 5- [[4- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide；
(I-28) [[[the fluoro- 2- of 5- [[3- methoxyl groups -4- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- is phonetic by 3- by N- Piperidinyl] amine] phenyl] acrylamide；
(I-29) N- [3- [[the fluoro- 2- of 5- [[4- [(dibutoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide；
(I-30) N- [3- [[the fluoro- 2- of 5- [[4- [(dibutoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide；
On the other hand, the present invention provides a kind of pharmaceutical composition, and it contains formula of the present invention (I) institute of effective dose The compound shown or its pharmaceutically acceptable salt, and pharmaceutical carrier.
For compound of the present invention due to their possibility purposes in medicine, the salt preferred agents of formula (I) compound can The salt of receiving.The compound of the present invention is alkali, and salt form needed for it can be prepared by appropriate method known in the art, bag Include and use mineral acid treatment free alkali, the inorganic acid is such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid；Or with organic acid Manage free alkali, the organic acids such as acetic acid, trifluoroacetic acid, maleic acid, butanedioic acid, mandelic acid, fumaric acid, malonic acid, acetone Acid, oxalic acid, hydroxyacetic acid, salicylic acid, pyranose thuja acid (pyranosidy1acid), such as glucuronic acid or galacturonic acid, 'alpha '-hydroxy acids, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or meat Cinnamic acid, sulfonic acid, such as p- toluenesulfonic acids, methanesulfonic acid, ethyl sulfonic acid etc..The embodiment of pharmaceutically acceptable salt include sulfate, Pyrosulfate, disulfate, sulphite, bisulfites, phosphate, chloride, bromide, iodide, acetate, propionic acid Salt, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propionate (propiolates), Oxalates, malonate, benzoate, chloro benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, Methoxy benzoic acid salt, phthalate, phenyl acetate salt, phenylpropionic acid salt, PB (phenylbutrates), Citrate, lactate, gamma hydroxybutyrate, hydroxyl acetate, tartrate, amygdalate and sulfonate, such as diformazan Benzene sulfonate, mesylate, propane sulfonic acid salt, naphthalene -1- sulfonate and naphthalene-2-sulfonic acid salt.
The pharmaceutical composition of the present invention usually contains a kind of the compounds of this invention.However, in some embodiments, this hair Bright pharmaceutical composition, which contains, has more than a kind of compound of the invention.In addition, the pharmaceutical composition of the present invention can also optionally include One or more other pharmaceutically active compounds.
The present invention also provides the phosphoryl pyrimidines or its pharmaceutically acceptable salt, described pharmaceutical composition Suppress the purposes of tumor proliferation by suppressing bruton's EGFR-TK.Specifically, the purposes is mainly that preparation is used for Treat the medicine of Burkitt's lymphoma, diffusivity large B cell lymphoid tumor, follicular lymphoma or chronic lymphocytic leukemia In purposes.
The present invention provides shown compound or its pharmaceutically acceptable salt, or pharmaceutical composition of the present invention exists Prepare the application in bruton's tyrosine kinase inhibitor.
The present invention provides the compound or its pharmaceutically acceptable salt shown in the formula (I), or of the present invention Purposes of the pharmaceutical composition in the medicine for preparing treatment tumour.Preferably, the tumour is selected from Burkitt's lymphoma, diffused Property large B cell lymphoid tumor, follicular lymphoma or chronic lymphocytic leukemia, the further preferred white blood of chronic lymphocytic Disease.It is highly preferred that what the purposes was mainly realized by suppressing bruton's EGFR-TK.
Embodiment
The explanation present invention is further described below in conjunction with specific embodiment, but these embodiments are not meant as limiting this hair Bright scope.
The experimental method of unreceipted actual conditions in the embodiment of the present invention, generally according to normal condition, or according to raw material or Condition proposed by commodity manufacturer.The reagent in unreceipted specific source, for the conventional reagent of market purchase.
The preparation of the target molecule of embodiment 1
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and thin-layered chromatography (TLC) makes The specification that silicon amine plate uses is 0.15mm-0.2mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm- 0.5mm。
The raw material that the present invention uses is mainly purchased from commercially available from Chemical Reagent Co., Ltd., Sinopharm Group, Beijing coupling science and technology Co., Ltd, Aladdin chemical reagent Co., Ltd, up to companies such as auspicious chemicals.
Refer to the aqueous solution without specified otherwise, solution in embodiment.
Without specified otherwise in embodiment, the temperature of reaction is room temperature, is 20 DEG C -30 DEG C.
The technical solution adopted by the present invention is as follows：
Synthetic route, reagent and the condition of compound (I):a)P(OEt)3、P(OMe)3P(OPr-i)3Or P (OBu-n)3, 130 DEG C, 80-91%；b)(COCl)2,DMF,60℃；c)R2H, THF, 0 DEG C, 92%；d)Fe-NH4Cl,MeOH-H2O, 80 DEG C extremely Rt, 62-85%；e)NaHCO3, acetonitrile, 0 DEG C, 10min, 85-93%；f)Fe-NH4Cl,MeOH-H2O, 80 DEG C to rt, 62- 85%；G) DIPEA, 1,4- dioxane, 60 DEG C, 49-72%；h)ArNH2,CF3COOH, 100 DEG C, 5-21%；In formula 2 and formula 3 R2With R3It is identical, it is methoxyl group, ethyoxyl, butoxy or isopropoxy；R in formula 5 and formula 62With R3Differ, remaining substitution Base is as defined above.
8 synthesis
Take 7 (23.44mmol) and NaHCO3(4.5g, 35.16mmol) is slowly added into acryloyl chloride in 50mL acetonitriles (3.8g, 23.44mmol), 0 DEG C, after reacting 10min, reaction finishes, and adds 400mL water, separates out white solid, filters, drying, White solid, extracting waste solid (19g, 68mmol) and ammonium chloride (7.3g, 136mmol) are obtained in reaction bulb, adds MeOH (25mL) and water (25mL), lower addition iron powder (15g, 272mmol) is stirred, heat up 60 DEG C and react 2 hours, filter while hot, aqueous phase It is extracted with ethyl acetate (100mL × 3), combined ethyl acetate layer, saturated common salt is washed once, anhydrous sodium sulfate drying, decompression It is evaporated to obtain white-yellowish solid 8.
10 synthesis
9 (23.44mmol) and DIPEA (4.5g, 35.16mmol) are taken in 50mL dioxane, be slowly added into 8 (3.8g, 23.44mmol), heat up 60 DEG C, after reacting 5 hours, reaction finishes, and cooling, adds 400mL water, separates out white-yellowish solid, takes out Filter, drying, obtains off-white powder, does not purify and directly reacts in next step.
The synthesis of object (I)
10 (23.44mmol) and trifluoroacetic acid (4.5g, 35.16mmol) is taken to be slowly added into and take in 2-BuOH (50ml) For arylamine (3 or 6,3.44mmol), heat up 100 DEG C, after reacting 8 hours, reaction finishes, and cooling, it is molten to pour into saturated sodium bicarbonate In liquid, solid is separated out, is filtered, washing, drying silica gel column chromatography separation, obtains target molecule (I).
Target molecule is synthesized according to above method, the physicochemical data of synthesized target molecule is as follows：
(I-1) N- [3- [[the chloro- 2- of 5- [[4- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.15(s,1H),8.90(s,1H),8.10(s,1H), 7.88 (s, 1H), 7.57-7.40 (m, 3H), 7.31 (d, J=5.2Hz, 2H), 6.69 (d, J=8.8Hz, 2H), 6.46 (dd, J =17.0,10.1Hz, 1H), 6.26 (dd, J=17.0,2.0Hz, 1H), 5.76 (dd, J=10.1,2.0Hz, 1H), 4.05- 3.88 (m, 6H), 1.92-1.79 (m, 4H), 1.23 (t, J=7.0Hz, 6H)；MS(ESI)m/z560.18[M+H]+。
(I-2) [[[the chloro- 2- of 5- [[3- methoxyl groups -4- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- is phonetic by 3- by N- Piperidinyl] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.17(s,1H),9.14(s,1H),8.92(s,1H),8.10(s,1H), 7.88 (s, 1H), 7.56-7.39 (m, 3H), 7.31 (d, J=5.2Hz, 1H), 6.69 (d, J=8.8Hz, 1H), 6.50 (s, 1H), 6.46 (dd, J=17.0,10.1Hz, 1H), 6.26 (dd, J=17.0,2.0Hz, 1H), 5.76 (dd, J=10.1, 2.0Hz, 1H), 4.05-3.88 (m, 6H), 3.75 (s, 3H), 1.92-1.79 (m, 4H), 1.23 (t, J=7.0Hz, 6H)；MS (ESI)m/z 590.19[M+H]+。
(I-3) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.16(s,1H),9.15(s,1H),8.91(s,1H),8.13(s,1H), 7.88 (s, 1H), 7.57-7.40 (m, 3H), 7.31 (d, J=5.2Hz, 1H), 6.69 (d, J=8.8Hz, 1H), 6.50 (s, 1H), 6.46 (dd, J=17.0,10.1Hz, 1H), 6.26 (dd, J=17.0,2.0Hz, 1H), 5.76 (dd, J=10.1, 2.0Hz, 1H), 4.05-3.88 (m, 6H), 1.92-1.79 (m, 4H), 1.23 (t, J=7.0Hz, 6H)；MS(ESI)m/z 594.14[M+H]+。
(I-4) [[[the chloro- 2- of 5- [[4- [[(1- morpholines) ethyoxyl phosphoryl] propoxyl group]] phenyl] amine -4- is phonetic by 3- by N- Piperidinyl] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.16(s,1H),8.89(s,1H),8.10(s,1H), 7.89 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.30 (d, J=4.9Hz, 2H), 6.69 (d, J=8.3Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.10- 3.76 (m, 4H), 3.56 (d, J=35.6Hz, 4H), 2.94 (t, J=38.4Hz, 4H), 2.05-1.68 (m, 4H), 1.21 (t, J =7.0Hz, 3H)；MS(ESI)m/z 601.21[M+H]+。
(I-5) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [[(1- morpholines) ethyoxyl phosphoryl] propoxyl group]] phenyl] Amine -4- pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.16(s,1H),8.89(s,1H),8.10(s,1H), 7.89 (s, 1H), 7.53 (dd, J=34.2,8.8Hz, 3H), 7.30 (d, J=4.9Hz, 1H), 7.29 (s, 1H), 6.69 (d, J =8.3Hz, 1H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.10-3.76 (m, 4H), 3.56 (d, J=35.6Hz, 4H), 2.94 (t, J=38.4Hz, 4H), 2.35 (s, 3H), 2.05-1.68 (m, 4H), 1.21 (t, J=7.0Hz, 3H)；MS(ESI)m/z 615.22[M+H]+。
(I-6) N- [3- [[the chloro- 2- of 5- [[3- methoxyl groups -4- [[(1- morpholines) ethyoxyl phosphoryl] propoxyl group]] benzene Base] amine -4- pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.23(s,1H),9.14(s,1H),8.89(s,1H),8.11(s,1H), 7.89 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.30 (d, J=4.9Hz, 1H), 6.70 (s, 1H), 6.69 (d, J =8.3Hz, 1H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.10-3.76 (m, 4H), 3.75 (s, 3H), 3.56 (d, J=35.6Hz, 4H), 2.94 (t, J=38.4Hz, 4H), 2.05-1.68 (m, 4H), 1.21 (t, J=7.0Hz, 3H)；MS(ESI)m/z 631.22[M+H]+。
(I-7) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [[(1- morpholines) ethyoxyl phosphoryl] propoxyl group]] phenyl] amine- 4- pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.20(s,1H),9.15(s,1H),8.89(s,1H),8.12(s,1H), 7.89 (s, 1H), 7.54 (dd, J=34.2,8.8Hz, 3H), 7.30 (d, J=4.9Hz, 1H), 6.71 (s, 1H), 6.69 (d, J =8.3Hz, 1H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.10-3.76 (m, 4H), 3.56 (d, J=35.6Hz, 4H), 2.94 (t, J=38.4Hz, 4H), 2.05-1.68 (m, 4H), 1.21 (t, J=7.0Hz, 3H)；MS(ESI)m/z 635.17[M+H]+。
(I-8) N- [3- [[the chloro- 2- of 5- [[4- [[(1- methyl piperazines) ethyoxyl phosphoryl] propoxyl group]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.16(s,1H),8.89(s,1H),8.10(s,1H), 7.89 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.30 (d, J=4.9Hz, 2H), 6.69 (d, J=8.3Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.10- 3.76 (m, 4H), 3.56 (d, J=35.6Hz, 4H), 2.94 (t, J=38.4Hz, 4H), 2.26 (s, 3H), 2.05-1.68 (m, 4H), 1.21 (t, J=7.0Hz, 3H)；MS(ESI)m/z 614.24[M+H]+。
(I-9) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [[(1- methyl piperazines) ethyoxyl phosphoryl] propoxyl group]] phenyl] Amine -4- pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.20(s,1H),9.15(s,1H),8.89(s,1H),8.12(s,1H), 7.89 (s, 1H), 7.54 (dd, J=34.2,8.8Hz, 3H), 7.30 (d, J=4.9Hz, 1H), 6.71 (s, 1H), 6.69 (d, J =8.3Hz, 1H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.10-3.76 (m, 4H), 3.56 (d, J=35.6Hz, 4H), 2.94 (t, J=38.4Hz, 4H), 2.25 (s, 3H), 2.05-1.68 (m, 4H), 1.21 (t, J=7.0Hz, 3H)；MS(ESI)m/z 648.21[M+H]+。
(I-10) N- [3- [[the chloro- 2- of 5- [[4- [[(1- ethyl piperazidines) ethyoxyl phosphoryl] propoxyl group]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.16(s,1H),8.89(s,1H),8.10(s,1H), 7.89 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.30 (d, J=4.9Hz, 2H), 6.69 (d, J=8.3Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.10- 3.76 (m, 4H), 3.56 (d, J=35.6Hz, 4H), 2.94 (t, J=38.4Hz, 4H), 2.05-1.68 (m, 6H), 1.21 (t, J =7.0Hz, 6H)；MS(ESI)m/z 628.26[M+H]+。
(I-11) N- [3- [[the chloro- 2- of 5- [[4- [(diisopropoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.15(s,1H),8.90(s,1H),8.10(s,1H), (7.88 s, 1H), 7.57-7.40 (m, 3H), 7.31 (d, J=5.2Hz, 2H), 6.69 (d, J=8.8Hz, 2H), 6.46 (dd, J =17.0,10.1Hz, 1H), 6.26 (dd, J=17.0,2.0Hz, 1H), 5.76 (dd, J=10.1,2.0Hz, 1H), 4.05- 3.88 (m, 4H), 1.92-1.79 (m, 4H), 1.23 (d, J=7.0Hz, 12H)；MS(ESI)m/z588.21[M+H]+。
(I-12) N- [3- [[the chloro- 2- of 5- [[4- [(dimethoxyphosphoryl) propoxyl group]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.15(s,1H),8.90(s,1H),8.10(s,1H), 7.88 (s, 1H), 7.57-7.40 (m, 3H), 7.31 (d, J=5.2Hz, 2H), 6.69 (d, J=8.8Hz, 2H), 6.46 (dd, J =17.0,10.1Hz, 1H), 6.26 (dd, J=17.0,2.0Hz, 1H), 5.76 (dd, J=10.1,2.0Hz, 1H), 4.05- 3.88(m,2H),3.35(s,6H),1.92–1.79(m,4H)；MS(ESI)m/z 532.15[M+H]+。
(I-13) N- [3- [[the chloro- 2- of 5- [[4- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.19(s,1H),9.31(s,1H),8.95(s,1H),8.14(s,1H), 7.86 (s, 1H), 7.61-7.41 (m, 3H), 7.40-7.22 (m, 2H), 7.01 (d, J=6.7Hz, 2H), 6.46 (dd, J= 16.9,10.1Hz, 1H), 6.26 (dd, J=17.0,1.8Hz, 1H), 5.75 (dd, J=10.1,1.8Hz, 1H), 3.99-3.81 (m, 4H), 3.06 (d, J=21.1Hz, 2H), 1.15 (t, J=7.0Hz, 6H)；MS(ESI)m/z516.16[M+H]+。
(I-14) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.19(s,1H),9.31(s,1H),8.95(s,1H),8.14(s,1H), 7.86 (s, 1H), 7.61-7.41 (m, 3H), 7.40-7.22 (m, 2H), 7.01 (d, J=6.7Hz, 1H), 6.46 (dd, J= 16.9,10.1Hz, 1H), 6.26 (dd, J=17.0,1.8Hz, 1H), 5.75 (dd, J=10.1,1.8Hz, 1H), 3.99-3.81 (m, 4H), 3.06 (d, J=21.1Hz, 2H), 2.35 (s, 3H), 1.15 (t, J=7.0Hz, 6H)；MS(ESI)m/z 530.17 [M+H]+。
(I-15) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.17(s,1H),9.32(s,1H),8.93(s,1H),8.15(s,1H), 7.86 (s, 1H), 7.61-7.41 (m, 3H), 7.40-7.22 (m, 1H), 7.01 (d, J=6.7Hz, 2H), 6.46 (dd, J= 16.9,10.1Hz, 1H), 6.26 (dd, J=17.0,1.8Hz, 1H), 5.75 (dd, J=10.1,1.8Hz, 1H), 3.99-3.81 (m, 4H), 3.06 (d, J=21.1Hz, 2H), 1.15 (t, J=7.0Hz, 6H)；MS(ESI)m/z550.11[M+H]+。
(I-16) N- [3- [[the chloro- 2- of 5- [[4- [[(1- morpholines) ethyoxyl phosphoryl] methyl]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.29(s,1H),8.95(s,1H),8.14(s,1H), 7.86 (s, 1H), 7.63-7.41 (m, 3H), 7.40-7.25 (m, 2H), 7.03 (d, J=7.0Hz, 2H), 6.46 (dd, J= 16.9 10.1Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.75 (d, J=10.0Hz, 1H), 4.00-3.76 (m, 2H), 3.40 (d, J=3.1Hz, 4H), 2.93 (dd, J=55.4,27.9Hz, 6H), 1.20 (t, J=7.0Hz, 3H)；MS(ESI)m/z 557.18[M+H]+。
(I-17) N- [3- [[the chloro- 2- of 5- [[3- methoxyl groups -4- [[(1- morpholines) ethyoxyl phosphoryl] methyl]] phenyl] Amine -4- pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.29(s,1H),8.95(s,1H),8.14(s,1H), 7.86 (s, 1H), 7.63-7.41 (m, 3H), 7.40-7.25 (m, 2H), 7.03 (d, J=7.0Hz, 1H), 6.46 (dd, J= 16.9 10.1Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.75 (d, J=10.0Hz, 1H), 4.00-3.76 (m, 2H), 3.70 (s, 3H), 3.40 (d, J=3.1Hz, 4H), 2.93 (dd, J=55.4,27.9Hz, 6H), 1.20 (t, J=7.0Hz, 3H)；MS(ESI)m/z 587.19[M+H]+。
(I-18) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [[(1- morpholines) ethyoxyl phosphoryl] methyl]] phenyl] amine- 4- pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.29(s,1H),8.95(s,1H),8.14(s,1H), 7.86 (s, 1H), 7.63-7.41 (m, 3H), 7.40-7.25 (m, 1H), 7.03 (d, J=7.0Hz, 2H), 6.46 (dd, J= 16.9 10.1Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.75 (d, J=10.0Hz, 1H), 4.00-3.76 (m, 2H), 3.40 (d, J=3.1Hz, 4H), 2.93 (dd, J=55.4,27.9Hz, 6H), 1.20 (t, J=7.0Hz, 3H)；MS(ESI)m/z 591.14[M+H]+。
(I-19) [[[the chloro- 2- of 5- [[4- [[(1- methyl piperazines) ethyoxyl phosphoryl] methyl]] phenyl] amine -4- is phonetic by 3- by N- Piperidinyl] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.29(s,1H),8.95(s,1H),8.14(s,1H), 7.86 (s, 1H), 7.63-7.41 (m, 3H), 7.40-7.25 (m, 2H), 7.03 (d, J=7.0Hz, 2H), 6.46 (dd, J= 16.9 10.1Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.75 (d, J=10.0Hz, 1H), 4.00-3.76 (m, 2H), 3.40 (d, J=3.1Hz, 4H), 2.93 (dd, J=55.4,27.9Hz, 6H), 2.27 (s, 3H), 1.20 (t, J=7.0Hz, 3H)；MS(ESI)m/z 570.21[M+H]+。
(I-20) N- [3- [[the chloro- 2- of 5- [[4- [(diisopropoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.19(s,1H),9.31(s,1H),8.95(s,1H),8.14(s,1H), (7.86 s, 1H), 7.61-7.41 (m, 3H), 7.40-7.22 (m, 2H), 7.01 (d, J=6.7Hz, 2H), 6.46 (dd, J= 16.9,10.1Hz, 1H), 6.26 (dd, J=17.0,1.8Hz, 1H), 5.75 (dd, J=10.1,1.8Hz, 1H), 3.99-3.81 (m, 2H), 3.06 (d, J=21.1Hz, 2H), 1.15 (d, J=7.0Hz, 12H)；MS(ESI)m/z544.19[M+H]+。
(I-21) N- [3- [[the chloro- 2- of 5- [[3- methoxyl groups -4- [[(1- methyl piperazines) ethyoxyl phosphoryl] methyl]] benzene Base] amine -4- pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.29(s,1H),8.95(s,1H),8.14(s,1H), 7.86 (s, 1H), 7.63-7.41 (m, 3H), 7.40-7.25 (m, 2H), 7.03 (d, J=7.0Hz, 1H), 6.46 (dd, J= 16.9 10.1Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.75 (d, J=10.0Hz, 1H), 4.00-3.76 (m, 2H), 3.70 (s, 3H), 3.40 (d, J=3.1Hz, 4H), 2.93 (dd, J=55.4,27.9Hz, 6H), 2.25 (s, 3H), 1.20 (t, J =7.0Hz, 3H)；MS(ESI)m/z 600.22[M+H]+。
(I-22) [[[the chloro- 2- of 5- [[4- [[(1- methyl piperazines) ethyoxyl phosphoryl] methyl]] phenyl] amine -4- is phonetic by 3- by N- Piperidinyl] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.29(s,1H),8.95(s,1H),8.14(s,1H), 7.86 (s, 1H), 7.63-7.41 (m, 3H), 7.40-7.25 (m, 2H), 7.03 (d, J=7.0Hz, 2H), 6.46 (dd, J= 16.9 10.1Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.75 (d, J=10.0Hz, 1H), 4.00-3.76 (m, 4H), 3.40 (d, J=3.1Hz, 4H), 2.93 (dd, J=55.4,27.9Hz, 6H), 1.20 (t, J=7.0Hz, 6H)；MS(ESI)m/z 584.23[M+H]+。
(I-23) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [[(1- methyl piperazines) ethyoxyl phosphoryl] methyl]] phenyl] Amine -4- pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.29(s,1H),8.95(s,1H),8.14(s,1H), 7.86 (s, 1H), 7.63-7.41 (m, 3H), 7.40-7.25 (m, 1H), 7.03 (d, J=7.0Hz, 2H), 6.46 (dd, J= 16.9 10.1Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.75 (d, J=10.0Hz, 1H), 4.00-3.76 (m, 4H), 3.40 (d, J=3.1Hz, 4H), 2.93 (dd, J=55.4,27.9Hz, 6H), 1.20 (t, J=7.0Hz, 6H)；MS(ESI)m/z 618.19[M+H]+。
(I-24) N- [3- [[the chloro- 2- of 5- [[4- [(dimethoxyphosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.19(s,1H),9.31(s,1H),8.95(s,1H),8.14(s,1H), 7.86 (s, 1H), 7.61-7.41 (m, 3H), 7.40-7.22 (m, 2H), 7.01 (d, J=6.7Hz, 2H), 6.46 (dd, J= 16.9,10.1Hz, 1H), 6.26 (dd, J=17.0,1.8Hz, 1H), 5.75 (dd, J=10.1,1.8Hz, 1H), 3.36 (s, 6H), 3.06 (d, J=21.1Hz, 2H)；MS(ESI)m/z 488.13[M+H]+。
(I-25) N- [3- [[the fluoro- 2- of 5- [[4- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ 10.13 (s, 1H), 9.38 (s, 1H), 8.98 (s, 1H), 8.06 (d, J= 3.7Hz, 1H), 7.93 (s, 1H), 7.51 (dd, J=13.1,9.1Hz, 3H), 7.42 (d, J=8.1Hz, 1H), 7.28 (t, J= 8.1Hz, 1H), 6.75 (d, J=9.0Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.26 (dd, J=17.0, 1.9Hz, 1H), 5.76 (dd, J=10.1,1.8Hz, 1H), 4.22-3.67 (m, 6H), 1.92-1.79 (m, 4H), 1.22 (t, J =7.0Hz, 6H)；MS(ESI)m/z 544.21[M+H]+。
(I-26) N- [3- [[the fluoro- 2- of 5- [[the chloro- 4- of 3- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ 10.13 (s, 1H), 9.38 (s, 1H), 8.98 (s, 1H), 8.06 (d, J= 3.7Hz, 1H), 7.93 (s, 1H), 7.51 (dd, J=13.1,9.1Hz, 3H), 7.42 (d, J=8.1Hz, 1H), 6.75 (d, J= 9.0Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.26 (dd, J=17.0,1.9Hz, 1H), 5.76 (dd, J= 10.1,1.8Hz, 1H), 4.22-3.67 (m, 6H), 3.69 (s, 3H), 1.92-1.79 (m, 4H), 1.22 (t, J=7.0Hz, 6H)；MS(ESI)m/z 578.17[M+H]+。
(I-27) N- [3- [[the fluoro- 2- of 5- [[4- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide
1H NMR(400MHz,DMSO-d6):δ 10.16 (s, 1H), 9.44 (s, 1H), 9.17 (s, 1H), 8.11 (d, J= 2.7Hz, 1H), 7.93 (s, 1H), 7.57 (dd, J=16.8,7.9Hz, 3H), 7.44 (d, J=7.5Hz, 1H), 7.29 (t, J= 7.9Hz, 1H), 7.06 (d, J=6.9Hz, 2H), 6.47 (dd, J=16.8,10.2Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.09-3.77 (m, 4H), 3.08 (d, J=21.0Hz, 2H), 1.16 (t, J= 6.8Hz,6H)；MS(ESI)m/z 500.18[M+H]+。
(I-28) [[[the fluoro- 2- of 5- [[3- methoxyl groups -4- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- is phonetic by 3- by N- Piperidinyl] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ 10.16 (s, 1H), 9.44 (s, 1H), 9.17 (s, 1H), 8.11 (d, J= 2.7Hz, 1H), 7.93 (s, 1H), 7.57 (dd, J=16.8,7.9Hz, 3H), 7.44 (d, J=7.5Hz, 1H), 7.29 (t, J= 7.9Hz, 1H), 7.06 (d, J=6.9Hz, 1H), 6.47 (dd, J=16.8,10.2Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.09-3.77 (m, 4H), 3.68 (s, 3H), 3.08 (d, J=21.0Hz, 2H), 1.16 (t, J=6.8Hz, 6H)；MS(ESI)m/z 530.20[M+H]+。
(I-29) N- [3- [[the fluoro- 2- of 5- [[4- [(dibutoxy phosphoryl) propoxyl group]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ 10.13 (s, 1H), 9.38 (s, 1H), 8.98 (s, 1H), 8.06 (d, J= 3.7Hz, 1H), 7.93 (s, 1H), 7.51 (dd, J=13.1,9.1Hz, 3H), 7.42 (d, J=8.1Hz, 1H), 7.28 (t, J= 8.1Hz, 1H), 6.75 (d, J=9.0Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.26 (dd, J=17.0, 1.9Hz, 1H), 5.76 (dd, J=10.1,1.8Hz, 1H), 4.22-3.67 (m, 6H), 1.92-1.79 (m, 4H), 1.68-1.52 (m, 4H), 1.48-1.25 (m, 4H), 0.97 (t, J=7.0Hz, 6H)；MS(ESI)m/z600.28[M+H]+。
(I-30) N- [3- [[the fluoro- 2- of 5- [[4- [(dibutoxy phosphoryl) methyl]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide
1H NMR(400MHz,DMSO-d6):δ 10.16 (s, 1H), 9.44 (s, 1H), 9.17 (s, 1H), 8.11 (d, J= 2.7Hz, 1H), 7.93 (s, 1H), 7.57 (dd, J=16.8,7.9Hz, 3H), 7.44 (d, J=7.5Hz, 1H), 7.29 (t, J= 7.9Hz, 1H), 7.06 (d, J=6.9Hz, 2H), 6.47 (dd, J=16.8,10.2Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.09-3.77 (m, 4H), 3.08 (d, J=21.0Hz, 2H), 1.68-1.52 (m, 4H), 1.48-1.25 (m, 4H), 0.95 (t, J=6.8Hz, 6H)；MS(ESI)m/z 556.25[M+H]+。
Method of the target molecule into salt
The preparation method of inorganic acid salt：Take target molecule (1mmol) to be dissolved in 10mL absolute methanols, under ice bath, slowly drip Add the 5mL absolute methanol solutions of inorganic acid (1mmol), be added dropwise, stirred 30 minutes at a temperature of this, then first is evaporated off in normal temperature Alcohol, produce the inorganic acid salt of target molecule.Compound I-4 hydrochloride (I-4-1), hydrobromate are prepared for by this method (I-4-2), sulfate (I-4-3) and mesylate (I-4-4)；
The preparation method of acylate：Take target molecule (1mmol) to be dissolved in 10mL absolute methanols, under ice bath, slowly drip Add the 5mL dry ethers of organic acid (1mmol), be added dropwise, stirred 30 minutes at a temperature of this, then solvent is evaporated off in normal temperature, Produce the acylate of target molecule.Compound I-4 maleate (I-4-5), succinate (I- are prepared for by this method 4-6) and fumarate (I-4-7).
The preparation of two target molecule mixtures
The above-mentioned two target molecule of equimolar amounts (1mmol) is taken to be stirred at room temperature 10 minutes in absolute methanol (5mL), Solvent is evaporated off in normal temperature, produces the mixture of target molecule.By this method be prepared for (I-1)-(I-4), (I-4)-(I-13), (I-1)-(I-13) three two target molecule mixtures.
The target molecule biological evaluation of embodiment 2
1st, in vitro to receptor tyrosine kinase inhibitory activity method of testing
Prepare kinase assay buffer
1. melting kinase assay buffer (Kinase Detection Buffer) in room temperature, precipitation has been seen whether.
2. if there is precipitation, just it is incubated (Kinase Detection Buffer) 15 minutes at 37 DEG C and often shakes, Dissolving precipitation.Or supernatant is carefully siphoned away, remove precipitation.
Prepare kinase assay reagent
1. using preceding in equilibrium at room temperature kinase assay buffer (Kinase Detection Buffe) and (Kinase Detection Substrate)。
2. kinase assay buffer (Kinase Detection Buffer) is all poured into equipped with kinase assay substrate In the brown bottle of (Kinase Detection Substrate), freeze-dried powder substrate is dissolved, kinase assay has thus been made Reagent.
Mixed 3. gently shaking, being vortexed or overturning, turn into homogeneous solution, substrate should dissolve in 1 minute.
4. kinase assay reagent should use immediately after preparing, or packing is stored in -20 DEG C, it is believed that the reagent prepared passes through Freeze thawing Posterior circle signal activity is not all lost several times.
Make the standard curve that ATP changes into ADP
1. the Ultra provided with 1 × kinase reaction buffer solution (kinase reaction buffer) dilution kit Pure ATP and ADP, 50 μM of ADP of 900 μ L 50 μM of ATP and 500 μ L are made.
2. by 50 μM of ATP and 50 μM of ADP solution that previous step prepares by being mixed table 1 Suo Shi in 384 orifice plate A1-A12, The ATP and ADP of each conversion percentages concentration are simulated, is mixed.
Table 1. prepares 50 μM of series A TP+ADP standard items
3. 5 μ L ADP-Glo is added per holeTMReagent terminates kinase reaction.In incubation at room temperature 40 minutes.
4. 10 μ L kinase assays reagents (Kinase Detection Reagent) are added per hole changes into ATP by ADP, and Luciferase and luciferin are introduced to detect ATP.
5. in incubation at room temperature 30-60 minutes, measure fluorescent with multi-function microplate reader and record fluorescent value.
6. draw the standard curve that ATP changes into ADP.
Determine the IC of kinase inhibitor50Value
1. prepare 1 × kinase reaction buffer solution (kinase reaction according to promega kit specifications Buffer), 2.5 × 50ng/ μ L kinases and 2.5 × 0.5 μ g/ μ L substrates and 125 μM of ATP.
2. 3 μ 1 × kinase reactions of L buffer solutions (kinase reaction buffer), 2 μ L are added in without enzyme control wells 2.5 × 0.5 μ g/ μ L substrates and 125 μM of ATP.1 μ L 1 × kinase reaction buffer solutions (kinase is added in negative control hole Reaction buffer), 2 μ L 2.5 × 50ng/ μ L kinases, the μ g/ μ L substrates of 2 μ L 2.5 × 0.5 and 125 μM of ATP.Testing 1 μ L5 × medicine to be measured, 2 μ L 2.5 × 50ng/ μ L kinases, the μ g/ μ L substrates of 2 μ L 2.5 × 0.5 and 125 μM of ATP are added in hole.
3. mixing flat board, it is incubated 60 minutes.
4. 5 μ L ADP-Glo is added per holeTMReagent terminates kinase reaction.In incubation at room temperature 40 minutes.
5. 10 μ L kinase assays reagents (Kinase Detection Reagent) are added per hole changes into ATP by ADP, and Luciferase and luciferin are introduced to detect ATP.In incubation at room temperature 30-60 minutes, measure fluorescent with multi-function microplate reader and remember Record fluorescent value.
6. interpretation of result, result is shown in table 2.
2nd, cell growth assay (CCK-8 detection methods)
Cell is inoculated with：Exponential phase cell is collected, concentration of cell suspension is adjusted, with every hole 5x103Individual cell, per hole body 100 μ L of product are inoculated into 96 orifice plates, and every group sets 4 multiple holes (edge hole is filled with sterile PBS)；
Cell culture：After cell attachment, 0%FBS RPMI-1640 starvation 8h, control group 10%FBS RPMI-1640 Culture, 37 DEG C, 5%CO2Continue to cultivate (empirically requiring to cultivate different time respectively) in incubator；
Colour generation：Three groups of cells add 10 μ L CCK-8 solution (5mg/mL) after 72h is cultivated, and culture is terminated after 4h, In low-speed oscillation 10min on shaking table, crystallization is set fully to dissolve；
Colorimetric：Each hole shading value (OD values) is determined on enzyme-linked immunosorbent assay instrument, 570nm wavelength is selected, with acellular I.e. RPMl-1640 nutrient solutions blank well returns to zero, and surveys the absorbance in each hole.Experiment is in triplicate
Record result：Inhibitory rate of cell growth=(the experimental group absorbance of control group absorbance one)/control group extinction Angle value × 100%, cell proliferation rate=(experimental group absorbance/control group absorbance) × 100；
Draw cell growth curve：Using the time as abscissa, inhibiting rate/proliferation rate is that ordinate draws cell growth song Line.
Do figure for inhibitor concentration in GraphPad Prism mapping softwares in GraphPad softwares, so as to by Log [inhibitor] estimates IC relative to reaction, variable slope model50。
Test result is as shown in table 2, and table 2 shows that obtained compound is suppressing BTK EGFR-TKs and antitumor thin Active effect in born of the same parents' propagation.
Table 2
a:IC50：Half effective inhibition concentration .b:Ramos, Raji are typical B- lymphocytic leukemia cells, BTK kinases Altimeter reaches
Above bioactivity result shows that the molecule in the present invention has stronger inhibition, major partization to BTK kinases Compound reaches the active rank of nanomolar range, and has effective inhibition concentration IC of the nearly compound of half50Value is less than 10nmol is suitable for Buddhist nun and Spebrutinib with according to Shandong.Antiproliferation result discloses, and majority of compounds is to lymph Cell leukemia cell (Ramos and Raji) has very effective inhibitory action, wherein compound I-1, I-3, I-4, I-7, I- 10th, I-4-2, I-4-6, (I-1)-(I-4), (I-1)-(I-4), I-13, I-14, I-25, I-26 and I-27 also show excellent It is that those skilled in the art can not expect in Spebrutinib activity, particularly I-1, I-3, I-4, I-7, I-10 effect 's.Indicate the potentiality that this quasi-molecule has exploitation into new and effective BTK inhibitor, to treatment-related tumor disease especially primary Base spy lymphomas, diffusivity large B cell lymphoid tumor, follicular lymphoma or chronic lymphocytic leukemia have larger application Value.
Described above is only the preferred embodiments of the present invention, it is noted that for the ordinary skill people of the art For member, without departing from the technical principles of the invention, some improvements and modifications can also be made, these improvements and modifications Also it should be regarded as protection scope of the present invention.

Claims (6)

1. a kind of compound or its pharmaceutically acceptable salt, the compound has such as following formula (I-4), (I-7) or (I-10) Shown structure：
2. a kind of pharmaceutical composition, it contains compound described in the claim 1 of effective dose or its pharmaceutically acceptable salt, And pharmaceutical carrier.
3. compound described in claim 1 or its pharmaceutically acceptable salt, or pharmaceutical composition described in claim 2 is being made Purposes in the medicine of standby treatment tumour.
4. purposes according to claim 3, wherein, the tumour is selected from Burkitt's lymphoma, diffusivity large B cell drenches One or more in bar knurl, follicular lymphoma or chronic lymphocytic leukemia.
5. purposes according to claim 4, wherein, the tumour is chronic lymphocytic leukemia.
6. purposes according to claim 3, wherein, the purposes is mainly realized by suppressing bruton's EGFR-TK 's.
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