CN106565782A - Phosphoryl pyrimidine compound, composition and use - Google Patents

Phosphoryl pyrimidine compound, composition and use Download PDF

Info

Publication number
CN106565782A
CN106565782A CN201610884363.5A CN201610884363A CN106565782A CN 106565782 A CN106565782 A CN 106565782A CN 201610884363 A CN201610884363 A CN 201610884363A CN 106565782 A CN106565782 A CN 106565782A
Authority
CN
China
Prior art keywords
amine
phenyl
phosphoryl
chloro
acrylamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201610884363.5A
Other languages
Chinese (zh)
Other versions
CN106565782B (en
Inventor
马晓东
葛阳
宋振东
黄珊珊
王长远
张建斌
唐泽耀
刘克辛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dalian Medical University
Original Assignee
Dalian Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dalian Medical University filed Critical Dalian Medical University
Priority to CN201610884363.5A priority Critical patent/CN106565782B/en
Publication of CN106565782A publication Critical patent/CN106565782A/en
Application granted granted Critical
Publication of CN106565782B publication Critical patent/CN106565782B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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 invention relates to a phosphoryl pyrimidine compound, a composition and use. The phosphoryl pyrimidine compound is shown as the general formula (I) in the specification, and each substituent in the general formula (I) is defined as the specification. The invention also relates to use of the compound shown as the general formula (I) or its pharmaceutically acceptable salt, or pharmaceutical compositions containing the same in treatment of tumor diseases through inhibition of Bruton's tyrosine kinase, especially in treatment of burkitt's lymphoma, diffuse large b-cell lymphomas, follicular lymphomas or chronic lymphocytic leukemia. (formula (I)).

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 led to by the signal transduction of control cell Road adjusts a series of physiological and biochemical procedures such as growth, differentiation, the apoptosis of cell.Receptor type tyrosine kinase is a class across cell The relatively large kinases of film, ectodomain that it has ligand binding, membrane spaning domain and plays zymogenesis-in phosphorylation Specific tyrosine residue and the thus intracellular domain of impact cell propagation.(such as lung cancer, mammary gland in general human cancer Cancer, cancer of the stomach, oophoroma, lymthoma) have found the unconventionality expression of the kinases.Protein tyrosine kinase has become antineoplastic One of important target spot of research and development.
BTK is one of non-receptor protein tyrosine kinase Tec family members, and main expression (removes T cell in hematopoietic cell Outward), in BCR signal paths, with the activation of BCR, BTK relies on Syk, Lyn activation, and the BTK after activation can further phosphorus Acidifying PLC γ 2, and then cause the activation including downstream signals such as MAPK, NF κ B.BTK rises in the generating process of bone-marrow-derived lymphocyte Irreplaceable effect.BTK can control sending out for B cell by the active cell cycle positive regulation factor and differentiation factor Educate, break up, also can control survival and the propagation of B cell by adjusting the expression for promoting apoptosis and anti-apoptotic proteins.BTK's continues Activation is a prerequisite of chronic lymphocytic leukemia (CLL) development, and BCR-BTK signal transmissions 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, develops (US 7514444, CN101610676A), 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 than at least 1400 times of other tested kinases is illustrated, Phase is just being carried out at present 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 that, for Buddhist nun's analog, high selectivity suppresses according to Shandong BTK, IC50For 23.9nmol/L, study into PhaseI.In addition CNX-774 (Akinleye, A., et al.J.Hematol Oncol., 2013,6, it is also 59.) a kind of 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 is necessary to develop the better medicine of new effect in the urgent need to, this area.
The content of the invention
An object of the present invention is to provide a kind of phosphoryl pyrimidines or its pharmaceutically acceptable salt, should Class compound has good antitumor activity.
Another object of the present invention is to provide containing 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.
For this purpose, on the one hand, the present invention provides the compound or its pharmaceutically acceptable salt shown in a kind of formula (I), institute State the compound shown in formula (I) and there is 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 shows, big portion Divide such compound that there is stronger suppression lymphocytic leukemia cell (Ramos and Raji) multiplication capacity, part of compounds Show that the anti-BTK more more excellent than Spebrutinib is active.As the novel molecule of a class formation, the chemical combination in the present invention Thing has develops into the potentiality of new and effective BTK inhibitor, to the tumor disease of therapy-related especially Burkitt's lymphoma, Diffusivity large B cell lymphoid tumor, follicular lymphoma or chronic lymphocytic leukemia have larger using value.
Structure shown in aforementioned I-1～I-30 has respectively following title：
(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 group -4- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- is phonetic for 3- for 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 for 3- for 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 group -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 group -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 for 3- for 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 group -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 for 3- for 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 group -4- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- is phonetic for 3- for 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 for showing or its pharmaceutically acceptable salt, and pharmaceutical carrier.
, due to their possibility purposes in medicine, the salt preferred agents of formula (I) compound can for compound of the present invention The salt of acceptance.The compound of the present invention is alkali, and salt form needed for it can be prepared by appropriate method known in the art, is wrapped Include and use mineral acid treatment free alkali, the inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc.；Or use at organic acid Reason 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, such as amino acid, aspartic acid or glutamic acid, such as aromatic acid, benzoic acid or meat Cinnamic acid, such as sulfonic acid, 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 Bright pharmaceutical composition contains the compound for having more than a kind of present invention.In addition, the pharmaceutical composition of the present invention can also optionally include One or more other pharmaceutically active compound.
The present invention also provides the phosphoryl pyrimidines or its pharmaceutically acceptable salt, described pharmaceutical composition By the purposes for suppressing bruton's EGFR-TK and then suppression tumor proliferation.Specifically, the purposes is mainly preparation and is used for The medicine for the treatment 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, diffuses Property large B cell lymphoid tumor, follicular lymphoma or chronic lymphocytic leukemia, the white blood of further preferred chronic lymphocytic Disease.It is highly preferred that the purposes is mainly by suppressing what bruton's EGFR-TK was realized.
Specific embodiment
The explanation present invention is further described below in conjunction with specific embodiment, but these embodiments are not meant as limiting this Bright scope.
The experimental technique 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 concrete source, is the conventional reagent of market purchase.
The preparation of the target molecule of embodiment 1
Tlc silica gel plate is made using Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, thin-layered chromatography (TLC) The specification that silicon amine plate is adopted is 0.15mm-0.2mm, and it is 0.4mm- that thin-layer chromatography isolates and purifies the specification of product employing 0.5mm。
The raw material that the present invention is used 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.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature, is 20 DEG C -30 DEG C.
The technical solution used in the present invention is as follows：
The synthetic route of compound (I), reagent and condition: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 replacement 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 reaction 10min, reaction is finished, and adds 400mL water, separates out white solid, and suction filtration is dried, White solid is obtained, extracting waste solid (19g, 68mmol) and ammonium chloride (7.3g, 136mmol) add MeOH in reaction bulb (25mL) and water (25mL), stirring is lower adds iron powder (15g, 272mmol), heats up 60 DEG C and reacts 2 hours, while hot suction filtration, water 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 is finished, cooling adds 400mL water, separates out white-yellowish solid, takes out Filter, drying, obtains off-white powder, does not purify direct next step reaction.
The synthesis of object (I)
10 (23.44mmol) and trifluoroacetic acid (4.5g, 35.16mmol) are taken in 2-BuOH (50ml), is slowly added into and is taken For arylamine (3 or 6,3.44mmol), heat up 100 DEG C, after reacting 8 hours, reaction is finished, cooling pours saturated sodium bicarbonate into molten In liquid, solid is separated out, suction filtration, washing, drying silica gel column chromatography is separated, and 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 group -4- [(diethoxy phosphoryl) propoxyl group]] phenyl] amine -4- is phonetic for 3- for 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 for 3- for 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 group -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 group -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 for 3- for 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 group -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 for 3- for 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 group -4- [(diethoxy phosphoryl) methyl]] phenyl] amine -4- is phonetic for 3- for 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 Plus the 5mL absolute methanol solutions of inorganic acid (1mmol), completion of dropping, stir 30 minutes at a temperature of this, then normal temperature is evaporated off first Alcohol, obtains final product the inorganic acid salt of target molecule.Hydrochloride (I-4-1), the hydrobromate of compound I-4 are prepared for by the 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 Plus the 5mL dry ethers of organic acid (1mmol), completion of dropping, stir 30 minutes at a temperature of this, then normal temperature is evaporated off solvent, Obtain final product the acylate of target molecule.Maleate (I-4-5), the succinate (I- of compound I-4 are prepared for by the 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 in absolute methanol (5mL), is stirred at room temperature 10 minutes, Normal temperature is evaporated off solvent, obtains final product the mixture of target molecule.By the method be prepared for (I-1)-(I-4), (I-4)-(I-13), (I-1)-(I-13) three two target molecule mixtures.
The target molecule evaluated biological activity of embodiment 2
1st, it is external to receptor tyrosine kinase inhibitory activity method of testing
Prepare kinase assay buffer
1. melt kinase assay buffer (Kinase Detection Buffer) in room temperature, see whether precipitation.
2. if there is precipitation, just often shake within 15 minutes and Jing in 37 DEG C of incubations (Kinase Detection Buffer), Dissolution precipitation.Or, supernatant is carefully siphoned away, remove precipitation.
Prepare kinase assay reagent
1. using front 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, thus made kinase assay Reagent.
3. gently concussion, vortex or reverse mixing, becomes homogeneous solution, and substrate should dissolve in 1 minute.
4. should use immediately after kinase assay reagent is prepared, or packing is stored in -20 DEG C, it is believed that the reagent for preparing is passed through Several times freeze thawing Posterior circle signal activity is not all lost.
Make the calibration curve that ATP changes into ADP
1. the Ultra that kit is provided is diluted with 1 × kinase reaction buffer solution (kinase reaction buffer) Pure ATP and ADP, make 900 μ L, 50 μM of ADP of 50 μM of ATP and 500 μ L.
2. the 50 μM of ATP and 50 μM of ADP solution for previous step being prepared are mixed as table 1 Suo Shi in 384 orifice plate A1-A12, The concentration of the ATP and ADP of each conversion percentages is simulated, is mixed.
Table 1. prepares 50 μM of series A TP+ADP standard items
3. the ADP-Glo of 5 μ L is added per holeTMReagent is terminating kinase reaction.In incubation at room temperature 40 minutes.
4. add 10 μ L kinase assay reagents (Kinase Detection Reagent) that ADP is changed into into ATP per hole, and Introduce luciferase and luciferin to detect ATP.
5. in incubation at room temperature 30-60 minutes, measure fluorescent with multi-function microplate reader and record fluorescent value.
6. the calibration curve that ATP changes into ADP is drawn.
Determine the IC of kinase inhibitor50Value
1. 1 × kinase reaction buffer solution (kinase reaction are prepared 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 L 1 × kinase reaction 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 solution (kinase are 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.In test 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. flat board is mixed, is incubated 60 minutes.
4. the ADP-Glo of 5 μ L is added per holeTMReagent is terminating kinase reaction.In incubation at room temperature 40 minutes.
5. add 10 μ L kinase assay reagents (Kinase Detection Reagent) that ADP is changed into into ATP per hole, and Introduce luciferase and luciferin 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, is as a result 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 4 multiple holes are set per group (edge hole is filled with aseptic 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 culture 72h, and culture is terminated after 4h, The low-speed oscillation 10min on shaking table, makes crystallization fully dissolve；
Colorimetric：Each hole shading value (OD values) is determined on enzyme-linked immunosorbent assay instrument, 570nm wavelength is selected, with acellular That is RPMl-1640 nutrient solutions blank well zeroing, 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：With the time as abscissa, inhibiting rate/rate of increase 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] goes out IC relative to reaction, variable slope model assessment50。
As shown in table 2, table 2 shows that obtained compound is suppressing BTK EGFR-TKs and antitumor thin to test result Active effect in born of the same parents' propagation.
Table 2
a:IC50：Half effective inhibition concentration .b:Ramos, Raji be typical case's B- lymphocytic leukemia cells, BTK kinases Altimeter reaches.
Above biologically active 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 is disclosed, 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 cannot expect in the effect of the activity of Spebrutinib, particularly I-1, I-3, I-4, I-7, I-10 's.Indicate that this quasi-molecule has and develop into the potentiality of new and effective BTK inhibitor, to the tumor disease of therapy-related especially primary Base spy's lymphomas, diffusivity large B cell lymphoid tumor, follicular lymphoma or chronic lymphocytic leukemia have larger application Value.
The above is only the preferred embodiments of the present invention, it is noted that for the ordinary skill people of the art For member, on the premise of without departing from the technology of the present invention principle, some improvements and modifications can also be made, these improvements and modifications Also should be regarded as protection scope of the present invention.

Claims (8)

1. a kind of compound or its pharmaceutically acceptable salt shown in formula (I), the compound shown in the 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.
2. the compound or its pharmaceutically acceptable salt shown in formula (I) as claimed in claim 1, wherein, the formula (I) compound shown in has the structure shown in I-1～I-30：
3. a kind of pharmaceutical composition, its contain the compound described in the claim 1 or 2 of effective dose shown in formula (I) or its Pharmaceutically acceptable salt, and pharmaceutical carrier.
4. the compound or its pharmaceutically acceptable salt shown in formula described in claim 1 or 2 (I), or described in claim 3 Pharmaceutical composition prepare bruton's tyrosine kinase inhibitor in application.
5. the compound or its pharmaceutically acceptable salt shown in formula described in claim 1 or 2 (I), or described in claim 3 Pharmaceutical composition prepare treatment tumour medicine in purposes.
6. purposes according to claim 5, wherein, the tumour is drenched selected from Burkitt's lymphoma, diffusivity large B cell One or more in bar knurl, follicular lymphoma or chronic lymphocytic leukemia.
7. purposes according to claim 6, wherein, the tumour is chronic lymphocytic leukemia.
8. purposes according to claim 5, wherein, the purposes is mainly realized by suppressing bruton's EGFR-TK 's.
CN201610884363.5A 2016-10-10 2016-10-10 Phosphoryl pyrimidines, composition and purposes Expired - Fee Related CN106565782B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610884363.5A CN106565782B (en) 2016-10-10 2016-10-10 Phosphoryl pyrimidines, composition and purposes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610884363.5A CN106565782B (en) 2016-10-10 2016-10-10 Phosphoryl pyrimidines, composition and purposes

Publications (2)

Publication Number Publication Date
CN106565782A true CN106565782A (en) 2017-04-19
CN106565782B CN106565782B (en) 2018-04-06

Family

ID=58531749

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610884363.5A Expired - Fee Related CN106565782B (en) 2016-10-10 2016-10-10 Phosphoryl pyrimidines, composition and purposes

Country Status (1)

Country Link
CN (1) CN106565782B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107964027A (en) * 2017-12-07 2018-04-27 大连医科大学 Phosphoryl pyrimidine anti-tumor compounds and preparation method thereof and purposes
CN109776495A (en) * 2019-01-31 2019-05-21 李佳睿 Antitumoral compounds and preparation method thereof and purposes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101300234A (en) * 2005-11-03 2008-11-05 Irm责任有限公司 Compounds and compositions for protein kinase inhbitors
CN102083800A (en) * 2008-06-27 2011-06-01 阿维拉制药公司 Heteroaryl compounds and uses thereof
WO2013173518A1 (en) * 2012-05-16 2013-11-21 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101300234A (en) * 2005-11-03 2008-11-05 Irm责任有限公司 Compounds and compositions for protein kinase inhbitors
CN102083800A (en) * 2008-06-27 2011-06-01 阿维拉制药公司 Heteroaryl compounds and uses thereof
WO2013173518A1 (en) * 2012-05-16 2013-11-21 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107964027A (en) * 2017-12-07 2018-04-27 大连医科大学 Phosphoryl pyrimidine anti-tumor compounds and preparation method thereof and purposes
CN109776495A (en) * 2019-01-31 2019-05-21 李佳睿 Antitumoral compounds and preparation method thereof and purposes

Also Published As

Publication number Publication date
CN106565782B (en) 2018-04-06

Similar Documents

Publication Publication Date Title
CN106565614A (en) Diphenylaminopyrimidine compound, composition and application
CN101336237B (en) As the pyrimidinyl aryl urea derivatives of FGF inhibitor
CN105968056A (en) Diarylpyrimidine compound, composition and application
CN101163684B (en) Quinazoline derivative having tyrosine kinase inhibitory activity
CN106795150B (en) 1,3,4- thiadiazole compound and its purposes in treating cancer
CN105315285A (en) 2,4-disubstituted 7H-pyrrolo[2,3-d]pyrimidine derivative, preparation method and medical uses thereof
CN106008523A (en) SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS
CN102858765A (en) Pyrazolyl quinazoline kinase inhibitors
TWI774758B (en) C5-anilinoquinazoline compounds and their use in treating cancer
Zhang et al. Synthesis and anticancer activities of 4-(4-substituted piperazin)-5, 6, 7-trialkoxy quinazoline derivatives
CN106660997A (en) Salt of monocyclic pyridine derivative and crystal thereof
CN108290899A (en) A kind of substituted Pyrrolopyrimidine compounds and its application
CN106565782B (en) Phosphoryl pyrimidines, composition and purposes
CN108047205A (en) 2- (2,4,5- substitution phenylamino) pyrimidine derivatives, its preparation method and its application in antitumor drug is prepared
CN105837577B (en) 1- (pyrimidine-4-yl) 3- aminopiperidine derivatives and its preparation method and application
CN106749223A (en) Tyrosine kinase inhibitor and its production and use
CN111620878A (en) Pyrrolopyrimidine derivatives as protein kinase inhibitors and application thereof
Wang et al. Discovery of novel pyrrolopyrimidine/pyrazolopyrimidine derivatives bearing 1, 2, 3‐triazole moiety as c‐Met kinase inhibitors
WO2022148243A1 (en) Pyrimidine small-molecule compound and application thereof
CN103382182B (en) Phenylurea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage
CN106749042A (en) Sulfoamido pyrimidines, composition and purposes
CN106565612B (en) Diphenylethyllene pyrimidines, composition and application thereof
Yang et al. Design, synthesis and evaluation of novel indole derivatives as AKT inhibitors
CN109970717A (en) 4- (cycloaliphatic ring and pyrimidine/pyridine replaces) amino -1H-3- pyrazole carboxamides FLT3 inhibitor and application thereof
CN105884712A (en) Compound capable of inhibiting activity of NEDD8 kinase as well as preparation method and pharmaceutical application of compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20180406

Termination date: 20201010