CN106565614A - Diphenylaminopyrimidine compound, composition and application - Google Patents

Diphenylaminopyrimidine compound, composition and application Download PDF

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Publication number
CN106565614A
CN106565614A CN201611030963.1A CN201611030963A CN106565614A CN 106565614 A CN106565614 A CN 106565614A CN 201611030963 A CN201611030963 A CN 201611030963A CN 106565614 A CN106565614 A CN 106565614A
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Prior art keywords
amine
phenyl
compound
acrylamide
acetyl group
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Inventor
马晓东
葛阳
张建斌
刘贺
黄珊珊
李镇
王长远
刘志浩
彭金咏
刘克辛
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Dalian Medical University
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Dalian Medical University
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Priority to CN201611030963.1A priority Critical patent/CN106565614A/en
Publication of CN106565614A publication Critical patent/CN106565614A/en
Priority to CN201710482786.9A priority patent/CN107400093A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Abstract

The invention relates to a diphenylaminopyrimidine compound, a composition and an application. Concretely, the diphenylaminopyrimidine compound is a compound as shown in a general formula (I) described in the specification, wherein substituents in the general formula (I) are as defined in the specification. The invention also relates to the compound as shown in the general formula (I) or pharmaceutically acceptable salts thereof, or the application of a pharmaceutical composition containing the compound in treatment of tumor diseases by inhibiting Bruton's tyrosine kinase BTK and/or Janus tyrosine kinase JAK3, especially in treatment of burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.

Description

Hexichol amine pyrimidine class compound, compositionss and purposes
Technical field
The present invention relates to hexichol amine pyrimidine class compound, compositionss 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 pulmonary carcinoma, mammary gland in general human cancer Cancer, gastric cancer, ovarian cancer, lymphoma) have found the unconventionality expression of the kinases.Protein tyrosine kinase has become antitumor drug 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 Tumor 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 spebrutinib (AVL-292) (US8563568, WO2014100748A1) be one by covalently bound, high selectivity BTK that can be oral Inhibitor, its IC50Less than 0.5nmol/L, the selectivity than at least 1400 times of other tested kinases is illustrated, just carried out at present PhaseI 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.) are for Buddhist nun's analog, high selectivity according to Shandong Suppress 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, IC50It is less than 1nmol/L, the patent being related to is such as：WO2010141406A2、US20140256759A1、CN102083800A.
JAK (Janus tyrosine kinase), including tetra- members of JAK1, JAK2, JAK3 and TYK2.JAKs is in various kinds of cell Play a significant role during the signal transduction of the factor.JAK1, JAK2 and TYK2 are widely present in various tissues and cell, and JAK3 is distributed mainly in lymphocyte, and research shows, JAK3 not only plays pivotal role in the maturation of B and T lymphocytes, its It is also requisite for T cell function is maintained.Therefore exploitation JAK selective depressants are for myeloproliferative tumor and in vain The treatment of disorders of blood has very big medical value and market potential.Tofacitinib (CP-690550) is the one of Pfizer's research and development Plant oral JAK3 pathway inhibitors.Tofacitinib acts on cytokine network with intracellular signal transduction path as target spot Core.Its inhibition strength to JAK3 is 5～100 times to JAK1 and JAK2.Tofacitinib (US20040102627, US8309716, WO2008058528) is treatment rheumatoid arthritiss (rheumatoid Arthritis pioneering medicine (first-in-class drug)), in 2012, by food and drug administration (FDA) approval listing.Cerdulatinib (PRT-062070) is a kind of suppression of the Mutiple Targets tyrosine kinase with Orally active Preparation, the IC to JAK1/JAK2/JAK3/TYK2 and Syk50Respectively 12nM/6nM/8nM/0.5nM and 32nM.Also can suppress Other 19 kinds of kinases of test, IC50Be below 200nM (Coffey, G., J.Pharmacol Exp.Ther.2014,351, 538-548.).Fedratinib (SAR302503, TG101348) is a kind of selectivity JAK2 inhibitor (Geron, I., et Al.Cancer Cell2008,13,321-330.), the IC in Cell free assay50For 3nM, act on JAK2 and be compared to for JAK1 It is high with JAK3 selectivitys 35 and 334 times, have been enter into clinical Phase II and study (WO 2012060847A1).
In addition with closely related patent of the invention such as：WO 2015039613A1、WO 2015182628A1、 CN104311573A。
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 hexichol amine pyrimidine class compound or its pharmaceutically acceptable salt, Such compound has good anti-tumor activity.
Another object of the present invention is to provide containing the hexichol amine pyrimidine class compound or its is pharmaceutically acceptable The pharmaceutical composition of salt.
It is still another object of the present invention to provide the hexichol amine pyrimidine class compound or its pharmaceutically acceptable salt, Or the purposes of the compositionss.
For this purpose, on the one hand, the present invention provides the compound or its pharmaceutically acceptable salt shown in a kind of logical formula I, institute State the compound shown in logical formula I and there is following structure：
Wherein,
X is selected from hydrogen, chlorine, fluorine, nitro or trifluoromethyl；
Y is O or NH；
L is selected from-COCH2- or-CH2CO-；
R1Selected from hydrogen, methyl, methoxyl group or chlorine；
R2It is selected from Or
Used as a kind of specific embodiment of the present invention, the compound shown in logical formula I of the present invention has I-1～I- Structure shown in 34：
Preferably, the compound shown in the logical formula I is I-12.
Antitumor activity screening of the present invention shows, the compounds of this invention in enzyme level with good anti-BTK and/or JAK3 kinase activities；On cellular level, the compounds of this invention have stronger suppression lymphocytic leukemia cell (Ramos and Raji) multiplication capacity, part of compounds shows that the anti-BTK more more excellent than Spebrutinib is active, and resists with excellent JAK3 is active.As the novel molecule of a class formation, the compound in the present invention have develop into new and effective BTK and/or The potentiality of JAK3 inhibitor, to the tumor disease of therapy-related especially burkitt's lymphoma, diffusivity large B cell lymph Tumor, follicular lymphoma or chronic lymphocytic leukemia have larger using value.
Structure shown in aforementioned I-1～I-34 has respectively following title：
(I-1) N- [3- [[the chloro- 2- of 5- [[4- [((1- morpholines) acetyl group) epoxide]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
(I-2) [[[the chloro- 2- of 5- [[3- methoxyl group -4- [((1- morpholines) acetyl group) epoxide]] 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- [((1- morpholines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
(I-4) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- [((1- methyl piperazines) acetyl group) epoxide]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
(I-5) N- [3- [[the chloro- 2- of 5- [[4- [((1- ethyl piperazidines) acetyl group) epoxide]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
(I-6) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- [((1- ethyl piperazidines) acetyl group) epoxide]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
(I-7) [[[the fluoro- 2- of 5- [[3- methoxyl group -4- [((1- morpholines) acetyl group) epoxide]] phenyl] amine -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] acrylamide
(I-8) N- [3- [[the fluoro- 2- of 5- [[the chloro- 4- of 3- [((1- ethyl piperazidines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
(I-9) N- [3- [[the chloro- 2- of 5- [[4- [((1- glycine methyl esters) acetyl group) epoxide]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
(I-10) N- [3- [[the chloro- 2- of 5- [[4- [((1- glycine) acetyl group) epoxide]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
(I-11) N- [3- [[the chloro- 2- of 5- [[4- [((2- diethylamides) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
(I-12) N- [3- [[the chloro- 2- of 5- [[4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide
(I-13) [[[the chloro- 2- of 5- [[3- methoxyl group -4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] acrylamide
(I-14) N- [3- [[the chloro- 2- of 5- [[3- methyl -4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
(I-15) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- [((2- methyl piperazines) acetyl group) amine]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
(I-16) [[[the chloro- 2- of 5- [[3- methyl -4- [((2- methyl piperazines) acetyl group) amine]] phenyl] amine -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] acrylamide
(I-17) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- [((2- ethyl piperazidines) acetyl group) amine]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
(I-18) [[[the chloro- 2- of 5- [[3- methyl -4- [((2- ethyl piperazidines) acetyl group) amine]] phenyl] amine -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] acrylamide
(I-19) N- [3- [[5- nitro -2- [[4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
(I-20) N- [3- [[5- nitro -2- [[4- [((2- methyl piperazines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
(I-21) N- [3- [[5- nitro -2- [[4- [((2- diethylamides) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
(I-22) N- [3- [[5- nitro -2- [[4- [((2- dibutylamines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
(I-23) N- [3- [[the fluoro- 2- of 5- [[4- [((2- diethylamides) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
(I-24) N- [3- [[the fluoro- 2- of 5- [[4- [((2- dibutylamines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
(I-25) N- [3- [[the fluoro- 2- of 5- [[4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide
(I-26) N- [3- [[the fluoro- 2- of 5- [[the chloro- 4- of 3- [((2- methyl piperazines) acetyl group) amine]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
(I-27) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [((1- methyl piperazines) acetyl group) epoxide]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
(I-28) N- [3- [[5- nitro -2- [[4- [((1- morpholines) acetyl group) epoxide]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
(I-29) N- [3- [[5- nitro -2- [[4- [((1- methyl piperazines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
(I-30) N- [3- [[5- nitro -2- [[4- [((1- ethyl piperazidines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
(I-31) N- [3- [[5- trifluoromethyl -2- [[4- [((1- morpholines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
(I-32) N- [3- [[2- [[3- methoxyl group -4- [((1- morpholines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
(I-33) N- [3- [[5- trifluoromethyl -2- [[4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
(I-34) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
On the other hand, the present invention provides a kind of pharmaceutical composition, and it contains the of the present invention logical formula 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 mineral acid such as hydrochloric acid, hydrobromic acid, sulphuric 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, succinic 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 aminoacid, 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, propanoic acid Salt, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propionate (propiolates), Oxalates, malonate, benzoate, chloro benzoate, ar-Toluic acid salt, dinitro-benzoate, hydroxy benzoate, Methoxybenzoic 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 hexichol amine pyrimidine class compound or its pharmaceutically acceptable carrier, the medicine group Compound is by suppressing bruton's tyrosine kinase BTK and/or Janus Tyrosine kinase JAK3 and then suppressing tumor proliferation and treatment The two disease for causing, particularly treats the leukemic purposes of B cell lymphoma.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 and 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 bruton's tyrosine kinase BTK and/or the application in Janus Tyrosine kinase JAK3 inhibitor.
The present invention provides the compound or its pharmaceutically acceptable salt shown in the logical formula I, or of the present invention Purposes of the pharmaceutical composition in the medicine for preparing treatment tumor.Preferably, the tumor 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 bruton's tyrosine kinase BTK and/or Janus Tyrosine kinase JAK3s Realize.
Description of the drawings
Fig. 1 is the compound I-12 of the embodiment of the present invention 2 to PBMC cell toxicity datas.
Fig. 2 is active for the anti-Raji B lymphocyte proliferations of the compound I-12 of the embodiment of the present invention 2.
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 layer 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 Company limited, Aladdin chemical reagent company limited, up to companies such as auspicious chemicals.
Without specified otherwise in embodiment, solution refers to 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)K2CO3,KI,CH3CN, 60 DEG C, 85-92%；b)Fe- NH4Cl,MeOH-H2O, 60 DEG C, 62-85%；c)NaHCO3, acetonitrile, 0 DEG C, 10min, 85-93%；d)Fe-NH4Cl,MeOH- H2O, 60 DEG C, 62-85%；E) DIPEA, 1,4- dioxane, 60 DEG C, 49-72%；f)ArNH2,CF3COOH,100℃,5– 21%, each substituent group is defined as described above.
5 synthesis
Take 4 (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 sucking filtration is dried, Obtain white solid；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 sucking 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 5.
7 synthesis
6 (23.44mmol) and DIPEA (4.5g, 35.16mmol) are taken in 50mL dioxane, be slowly added into 5 (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, the direct next step reaction of non-purification.
The synthesis of object (I)
7 (23.44mmol) and trifluoroacetic acid (4.5g, 35.16mmol) are taken in 2-BuOH (50ml), replacement is slowly added into Arylamine 3 (3.44mmol), heats up 100 DEG C, and after reacting 8 hours, reaction is finished, cooling, in pouring saturated sodium bicarbonate solution into, analysis Go out solid, sucking 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- [((1- morpholines) acetyl group) epoxide]] 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), 4.81 (s, 2H), 3.66 (t, J=35.6Hz, 4H), 3.43 (t, J=38.4Hz, 4H)；MS(ESI)m/z 509.17[M+H]+。
(I-2) [[[the chloro- 2- of 5- [[3- methoxyl group -4- [((1- morpholines) acetyl group) epoxide]] phenyl] amine -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.14(s,1H),8.89(s,1H),8.11(s,1H), 7.89 (s, 1H), 7.53 (dd, J=34.2,8.8Hz, 3H), 7.30 (d, J=4.9Hz, 2H), 6.69 (d, J=8.3Hz, 1H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.77 (d, J=10.0Hz, 1H), 4.84 (s, 2H), 3.78 (s, 3H), 3.65 (t, J=35.6Hz, 4H), 3.46 (t, J=38.4Hz, 4H)；MS(ESI)m/z 539.18[M+ H]+。
(I-3) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [((1- morpholines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.22(s,1H),9.17(s,1H),8.89(s,1H),8.10(s,1H), 7.88 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.69 (d, J=8.3Hz, 1H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.27 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.82 (s, 2H), 3.64 (t, J=35.6Hz, 4H), 3.42 (t, J=38.4Hz, 4H)；MS(ESI)m/z 543.13[M+H]+。
(I-4) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- [((1- methyl piperazines) acetyl group) epoxide]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.19(s,1H),9.13(s,1H),8.89(s,1H),8.10(s,1H), 7.89 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.69 (d, J=8.3Hz, 1H), 6.44 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.83 (s, 2H), 3.78 (s, 3H), 3.37 (t, J=35.6Hz, 4H), 2.64 (t, J=38.4Hz, 4H), 2.25 (s, 3H)；MS(ESI)m/ z 552.21[M+H]+。
(I-5) N- [3- [[the chloro- 2- of 5- [[4- [((1- ethyl piperazidines) acetyl group) epoxide]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.15(s,1H),8.89(s,1H),8.12(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), 4.83 (s, 2H), 3.36 (t, J=35.6Hz, 4H), 2.64 (t, J=38.4Hz, 4H), 2.05-1.68 (m, 2H), 1.21 (t, J= 7.0Hz,3H)；MS(ESI)m/z 536.22[M+H]+。
(I-6) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- [((1- ethyl piperazidines) acetyl group) epoxide]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.14(s,1H),8.89(s,1H),8.12(s,1H), 7.88 (s, 1H), 7.53 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.69 (d, J=8.3Hz, 1H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.82 (s, 2H), 3.74 (s, 3H), 3.36 (t, J=35.6Hz, 4H), 2.63 (t, J=38.4Hz, 4H), 2.05-1.68 (m, 2H), 1.21 (t, J=7.0Hz, 3H)；MS(ESI)m/z 566.23[M+H]+。
(I-7) [[[the fluoro- 2- of 5- [[3- methoxyl group -4- [((1- morpholines) acetyl group) epoxide]] phenyl] amine -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.22(s,1H),9.12(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, 1H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.77 (d, J=10.0Hz, 1H), 4.85 (s, 2H), 3.78 (s, 3H), 3.65 (t, J=35.6Hz, 4H), 3.46 (t, J=38.4Hz, 4H)；MS(ESI)m/z 523.21[M+ H]+。
(I-8) N- [3- [[the fluoro- 2- of 5- [[the chloro- 4- of 3- [((1- ethyl piperazidines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.14(s,1H),8.89(s,1H),8.12(s,1H), 7.88 (s, 1H), 7.53 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.69 (d, J=8.3Hz, 1H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.82 (s, 2H), 3.36 (t, J=35.6Hz, 4H), 2.63 (t, J=38.4Hz, 4H), 2.05-1.68 (m, 2H), 1.21 (t, J= 7.0Hz,3H)；MS(ESI)m/z 554.21[M+H]+。
(I-9) N- [3- [[the chloro- 2- of 5- [[4- [((1- glycine methyl esters) acetyl group) epoxide]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.19(s,1H),9.16(s,1H),8.89(s,1H),8.10(s,1H), 8.06 (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), 6.47 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H),4.81(s,2H),4.15(s,2H),3.66(s,3H)；MS(ESI)m/z 511.15[M+H]+。
(I-10) N- [3- [[the chloro- 2- of 5- [[4- [((1- glycine) acetyl group) epoxide]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ11.02(s,1H),10.19(s,1H),9.16(s,1H),8.89(s,1H), 8.10 (s, 1H), 8.06 (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), 6.47 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.81 (s, 2H), 4.13 (s, 2H)；MS(ESI)m/z 497.13[M+H]+。
(I-11) N- [3- [[the chloro- 2- of 5- [[4- [((2- diethylamides) acetyl group) amine]] 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),8.10(s,1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.51 (dd, J=34.2,8.8Hz, 3H), 7.33 (d, J=4.9Hz, 2H), 6.69 (d, J =8.3Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.27 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.31 (s, 2H), 2.05-1.68 (m, 4H), 1.20 (t, J=7.0Hz, 6H)；MS(ESI)m/z 494.21[M+H]+。
(I-12) N- [3- [[the chloro- 2- of 5- [[4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.16(s,1H),8.89(s,1H),8.10(s,1H), 8.01 (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), 3.68 (t, J=35.6Hz, 4H), 3.32 (s, 2H), 2.43 (t, J=38.4Hz, 4H)；MS(ESI)m/z 508.19[M+ H]+。
(I-13) [[[the chloro- 2- of 5- [[3- methoxyl group -4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.19(s,1H),9.17(s,1H),8.89(s,1H),8.10(s,1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 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), 3.75 (s, 3H), 3.68 (t, J=35.6Hz, 4H), 3.32 (s, 2H), 2.45 (t, J=38.4Hz, 4H)；MS(ESI)m/ z 538.20[M+H]+。
(I-14) N- [3- [[the chloro- 2- of 5- [[3- methyl -4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.16(s,1H),8.89(s,1H),8.10(s,1H), 8.01 (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, 1H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.68 (t, J=35.6Hz, 4H), 3.32 (s, 2H), 2.43 (t, J=38.4Hz, 4H), 2.33 (s, 3H)；MS(ESI)m/ z 522.20[M+H]+。
(I-15) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- [((2- methyl piperazines) acetyl group) amine]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.13(s,1H),8.89(s,1H),8.10(s,1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.69 (d, J =8.3Hz, 1H), 6.44 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.74 (s, 3H), 3.37 (t, J=35.6Hz, 4H), 3.28 (s, 2H), 2.62 (t, J=38.4Hz, 4H), 2.23 (s, 3H)；MS(ESI)m/z 551.23[M+H]+。
(I-16) [[[the chloro- 2- of 5- [[3- methyl -4- [((2- methyl piperazines) acetyl group) amine]] phenyl] amine -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.19(s,1H),9.16(s,1H),8.89(s,1H),8.10(s,1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.69 (d, J =8.3Hz, 1H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.38 (t, J=35.6Hz, 4H), 3.29 (s, 2H), 2.62 (t, J=38.4Hz, 4H), 2.34 (s, 3H), 2.24 (s, 3H)；MS(ESI)m/z 535.23[M+H]+。
(I-17) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- [((2- ethyl piperazidines) acetyl group) amine]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.17(s,1H),8.89(s,1H),8.12(s,1H), 8.03 (s, 1H), 7.88 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.69 (d, J =8.3Hz, 1H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.73 (s, 3H), 3.36 (t, J=35.6Hz, 4H), 3.31 (s, 2H), 2.63 (t, J=38.4Hz, 4H), 2.05-1.68 (m, 2H), 1.21 (t, J=7.0Hz, 3H)；MS(ESI)m/z 565.25[M+H]+。
(I-18) [[[the chloro- 2- of 5- [[3- methyl -4- [((2- ethyl piperazidines) acetyl group) amine]] phenyl] amine -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.18(s,1H),8.89(s,1H),8.11(s,1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.69 (d, J =8.3Hz, 1H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.36 (t, J=35.6Hz, 4H), 3.31 (s, 2H), 2.63 (t, J=38.4Hz, 4H), 2.33 (s, 3H), 2.05-1.68 (m, 2H), 1.22 (t, J=7.0Hz, 3H)；MS(ESI)m/z 549.25[M+H]+。
(I-19) N- [3- [[5- nitro -2- [[4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.20(s,1H),9.14(s,1H),8.89(s,1H),8.12(s,1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.53 (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), 3.68 (t, J=35.6Hz, 4H), 3.34 (s, 2H), 2.45 (t, J=38.4Hz, 4H)；MS(ESI)m/z 519.21[M+ H]+。
(I-20) N- [3- [[5- nitro -2- [[4- [((2- methyl piperazines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.13(s,1H),8.89(s,1H),8.10(s,1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.69 (d, J =8.3Hz, 2H), 6.44 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.37 (t, J=35.6Hz, 4H), 3.28 (s, 2H), 2.62 (t, J=38.4Hz, 4H), 2.23 (s, 3H)；MS(ESI)m/ z 532.24[M+H]+。
(I-21) N- [3- [[5- nitro -2- [[4- [((2- diethylamides) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.20(s,1H),9.15(s,1H),8.90(s,1H),8.11(s,1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.50 (dd, J=34.2,8.8Hz, 3H), 7.33 (d, J=4.9Hz, 2H), 6.69 (d, J =8.3Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.27 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.31 (s, 2H), 2.05-1.68 (m, 4H), 1.22 (t, J=7.0Hz, 6H)；MS(ESI)m/z 505.23[M+H]+。
(I-22) N- [3- [[5- nitro -2- [[4- [((2- dibutylamines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.15(s,1H),8.90(s,1H),8.12(s,1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.50 (dd, J=34.2,8.8Hz, 3H), 7.34 (d, J=4.9Hz, 2H), 6.69 (d, J =8.3Hz, 2H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.27 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.31 (s, 2H), 2.35 (t, J=7.0Hz, 4H), 1.45-1.36 (m, 4H), 1.34-1.15 (m, 4H), 1.00 (t, J= 7.0Hz,6H)；MS(ESI)m/z 561.29[M+H]+。
(I-23) N- [3- [[the fluoro- 2- of 5- [[4- [((2- diethylamides) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.17(s,1H),9.15(s,1H),8.89(s,1H),8.10(s,1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.51 (dd, J=34.2,8.8Hz, 3H), 7.33 (d, J=4.9Hz, 2H), 6.69 (d, J =8.3Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.30 (s, 2H), 2.05-1.68 (m, 4H), 1.21 (t, J=7.0Hz, 6H)；MS(ESI)m/z 478.24[M+H]+。
(I-24) N- [3- [[the fluoro- 2- of 5- [[4- [((2- dibutylamines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] amine] Phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.15(s,1H),8.90(s,1H),8.12(s,1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.50 (dd, J=34.2,8.8Hz, 3H), 7.34 (d, J=4.9Hz, 2H), 6.68 (d, J =8.3Hz, 2H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.27 (d, J=16.8Hz, 1H), 5.77 (d, J=10.0Hz, 1H), 3.31 (s, 2H), 2.35 (t, J=7.0Hz, 4H), 1.45-1.36 (m, 4H), 1.34-1.15 (m, 4H), 1.00 (t, J= 7.0Hz,6H)；MS(ESI)m/z 534.30[M+H]+。
(I-25) N- [3- [[the fluoro- 2- of 5- [[4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] amine] benzene Base] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.22(s,1H),9.16(s,1H),8.87(s,1H),8.10(s,1H), 8.02 (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), 6.47 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.68 (t, J=35.6Hz, 4H), 3.34 (s, 2H), 2.41 (t, J=38.4Hz, 4H)；MS(ESI)m/z 492.21[M+ H]+。
(I-26) N- [3- [[the fluoro- 2- of 5- [[the chloro- 4- of 3- [((2- methyl piperazines) acetyl group) amine]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.18(s,1H),9.13(s,1H),8.89(s,1H),8.10(s,1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.68 (d, J =8.3Hz, 1H), 6.44 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 3.38 (t, J=35.6Hz, 4H), 3.29 (s, 2H), 2.61 (t, J=38.4Hz, 4H), 2.23 (s, 3H)；MS(ESI)m/ z 539.21[M+H]+。
(I-27) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [((1- methyl piperazines) acetyl group) epoxide]] phenyl] amine -4- Pyrimidine radicals] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.19(s,1H),9.13(s,1H),8.89(s,1H),8.10(s,1H), 7.89 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 1H), 6.69 (d, J=8.3Hz, 2H), 6.44 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.83 (s, 2H), 3.37 (t, J=35.6Hz, 4H), 2.64 (t, J=38.4Hz, 4H), 2.36 (s, 3H), 2.25 (s, 3H)；MS(ESI)m/ z 536.22[M+H]+。
(I-28) N- [3- [[5- nitro -2- [[4- [((1- morpholines) acetyl group) epoxide]] 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), 7.88 (s, 1H), 7.51 (dd, J=34.2,8.8Hz, 3H), 7.30 (d, J=4.9Hz, 2H), 6.68 (d, J=8.3Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.23 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.83 (s, 2H), 3.64 (t, J=35.6Hz, 4H), 3.41 (t, J=38.4Hz, 4H)；MS(ESI)m/z 520.19[M+H]+。
(I-29) N- [3- [[5- nitro -2- [[4- [((1- methyl piperazines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.19(s,1H),9.13(s,1H),8.89(s,1H),8.10(s,1H), 7.89 (s, 1H), 7.52 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.69 (d, J=8.3Hz, 2H), 6.44 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.83 (s, 2H), 3.37 (t, J=35.6Hz, 4H), 2.64 (t, J=38.4Hz, 4H), 2.25 (s, 3H)；MS(ESI)m/z 533.23[M+ H]+。
(I-30) N- [3- [[5- nitro -2- [[4- [((1- ethyl piperazidines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.23(s,1H),9.15(s,1H),8.87(s,1H),8.12(s,1H), 7.89 (s, 1H), 7.53 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.69 (d, J=8.3Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 5.74 (d, J=10.0Hz, 1H), 4.82 (s, 2H), 3.36 (t, J=35.6Hz, 4H), 2.64 (t, J=38.4Hz, 4H), 2.05-1.68 (m, 2H), 1.21 (t, J= 7.0Hz,3H)；MS(ESI)m/z 547.24[M+H]+。
(I-31) N- [3- [[5- trifluoromethyl -2- [[4- [((1- morpholines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),9.14(s,1H),8.89(s,1H),8.11(s,1H), 7.88 (s, 1H), 7.50 (dd, J=34.2,8.8Hz, 3H), 7.31 (d, J=4.9Hz, 2H), 6.68 (d, J=8.3Hz, 2H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.23 (d, J=16.8Hz, 1H), 5.77 (d, J=10.0Hz, 1H), 4.83 (s, 2H), 3.64 (t, J=35.6Hz, 4H), 3.42 (t, J=38.4Hz, 4H)；MS(ESI)m/z 543.20[M+H]+。
(I-32) N- [3- [[2- [[3- methoxyl group -4- [((1- morpholines) acetyl group) epoxide]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ10.22(s,1H),9.12(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, 1H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.77 (d, J=10.0Hz, 1H), 4.85 (s, 2H), 3.78 (s, 3H), 3.65 (t, J=35.6Hz, 4H), 3.46 (t, J=38.4Hz, 4H)；MS(ESI)m/z 523.21[M+ H]+。
(I-33) N- [3- [[5- trifluoromethyl -2- [[4- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidines Base] amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ 10.22 (d, J=10.0Hz, 1H), 9.15 (s, 1H), 8.87 (s, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.88 (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), 6.47 (dd, J=16.9,10.1Hz, 1H), 6.26 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 5.63 (d, J=10.0Hz, 1H), 3.68 (t, J=35.6Hz, 4H), 3.32 (s, 2H), 2.41 (t, J=38.4Hz, 4H)；MS(ESI)m/z 505.22[M+H]+。
(I-34) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [((2- morpholines) acetyl group) amine]] phenyl] amine -4- pyrimidine radicals] Amine] phenyl] acrylamide
1H NMR(400MHz,DMSO-d6):δ 10.21 (d, J=10.0Hz, 1H), 9.16 (s, 1H), 8.89 (s, 1H), 8.10 (s, 1H), 8.01 (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, 1H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 5.65 (d, J=10.0Hz, 1H), 3.68 (t, J=35.6Hz, 4H), 3.32 (s, 2H), 2.43 (t, J=38.4Hz, 4H)；MS(ESI)m/z 508.18[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 mineral acid (1mmol), completion of dropping, stir 30 minutes at a temperature of this, then room temperature is evaporated off first Alcohol, obtains final product the inorganic acid salt of target molecule.Hydrochlorate (I-3-1), the hydrobromate of compound I-3 are prepared for by the method (I-3-2), sulfate (I-3-3) and mesylate (I-3-4)；
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 room temperature is evaporated off solvent, Obtain final product the acylate of target molecule.Maleate (I-3-5), the succinate (I- of compound I-3 are prepared for by the method 3-6) and fumarate (I-3-7).
The preparation of two target molecule mixture
The above-mentioned two target molecule of equimolar amountss (1mmol) is taken in absolute methanol (5mL), is stirred at room temperature 10 minutes, Room temperature is evaporated off solvent, obtains final product the mixture of target molecule.By the method be prepared for (I-3)-(I-17), (I-17)-(I-18), (I-3)-(I-18) three two target molecule mixture.
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 at equilibrium at room temperature kinase assay buffer (Kinase Detection Buffer) and kinase assay bottom Thing (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), lyophilized 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 subpackage is stored in -20 DEG C, the reagent for preparing is through freeze thawing several times Posterior circle signal activity is not all lost.
Make the standard curve that ATP changes into ADP
1. the Ultra that test kit is provided is diluted with 1 × kinase reaction buffer (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 substance
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 standard curve that ATP changes into ADP is drawn.
Determine the IC of kinase inhibitor50Value
1. 1 × kinase reaction buffer (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 (kinase reaction buffer), 2 μ are added in without enzyme control wells L2.5 × 0.5 μ g/ μ L substrates and 125 μM of ATP.1 μ L 1 × kinase reaction buffer (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, as a result as 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 5 × 103Individual cell, per hole The μ L of volume 100 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, matched group is trained with 10%FBSRPMI-1640 Support, 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 RPMI-1640 culture fluid 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 matched group absorbance one)/matched group extinction Angle value × 100%, cell proliferation rate=(experimental group absorbance/matched group absorbance) × 100；
Draw cell growth curve：With the time as abscissa, suppression ratio/rate of increase is that vertical coordinate 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 a result as shown in table 2 and Fig. 2
3rd, active medicine toxicity test
PERIPHERAL BLOOD MONONUCLEAR CELL (Peripheral blood mononuclear cell, PBMC) comprising lymphocyte, Mononuclear cell (monocyte), dendritic cell and other a small amount of cells (hematopoietic stem cell etc.).Carrying out toxicity test to it can To prove that whether the medicine of the present invention has lethality to normal immunocyte.Separating the common method of PBMC both at home and abroad at present is Glucosan-Hypaque density gradients centrifuging, experimental procedure is as follows：
(1) take a blood sample and dilute：Venous blood sampling 2mL, in adding the test tube containing ACD anticoagulant solutions, mixes, and makes blood anticoagulant. With PBS solution by 1 times of anticoagulant hemodilution.
(2) it is loaded：During absorption 2mL lymphocytes separating solutions (Tianjin TBD) is placed in graduated centrifuge tube, then centrifuge tube is inclined Tiltedly 45° angle, is added slowly to the whole blood of dilution above separating liquid with capillary burette along tube wall, it should be noted that keep both interfaces clear It is clear.
(3) it is centrifuged：At 18 DEG C～20 DEG C, 20min is centrifuged with 2000r/min with horizontal centrifuge.From ttom of pipe after centrifugation Divide four layers to liquid level, be followed successively by erythrocyte and GCL, layering liquid layer, mononuclearcell layer, plasma layer.
(4) reclaim：Muddy band is gently inserted into capillary pipette, along tube wall this confluent monolayer cells is gently suctioned out, moved into another fragmented In heart pipe.All mononuclearcells are drawn, avoids drawing excessive layering liquid or blood plasma again, in order to avoid it is mixed into other cells Composition.
(5) wash：With PBS liquid washed cell 3 times.First time 2000r/min, 10min；2nd～3 1500r/min, 10min, can remove the platelet that major part mixes.
(6) sedimentation cell is suspended from standby in culture medium.
(7) bed board is counted：Adjustment concentration of cell suspension, with every hole 2.5 × 105Individual cell, is inoculated into per the μ L of pore volume 500 24 orifice plates, 2 multiple holes are set per group.
(8) cell culture：After cell inoculation, matched group is cultivated with 10%FBS RPMI-1640, and experimental group is respectively with 50 μ L Variable concentrations gradient according to Shandong for Buddhist nun (5-20 μm of ol/L), active medicine (compound I-12,5-20 μm of ol/L) intervene, 37 DEG C, 5%CO2Continue to cultivate (empirically requiring to cultivate different time respectively) in incubator.
(9) dye：μ g/ μ l AO (acridine orange) of 20 μ L 1, μ g/ μ l PI (propidium iodide) of 20 μ L 1 are added after culture 24h Dyeing 5min, observes and takes pictures, as a result as shown in Figure 1 under inverted fluorescence microscope.
4th, result and conclusion
The compound of table 2 suppresses the biological activity result of BTK and JAK3 kinases and anti-B lymphoma cells propagation
a:IC50：Half effective inhibition concentration .b:Ramos, Raji be typical case's B- lymphocytic leukemia cells, BTK kinases Altimeter reaches.
Table 2 suppresses the biological activity result of BTK and JAK3 kinases and anti-B lymphoma cells propagation, the knot for compound Fruit shows that the most of molecule in the present invention has stronger inhibition to BTK and/or JAK3 kinases, reaches nanomolar range Active rank, wherein compound I-1, I-3, I-5, I-9, I-10 and I-12 have very strong suppression to BTK and JAK3 kinases Make and use, IC50Value is less than 1Nm, compares and acts only on BTK kinases for Buddhist nun and Spebrutinib according to Shandong, and this quasi-molecule shows The inhibition of economic benefits and social benefits, indicates that this quasi-molecule has the biological activity of higher suppression B lymphoma cells.On the other hand, resist thin Born of the same parents' proliferation activity result is disclosed, and majority of compounds has very effective to lymphocytic leukemia cell (Ramos and Raji) Inhibitory action, wherein compound I-12 have reached 0.784 μM to effective inhibition concentration of Raji cells, compound I-15, I-16, I-17 and I-26 also show unforeseeable better than the activity that Buddhist nun and Spebrutinib are replaced according to Shandong.In addition, compound I-3, I-11, I-13, I-14, I-15, I-16, I-17, I-18, I-24 and I-26 show obvious to the inhibitory action of Ramos cells Activity better than Spebrutinib.
The result of Fig. 1 shows that the compound I-12 of the present invention is less to normal peripheral blood cell PBMC cytotoxicities, works as medicine When thing concentration is 20 μm of ol/L, weak cytotoxicity is shown, in 10 μm of ol/L, compound I-12 is to PBMC cells without bright Under aobvious toxicity, but this concentration, certain toxicity is shown for Buddhist nun according to Shandong, it is clear that compound I-12 is shown than replacing according to Shandong The safer biological activity of Buddhist nun.
Fig. 2 for compound I-12 anti-Raji B lymphocyte proliferations Activity Results, should test result indicate that：Compound I- The activity of 12 suppression Raji cells functions time and drug level, and into obvious relation of passing, the i.e. drug level of relying on increases, carefully Born of the same parents' survival rate reduces, and after drug level is 5 μm of ol/L, action time 72h, Raji cells are almost suppressed completely, this result Show to strengthen drug level, increase drug treating time to treating bone-marrow-derived lymphocyte and be remarkably reinforced effect.
Result above indicates that this quasi-molecule has the potentiality for developing into new and effective BTK and/or JAK3 inhibitor, to treatment Related tumor disease especially burkitt's lymphoma, diffusivity large B cell lymphoid tumor, follicular lymphoma or chronic lymphatic Chronic myeloid leukemia has larger using 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 (9)

1. a kind of compound or its pharmaceutically acceptable salt shown in logical formula I, the compound shown in the logical formula I has Following structure：
Wherein,
X is selected from hydrogen, chlorine, fluorine, nitro or trifluoromethyl；
Y is O or NH；
L is selected from-COCH2- or-CH2CO-；
R1Selected from hydrogen, methyl, methoxyl group or chlorine；
R2It is selected from
2. the compound or its pharmaceutically acceptable salt shown in logical formula I according to claim 1, wherein, it is described logical Compound shown in formula I has the structure shown in I-1～I-34：
3. the compound or its pharmaceutically acceptable salt shown in logical formula I according to claim 2, wherein, it is described logical Compound shown in formula I is I-12.
4. a kind of pharmaceutical composition, the change shown in formula I is led to any one of its claims 1 to 3 for containing effective dose Compound or its pharmaceutically acceptable salt, and pharmaceutical carrier.
5. the compound or its pharmaceutically acceptable salt shown in formula I, or right are led to any one of claims 1 to 3 It is required that the pharmaceutical composition described in 4 is preparing bruton's tyrosine kinase BTK and/or the suppression of Janus Tyrosine kinase JAK3s Application in agent.
6. the compound or its pharmaceutically acceptable salt shown in formula I, or right are led to any one of claims 1 to 3 Require purposes of the pharmaceutical composition described in 4 in the medicine for preparing treatment tumor.
7. purposes according to claim 6, wherein, the tumor is drenched selected from burkitt's lymphoma, diffusivity large B cell One or more in bar tumor, follicular lymphoma and chronic lymphocytic leukemia.
8. purposes according to claim 7, wherein, the tumor is chronic lymphocytic leukemia.
9. the purposes according to any one of claim 6～8, wherein, the purposes is mainly by suppressing bruton's cheese What histidine kinase BTK and/or Janus Tyrosine kinase JAK3 was realized.
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