CN106905245A - The dibasic pyrimidines of 2,4- - Google Patents

The dibasic pyrimidines of 2,4- Download PDF

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Publication number
CN106905245A
CN106905245A CN201510982545.1A CN201510982545A CN106905245A CN 106905245 A CN106905245 A CN 106905245A CN 201510982545 A CN201510982545 A CN 201510982545A CN 106905245 A CN106905245 A CN 106905245A
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alkyl
compound
pharmaceutically acceptable
acceptable salt
formula
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CN106905245B (en
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张寅生
高勇
任景
王庆璘
王昭
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to medicinal chemistry arts, it is related to 2, the dibasic pyrimidines of 4-, and in particular to the compound or its pharmaceutically acceptable salt, its pharmaceutical composition as shown in formula (I) and its purposes in the disease for the treatment of EGFR or/and ALK mediations.

Description

The dibasic pyrimidines of 2,4-
Technical field
The invention belongs to medicinal chemistry arts, it is related to the dibasic pyrimidines of 2,4-, and in particular to such as formula (I) institute The compound for showing or its pharmaceutically acceptable salt, its pharmaceutical composition and its disease in treatment EGFR or/and ALK mediations In purposes.
Background technology
EGF-R ELISA (Epidermal Growth Factor Receptor, EGFR) is epidermal growth factor (EGF) acceptor of cell propagation and signal transduction, also referred to as HER1, ErbB1.EGFR belongs to one kind of ErbB receptor family, The family includes EGFR (ErbB-1), HER2/c-neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4).EGFR is one Glycoprotein is planted, belongs to EGFR-TK receptor, cell membrane insertion, molecular weight 170KDa.
EGFR is located at surface of cell membrane, and by being activated with ligand binding, including after EGF and TGF-α activation, EGFR is by monomer It is converted into dimer.The dimer had both included two combinations (homology dimerization) of cognate receptor molecule, also including people The combination (heterologous dimerization) of the different members in class EGF related receptor (HER) family tyrosine kinase.EGFR dimerization It can be activated afterwards positioned at intracellular kinase pathway, including in Intracellular domain key tyrosine residue phosphorylation, and cause Stimulation to participating in many Cellular Signaling Transduction Mediated paths of cell propagation and existence.
There is expression high or the unconventionality expression of EGFR in many entity tumors.Propagation, the blood vessel of EGFR and tumour cell The suppression of generation, tumor invasion, transfer and Apoptosis is relevant.Its mechanism has：The expression high of EGFR causes downstream signal The enhancing of conduction；The increase of mutant egf R acceptors or ligand expression causes the continuous activation of EGFR；The effect of autocrine loop increases By force；The destruction of receptor down-regulated mechanism；Activation of abnormal signal conduction path etc..The overexpression of EGFR is in the evolution of malignant tumour Play an important role, all have found EGFR's in the tissue such as spongiocyte, kidney, lung cancer, prostate cancer, cancer of pancreas, breast cancer Overexpression.
The unconventionality expression of wherein EGFR and Erb-B2 plays critical effect in the conversion and growth of tumour.With lung cancer As a example by, EGFR has an expression in 50% non-small cell lung cancer (NSCLC) case, and its expression to more after it is not good related.This Two factors cause that EGFR and its family member turn into the leading candidate for carrying out targeted therapy.Two kinds of small molecules of targeting EGFR Inhibitor, Gefitinib and Tarceva, having obtained the quick approval of U.S. FDA is used to treat advanced NSCLC patients, the trouble Person loses reaction to conventional chemotherapy.
The clinical data of early stage shows that 10% NSCLC patient has reaction to Gefitinib and Tarceva.Molecular biosciences Analysis shows are learned, as a rule, the patient for having reaction to medicine is mutated in coding EGFR gene with specific：19th The missing of the 747th~750 amino acids of extron accounts for the 45% of mutation, and also 10% mutation occurs outside the 18th and the 20th Aobvious son.Most common EGFR activated mutants (L858R and delE746_A750) cause for wild type WT-EGFR, right The affinity of small molecule tyrosine kinase inhibitors (TKI) increases and atriphos (ATP) affinity is declined.T790M Mutation is a point mutation in the extrons of EGFR the 20th, and it produces and Gefitinib or the acquired of Tarceva treatment are resisted Property.Current research shows that L858R merges T790M and is mutated to the affinity of ATP than simple L858R by force, and TKI is ATP competitive Kinase inhibitor, therefore cause TKI with the reduction of kinases area Percentage bound.
Between modification lymphom kinase (Naplastic Lymphoma Kinase, ALK) be receptor tyrosine kinase protein swash The superfamily member of enzyme.ALK gene variation can trigger various hematological systems or non-blood system tumor.It has been reported that nerve is female The abnormal expression of total length ALK receptor proteins in cytoma and glioblastoma；There are about 60% primary cutaneous type disease There is NPM-ALK Gene Fusion phenomenons in example；Non-small cell lung cancer about 5% is derived from EML4-ALK Gene Fusion phenomenons. ML4-ALK Gene Fusions can also cause other cancers, such as intestinal cancer, breast cancer or kidney.At present, the ALK inhibitor for having listed As gram azoles is successfully used for treating non-small cell lung cancer for Buddhist nun (Crizotinib) and Ceritinib (Ceritinib).
The content of the invention
The present invention provides the compound or its pharmaceutically acceptable salt shown in a kind of formula (I)：
Wherein,
X or Y are each independently selected from N or CH；
R1Selected from H, halogen ,-CF3Or-CN；
R2Or R6It is each independently selected from H or-OC1-6Alkyl；
R3Or R5Be each independently selected from H or
R4Selected from 3~8 circle heterocycles alkyl or
R7Selected from H ,-OC1-6Alkyl,
3~8 circle heterocycles alkyl includes 1,2 or 3 hetero atoms selected from N, O or S, and optionally by R8Substitution；
The R8Selected from-C1-4Alkyl ,-C (O)-C1-4Alkyl ,-NR9R10、-C(O)O-C1-4Alkyl ,-C (O) NH-C1-4Alkane Base ,-SO2-C1-4Alkyl ,-SO2NH2、-C(O)-C1-4Alkylidene-OH or
The Z is selected from O, S or NR11；
The R9、R10Or R11It is each independently selected from H or-C1-4Alkyl.
As a kind of preferred embodiment of formula (I), R1Selected from H ,-F ,-Cl ,-Br ,-CF3Or-CN.
As a kind of preferred embodiment of formula (I), R2Or R6It is each independently selected from H or-OC1-4Alkyl.
As a kind of more preferably implementation method, R of formula (I)2Or R6It is each independently selected from H ,-OC1Alkyl ,-OC2Alkane Base ,-OC3Alkyl or-OC4Alkyl.
As a kind of preferred embodiment of formula (I), R4Selected from 5~6 circle heterocycles alkyl or
As a kind of preferred embodiment of formula (I), R7Selected from H ,-OC1-4Alkyl,
As a kind of more preferably implementation method, R of formula (I)7Selected from H ,-OC1Alkyl ,-OC2Alkyl ,-OC3Alkyl ,-OC4Alkyl,
Used as a kind of preferred embodiment of formula (I), the Heterocyclylalkyl includes 1 or 2 hetero atom selected from N or O, and And optionally by R8Substitution.
Used as a kind of more preferably implementation method of formula (I), the Heterocyclylalkyl is selected from morpholinyl, piperidyl or piperazinyl.
As a kind of preferred embodiment of formula (I), R8Selected from-C1Alkyl ,-C2Alkyl ,-C3Alkyl ,-C4Alkyl ,-C (O)-C1Alkyl ,-C (O)-C2Alkyl ,-C (O)-C3Alkyl ,-C (O)-C4Alkyl ,-NR9R10、-C(O)O-C1Alkyl ,-C (O) O- C2Alkyl ,-C (O) O-C3Alkyl ,-C (O) O-C4Alkyl ,-C (O) NH-C1Alkyl ,-C (O) NH-C2Alkyl ,-C (O) NH-C3Alkane Base ,-C (O) NH-C4Alkyl ,-SO2-C1Alkyl ,-SO2-C2Alkyl ,-SO2-C3Alkyl ,-SO2-C4Alkyl ,-SO2NH2、-C(O)- C1Alkylidene-OH ,-C (O)-C2Alkylidene-OH ,-C (O)-C3Alkylidene-OH ,-C (O)-C4Alkylidene-OH or
Used as a kind of preferred embodiment of formula (I), Z is selected from O or NR11。
As a kind of preferred embodiment of formula (I), R9、R10Or R11It is each independently selected from H ,-C1Alkyl ,-C2Alkane Base ,-C3Alkyl or-C4Alkyl.
As an embodiment of the invention, there is provided compound shown in a kind of formula (II) or its is pharmaceutically acceptable Salt：
Wherein,
X or Y are each independently selected from N or CH；
R1Selected from H ,-F ,-Cl ,-Br ,-CF3Or-CN；
R2、R6Or R7It is each independently selected from H ,-OC1Alkyl ,-OC2Alkyl ,-OC3Alkyl or-OC4Alkyl.
As an embodiment of the invention, there is provided compound shown in a kind of formula (III) or its is pharmaceutically acceptable Salt：
Wherein,
X or Y are each independently selected from N or CH；
R1Selected from H, halogen ,-CF3Or-CN；
R2Or R6It is each independently selected from H or-OC1-6Alkyl；
R7Selected from H ,-OC1-6Alkyl,
A is selected from O, NH, NR8Or CH-R8；
The Z is selected from O, S or NR11；
The R8Selected from-C1-4Alkyl ,-C (O)-C1-4Alkyl ,-NR9R10、-C(O)O-C1-4Alkyl ,-C (O) NH-C1-4Alkane Base ,-SO2-C1-4Alkyl ,-SO2NH2、-C(O)-C1-4Alkylidene-OH or
The R9、R10Or R11It is each independently selected from H or-C1-4Alkyl.
As a kind of preferred embodiment of formula (III), R1Selected from H ,-F ,-Cl ,-Br ,-CF3Or-CN.
As a kind of preferred embodiment of formula (III), R2Or R6It is each independently selected from H or-OC1-4Alkyl.
As a kind of more preferably implementation method, R of formula (III)2Or R6It is each independently selected from H ,-OC1Alkyl ,-OC2Alkane Base ,-OC3Alkyl or-OC4Alkyl.
As a kind of preferred embodiment of formula (III), R7Selected from H ,-OC1-4Alkyl,
As a kind of more preferably implementation method, R of formula (III)7Selected from H ,-OC1Alkyl ,-OC2Alkyl ,-OC3Alkyl ,-OC4Alkyl,
As a kind of preferred embodiment of formula (III), R8Selected from-C1Alkyl ,-C2Alkyl ,-C3Alkyl ,-C4Alkyl ,-C (O)-C1Alkyl ,-C (O)-C2Alkyl ,-C (O)-C3Alkyl ,-C (O)-C4Alkyl ,-NR9R10、-C(O)O-C1Alkyl ,-C (O) O- C2Alkyl ,-C (O) O-C3Alkyl ,-C (O) O-C4Alkyl ,-C (O) NH-C1Alkyl ,-C (O) NH-C2Alkyl ,-C (O) NH-C3Alkane Base ,-C (O) NH-C4Alkyl ,-SO2-C1Alkyl ,-SO2-C2Alkyl ,-SO2-C3Alkyl ,-SO2-C4Alkyl ,-SO2NH2、-C(O)- C1Alkylidene-OH ,-C (O)-C2Alkylidene-OH ,-C (O)-C3Alkylidene-OH ,-C (O)-C4Alkylidene-OH or
Used as a kind of preferred embodiment of formula (III), the Z is selected from O or NR11。
As a kind of preferred embodiment of formula (III), R9、R10Or R11It is each independently selected from H ,-C1Alkyl ,-C2Alkane Base ,-C3Alkyl or-C4Alkyl.
As an embodiment of the invention, there is provided compound shown in a kind of formula (IV) or its is pharmaceutically acceptable Salt：
Wherein,
X or Y are each independently selected from N or CH；
R1Selected from H, halogen ,-CF3Or-CN；
R2Or R6It is each independently selected from H or-OC1-6Alkyl；
R7Selected from H ,-OC1-6Alkyl,
The Z is selected from O, S or NR11；
The R9、R10Or R11It is each independently selected from H or-C1-4Alkyl.
As a kind of preferred embodiment of formula (IV), R1Selected from H ,-F ,-Cl ,-Br ,-CF3Or-CN.
As a kind of preferred embodiment of formula (IV), R2Or R6It is each independently selected from H or-OC1-4Alkyl.
As a kind of more preferably implementation method, R of formula (IV)2Or R6It is each independently selected from H ,-OC1Alkyl ,-OC2Alkane Base ,-OC3Alkyl or-OC4Alkyl.
As a kind of preferred embodiment of formula (IV), R7Selected from H ,-OC1-4Alkyl,
As a kind of more preferably implementation method, R of formula (IV)7Selected from H ,-OC1Alkyl ,-OC2Alkyl ,-OC3Alkyl ,-OC4Alkyl,
Used as a kind of preferred embodiment of formula (IV), the Z is selected from O or NR11。
As a kind of preferred embodiment of formula (IV), R9、R10Or R11It is each independently selected from H ,-C1Alkyl ,-C2Alkane Base ,-C3Alkyl or-C4Alkyl.
Preferably following compounds or its pharmaceutically acceptable salt of the invention：
Another aspect provides a kind of method of the disease for treating EGFR or/and ALK mediations, methods described bag Include formula (I) compound or its pharmaceutically acceptable salt for giving therapeutically effective amount.
Another aspect of the present invention provides formula (I) compound or its pharmaceutically acceptable salt in treatment EGFR Or/and the purposes in the disease of ALK mediations.
Another aspect of the present invention provides formula (I) compound or its pharmaceutically acceptable salt and is preparing treatment Purposes in the medicine of the disease of EGFR or/and ALK mediations.
In some embodiments of the invention, the disease of the EGFR mediations is selected from EGFR-L858R or/and EGFR- The disease of T790M mutation activation mediations.
In some embodiments of the invention, the disease of the ALK mediations is selected from NPM-ALK or/and EML4-ALK bases Because of the disease of fusion mediation.
In some embodiments of the invention, the disease of the EGFR or/and ALK mediations includes cancer, inflammation, sense Dye, immunity disease, organ transplant, viral disease, angiocardiopathy or metabolic disease.
In some embodiments of the invention, the cancer is included but is not limited to：Lung cancer, head and neck cancer, breast cancer, prostatitis Gland cancer, cancer of the esophagus, the carcinoma of the rectum, colon cancer, nasopharyngeal carcinoma, the cancer of the uterus, cancer of pancreas, lymthoma, leukemia, osteosarcoma, melanoma, kidney Cancer, stomach cancer, liver cancer, carcinoma of urinary bladder, thyroid cancer or colorectal cancer.
In some embodiments of the invention, the lung cancer is selected from non-small cell lung cancer.
In certain preferred embodiments of the invention, the disease is selected from the disease of EGFR or/and ALK mediations selected from non- ED-SCLC.
Another aspect provides a kind of pharmaceutical composition, chemical combination shown in the formula (I) that it includes therapeutically effective amount Thing or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier or excipient.Drug regimen of the invention Thing can further contain one or more extra therapeutic agent.
Pharmaceutical composition of the invention can be by pharmaceutically acceptable with suitable by compound or its salt of the invention Carrier combinations and prepare, can for example be configured to solid-state, semisolid, liquid or gaseous state preparation, such as tablet, pill, capsule, powder Agent, granule, paste, emulsion, suspending agent, solution, suppository, injection, inhalant, gel, microballoon and aerosol etc..
Giving the classical pathway of compound of the invention or its pharmaceutically acceptable salt or its pharmaceutical composition is included but not Be limited to oral, rectum, saturating mucous membrane, through enteral administration, or local, percutaneous, suction, parenteral, sublingual, intravaginal, intranasal, eye Interior, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
Pharmaceutical composition of the invention can be manufactured using method well-known in the art, such as conventional mixing method, molten Solution, granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc..
For being administered orally, can mix with pharmaceutically acceptable carrier well known in the art by by reactive compound To prepare the pharmaceutical composition.These carriers can make compound of the invention be formulated into tablet, pill, lozenge, sugar-coat agent, glue Wafer, liquid, gel, slurry agent, suspending agent etc., for the oral administration to patient.
Solid oral composition can be prepared by conventional mixing, filling or tabletting method.For example, can be by following Method is obtained：Described reactive compound is mixed with solid excipient, the mixture of gained of optionally milling, if necessary Other suitable assistant agents are added, the mixture is then processed into particle, obtained the core of tablet or sugar-coat agent.Suitable is auxiliary Material is included but is not limited to：Adhesive, diluent, disintegrant, lubricant, glidant, sweetener or flavouring etc..Such as microcrystalline cellulose Element, glucose solution, mucialga of arabic gummy, gelatin solution, sucrose and gelatinized corn starch；Talcum, starch, magnesium stearate, calcium stearate or Stearic acid；Lactose, sucrose, starch, mannitol, D-sorbite or Dicalcium Phosphate；Silica；Cross-linked carboxymethyl cellulose Sodium, pre-paying starch, primojel, alginic acid, cornstarch, farina, methylcellulose, agar, carboxymethyl are fine Dimension element, PVPP etc..Can be according to known method in usual medicinal practice optionally to the core of sugar-coat agent The heart is coated, and especially uses enteric coating.
Pharmaceutical composition could be applicable to parenteral, such as the sterile solution agent of suitable unit dosage forms, supensoid agent or Freeze-drying prods.
Formula (I) compound as herein described or its pharmaceutically acceptable salt can be by any applicable approaches and methods Administration, for example orally or parenterally (for example, intravenous) administration.The therapeutically effective amount of formula (I) compound is from about 0.0001 arrives 20mg/Kg body weight/days, such as body weight/day from 0.001 to 10mg/Kg.
The dose frequency of formula (I) compound determines by the demand of individual patients, for example, once a day or 2 times, or daily more Repeatedly.Administration can be intermittent, for example, wherein in a period of some days, patient receives the daily agent of formula (I) compound Amount, then during some days, patient does not receive the daily dosage of formula (I) compound.
Relevant definition：
Unless otherwise indicated, following term used herein and phrase have following meanings.One specific term or short Language be should not be considered as in the case of without especially defining it is uncertain or unclear, and should be according to common implication Go to understand.When herein presented trade name, it is intended that refer to its corresponding commodity or its active component.
C used hereinm-nRefer in the part that there is m-n carbon atom.For example, " C1-6Alkyl " refers to that the alkyl has 1-6 Individual carbon atom.
Digital scope herein, refers to each integer in given range.Such as " C1-6" refer to that the group can have 1 Individual carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
Term " Cm" represent that the group that the word of amount of carbon atom and functional group are formed includes its all isomerism bodily form Formula, for example：1)“-C3Alkyl " includes its all isomer forms, such as CH3CH2CH2- and (CH3)2CH-；2)“-C4Alkane Base " includes its all isomer forms, such as CH3CH2CH2CH2-、CH3CH2(CH3)CH-、(CH3)2CHCH2- and (CH3)3C-。
Term " halogen " refers to fluorine, chlorine, bromine and iodine.
Term " alkyl " refers to the aliphatic hydrocarbon group of the saturation of the straight or branched being made up of carbon atom and hydrogen atom, and it leads to Singly-bound is crossed to be connected with the remainder of molecule.The non-limiting examples of alkyl include but is not limited to methyl, ethyl, propyl group, 2- third Base, normal-butyl, isobutyl group, tert-butyl group etc..
Term " alkylidene " refers to the aliphatic hydrocarbon group of the saturation of the straight or branched being made up of carbon atom and hydrogen atom, its It is connected with the remainder of molecule by two tie points.The non-limiting examples of the term include methylene (- CH2-)、1,1- Ethylidene (- CH (CH3) -), 1,2- ethylidene (- CH2CH2-), 1,1- propylidene (- CH (CH2CH3) -), 1,2- propylidene (- CH2CH(CH3) -), 1,3- propylidene (- CH2CH2CH2-), 1,4- butylidenes (- CH2CH2CH2CH2-) etc..Term " C4Alkylidene " Refer to that there is the alkylidene of 4 carbon atoms.
Term " Heterocyclylalkyl " refers to the monocyclic of saturation, fused polycycle, bridged ring or spiro ring system group, and which part ring is former Son is the hetero atom selected from N, O, S, and remaining annular atom is C.The non-limiting examples of heterocyclic radical include Oxyranyle, epithio second Alkyl, azirane base, azetidine base, Evil fourths ring group, thiophene fourth ring group, tetrahydrofuran base, pyrrolidinyl, oxazole alkyl, tetrahydrochysene Pyrazolyl, pyrrolinyl, dihydrofuran base, dihydro-thiophene base, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, morpholinyl, piperazine Piperazine base, dihydropyridine base, tetrahydro pyridyl, dihydro pyranyl, THP trtrahydropyranyl, dihydro thiapyran base, nitrogen heterocyclic heptyl, oxa- Cycloheptyl alkyl, thia cycloheptyl alkyl, bicyclic [2.2.1] heptyl of oxazepine and azaspiro [3.3] heptyl etc..Term " 3 yuan~8 Circle heterocycles alkyl " refers to 3~8 Heterocyclylalkyls of annular atom.
When any variable (such as R) the once above occurs in the composition or structure of compound, it is in each situation Under definition be all independent.If thus, for example, a group is replaced by 0-2 R, the group can be optionally At most replaced by two R, and R under each case has independent option.Additionally, the group of substitution base and/or its variant Close and be only just allowed in the case where such combination can produce the compound of stabilization.
Term " pharmaceutically acceptable ", is directed to for those compounds, material, composition and/or formulation, they Within the scope of reliable medical judgment, it is adaptable to contacted with the tissue of human and animal and used, without excessive toxicity, thorn Swash property, allergic reaction or other problems or complication, match with rational interests/Hazard ratio.
As pharmaceutically acceptable salt, for example, salt and acid ammonia that the salt formed with inorganic acid and organic acid are formed Salt that base acid is formed etc..
Pharmaceutically acceptable salt of the invention can pass through conventional chemical side by the parent compound containing acid group or base Method synthesizes.Generally, the preparation method of such salt is：In the mixture of water or organic solvent or both, via trip Prepared with the appropriate acid reaction of stoichiometry from these compounds of alkali form.
Some compounds of the invention can exist with nonsolvated forms or solvation form, including hydrate shape Formula.In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.It is of the invention Some compounds can exist with polycrystalline or amorphous form.
Some compounds of the invention can have asymmetric carbon atom (optical centre) or double bond.It is racemic modification, non-right Isomers, geometric isomer and single isomers is reflected to be included within the scope of the present invention.
The diagrammatic representation of the compound of raceme, ambiscalemic and scalemic or enantiomer-pure herein is come From Maehr, J.Chem.Ed.1985,62:114-120.Unless otherwise indicated, in representing a solid with wedge key and dotted line key The absolute configuration of the heart.When compound described herein contains olefinic double bond or other geometry asymmetric centers, unless otherwise prescribed, it Include E, Z geometric isomer.Similarly, all of tautomeric form is included within the scope of the present invention.
Compound of the invention there may be specific geometry or stereoisomer form.It is contemplated by the invention that all of this kind of Compound, including cis and trans isomers, (-)-and (+)-to enantiomer, (R)-and (S)-enantiomer, diastereoisomer, (D)-isomers, (L)-isomers, and its racemic mixture and other mixtures, such as enantiomter or diastereomer are rich The mixture of collection, all these mixtures are within the scope of the present invention.Alkyl etc. substitution base in there may be it is other not Symmetric carbon atom.All these isomers and their mixture, are included within the scope of the present invention.
The chiral synthesis that can pass through or chiral reagent or other routine techniques prepares optically active (R)-with (S)- Isomers and D and L isomers.If expecting a kind of enantiomer of certain compound of the invention, can be by asymmetric syntheses Or prepared by the derivatization with chiral auxiliary, wherein gained non-enantiomer mixture is separated, and auxiliary group splits Open to provide pure required enantiomter.Or, when in molecule containing basic functionality (such as amino) or acidic functionality is (such as Carboxyl) when, the salt with appropriate optically active sour or alkali formation diastereoisomer, then by known in the field point One step crystallizing or chromatography carry out diastereoisomer fractionation, then reclaim and obtain pure enantiomer.Additionally, enantiomter and Typically by what is completed using chromatography, the chromatography uses chiral stationary phase for the separation of diastereoisomer, and optionally Ground is combined (for example generate carbaminate by amine) with chemical derivatization.
Term " pharmaceutically acceptable carrier " refers to that organism is acted on without obvious stimulation, and will not damage the activity The bioactivity of compound and those carriers of performance." pharmaceutically acceptable carrier " refers to together to be administered with active ingredient , be conducive to active ingredient be administered inert substance, including but not limited to State Food and Drug Administration license connects Any glidant for human or animal (such as domestic animal), sweetener, diluent, preservative, dyestuff/colouring agent, the flavoring received Reinforcing agent, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent.It is described The non-limiting examples of carrier include calcium carbonate, calcium phosphate, various sugared and each kind of starch, cellulose derivative, gelatin, vegetable oil With polyethylene glycol etc..Other information on carrier, may be referred to Remington:The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams＆Wilkins (2005), the content of the document pass through the side for quoting Formula is incorporated herein.
Term " excipient " typically refers to prepare carrier, diluent and/or medium required for drug composition effective.
For medicine or pharmacologically active agents, term " effective dose " or " therapeutically effective amount " refer to nontoxic but can reach To the medicine or enough consumptions of medicament of Expected Results.For the peroral dosage form in the present invention, a kind of active material in composition " effective dose " refer to when another active material is combined in said composition for the required consumption that produces a desired effect.Have The determination of effect amount varies with each individual, and age and ordinary circumstance depending on acceptor, also depends on specific active material, is closed in case Suitable effective dose can be determined by those skilled in the art according to routine test.
Term " active component ", " therapeutic agent ", " active material " or " activating agent " refers to a kind of chemical entities, and it can have Imitate disorderly ground therapeutic purpose, disease or illness.
Phrase " therapeutically effective amount " used herein refer to researcher, animal doctor, doctor or other clinicians The reactive compound or the amount of medicine that cause biology or medical response found in tissue, system, animal, individuality or people, it Including following one or more：
(1) prevention disease：Experience for example in easy infection disease, disorderly or illness but not yet or disease pathology occur or symptom Individuality in prevention disease, disorderly or illness.
(2) disease is suppressed：For example just experiencing or disease occurring, suppress in the individuality of the pathology of disorderly or illness or symptom Disease, disorder or illness (preventing the further development of pathology and/or symptom).
(3) disease is alleviated：For example just experiencing or disease occurring, alleviate in the individuality of the pathology of disorderly or illness or symptom Disease, disorder or illness (reversing pathology and/or symptom).
Compound of the invention can be prepared by various synthetic methods well-known to those skilled in the art, including under Implementation method and art technology that specific embodiment that face is enumerated, the combination of itself and other chemical synthesis process are formed Equivalent mode known to upper personnel, preferred embodiment including but not limited to embodiments of the invention.
Compound can use ability by organic synthesis field technical staff pass course 1 shown in segment boundses (I) of the invention Prepared by the standard method in domain, the substituted radical is defined as described above：
As shown in Scheme 1, the compound of formula 2 reacts to obtain the compound of formula 3 with acryloyl chloride, and the compound of formula 3 reduction nitro obtains formula 4 Compound, the compound of formula 4 obtains the compound of formula 6 with the compound of formula 5 under lewis acidic catalysis, and the compound of formula 6 is in alkalescence condition Formula (I) compound down or is reacted to obtain with the compound of formula 7 under Pd metal catalyzed conditions.
Compound shown in segment boundses (I) of the invention can also be by organic synthesis field technical staff pass course 2 with originally Prepared by the standard method in field, the substituted radical is defined as described above：
As shown in Scheme 2, the compound of formula 5 reacts to obtain the compound of formula 8, the compound of formula 8 in the basic conditions with the compound of formula 7 Formula (I) compound can be obtained with the compound condensation of formula 4；The compound of formula 8 can also first and the compound of formula 9 reacts to obtain the chemical combination of formula 10 Thing, the nitro of the compound of formula 10 reacts to obtain formula (I) compound first through reducing to obtain amino, then with acryloyl chloride.
Alkali used by preparation method of the invention includes inorganic base and organic base, and specifiable example includes sodium hydride, uncle Butylmagnesium chloride, lithium hydride, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide, NaHMDS, LiHMDS, methylimidazole (such as 1- first Base imidazoles, 2-methylimidazole, 4-methylimidazole), DBU, triethylamine, diisopropylamine or diisopropyl ethyl amine.
Acid used by preparation method of the invention includes inorganic acid and organic acid, and specifiable example includes hydrochloric acid, hydrogen bromine Acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, butanedioic acid, fumaric acid, horse Come sour, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid Or naphthalene sulfonic acids.
In some embodiments of the invention, those skilled in the art can according to rather than in strict accordance with route 1 or The step of route 2, is prepared, and according to the structure of end-product, route 1 or route 2 can be increased, reduced or is changed The order of each step, this falls within the scope of the present invention.
The chemical reaction of the specific embodiment of the invention is completed in a suitable solvent, and described solvent must be suitable for Chemical change of the invention and its required reagent and material.In order to obtain compound of the invention, it is sometimes desirable to this area skill Art personnel modify or select on the basis of existing implementation method to synthesis step or reaction process.
An important consideration factor in any synthetic route planning in this area is to be reactive functional groups (in the present invention Amino) select suitable protection group.For trained practitioner, (the Protective of Greene and Wuts Groups in Organic Synthesis, Wiley and Sons, 1991) be this respect authority.The institute that the present invention is quoted There is bibliography incorporated herein on the whole.
Reaction specifically described herein can be monitored according to any suitable method as known in the art.For example, can be by wide spectrum Method such as NMR spectrum is (for example1H or13C), infrared spectrum, spectrophotometry (such as UV- visible rays) or mass spectrum, Or formed by chromatogram such as high performance liquid chromatography (HPLC) or thin-layer chromatography monitoring product.
For clarity, the present invention is further illustrated with embodiment.But embodiment is not limited to define or specifies Invention scope.
In some embodiments of the invention, reaction initiation material used or reagent can be it is commercially available (can be from Aldrich buy), or those skilled in the art prepared using method known to chemical field.Institute of the present invention The all solvents for using are commercially available, be can be used without being further purified.It is related to the institute to the experiment of water and/or oxygen sensitive There is operation all in predrying glass apparatus in being carried out under blanket of nitrogen.
Compound manually orSoftware is named, and commercial compound uses supplier's directory name.
Specific embodiment
Following specific embodiment, the purpose is to enabling those skilled in the art to be more clearly understood that and implementing this hair It is bright.They should not be construed as limiting the scope of the present invention, and simply exemplary illustration of the invention and Typical Representative.
The N- of embodiment 1 (3- ((4- chloro-5-trifluoromethylpyridine -2- bases) amino) phenyl) acrylamide (6-1)
Step (1) N- (3- nitrobenzophenones) acrylamide (3-1)
To adding formula 2-1 compounds (10.0g, 72.4mmol) to be dissolved in anhydrous tetrahydro furan in reaction bulb, Et is added3N (11.0g, 108.6mmol), 0 DEG C is added dropwise acryloyl chloride (10.29g, 113.7mmol), drips off room temperature reaction 1.5~2hrs, TLC Monitoring reaction is complete, and reaction solution revolving is dry, plus saturation Na2CO3The aqueous solution is adjusted to pH=10, and EA extraction dryings rotate to obtain crude product, Silicagel column is crossed, PE-EA wash-outs, merging is concentrated to give formula 3-1 compounds (6.50g).
1H-NMR(300M,CD3OD)：8.68(s,1H),7.96-7.92(t,2H),7.58-7.52(t,1H),6.44- 6.42(t,2H),5.84-5.81(m,1H)。
HRMS(ESI,[M+H]+)m/z:193.0604。
Step (2) N- (3- aminophenyls) acrylamide (4-1)
To adding formula 3-1 compounds (6.0g, 31.22mmol), ethanol and tetrahydrofuran to make solvent in reaction bulb, add SnCl2·2H2O (35.2g, 156.1mmol), is heated to reflux 3~4hrs, and TLC monitoring reactions are complete, and reaction solution revolving is dry, plus The NaOH aqueous solution is adjusted to pH=12, and EA extraction dryings rotate to obtain crude product, cross silicagel column, PE-EA wash-outs (4:1 to 3:2), merge It is concentrated to give formula 4-1 compounds (3.20g).
1H-NMR(300M,DMSO-d6):6.98(s,1H),6.89-6.94(t,1H),6.74-6.77(d,1H),6.37- 6.46(m,1H),6.17-6.28(m,2H),5.67-5.70(d,1H)。
HRMS(ESI,[M+H]+)m/z：163.0867.
Step (3) N- (3- ((the chloro- 5- trifluoromethyl pyrimidines -2- bases of 4-) amino) phenyl) acrylamide (6-1)
Under nitrogen protection, compound 5-1 (0.50g, 2.30mmol) is dissolved in 1,2- dichloroethanes and the tert-butyl alcohol is (each In 20mL).The diethyl ether solution (4.60mL, 4.60mmol) of 1.0M zinc chloride is added dropwise at 0 DEG C, then reactant mixture is at low temperature Stirring.Will compound 4-1 (0.374g, 2.30mmol) add reaction in, be then added dropwise over again triethylamine (0.256g, 1,2- dichloroethanes 2.53mmol) and t-butanol solution.After reaction a few hours, room temperature reaction is gradually restored to.TLC monitorings are anti- After the completion of answering, revolving removes solvent, then again to addition water (30mL), ultrasonic 30min in reaction bulb.Suction filtration, washing obtains white Color solid, by recrystallization purifying after drying, finally gives formula 6-1 compounds, is white solid.
1H-NMR(300MHz,DMSO-d6):10.69(s,1H),10.19(s,1H),8.79(s,1H),7.99(s,1H), 7.42~7.47 (t, 1H), 7.27~7.33 (t, 1H), 6.43~6.52 (m, 2H), 6.24~6.30 (dd, 1H), 5.74~ 5.78(dd,1H)。
HRMS(ESI,[M+H]+)m/z:343.0555。
The N- of embodiment 2 (3- ((the chloro- 5- trifluoromethyl pyrimidines -2- bases of 4-) amino) -4- methoxyphenyls) acrylamide (6-2)
Step (1) 4- aminoanisoles nitrate (12)
10g compounds 11 are taken in 250mL there-necked flasks, to 80mL TBME and 20mL THF are added in reaction bulb, will be reacted Liquid is cooled to 0-5 DEG C, and to 65% nitric acid 7.8g is added dropwise in reaction solution, keeping temperature is less than 20 DEG C during dropwise addition, completion of dropping, Controlling reaction temperature reacts about 1h at 0 DEG C or so, and reacting liquid filtering washs filter cake with TBME, and filter cake room temperature in vacuo is dried At night, obtain 14.68g products, yield 97.1%.
Step (2) 4- methoxyl group -3- nitroanilines (2-2)
The concentrated sulfuric acids of 63g 95% are weighed in 500mL there-necked flasks, 0 DEG C is cooled to.12g compounds 12 are taken, 120mL is suspended in In dichloromethane, suspension is configured to, by the cold concentrated sulfuric acid of this hanging drop addition, temperature is controlled during dropwise addition at 0 DEG C Left and right, completion of dropping keeps this thermotonus about 3h, reaction solution point liquid to remove a layer acid layer, and 120mL is water-cooled to 0 DEG C or so, Acid layer is slowly added in cold water, during keeping temperature be no more than 20 DEG C, after completion of dropping to dilution reaction solution in be added dropwise Until pH is untill 6-11, temperature is no more than 20 DEG C to ammoniacal liquor during dropwise addition, is extracted with 120mL × 2DCM, organic phase saturation Brine It, concentration.Obtain 8.7g dark brown sticky oil things, yield 80.3%.
1H-NMR(500M,DMSO):7.07(s,1H),7.05-7.06(m,2H),3.78(s,3H)。
HRMS (ESI, [M+H]+)：m/z 169.0613.
Step (3) N- (4- methoxyl group -3- nitrobenzophenones) acrylamide (3-2)
8.7g compound 2-2 are taken, nitrogen protection in 250mL there-necked flasks is added, to 40mL dry THFs are added in bottle, taken 4.8mL triethylamines are added in reaction bulb, and reaction solution is cooled into 0 DEG C, and 8.65mL acryloyl chlorides are added dropwise, and keep anti-during dropwise addition Answer liquid temperature degree at 0 DEG C or so, completion of dropping is warmed to room temperature reaction 3h, and reaction terminates, reaction solution concentration, residue 100mL water Washed with 100mL ethyl acetate and extracted, organic phase saturated common salt water washing is dried, concentration, find there is solid to analyse in concentration process Go out and stop concentration immediately, solution is put in 15min in ice-water bath, filtering takes filter cake, by thickening filtration twice, obtains 8.6g Yellow solid, yield 75.1%.
1H-NMR (500M, DMSO):10.33(s,1H),8.32-8.33(m,1H),7.81-7.83(m,1H),7.35- 7.37(m,1H),6.26-6.30(m,1H),5.77-5.80(m,1H),3.90(s,3H)。
HRMS (ESI, [M+H]+)m/z：223.0761.
Step (4) N- (3- amino-4-methoxyls phenyl) acrylamide (4-2)
1.8g compound 3-2 are taken, in adding 250mL there-necked flasks, to sequentially adding 50mL methyl alcohol in reaction bulb and 55mL is full And aqueous ammonium chloride solution, be stirred at room temperature, weigh zinc powder 2.68g add reaction bulb in.60 DEG C of oil bath reactions, TLC monitoring reaction knots Beam, reacting liquid filtering, filtrate concentration removes methyl alcohol, and ethyl acetate 10mL × 2 extraction, point liquid, organic phase is dried, concentration, residual The purifying of thing silicagel column obtains 1.08g white solids, yield 69.4%.
1H-NMR (500M, DMSO):9.69(s,1H),7.02-7.03(m,1H),6.80-6.83(m,1H),6.70- 6.71 (m, 1H), 6.37-6.42 (dd, J=10Hz, J=25Hz, 1H), 6.16-6.20 (dd, J=1.9Hz, J=17Hz, 1H), 5.64-5.67 (dd, J=1.9Hz, J=10.1Hz, 1H), 4.72 (s, 2H), 3.72 (s, 3H).
HRMS (ESI, [M+H]+)m/z:193.1003。
Step (5) N- (3- ((4- chloro- 5- (trifluoromethyl) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (6-2)
With compound 4-2 and 5-1 as raw material, the method prepare compound 6-2 of the step of reference implementation example 1 (3).
1H NMR(300MHz,DMSO-d6) δ 10.06 (s, 1H), 9.78 (s, 1H), 8.68 (s, 1H), 7.81 (d, J= 2.5Hz, 1H), 7.52 (dd, J=8.9,2.6Hz, 1H), 7.06 (d, J=8.9Hz, 1H), 6.41 (dd, J=16.9, 10.0Hz, 1H), 6.22 (dd, J=16.9,2.2Hz, 1H), 5.72 (dd, J=9.9,2.2Hz, 1H), 3.75 (s, 3H).
HRMS(ESI,[M+H]+)m/z：373.0685.
The N- of embodiment 3 (5- ((the chloro- 5- trifluoromethyls of 4-) pyrimidine -2-base) amino) -2,4- dimethoxys) acrylamide (6-3)
Step (1) 1,5- dimethoxy -2,4- dinitro benzenes (14)
Sodium methoxide (11.40g, 211mmol) is dissolved in methyl alcohol (200mL) and is made solution, compound is added in reaction bulb 13 (5.0g, 21.10mmol) add sodium methoxide/methanol solution afterwards, are heated to reflux 2 hours, and TLC monitoring raw material points disappear, reaction Liquid lets cool revolving and does, and drying rotates to obtain compound 14 (4.51g, 19.73mmol) after the EA that adds water extractions
1H-NMR(300MHz,DMSO-d6):8.67(s,1H),7.05(s,1H),4.11(s,6H)。
Step (2) 2,4- dimethoxy -5- nitroanilines (2-3)
Addition NaHS hydrate (5.37g, 67.07mmol) in reaction bulb, sulphur simple substance (0.82g, 25.65mmol), NaOH (1.50g, 37.50mmol), and the 150mL that adds water, 80 DEG C be heated to it is completely molten it is clear after let cool to room Temperature, adds water (50mL) suspension of compound 14 (4.50g, 19.73mmol) in an other reaction bulb, slow at 90 DEG C The mixed solution that dropwise addition lets cool, drips off rear reaction solution stopping heating and lets cool, and is stirred overnight, suction filtration washing in second day, filter cake drying Obtain crude product.The molten clear rear sand processed of crude product crosses silicagel column, obtains compound 2-3 (2.31g, 11.66mmol).
1H-NMR(300MHz,DMSO-d6):7.27 (s, 1H), 6.75 (s, 1H), 4.84 (s, 2H), 3.92 (s, 3H), 3.87(s,3H)。
HRMS(ESI+,[M+H]+)m/z：199.0713.
Step (3) N- (2,4- dimethoxy -5- nitrobenzophenones) acrylamide (3-3)
In reaction bulb add compound 2-3 (2.20g, 11.10mmol) and triethylamine (1.68g, 16.60mmol) it is new Steam THF (50mL) solution, N2Under protection, 0 DEG C is added dropwise acryloyl chloride (2.01g, 22.20mmol), and room is gradually warmed up to after dripping off Temperature, overnight, second day terminating reaction that adds water, reaction solution revolving is dry for reaction, the EA that adds water extraction dryings, obtain compound 3-3 (2.20g, 8.72mmol)。
1H-NMR(300MHz,DMSO-d6)：9.56 (s, 1H), 8.74 (s, 1H), 6.92 (s, 1H), 6.65-6.70 (m, 1H), 6.23-6.27 (dd, 1H), 5.73-5.75 (dd, 1H), 4.02 (s, 3H), 3.98 (s, 3H),
HRMS(ESI+,[M+H]+)m/z：253.0820.
Step (4) N- (5- amino -2,4- Dimethoxyphenyls) acrylamide (4-3)
Compound 3-3 (2.10g, 8.33mmol), iron powder (0.93g, 16.66mmol), ammonium chloride are added in reaction bulb (0.89g, 16.66mmol), overnight, TLC monitoring confirms to react completely 90 DEG C of heating responses of ethanol-water mixed solvent, reaction solution Dry, extraction drying sand processed is rotated after suction filtration, silicagel column, PE-EA wash-outs (4 is crossed:1 to 2:1) compound IV-3 (900mg), is obtained.
1H-NMR(300MHz,DMSO-d6)：9.03 (s, 1H), 7.32 (s, 1H), 6.62 (s, 1H), 6.58-6.61 (m, 1H), 6.15-6.19 (dd, 1H), 5.63-5.65 (dd, 1H), 4.31 (s, 1H), 3.77 (s, 1H), 3.74 (s, 1H).
HRMS(ESI+,[M+H]+)m/z：223.1086.
Step (5) N- (5- ((the chloro- 5- trifluoromethyl pyrimidines -2- bases of 4-) amino) -2,4- Dimethoxyphenyls) acryloyl Amine (6-3)
With compound 4-3 and 5-1 as raw material, the method prepare compound 6-3 of the step of reference implementation example 1 (3).
MS(ESI+,[M+H]+)m/z：403.76.
Preparation method with reference to shown in embodiment 1~3, according to existing raw material, can prepare intermediate as follows Compound：
The 1- of embodiment 4 (4- (4- amino -3- methoxyphenyls) piperazine -1- bases) ethyl ketone (7-1)
Step (1) 1- (4- (3- methoxyl group -4- nitrobenzophenones) piperazine -1- bases) ethyl ketone (17)
At room temperature respectively to the addition compound of formula 15 (9.0g, 52.6mmol), 30mL N, N- dimethylacetamides in reaction bulb Amine, the compound of formula 16 (7.4g, 57.8mmol), DIPEA (8.1g, 63.1mmol), 90 DEG C of 5~6h of reaction, TLC monitoring reactions are complete, are down to room temperature, and reaction solution is poured into 200mL water, extracted with ethyl acetate (60mL × 3), are associated with Machine layer, uses saturated common salt water washing, and with anhydrous sodium sulfate drying, revolving obtains the compound of formula 17 (12.71g), is yellow solid (yield 86.4%).
1H-NMR(300M,CDCl3):7.96 (d, J=9Hz, 1H), 6.41 (d, J=9Hz, 1H), 6.31 (s, 1H), 3.95 (s, 3H), 3.67-3.78 (dd, J=33Hz, 4H), 3.42-3.46 (m, 4H), 2.15 (s, 3H).
HRMS(ESI,[M+H]+)m/z：280.1289.
Step (2) 1- (4- (4- amino -3- methoxyphenyls) piperazine -1- bases) ethyl ketone (7-1)
To the compound of formula 17 (10.0g, 35.8mmol) is added in reaction bulb, 150mL absolute methanols, reaction bulb replaces nitrogen Twice, hydrogen is passed through, stirring is lower to add palladium carbon (1.0g, 10%), and 24h is reacted at room temperature, and suction filtration rotates mother liquor, obtains brown Crude product.Use DCM：MeOH=10：1 column chromatography obtains formula 7-1 compounds (7.0g), is violet solid (yield 78.5%).
1H-NMR(300M,CDCl3):6.64 (d, J=9Hz, 1H), 6.51 (s, 1H), 6.40 (d, J=9Hz, 1H), 3.83 (s, 3H), 3.60-3.76 (dd, J=48Hz, 4H), 3.00 (s, 4H), 2.12 (s, 3H).
HRMS(ESI,[M+H]+)m/z：250.1546.
The 4- of embodiment 5 (4- methylpiperazine-1-yls) aniline (7-2)
Step (1) 1- methyl -4- (4- nitrobenzophenones) piperazine (20)
250mL reaction bulbs are taken, 80mL DMF are added thereto to, 10g compounds 18 are taken respectively, 9.6mL compounds 19, 11.8g potassium carbonate, sequentially adds in reaction bulb, and 80 DEG C of reaction 1.5h, reaction terminates, and reaction solution is cooled to room temperature, is filtered to remove Potassium carbonate, filtrate is slowly added in 200mL water, separates out a large amount of solids, and filtering, gained solid is dried, and obtains 13.23g rufous Solid 20, yield 84.3%.
1H NMR(300Hz,CDCl3):8.06 (d, J=9.4Hz, 2H), 7.03 (d, J=9.4Hz, 2H), 3.44 (t, J= 5.0Hz, 4H), 2.42 (t, J=5.0Hz, 4H), 2.21 (s, 3H).
HRMS (ESI, [M+H]+)m/z:222.1240。
Step (2) intermediate 4- (4- methylpiperazine-1-yls) aniline (7-2)
To in 500mL reaction bulbs, 13.12g compounds 20 are added, add 200mL methyl alcohol, and 1.45g 10%Pd/C, led to Hydrogen, overnight, reaction terminates room temperature reaction, is filtered to remove palladium carbon, filtrate concentration, residue column chromatography purifying (MeOH:DCM= 10:1) 9.9g gray solids 7-2, is obtained.Yield 89%.
1H-NMR (300M, CD3OD):6.83 (d, J=8.5Hz, 2H), 6.70 (d, J=8.5Hz, 2H), 3.02 (m, 4H), 2.57-2.60(m,4H),2.32(s,3H)。
HRMS (ESI, [M+H]+)m/z:192.1498。
Embodiment 6 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline (7-3)
Step 1) 1- (3- methoxyl group -4- nitrobenzophenones) -4- methyl piperazines (21)
7.8mL compounds 19 are taken, is added in 250mL reaction bulbs, to 100mL DMF are added in bottle, weigh 10g compounds 15 With 9.68g potassium carbonate, sequentially add in reaction bulb, stirring reaction in 80 DEG C of oil baths, TLC monitoring reactions, 5h raw material reactions are complete, instead Answer liquid to be cooled to room temperature, be filtered to remove potassium carbonate, 100mL water dilution filtrate, 75mL × 3 ethyl acetate extraction takes organic phase, 50mL × 3 water washing organic phase, organic phase anhydrous sodium sulfate drying, concentration obtains 10.87g yellow solid 7-3, yield 74.7%.
1H-NMR (300M, CDCl3)：8.01 (d, J=9.3Hz, 1H), 6.43 (d, J=9.3Hz, 1H), 6.32 (s, 1H), 3.95 (s, 3H), 3.40-3.43 (t, J=5Hz, 4H), 2.54-2.57 (t, J=5Hz, 4H), 2.36 (s, 3H).
HRMS (ESI, [M+H]+)m/z：252.1333.
Step (2) intermediate 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline (7-3)
10g compounds 21 are taken, is added in 250mL reaction bulbs, be added thereto to 100mL methyl alcohol, weighed 1g 10%Pd/C and add Enter in reaction bulb, lead to hydrogen, room temperature reaction 4h, reaction end is filtered to remove palladium carbon.Filtrate concentrates, the purifying of residue silicagel column (EA:DCM=1:1) 8.1g gray solid 7-3, yield 91.9%, are obtained.
1H-NMR(300M,DMSO):6.48-6.53 (m, 2H), 6.26 (d, J=8.3Hz, 1H), 3.73 (s, 3H), 2.93-2.95(m,4H),2.41-2.49(m,4H),2.20(s,3H)。
HRMS (ESI, [M+H]+)m/z:222.1604。
2- methoxyl groups-the 4- of embodiment 7 (4- Nmethanesulphonylpiperazine -1- bases) aniline (7-4)
Step (1) 1- (3- methoxyl group -4- nitrobenzophenones) -4- Nmethanesulphonylpiperazines (23)
10g compounds 15 are weighed, is added in 250mL there-necked flasks, to addition 100mL DMSO in bottle, then added in reaction bulb Enter 11.5g compounds 22 and 24.2g potassium carbonate, reaction bulb is placed in 80 DEG C of oil baths and reacts 20h.Reaction end is filtered to remove carbon Sour potassium, filtrate is added in 100mL water, and a large amount of yellow solids are separated out, filtering, water washing filter cake, 70 DEG C of vacuum drying 6h of filter cake, is obtained To 18g yellow solids 23, yield 98.7%.
HRMS (ESI, [M+H]+)：m/z 316.0974.
Step (2) 2- methoxyl groups -4- (4- Nmethanesulphonylpiperazine -1- bases) aniline (7-4)
8g compounds 23 are weighed, is added in 250mL there-necked flasks, to addition 80mL absolute methanols in bottle, then added in bottle 0.8g Pd/C 10%, H220h is reacted under normal pressure.Reaction terminates to addition 100mL dichloromethane stirring 10min in reaction solution (being completely dissolved product), is filtered to remove palladium carbon, and filtrate concentration, residue is beaten with ether, obtains grey 6.26g white solids 7-4, Yield 86.5%.
HRMS(ESI,[M+H]+)m/z：286.1262.
2- methoxyl group -4- morpholinyl phenylamines (7-5) of embodiment 8
Step (1) 4- (3- methoxyl group -4- nitrobenzophenones) morpholine (25)
Respectively to addition compound 15 (10.0g, 58.44mmol), compound 24 (6.11g, 70.12mmol) in reaction bulb It is dissolved in DMF, adds K2CO3(11.31g, 81.81mmol).Reacted under the conditions of 70 DEG C.TLC is tracked.Question response completely, will react System is poured into frozen water, has yellow solid to separate out.Cross filter solid, the compound 25 of drying 12.55g, yield：90.22%.
1H-NMR (300M, CDCl3)：8.01 (d, J=9.27Hz, 1H), 6.45 (d, J=9.27Hz, 1H), 6.37 (s, 1H), 3.96 (s, 3H), 3.87 (t, J=4.75Hz, 4H), 3.35 (t, J=4.83Hz, 4H).
HRMS(ESI,[M+H]+)m/z：239.1027.
Step (2) 2- methoxyl group -4- morpholinyl phenylamines (7-5)
To adding compound 25 (14.58g, 61.23mmol) to be dissolved in THF in reaction bulb, 1.5g Pd/C are added.Normal temperature Under the conditions of catalytic hydrogenation.TLC is tracked.Completely, diatomite filtering, vacuum distillation removes solvent to question response.Solid crude product is obtained, then It is beaten with ether and obtains pink powder, the compound 7-5 of drying 9.57g, yield：75.1%.
1H-NMR (300M, CDCl3)：6.65 (d, J=8.31Hz, 1H), 6.50 (d, J=2..34Hz, 1H), 6.40 (d, J =8..25Hz, 1H), 3.86 (s, 3H), 3.84 (d, J=4.17Hz, 4H), 3.04 (d, J=4.32Hz, 4H).
HRMS(ESI,[M+H]+)m/z：209.1286.
The 1- of embodiment 9 (4- amino -3- methoxyphenyls)-N, N- lupetazin -4- amine (7-6)
Step (1) 1- (3- methoxyl group -4- nitrobenzophenones) piperidines -4- alcohol (27)
Compound 15 (30.00g, 176mmol) is taken in reaction bulb, after 190mL DMF dissolvings, piperidine alcohols 26 is sequentially added (19.49g, 193mmol), potassium carbonate (29.00g, 211mmol), 70 DEG C of reaction 5h, TLC monitorings, reaction is complete；Suction filtration, filters off Insoluble solid, a small amount of DMF rinses filter cake, filtrate is poured into 800mL water, is stood and is separated out solid；Suction filtration, filter cake is placed at 60 DEG C Vacuum drying 24h obtains 39.45g yellow solids 27, and yield is 88%.
MS(ESI,[M+H]+)m/z：253.21.
Step (2) 1- (3- methoxyl group -4- nitrobenzophenones) piperidin-4-one (28)
In reaction bulb, the dissolving of 300mL dichloromethane is dividedly in some parts Weigh Compound 27 (30.00g, 118mmol) Dess-Martin oxidants (100g, 236mmol), after charging is finished, about 3h stops reaction；Add solution of sodium bisulfite (30g sodium hydrogensulfites are dissolved in suitable quantity of water) quenching reaction, and reaction solution pH is adjusted to neutrality with saturated sodium carbonate solution, separate two Chloromethanes layer；200mL dichloromethane aqueous layer extracted in three times, combined dichloromethane layer, sodium carbonate liquor is washed twice, saturated common salt Wash once, anhydrous sodium sulfate drying；Vacuum distillation obtains crude product, and crude product is beaten with 130mL methyl alcohol, stirs 1h, suction filtration, filter cake 8h is vacuum dried at being placed in 50 DEG C, 21.10g greenish yellow solids 28 are obtained, yield is 70.76%.
MS(ESI,[M+H]+)m/z：251.22.
Step (3) 1- (3- methoxyl group -4- nitrobenzophenones)-N, N- lupetidine -4- amine (29)
Compound 28 (5.10g, 20.38mmol) is taken in reaction bulb, after the dissolving of 40mL tetrahydrofurans, 41mL is sequentially added The tetrahydrofuran solution (81.52mmol) of dimethylamine, trimethyl orthoformate (4.33g, 40.76mmol), 3mL formic acid (81.52mmol)；70 DEG C of reaction 7h, stop reaction；After vacuum distillation, 100mL water is added, (TLC is shown as former to separate out solid Material), suction filtration, ethyl acetate (50mLx3) extraction filtrate, combined ethyl acetate layer, 50mL is washed once, combining water layer, 10% NaOH solution regulation water layer pH is 9, and dichloromethane (50mL x 5) extraction, combined dichloromethane layer, saturated common salt is washed once, Anhydrous sodium sulfate drying；Vacuum distillation obtains 4.27g solids 29, and yield is 75.04%.
HRMS(ESI,[M+H]+)m/z：280.1665.
Step (4) 1- (4- amino -3- methoxyphenyls)-N, N- lupetidine -4- amine (7-6)
4.09g compounds 29 are weighed in reaction bulb, add the dissolving of 40mL methyl alcohol, (addition is 0.4g 10%Pd/C II-2 weight 10%), hydrogenating reduction；TLC is monitored, about 6h, and reaction is complete, stops reaction；Suction filtration, a small amount of methanol rinses, decompression 3.38g brown solid 7-6 are distilled to obtain, yield is 92.60%.
1H-NMR(300M,CDCl3)：6.63 (d, 1H), 6.52 (s, 1H), 6.41-6.44 (t, 1H), 3.84 (s, 3H), 3.52 (d, 3H), 2.59-2.67 (t, 2H), 2.39 (s, 8H), 1.95-2.00 (d, 2H), 1.65-1.78 (m, 2H).
HRMS(ESI,[M+H]+)m/z：250.1290.
2- methoxyl groups-the 4- of embodiment 10 (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline (7-7)
Step (1) 1- (3- methoxyl group -4- nitrobenzophenones) piperidin-4-one (28)
To compound 15 (40g, 232mmol) is added in reaction bulb, after 300mL DMF dissolvings, compound 30 is added (39.42g,290mmol)、K2CO3(80.80g, 586mmol), stirring is heated to 70 DEG C, after reaction 24h, stops reaction；TLC is supervised Survey (petroleum ether:Ethyl acetate=1:2) there is starting material left.By reaction solution suction filtration, and filter cake is rinsed with a small amount of DMF；Filtrate is fallen Enter in 900mL water, stand and separate out solid；Filter cake is simultaneously placed in 60 DEG C of vacuum drying 24h by suction filtration, obtains 44.50g yellow solids 28, yield is 76.72%.
1H NMR(300MHz,CDCl3):δ 8.04 (d, J=9.2Hz, 1H), 6.46 (dd, J=9.2,2.3Hz, 1H), 6.38 (d, J=2.2Hz, 1H), 3.97 (s, 3H), 3.79 (t, J=6.0Hz, 4H), 2.65 (t, J=6.0Hz, 4H).
MS(ESI,[M+H]+)m/z：251.22.
Step (2) 1- (1- (3- methoxyl group -4- nitrobenzophenones) piperidin-4-yl) -4- methyl piperazines (32)
28 (3.00g, 12mmol) are weighed in microwave reaction pipe, sequentially add methyl piperazine 19 (2.40g, 24mmol), Trimethyl orthoformate (2.55g, 24mmol), 12mL acetonitriles and 1.8mL formic acid；110 DEG C of heating using microwave, 1h；After vacuum distillation, 30mL water is added, ethyl acetate (30mLx3) aqueous layer extracted to water layer is washed once without raw material point, ethyl acetate layer with 20mL；Close And water layer, it is added dropwise over 10%NaOH solution to water layer and is become cloudy by clarifying, dichloromethane (30mLx3) aqueous layer extracted merges two Chloromethanes layer, saturated common salt is washed once, anhydrous sodium sulfate drying.Vacuum distillation obtains khaki solid, 40 DEG C of vacuum drying 8h Product 32 (2.43g) is obtained, yield is 60.68%.
MS(ESI,[M+H]+)m/z：335.40.
The preparation of step (3) 2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline (7-7)
3.67g compounds 32 are taken in reaction bulb, 40mL methyl alcohol dissolves, addition 10%Pd/C 0.42g, hydrogen reducing, TLC is monitored, and about 6h reactions are complete；Suction filtration, vacuum distillation obtains 3.02g lavender solid 7-7, and yield is 90.42%.
1H NMR(300MHz,CDCl3):δ 6.63 (d, J=8.3Hz, 1H), 6.52 (d, J=2.3Hz, 1H), 6.41 (dd, J=8.3,2.4Hz, 1H), 3.83 (s, 3H), 3.53-3.49 (m, 3H), 2.66-2.40 (m, 10H), 2.31 (s, 3H), 1.94- 1.64(m,4H)。
HRMS(ESI,[M+H]+)m/z:305.2338。
The preparation of the 1- of embodiment 11 (4- aminophenyls)-N, N- lupetidine -4- amine (7-8)
Step (1) 1- (4- nitrobenzophenones) piperidines -4- alcohol (33)
Weigh Compound 18 (10.00g, 70.87mmol) in reaction bulb, sequentially add piperidine alcohols 26 (7.87g, 77.96mmol), potassium carbonate (11.74g, 85.04mmol), 85mL DMF, 70 DEG C of heating stirrings, 5h, stop reaction；Suction filtration, filters off Insoluble solid, and with a small amount of DMF rinses, filtrate is poured into 650mL water, is stood and is separated out solid, suction filtration, filter cake is placed at 60 DEG C Vacuum drying 24h obtains 13.56g crocus solid 33, and yield is 86.14%.
MS(ESI,[M+H]+)m/z:223.21。
The preparation of step (2) 1- (4- nitrobenzophenones) piperidin-4-one (34)
Compound 33 (13.52g, 60.87mmol) is taken in reaction bulb, the dissolving of 200mL dichloromethane is dividedly in some parts Dess-Martin oxidants (52g, 121.7mmol), after charging is finished, TLC monitorings, about 3h stops reaction；Add bisulfite Sodium solution (7g sodium hydrogensulfites are dissolved in suitable quantity of water) quenching reaction, adds sodium carbonate liquor to adjust pH to neutrality；Separate dichloro Methane layer, 200mL dichloromethane aqueous layer extracted in three times, combined dichloromethane layer, saturated common salt is washed once, anhydrous sodium sulfate Dry, vacuum distillation obtains yellow solid, 8h is vacuum dried at being placed in 45 DEG C and obtains product 34 (11.26g), yield is 84.02%.
1H-NMR(300M,CDCl3)：8.15-8.18 (d, 2H), 6.84-6.87 (d, 2H), 3.80-3.84 (t, 4H), 2.61-2.65(t,4H)。
MS(ESI,[M+H]+)m/z:221.21。
Step (3) N, N- dimethyl -1- (4- nitrobenzophenones) piperidines -4- amine (35)
Compound 35 (5.18g, 23.53mmol) is taken in reaction bulb, after the dissolving of 40mL tetrahydrofurans, 24mL is sequentially added The tetrahydrofuran solution (47.07mmol) of dimethylamine, trimethyl orthoformate (5.00g, 47.04mmol), 3.5mL formic acid (94.12mmol), 70 DEG C of heating stirrings, 7h stops reaction；Reaction solution vacuum distillation, adds 70mL water, and (TLC shows to separate out solid It is shown as raw material), ethyl acetate (40mLx2) aqueous layer extracted, combined ethyl acetate layer, 40mL is washed once, combining water layer, 10% NaOH solution regulation water layer pH is 9, dichloromethane (40mLx5) aqueous layer extracted, combined dichloromethane layer, saturated common salt washing one It is secondary, anhydrous sodium sulfate drying.Vacuum distillation obtains yellow solid, 8h is vacuum dried at 45 DEG C and obtains product Compound 35 (1.18g), receives Rate is 20.14%.
1H-NMR(300M,CDCl3)：8.08-8.13 (m, 2H), 6.78-6.84 (m, 2H), 3.94-3.99 (d, 2H), 2.94-3.03 (m, 2H), 2.36-2.46 (m, 1H), 2.34 (s, 6H), 1.94-1.98 (t, 2H), 1.52-1.65 (m, 2H).
HRMS(ESI,[M+H]+)m/z：250.1562.
Step (4) 1- (4- aminophenyls)-N, N- lupetidine -4- amine (7-8)
1.13g compounds 35 are weighed in reaction bulb, the dissolving of 20mL methyl alcohol is added, 0.12g 10%Pd/C are passed through hydrogen, TLC is monitored, and about 6h stops reaction；Suction filtration, a small amount of methanol rinses, filtrate decompression distills to obtain 0.83g light brown yellow solids, and yield is 83.50%.
1H-NMR(300M,CDCl3)：6.80-6.82 (d, 2H), 6.62-6.64 (d, 2H), 3.49-3.51 (d, 2H), 3.23 (s, 2H), 2.57-2.62 (t, 2H), 2.31 (s, 6H), 2.21-2.27 (m, 1H), 1.89-1.91 (d, 2H), 1.63- 1.70(m,2H)。
HRMS(ESI,[M+H]+)m/z：220.1752.
The 4- of embodiment 12 (4- amino -3- methoxyphenyls) piperazine -1- carboxylic acid tert-butyl esters (7-9)
Step (1) 4- (3- methoxyl group -4- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters (37)
Respectively in reaction bulb add compound 15 (12.0g, 70.12mmol), compound 36 (14.38g, 77.13mmol) it is dissolved in DMF, adds K2CO3(14.58g, 105.18mmol).Reacted under the conditions of 80 DEG C, TLC tracking., treat anti- Should be complete, reaction system is poured into frozen water, there is yellow solid to separate out, filter solid is crossed, it is beaten with ether, drying 21.2g Compound 37, yield：89.68%.
1H-NMR (300M, CDCl3)：8.01 (d, J=9.33Hz, 1H), 6.42 (d, J=9.45Hz, 1H), 6.34 (s, 1H), 3.96 (s, 3H), 3.61 (t, J=4.35Hz, 4H), 3.39 (t, J=5.10Hz, 4H), 1.49 (s, 9H).
HRMS(ESI,[M+H]+)m/z：338.1714.
Step (2) 4- (4- amino -3- methoxyphenyls) piperazine -1- carboxylic acid tert-butyl esters (7-9)
To adding 36 (23.91g, 77.83mmol) to be dissolved in ethanol in reaction bulb, 2g Pd/C are added.Urged under normal temperature condition Change hydrogenation, TLC tracking, question response is complete, and diatomite filtering, vacuum distillation removes solvent, obtains solid crude product, then beaten with ether Slurry obtains pink powder, the compound 7-9 of drying 21.4g, yield：98.2%.
1H-NMR (300M, CDCl3)：6.64 (d, J=8.28Hz, 1H), 6.52 (s, 1H), 6.42 (d, J=8..22Hz, 1H), 3.84 (s, 3H), 3.58 (t, J=4.77Hz, 4H), 2.98 (s, 4H), 1.48 (s, 9H).
HRMS(ESI,[M+H]+)m/z：308.1969.
The 4- of embodiment 13 (6- aminopyridine -3- bases) piperazine -1- carboxylic acid tert-butyl esters (7-10)
Step (1) 4- (6- nitropyridine -3- bases) piperazine -1- carboxylic acid tert-butyl esters (39)
Respectively in reaction bulb add compound 38 (10.2g, 49.52mmol), compound 36 (10.40g, 54.47mmol) it is dissolved in DMF, adds DIPEA (7.78g, 59.42mmol).Reacted under the conditions of 50 DEG C, TLC tracking, question response Completely, reaction system is poured into frozen water, there is yellow solid to separate out, cross filter solid, be beaten with EA, the change of drying 6.20g Compound 39, yield：40.63%.
1H-NMR (300M, CDCl3)：8.16 (m, 2H), 6.45 (m, 1H), 3.64 (t, J=4.89Hz, 4H), 3.45 (t, J =5.67Hz, 4H), 1.49 (s, 9H).
HRMS(ESI,[M+H]+)m/z：309.1554.
Step (2) 4- (6- aminopyridine -3- bases) piperazine -1- carboxylic acid tert-butyl esters (7-10)
To adding compound 39 (5.65g, 18.34mmol) to be dissolved in methyl alcohol in reaction bulb, 0.5g Pd/C, normal temperature are added Under the conditions of catalytic hydrogenation, TLC tracking, question response completely, diatomite filtering, vacuum distillation remove solvent, obtain solid crude product, then Use petroleum ether:Ether (30:1) mashing obtains pink powder, the compound 7-10 of drying 4.75g, yield：93.1%.
1H-NMR (300M, CDCl3)：7.76 (d, J=2.76Hz, 1H), 7.18 (dd, J=2.88,8.82Hz, 1H), 6.50 (d, J=8.79Hz, 1H), 6.40 (d, J=8..25Hz, 1H), 3.57 (t, J=4.92Hz, 4H), 2.95 (t, J= 5.1Hz, 4H), 1.48 (s, 9H).
HRMS(ESI,[M+H]+)m/z：279.1808.
The 4- of embodiment 14 (4- aminophenyls) piperazine -1- carboxylic acid tert-butyl esters (7-11)
Step (1) 4- (4- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters (40)
Respectively in reaction bulb add compound 18 (10.0g, 70.87mmol), compound 36 (15.84g, 85.05mmol) it is dissolved in DMF, adds K2CO3(15.67g, 113.39mmol), reacts under the conditions of 80 DEG C, TLC tracking, question response Completely, reaction system is poured into frozen water, there is yellow solid to separate out, cross filter solid, be beaten with ether, drying 18.58g's Compound 40, yield：85.3%.
1H-NMR (300M, CDCl3)：8.13 (d, J=9.27Hz, 2H), 6.82 (d, J=9.33Hz, 2H), 3.61 (t, J =4.71Hz, 4H), 3.42 (t, J=5.46Hz, 4H), 1.49 (s, 9H).
HRMS(ESI,[M+H]+)m/z：308.1077.
Step (2) intermediate 4- (4- aminophenyls) piperazine -1- carboxylic acid tert-butyl esters (7-11)
To adding compound 40 (17.57g, 63.39mmol) to be dissolved in methyl alcohol in reaction bulb, 1.7g Pd/C, normal temperature are added Under the conditions of catalytic hydrogenation, TLC tracking, question response completely, diatomite filtering, vacuum distillation remove solvent, obtain solid crude product, then It is beaten with ether and obtains pink powder, the compound 7-11 of drying 12.31g, yield：73.8%.
1H-NMR (300M, CDCl3)：6.82 (d, J=8.64Hz, 2H), 6.65 (d, J=8.61Hz, 2H), 3.57 (t, J =4.8Hz, 4H), 2.97 (t, J=4.83Hz, 4H), 1.48 (s, 9H).
HRMS(ESI,[M+H]+m/z：278.1862.
The 1- of embodiment 15 (4- (6- aminopyridine -3- bases) piperazine -1- bases) ethyl ketone (7-12)
Step (1) 1- (4- (6- nitropyridine -3- bases) piperazine -1- bases) ethyl ketone (41)
At room temperature respectively to the addition compound of formula 38 (10.0g, 49.2mmol), 100mL N, N- dimethyl second in reaction bulb Acid amides, 1- Acetylpiperazines 16 (8.2g, 64.0mmol), DIPEA (19.1g, 147.8mmol), 90 DEG C of reactions 7~8h, TLC monitoring reaction are complete, are down to room temperature, and reaction solution is poured into 300mL water, are extracted with ethyl acetate (80mL × 3), Merge organic layer, use saturated common salt water washing, anhydrous sodium sulfate drying, revolving to obtain the compound of formula 41 (9.9g), be ecru Solid (yield 80.6%).
1H-NMR (300M, CDCl3)：8.14-8.20 (m, 2H), 7.70-7.24 (m, 1H), 3.78 (d, J=39Hz, 4H), 3.47-3.52 (m, 4H), 2.16 (s, 3H).
HRMS(ESI,[M+H]+)m/z：251.1144.
Step (2) 1- (4- (6- aminopyridine -3- bases) piperazine -1- bases) ethyl ketone (7-12)
To the compound of Formula X -16 (8.0g, 32.0mmol) is added in reaction bulb, 90ml absolute methanols, reaction bulb replaces nitrogen Twice, lower addition palladium carbon (0.8g, 10%) is stirred, 24h is reacted at room temperature, suction filtration, with absolute methanol drip washing palladium carbon, revolving is female Liquid, obtains sepia crude product.With DCM：MeOH=10：1 column chromatography obtains Formula X I-12 compounds (5.3g), is darkviolet solid (yield 74.7%).
1H-NMR (300M, CDCl3)：7.76 (d, J=3Hz, 1H), 7.15-7.18 (m, 1H), 6.49 (d, J=3Hz, 1H), 3.60-3.75 (dd, J=45Hz, 4H), 2.95-3.02 (m, 4H), 2.12 (s, 3H).
HRMS(ESI,[M+H]+)m/z：221.1399.
The 5- of embodiment 16 (4- methylpiperazine-1-yls) piperidines -2- amine (7-13)
Step (1) 1- methyl -4- (6- nitropyridine -3- bases) piperazine (42)
10g compounds 38 are weighed, in addition 250mL reaction bulbs, to addition 80mL DMF, 9mL DIPEA and 8.47g in bottle Compound 19, reaction is placed in reacts 20h in 90 DEG C of oil baths, reaction terminates to be extracted with 100mL × 3 ethyl acetate, point liquid, organic phase Saturated common salt water washing is used, anhydrous sodium sulfate drying, concentration, residue is beaten with methyl tertiary butyl ether(MTBE), obtains 6g yellow solids Compound 42, yield 54.6%.
1H-NMR (300M, CDCl3)：8.12-8.17 (m, 2H), 7.18-7.27 (m, 1H), 3.46-3.49 (t, J= 5.0Hz, 4H), 2.57-2.60 (t, J=5.0Hz, 4H), 2.34 (s, 3H).
HRMS (ESI, [M+H]+) m/z:223.1178.
Step (2) 5- (4- methylpiperazine-1-yls) piperidines -2- amine (7-13)
5g compounds 42 are taken, are added in 250mL reaction bulbs, to 80mL methyl alcohol is added in bottle, add 10% palladium carbon 0.5g, Logical hydrogen, room temperature reaction 16h, reaction terminates, and is filtered to remove palladium carbon, and filtrate concentration, gained residue is beaten with methyl tertiary butyl ether(MTBE) Slurry, obtains 4.05g lavender solid chemical compound 7-13, yield 93.6%.
1H-NMR (300M, DMSO)：7.60 (d, J=1.7Hz, 1H), 7.13-7.15 (dd, J=1.7Hz, J=5.3Hz, 1H), 6.6.40 (d, J=5.0Hz, 1H), 2.90-2.92 (t, J=2.8Hz, 4H), 2.41-2.43 (t, J=2.8Hz, 4H), 2.19(s,3H)。
HRMS (ESI, [M+H]+) m/z：193.1476.
The 1- of embodiment 17 (4- (4- aminophenyls) piperazine -1- bases) ethyl ketone (7-14)
Step (1) 1- (4- (4- nitrobenzophenones) piperazine -1- bases) ethyl ketone (43)
At room temperature respectively to the addition compound of formula 18 (6.0g, 42.5mmol), 24mL N, N- dimethylacetamides in reaction bulb Amine, 1- Acetylpiperazines 16 (6.5g, 51.0mmol), DIPEA (7.1g, 55.3mmol), 90 DEG C reaction 4~ 5h, TLC monitoring reaction are complete, are down to room temperature, and reaction solution is poured into 180mL water, are extracted with ethyl acetate (50mL × 3), close And organic layer, use saturated common salt water washing, anhydrous sodium sulfate drying, revolving to obtain the compound of formula 43 (8.8g), it is pale yellow colored solid Body (yield 83.7%).
1H-NMR(300M,CDCl3):8.11-8.16(m,2H),6.80-6.86(m,2H),3.67-3.80(dd,4H), 3.46(s,4H),2.15(s,3H)。
HRMS(ESI,[M+H]+)m/z：250.1188.
Step (2) 1- (4- (4- aminophenyls) piperazine -1- bases) ethyl ketone (7-14)
To the compound of formula 43 (5.0g, 20.0mmol) is added in reaction bulb, 80mL absolute methanols, reaction bulb replaces nitrogen two Secondary, stirring is lower to add palladium carbon (0.5g, 10%), is passed through hydrogen, and 24h is reacted at room temperature, and suction filtration rotates mother liquor, obtains sepia Crude product.Use DCM：MeOH=10：1 column chromatography obtains 3.6g formula 7-14 compounds, is light purple solid (yield 82.3%).
1H-NMR(300M,CDCl3):6.81 (d, J=9Hz, 2H), 6.64 (d, J=9Hz, 2H), 3.59-3.75 (dd, 4H),2.99(s,4H),2.12(s,3H)。
HRMS(ESI,[M+H]+)m/z：220.1289.
Preparation method with reference to shown in embodiment 4~17, according to existing raw material, can prepare intermediate as follows Compound：
The N- of embodiment 18 (3- ((4- ((4- (4- methylpiperazine-1-yls) phenyl) amino) -5- trifluoromethyl pyrimidines -2- Base) amino) phenyl) acrylamide (I-16)
Under nitrogen, respectively to addition compound 6-1 (0.2g, 0.58mmol), compound 7-2 in microwave reaction bottle (0.358g, 1.87mmol), ethanol (8mL).Heating using microwave to 120 DEG C (150PSI, 150POWER), after reaction two hours, TLC Monitoring reaction is basically completed.To saturated aqueous sodium carbonate is added dropwise in reactant mixture, there is white solid to separate out, obtained by suction filtration To solid product.The solid product for obtaining is by 50 DEG C of dryings of baking oven of depressurizing.Target compound (0.29g) is finally given, is white Color solid.
1H-NMR(300MHz,DMSO-d6):9.99(s,1H),9.59(s,1H),8.46(s,1H),8.30(s,1H), 7.66 (s, 1H), 7.28~7.37 (m, 4H), 6.98~7.04 (t, J=8.13Hz, 1H), 6.89~6.91 (d, J= 8.91Hz, 2H), 6.42~6.51 (m, 1H), 6.21~6.28 (dd, 1H), 5.71~5.76 (dd, 1H), 3.10~3.13 (t, J=4.59Hz, 4H), 2.45~2.48 (t, 4H), 2.24 (s, 3H).
HRMS(ESI,[M+H]+)m/z:498.2211。
The N- of embodiment 19 (3- ((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- fluoroforms Yl pyrimidines -2- bases) amino) phenyl) acrylamide (I-1)
With compound 6-1 and 7-1 as raw material, target compound is prepared with reference to the method for embodiment 18.
1H-NMR(300MHz,DMSO-d6):10.00(s,1H),9.61(s,1H),8.47(s,1H),8.30(s,1H), 7.67 (s, 1H), 7.28~7.37 (m, 4H), 7.00~7.05 (t, 1H), 6.91~6.94 (d, J=8.76Hz, 2H), 6.41 ~6.50 (dd, 1H), 6.22~6.27 (d, 1H), 5.71~5.76 (d, 1H), 3.58 (s, 4H), 3.13 (t, 2H), 3.07 (t, 2H),2.05(s,3H)。
HRMS(ESI,[M+H]+)m/z:556.2248。
The N- of embodiment 20 (3- ((4- ((2- methoxyl group -4- morpholino phenyls) amino) -5- trifluoromethyl pyrimidine -2- bases) Amino) phenyl) acrylamide (I-6)
Under nitrogen, compound 6-1 (0.4g, 1.17mmol) is added to compound 7-5's (0.292g, 1.404mmol) In Isosorbide-5-Nitrae-dioxane (12mL) solution, alkali DIPEA (0.227g, 1.75mmol) is added.Reaction is heated to 102 DEG C, reaction Overnight.After TLC monitoring reactions completely, revolving removes solvent, and the crude product for obtaining is purified by column chromatography for separation.The solid that will be obtained Product finally gives target compound (0.439g) by 50 DEG C of dryings of baking oven of depressurizing, and is white solid.
1H-NMR(300MHz,DMSO-d6):10.02(s,1H),9.67(s,1H),8.31(s,1H),7.91(s,1H), 7.63~7.68 (br, 2H), 7.30~7.36 (t, J=9.81Hz, 1H), 7.03~7.08 (t, J=8.10Hz, 1H), 6.68 (s, 1H), 6.41~6.50 (m, 2H), 6.21~6.27 (d, 1H) 5.71~5.75 (m, 1H), 3.78 (s, 3H), 3.75~ 3.76 (t, 4H), 3.11~3.14 (t, 4H).
HRMS(ESI,[M+H]+)m/z:515.1975。
Embodiment 21A tert-butyl groups 4- (4- ((2- ((3- acrylamides phenyl) amino) -5- (trifluoromethyl) pyrimidines -4- Base) -3- anisyls) piperazine -1- carboxylic acid tert-butyl esters (I-7)
Formula 6-1 compounds (2.436g, 7.11mmol) is added under nitrogen protection contains formula 7-9 compounds (2.003g 106 DEG C of reactions are heated to after in the reaction bulb of 1,4- dioxane (50mL) solution 6.498mmol) overnight.TLC monitoring reactions Completely.Crude product column chromatography for separation is obtained into target compound 2.469g.
1H-NMR(300M,CDCl3):8.26(s,1H),8.06-8.09(d,1H),7.82(s,1H),7.56(m,2H), 7.36-7.44(m,2H),7.16-7.27(m,2H),6.41-6.54(m,3H),6.19-6.28(m,1H),5.72-5.76(d, 1H),3.88(s,3H),3.57-3.60(t,4H),3.09-3.12(t,4H),1.49(s,9H)。
HRMS(ESI,[M+H]+)m/z:614.2706。
(3 ((4- ((2- methoxyl groups -4- (piperazine -1- bases) phenyl) amino) -5- (trifluoromethyl) is phonetic for embodiment 21B N- Pyridine -2- bases) amino) phenyl) acrylamide (I-8)
Under nitrogen protection in seal pipe respectively plus compound obtained by TFA (15.134g, 133mmol) and embodiment 21A The DCM solution of (2.715g, 4.424mmol), is heated to 65 DEG C of reaction 3hr, TLC detections and finds that reaction is complete, and reaction solution is subtracted Pressure is molten clear with EA after being spin-dried for and is adjusted to alkalescence with the 2M NaOH aqueous solution, and organic phase Brine is washed and MgSO after being extracted with EA4It is dry It is dry, organic phase suction filtration is spin-dried for rear column chromatography and obtains crude product 2.160g, 500mg is crossed into post product EA mashing obtains target chemical combination Thing sterling (309mg).
1H-NMR(300M,DMSO-d6):10.06(s,1H),9.70(s,1H),8.87(br,1H),8.31(s,1H), 7.96(s,1H),7.62(m,2H),7.33-7.37(t,2H),7.01-7.06(t,1H),6.73(s,1H),6.41-6.50(m, 2H),6.20-6.26(d,1H),5.71-5.75(d,1H),3.79(s,3H),3.35-3.36(d,4H),3.26-3.27(d, 4H)。
HRMS(ESI,[M+H]+)m/z:514.2164。
The N- of embodiment 22 (3- ((4- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) ammonia Base) -5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) acrylamide (I-13)
To formula 6-1 compounds (400mg, 1.17mmol) is added in microwave tube, ethanol (15mL) makees solvent, adds intermediate 7-7 (426mg, 1.4mmol), microwave reaction 2 hours, TLC monitorings reaction is substantially completely.Reaction solution continues to stir after being returned to room temperature Mix 30 minutes, there are a large amount of white solids to separate out.Reaction solution is filtered, filter cake washes (5mL × 3), saturated carbon with ethanol respectively Acid sodium aqueous solution washes (10mL × 3), ethanol and washes (5mL × 2), ether and washes (10mL × 3), after decompression drying pale solid mesh Mark compound (603mg), yield 85%.
1H NMR(300MHz,DMSO-d6)δ10.14(s,1H),9.68(s,1H),8.30(s,1H),7.90(s,1H), 7.72-7.53 (m, 2H), 7.35 (d, J=8.1Hz, 2H), 7.05 (t, J=8.1Hz, 1H), 6.66 (d, J=2.5Hz, 1H), 6.56-6.40 (m, 2H), 6.24 (dd, J=17.0,2.5Hz, 1H), 5.73 (dd, J=10.1,2.2Hz, 1H), 3.76 (s, 3H),3.59-3.14(m,4H),2.96-2.62(m,9H),2.50(s,3H),1.91(m,2H),1.56(m,2H)。
HRMS(ESI,[M+H]+)m/z：611.3035.
The N- of embodiment 23 (3- ((4- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) -5- (fluoroforms Base) pyrimidine -2-base) amino) phenyl) acrylamide (I-17)
With compound 6-1 and 7-3 as raw material, target compound is prepared with reference to the method for embodiment 22.
1H NMR(300MHz,DMSO-d6)δ10.19(s,1H),9.69(s,1H),8.32(s,1H),7.97(s,1H), 7.75-7.57 (m, 2H), 7.34 (t, J=6.2Hz, 2H), 7.05 (t, J=8.1Hz, 1H), 6.75 (d, J=2.5Hz, 1H), 6.58-6.42 (m, 2H), 6.24 (dd, J=17.0,2.1Hz, 1H), 5.74 (dd, J=10.0,2.1Hz, 1H), 3.80 (s, 3H),3.40-3.19(m,8H),2.82(s,3H)。
HRMS(ESI,[M+H]+)m/z：528.2330.
The N- of embodiment 24 (3- ((4- ((2- methoxyl groups -4- (4- (mesyl) piperazine -1- bases) phenyl) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) acrylamide (I-31)
With compound 6-1 and 7-4 as raw material, target compound is prepared by the method for embodiment 22.
1H NMR(300MHz,DMSO-d6)δ10.03(s,1H),9.69(s,1H),8.32(s,1H),7.92(s,1H), 7.74-7.58 (m, 2H), 7.33 (dd, J=13.0,8.2Hz, 2H), 7.07 (t, J=8.1Hz, 1H), 6.73 (d, J= 2.5Hz, 1H), 6.46 (dd, J=17.0,9.9Hz, 2H), 6.24 (dd, J=17.0,2.2Hz, 1H), 5.74 (dd, J= 10.0,2.2Hz,1H),3.80(s,3H),3.29-3.20(m,8H),2.95(s,3H)。
HRMS(ESI,[M+H]+)m/z：592.1946.
(((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- bromines are phonetic for 3- for the N- of embodiment 25 Pyridine -2- bases) amino) phenyl) acrylamide (I-5)
Step (1) 1- (4- (4- ((the bromo- 2- chlorine pyrimidine-4-yls of 5-) amino) -3- methoxyphenyls) piperazine -1- bases) ethyl ketone (8-1)
Under nitrogen, compound 5-2 (1.0g, 4.39mmol) and DIPEA (0.85g, 6.59mmol) is added into compound 7-1 In the n-BuOH solution of (1.09g, 4.39mmol).Reaction is heated to 110 DEG C, after reacting 3 hours after TLC monitorings reaction completely, Reaction is let cool to room temperature.Frozen water (25mL) is added, after stirring half an hour, suction filtration, washing.The solid that will be obtained is by the baking oven that depressurizes 50 DEG C of dryings, finally give formula 8-1 compounds (1.81g), are white solid (yield 93.63%).
1H-NMR(300MHz,CDCl3):8.29~8.32 (d, J=9.3Hz, 1H), 8.23 (s, 1H), 7.93 (s, 1H), 6.57~6.60 (m, 2H), 3.94 (s, 3H), 3.78~3.81 (t, J=4.53Hz, 2H), 3.63~3.66 (t, J= 4.62Hz, 2H), 3.14~3.20 (m, 4H), 2.15 (s, 3H).
HRMS(ESI,[M+H]+)m/z:440.0483。
Step (2) N- (3- ((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- Bromopyrimidines - 2- yls) amino) phenyl) acrylamide
Under nitrogen, respectively to addition compound 8-1 (0.50g, 1.13mmol) in reaction bulb, compound 4-1 (0.184g, 1.13mmol), 2-BuOH (15mL), adds TFA (0.194g, 1.70mmol) catalysis.Reaction is heated to 100 DEG C, and reaction 6 is small When after after TLC monitoring reactions completely, reaction is let cool to room temperature, adds saturated aqueous sodium carbonate to adjust pH to alkalescence.Extracted with DCM Take, merge organic phase, washed once with saturated common salt, isolate organic phase, add anhydrous magnesium sulfate to dry.Removed by suction filtration Drier, revolving removes solvent, and the crude product for obtaining passes through column chromatography for separation.The solid product that will be obtained is by 50 DEG C of the baking oven that depressurizes Dry, finally give target compound (0.24g), be white solid.
1H-NMR(300MHz,DMSO-d6):10.02 (s, 1H), 9.34 (s, 1H), 8.17 (s, 1H), 7.91~7.94 (d, J=8.7,1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.35~7.37 (d, J=8.10Hz, 1H), 7.28~7.31 (d, J =8.04Hz, 1H), 7.08~7.14 (t, 2H), 6.41~6.50 (m, 1H), 6.21~6.27 (dd, 1H), 5.71~5.75 (dd,1H),3.79(s,3H),3.59(s,4H),3.15(t,2H),3.09(t,2H),2.06(s,3H)。
HRMS(ESI,[M+H]+)m/z:568.1494。
(((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- fluorine is phonetic for 3- for the N- of embodiment 26 Pyridine -2- bases) amino) phenyl) acrylamide (I-3)
Step (1) 1- (4- (4- ((the chloro- 5-FU -4- bases of 2-) amino) -3- methoxyphenyls) piperazine -1- bases) ethyl ketone (8-2)
With compound 5-3 and 7-1 as raw material, the method prepare compound 8-2 of the step of reference implementation example 25 (1).
1H-NMR(300MHz,CDCl3):8.30~8.33 (d, J=8.67Hz, 1H), 7.99~8.00 (d, J= 2.67Hz, 1H), 7.51 (s, 1H), 6.55~6.59 (m, 2H), 3.92 (s, 3H), 3.78~3.81 (t, J=4.92Hz, 2H), 3.63~3.66 (t, J=4.68Hz, 2H), 3.13~3.19 (m, 4H), 2.15 (s, 3H).
HRMS(ESI,[M+H]+)m/z:380.1275。
Step (2) N- (3- ((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5-FU - 2- yls) amino) phenyl) acrylamide
With compound 4-1 and 8-2 as raw material, the method for the step of reference implementation example 25 (2) prepares target compound.
1H-NMR(300MHz,DMSO-d6):9.98 (s, 1H), 9.09 (s, 1H), 8.21 (s, 1H), 7.99~8.01 (d, J=3.6Hz, 1H), 7.74 (s, 1H), 7.59~7.62 (d, J=8.67Hz, 1H), 7.35~7.38 (d, J=8.22Hz, 1H), 7.24~7.27 (d, J=8.16Hz, 1H), 7.02~7.08 (t, J=8.1Hz, 1H), 6.69~6.70 (d, J= 2.04Hz, 1H), 6.42~6.50 (m, 2H), 6.20~6.26 (dd, J=1.89Hz, 1H), 5.70~5.74 (dd, J= 1.83,1H),3.80(s,3H),3.59(br,4H),3.17(t,2H),3.10(t,2H),2.06(s,3H)。
HRMS(ESI,[M+H]+)m/z:506.2284。
(((4- ((4- (4- Acetylpiperazines -1-yl) -2- methoxyphenyls) amino) -5- chlorine is phonetic for 3- for the N- of embodiment 27 Pyridine -2- bases) amino) phenyl) acrylamide (I-4)
Step (1) 1- (4- (4- ((2,5- chlorine pyrimidine-4-yl) amino) -3- methoxyphenyls) piperazine -1- bases) ethyl ketone (8- 3)
With compound 5-4 and 7-1 as raw material, the method prepare compound 8-3 of the step of reference implementation example 25 (1).
1H-NMR(300MHz,CDCl3):8.29~8.32 (d, J=8.58Hz, 1H), 8.12 (s, 1H), 7.88 (s, 1H), 6.56~6.59 (m, 2H), 3.93 (s, 3H), 3.78~3.79 (t, 2H), 3.63~3.64 (t, 2H), 3.14~3.16 (m, 4H),2.15(s,3H)；
HRMS(ESI,[M+H]+)m/z:396.0982。
Step (2) N- (3- ((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- chlorine pyrimidine - 2- yls) amino) phenyl) acrylamide
With compound 4-1 and 8-3 as raw material, the method for the step of reference implementation example 25 (2) prepares target compound.
1H-NMR(300MHz,DMSO-d6):10.02(s,1H),9.31(s,1H),8.08(s,1H),7.99(s,1H), 7.79~7.82 (d, J=8.731H), 7.73 (s, 1H), 7.35~7.38 (d, J=8.13Hz, 1H), 7.27~7.29 (d, J =7.65Hz, 1H), 7.06~7.11 (t, J=8.1Hz, 1H), 6.71~6.72 (d, J=2.01Hz, 1H), 6.41~6.50 (m, 2H), 6.20~6.27 (dd, J=1.80Hz, 1H), 5.71~5.76 (dd, J=1.80,1H), 3.83 (s, 3H), 3.59 (br,4H),3.16(t,2H),3.10(t,2H),2.06(s,3H)。
HRMS(ESI,M+H+)m/z:522.1998。
The N- of embodiment 28 (3- ((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) pyrimidine -2- Base) amino) phenyl) acrylamide (I-2)
Step (1) 1- (4- (4- ((2- chlorine pyrimidine-4-yl) amino) -3- methoxyphenyls) piperazine -1- bases) ethyl ketone (8-4)
With compound 5-5 and 7-1 as raw material, the method prepare compound 8-4 of the step of reference implementation example 25 (1).
1H-NMR(300MHz,CDCl3):8.04~8.06 (d, J=5.88Hz, 1H), 7.55~7.62 (br, 1H), 7.12 (s, 1H), 6.52~6.54 (d, J=6.51Hz, 2H), 6.44~6.46 (d, J=5.91Hz, 1H), 3.85 (s, 3H), 3.78 ~3.81 (t, J=4.652H), 3.63~3.66 (t, J=4.35Hz, 2H), 3.14~3.21 (m, 4H), 2.15 (s, 3H).
HRMS(ESI,[M+H]+)m/z:362.1374。
Step (2) N- (3- ((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) pyrimidine -2-base) Amino) phenyl) acrylamide
With compound 4-1 and 8-4 as raw material, the method for the step of reference implementation example 25 (2) prepares target compound.
1H-NMR(300MHz,DMSO-d6):9.97 (s, 1H), 8.99 (s, 1H), 8.26 (s, 1H), 7.86~7.92 (dd, 1H), 7.66~7.69 (d, J=8.31Hz, 1H), 7.44~7.47 (d, J=7.89Hz, 1H), 7.30~7.32 (d, J =7.86Hz, 1H), 7.09~7.14 (t, J=8.07Hz, 1H), 6.67 (s, 1H), 6.43~6.52 (m, 2H), 6.27 (s, 1H), 6.15~6.22 (m, 1H), 5.71~5.74 (d, J=9.99Hz, 1H), 3.81 (s, 3H), 3.58~3.59 (m, 4H), 3.14(t,2H),3.09(t,2H),2.05(S,3H)。
HRMS(ESI,[M+H]+)m/z:488.2366。
(((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- chlorine is phonetic for 6- for the N- of embodiment 29 Pyridine -2- bases) amino) pyridine -2- bases) acrylamide (I-12)
Step (1) 1- (4- (4- ((2- ((6- aminopyrimidine -2- bases) amino) -5- chlorine pyrimidine-4-yl) amino) -3- methoxies Base phenyl) piperazine -1- bases) ethyl ketone
Weighing compound 8-3 (500mg, 1.26mmol), DAP 44 (138mg, 1.26mmol), solvent 1, 4- dioxane 20mL, plus cesium carbonate (822mg, 2.52mmol), plus the palladium of catalyst three (dibenzalacetone) two (116mg, 126umol) with part 4, double diphenylphosphine -9 of 5-, 9- dimethyl xanthene (73mg, 126umol, also known as Xantphos), microwave Reaction, 120 DEG C of temperature, time 2hr, TLC monitoring raw material points are disappeared, and reaction solution suction filtration, filtrate is crossed silicagel column, obtains crude product, then use High pressure prepares post reverse phase separation and obtains target compound (220mg).
1H-NMR(300MHz,DMSO-d6):8.59 (s, 1H), 8.10-8.14 (d, 2H), 7.70-7.73 (d, 1H), 7.03-7.15 (m, 3H), 6.66-6.72 (m, 1H), 6.52-6.55 (dd, 1H), 6.02-6.05 (d, 1H), 5.63 (s, 1H), 3.80 (s, 3H), 3.60 (s, 4H), 3.14-3.18 (m, 4H), 2.06 (s, 3H).
HRMS(ESI+,[M+H]+)m/z：469.1947.
Step (2) N- (6- ((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- chlorine pyrimidine - 2- yls) amino) pyridine -2- bases) acrylamide
Step 1 gained compound (200mg, 426umol) is taken to feed intake, plus 10mL DMF molten clear, plus 30mL THF and three second Amine 65mg (640umol), is added dropwise acryloyl chloride at -5 DEG C, keep -5 DEG C of reaction 3hr, and overnight, reaction solution revolving is near for rear rt reactions It is dry, plus saturation Na2CO3Solution dilutes, and EA extraction dryings, filtrate revolving, residue sand crosses silicagel column, elutes to obtain target chemical combination Thing (90mg).
1H-NMR(300MHz,DMSO-d6)：10.28 (s, 1H), 8.83 (s, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 7.69-7.72 (m, 1H), 7.58-7.61 (d, 1H), 7.47-7.49 (m, 2H), 6.73-6.74 (d, 1H), 6.59-6.68 (m, 1H), 6.50-6.54 (dd, 1H), 6.25-6.31 (dd, 1H), 5.73-5.76 (t, 1H), 3.79 (s, 3H), 3.61 (s, 4H), 3.15-3.20 (m, 4H), 2.06 (s, 3H).
HRMS(ESI+,[M+H]+)m/z：523.2028.
(((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- chlorine is phonetic for 5- for the N- of embodiment 30 Pyridine -2- bases) amino) -2- methoxyphenyls) acrylamide (I-9)
Step (1) N- (2- methoxyl group -5- nitrobenzophenones) acrylamide (3-4)
Under nitrogen, DIPEA (0.85g, 6.55mmol) is added the DCM (50mL) of compound 2-4 (1.0g, 5.95mmol) Solution.At 0 DEG C stir half an hour after, to be added dropwise in reaction solution add acryloyl chloride (0.57g, 6.25mmol).Reaction by Gradually it is warmed to room temperature, after TLC monitoring reactions completely.Add saturated aqueous sodium carbonate reaction is quenched, divide liquid, it is organic be added to it is anhydrous Magnesium sulfate is dried.Drier is removed by suction filtration, revolving removes solvent, obtains solid crude product and use PE again:EA=4：1 mashing.Most The solid product that will be obtained afterwards finally gives formula 3-4 compounds (1.67g) by 50 DEG C of dryings of baking oven of depressurizing, and is yellow solid.
1H-NMR(300MHz,CDCl3):9.37~9.38 (d, J=2.67Hz, 1H), 7.98~8.02 (dd, 1H), 7.93 (s, 1H), 6.94~6.97 (d, J=9.03Hz, 1H), 6.44~6.50 (m, 1H), 6.27~6.36 (m, 1H), 5.81 ~5.85 (d, J=9.96Hz, 1H) .4.03 (s, 3H).
HRMS(ESI,[M+H]+)m/z:223.0712。
Step (2) N- (5- amino -2- methoxyphenyls) acrylamide (4-4)
Under nitrogen, compound 3-4 (1.2g, 5.4mmol) is dissolved in ethanol (8mL) and tetrahydrofuran (8mL), by several times to The dihydrate (4.87g, 21.6mmol) of stannous chloride is added in reaction, reaction is heated to 70 DEG C of reactions after adding.Reaction 2.5 After hour, TLC monitoring reactions are completed.Solvent is removed by rotating, deionized water (20mL) is added.Solid hydrogen-oxygen is added at 0 DEG C Change sodium to pH be strong basicity.Extracted with DCM again, merge organic phase saturated common salt and wash once, organic phase uses anhydrous slufuric acid again Magnesium is dried.Drier is removed by suction filtration, revolving removes solvent.The solid product that will finally obtain is done by 50 DEG C of the baking oven that depressurizes It is dry, finally give formula 4-4 compounds (0.73g).
1H-NMR(300MHz,CDCl3):7.96 (s, 1H), 7.87 (br, 1H), 6.68~6.71 (d, 8.58Hz, 1H), 6.36~6.42 (m, 2H), 6.21~6.30 (dd, 1H), 5.71~5.75 (dd, 1H), 3.81 (s, 3H).
HRMS(ESI,[M+H]+)m/z:193.0967。
Step (3) N- (5- ((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- chlorine pyrimidine - 2- yls) amino) -2- methoxyphenyls) acrylamide
With compound 4-4 and 8-3 as raw material, target compound is prepared by the method for the step of reference implementation example 25 (2).
1H-NMR(300MHz,DMSO-d6):9.28(s,1H),9.08(s,1H),8.09(s,1H),8.04(s,1H), 7.84~7.88 (m, 1H), 7.33~7.35 (d, J=5.01Hz, 1H), 6.83~6.84 (d, J=5.34Hz, 1H), 6.64~ 6.70 (m, 1H), 6.45~6.47 (d, J=5.04Hz, 1H), 6.18~6.21 (d, 1H), 5.68~5.74 (m, 1H), 3.83 (s,3H),3.79(s,3H),3.59(s,4H),3.17(t,2H),3.11(t,2H),2.05(s,3H)。
HRMS(ESI,[M+H]+)m/z:552.2110。
(((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- chlorine is phonetic for 3- for the N- of embodiment 31 Pyridine -2- bases) amino) -4- methoxyphenyls) acrylamide (I-10)
Step (1) 1- (4- (4- ((the chloro- 2- of 5- ((2- methoxyl group -5- nitrobenzophenones) amino) pyrimidine-4-yl) amino) -3- Methoxyphenyl) piperazine -1- bases) ethyl ketone (10-1)
With compound 2-4 and 8-3 as raw material, the method prepare compound 10-1 of the step of reference implementation example 25 (2).
1H-NMR(300MHz,CDCl3):9.16~9.17 (d, J=2.28Hz, 1H), 8.11~8.13 (d, J= 8.64Hz, 1H), 8.07 (s, 1H), 7.86~7.91 (dd, 1H), 7.71 (br, 1H), 7.65 (s, 1H), 6.89~6.92 (d, J =8.97Hz), 6.52~6.57 (m, 2H), 4.00 (s, 3H), 3.92 (s, 3H), 3.80 (t, 2H), 3.65 (t, 3H), 3.16~ 3.21(m,4H),2.15(s,3H)。
HRMS(ESI,[M+H]+)m/z:528.1745。
Step (2) 1- (4- (4- ((2- ((5- amino -2- methoxyphenyls) amino) -5- chlorine pyrimidine-4-yl) amino) -3- Methoxyphenyl) piperazine -1- bases) ethyl ketone
Under nitrogen, respectively to addition compound 10-1 (0.86g, 1.63mmol) in reaction bulb, iron powder (0.46g, 8.15mmol), ammonium chloride (0.44g, 8.15mmol), ethanol (15mL), water (5mL).Reaction is heated to 85 DEG C of reactions.Two is small When, TLC monitoring reactions are completed.To adding saturated aqueous sodium carbonate that reaction is quenched in reaction, extracted with DCM, merge organic phase, Anhydrous magnesium sulfate is added to dry.Drier is removed by suction filtration, revolving removes solvent.The solid product that will finally obtain is by subtracting Pressure 50 DEG C of dryings of baking oven, finally give target compound (0.76g), yield 93.83%.
1H-NMR(300MHz,DMSO-d6):8.12 (s, 1H), 8.03 (s, 1H), 7.53~7.57 (m, 2H), 7.21~ 7.22 (d, J=2.19Hz, 1H), 6.67~6.72 (m, 2H), 6.54~6.57 (d, 8.7Hz, 1H), 6.13~6.17 (dd, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 3.59 (br, 4H), 3.14~3.18 (m, 4H), 2.06 (s, 3H).
HRMS(ESI,[M+H]+)m/z:498.2033。
Step (3) N- (3- ((4- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- chlorine pyrimidine - 2- yls) amino) -4- methoxyphenyls) acrylamide (I-10)
With step 2 gained compound and acrylic acid acyl chloride reaction, the method for the step of reference implementation example 29 (2) prepares targeted Compound.
1H-NMR(300MHz,DMSO-d6):9.92 (s, 1H), 8.08 (s, 1H), 7.84~8.02 (m, 3H), 7.46~ 7.48 (dd, 1H), 6.97~6.99 (d, J=5.31Hz, 1H), 6.67~6.68 (d, J=1.41Hz, 1H), 6.41~6.46 (dd, 1H), 6.35~6.37 (dd, 1H), 6.21~6.24 (dd, 1H), 5.70~5.72 (dd, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.56~3.57 (m, 4H), 3.11 (t, 2H), 3.05 (t, 3H), 2.05 (s, 3H).
HRMS(ESI,[M+H]+)m/z:552.2130。
The N- of embodiment 32 (3- ((the chloro- 4- of 5- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) Pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (I-28)
The chloro- N- of step (1) 2,5- bis- (4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) pyrimidine -4- amine (8-5)
With compound 7-6 and 5-4 as raw material, the method prepare compound 8-5 of the step of reference implementation example 25 (1).
1H-NMR(300MHz,DMSO-d6):8.81 (s, 1H), 8.26 (s, 1H), 7.24~7.27 (d, J=8.67Hz, 1H), 6.64~6.65 (d, J=2.25Hz, 1H), 6.51~6.54 (dd, 1H), 3.77 (s, 3H), 3.71~3.77 (t, 2H), 2.67~2.74 (t, 2H), 2.19 (s, 6H), 1.81~1.85 (m, 2H), 1.40~1.53 (m, 2H).
HRMS(ESI,[M+H]+)m/z:396.1351。
(((the chloro- 4- of 5- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) are phonetic for 3- for step (2) N- Pyridine -2- bases) amino) -4- methoxyphenyls) acrylamide (I-28)
With compound 8-5 and 4-2 as raw material, the method for the step of reference implementation example 25 (2) prepares target compound (I-28).
1H-NMR(300MHz,DMSO-d6):9.98 (s, 1H), 8.09 (s, 1H), 8.01~8.02 (d, J=2.04Hz, 1H), 7.92 (s, 1H), 7.84~7.87 (m, 2H), 7.47~7.51 (dd, 1H), 6.97~7.00 (d, J=8.88Hz, 1H), 6.65~6.66 (d, J=1.98Hz, 1H), 6.35~6.49 (m, 2H), 6.20~6.26 (dd, 1H), 5.70~5.74 (dd, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.75 (m, 2H), 3.06 (m, 2H), 2.68 (s, 6H), 1.99~2.03 (m, 2H), 1.59~1.70 (m, 2H).
HRMS(ESI,[M+H]+)m/z:552.2531。
Embodiment 33 N, N'- (((5- (trifluoromethyl) pyrimidine -2,4- diyls) double amino) double (3,1- phenylenes)) dipropyl Acrylamide (I-43)
Step (1) N- (3- ((2- chloro- 5- (trifluoromethyl) pyrimidine-4-yl-amino) phenyl) acrylamides (8-6)
Under nitrogen, to adding the compound of formula 45 (3.2g, 19.73mmol) to be dissolved in n-butanol in reaction bulb, 0 DEG C is added dropwise 2, The chloro- 5- trifluoromethyl pyrimidines 5-1 (4.28g, 19.73mmol) of 4- bis- and DIPEA (3.06g, 23.68mmol), room temperature reaction 2~ 3hrs, TLC detection raw material point disappear, and reaction solution revolving is near dry, plus saturation Na2CO3The aqueous solution is adjusted to pH=10, and EA extracts drying, Cross silicagel column, PE-EA wash-outs (5:1 to 2:1), merge and be concentrated to give target product 6.35g, object 8-6 is prepared into by HPLC.
1H-NMR (300M, DMSO-d6):10.22 (s, 1H), 9.57 (s, 1H), 8.58 (s, 1H), 7.79 (s, 1H), 7.49-7.52 (d, 1H), 7.33-7.38 (t, 1H), 7.13-7.16 (d, 1H), 6.40-6.49 (m, 1H), 6.23-6.29 (d, 1H), 5.75-5.78 (d, 1H).
HRMS(ESI,[M+H]+)m/z:343.0566。
Step (2) N, N'- (((5- (trifluoromethyl) pyrimidine -2,4- diyls) double amino) double (3,1- phenylenes)) two propylene Acid amides (I-43)
With compound 8-6 and 45 as raw material, the method for the step of reference implementation example 25 (2) prepares target compound (I-43).
1H-NMR(300MHz,DMSO-d6):10.13(s,1H),9.96(s,1H),9.67(s,1H),8.73(s,1H), 8.37 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.52~7.55 (d, J=7.83Hz, 1H), 7.42~7.45 (d, J= 8.10Hz, 1H), 7.21~7.33 (m, 1H), 6.94~7.00 (t, J=7.77Hz, 1H), 6.40~6.49 (m, 2H), 6.21 ~6.29 (m, 2H), 5.71~5.77 (m, 2H).
HRMS(ESI,[M+H]+)m/z:469.1588。
Embodiment 34 N, N'- (((5- Bromopyrimidine -2,4- diyls) double amino) double (3,1- phenylenes)) diacrylamine (I-44)
Step (1):N- (3- ((the bromo- 2- chlorine pyrimidine-4-yls of 5-) amino) phenyl) acrylamide (8-7)
With compound 5-2 and 45 as raw material, the method prepare compound 8-7 of the step of reference implementation example 33 (1).
HRMS(ESI,[M+H]+)m/z:352.9794。
Step (2) N, N'- (((5- Bromopyrimidine -2,4- diyls) double amino) double (3,1- phenylenes)) diacrylamine (I- 44)
With compound 8-7 and 45 as raw material, the method for the step of reference implementation example 25 (2) prepares target compound (I-44).
1H-NMR(300MHz,DMSO-d6):10.11(s,1H),9.98(s,1H),9.30(s,1H),8.62(s,1H), 8.22 (s, 1H), 7.84 (s, 1H), 7.69 (s, 1H), 7.45~7.47 (d, 2H), 7.36~7.39 (d, J=8.55Hz, 1H), 7.22~7.30 (m, 2H), 7.00~7.05 (t, 1H), 6.40~6.49 (m, 2H), 6.20~6.29 (m, 2H), 5.70~ 5.77(m,2H)。
HRMS(ESI,[M+H]+)m/z:479.0818。
The N- of embodiment 35 (3- ((4- ((4- (4- Acetylpiperazine -1- bases) phenyl) amino) -5- (trifluoromethyl) pyrimidine - 2- yls) amino) phenyl) acrylamide (I-39)
With compound 6-1 and 7-14 as raw material, the method for reference implementation example 22 prepares target compound (I-39).
1H-NMR(300MHz,DMSO-d6):10.00(s,1H),9.61(s,1H),8.47(s,1H),8.30(s,1H), 7.67 (s, 1H), 7.28~7.37 (m, 4H), 7.00~7.05 (t, 1H), 6.91~6.94 (d, J=8.76Hz, 2H), 6.41 ~6.50 (dd, 1H), 6.22~6.27 (d, 1H), 5.71~5.76 (d, 1H), 3.58 (s, 4H), 3.13 (t, 2H), 3.07 (t, 2H),2.05(s,3H)。
HRMS(ESI,[M+H]+)m/z:526.2182。
The N- of embodiment 36 (4- methoxyl groups -3- ((4- ((4- (4- methylpiperazine-1-yls) phenyl) amino) -5- (fluoroforms Base) pyrimidine -2-base) amino) phenyl) acrylamide (I-47)
With compound 6-2 and 7-2 as raw material, the method for reference implementation example 22 prepares target compound (I-47).
1H NMR(500MHz,DMSO-d6) δ 10.09 (s, 1H), 8.40 (brs, 1H), 8.30 (d, J=14.9Hz, 2H), 7.88 (brs, 1H), 7.51 (dd, J=8.9,2.6Hz, 1H), 7.37-7.31 (m, 2H), 6.99 (d, J=8.9Hz, 1H), 6.78 (d, J=8.6Hz, 2H), 6.49 (dd, J=17.0,10.1Hz, 1H), 6.25 (dd, J=17.0,2.1Hz, 1H), 5.78-5.71(m,1H),3.75(s,3H),3.28-3.06(m,4H),2.75-2.59(m,4H),2.39(s,3H)。
HRMS(ESI,[M+H]+)m/z：528.2358.
The N- of embodiment 37 (4- methoxyl groups -3- ((4- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) - 5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) acrylamide (I-48)
With compound 6-2 and 7-3 as raw material, the method for reference implementation example 22 prepares target compound (I-48).
1H-NMR(300MHz,DMSO-d6):10.02(s,1H),8.64(br,1H),8.30(s,1H),7.86(s,1H), 7.79~7.81 (d, 1H), 7.66 (s, 1H), 7.55~7.57 (m, 1H), 7.02~7.04 (D, 1H), 6.62 (s, 1H), 6.40 ~6.45 (m, 1H), 6.22~6.25 (dd, 2H), 5.72~5.74 (d, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.09 (s, 4H), 2.47~2.51 (d, 4H), 2.25 (s, 3H).
HRMS(ESI,[M+H]+)m/z:558.2838。
The N- of embodiment 38 (2,4- dimethoxys -5- ((4- ((4- (4- methylpiperazine-1-yls) phenyl) amino) -5- (three Methyl fluoride) pyrimidine -2-base) amino) phenyl) acryloyl group acid amides (I-52)
With compound 6-3 and 7-2 as raw material, the method for reference implementation example 22 prepares target compound (I-52).
1H-NMR(500MHz,DMSO-d6)δ9.31(s,1H),8.46(brs,1H),8.22(s,1H),8.15(s,1H), 8.08 (s, 1H), 7.31 (d, J=8.4Hz, 2H), 6.83-6.63 (m, 4H), 6.19 (dd, J=17.0,2.0Hz, 1H), 5.68 (dd, J=10.1,2.1Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 3.11-3.03 (m, 4H), 2.49-2.45 (m, 4H), 2.25(s,3H)。
HRMS(ESI,[M+H]+)m/z：558.2521.
The N- of embodiment 39 (3- ((4- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) acrylamide (I-58)
With compound 6-1 and 7-6 as raw material, the method for reference implementation example 22 prepares target compound (I-58).
1H-NMR(300MHz,DMSO-d6):10.06(s,1H),9.70(s,1H),8.31(s,1H),7.93(s,1H), 7.67 (br, 1H), 7.60 (br, 1H), 7.32~7.37 (m, 2H), 7.04~7.07 (t, 1H), 6.66~6.67 (d, 1H), 6.44~6.49 (m, 2H), 6.23~6.27 (dd, 1H), 5.73~5.77 (dd, 1H), 3.78 (s, 3H), 3.72~3.75 (d, 2H), 2.66~2.71 (t, 2H), 2.26 (s, 6H), 1.86`1.88 (d, 2H), 1.48~1.54 (m, 2H).
HRMS(ESI,[M+H]+)m/z:556.3066。
The N- of embodiment 40 (3- ((4- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) acrylamide (I-59)
With compound 6-3 and 7-6 as raw material, the method for reference implementation example 22 prepares target compound (I-59).
1H-NMR(300MHz,DMSO-d6):9.341(s,1H),8.66(s,1H),8.24(s,1H),8.08(s,1H), 7.81 (br, 1H), 7.55 (s, 1H), 6.82 (s, 1H), 6.64~6.70 (dd, 1H), 6.60 (s, 1H), 6.26 (br, 1H), 6.15~6.19 (dd, 1H), 5.66~5.68 (d, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.66~ 3.68 (d, 2H), 2.60~2.65 (t, 2H), 2.29 (s, 6H), 1.86~1.88 (d, 2H), 1.47`1.54 (m, 2H).
HRMS(ESI,[M+H]+)m/z:616.2865。
The N- of embodiment 41 (3- ((4- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) -5- (trifluoromethyl) pyrimidine -2-yl) amino) -4- methoxyphenyls) acrylamide (I-60)
With compound 6-2 and 7-6 as raw material, the method for reference implementation example 22 prepares target compound (I-60).
1H NMR(500MHz,DMSO-d6)δ10.03(s,1H),8.65(brs,1H),8.30(s,1H),7.85(brs, 1H), 7.79 (d, J=8.9Hz, 1H), 7.65 (s, 1H), 7.58 (dd, J=8.9,2.6Hz, 1H), 7.03 (d, J=8.9Hz, 1H), 6.61 (d, J=2.5Hz, 1H), 6.44 (dd, J=17.0,10.1Hz, 1H), 6.29-6.19 (m, 2H), 5.73 (dd, J =10.1,2.1Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.68-3.59 (m, 2H), 2.66-2.55 (m, 2H), 2.32- 2.22(m,1H),2.26(s,6H),1.88–1.78(m,2H),1.53-1.41(m,2H)。
HRMS(ESI,[M+H]+)m/z：586.2778.
The N- of embodiment 42 (4- methoxyl groups -3- ((4- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- Base) phenyl) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) acryloyl group acid amides (I-63)
With compound 6-2 and 7-7 as raw material, the method for reference implementation example 22 prepares target compound (I-63).
1H NMR(500MHz,DMSO-d6)δ10.02(s,1H),8.64(brs,1H),8.30(s,1H),7.86(brs, 1H), 7.79 (d, J=8.8Hz, 1H), 7.65 (s, 1H), 7.57 (dd, J=8.9,2.6Hz, 1H), 7.03 (d, J=8.9Hz, 1H), 6.60 (d, J=2.5Hz, 1H), 6.43 (dd, J=16.9,10.1Hz, 1H), 6.28-6.20 (m, 2H), 5.73 (dd, J =10.1,2.1Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.67-3.59 (m, 2H), 3.42-3.29 (m, 4H), 2.64- 2.52(m,3H),2.42-2.24(m,4H),2.17(s,3H),1.86-1.77(m,2H),1.54-1.42(m,2H)。
HRMS(ESI,[M+H]+)m/z：641.3208.
The N- of embodiment 43 (3- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia Base) -5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) acrylamide (I-79)
Step (1) N1- (3- methoxyl group -4- nitrobenzophenones)-N1, N2, N2- Trimethylethane -1,2- diamines (46)
With compound 15 and N1, N1, N2- Trimethylethane -1,2- diamines is raw material, the side of the step of reference implementation example 6 (1) Method prepare compound 46.
1H-NMR(300MHz,DMSO-d6):7.88~7.91 (d, 1H), 6.35~6.39 (dd, 1H), 6.24~6.25 (d, J=2.28Hz, 1H), 3.90 (s, 3H), 3.54~3.58 (t, J=6.84Hz, 2H), 3.07 (s, 3H), 2.41~2.45 (t, J=6.84Hz, 2H), 2.20 (s, 6H).
HRMS(ESI,[M+H]+)m/z:254.1505。
Step (2) N1- (2- (dimethylamino) ethyl) -3- methoxyl groups-N1- methylbenzene -1,4- diamines (7-24)
With compound 46 as raw material, with reference to the method prepare compound 7-24 by the step of embodiment 6 (2).
1H-NMR(300MHz,DMSO-d6):6.45~6.49 (dd, 1H), 6.31~6.32 (d, J=2.43Hz, 1H), 6.11~6.14 (dd, 1H), 3.73 (s, 3H), 3.20~3.25 (t, J=7.02Hz, 2H), 2.75 (s, 3H), 2.30~2.35 (t, J=7.32Hz, 2H), 2.15 (s, 6H).
HRMS(ESI,[M+H]+)m/z:224.1745。
Step (3) N- (3- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia Base) -5- (trifluoromethyl) pyrimidine -2-base) amino) phenyl) acrylamide (I-79)
With compound 6-1 and 7-24 as raw material, the method for reference implementation example 22 prepares target compound (I-79).
1H-NMR(300MHz,DMSO-d6):10.04(s,1H),9.66(s,1H),8.29(s,1H),7.91(s,1H), 7.65 (br, 1H), 7.47 (br, 1H), 7.40~7.42 (d, J=4.8Hz, 1H), 7.29~7.30 (d, J=4.5Hz, 1H), 7.00 (br, 1H), 6.43~6.48 (m, 1H), 6.39 (s, 1H), 6.23~6.26 (m, 2H), 5.72~5.74 (d, J= 6.0Hz, 1H), 3.76 (s, 3H), 3.44~3.47 (t, J=3.9Hz, 2H), 2.95 (s, 3H), 2.42~2.45 (t, J= 3.9Hz,2H),2.22(s,6H)。
HRMS(ESI,[M+H]+)m/z:530.3002。
The N- of embodiment 44 (3- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia Base) -5- (trifluoromethyl) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (I-80)
With compound 6-2 and 7-24 as raw material, the method for reference implementation example 22 prepares target compound (I-80).
1H-NMR(300MHz,DMSO-d6):9.99(s,1H),8.53(br,1H),8.27(s,1H),7.90(s,1H), 7.69~7.71 (d, 1H), 7.62 (br, 1H), 7.53~7.56 (dd, 1H), 7.00~7.02 (d, 1H), 6.40~6.45 (dd, 1H), 6.34 (s, 1H), 6.21~6.25 (m, 1H), 6.05~6.06 (d, 1H), 5.71~5.73 (d, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.38~3.41 (t, 2H), 2.87 (s, 3H), 2.38~2.40 (t, 2H), 2.22 (s, 6H).
HRMS(ESI,[M+H]+)m/z:560.3014。
Experimental example 1 is evaluated EGF-R ELISA EGFR and carcinogenic driving Gene A LK inhibitory activity.
This test objective is the part of compounds for evaluating and comparing this patent synthesis to cultured tumor cells in vitro H1975 (EGFR L858R/T790M), the influence of NCI-H3122 (ALK), NCI-H292 (EGFR) or A431 (EGFR) propagation.
Compound method：The stoste of 10mM is made into DMSO by test agent；When using required concentration is made into nutrient solution.
Cell line:A431 cells are purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank, with containing 10% hyclone (FBS) RPMI 1640/DMEM medium cultures.Lung cancer NCI-H292 (EGFR WT) is purchased from Shanghai life section of the Chinese Academy of Sciences Institute's cell bank, H1975 cells are purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank, and NCI-H3122 is purchased from US National ICR (NCI), with the medium cultures of RPMI 1640 containing 10% hyclone (FBS).
Reagent and instrument：RPMI-1640 is purchased from Gibco BRL companies；FBS is purchased from Hyclone companies；Multi-function microplate reader Synergy H4 are purchased from BioTek companies；Sulforhodamine B (SRB) is purchased from Sigma companies.
Test method srb assay：Using the inhibitory action of SRB protein stainings method detection drug on tumor cell propagation growth. Key step is as follows：Inoculation exponential phase cell adds the medicine of various concentrations (1-10000nM), often in 96 well culture plates Individual concentration sets 3 multiple holes, while setting the Vehicle controls of respective concentration.Tumour cell is in 37 DEG C, 5%CO2Under the conditions of culture it is 72 small When.Cell is dyeed with SRB room temperatures, is eventually adding the dissolving of Tris solution, and OD is determined under ELIASA (BioTek) 510nm wavelength Value, inhibitory rate of cell growth is calculated with following equation：
Inhibiting rate=(OD valuesControl wells- OD is worthDosing holes)/OD valuesControl wells× 100%.
According to each concentration inhibiting rate, according to non-linear regression method calculation of half inhibitory concentration IC50。
Experiment is carried out in three batches altogether, as a result as shown in table 1 below, table 2 and table 3：
The IC that the increment of the Compounds in vitro culture tumour cell of table 1. suppresses50(first)
The IC that the increment of the Compounds in vitro culture tumour cell of table 2. suppresses50(second batch)
The IC that the increment of the Compounds in vitro culture tumour cell of table 2. suppresses50(the 3rd batch)
。

Claims (24)

1. compound or its pharmaceutically acceptable salt as shown in (I)：
Wherein,
X or Y are each independently selected from N or CH；
R1Selected from H, halogen ,-CF3Or-CN；
R2Or R6It is each independently selected from H or-OC1-6Alkyl；
R3Or R5Be each independently selected from H or
R4Selected from 3~8 circle heterocycles alkyl or
R7Selected from H ,-OC1-6Alkyl,
3~8 circle heterocycles alkyl includes 1,2 or 3 hetero atoms selected from N, O or S, and optionally by R8Substitution；
The R8Selected from-C1-4Alkyl ,-C (O)-C1-4Alkyl ,-NR9R10、-C(O)O-C1-4Alkyl ,-C (O) NH-C1-4Alkyl ,- SO2-C1-4Alkyl ,-SO2NH2、-C(O)-C1-4Alkylidene-OH or
The Z is selected from O, S or NR11；
The R9、R10Or R11It is each independently selected from H or-C1-4Alkyl.
2. the compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, it is characterised in that R1Choosing From H ,-F ,-Cl ,-Br ,-CF3Or-CN.
3. the compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, it is characterised in that R2Or R6It is each independently selected from H or-OC1-4Alkyl.
4. the compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, it is characterised in that R4Choosing From 5~6 circle heterocycles alkyl or
5. the compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, it is characterised in that R7Choosing From H ,-OC1-4Alkyl,
6. the compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, it is characterised in that institute State Heterocyclylalkyl and include 1 or 2 hetero atom selected from N or O, and optionally by R8Substitution.
7. the compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, it is characterised in that Z is selected From O or NR11。
8. the compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, it is characterised in that choosing Compound or its pharmaceutically acceptable salt shown in formula (II)：
Wherein,
X or Y are each independently selected from N or CH；
R1Selected from H ,-F ,-Cl ,-Br ,-CF3Or-CN；
R2、R6Or R7It is each independently selected from H ,-OC1Alkyl ,-OC2Alkyl ,-OC3Alkyl or-OC4Alkyl.
9. the compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, it is characterised in that choosing Compound or its pharmaceutically acceptable salt shown in formula (III)：
Wherein,
X or Y are each independently selected from N or CH；
R1Selected from H, halogen ,-CF3Or-CN；
R2Or R6It is each independently selected from H or-OC1-6Alkyl；
R7Selected from H ,-OC1-6Alkyl,
A is selected from O, NH, NR8Or CH-R8；
The Z is selected from O, S or NR11；
The R8Selected from-C1-4Alkyl ,-C (O)-C1-4Alkyl ,-NR9R10、-C(O)O-C1-4Alkyl ,-C (O) NH-C1-4Alkyl ,- SO2-C1-4Alkyl ,-SO2NH2、-C(O)-C1-4Alkylidene-OH or
The R9、R10Or R11It is each independently selected from H or-C1-4Alkyl.
10. the compound or its pharmaceutically acceptable salt shown in formula (III) according to claim 9, it is characterised in that R1 Selected from H ,-F ,-Cl ,-Br ,-CF3Or-CN.
Compound or its pharmaceutically acceptable salt shown in 11. formulas (III) according to claim 9, it is characterised in that R2 Or R6It is each independently selected from H or-OC1-4Alkyl.
Compound or its pharmaceutically acceptable salt shown in 12. formulas (III) according to claim 9, it is characterised in that R7 Selected from H ,-OC1-4Alkyl,
Compound or its pharmaceutically acceptable salt shown in 13. formulas (III) according to claim 9, it is characterised in that The Z is selected from O or NR11。
Compound or its pharmaceutically acceptable salt shown in 14. formulas (I) according to claim 1, it is characterised in that choosing Compound or its pharmaceutically acceptable salt shown in formula (IV)：
Wherein,
X or Y are each independently selected from N or CH；
R1Selected from H, halogen ,-CF3Or-CN；
R2Or R6It is each independently selected from H or-OC1-6Alkyl；
R7Selected from H ,-OC1-6Alkyl,
The Z is selected from O, S or NR11；
The R9、R10Or R11It is each independently selected from H or-C1-4Alkyl.
Compound or its pharmaceutically acceptable salt shown in 15. formulas (IV) according to claim 14, it is characterised in that R1Selected from H ,-F ,-Cl ,-Br ,-CF3Or-CN.
Compound or its pharmaceutically acceptable salt shown in 16. formulas (IV) according to claim 14, it is characterised in that R2Or R6It is each independently selected from H or-OC1-4Alkyl.
Compound or its pharmaceutically acceptable salt shown in 17. formulas (IV) according to claim 14, it is characterised in that R7Selected from H ,-OC1-4Alkyl,
Compound or its pharmaceutically acceptable salt shown in 18. formulas (IV) according to claim 14, it is characterised in that The Z is selected from O or NR11。
19. compounds as follows or its pharmaceutically acceptable salt：
20. compounds according to any one of claim 1-19 or its pharmaceutically acceptable salt treatment EGFR or/ Purposes in the disease mediated with ALK.
Purposes in the disease of 21. treatment EGFR according to claim 20 or/and ALK mediations, it is characterised in that described The disease of EGFR mediations is selected from the disease of EGFR-L858R or/and EGFR-T790M mutation activation mediations.
Purposes in the disease of 22. treatment EGFR according to claim 20 or/and ALK mediations, it is characterised in that described The disease of ALK mediations is selected from the disease of NPM-ALK or/and EML4-ALK Gene Fusions mediation.
Purposes in the disease of 23. treatment EGFR according to claim 20 or/and ALK mediations, it is characterised in that described The disease of EGFR or/and ALK mediations includes cancer, inflammation, infection, immunity disease, organ transplant, viral disease, painstaking effort Pipe disease or metabolic disease.
24. pharmaceutical compositions, it includes the compound or its pharmaceutically acceptable salt any one of claim 1-19 And one or more pharmaceutically acceptable carrier or excipient.
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