CN105884695B - Heterocyclic derivatives species tyrosine kinase inhibitor - Google Patents

Heterocyclic derivatives species tyrosine kinase inhibitor Download PDF

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CN105884695B
CN105884695B CN201610059987.3A CN201610059987A CN105884695B CN 105884695 B CN105884695 B CN 105884695B CN 201610059987 A CN201610059987 A CN 201610059987A CN 105884695 B CN105884695 B CN 105884695B
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amino
base
methoxyl group
ethyl
methyl
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CN105884695A (en
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吴永谦
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BEIJING TIANXINYUAN PHARMACEUTICAL SCIENCE AND TECHNOLOGY DEVELOPMENT Co Ltd
Beijing Sihuan Pharmaceutical Co Ltd
Beijing Ao He Research Institute Co Ltd
Jilin Shengtong Chemical Co Ltd
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Shandong Xuanzhu Pharma 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to pharmaceutical technology fields, and in particular to heterocyclic derivatives species tyrosine kinase inhibitor, its pharmaceutically acceptable salt, its ester and their stereoisomer shown in general formula (I), wherein Y, W, Q, m, L, R1、R2、R3、R4、R5、R6、R7、R7′、R8、R8' be defined as in the description.The invention further relates to the preparation methods of these compounds, pharmaceutical preparation and pharmaceutical composition and these compounds containing these compounds are used to prepare prevention as tyrosine kinase inhibitor and/or treat the application in the drug of drug resistance disease caused by the Cancerous disease and EGFR T790M mutation that EGFR mutation causes.

Description

Heterocyclic derivatives species tyrosine kinase inhibitor
1, technical field
The invention belongs to pharmaceutical technology fields, and in particular to pyrimidine heterocyclic derivative species tyrosine kinase inhibitor, its medicine Acceptable salt, its ester and their stereoisomer on, preparation method, pharmaceutical preparation and the medicine group of these compounds Object and these compounds are closed as tyrosine kinase inhibitor and is used to prepare prevention and/or treats the cancer that EGFR mutation causes Application in the drug of drug resistance disease caused by disease and EGFR T790M are mutated.
2, background technique
Cancer, also known as malignant tumour have seriously threatened the health and lives of the mankind.2004, the whole world had 7,400,000 people dead In cancer.2008, China carried out Third National cause of the death condition survey, showed the Cancer in China death rate between Past 30 Years Eighty per cant or so is increased, for the people for dying of cancer every year close to 2,000,000, situation is very severe.
Lung cancer is clinical common one of malignant tumour, first of morbidity and mortality column malignant tumour.From tissue Pathologic angle, lung cancer are divided into two types: Small Cell Lung Cancer (small cell lung cancer SCLC) and non-small cell Lung cancer (non-small cell lung cancer, NSCLC).NSCLC includes other than the SCLC such as squamous carcinoma, gland cancer, large cell carcinoma Lung cancer, account for the 80-85% of lung cancer sum.70% NSCLC already belongs to advanced stage when making a definite diagnosis, be difficult by operation or radiotherapy into Row radical treatment.In addition, being more than 50% early stage patient although after the active treatments such as operation, radiotherapy and adjuvant chemotherapy Still there is local recurrence or DISTANT METASTASES IN.Thus the systemic therapy based on chemotherapy is of great significance in the treatment of NSCLC.
In recent years, with the further investigation to tumour cell signal transduction path, with EGF-R ELISA (epidermal growth factor receptor, EGFR) is the small molecule tyrosine kinase inhibitors of target spot (tyrosine kinase inhibitor, TKI) molecular targeted agents achieve preferable achievement in the treatment of NSCLC. EGFR is a kind of transmembrane protein, belongs to receptor tyrosine kinase (ERBB) family, and there are four types of hypotypes for family: EGFR (ERBB1 or HER-1), HER-2 (ERBB2), HER-3 (ERBB3) and HER-4 (ERBB4) are played main in the conversion and growth of tumour Effect.FDA has successively quickly ratified two reversible single target spot small molecule EGFR TKI, i.e., Gefitinib (efitinib, Iressa) and Tarceva (Erlotinib, Tarcewa), for treating the advanced NSCLC of first-line treatment failure.2013, FDA has approved the EGFR TKI of first irreversible multiple target point again, and Afatinib preferably treats NSCLC.
The EGFR TKI listed only treats sensitivity to the NSCLC crowd of EGFR saltant type, and it is outer which, which is more than 90%, The missing of aobvious son 19 and the L858R mutation of exon 21, are common in Asia, non-smoking, female patient.Patient is applying EGFR At TKI initial stage, curative effect is more apparent, and no progression of disease phase (progression-free survival, PFS) extends, and objectively responds rate (objective response rate, ORR) is improved, and quality of life is greatly improved, but most of patient is in mean treatment It will appear the drug resistance to such drug after 10 months.In addition, can be produced because existing EGFR TKI acts on Wild type EGFR simultaneously The side effects such as rawhide rash, diarrhea restrict its clinic, and research and development selectivity is stronger and can preferably be controlled with the EGFR TKI of overriding resistance Treat NSCLC.
In there is drug resistant patient, 50% T790M comprising being encoded by extron 20 is mutated, and other mutation are (such as D761Y, L747S, T845A) it only accounts for less than 5%；In addition drug resistance caused by being expanded there are also 20% comprising MET oncogene, wherein There is also T790M mutation for half.Illustrate that T790M mutation is the main reason for EGFR TKI generates drug resistance.T790M is mutated Threonine on the position EGFR790 causes drug resistant mechanism also to imperfectly understand replaced methionine.Possible mechanism For methionine is bigger than the occupy-place of threonine space, forms steric hindrance, changes the compatibility of EGFR kinases area ATP, cause EGFR-TKI micromolecular drug cannot effectively block EGFR activation signals, act on to lose tumor cytotoxicity, generate Drug resistance.
So far, it is listed still without the EGFR TKI drug for T790M mutation.WO2012061299A1 (publication date 2012.05.10 the drug CO-1686 in II phase of clinical trial developed by Avila Therapeutics company) is disclosed, For T790M be mutated, treatment occur the drug resistant NSCLC of EGFR TKI, and the property of can choose inhibit mutant egf R, have compared with High safety.This technology has clinically obtained certain verifying.CO-1686 specific structure is as follows:
Therefore, the EGFR TKI for T790M mutation for developing different structure, makes it have higher selective, stronger Pharmacological activity, higher safety or better physicochemical property, have very important significance for treatment NSCLC, and city Field is huge.
3, summary of the invention
The technical problem to be solved in the present invention is to provide a kind of pyrimidine heterocyclic derivative species tyrosine kinase inhibitors, are used for The drug of drug resistance disease caused by the Cancerous disease and EGFR T790M that preparation prevention and/or treatment EGFR mutation cause are mutated In application.
Technical scheme is as follows:
1. following formula of scheme (I) compound represented, its pharmaceutically acceptable salt, its ester and their alloisomerism Body,
Wherein,
Y is selected from C or N；
W, Q is separately selected from C (R7R7′)、NR8', O, S, S (O) or S (O)2；
M is selected from the integer of 0-5；
L be selected from be not present, O, NR8', S, S (O) or S (O)2；
R3Selected from hydrogen atom, halogen atom, cyano, nitro, hydroxyl, carboxyl, amino, C1-6Alkyl, C1-6Alkyl amino, two C1-6Alkyl amino, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C1-6Alkyl sulfonyl amino, C1-6Alkyl sulfonyl amino amino, C1-6Alkyl amido, 3-14 member cyclic group Group, 3-14 cyclic group-C1-6Alkyl, 3-14 cyclic group-O-, 3-14 cyclic group-NH- or 3-14 member cyclic group Group-S-；
R4Selected from hydrogen atom, the C that is optionally substituted with a substituent1-6Alkyl, 3-10 circle heterocyclic ring base, 6-8 member aryl or 5-8 member Heteroaryl, the substituent group are selected from halogen atom, hydroxyl, amino, nitro, C1-6Alkyl, C1-6Alkyl-carbonyl, C1-6Alkyl acyl ammonia Base, C1-6Alkyl sulphonyl, C1-6Alkyl sulfonyl amino or 3-14 cyclic group；
R1、R2、R5、R6、R7、R7′、R8、R8' separately it is selected from hydrogen atom, halogen atom, cyano, nitro, hydroxyl, carboxylic Base, amino, C1-6Alkyl, C1-6Alkyl amino, C2-6Alkenyl, C2-6Alkynyl, two C1-6Alkyl amino, halogenated C1-6Alkyl, C1-6Alcoxyl Base, halogenated C1-6Alkoxy, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C1-6Alkyl sulfonyl amino, C1-6Alkyl amido, 3-14 cyclic group or 3-14 cyclic group-C1-6Alkyl.
Compound described in 2. above scheme 1 of scheme, its pharmaceutically acceptable salt, its ester and their solid are different Structure body, wherein
Y is selected from C or N；
X, V is separately selected from C, N or O；
W, Q is separately selected from C (R7R7′)、NR8', O or S；
M is selected from the integer of 0-4；
L be selected from be not present, O or NR8′；
R3Selected from hydrogen atom, halogen atom, hydroxyl, amino, C1-6Alkyl, C1-6Alkyl amino, halogenated C1-6Alkyl, C1-6Alkane Oxygroup, halogenated C1-6Alkoxy, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C1-6Alkyl sulfonyl amino, C1-6Alkyl amido, 3-10 cyclic group, 3-10 cyclic group-C1-6Alkyl, 3-10 cyclic group-O-, 3-10 member Cyclic group-NH- or 3-10 cyclic group-S-；
R4Selected from hydrogen atom, the C that is optionally substituted with a substituent1-6Alkyl, 3-8 circle heterocyclic ring base or 5-8 unit's heteroaryl, it is described Substituent group is selected from halogen atom, hydroxyl, amino, C1-6Alkyl, C1-6Alkyl-carbonyl, C1-6Alkyl amido, C1-6Alkyl sulphonyl, C1-6Alkyl sulfonyl amino or 3-10 circle heterocyclic ring base；
R1、R2、R5、R6、R7、R7′、R8、R8' separately it is selected from hydrogen atom, halogen atom, hydroxyl, amino, C1-6Alkane Base, C1-6Alkyl amino, two C1-6Alkyl amino, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C1-6Alkyl sulfonyl amino, C1-6Alkyl amido, 3-8 circle heterocyclic ring base or 3-8 Circle heterocyclic ring base-C1-6Alkyl.
Compound described in 3. above scheme 2 of scheme, its pharmaceutically acceptable salt, its ester and their solid are different Structure body, wherein
Y is selected from C or N；
W, Q is separately selected from NH or O；
M is selected from 2 or 3；
L is selected from and is not present；
R3Selected from hydrogen atom, halogen atom, hydroxyl, amino, C1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkoxy, halogenated C1-4 Alkoxy, C1-4Alkyl sulphonyl, C1-4Alkyl sulfonyl amino, C1-4Alkyl amido, 5-6 circle heterocyclic ring base, 5-6 circle heterocyclic ring base- C1-4Alkyl or 5-6 circle heterocyclic ring base-O-；
R4Selected from hydrogen atom, the C that is optionally substituted with a substituent1-4Alkyl or 5-6 circle heterocyclic ring base, the substituent group are selected from halogen Plain atom, hydroxyl, amino, C1-4Alkyl, C1-4Alkyl-carbonyl, C1-4Alkyl sulphonyl or C1-4Alkyl sulfonyl amino；
R1、R2、R5、R6Separately it is selected from hydrogen atom, halogen atom, C1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkoxy Or halogenated C1-4Alkoxy；
R7、R7' it is selected from hydrogen atom, methyl or ethyl；
R8Selected from hydrogen atom, methyl or ethyl.
Compound described in 4. above scheme 3 of scheme, its pharmaceutically acceptable salt, its ester and their solid are different Structure body, wherein
R3Selected from hydrogen atom, chlorine atom, hydroxyl, amino, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, methyl sulphur Acyl group, sulfonyl propyl base or isopropelsulfonyl；
R4Selected from hydrogen atom, the pyrrolidinyl, tetrahydrofuran base, THP trtrahydropyranyl, the tetrahydro pyrrole that are optionally substituted with a substituent Pyridine ketone group, dihydropyridine ketone group, piperidone base, piperidyl, piperazinyl or morpholinyl, it is former that the substituent group is selected from chlorine atom, fluorine Son, methyl, ethyl, acetyl group, mesyl, the third sulfonyl or methanesulfonamido；
R1、R2、R5、R6Separately it is selected from hydrogen atom, chlorine atom, fluorine atom, methyl, trifluoromethyl, methoxyl group or three Fluorine methoxyl group；
R7、R7' it is selected from hydrogen atom, methyl or ethyl；
R8Selected from hydrogen atom, methyl or ethyl.
Compound described in 5. above scheme 2 of scheme, its pharmaceutically acceptable salt, its ester and their solid are different Structure body, wherein
Y is selected from C or N；
W, Q is separately selected from NH or O；
M is selected from 2 or 3；
L is selected from O or NH；
R3Selected from hydrogen atom, halogen atom, C1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkoxy, C1-4 Alkyl amido, C1-4Alkyl sulphonyl or 5-6 circle heterocyclic ring base-O-；
R4Selected from the C being optionally substituted with a substituent1-4Alkyl or 5-6 circle heterocyclic ring base, the substituent group be selected from halogen atom, C1-4Alkyl-carbonyl, C1-4Alkyl amido, C1-4Alkyl sulphonyl, C1-4Alkyl sulfonyl amino or 5-6 circle heterocyclic ring base；
R1、R2、R5、R6Separately it is selected from hydrogen atom, halogen atom, C1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkoxy Or halogenated C1-4Alkoxy；
R7、R7' it is selected from hydrogen atom, methyl or ethyl；
R8Selected from hydrogen atom, methyl or ethyl.
Compound described in 6. above scheme 5 of scheme, its pharmaceutically acceptable salt, its ester and their solid are different Structure body, wherein
R3Selected from hydrogen atom, fluorine atom, methyl, ethyl, trifluoromethyl, methoxyl group, ethyoxyl, trifluoromethoxy, methylsulphur Acyl group or tetrahydrofuran base-O-；
R4Selected from methyl, ethyl, propyl, isopropyl, butyl, pyrrolidinyl, the tetrahydrofuran being optionally substituted with a substituent Base, tetrahydro-thienyl, tetrahydropyridine ketone group, piperidone base, piperidyl, piperazinyl or morpholinyl, it is former that the substituent group is selected from chlorine Son, fluorine atom, acetyl group, acetylamino, mesyl, the third sulfonyl, methanesulfonamido, tetrahydrofuran base, pyrrolidinyl, piperazine Piperidinyl or piperazinyl；
R1、R2、R5、R6Separately it is selected from hydrogen atom, chlorine atom, fluorine atom, methyl, ethyl, trifluoromethyl, methoxy Base or trifluoromethoxy；
R7、R7' it is selected from hydrogen atom, methyl or ethyl；
R8Selected from hydrogen atom, methyl or ethyl.
The present invention also provides contain the logical formula (I) compound, its pharmaceutically acceptable salt, its ester or its alloisomerism The pharmaceutical composition of body.
The present invention also provides contain the logical formula (I) compound, its pharmaceutically acceptable salt, its ester or its alloisomerism The pharmaceutical preparation of body and pharmaceutical carrier and/or diluent.
The present invention also provides the logical formula (I) compound, its pharmaceutically acceptable salt, its ester or its stereoisomer with And contain the pharmaceutical composition of the logical formula (I) compound, its pharmaceutically acceptable salt or its stereoisomer as treatment The drug of drug resistance disease caused by the Cancerous disease and EGFR T790M that EGFR mutation causes are mutated.
The present invention also provides the logical formula (I) compound, its pharmaceutically acceptable salt, its ester or its stereoisomer with And the pharmaceutical composition containing the logical formula (I) compound, its pharmaceutically acceptable salt or its stereoisomer is controlled in preparation Treat the application in terms of the drug of drug resistance disease caused by the Cancerous disease and EGFR T790M mutation that EGFR mutation causes.
Drug resistance disease caused by the Cancerous disease and EGFRT790M caused the present invention also provides treatment EGFR mutation is mutated Method, including give a effective amount of logical formula (I) compound of object in need, its pharmaceutically acceptable salt, its ester Or its stereoisomer or contain the logical formula (I) compound, its pharmaceutically acceptable salt, its ester or its stereoisomer Pharmaceutical composition the step of.
Compound is selected from:
It is of the present invention it is " halogenated " refer to replaced by " halogen atom ", " halogen atom " refers to that fluorine atom, chlorine atom, bromine are former Son, iodine atom etc..
" C of the present invention1-6Alkyl " indicates the alkyl containing 1-6 carbon atom of linear chain or branched chain, including such as " C1-4 Alkyl ", " C1-3Alkyl " etc., specific example include but is not limited to: methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Sec-butyl, tert-butyl, n-pentyl, isopentyl, 2- methyl butyl, neopentyl, 1- ethyl propyl, n-hexyl, isohesyl, 3- methyl Amyl, 2- methyl amyl, 1- methyl amyl, 3,3- dimethylbutyl, 2,2- dimethylbutyl, 1,1- dimethylbutyl, 1,2- Dimethylbutyl, 1,3- dimethylbutyl, 2,3- dimethylbutyl, 2- ethyl-butyl, 1,2- dimethyl propyl etc..Institute of the present invention " the C stated1-4Alkyl " refers to the specific example containing 1-4 carbon atom in examples detailed above.
" halogenated C of the present invention1-6Alkyl " refers to one or more " halogen atom " substitution " C1-6One on alkyl " or Group derived from multiple hydrogen atoms, " halogen atom " and " C1-6Alkyl " is as defined hereinabove." halogen of the present invention For C1-4Alkyl " refers to the specific example containing 1-4 carbon atom in examples detailed above.
" C of the present invention2-6Alkenyl " refers to that the carbon atom number containing at least one double bond is the linear chain or branched chain of 2-6 Or cricoid alkenyl, including such as " C2-4Alkenyl " etc..The example includes but is not limited to: vinyl, 1- acrylic, 2- acrylic, 1- cyclobutenyl, 2- cyclobutenyl, 1,3- butadiene, 1- pentenyl, 2- pentenyl, 3- pentenyl, 1,3- pentadiene, 1,4- penta 2 Alkene, 1- hexenyl, 2- hexenyl, 3- hexenyl, 1,4- hexadiene, cyclopentenyl, 1,3- cyclopentadienyl group, cyclohexenyl group, 1, 4- cyclohexadienyl etc..
" C of the present invention2-6Alkynyl " refers to that the carbon atom number containing three keys is the alkynyl of the linear chain or branched chain of 2-6, packet Include such as " C2-4Alkynyl " etc..The example includes but is not limited to: acetenyl, propinyl, 2- butynyl, valerylene base, 3- pentyne Base, 4- methyl-valerylene base, 2- hexin base, 3- hexin base, 5- methyl -2- hexin base etc..
" C of the present invention1-6Alkoxy, C1-6Alkyl amino, two C1-6Alkyl amino, C1-6Alkyl-carbonyl, C1-6Alkyl Carbonyl oxygroup, C1-6Alkyl sulphonyl, C1-6Alkyl sulfonyl amino, C1-6Alkyl sulfonyl amino amino, C1-6Alkyl amido " refers to With C1-6Alkyl-O-, C1-6Alkyl-NH-, (C1-6Alkyl)2N-、C1-6Alkyl-C (O)-, C1-6Alkyl-C (O)-O-, C1-6Alkyl- SO2-、C1-6Alkyl-SO2-NH-、C1-6Alkyl-NH-SO2-NH-、C1-6The group that alkyl-C (O)-NH- mode connects, wherein “C1-6Alkyl " is as defined hereinabove." C of the present invention1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, C1-4Alkane Base carbonyl, C1-4Alkyl carbonyl epoxide, C1-4Alkyl sulphonyl, C1-4Alkyl sulfonyl amino, C1-4Alkyl sulfonyl amino amino, C1-4 Alkyl amido " refers to the specific example containing 1-4 carbon atom in examples detailed above.
" halogenated C of the present invention1-6Alkoxy " refers to one or more " halogen atom " substitution " C1-6One on alkoxy " Group derived from a or multiple hydrogen atoms, " halogen atom " and " C1-6Alkoxy " is as defined hereinabove.It is of the present invention " halogenated C1-4Alkoxy " refers to the specific example containing 1-4 carbon atom in examples detailed above.
" 3-14 cyclic group " of the present invention refers to the cyclic group containing 3-14 annular atom, including 3-14 member Heterocycle, 3-14 member naphthenic base, 3-14 member aryl, 3-14 unit's heteroaryl, 3-14 member condensed ring radical, 3-14 member bridged ring base, 3-14 member Loop coil base, 3-14 member condensed hetero ring base, 3-14 member bridge heterocycle, 3-14 member spiro heterocyclic radical, 6-8 member aryl, the thick aryl of 6-14 member, 3- 8 yuan of naphthenic base, 3-10 circle heterocyclic ring base, 3-8 circle heterocyclic ring base, 5-8 unit's heteroaryl, the thick heteroaryl of 5-14 member." 3- of the present invention 10 cyclic groups " refer to the specific example containing 3-10 annular atom in " 3-14 cyclic group ".
6-8 member aryl refers to the monocyclic aryl containing 6-8 carbon atom, and the example includes but is not limited to: phenyl, ring Xin Si Alkenyl etc..
The thick aryl of 6-14 member refers to containing 6-14 ring carbon atom, by two or more cyclic structures shares two each other A adjacent carbon atom is formed by the unsaturated condensed ring group with armaticity, and specific example includes but are not limited to: naphthalene, Anthracene, phenanthrene etc.." the 6-10 member aryl " refers to the cyclic structure that annular atom number is 6-10 in examples detailed above.
3-8 member naphthenic base refers to that the paraffin section containing 3-8 carbon atom removes cyclic alkyl derived from a hydrogen atom, Including such as " 3-6 member naphthenic base ", " 4-6 member naphthenic base " etc..The example includes but is not limited to: cyclopropyl alkyl, cyclobutane base, ring Pentyl, cyclohexyl, cycloheptyl alkyl, cyclooctane base etc..
3-14 member condensed ring radical refers to that sharing two adjacent atoms each other by two or more cyclic structures is formed Contain 3-14 carbon atom or/and heteroatomic cyclic structure, including such as " 4-11 member cycloalkyl ", " 6-11 member condensed ring Alkyl ", " 5-10 member cycloalkyl ", " 7-10 member cycloalkyl ", " 3-12 member cycloalkyl ", " 9-10 member cycloalkyl " etc.. The example includes but is not limited to: Deng.
3-14 member loop coil base refers to shares one by two or more cyclic structures containing 3-14 carbon atom each other Carbon atom connects the spirane structure to be formed, at the same including carbon atom can by oxo, including such as " 4-11 member loop coil base ", " 6-11 member loop coil base ", " 5-10 member loop coil base ", " 7-10 member loop coil base ", " 7-9 member loop coil base ", " 7-8 member loop coil base ", " 9- 10 yuan of loop coil bases " etc..Specific example includes but are not limited to: Deng.
3-14 member bridged ring base refers to shares two by two or more cyclic structures containing 3-14 carbon atom each other Non-adjacent carbon atom connects the caged scaffold to be formed, while can be by oxo including carbon atom, including such as " 5-11 member bridge Ring group ", " 6-11 member bridged ring base ", " 5-10 member bridged ring base ", " 7-10 member bridged ring base ", " 7-9 member bridged ring base ", " 7-8 member bridged ring Base ", " 9-10 member bridged ring base " etc..Specific example includes but are not limited to: Deng.
3-10 circle heterocyclic ring base refers to the cyclic group containing 3-8 annular atom (wherein at least containing a hetero atom), together When include that carbon atom, nitrogen-atoms and sulphur atom can be by oxos, including such as " 3-8 circle heterocyclic ring base ", " 3-7 circle heterocyclic ring base ", " 3- 6 circle heterocyclic ring bases ", " 4-7 circle heterocyclic ring base ", " 4-6 circle heterocyclic ring base ", " 5-7 circle heterocyclic ring base ", " 5-6 circle heterocyclic ring base ", " 5-6 member is nitrogenous Heterocycle ", " 6-8 circle heterocyclic ring base " etc..Specific example includes but are not limited to: aziridine base, 2H- aziridine base, Diazacyclo propyl, 3H- diazacyclo acrylic, azetidinyl, 1,4- dioxane base, 1,3- dioxane Hexyl, 1,3- dioxolane base, 1,4- Dioxin base, tetrahydrofuran base, pyrrolin base, pyrrolidines Base, imidazolidinyl, 4,5- glyoxalidine base, pyrazolidinyl, 4,5- pyrazoline base, 2,5- dihydrothiophene, tetrahydro-thienyl, 4,5- dihydro-thiazolyl, thiazolidinyl, piperidyl, tetrahydro pyridyl, piperidone base, tetrahydropyridine ketone group, dihydropyridine ketone group, Piperazinyl, morpholinyl base, 4,5- dihydro-oxazole base, 4,5- dihydro-isoxazole base, 2,3- dihydro-isoxazole base, oxazolidinyl, 2H- 1,2- oxazines base, 6H-1,3- oxazines base, 4H-1,3- thiazinyl, 6H-1,3- thiazinyl, 2H- pyranose, 2H- pyran-2-one Base, 3,4- dihydro -2H- pyranose etc., preferably " 5-6 circle heterocyclic ring base ".
3-14 member condensed hetero ring base refers to containing 3-14 annular atom (wherein at least containing a hetero atom) by two or two A above cyclic structure shares two adjacent atoms each other and connects the condensed cyclic structure to be formed, while including carbon atom, nitrogen Atom and sulphur atom can by oxo, including such as " 4-12 member condensed hetero ring base ", " 6-11 member condensed hetero ring base ", " 5-10 member is thick miscellaneous Ring group ", " 7-10 member condensed hetero ring base ", " 9-10 member condensed hetero ring base ", " the nitrogenous condensed hetero ring base of 3-10 member ", " 9-10 member is nitrogenous thick miscellaneous Ring group " etc..Specific example includes but are not limited to: imidazolidine simultaneously [4,5-c] pyridyl group, 3,4- dihydroquinazoline base, 1,2- Dihydro-quinoxaline base, benzo [d] [1,3] dioxa cyclopentenyl, 1,3- dihydroisobenzofuran base, 2H- chromogen alkenyl, 2H- Chromogen alkene -2- ketone group, 4H- chromene base, 4H- chromene -4- ketone group, Chromanyl, 4H-1,3- benzoxazinyl-, 4,6- dihydro -1H- Furans simultaneously [3,4-d] imidazole radicals, 3a, 4,6,6a- tetrahydro -1H- furans simultaneously [3,4-d] imidazole radicals, 4,6- dihydro -1H- thieno [3,4-d] imidazole radicals, 4,6- dihydro -1H- pyrrolo- [3,4-d] imidazole radicals, benzimidazole alkyl, octahydro-benzo [d] imidazoles Base, decahydroquinolyl, hexahydro Thienoimidazole, hexahydro furyl and imidazoles, 4,5,6,7- tetrahydro -1H- benzo [d] imidazole radicals, eight Hydrogen cyclopenta [c] pyrrole radicals, indolinyl, dihydro-iso indolyl, benzoxazoles alkyl, benzothiazole alkyl, 1,2,3, 4- tetrahydro isoquinolyl, 1,2,3,4- tetrahydric quinoline group, 4H-1,3- benzoxazine etc..
3-14 member spiro heterocyclic radical refers to containing 3-14 annular atom (wherein at least containing a hetero atom) by two or two A above cyclic structure shares an annular atom each other and connects the spirane structure to be formed, while including carbon atom, nitrogen-atoms Can be by oxo with sulphur atom, including such as " 5-11 member spiro heterocyclic radical ", " 6-11 member spiro heterocyclic radical ", " 5-10 member spiroheterocyclic Base ", " 7-11 member spiro heterocyclic radical ", " 7-10 member spiro heterocyclic radical ", " 7-9 member spiro heterocyclic radical ", " 7-8 member spiro heterocyclic radical ", " 9-10 member Spiro heterocyclic radical " etc..Specific example includes but are not limited to: Deng.
3-14 member bridge heterocycle refers to containing 3-14 annular atom (wherein at least containing a hetero atom) by two or two A above cyclic structure shares two non-adjacent annular atoms each other and connects the caged scaffold to be formed, while including carbon original Son, nitrogen-atoms and sulphur atom can be by oxos, including such as " 5-10 member bridge heterocycle ", " 6-11 member bridge heterocycle ", " 6-9 member Bridge heterocycle ", " 6-10 member bridge heterocycle ", " 7-10 member bridge heterocycle ", " 7-9 member bridge heterocycle ", " 7-8 member bridge heterocycle ", " 8 yuan of bridge heterocycles ", " 9-10 member bridge heterocycle " etc..Specific example includes but are not limited to: Deng.
5-8 unit's heteroaryl, which refers to, has armaticity ring containing 5-8 annular atom (wherein at least containing a hetero atom) Shape group, at the same including carbon atom, nitrogen-atoms and sulphur atom can by oxo, including such as " 5-7 unit's heteroaryl ", " 5-6 member is miscellaneous Aryl " etc..Specific example include but are not limited to furyl, thienyl, pyrrole radicals, thiazolyl, isothiazolyl, thiadiazolyl group, Oxazolyl, isoxazolyl, oxadiazoles base, imidazole radicals, pyrazolyl, 1,2,3- triazolyl, 1,2,4- triazolyl, 1,2,3- oxadiazoles Base, 1,2,4- oxadiazoles base, 1,2,5- oxadiazoles base, 1,3,4- oxadiazoles base, pyridyl group, 2- pyridone, 4- pyridone, pyrimidine Base, 1,4- Dioxin base, 2H-1,2- oxazines base, 4H-1,2- oxazines base, 6H-1,2- oxazines base, 4H-1,3- oxazines Base, 6H-1,3- oxazines base, 4H-1,4- oxazines base, pyridazinyl, pyrazinyl, 1,2,3- triazine radical, cyanuro 1,3,5,1,2,4, 5- tetrazine base, azepine cycloheptatriene base, 1,3- diaza cycloheptatriene base, azepine cyclooctatetraenyl etc., preferably " 5~6 yuan miscellaneous Aryl ".
The thick heteroaryl of 5-14 member refers to containing 5-14 annular atom (wherein at least containing a hetero atom) by two or two A above cyclic structure shares two adjacent atoms each other and connects the unsaturated condensed ring knot with armaticity to be formed Structure, at the same including carbon atom, nitrogen-atoms and sulphur atom can by oxo, including such as " 5-10 member thick heteroaryl ", " 7-10 member is thick Heteroaryl ", " the thick heteroaryl of 9-10 member " etc..Specific example includes but is not limited to: benzofuranyl, benzisoxa furyl, benzo Thienyl, indyl, iso-indoles, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazole base, quinolyl, 2- quinolinone, 4- quinolinone, 1- isoquinolines, isoquinolyl, acridinyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxaline Base, phenol piperazine base, pteridine radicals, purine radicals, naphthyridines base, azophenlyene, phenthazine etc..
It is key in the absence of L of the present invention, phenyl is directly and substituent R4Connection.
" EGFR " of the present invention refers to EGF-R ELISA (epidermal growth factor Receptor), it is transmembrane protein that one kind belongs to receptor tyrosine kinase (ERBB) family, in the conversion and growth of tumour Play main function.The amino acid sequence of EGFR is known to the skilled in the art, and is found in various common datas Library, such as ncbi database.
Wild type EGFR of the present invention refers to the individual (individual of namely unartificial mutagenesis) obtained in the Nature That entrained is exactly the EGFR of wild type.
Mutant egf R of the present invention refers to and is directly or indirectly known as by wild type gene by what mutation generated Mutant egf R.
The T790M mutation of EGFR of the present invention refers to that the 790th amino acids residue of EGFR is mutated into M by T, i.e., Threonine on EGFR 790 is replaced methionine.
The present invention also provides the preparation methods of formula (I) compound, but are not limited only to following method:
Meaning representated by abbreviation is as follows in the present invention:
DCE is 1,2- dichloroethanes, and TEA is triethylamine, and THF is tetrahydrofuran, and DCM is methylene chloride, DMF N, N- bis- Methylformamide, DIPEA are n,N-diisopropylethylamine, and EA is ethyl acetate.
Reaction equation:
Wherein, Y, W, Q, m, L, R in above-mentioned reaction equation1、R2、R3、R4、R5、R6、R7、R7′、R8As mentioned before.
Reaction step:
1, the preparation of intermediate 1, intermediate 3 and intermediate 5
Intermediate 1, intermediate 3 and intermediate 5 are bought or are prepared respectively.
2, the preparation of intermediate 2
Raw material 1 is dissolved in organic solvent appropriate, lewis acid solution (preferably zinc chloride second appropriate is added under ice bath Ethereal solution), after stirring 1 hour, intermediate 1 is added.Suitable organic base (preferably TEA) is dissolved in organic solvent appropriate In, it is added dropwise in reaction solution, is warmed to room temperature reaction to terminating.Reaction solution concentration, crude product are separated through proper method (such as column chromatography) Obtain intermediate 2.The preferred DCE of the organic solvent and tert-butyl alcohol mixed solvent.
3, the preparation of intermediate 4
Intermediate 2 and intermediate 3 are dissolved in organic solvent appropriate (such as Isosorbide-5-Nitrae-dioxane), appropriate amount of acid is added (such as Hydrochloric acid), it is heated to after reaction, concentration, crude product is through proper method (such as column chromatography) isolated intermediate 4.
4, the preparation of intermediate 6
Intermediate 4, intermediate 5 and alkali appropriate (preferably DIPEA) are dissolved in organic solvent appropriate (such as DMF), added Heat is to water and appropriate organic solvent (such as DCM) after reaction, is added, and liquid separation, organic phase saturated common salt water washing is dry, Concentration, crude product is through proper method (such as column chromatography) isolated intermediate 6.
5, the preparation of intermediate 7
Intermediate 6 is dissolved in appropriate organic solvent (such as methanol), appropriate catalyst (such as palladium charcoal) is added, is passed through hydrogen, Room temperature reaction.Catalyst is filtered out after reaction, and filtrate is concentrated to get intermediate 7.
6, the preparation of intermediate 8
Intermediate 7 is dissolved in the in the mixed solvent of organic solvent appropriate (such as THF) and water, 3- chlorpromazine chloride, room is added Temperature reaction, obtains the solution of intermediate 8 after reaction, is directly used in without processing and reacts in next step.
7, the preparation of general formula (I) compound represented
Into the solution of intermediate 8, alkali appropriate (such as NaOH solution) is added, being heated to reaction terminates, it is cooled to room temperature, Water is added, is extracted with organic solvent appropriate (such as EA), merges organic phase, saturated common salt water washing is dry, concentration, crude product warp Isolated general formula (I) compound represented of proper method (such as column chromatography).
" pharmaceutically acceptable salt " of compound shown in formula (I) of the present invention refers to acidity present in formula (I) compound Functional group (such as-COOH ,-OH ,-SO3H etc.) with appropriate inorganic or organic cation (alkali) formed salt, including with alkali Salt, the ammonium salt that metal or alkaline-earth metal are formed, and the salt formed with nitrogenous organic base；And present in formula (I) compound Basic functionality (such as-NH2Deng) with appropriate inorganic or organic anion (acid) formed salt, including with inorganic acid, and Organic carboxyl acid.
" ester " that the present invention leads to compound shown in formula (I) indicates that the compound shown in formula (I) there are when carboxyl, can be sent out with alcohol Raw esterification and the ester formed, the compound shown in formula (I), can be with organic acid, inorganic acid, acylates etc. there are when hydroxyl The ester that esterification occurs and is formed.Under the conditions of ester is existing for the acid or alkali, can occur hydrolysis generate corresponding acid or Alcohol.
" stereoisomer " that the present invention leads to compound shown in formula (I) is divided into conformer and configurational isomer, and structure Type isomers is also divided into cis-trans-isomer and optical isomer." stereoisomer ", refer to when the compounds of this invention contain one or Multiple asymmetric centers, this kind of asymmetric center respectively will independently generate two optical isomers, and the scope of the present invention includes All possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.Of the present inventionization If closing object contains olefinic double bonds, unless stated otherwise, the present invention includes cis-isomer and transisomer.It is of the present invention Compound can exist with tautomeric forms, have the connection of different hydrogen by one or more double-bond shifts Point.For example, ketone and its Enol forms are ketone-enol tautomers.Each tautomer and its mixture are included in this In the compound of invention.
Further requirement of the present invention protection include formula (I) compound represented, its pharmaceutically acceptable salt, its ester and The pharmaceutical composition of their stereoisomer and one or more pharmaceutical carriers and/or diluent, can be made and pharmaceutically may be used Any dosage form received.The patient for needing this treatment is applied in a manner of oral, parenteral, rectum or transpulmonary administration etc..With When oral administration, conventional solid pharmaceutical preparation, such as tablet, capsule, pill, granule can be made into；It may be made as oral solution Body preparation, such as oral solution, oral suspensions, syrup.When oral preparation is made, can be added suitable filler, Adhesive, disintegrating agent, lubricant etc..When for parenteral administration, injection, including injection, sterile powder for injection can be made into End and concentrated solution for injection.When injection is made, the conventional method production in existing pharmaceutical field can be used, prepare injection When, additives can be added without, suitable additives can also be added according to the property of drug.When for rectally, it can be made into Suppository etc..When for transpulmonary administration, inhalant or spray etc. can be made into.
The present invention leads to compound, its pharmaceutically acceptable salt, its ester and their stereoisomer shown in formula (I), Can by oral administration, parenteral (intravenous, intramuscular, subcutaneous or rectum etc.), the administration modes such as transpulmonary, local are applied to lactation and move Object, such as people.The content of the compound of the present invention is the weight for being 0.01 to about 100% relative to single preparation in pharmaceutical preparation Amount.Dosage changes according to administration object, administration route, disease, illness etc., for example, the compound of the present invention (as activity at Point) can be with following dosage in diabetic (weight about 60kg): about 0.01-30mg is daily, preferably from about 0.1- 20mg is daily, and more preferably from about 1-20mg is daily.The dosage can be given once a day or be divided into and give several times.
Formula (I) compound or its pharmaceutically acceptable salt of the present invention, its ester or their stereoisomer can be independent Administration, or with other therapeutic agents drug combination, especially with the second therapeutic agent selected from antitumor agent and/or immunosuppressor Composite reagent, the second therapeutic agent are selected from: antimetabolite is included but are not limited to such as capecitabine, gemcitabine；It is raw Long factor inhibitors are included but are not limited to such as pazopanib, Imatinib；Antibody includes but are not limited to for example conspicuous Sai Ting, bevacizumab etc.；Mitotic inhibitor includes but are not limited to such as taxol, vinorelbine, docetaxel, more It is soft to compare magnitude；Antitumor steroids is included but are not limited to such as Letrozole, tamoxifen, fulvestrant；Alkylating agents, It includes but are not limited to such as cyclophosphamide, Carmustine；Metal platinum class includes but are not limited to such as carboplatin, cis-platinum, Austria Husky benefit platinum etc.；Topoisomerase enzyme inhibitor is included but are not limited to such as Topotecan；Immunosupress class, including but not only It is limited to such as everolimus.Each ingredient to be combined can be administered simultaneously or successively sequentially separate medication, with same preparation shape Formula is administered in combination in the form of separated different preparations.
Formula (I) compound, its pharmaceutically acceptable salt, its ester or its stereoisomer of the present invention can be used for treating excessively Proliferative disease and chronic obstructive pulmonary disease, excessively proliferative disease include cancer and non-cancerous disease, and the cancer is selected from: brain tumor, Lung cancer, lung cancer in non-cellule type, dermoid cancer, bladder cancer, gastric cancer, oophoroma, peritoneal cancer, cancer of pancreas, breast cancer, head It is neck cancer, cervix cancer, carcinoma of endometrium, colorectal cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, non- Hodgkin lymphoma, central nerve neuroma (glioma, glioblastoma multiforme, glioma sarcomatosum), prostate Cancer or thyroid cancer；Non-cancerous disease is the hyperplasia of prostate of such as skin or prostate.
The present invention also provides pharmaceutical composition, it contain invention described above lead to formula (I) compound or its pharmaceutically Acceptable salt, its ester or their stereoisomer and one or more pharmaceutical carriers and/or diluent.The composition can With by by the logical formula (I) compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer and it is one or more often Pharmaceutical carrier and/or diluent mixing are advised to prepare.The composition can be made clinically or pharmaceutically acceptable any Dosage form is applied to the patient for needing this treatment in a manner of oral, parenteral, transpulmonary or local administration etc..
It is demonstrated experimentally that the compounds of this invention has excellent antitumor action, it is contemplated that excessively proliferative disease and chronic resistance Plug property tuberculosis has excellent therapeutic effect；And reduce the generation of drug resistance；In addition, the compounds of this invention preparation process letter Single, quality is stablized, and is easy to carry out large-scale industrial production.
Below by way of the beneficial effect of experiment the present invention is further explained compound, but this should not be interpreted as of the present inventionization Closing object only has following beneficial effect.
The external zymetology activity experiment of 1 the compounds of this invention of experimental example
Test sample: part of compounds of the present invention, chemical name and preparation method are shown in the preparation embodiment of each compound.
Comparison medicine: CO-1686 is prepared according to the method in WO2012061299A1 (publication date 2012.05.10).
Meaning representated by the abbreviation of following middle experiments is as follows:
EDTA: ethylenediamine tetra-acetic acid
DMSO: dimethyl sulfoxide
SD: standard deviation
Experimental method: using the method for Mobility Shift Assay in the case where Km ATP, in kinases EGFR and EGFR_T790M is upper to screen compound.
1 preparation of reagents
(1) 1 times of kinase buffer liquid (For EGFR and EGFR_d746-750and EGFR (d746-750/T790M))
50mM HEPES (pH 7.5), 0.0015%Brij-35,10mM MgCl2、10mM MnCl2、10mM MnCl2、 2mM DTT；
(2) 1 times of kinase buffer liquids (For EGFR T790M and EGFR_L858R and EGFR_T790M/L858R)
50mM HEPES (pH 7.5), 0.0015%Brij-35,5mM MgCl2、2mM DTT
(3) terminate liquid
100mM HEPES (pH 7.5), 0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA
(4) 2.5 times of polypeptide solutions
The peptide and ATP of FAM- label is added in 1 times of kinase buffer liquid
(5) 2.5 times of enzyme solutions
Enzyme is added in 1 times of kinase buffer liquid
2 compounds are prepared
Compound is configured to 50 times of mother liquors with DMSO, then takes 100 μ L mother liquors to be added in 96 new orifice plates, 1:4 times is used DMSO carries out gradient dilution, amounts to 10 gradients.Then each concentration takes 10 μ L to be placed in a 96 new orifice plates, and every hole adds 90 1 times of kinase buffer liquid of μ L mixes.
3 experimental methods
(1) compound solution prepared in above-mentioned 96 orifice plate is transferred in 384 orifice plates, 5 μ L, two multiple holes are added in every hole. That is the A1 of 96 orifice plates is added to the A1 and A2 of 384 orifice plates, and the A2 of 96 orifice plates is added to the A3 and A4 of 384 orifice plates, and so on；
(2) prepare 2.5 times of enzyme solutions, kinases is added to 1 times of kinase buffer liquid；
(3) prepare 2.5 times of polypeptide solutions, the peptide of FAM- label and ATP are added to 1 times of kinase buffer liquid r；
(4) 2.5 times of enzyme solutions are taken, preprepared is added to and fills in 384 orifice plates of 5 μ L compound solutions, every hole 10μL；
(5) it is incubated at room temperature 10min；
(6) 2.5 times of polypeptide solutions are taken, are added in 384 above-mentioned orifice plates, every 10 μ L of hole；
(7) 28 DEG C of incubation a period of times；
(8) 25 μ L terminate liquids are added and terminate reaction；
(9) Caliper is read.
4 data processings
5 inhibiting rates calculate
1) data that enzyme activity changes are copied out in Caliper program；
2) data that enzyme activity changes are changed into the inhibiting rate data of enzyme activity, formula is as follows:
Inhibiting rate (%)=(value that maximum value-measures)/(maximum value-minimum value) × 100." maximum value ": DMSO control； " minimum value ": blank control.
3) it outputs data in XLFit excel, then obtains IC50Value.Formula is as follows:
Y=Bottom+ (Top-Bottom)/(1+ (IC50/X)^HillSlope)
6 experimental results and conclusion:
IC of 1 the compounds of this invention of table to EGFR and EGFR T790M50Value
IC of 2 the compounds of this invention of table to EGFR and EGFR T790M50Value
IC of 3 the compounds of this invention of table to EGFR and EGFR T790M50Value
IC of 4 the compounds of this invention of table to EGFR and EGFR T790M50Value
Experiment conclusion:
The compounds of this invention is better than comparison medicine to the selective depression of EGFR_T790M.
The cell in vitro activity experiment of 2 the compounds of this invention of experimental example
Test sample: part of compounds of the present invention, chemical name and preparation method are shown in the preparation embodiment of each compound.
Comparison medicine: CO-1686 is prepared according to the method in WO2012061299A1 (publication date 2012.05.10).
Meaning representated by the abbreviation of following middle experiments is as follows:
PBS: phosphate buffer
DMSO: dimethyl sulfoxide
1. cell culture
The preparation of 1.1 cell suspensions
1. removing the culture medium in culture bottle；
2. PBS rinse cell is added；
3. plus pancreatin digestion is collected by centrifugation；
4. being resuspended with the culture medium containing 10% fetal calf serum, counts and be adjusted to 2 × 104/ mL (H1975) or 3 × 104/mL (A431) concentration (cell viability has to be larger than 90%)；
5. 96 orifice plates, every 100 μ L of hole, i.e. 2000/ hole of H1975 cell is added in cell suspension；3000/ hole of A431 cell；
6. 37 DEG C, 5%CO2Overnight incubation in incubator.
2. the preparation of compound
Compound is made into the mother liquor of 10mM (XZP-3613) or 5mM (XZP-3778) with DMSO.Before use, using first Mother liquor is diluted to 4mM by DMSO, then carries out gradient dilution with DMSO for 1:4 times, amounts to 10 gradients.Finally with corresponding culture medium Do 100 times of dilution (compound that i.e. 2 μ L have diluted adds 198 μ L culture mediums).
3. control group is arranged
Vehicle controls: 0.25%DMSO；
Blank control: the not culture medium of cell.
4. compound handles cell (24 hours plus compound after plating cells)
50 growth mediums of the μ L containing 10%FBS are mended in the every hole I, and then plus the compound that has diluted of 50 μ L is into hole.Detection Final compound concentration are as follows:
Test compound concentration: 10000,2500,625,156.25,39.06,9.76,2.44,0.61,0.15,0.04 [nM]
II places cell plates incubator 72 hours, the detection of CTG method
Board under test is placed equilibrium at room temperature 30 minutes, 80 μ L culture mediums are discarded.Add 60 μ L CTG reagent (CelltiterGlo Kit), it places fast oscillator oscillation 2min and puts 10min in room temperature again.With Envision instrument readings.
5. data are analyzed
IC50It calculates: inhibiting rate (%)=(Vehicle controls hole readings-test compound well readings)/(read in Vehicle controls hole Value-blank value) × 100, it is carried out curve fitting using 5 software of GraphPad Prism, obtains IC50Value.
Vehicle controls hole readings: the value that compound only adds 0.25%DMSO, blank value: blank value is not added.
%inhibition (inhibiting rate)=100 × (HC- tests compound well readings)/(HC-LC)
6. experimental result
5 the compounds of this invention of table is to H1975, the IC of A431 cell50Value
6 the compounds of this invention of table is to H1975, the IC of A431 cell50Value
Experiment conclusion:
The characteristics of the compounds of this invention is the cell to cell (H1975), Wild type EGFR with EGFR mutant enzyme (A431) good inhibiting effect is all had, inhibitory effect is substantially better than comparison medicine CO-1686.
4, specific embodiment
The specific embodiment of form by the following examples makees further specifically above content of the invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.It is all to be based on above content of the present invention The technology realized all belongs to the scope of the present invention.
The preparation of 1 tert-butyl of preparation example (the bromo- 3- nitrobenzophenone of 4-) carbamate
By 3- nitro -4- bromaniline (5.0g, 23mmol), di-tert-butyl dicarbonate (7.6g, 35mmol), triethylamine (2.32g, 23mmol) is dissolved in tetrahydrofuran (50mL), and 60 DEG C of heating are reacted 2 hours.It is spin-dried for solvent, is added water (50mL), is used Ethyl acetate extraction, liquid separation, organic phase is dry, and concentration, pillar layer separation (petroleum ether: ethyl acetate=10:1) obtains product (5.8g, yield 79%).
2 tert-butyl 4- of preparation example ((2- (dimethylamino) ethyl) (methyl) amino) -3- nitrobenzophenone) carbamate Preparation
By tert-butyl (the bromo- 3- nitrobenzophenone of 4-) carbamate (5.8g, 18.3mmol), N1,N1,N2Trimethyl second Base -1,2- diamines (3.73g, 36.6mmol), potassium carbonate (5.05g, 36.6mmol) are added to DMAC N,N' dimethyl acetamide In (75mL), 100 DEG C oil bath 8 hours.It is added ethyl acetate (500mL), is washed with saturated salt solution (500mL), liquid separation is organic Mutually dry, concentration, column chromatography (methylene chloride: methanol=10:1) obtains product (1.87g, yield 30%).
3 tert-butyl of preparation example (3- amino 4- ((2- (dimethylamino) ethyl) (methyl) amino)-phenyl) carbamic acid The preparation of ester
By tert-butyl 4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- nitrobenzophenone) carbamate (1.87g, 5.5mmol) is dissolved in methanol (25mL), is added palladium-carbon catalyst (187mg), and replacing hydrogen is stirred at room temperature 2 hours. It filters, is washed with a small amount of methanol, organic phase concentration, pillar layer separation (methylene chloride: methanol=10:1) obtains product, and (1.4g is produced Rate 82%).
4 tert-butyl of preparation example (3- acrylamido -4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino The preparation of formic acid esters
By tert-butyl (3- amino 4- ((2- (dimethylamino) ethyl) (methyl) amino)-phenyl) carbamate (1.4g, 4.54mmol) is dissolved in methylene chloride (30mL), is added triethylamine (459mg, 4.54mmol), and propylene is added under ice bath Acyl chlorides (493mg, 5.45mmol) is warmed to room temperature stirring 30 minutes, is added saturated solution of sodium bicarbonate (50mL), uses methylene chloride Extraction, organic phase is dry with anhydrous sodium sulfate, concentration, pillar layer separation (methylene chloride: methanol=10:1) product (1.19g, Yield 72%).
5 N- of preparation example (5- amino -2- (2- (dimethylamino) ethyl) (methyl) amino) phenyl) acrylamide system It is standby
By tert-butyl (3- acrylamido -4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) carbamate (1.19g, 3.28mmol) is dissolved in the mixed solution of methylene chloride and trifluoroacetic acid (25mL, V/V=1:1), is stirred at room temperature 30 Minute, it is spin-dried for solvent, is added saturated solution of sodium bicarbonate (10mL), is extracted with dichloromethane, organic phase is dry with anhydrous sodium sulfate Dry, concentration, pillar layer separation (methylene chloride: methanol=10:1) obtains product (803mg, yield 93%).
The preparation of the fluoro- 2- aminoanisole of 6 4- of preparation example
The fluoro- 2- methoxyl group -1- nitrobenzene (15.00g, 87.67mmol) of 4- is added in methanol (200mL), nitrogen is protected Shield is lower to be added palladium carbon (200mg), reacts 16 hours, filters under atmosphere of hydrogen, and filtrate concentration, obtaining title compound, (11.67g is produced Rate 94.3%).
The preparation of the fluoro- 2- methoxyl group -5- nitroaniline of 7 4- of preparation example
Under ice bath, the fluoro- 2- aminoanisole (6.5g, 46mmol) of 4- is dissolved in batches in the concentrated sulfuric acid (50mL), under ice bath After stirring 30 minutes, potassium nitrate (5.2g, 51mmol) is added portionwise, finishes, is warmed to room temperature, is stirred to react 12 hours.It has reacted Finish, reaction solution is poured into ice cube, ammonium hydroxide is added dropwise and is adjusted to pH to 8, ethyl acetate (200mL × 3) extraction, anhydrous sodium sulfate drying Afterwards, it is concentrated, through column chromatography (petroleum ether: ethyl acetate=3:1) purifying, obtains title compound (6.9g, yield 80%).
8 tert-butyl 4- of preparation example (3- methoxyl group -4- nitrobenzophenone) -3,6- dihydropyridine -1 (2H)-formic acid esters preparation
By the chloro- 2- methoxyl group -1- nitrobenzene (8.0g, 42.6mmol) of 4- and tert-butyl 4- (tetramethyl -1,3 4,4,5,5-, 2- dioxaborolanes -2- base) -5,6- dihydropyridine -1 (2H)-formic acid esters (13.2g, 42.6mmol) is dissolved in DMF Potassium carbonate (11.8g, 85.3mmol) and Pd (PPh are added into the system for (50mL) and water (10mL) in the mixed solvent3)4 (986mg, 0.85mmol) under nitrogen protection, is stirred to react 16 hours at 90 DEG C.End of reaction is added water (100mL), uses Ethyl acetate (100mL × 2) extraction, merges organic phase, and anhydrous sodium sulfate dries, filters, and filtrate concentration, residue is through silicagel column (petroleum ether: ethyl acetate=10:1) purifying is chromatographed, title compound (10.0g, yield 70.0%) is obtained.
The preparation of 9 4- of preparation example (3- methoxyl group -4- nitrobenzophenone) -1,2,3,6- tetrahydropyridine
By tert-butyl 4- (3- methoxyl group -4- nitrobenzophenone) -3,6- dihydropyridine -1 (2H- formic acid esters (1.08g, It 3.23mmol) is dissolved in the mixed solution of methylene chloride and trifluoroacetic acid (15mL, V/V=1:1), is stirred at room temperature 30 minutes, revolve Dry solvent is added saturated solution of sodium bicarbonate (10mL), is extracted with dichloromethane, and organic phase is dry with anhydrous sodium sulfate, concentration, It obtains product (728mg, yield 96%).
10 1- of preparation example (4- (3- methoxyl group -4- nitrobenzophenone) -3,6- dihydropyridine -1 (2H)-yl) ethyl -1- ketone Preparation
4- (3- methoxyl group -4- nitrobenzophenone) -1,2,3,6- tetrahydropyridine (6.8g, 29.0mmol) is dissolved in methylene chloride In (100mL), triethylamine (5.87g, 58.1mmol) is slowly added under ice bath, then be added chloroacetic chloride (4.56g, 58.1mmol), it stirs 1 hour at 0 DEG C, is stirred at room temperature 2 hours.End of reaction is washed with water (50mL × 2), is dried, filtered, Concentration, obtains title compound (7.7g, yield 96.0%).
The preparation of 11 1- of preparation example (4- (4- amino -3- methoxyphenyl) piperidin-1-yl) ethyl -1- ketone
By 1- (4- (3- methoxyl group -4- nitrobenzophenone) -3,6- dihydropyridine -1 (2H)-yl) ethyl -1- ketone (7.7g, It 27.9mmol) is dissolved in methanol (100mL), Pd/C (200mg) is added into the system under nitrogen protection, then system is in hydrogen Reaction 16 hours is stirred at room temperature under environment.End of reaction, filtering are concentrated filtrate, obtain title compound (6.5g, yield 94.0%).
The preparation of the chloro- N- of 12 4- of preparation example (2- methoxyphenyl) -5- (trifluoromethyl) pyrimidine -2- amine
At 0 DEG C, zinc chloride diethyl ether solution (22mL, 20mmol, 1M) is added dropwise to 2,4- chloro- 5- (trifluoromethyl) pyrimidine The tert-butyl alcohol of (2.0g, 9.22mmol) and 1 in the solution (80mL, 1:1) of 2- dichloroethanes, stirs 1 hour at 0 DEG C.Then will 2- aminoanisole (1.14g, 9.22mmol) and triethylamine (1.03g, 10.14mmol) are added sequentially in reaction system, room Temperature stirring 16 hours.Evaporated under reduced pressure solvent, solid obtain title compound (2.1g, yield 75.0%) with recrystallizing methanol.
13 N of preparation example4(the bromo- 3- nitrobenzophenone of 4-)-N2(2- methoxyphenyl) -5- (trifluoromethyl) pyrimidine -2,4- Diamines preparation
By the chloro- N- of 4- (2- methoxyphenyl) -5- (trifluoromethyl) pyrimidine -2- amine (2.2g, 7.24mmol) and the bromo- 3- of 4- Nitroaniline (2.36g, 10.87mmol) is added in dioxane (60mL), then instills concentrated hydrochloric acid (2mL).It then will reaction Liquid is heated to 100 DEG C and reacts 2 hours.Reaction solution is evaporated by end of reaction, residue with ethyl acetate washing, titledly dry It closes object (3.2g, yield 91.2%).
14 1- of preparation example (4- (4- ((4- chloro- 5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenyl) piperazine Pyridine -1- base) ethyl -1- ketone preparation
1- (4- (4- amino -3- methoxyphenyl) piperidin-1-yl) ethyl -1- ketone (560mg, 2.26mmol) is dissolved in two In chloromethanes (10mL), it is added triethylamine (228mg, 2.26mmol), is slowly added to the chloro- 5- trifluoromethyl pyrimidine of 2,4- bis- (588mg, 2.71m mol) is stirred at room temperature 2 hours, is added saturated solution of sodium bicarbonate (20mL), is extracted with dichloromethane, has Machine is mutually dry with anhydrous sodium sulfate, and concentration, reversed phase chromatography separation (water: acetonitrile=10:1-3:2) obtains product (212mg, yield 22%).
The system of 15 4- of preparation example (3- methoxyl group -4- nitrobenzophenone) -1- (methyl sulphonyl) -1,2,3,6- tetrahydropyridine It is standby
By 4- (3- methoxyl group -4- nitrobenzophenone) -1,2,3,6- tetrahydropyridine (2.3g, 9.8mmol) and triethylamine (2.47g, 24.5mmol) is added in methylene chloride (50mL), and methylsufonyl chloride (1.68g, 14.7mmol) is added dropwise under ice bath, Reaction 12 hours is warmed to room temperature after being added dropwise.Concentration, crude product are purified through silica gel column chromatography (petroleum ether: ethyl acetate=4:1) It obtains title compound (2.5g, yield 81.7%).
The preparation of 16 2- methoxyl group -4- of preparation example (1- (methyl sulphonyl) -1,2,3,6- tetrahydropyridine -4- base) aniline
By 4- (3- methoxyl group -4- nitrobenzophenone) -1- (methyl sulphonyl) -1,2,3,6- tetrahydropyridine (2.5g, It 8.0mmol) is dissolved into methanol (100mL), is added palladium charcoal (400mg), be stirred at room temperature 16 hours under hydrogen environment, filtered, filter Liquid is concentrated to give title compound (2.1g, yield 92.3%).
The chloro- N- of 17 4- of preparation example (2- methoxyl group -4- (1- (methyl sulphonyl) piperidin-4-yl) phenyl) -5- (fluoroform Base) pyrimidine -2- amine preparation
By 2- methoxyl group -4- (1- (methyl sulphonyl) -1,2,3,6- tetrahydropyridine -4- base) aniline (753mg, It 2.65mmol) is added to the in the mixed solvent of 1,2- dichloroethanes (20mL) and the tert-butyl alcohol (20mL), zinc chloride is added under ice bath 2,4- bis- chloro- 5- (trifluoromethyl) pyrimidine is added after stirring 1 hour in diethyl ether solution (1mol/L, 5.83mL, 5.83mmol) (575mg,2.65mmol).Triethylamine (293mg, 2.9mmol) is dissolved into 1,2- dichloroethanes (10mL) and the tert-butyl alcohol The in the mixed solvent of (10mL) is slowly added dropwise in above-mentioned solution, is warmed to room temperature naturally, stirs 16 hours.Reaction solution is directly dense Contracting, crude product obtain title compound (700mg, yield 56.8%) through silica gel column chromatography (petroleum ether: ethyl acetate=3:1).
The preparation of 18 3- methoxyl group -4- nitrophenol of preparation example
By sodium hydroxide solution (39mL, 117mmol, 3M) be added to the fluoro- 2- methoxyl group -1- nitrobenzene of 4- (10.0g, In thionyl chloride (100mL) solution 58.4mmol), then react 20 hours for 80 DEG C of oil bath.After completion of the reaction, concentrated hydrochloric acid is used PH=5 is adjusted, is then extracted with ethyl acetate (100mL × 3), organic phase is merged, is concentrated under reduced pressure, residue is through silica gel column chromatography (petroleum ether: ethyl acetate=10:1) purifying, obtains title compound (9.0g, yield 90.1%).
The preparation of the fluoro- 2- aminoanisole of 19 4- of preparation example
The fluoro- 2- methoxyl group -1- nitrobenzene (5.13g, 30mmol) of 4- is dissolved in methanol (50mL), palladium-carbon catalyst is added (513mg), replacing hydrogen are stirred at room temperature 30 minutes, filter, and organic phase is spin-dried for obtaining product (3.60g, yield 85%).
1 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((2- ((2- (isopropyl sulphonyl Base) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide (compound 1) preparation
(1) preparation of the chloro- N- of 4- (2- (isopropelsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidine -2- amine
By 2- (isopropelsulfonyl) aniline (1.99g, 10mmol), 2,4- bis- chloro- 5- (trifluoromethyl) pyrimidine (2.6g, It 12mmol) is added in tetrahydrofuran (30mL) with the trifluoroacetic acid of catalytic amount (80mg), 60 DEG C are heated 1.5 hours.It is spin-dried for molten Agent is added ethyl acetate (50mL), and saturated sodium bicarbonate (50mL) washing, organic phase is dry, concentration, pillar layer separation (petroleum ether: ethyl acetate=10:1-5:1) obtains product (188mg, yield 5%).
(2) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((2- ((2- (isopropelsulfonyl) benzene Base) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and acrylamide preparation
By the chloro- N- of 4- (2- (isopropelsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidine -2- amine (188mg, 0.495mmol), N- (5- amino-(2- ((dimethylamino) ethyl) (methyl) amino) phenyl) acrylamide (196mg, 0.75mmol), potassium carbonate (138mg, 1.0mmol), Pd2(dba)3(18mg) and X-Phos (36mg) are added to 1,4- dioxy six In ring (10mL), nitrogen protection, 100 DEG C are heated 5 hours.It is spin-dried for solvent, is added sodium chloride saturated solution (50mL), uses dichloromethane Alkane extraction, organic phase is dry with anhydrous sodium sulfate, and concentration, reversed phase chromatography separation (water: acetonitrile=10:1-1:1) obtains product (12mg, yield 4%).
Molecular formula: C28H34F3N7O3S molecular weight: 606LC-MS (m/z): 303 (M+H+)/2
1H-NMR(400MHz,CDCl3) δ: 9.80 (s, 1H), 9.35 (s, 1H), 8.49 (d, 1H, J=2.4Hz), 8.42 (d, 1H, J=8.0Hz), 8.35 (s, 1H), 7.82 (dd, 1H, J1=1.6Hz, J2=8.0Hz), 7.50-7.53 (m, 2H), 7.11-7.16(m,2H),6.94(s,1H),6.39-6.44(m,1H),5.90-6.20(m,1H),5.74-5.77(m,1H), 3.64-3.66 (m, 1H), 3.00-3.30 (m, 4H), 2.74 (s, 6H), 2.70 (s, 3H), 1.31 (d, 6H, J=8.8Hz)
2 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((2- ((2- methoxyphenyl) ammonia Base) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide (compound 2) preparation
(1)N4(the bromo- 3- nitrobenzophenone of 4-)-N2(2- methoxyphenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines system It is standby
By the chloro- N- of 4- (2- methoxyphenyl) -5- (trifluoromethyl) pyrimidine -2- amine (2.2g, 7.24mmol) and the bromo- 3- of 4- Nitroaniline (2.36g, 10.87mmol) is added in dioxane (60mL), then instills concentrated hydrochloric acid (2mL).It then will reaction Liquid is heated to 100 DEG C and reacts 2 hours.Reaction solution is evaporated by end of reaction, residue with ethyl acetate washing, titledly dry It closes object (3.2g, yield 91.2%).
(2)N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- nitrobenzophenone)-N2(2- methoxybenzene Base) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By N4(the bromo- 3- nitrobenzophenone of 4-)-N2(2- methoxyphenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (3.0g, 6.2mmol) and N1,N1,N2Trimethylethane -1,2- diamines (6.33g, 62.0mmol) is added in DMA (50mL), Then reaction solution 115 DEG C are heated to react 16 hours.End of reaction dilutes reaction solution with water (100mL), ethyl acetate (100mL) extraction, evaporated under reduced pressure ethyl acetate layer, crude product are purified by silica gel column chromatography (methylene chloride: methanol=20:1-3:1) It obtains title compound (2.5g, yield 7.98%).
(3)N1(2- (dimethylamino) ethyl)-N4(2- ((2- methoxyphenyl) amino) -5- (trifluoromethyl) is phonetic Pyridine -4- base)-N1Aminomethyl phenyl -1,2, the preparation of 4- triamine
By N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- nitrobenzophenone)-N2(2- methoxybenzene Base) -5- (trifluoromethyl) pyrimidine -2,4- diamines (0.4g, 0.79mmol) and Pd/C (100mg, 10%) be added to methanol In (30mL), then reaction 1 hour is stirred at room temperature in system under hydrogen environment.End of reaction, filtering, is concentrated to get title compound Object (300mg, yield 79.7%).
(4) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((2- ((2- methoxyphenyl) amino) - 5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and acrylamide preparation
Acryloyl chloride (114mg, 1.26mmol) room temperature is added dropwise to N1(2- (dimethylamino) ethyl)-N4-(2-((2- Methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1Aminomethyl phenyl -1,2,4- triamine (300mg, In tetrahydrofuran (5mL) solution 0.63mmol), 25 DEG C are stirred to react 1 hour.Reaction solution is concentrated end of reaction, adds Methylene chloride (20mL) simultaneously successively uses sodium bicarbonate solution, brine It, and organic phase is dried, filtered with anhydrous sodium sulfate, is filtered Liquid is evaporated, and residue separates to obtain title compound (98mg, yield 29.3%) through TLC (methylene chloride: methanol=20:1).
Molecular formula: C26H30F3N7O2Molecular weight: 529.6LC-MS (m/z): 530.1 (M+H+)
1H-NMR(400MHz,CDCl3) δ: 10.19 (s, 1H), 8.55 (s, 1H), 8.27 (s, 1H), 8.21 (d, J= 7.6Hz, 1H), 8.43 (dd, J=2.0Hz, J=8.4Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 6.89-6.94 (m, 2H), 6.82 (d, J=7.6Hz, 1H), 6.72 (s, 1H), 6.43 (s, 1H), 6.37-6.42 (m, 1H), 5.90 (s., 1H), 5.70 (d, J=5.2Hz, 2H), 2.94 (t, J=4.8Hz, 2H), 2.71-2.75 (m, 7H), 2.47 (s., 2H), 2.34 (s., 6H), 1.93 (s,3H).
3 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and acrylamide (compound 3) preparation
(1)N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyphenyl) -5- (trifluoromethyl) pyrimidine -2, The preparation of 4- diamines
By the fluoro- 2- methoxyl group -5- nitroaniline (149mg, 0.8mmol) of 4- and the chloro- N- of 4- (2- methoxyphenyl) -5- (trifluoromethyl) pyrimidine -2- amine (250mg, 0.8mmol) is dissolved in dioxane (10mL), is added dropwise concentrated hydrochloric acid (0.1mL), 100 DEG C reaction 4 hours, end of reaction is cooled to room temperature, solvent evaporated, be added saturation NaHCO3Solution tune pH to 8, water phase acetic acid Ethyl ester extracts (20mL × 2), and organic phase merges, and anhydrous sodium sulfate is dry, concentration, through column chromatography (methylene chloride: methanol=30: 1) it purifies, obtains title compound (240mg, yield 66%).
(2)N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2-(2- Methoxyphenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyphenyl) -5- (trifluoromethyl) pyrimidine -2, 4- diamines (200mg, 0.4mmol) and N1,N1,N2Trimethylethane -1,2- diamines (61mg, 0.6mmol) is dissolved in DMF (10mL) In, it is added dropwise DIEA (78mg, 0.6mmol), is heated to 85 DEG C and reacts 8 hours.It is cooled to room temperature, water (20mL) and acetic acid second is added Ester (50mL), liquid separation, water phase are extracted with ethyl acetate (150mL × 2), and organic phase merges, saturated common salt water washing, anhydrous slufuric acid Sodium is dry, and concentration, crude product is purified through column chromatography (methylene chloride: methanol=10:1), obtains title compound (160mg, yield 68%).
(3)N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2-2- methoxyphenyl) amino) -5- (three Methyl fluoride) pyrimidine-4-yl)-N1The preparation of methylbenzene -1,2,4- triamine
By N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2(2- first Phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (150mg, 0.3mmol) is dissolved in methanol (50mL), palladium carbon is added After (10%, 15mg) replacing hydrogen, react 4 hours at room temperature.End of reaction, filtering, filtrate concentration obtain title compound (120.0mg, yield 85%).
(4) the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and propionamide preparation
Under ice bath, by N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2-2- methoxyphenyl) ammonia Base) -5- (trifluoromethyl) pyrimidine-4-yl)-N1Methylbenzene -1,2,4- triamine (120.0mg, 0.2mmol) is dissolved in tetrahydrofuran In the mixed solution of (5mL) and water (0.5mL), 3- chlorpromazine chloride (38.0mg, 0.3mmol) is slowly added dropwise, is warmed to room temperature reaction 2 Hour, ethyl acetate extracts (150mL × 2), and organic phase merges, and anhydrous sodium sulfate is dry, concentration, through column chromatography (methylene chloride: Methanol=20:1) purifying, obtain title compound (130mg, yield 92%).
(5) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxybenzene Base) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and acrylamide preparation
By the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propionamide (130mg, 0.2mmol) is dissolved in tetrahydro furan Mutter (5mL), is added dropwise sodium hydroxide solution (1mL, 50%), rises to 65 DEG C and reacts 10 hours, and end of reaction is added water (10mL), Ethyl acetate extracts (30mL × 3), and organic phase merges, and anhydrous sodium sulfate is dry, concentration, through column chromatography (methylene chloride: methanol= It 10:1) purifies, obtains title compound (94mg, yield 77%).
Molecular formula: C27H32F3N7O3Molecular weight: 559.6LC-MS (m/z): 560.3 (M+H+)
1H-NMR(400MHz,DMSO-d6)δ:10.00(s,1H),8.37(s,1H),8.31(s,1H),8.26(s,1H), 8.01 (s, 1H), 7.76 (d, 1H, J=7.6Hz), 7.03 (s, 1H), 6.87-6.94 (m, 2H), 6.62-6.63 (m, 1H), 6.45(brs,1H),6.21(dd,1H,J1=16.8Hz, J2=14.8Hz), 5.71-5.74 (m, 1H), 3.79 (s, 3H), 3.73 (s,3H),2.95(brs,2H),2.72(s,3H),2.26-2.43(m,8H).
4 N- of embodiment (5- ((2- ((4- (1- Acetylpiperidin -4- base) -2- methoxyphenyl) amino) -5- (fluoroform Base) pyrimidine-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acrylamide (compound 5) Preparation
(1) 1- (4- (4- ((4- chloro- 5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenyl) piperidin-1-yl) The preparation of ethyl -1- ketone
1- (4- (4- amino -3- methoxyphenyl) piperidin-1-yl) ethyl -1- ketone (560mg, 2.26mmol) is dissolved in two In chloromethanes (10mL), it is added triethylamine (228mg, 2.26mmol), is slowly added to the chloro- 5- trifluoromethyl pyrimidine of 2,4- bis- (588mg, 2.71m mol) is stirred at room temperature 2 hours, is added saturated solution of sodium bicarbonate (20mL), is extracted with dichloromethane, has Machine is mutually dry with anhydrous sodium sulfate, and concentration, reversed phase chromatography separation (water: acetonitrile=10:1-3:2) obtains product (212mg, yield 22%).
(2) (((2- ((4- (1- Acetylpiperidin -4- base) -2- methoxyphenyl) amino) -5- (trifluoromethyl) is phonetic by 5- by N- Pyridine -4- base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) and acrylamide preparation
By 1- (4- (4- ((4- chloro- 5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenyl) piperidin-1-yl) Ethyl-1- ketone (212mg, 0.49mmol), N- (5-amino-2 ((2- (dimethylamino) ethyl (methyl)) amino) phenyl) third Acrylamide (196mg, 0.75mmol), potassium carbonate (138mg, 1.0mmol), Pd2(dba)3(21mg) and X-Phos (42mg) are added In Isosorbide-5-Nitrae-dioxane (10mL), nitrogen protection, 100 DEG C oil bath heating 5 hours.It is spin-dried for solvent, sodium chloride saturated solution is added (50mL), is extracted with dichloromethane, and organic phase is dry with anhydrous sodium sulfate, concentration, reversed phase chromatography separation (water: acetonitrile=10:1- 3:2) obtain product (40mg, yield 12%).
Molecular formula: C33H41F3N8O3Molecular weight: 654LC-MS (m/z): 655 (M+H+)
1H-NMR(400MHz,MeOD)δ:8.40(s,1H),8.24(s,1H),8.10(s,1H),7.34(dd,1H,J1= 2.4Hz,J2=8.8Hz), 7.11 (d, 1H, J=8.8Hz), 6.89 (d, 1H, J=1.6Hz), 6.71 (d, 1H, J=8.0Hz), 6.55(dd,1H,J1=10.0Hz, J2=16.8Hz), 6.35 (dd, 1H, J1=1.6Hz, J2=16.8Hz), 5.78 (dd, 1H, J1=1.6Hz, J2=10.0Hz), 4.64-4.68 (m, 2H), 3.98-4.08 (m, 1H), 3.87 (s, 3H), 3.15-3.25 (m, 1H), 2.95 (t, 2H, J=10.0Hz), 2.63-2.67 (m, 2H), 2.63 (s, 3H), 2.40 (t, 2H, J=10.0Hz), 2.25 (s,6H),2.13(s,3H),1.93-1.87(m,2H),1.57-1.70(m,2H).
5 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- morphlinophenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and acrylamide (compound 6) preparation
(1) preparation of 4- (3- methoxyl group -4- nitrobenzophenone) morpholine
By the fluoro- 2- methoxyl group -1- nitrobenzene (8.55g, 49.97mmol) of 4-, N, N- diisopropylethylamine (12.90g, 100.00mmol) and morpholine (4.79g, 54.99mmol) is added to dissolution in n,N-Dimethylformamide (80mL), is warming up to 85 DEG C reaction 6 hours.It is cooled to room temperature, is poured into water (400mL), filter, filter cake is washed with water, dry crude product, and gained is thick Product are added in ethyl acetate (250mL), and being warming up to 85 DEG C dissolves it all, is cooled to room temperature, a large amount of solids are precipitated, and are taken out Filter, filter cake are washed with ethyl acetate, are dried in vacuo to obtain title compound (7.83g, yield 65.8%).
(2) preparation of 2- methoxyl group -4- morpholino aniline
4- (3- methoxyl group -4- nitrobenzophenone) morpholine (7.78g, 32.66mmol) is dissolved in methanol (250mL), is added Palladium carbon (300mg) reacts at room temperature 6 hours, filters, and filtrate is concentrated to give title compound (6.51g, yield 95.7%).
(3) preparation of the chloro- N- of 4- (2- methoxyl group -4- morphlinophenyl) -5- (trifluoromethyl) pyrimidine -2- amine
Bis- chloro- 5- (trifluoromethyl) pyrimidine (2.17g, 10.00mmol) of 2,4- is added to 1,2- dichloroethanes (20mL) In the tert-butyl alcohol (20mL) mixed solution, zinc chloride diethyl ether solution (1mol/L, 22mL) is added under ice bath, after stirring 1 hour, adds Enter 2- methoxyl group -4- morpholino aniline (2.08g, 9.99mmol), triethylamine (1.11g, 11.00mmol) is dissolved into 1,2- bis- It in chloroethanes (10mL) and the tert-butyl alcohol (10mL) solution, is slowly added dropwise in above-mentioned solution, is warmed to room temperature naturally, stirring 16 is small When.Reaction solution concentration, crude product through silica gel column chromatography (petroleum ether: ethyl acetate=5:1) purify, obtain title compound (1.53g, Yield 39.4%).
(4)N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- morphlinophenyl) -5- (fluoroform Base) pyrimidine -2,4- diamines preparation
By the chloro- N- of 4- (2- methoxyl group -4- morphlinophenyl) -5- (trifluoromethyl) pyrimidine -2- amine (760mg, 1.95mmol) and the fluoro- 2- methoxyl group -5- nitroaniline (363mg, 1.95mmol) of 4- is added to 1,4- dioxane (20mL) In, it instills hydrochloric acid (0.3mL), is warming up to 100 DEG C and reacts 16 hours.Reaction solution is directly concentrated, and crude product is through silica gel column chromatography (dichloro Methane: methanol=50:1) purifying, obtain title compound (700mg, yield 66.7%).
(5)N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2(2- first Oxygroup -4- morphlinophenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- morphlinophenyl) -5- (fluoroform Base) pyrimidine -2,4- diamines (677mg, 1.26mmol), N1,N1,N2Trimethylethane -1,2- diamines (142mg, 1.39mmol) It is dissolved in n,N-Dimethylformamide (10mL) with n,N-diisopropylethylamine (325mg, 2.52mmol), is warming up to 85 DEG C of reactions 6 hours, methylene chloride (90mL) and water (50mL), extraction is added, organic phase is washed with saturated salt solution (80mL), anhydrous sodium sulfate Dry, concentration, crude product is purified through silica gel column chromatography (methylene chloride: methanol=20:1), obtains title compound (660mg, yield 84.1%).
(6)N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2- methoxyl group -4- morphlinophenyl) amino) - 5- (trifluoromethyl) pyrimidine-4-yl)-N1The preparation of methylbenzene -1,2,4- triamine
By N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2(2- methoxy Base -4- morphlinophenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (660mg, 1.06mmol) is dissolved in methanol (40mL), It is added palladium carbon (100mg), is reacted at room temperature 6 hours under atmosphere of hydrogen, filtered, filtrate is concentrated to give title compound (570mg, yield 91.05%).
(7) the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- morphlinophenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and propionamide preparation
By N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2- methoxyl group -4- morphlinophenyl) amino) - 5- (trifluoromethyl) pyrimidine-4-yl)-N1Methylbenzene -1,2,4- triamine (376mg, 0.64mmol) is dissolved in tetrahydrofuran It in (10mL) and water (1mL), is added 3- chlorpromazine chloride (81mg, 0.64mmol), reaction 2 hours is stirred at room temperature.Reaction solution concentration It obtains crude product (436mg), is directly used in and reacts in next step.
(8) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxyl group -4- Quinoline is for phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and acrylamide preparation
By the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxyl group - 4- morphlinophenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propionamide (436mg crude product) is dissolved in four In hydrogen furans (10mL), the sodium hydroxide solution (6mol/L, 2mL) of addition is warming up to 70 DEG C and reacts 2 hours.Reaction solution is cooling It to room temperature, is added water (20mL), ethyl acetate (30mL × 2) extraction merges organic phase, saturated salt solution (30mL) is washed, anhydrous Sodium sulphate is dry, and concentration, crude product is purified through silica gel column chromatography (methylene chloride: methanol=20:1), obtain title compound (180mg, Two step total recoverys 43.8%).
Molecular formula: C31H39F3N8O4Molecular weight: 644.7LC-MS (m/z): 645.4 (M+H+)
1H-NMR(400MHz,CDCl3) δ: 10.50 (brs, 1H), 9.40 (brs, 1H), 8.30 (s, 1H), 8.16 (d, J= 8.4Hz,1H),7.90-7.70(m,1H),7.60-7.40(m,1H),6.74(s,1H),6.50-6.41(m,4H),5.70(d, J=12.0Hz, 1H), 3.89-3.85 (m, 11H), 3.10 (s, 6H), 2.70 (s, 3H), 2.68-2.10 (m, 7H)
6 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- (1- methyl -2- oxo-piperidine -4- base) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propylene The preparation of amide (compound 8)
(1) preparation of bromo- 1- picoline -2 (1H) -one of 4-
4- bromopyridine -2 (1H) -one (3.0g, 17.2mmol) is dissolved in tetrahydrofuran (100mL), nitrogen protection decline Temperature is added sodium hydride (mass fraction 60%, 0.69g, 17.2mmol) to 0 DEG C, is warmed to room temperature stirring 15 minutes, iodine is slowly added dropwise Methane (3.30mL, 53.0mmol) is stirred at room temperature 16 hours after being added dropwise, and water (80mL) and ethyl acetate (80mL) is added, Liquid separation, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, and concentration obtains title compound (2.85g, yield 88.2%).
(2) tert-butyl (2- methoxyl group -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) phenyl) The preparation of carbamate
By tert-butyl (the bromo- 2- methoxyphenyl of 4-) carbamate (2.5g, 8.3mmol), connection boric acid pinacol ester (2.32g, 9.1mmol) and potassium acetate (1.63g, 16.6mmol) are added in n,N-Dimethylformamide (100mL), and nitrogen is protected Shield is lower to be added bis- (diphenylphosphine) the ferrocene palladium chloride dichloromethane complex of 1,1'- (410mg, 0.50mmol), is warming up to 80 DEG C are reacted 16 hours, are cooled to room temperature addition water and methylene chloride, liquid separation, organic phase are anhydrous with saturated common salt water washing 3 times Sodium sulphate is dry, and concentration, crude product is purified through silica gel column chromatography (petroleum ether: ethyl acetate=100:1), obtains title compound (1.75g, yield 60.3%).
(3) tert-butyl (2- methoxyl group -4- (1- methyl -2- oxo -1,2- dihydropyridine -4- base) phenyl) carbamate Preparation
By tert-butyl (2- methoxyl group -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) phenyl) ammonia Bromo- 1- picoline -2 (1H) -one (0.64g, 3.4mmol) of carbamate (1.2g, 3.4mmol), 4- and potassium carbonate (0.94g, It 6.8mmol) is added in Isosorbide-5-Nitrae-dioxane (100mL) and water (20mL), 1,1'- bis- (diphenylphosphines) is added under nitrogen protection Ferrocene palladium chloride (249mg, 0.34mmol) is warming up to 90 DEG C and reacts 6 hours, filters, and filtrate concentration, crude product is through silicagel column (petroleum ether: ethyl acetate=5:1) purifying is chromatographed, title compound (1.1g, yield 98.2%) is obtained.
(4) preparation of tert-butyl (2- methoxyl group -4- (1- methyl -2- oxo-piperidine -4- base) phenyl) carbamate
By tert-butyl (2- methoxyl group -4- (1- methyl -2- oxo -1,2- dihydropyridine -4- base) phenyl) carbamate (1.1g, 3.3mmol) is dissolved in methanol (50mL), is added platinum dioxide (0.55g, mass ratio 50%), room temperature under hydrogen environment Stirring 16 hours, filters, and filtrate is concentrated to give title compound (1.1g, yield 99.8%).
(5) preparation of 4- (4- amino -3- methoxyphenyl) -1- methyl piperidine -2- ketone
By tert-butyl (2- methoxyl group -4- (1- methyl -2- oxo-piperidine -4- base) phenyl) carbamate (1.1g, It 3.3mmol) is dissolved in methylene chloride (10mL) and trifluoroacetic acid (10mL), stirs 0.5 hour at room temperature, product is concentrated under reduced pressure to obtain (750mg, yield 97.3%).
(6) 4- (4- ((4- chloro- 5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenyl) -1- methyl piperidine - The preparation of 2- ketone
At 0 DEG C, zinc chloride diethyl ether solution (1mol/L, 4.0mL, 4.0mmol) is added drop-wise to the chloro- 5- of 2,4- (trifluoromethyl) The tert-butyl alcohol and 1 of pyrimidine (868mg, 4.0mmol) in 2- dichloroethanes mixed solution (40mL, 1:1), stirs 1 hour at 0 DEG C, Then by 4- (4- amino -3- methoxyphenyl) -1- methyl piperidine -2- ketone (750mg, 3.2mmol) and triethylamine (404mg, It 4.0mmol) is added sequentially in reaction system, 25 DEG C are stirred 16 hours.Evaporating solvent under reduced pressure, the inverted column chromatography (first of crude product Alcohol/water, 0-70% add 0.4% trifluoroacetic acid) purifying, obtain title compound (190mg, yield 14.3%).
(7) 4- (4- ((4- ((the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) amino) -5- (trifluoromethyl) pyrimidine -2-base) ammonia Base) -3- methoxyphenyl) -1- methyl piperidine -2- ketone preparation
By 4- (4- ((4- chloro- 5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenyl) -1- methyl piperidine -2- Ketone (190mg, 0.46mmol) and the fluoro- 2- methoxyl group -5- nitroaniline (85.6mg, 0.46mmol) of 4- are added to 1,4- dioxy six It in ring (20mL), instills concentrated hydrochloric acid (0.5mL), reaction solution is heated to 100 DEG C and reacts 2 hours.End of reaction steams reaction solution Dry, crude product is purified through silica gel column chromatography (petroleum ether: ethyl acetate=1:1), obtains title compound (240mg, yield 92.4%).
(8) 4- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone) Amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenyl) -1- methyl piperidine -2- ketone preparation
By 4- (4- ((4- ((the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) amino) -5- (trifluoromethyl) pyrimidine -2-base) ammonia Base) -3- methoxyphenyl) -1- methyl piperidine -2- ketone (240mg, 0.43mmol), N1,N1,N2Trimethylethane -1,2- diamines (66mg, 0.65mmol) and N, N- diisopropylethylamine (166mg, 1.29mmol) are added to N,N-dimethylformamide (5mL) In, it is heated to 85 DEG C and reacts 16 hours.End of reaction dilutes reaction solution with water (20mL), ethyl acetate (50mL × 3) extraction It takes, merges organic phase, be concentrated under reduced pressure, residue is purified through silica gel column chromatography (petroleum ether: ethyl acetate=10:1-1:1), must be marked It inscribes compound (235mg, yield 84.5%).
(9) 4- (4- ((4- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyl) Amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenyl) -1- methyl piperidine -2- ketone preparation
By 4- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone) Amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenyl) -1- methyl piperidine -2- ketone (235mg, It 0.36mmol) is added in methanol (30mL) with palladium carbon (24mg, mass ratio 10%), lower 25 DEG C of hydrogen environment are reacted 1.5 hours. End of reaction, filtering, filtrate are concentrated to get title compound (210mg, yield 94.6%).
(10) the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- first Oxygroup -4- (1- methyl -2- oxo-piperidine -4- base) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) third The preparation of amide
3- chlorpromazine chloride (43mg, 0.34mmol) is added dropwise to 4- (4- ((4- ((5- amino -4- ((2- (two at 25 DEG C Methylamino) ethyl) (methyl) amino) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -3- first Phenyl) tetrahydrofuran (5mL) of -1- methyl piperidine -2- ketone (210mg, 0.34mmol) and the mixed solution of water (0.5mL) In, 25 DEG C are reacted 2 hours.Reaction solution is directly used in react in next step.
(11) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxyl group -4- (1- methyl -2- oxo-piperidine -4- base) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide Preparation
Sodium hydroxide solution (mass fraction 33%, 0.2mL, 1.65mmol) is added in step reaction solution upwards, 65 DEG C of stirrings 7 Hour, concentration, the inverted column chromatography of crude product (methanol/water, 0-60% add 0.4% trifluoroacetic acid) purifying obtains title compound (45mg, two step yields 19.7%).
Molecular formula: C33H41F3N8O4Molecular weight: 670.7LC-MS (m/z): 671.4 (M+H+)
1H-NMR(400MHz,CDCl3)δ:10.02(s,1H),8.92(s,1H),8.30(s,2H),8.00(s,1H), 7.68 (s, 1H), 7.01 (s, 1H), 6.95 (s, 1H), 6.57 (s, 1H), 6.48-6.32 (m, 1H), 6.17 (d, J=16.8Hz, 1H), 5.71 (d, J=10.0Hz, 1H), 3.84 (s, 3H), 3.72 (s, 3H), 2.96-2.85 (m, 4H), 2.84 (s, 3H), 2.73(s,3H),2.39-2.29(m,4H),2.20(s,6H),1.99-1.86(m,2H).
7 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- (1- methyl -2- oxo-piperidine -4- base) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propylene The preparation of amide (compound 9)
(1) preparation of 4- (3- methoxyl group -4- nitrobenzophenone) -1- (methyl sulphonyl) -1,2,3,6- tetrahydropyridine
By 4- (3- methoxyl group -4- nitrobenzophenone) -1,2,3,6- tetrahydropyridine (2.3g, 9.8mmol) and triethylamine (2.47g, 24.5mmol) is added in methylene chloride (50mL), and methylsufonyl chloride (1.68g, 14.7mmol) is added dropwise under ice bath, Reaction 12 hours is warmed to room temperature after being added dropwise.Concentration, crude product are purified through silica gel column chromatography (petroleum ether: ethyl acetate=4:1) It obtains title compound (2.5g, yield 81.7%).
(2) preparation of 2- methoxyl group -4- (1- (methyl sulphonyl) -1,2,3,6- tetrahydropyridine -4- base) aniline
By 4- (3- methoxyl group -4- nitrobenzophenone) -1- (methyl sulphonyl) -1,2,3,6- tetrahydropyridine (2.5g, It 8.0mmol) is dissolved into methanol (100mL), is added palladium charcoal (400mg), be stirred at room temperature 16 hours under hydrogen environment, filtered, filter Liquid is concentrated to give title compound (2.1g, yield 92.3%).
(3) the chloro- N- of 4- (2- methoxyl group -4- (1- (methyl sulphonyl) piperidin-4-yl) phenyl) -5- (trifluoromethyl) is phonetic The preparation of pyridine -2- amine
By 2- methoxyl group -4- (1- (methyl sulphonyl) -1,2,3,6- tetrahydropyridine -4- base) aniline (753mg, It 2.65mmol) is added to the in the mixed solvent of 1,2- dichloroethanes (20mL) and the tert-butyl alcohol (20mL), zinc chloride is added under ice bath 2,4- bis- chloro- 5- (trifluoromethyl) pyrimidine is added after stirring 1 hour in diethyl ether solution (1mol/L, 5.83mL, 5.83mmol) (575mg,2.65mmol).Triethylamine (293mg, 2.9mmol) is dissolved into 1,2- dichloroethanes (10mL) and the tert-butyl alcohol The in the mixed solvent of (10mL) is slowly added dropwise in above-mentioned solution, is warmed to room temperature naturally, stirs 16 hours.Reaction solution is directly dense Contracting, crude product obtain title compound (700mg, yield 56.8%) through silica gel column chromatography (petroleum ether: ethyl acetate=3:1).
(4)N4(the fluoro- 3- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- (1- (methyl sulphonyl) piperidin-4-yl) phenyl) - The preparation of 5- (trifluoromethyl) pyrimidine -2,4- diamines
By the chloro- N- of 4- (2- methoxyl group -4- (1- (methyl sulphonyl) piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidine - 2- amine (700mg, 1.50mmol) and the fluoro- 3- nitroaniline (234mg, 1.50mmol) of 4- are added to 1,4- dioxane (20mL) In, it instills hydrochloric acid (0.3mL), is warming up to 100 DEG C and reacts 12 hours.Reaction solution decompression filters, and gained filter cake is title compound (658mg, yield 75.0%).
(5)N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- nitrobenzophenone)-N2(2- methoxyl group -4- (1- (methyl sulphonyl) piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By N4(the fluoro- 3- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- (1- (methyl sulphonyl) piperidin-4-yl) phenyl) - 5- (trifluoromethyl) pyrimidine -2,4- diamines (320mg, 0.55mmol), N1,N1,N2Trimethylethane -1,2- diamines (67mg, It 0.66mmol) is dissolved in n,N-Dimethylformamide (10mL), heats up with n,N-diisopropylethylamine (177mg, 1.38mmol) It is reacted 6 hours to 85 DEG C, methylene chloride (90mL) is added and water (50mL), liquid separation, organic phase saturated salt solution (80mL) are washed, nothing Aqueous sodium persulfate is dry, and concentration, crude product obtains brown solid title compound through silica gel column chromatography (methylene chloride: methanol=40:1) (620mg, yield 82.6%).
(6)N1(2- (dimethylamino) ethyl)-N4(2- ((2- methoxyl group -4- (1- (methyl sulphonyl) piperidines -4- Base) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1The preparation of methylbenzene -1,2,4- triamine
N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- nitrobenzophenone)-N2(2- methoxyl group -4- (1- (methyl sulphonyl) piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (620mg, 0.93mmol) is dissolved in first It in alcohol (40mL), is added palladium charcoal (100mg), reaction 6 hours is stirred at room temperature under hydrogen environment, filter, filtrate is concentrated to give titled It closes object (504mg, yield 85.1%).
(7) the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- (2- ((2- methoxyl group -4- (1- (methyl sulphonyl) piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propionamide preparation
By N1(2- (dimethylamino) ethyl)-N4(2- ((2- methoxyl group -4- (1- (methyl sulphonyl) piperidin-4-yl) Phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1Methylbenzene -1,2,4- triamine (230mg, 0.36mmol) is dissolved in It in tetrahydrofuran (10mL) and water (1mL), is added 3- chlorpromazine chloride (137mg, 1.08mmol), reaction 2 hours is stirred at room temperature.Instead Liquid is answered to be directly used in next step.
(8) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((2- ((2- methoxyl group -4- (1- (methyl Sulfonyl) piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and acrylamide preparation
Sodium hydroxide solution (6mol/L, 2mL) is added in gained reaction solution one step up, is warming up to 70 DEG C and reacts 2 hours. Reaction solution is cooled to room temperature, and is added water (20mL), and ethyl acetate (30mL × 2) extraction merges organic phase, uses saturated salt solution (30mL) is washed, and anhydrous sodium sulfate is dry, and concentration, crude product purifies to obtain title through silica gel column chromatography (methanol: methylene chloride=1:40) Compound (100mg, two step total recoverys 40.2%).
Molecular formula: C32H41F3N8O4S molecular weight: 690.8LC-MS (m/z): 691.8 (M+H+)
1H-NMR(400MHz,CDCl3)δ:10.32(s,1H),8.64(s,1H),8.30(s,1H),8.23-8.16(m, 2H),7.71(s,1H),7.46-7.44(m,1H),6.86(s,1H),6.69(s,1H),6.68-6.60(m,1H),6.49- 6.31(m,2H),5.75-5.73(m,1H),3.95-3.93(m,2H),3.88(s,3H),2.91-2.73(m,10H),2.60- 2.50(m,1H),2.36-2.29(m,8H),1.97-1.91(m,2H),1.87-1.72(m,2H).
8 N- of embodiment (5- ((2- ((4- (1- Acetylpiperidin -4- base) -2- methoxyphenyl) amino) -5- (fluoroform Base) pyridin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acrylamide (compound 11) Preparation
(1) preparation of the chloro- N- of 2- (the fluoro- 3- nitrobenzophenone of 4-) -5- (trifluoromethyl) pyridine -4- amine
By the fluoro- 3- nitroaniline (1.0g, 6.41mmol) of 4- and 2- chlorine-4-iodine -5- (trifluoromethyl) pyridine (2.36g, It 7.69mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (40mL) with cesium carbonate (4.17g, 12.81mmol), in N2To the system under protection Middle addition Pd2(dba)3(283mg, 0.31mmol) and Xantphos (359mg, 0.62mmol), 110 DEG C of oil bath heating reactions 16 Hour.End of reaction, concentration, residue are purified through silica gel column chromatography (PE:EA=5:1), and obtaining title compound, (1.0g is produced Rate 46.5%).
(2) 1- (4- (4- ((4- ((the fluoro- 3- nitrobenzophenone of 4-) amino) -5- (trifluoromethyl) pyridine -2- base) amino) -3- Methoxyphenyl) piperidin-1-yl) ethyl -1- ketone preparation
By 1- (4- (4- amino -3- methoxyphenyl) piperidin-1-yl) ethyl -1- ketone (0.75g, 3.02mmol), 2- is chloro- N- (the fluoro- 3- nitrobenzophenone of 4-) -5- (trifluoromethyl) pyridine -4- amine (0.85g, 2.53mmol) and cesium carbonate (1.65g, It 5.06mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (20mL), in N2Pd is added into the system under protection2(dba)3(283mg, 0.31mmol) and bis- diphenylphosphine -9, the 9- xanthphos (359mg, 0.62mmol) of 4,5-, 110 DEG C of oil bath reactions 16 are small When.End of reaction, concentration, residue are purified through silica gel column chromatography (PE:EA=5:1), obtain title compound (0.6g, yield 43.3%).
(3) 1- (4- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- nitrobenzophenone) amino) - 5- (trifluoromethyl) pyridine -2- base) amino) -3- methoxyphenyl) piperidin-1-yl) ethyl -1- ketone preparation
By 1- (4- (4- ((4- ((the fluoro- 3- nitrobenzophenone of 4-) amino) -5- (trifluoromethyl) pyridine -2- base) amino) -3- Methoxyphenyl) piperidin-1-yl) ethyl -1- ketone (0.6g, 1.1mmol) and N1,N1,N2Trimethylethane -1,2- diamines (0.35g, 3.43mmol) is added in acetonitrile (20mL), and 85 DEG C of oil bath are reacted 16 hours.End of reaction, by reaction solution water (100mL) dilution, ethyl acetate (100mL × 3) extraction, merges organic phase, is concentrated under reduced pressure, and obtaining title compound, (0.59g is produced Rate 85.5%).
(4) 1- (4- (4- ((4- ((3- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) - 5- (trifluoromethyl) pyridine -2- base) amino) -3- methoxyphenyl) piperidin-1-yl) ethyl -1- ketone preparation
By 1- (4- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- nitrobenzophenone) amino) - 5- (trifluoromethyl) pyridine -2- base) amino) -3- methoxyphenyl) piperidin-1-yl) ethyl -1- ketone (0.59g, 0.94mmol) Be added in methanol (20mL) with palladium carbon (100mg, 10%), then under hydrogen environment 25 DEG C be stirred to react 1 hour.It has reacted Finish, filtering, filtrate concentration obtains title compound (400mg, yield 71.2%).
(5) N- (5- ((2- ((4- (1- Acetylpiperidin -4- base) -2- methoxyphenyl) amino) -5- (trifluoromethyl) pyrrole Pyridine -4- base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) and acrylamide preparation
Acryloyl chloride (60mg, 0.66mmol) is added dropwise to 1- (4- (4- ((4- ((3- amino -4- ((2- (two at 25 DEG C Methylamino) ethyl) (methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyridine -2- base) amino) -3- methoxyphenyl) Piperidin-1-yl) ethyl -1- ketone (100mg, 0.17mmol) tetrahydrofuran (5mL) solution in, 25 DEG C react 1 hour.It has reacted Finish, reaction solution is concentrated, methylene chloride (20mL) is added, and successively uses saturated sodium bicarbonate solution (20mL), saturated common salt Water (20mL) washing, organic phase are concentrated under reduced pressure, and residue is separated through silica gel column chromatography (DCM:MeOH=20:1), obtain title compound Object (50mg, yield 45.9%).
Molecular formula: C34H42F3N7O3Molecular weight: 653.8LC-MS (m/z): 654.4 (M+H+)
1H-NMR(400MHz,CDCl3) δ: 10.38 (s, 1H), 8.54 (s, 1H), 8.23 (s, 1H), 7.83 (d, J= 7.6Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 6.88-6.91 (m, 2H), 6.66 (s, 2H), 6.44-6.52 (m, 2H), 6.29-6.36 (m, 2H), 5.74 (d, J=9.6Hz, 1H), 4.75 (d, J=12.0Hz, 1H), 3.90 (d, J=12.8Hz, 1H), 3.82 (s, 3H), 3.14 (t, J=12.8Hz, 1H), 2.84 (s, 1H), 2.72 (s, 3H), 2.56-2.64 (m, 2H), 2.28–2.32(m,6H),2.13(s,3H),2.00(s,2H),1.80–1.88(m,2H),1.54–1.57(m,2H).
9 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- (2- (mesyl) ethyoxyl) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide The preparation of (compound 12)
(1) preparation of 3- methoxyl group -4- nitrophenol
The fluoro- 2- methoxyl group -1- nitrobenzene (5g, 29.22mmol) of 4- is dissolved in dimethyl sulfoxide (30mL), hydrogen-oxygen is added Change sodium water solution (30mL, 60mmol, 2M), is heated to 80 DEG C and is stirred to react 16 hours.Reaction solution 1M dilute hydrochloric acid is adjusted into pH =6, ethyl acetate (50mL × 3) extraction is added, merges organic phase, is dried, filtered, be spin-dried for anhydrous sodium sulfate, gained crude product Purify (petroleum ether: ethyl acetate=20:1) with silica gel column chromatography up to faint yellow solid shape title compound (3.9g, yield 79.6%).
(2) preparation of 4- (2- bromine oxethyl) -2- methoxyl group -1- nitrobenzene
3- methoxyl group -4- nitrophenol (1.9g, 11.24mmol) is dissolved in acetonitrile (30mL), addition potassium carbonate (3g, 21.71mmol) with 1,2- Bromofume (2.5g, 13.3mmol), it is heated to 80 DEG C and is stirred to react 16 hours.Reaction solution is revolved Dry, gained crude product silica gel column chromatography purifies (petroleum ether: ethyl acetate=20:1) up to faint yellow solid shape title compound (1.8g, yield 58.1%).
(3) preparation of (2- (3- methoxyl group -4-nitrophenoxy) ethyl) (methyl) sulfane
4- (2- bromine oxethyl) -2- methoxyl group -1- nitrobenzene (1.5g, 5.43mmol) is dissolved in ethyl alcohol (20mL), is added Enter sodium methyl mercaptide aqueous solution (3.5mL, 7mmol, 2M), 25 DEG C are stirred to react 3 hours.Reaction solution is spin-dried for, gained crude product silicon Gel column chromatography eluting (petroleum ether: ethyl acetate=10:1) obtains yellow solid title compound (1g, yield 76.9%).
(4) preparation of 2- methoxyl group -4- (2- (mesyl) ethyoxyl) -1- nitrobenzene
(2- (3- methoxyl group -4-nitrophenoxy) ethyl) (methyl) sulfane (0.9g, 3.7mmol) is dissolved in methylene chloride In (10mL), ice-water bath is cooled to 0 DEG C, is added metachloroperbenzoic acid (85%, 2g, 9.85mmol), 25 DEG C are stirred to react 16 Hour.Reaction solution is quenched with saturated aqueous sodium thiosulfate (5mL), liquid separation, organic phase saturated aqueous sodium carbonate (5mL) washing is added anhydrous sodium sulfate and dries, filters, and filtrate is spin-dried for, and gained crude product silica gel column chromatography purifies (petroleum ether: second Acetoacetic ester=5:1) up to faint yellow solid shape title compound (0.8g, yield 78.4%).
(5) preparation of 2- methoxyl group -4- (2- (mesyl) ethyoxyl) aniline
2- methoxyl group -4- (2- (mesyl) ethyoxyl) -1- nitrobenzene (0.8g, 2.9mmol) is dissolved in methanol In (10mL), it is added palladium carbon (0.1g), lower 25 DEG C of pressurized with hydrogen are stirred to react 16 hours.Reaction solution is filtered, filtrate is spin-dried for i.e. It obtains faint yellow solid shape title compound (0.65g, yield 91.5%).
(6) the chloro- N- of 4- (2- methoxyl group -4- (2- (mesyl) ethyoxyl) phenyl) -5- (trifluoromethyl) pyrimidine -2- amine Preparation
2,4- chloro- 5- (trifluoromethyl) pyrimidine (0.53g, 2.44mmol) is dissolved in the tert-butyl alcohol and 1,2- dichloroethanes The in the mixed solvent of (5mL, 1:1) is cooled to 0 DEG C, is added zinc chloride diethyl ether solution (2.9mL, 2.9mmol, 1M), is stirred to react 1 hour.The tert-butyl alcohol and 1,2- bis- of 2- methoxyl group -4- (2- (mesyl) ethyoxyl) aniline (0.6g, 2.44mmol) is added Chloroethanes (5mL, 1:1) mixed solution, adds triethylamine (0.28g, 2.77mmol), finishes 25 DEG C and is stirred to react 16 hours. Reaction solution is spin-dried for, gained crude product silica gel column chromatography purifies (petroleum ether: ethyl acetate=3:1) up to yellow solid title Compound (0.7g, yield 67.3%).
(7)N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- (2- (mesyl) ethyoxyl) benzene Base) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By the chloro- N- of 4- (2- methoxyl group -4- (2- (mesyl) ethyoxyl) phenyl) -5- (trifluoromethyl) pyrimidine -2- amine (0.5g, 1.17 mmol) and the fluoro- 2- methoxyl group -5- nitroaniline (0.22g, 1.18mmol) of 4- are dissolved in dioxane (5mL) In, it is added dilute hydrochloric acid (5mL, 4M), is heated to 100 DEG C and is stirred to react 2 hours.Reaction solution is spin-dried for, saturated sodium bicarbonate is added Aqueous solution adjusts pH=8, is extracted with ethyl acetate (20mL × 2), merges organic phase, is dried, filtered with anhydrous sodium sulfate, filtrate It is spin-dried for, gained crude product silica gel column chromatography purifies (petroleum ether: ethyl acetate=2:1) up to faint yellow solid shape title compound (0.53g, yield 77.9%).
(8)N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2(2- first Oxygroup -4- (2- (mesyl) ethyoxyl) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- (2- (mesyl) ethyoxyl) benzene Base) -5- (trifluoromethyl) pyrimidine -2,4- diamines (0.42g, 0.73mmol) is dissolved in n,N-Dimethylformamide (5mL), it is added N, N, N'- trimethyl ethylenediamine (0.1g, 0.98mmol) and diisopropylethylamine (0.18g, 1.39mmol), are heated to 80 DEG C and stir Mix reaction 16 hours.Reaction solution is spin-dried for, gained crude product silica gel column chromatography purifies (methylene chloride: methanol=10:1) up to palm fibre Yellow solid title compound (0.36g, yield 75.0%).
(9)N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2- methoxyl group -4- (2- (mesyl) ethoxy Base) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1The preparation of toluene -1,2,4- triamine
By N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2(2- methoxy Base -4- (2- (mesyl) ethyoxyl) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (0.36g, 0.55mmol) is dissolved in In methanol (10mL), it is added palladium carbon (50mg), lower 25 DEG C of pressurized with hydrogen are stirred to react 2 hours.Reaction solution is filtered, filtrate is spin-dried for Up to faint yellow solid shape title compound (0.3g, yield 88.2%).
(10) the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- (2- (mesyl) ethyoxyl) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propionamide Preparation
By N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2- methoxyl group -4- (2- (mesyl) ethoxy Base) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1Toluene -1,2,4- triamine (0.2g, 0.32mmol) is dissolved in four The in the mixed solvent of hydrogen furans (5mL) and water (1mL) is cooled to 0 DEG C, is added 3- chlorpromazine chloride (60mg, 0.47mmol), rises Temperature is stirred to react 3 hours to 25 DEG C.Ethyl acetate (20mL) and saturated sodium-chloride water solution (20mL), liquid separation is added, water phase is used Ethyl acetate (20mL × 2) extraction, merges organic phase, is dried, filtered with anhydrous sodium sulfate, filtrate is spin-dried for, gained crude product silicon Gel column chromatography eluting (methylene chloride: methanol=10:1) is up to faint yellow solid shape title compound (0.19g, yield 82.6%).
(11) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxyl group -4- (2- (mesyl) ethyoxyl) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and acrylamide preparation
By the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxyl group - 4- (2- (mesyl) ethyoxyl) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propionamide (0.13g, 0.18mmol) is dissolved in tetrahydrofuran (5mL), is added sodium hydrate aqueous solution (0.2mL, 0.2mmol, 1M), heating It is stirred to react 1 hour to 60 DEG C.Ethyl acetate (20mL) and saturated sodium-chloride water solution (20mL), liquid separation, water phase second is added Acetoacetic ester (20mL × 2) extraction, merges organic phase, is dried, filtered with anhydrous sodium sulfate, filtrate is spin-dried for, gained crude product silica gel Column chromatographic purifying (methylene chloride: methanol=10:1) is up to faint yellow solid shape title compound (56mg, yield 46.7%).
Molecular formula: C30H38F3N7O6S molecular weight: 681.7LC-MS (m/z): 682.3 (M+H+)
1H-NMR(400MHz,CDCl3)δ:9.92(brs,1H),8.28(s,1H),8.18-8.19(m,1H),7.73 (brs, 1H), 7.38 (brs, 1H), 6.69 (s, 1H), 6.35-6.49 (m, 3H), 5.69 (d, J=11.6Hz, 1H) 4.43- 4.44(m,2H),3.85(s,6H),3.40-3.49(m,2H),3.18-3.03(m,5H),2.41-2.82(m,11H).
10 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- first Oxygroup -4- ((2- (methyl sulphonyl) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) The preparation of acrylamide (compound 13)
(1) preparation of 3- methoxyl group-N- (2- (methyl mercapto) ethyl) -4- nitroaniline
2- aminoethanethiol hydrochloride (4.5g, 40mmol) and iodomethane (5.7g, 40mmol) are dissolved in water (20mL), It is slowly added to water (20mL) solution of sodium hydroxide (1.6g, 40mmol) at 30 DEG C, is added dropwise, it is small to continue stirring 1 at 30 DEG C Shi Hou, is added the fluoro- 2- methoxyl group -1- nitrobenzene (3.0g, 17.5mmol) of 4- and triethylamine (5mL), 100 DEG C reaction 4 hours, instead It should finish, be extracted with methylene chloride (100mL × 3), merge organic phase, anhydrous sodium sulfate dries, filters, filtrate concentration, column layer (petroleum ether: ethyl acetate=10:1) purifying is analysed, title compound (3.0g, yield 70.8%) is obtained.
(2) preparation of 3- methoxyl group-N- (2- (methyl sulphonyl) ethyl) -4- nitroaniline
3- methoxyl group-N- (2- (methyl mercapto) ethyl) -4- nitroaniline (3.0g, 12.4mmol) is dissolved in methylene chloride It in (100mL), is slowly added into metachloroperbenzoic acid (4.3g, 24.9mmol), is reacted 1 hour at 25 DEG C.End of reaction is added Hypo solution (150mL), methylene chloride (100mL × 3) extraction, merges organic phase, and anhydrous sodium sulfate dries, filters, Filtrate concentration, column chromatograph (petroleum ether: ethyl acetate=3:1) purifying, obtain title compound (2.7g, yield 79.4%).
(3) 3- methoxyl group-N1The preparation of (2- (methyl sulphonyl) ethyl) benzene -1,4- diamines
3- methoxyl group-N- (2- (methyl sulphonyl) ethyl) -4- nitroaniline (2.7g, 9.8mmol) is dissolved in methanol It in (50mL), is added palladium carbon (270mg), lower 25 DEG C of hydrogen environment are reacted 12 hours.End of reaction, filtering, filtrate concentration must mark It inscribes compound (2.0g, yield 83.3%).
(4)N1(4- chloro- 5- (trifluoromethyl) pyrimidine -2-base) -2- methoxyl group-N4(2- (methyl sulphonyl) ethyl) benzene- The preparation of 1,4- diamines
Under ice bath, 2,4-, bis- chloro- 5- (trifluoromethyl) pyrimidine (890mg, 4.1mmol) is dissolved in the tert-butyl alcohol and 1,2- dichloro In the mixed solution of ethane (30mL, V/V=1:1), the zinc chloride diethyl ether solution (8.2mL) of 1M is added dropwise, is added dropwise, under ice bath After continuing stirring 1 hour, 3- methoxyl group-N is added dropwise1(2- (methyl sulphonyl) ethyl) benzene -1,4- diamines (1.0g, 4.1mmol) The tert-butyl alcohol and 1, the mixed solution (20mL, V/V=1:1) of 2- dichloroethanes is added dropwise, and 25 DEG C are reacted 12 hours, reaction It finishes, solvent evaporated, obtains title compound (700mg, yield 40.2%).
(5)N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- ((2- (methyl sulphonyl) ethyl) Amino) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By the fluoro- 2- methoxyl group -5- nitroaniline (307mg, 1.65mmol) of 4- and N1(the chloro- 5- of 4- (trifluoromethyl) is phonetic Pyridine -2- base) -2- methoxyl group N4(2- (methyl sulphonyl) ethyl) benzene -1,4- diamines (700mg, 1.65mmol) is dissolved in dioxy six It in ring (20mL), is added dropwise concentrated hydrochloric acid (0.1mL), 100 DEG C are reacted 4 hours, and end of reaction is cooled to room temperature, solvent evaporated, are added Saturated sodium bicarbonate solution tune pH to 8, water phase are extracted with ethyl acetate (30mL × 2), merge organic phase, and anhydrous sodium sulfate is dry Dry, concentration obtains title compound (400mg, yield 42.2%) through column chromatography (methylene chloride: methanol=30:1) purifying.
(6)N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2-(2- Methoxyl group -4- ((2- (methyl sulphonyl) ethyl) amino) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- ((2- (methyl sulphonyl) ethyl) ammonia Base) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (400mg, 0.7mmol) and N1,N1,N2Trimethylethane -1,2- two Amine (100mg, 1.0mmol) is dissolved in DMF (10mL), is added dropwise n,N-diisopropylethylamine (130mg, 1.0mmol), is heated to 85 DEG C reaction 8 hours.It is cooled to room temperature, water (50mL) and ethyl acetate (50mL) is added, liquid separation, water phase is extracted with ethyl acetate (50mL × 2) merge organic phase, and saturated common salt water washing, anhydrous sodium sulfate is dry, and concentration, crude product chromatographs (dichloromethane through column Alkane: methanol=10:1) purifying, obtain title compound (280mg, yield 60.9%).
(7)N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2- methoxyl group -4- ((2- (sulfonyloxy methyl Base) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1The preparation of methylbenzene -1,2,4- triamine
By N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2(2- first Oxygroup -4- ((2- (methyl sulphonyl) ethyl) amino) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (280mg, It 0.43mmol) is dissolved in methanol (50mL), is added palladium carbon (30mg), lower 25 DEG C of hydrogen environment are reacted 4 hours.End of reaction, mistake Filter, filtrate concentration, obtains title compound (200mg, yield 74.3%).
(8) the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- ((2- (methyl sulphonyl) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) third The preparation of amide
Under ice bath, by N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2- methoxyl group -4- ((2- (methyl Sulfonyl) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1Methylbenzene -1,2,4- triamine (200mg, 0.32mmol) is dissolved in the mixed solution of tetrahydrofuran (10mL) and water (1mL), and 3- chlorpromazine chloride is slowly added dropwise (51mg, 0.4mmol) rises to 25 DEG C and reacts 2 hours, and ethyl acetate extracts (50mL × 2), merges organic phase, anhydrous sodium sulfate Dry, concentration obtains title compound (60mg, yield 26.2%) through column chromatography (methylene chloride: methanol=20:1) purifying.
(9) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxyl group -4- ((2- (methyl sulphonyl) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide Preparation
By the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- ((2- (methyl sulphonyl) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) third Amide (60mg, 0.08mmol) is dissolved in tetrahydrofuran (5mL), is added dropwise sodium hydroxide solution (1mL, 50%), is risen to 65 DEG C of reactions 10 hours, end of reaction was added water (20mL), and ethyl acetate extracts (30mL × 3), merged organic phase, and anhydrous sodium sulfate is dry, Concentration obtains title compound (25mg, yield 43.9%) through column chromatography (methylene chloride: methanol=10:1) purifying.
Molecular formula: C30H39F3N8O5S molecular weight: 680.7LC-MS (m/z): 681.3 (M+H+)
1H-NMR(400MHz,CDCl3) δ: 8.49 (d, J=8.4Hz, 1H), 8.32 (s, 1H), 7.75 (s, 2H), 7.58 (s, 1H), 6.83 (d, J=8.0Hz, 1H), 6.76 (s, 1H), 6.69 (s, 1H), 6.35-6.39 (m, 1H), 6.05-6.12 (m, 1H), 5.57 (d, J=10.4Hz, 1H), 4.20-4.24 (m, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 3.40-3.48 (m, 2H),3.19(m,2H),3.07(s,3H),2.85(m,2H),2.70(s,3H),2.59(s,6H).
11 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- first Oxygroup -4- (2- (sulfonyloxy methyl amino) ethyoxyl) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) third The preparation of acrylamide (compound 14)
(1) preparation of tert-butyl (2- (3- methoxyl group -4-nitrophenoxy) ethyl) carbamate
By the fluoro- 2- methoxyl group -1- nitrobenzene (5g, 29.2mmol) of 4- and (2- ethoxy) t-butyl carbamate (4.71g, 29.2mmol) is dissolved in toluene (250mL), and potassium hydroxide (3.28g, 58.4mmol), water (50mL) He Siding is added Base ammonium bromide (0.94g, 2.92mmol), is heated to back flow reaction 16 hours.It is down to room temperature, is added water (200mL), ethyl acetate extraction It takes (200mL × 2), organic phase merges, and anhydrous sodium sulfate is dry, and concentration, crude product is through silica gel column chromatography (petroleum ether: ethyl acetate =5:1) purify to obtain target compound (4.2g, yield 46%).
(2) preparation of 2- (3- methoxyl group -4-nitrophenoxy) ethamine
Tert-butyl (2- (3- methoxyl group -4-nitrophenoxy) ethyl) carbamate (4g, 12.8mmol) is dissolved in two It in chloromethanes (100mL), is added trifluoroacetic acid (10mL), 25 DEG C are stirred 16 hours, are added water (100mL), methylene chloride extraction (100mL × 2), anhydrous sodium sulfate is dry, is concentrated to give target compound (2.5g, yield 92%).
(3) preparation of N- (2- (3- methoxyl group -4-nitrophenoxy) ethyl) Methanesulfomide
2- (3- methoxyl group -4-nitrophenoxy) ethamine (2.5g, 11.8mmol) is dissolved in methylene chloride (100mL), It is added triethylamine (3.58g, 35.4mmopl), methylsufonyl chloride (1.63g, 14.2mmol) is added dropwise under ice bath, 25 DEG C of reactions 16 are small When, add water (100mL), methylene chloride extracts (100mL × 2), and anhydrous sodium sulfate is dry, and being concentrated to give target compound, (3.3g is produced Rate 96.5%).
(4) preparation of N- (2- (4- amino -3- methoxyphenoxy) ethyl) Methanesulfomide
By N- (2- (3- methoxyl group -4-nitrophenoxy) ethyl) Methanesulfomide (3g, 10.3mmol), it is dissolved in methanol In (50mL), be added palladium charcoal (300mg), lead to hydrogen react 16 hours, filter off palladium charcoal, filtrate be concentrated to give target compound (2.5g, Yield 93%).
(5) N- (2- (4- ((4- chloro- 5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenoxy) ethyl) first The preparation of sulfonamide
Bis- chloro- 5- (trifluoromethyl) pyrimidine (0.83g, 3.84mmol) of 2,4- is dissolved in 1,2- dichloroethanes/tert-butyl alcohol In mixed solvent (1:1,20mL), zinc chloride diethyl ether solution (1mol/L, 7.68mL, 7.68mmol) is added under ice bath, stirring 1 is small When, N- (2- (4- amino -3- methoxyphenoxy) ethyl) Methanesulfomide (1.0g, 3.84mmol) is added, triethylamine is added dropwise (1.16g, 11.52mmol), rise to 25 DEG C stir 16 hours, concentration, crude product through silica gel column chromatography (petroleum ether: ethyl acetate= 5:1) obtain target compound (600mg, yield 35.5%).
(6) N- (2- (4- ((4- ((the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) amino) -5- (trifluoromethyl) pyrimidine -2- Base) amino) -3- methoxyphenoxy) ethyl) Methanesulfomide preparation
By N- (2- (4- ((4- chloro- 5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenoxy) ethyl) methylsulphur Amide (200mg, 0.454mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (20mL), and the fluoro- 2- methoxyl group -5- nitroaniline of 4- is added (84.6mg, 0.454mmol) and concentrated hydrochloric acid (0.05mL) is warming up to 100 DEG C and stirs 16 hours, and concentration, crude product is through silica gel column layer Analysis (petroleum ether: ethyl acetate=1:1) purifies to obtain target compound (150mg, yield 56%).
(7) N- (2- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzene Base) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenoxy) ethyl) Methanesulfomide preparation
By N- (2- (4- ((4- ((the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) amino) -5- (trifluoromethyl) pyrimidine -2-base) Amino) -3- methoxyphenoxy) ethyl) Methanesulfomide (150mg, 0.254mmol) is dissolved in N,N-dimethylformamide (10mL) In, n,N-diisopropylethylamine (98.5mg, 0.762mmol) and N is added1,N1,N2Trimethylethane -1,2- diamines (26mg, 0.254mmol), 100 DEG C are warming up to react 16 hours, adds water, solid is precipitated, filters to obtain target compound (85mg, yield 49.7%).
(8) N- (2- (4- ((4- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxybenzene Base) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenoxy) ethyl) Methanesulfomide preparation
By N- (2- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzene Base) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenoxy) ethyl) Methanesulfomide (85mg, It 0.126mmol) is dissolved in methanol (5mL), is added palladium carbon (8.5mg), reacted at room temperature 16 hours under atmosphere of hydrogen, filtered, filter Liquid is concentrated to give title compound (77mg, yield 95%).
(9) the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- (2- (sulfonyloxy methyl amino) ethyoxyl) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propionyl The preparation of amine
By N- (2- (4- ((4- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxybenzene Base) amino) -5- (trifluoromethyl) pyrimidine -2-base) amino) -3- methoxyphenoxy) ethyl) Methanesulfomide (77mg, It 0.12mmol) is dissolved in tetrahydrofuran/water (10:1,10mL), is added 3- chlorpromazine chloride (45.7mg, 0.36mmol), 25 DEG C are stirred It mixes 1 hour, reaction solution is directly used in next step.
(10) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxyl group - 4- (2- (sulfonyloxy methyl amino) ethyoxyl) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide Preparation
Sodium hydroxide solution (5mol/L, 10mL) is added in reaction solution one step up, 65 DEG C are stirred 1 hour, concentration, slightly Product purify to obtain target compound (35mg, two step yields 41.9%) through silica gel column chromatography (methanol: methylene chloride=1:50).
Molecular formula: C30H39F3N8O6S molecular weight: 696.7LC-MS (m/z): 349.2 (M/2+H+)
1H-NMR(400MHz,DMSO-d6)δ:10.1(brs,1H),8.27(s,2H),8.08-8.01(m,2H),7.56 (d, J=8.0Hz, 1H), 7.27 (t, J=5.8Hz, 1H), 6.99 (s, 1H), 6.55 (s, 1H), 6.22 (d, J=16.8Hz, 1H), 5.73 (d, J=12.0Hz, 1H), 4.02-3.94 (m, 2H), 3.76 (s, 7H), 3.30-3.25 (m, 2H), 3.18-3.06 (m,2H),2.91(s,4H),2.67(s,4H),2.60-2.30(m,5H).
12 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- (3- (methyl sulphonyl) propoxyl group) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acryloyl The preparation of amine (compound 15)
(1) preparation of (3- (3- methoxyl group -4-nitrophenoxy) propyl) (methyl) sulfane
3- methoxyl group -4- nitrophenol (1.7g, 10.05mmol) is dissolved in tetrahydrofuran (30mL), 3- (first is added Sulfenyl) propyl- 1- alcohol (1.07g, 10.08mmol) and 3- normal-butyl phosphine (3.25g, 16.06mmol) and azodicarbonyldipiperidine (4.06g, 16.09mmol) reacts 12h at 25 DEG C.Reaction is completed, filtering, and filtrate concentration, residue is through silica gel column chromatography (stone Oily ether: ethyl acetate=2:1) obtain title compound (2.1g, yield 81.2%).
(2) preparation of 2- methoxyl group -4- (3- (methyl sulphonyl) propoxyl group) -1- nitrobenzene
(3- (3- methoxyl group -4-nitrophenoxy) propyl) (methyl) sulfane (2.0g, 7.77mmol) is dissolved in dichloro It in methane (30mL), is added benzoyl hydroperoxide (2.0g, 11.59mmol), is reacted 3 hours at 25 DEG C.Reaction is completed, and water is added (100mL) is extracted with methylene chloride (3 × 50mL), and organic phase merges, and concentration, residue is through silica gel column chromatography (petroleum ether: second Acetoacetic ester=3:1) obtain title compound (1.5g, yield 66.7%).
(3) preparation of 2- methoxyl group -4- (3- (methyl sulphonyl) propoxyl group) aniline
2- methoxyl group -4- (3- (methyl sulphonyl) propoxyl group) -1- nitrobenzene (1.5g, 5.18mmol) is dissolved in methanol In (30mL), Raney's nickel is added, leads to hydrogen, is reacted overnight at 25 DEG C.Reaction is completed, filtering, and filtrate concentration, residue is directly used In in next step (1.0g, yield 74.6%).
(4) the chloro- N- of 4- (2- methoxyl group -4- (3- (methyl sulphonyl) propoxyl group) phenyl) -5- (trifluoromethyl) pyrimidine -2- The preparation of amine
Bis- chloro- 5- (trifluoromethyl) pyrimidine (0.84g, 3.87mmol) of 2,4- is dissolved in the tert-butyl alcohol (10mL) and 1,2- bis- In the mixed solution of chloroethanes (10mL), under ice-water bath, it is added zinc chloride diethyl ether solution (1N, 8.5ml, 8.50mmol), stirring 1h, then triethylamine (0.43g, 4.26mmol) is added dropwise in reaction solution, continue to stir 20min., by 2- methoxyl group -4- (3- (methyl sulphonyl) propoxyl group) aniline (1.0g, 3.86mmol) is dissolved in the tert-butyl alcohol (2mL) and 1,2- dichloroethanes (2mL), slowly It is added dropwise in reaction solution, reacts 12h at 25 DEG C.Solution is spin-dried for, ethyl acetate (50mL) and water (30mL), liquid separation, water is added It is mutually extracted with ethyl acetate (2 × 20mL), organic phase merges, and concentration, residue re-crystallizing in ethyl acetate obtains title compound Object (500mg, yield 29.5%).
(5)N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- (3- (methyl sulphonyl) propoxyl group) Phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By the chloro- N- of 4- (2- methoxyl group -4- (3- (methyl sulphonyl) propoxyl group) phenyl) -5- (trifluoromethyl) pyrimidine -2- Amine (170.0mg, 0.386mmol) and the fluoro- 2- methoxyl group -5- nitroaniline (72.0mg, 0.387mmol) of 4- are dissolved in 1,4- dioxy In six rings (5mL), 3 drop concentrated hydrochloric acids are added, is heated to 100 DEG C, reacts 12h.Solution is spin-dried for, be added ethyl acetate (50mL) and Water (20mL), liquid separation, water phase are extracted with ethyl acetate (2 × 30mL), and organic phase merges, concentration, residue ethyl acetate weight Crystallization, obtains title compound (180mg, yield 79.1%).
(6)N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2(2- first Oxygroup -4- (3- (methyl sulphonyl) propoxyl group) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- (3- (methyl sulphonyl) propoxyl group) Phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (180.0mg, 0.305mmol) is dissolved in N,N-dimethylformamide (5mL) In, N is added1, N1, N2Trimethylethane -1,2- diamines (47.0mg, 0.460mmol) and N, N- diisopropylethylamine (118.0mg, 0.913mmol) is heated to 85 DEG C, reacts 3h.Ethyl acetate (20mL) and water (40mL), liquid separation, water phase is added With ethyl acetate (2 × 10mL) extract, organic phase merge, concentration, residue through silica gel column chromatography (methylene chloride: methanol=30: 1) title compound (140mg, yield 68.4%) is obtained.
(7)N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2- methoxyl group -4- (3- (methyl sulphonyl) third Oxygroup) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1The preparation of methylbenzene -1,2,4- triamine
By N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2(2- methoxy Base -4- (3- (methyl sulphonyl) propoxyl group) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (140mg, 0.208mmol) is molten Solution is added palladium carbon (50mg) in methanol (10mL), is passed through hydrogen, 12h is reacted at 25 DEG C, filters, and filtrate concentration obtains title Compound (110mg, yield 82.4%).
(8) the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- (3- (methyl sulphonyl) propoxyl group) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propionamide Preparation
By N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2- methoxyl group -4- (3- (methyl sulphonyl) third Oxygroup) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1Methylbenzene -1,2,4- triamine (110.0mg, It 0.171mmol) is dissolved in the mixed solution of tetrahydrofuran (10mL) and water (2mL), addition 3- chlorpromazine chloride (47.0mg, 0.37mmol), 2h is reacted at 25 DEG C.Solution is spin-dried for, is added ethyl acetate (20mL), saturated sodium bicarbonate (10mL) washing, Water phase with ethyl acetate (2 × 10mL) extract, organic phase merge, concentration, residue directly carry out next step reaction (125.2mg, Yield 100%).
(9) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxyl group -4- (3- (methyl sulphonyl) propoxyl group) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and acrylamide system It is standby
By the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxyl group - 4- (3- (methyl sulphonyl) propoxyl group) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propionamide (125.2mg, 0.171mmol) is dissolved in tetrahydrofuran (10mL), is added sodium hydroxide solution (5N, 1.0mL), is heated to 60 DEG C, react 12h.Ethyl acetate (20mL) and water (10mL) is added, liquid separation, water phase is extracted with ethyl acetate (2 × 10mL), organic Mutually merge, concentration, residue obtains title compound (65mg, yield through silica gel column chromatography (methylene chloride: methanol=20:1) 57.1%).
Molecular formula: C31H40F3N7O6S molecular weight: 695.8LC-MS (m/z): 696.4 (M+H+)
1H-NMR(400MHz,CDCl3) δ: 10.10 (s, 1H), 8.30 (s, 1H), 8.19 (d, J=7.6Hz, 1H), 7.77 (brs, 1H), 7.55 (brs, 1H), 6.80 (s, 1H), 6.29-6.47 (m, 4H), 5.69 (d, J=10.0Hz, 1H), 4.06 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.25 (t, J=6.8Hz, 2H), 2.95 (s, 3H), 2.89 (s, 2H), 2.73 (s, 3H),2.28-2.32(m,10H).
13 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- first Oxygroup -4- ((tetrahydrofuran -3- base) oxygroup) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acryloyl The preparation of amine (compound 16)
(1) preparation of 3- (3- methoxyl group -4-nitrophenoxy) tetrahydrofuran
By 3- methoxyl group -4- nitrophenol (1.0g, 5.91mmol), 3- hydroxyl tetrahydrofuran (0.52g, 5.91mmol) and Triphenylphosphine (1.86g, 7.09mmol) is dissolved in anhydrous THF (40mL), by reaction solution nitrogen protection and is down to 0 DEG C, then It is slowly dropped into diethyl azodiformate (1.5g, 8.8mmol), is finished, reaction solution is moved to 25 DEG C and is reacted 16 hours.It has reacted Reaction solution is concentrated after finishing, residue column chromatographs (PE:EA=8:1) purifying, obtains title compound (1.2g, yield 84.8%).
(2) preparation of 2- methoxyl group -4- ((tetrahydrofuran -3- base) oxygroup) aniline
3- (3- methoxyl group -4-nitrophenoxy) tetrahydrofuran (1.2g, 5.02mmol) is dissolved in MeOH (20mL), with Palladium carbon (0.2g, 10%) is added afterwards and is passed through hydrogen, reacts at room temperature 2 hours.After completion of the reaction, it filters, filtrate concentration obtains title Compound (0.9g, yield 85.8%).
(3) the chloro- N- of 4- (2- methoxyl group -4- ((tetrahydrofuran -3- base) oxygroup) phenyl) -5- (trifluoromethyl) pyrimidine -2- The preparation of amine
At 0 DEG C, zinc chloride diethyl ether solution (8.6mL, 8.6mmol, 1M) is added dropwise to 2,4- chloro- 5- (trifluoromethyl) pyrimidine In the mixed solution (40mL, tBuOH:DCE=1:1) of the tBuOH and DCE of (0.94g, 4.33mmol), stirred 1 hour at 0 DEG C, Then by 2- methoxyl group -4- ((tetrahydrofuran -3- base) oxygroup) aniline (0.9g, 4.3mmol) and triethylamine (0.53g, It 5.24mmol) is added sequentially in reaction system, 25 DEG C are stirred 16 hours.It being concentrated under reduced pressure, solid is recrystallized with methanol (50mL), Obtain title compound (1.0g, yield 59.6%).
(4)N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- ((tetrahydrofuran -3- base) oxygroup) Phenyl) preparation of -5- (trifluoromethyl) pyrimidine -2,4- diamines
By the chloro- N- of 4- (2- methoxyl group -4- ((tetrahydrofuran -3- base) oxygroup) phenyl) -5- (trifluoromethyl) pyrimidine -2- amine The fluoro- 2- methoxyl group -5- nitroaniline (0.57g, 3.06mmol) of (1.0g, 2.57mmol) and 4- is added to dioxane In (30mL), then concentrated hydrochloric acid (1mL, 36%) is instilled, reaction solution is then heated to 100 DEG C and is reacted 2 hours.End of reaction, will Reaction solution concentration, residue with ethyl acetate (50mL) washing, dry title compound (0.9g, yield 65.0%).
(5)N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2-(2- Methoxyl group -4- ((tetrahydrofuran -3- base) oxygroup) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- ((tetrahydrofuran -3- base) oxygroup) benzene Base) -5- (trifluoromethyl) pyrimidine -2,4- diamines (0.9g, 1.67mmol) and N1,N1,N2Trimethylethane -1,2- diamines (0.52g, 5.09mmol) is added in acetonitrile (20mL), is heated to 85 DEG C and is reacted 2 hours.End of reaction, by reaction solution water (100mL) dilution, ethyl acetate (100mL × 3) extraction, merges organic phase, is concentrated under reduced pressure, obtains title compound (0.7g, yield 67.5%).
(6)N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2- methoxyl group -4- ((tetrahydrofuran -3- Base) oxygroup) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1The preparation of aminomethyl phenyl -1,2,4- triamine
By N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2(2- first Oxygroup -4- ((tetrahydrofuran -3- base) oxygroup) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (0.6g, 0.96mmol) and Palladium carbon (100mg, 10%) is added in methanol (30mL), then under hydrogen environment 25 DEG C be stirred to react 1 hour.It has reacted Finish, filtering, filtrate concentration obtains title compound (500mg, yield 87.6%).
(7) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxyl group -4- ((tetrahydrofuran -3- base) oxygroup) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) and acrylamide system It is standby
Acryloyl chloride (30.6mg, 0.34mmol) is added dropwise to N at 25 DEG C1(2- (dimethylamino) ethyl) -5- first Oxygroup-N4(2- ((2- methoxyl group -4- ((tetrahydrofuran -3- base) oxygroup) phenyl) amino) -5- (trifluoromethyl) pyrimidine -4- Base)-N1Aminomethyl phenyl -1,2, in tetrahydrofuran (5mL) solution of 4- triamine (100mg, 0.17mmol), 25 DEG C of reactions 1 are small When.Reaction solution is concentrated end of reaction, add methylene chloride (10mL) and successively with saturated sodium bicarbonate solution (20mL), Saturated salt solution (20mL) washing, organic phase are concentrated under reduced pressure, and residue is separated through thin-layer chromatography (DCM:MeOH=20:1), must mark It inscribes compound (50mg, yield 45.8%).
Molecular formula: C31H38F3N7O5Molecular weight: 645.7LC-MS (m/z): 646.4 (M+H+)
1H-NMR (400MHz, MeOD) δ: 8.22 (s, 1H), 7.74 (d, J=8.8Hz, 1H), 6.97 (s, 1H), 6.54- 6.60 (m, 2H), 6.30-6.40 (m, 2H), 5.81 (d, J=10.0Hz, 1H), 4.97 (s, 1H), 3.87-3.98 (m, 7H), 3.83(s,3H),3.25(s,2H),2.84(s,2H),2.71(s.,3H),2.55(s,6H),2.19–2.25(m,1H),2.06– 2.10(m,1H).
14 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- first Oxygroup -4- ((tetrahydrofuran -3- base) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acryloyl The preparation of amine (compound 17)
(1) preparation of N- (3- methoxyl group -4- nitrobenzophenone) tetrahydrofuran -3- amine
By the fluoro- 2- methoxyl group -1- nitrobenzene (3.93g, 23.0mmol) of 4-, 3- amido tetrahydrofuran (2.0g, 23.0mmol), triethylamine (2.32g, 23.0mmol) is added in n,N-Dimethylformamide (50mL).100 DEG C of heating 8 are small When.It is added ethyl acetate (200mL), with saturated common salt water washing, organic phase is dry, is spin-dried for, crude product is through silica gel column chromatography (petroleum Ether: ethyl acetate=5:1) purify to obtain product (3.89g, yield 71.1%).
(2) 3- methoxyl group-N1The preparation of (tetrahydrofuran -3- base) benzene -1,4- diamines
N- (3- methoxyl group -4- nitrobenzophenone) tetrahydrofuran -3- amine (3.89g, 16.3mmol) is dissolved in methanol (25mL) In, it is added palladium-carbon catalyst (389mg), replacing hydrogen is stirred at room temperature 2 hours, filters, is washed, be spin-dried for molten with a small amount of methanol Agent, crude product purify to obtain product (2.78g, yield 82.0%) through silica gel column chromatography (methylene chloride: methanol=10:1).
(3)N1(4- chloro- 5- (trifluoromethyl) pyrimidine -2-base) -2- methoxyl group-N4(tetrahydrofuran -3- base) benzene -1,4- The preparation of diamines
By 3- methoxyl group-N1The tert-butyl alcohol that (tetrahydrofuran -3- base) benzene -1,4- diamines (2.78g, 13.4mmol) is dissolved in In the mixed solution (1:1,30mL) of 1,2- dichloroethanes, the diethyl ether solution of the zinc chloride of addition (1.0mol/L, 13.4mL, 3.4mmol), the chloro- 5- trifluoromethyl pyrimidine (2.91g, 13.4mmol) of 2,4- bis-, triethylamine are sequentially added after stirring 30 minutes (1.35g, 13.4mmol) is stirred at room temperature 2 hours, and water (200mL) quenching reaction is added, is extracted with dichloromethane, is spin-dried for solvent, Product (2.72g, yield 52.1%) is obtained with recrystallizing methanol.
(4) preparation of the fluoro- 2- aminoanisole of 4-
The fluoro- 2- methoxyl group -1- nitrobenzene (5.13g, 30mmol) of 4- is dissolved in methanol (50mL), palladium-carbon catalyst is added (513mg), replacing hydrogen are stirred at room temperature 30 minutes, filter, and organic phase is spin-dried for obtaining product (3.60g, yield 85%).
(5) preparation of the fluoro- 2- methoxyl group -5- nitroaniline of 4-
The fluoro- 2- aminoanisole (3.60g, 25.5mmol) of 4- is dissolved in the concentrated sulfuric acid (25mL), is slowly added under ice bath Concentrated nitric acid (65%, 1.77mL, 25.5mmol) is stirred at room temperature 30 minutes, is slowly added to water (150mL), filters, solid dichloro Methane dissolution, saturated sodium bicarbonate solution washing, organic phase is dry with anhydrous sodium sulfate, is spin-dried for, crude product is through silica gel column chromatography (stone Oily ether: ethyl acetate=10:1) purify to obtain product (1.94g, yield 41%).
(6)N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- ((tetrahydrofuran -3- base) amino) Phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines preparation
By the fluoro- 2- methoxyl group -5- nitroaniline of 4- (372mg, 2.0m mol), N1(4- chloro- 5- (trifluoromethyl) pyrimidine- 2- yl) -2- methoxyl group-N4(tetrahydrofuran -3- base) benzene -1,4- diamines (778mg, 2.0m mol), hydrochloric acid (74mg) are added to In Isosorbide-5-Nitrae-dioxane (10mL), nitrogen protection, 100 DEG C oil bath 2 hours.It is spin-dried for solvent, saturated solution of sodium bicarbonate is added (10mL), is extracted with dichloromethane, and organic phase is dry with anhydrous sodium sulfate, is spin-dried for, crude product is through silica gel column chromatography (petroleum ether: second Acetoacetic ester=4:1) purify to obtain product (699mg, yield 65%).
(7)N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2-(2- Methoxyl group -4- ((tetrahydrofuran -3- base) amino) phenyl) preparation of -5- (trifluoromethyl) pyrimidine -2,4- diamines
By N4(the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-)-N2(2- methoxyl group -4- ((tetrahydrofuran -3- base) amino) benzene Base) -5- (trifluoromethyl) pyrimidine -2,4- diamines (699mg, 1.30mmol), N, N, N- trimethyl ethylenediamine (133mg, 1.30mmol), diisopropylethylamine (168mg, 1.30mmol) is dissolved in n,N-Dimethylformamide (15mL), 100 DEG C of stirrings 2 Hour, it is cooled to room temperature, is added ethyl acetate (200mL), is washed with saturated salt solution (200mL), organic phase is dry, is spin-dried for, slightly Product purify to obtain product (371mg, yield 46%) through silica gel column chromatography (methylene chloride: methanol=10:1).
(8)N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2- methoxyl group -4- ((tetrahydrofuran -3- Base) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1The preparation of methylbenzene -1,2,4- triamine
By N4(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N2(2- first Oxygroup -4- ((tetrahydrofuran -3- base) amino) phenyl) -5- (trifluoromethyl) pyrimidine -2,4- diamines (371mg, 0.60mmol) It is dissolved in methanol (10mL), is added palladium-carbon catalyst (37mg), replacing hydrogen is stirred at room temperature 30 minutes, filters, and organic phase is spin-dried for Product (323mg, yield 91.5%).
(9) the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- ((tetrahydrofuran -3- base) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propionamide Preparation
By N1(2- (dimethylamino) ethyl) -5- methoxyl group-N4(2- ((2- methoxyl group -4- ((tetrahydrofuran -3- base) Amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl)-N1Methylbenzene -1,2,4- triamine (323mg, 0.546mmol) It is added in methylene chloride (5mL).3- chlorpromazine chloride (69.3mg, 0.546mmol) is slowly added dropwise under ice bath, is added dropwise and rises to It is stirred at room temperature 2 hours, is added saturated sodium bicarbonate (5mL), extracted with ethyl acetate (30mL), organic phase is dry with anhydrous sodium sulfate It is dry, it is spin-dried for, crude product purifies to obtain product (200mg, yield 53.8%) through silica gel column chromatography (methylene chloride: methanol=10:1).
(10) N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxyl group - 4- ((tetrahydrofuran -3- base) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acrylamide Preparation
By the chloro- N- of 3- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- methoxy Base -4- ((tetrahydrofuran -3- base) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) propionamide (200mg, 0.294mmol) is dissolved in tetrahydrofuran (10mL), the sodium hydrate aqueous solution of addition (1.0mol/L, 0.29mL, 0.29mol), 60 DEG C are warming up to stir 1 hour.It is cooled to room temperature, is added sodium chloride saturated solution (20mL), is extracted with methylene chloride It takes, organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and reversed phase chromatography separation (water: acetonitrile=10:1-3:2) obtains product, and (41mg is produced Rate 21.7%).
Molecular formula: C31H39F3N8O4Molecular weight: 644.7LC-MS (m/z): 645.3 (M+H+)
1H-NMR(400MHz,MeOD)δ:8.15(s,1H),7.50(s,1H),6.94(s,1H),6.81-6.86(m, 1H), 6.25-6.45 (m, 3H), 6.13 (s, 1H), 5.80 (d, 1H, J=9.2Hz), 4.01-4.10 (m, 1H), 3.92-3.95 (m,2H),3.92(s,3H),3.80-3.83(m,1H),3.78(s,3H),3.63-3.65(m,1H),3.33-3.40(m,2H), 3.07-3.15(m,2H),2.68-2.80(m,9H),2.20-2.30(m,1H),1.82-1.92(m,1H).
15 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((2- ((2- first Oxygroup -4- ((tetrahydrofuran -3- base) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) acryloyl The preparation of amine (compound 23)
(1) preparation of tert-butyl 4- Acetylpiperazine -1- carboxylate
N-Boc- piperazine (3.70g, 20mmol) is dissolved in methylene chloride (50mL), addition triethylamine (2.02g, 20mmol), chloroacetic chloride (1.57g, 20mmol) is added under ice bath, rises to 25 DEG C and stirs 30 minutes, it is molten that sodium bicarbonate saturation is added Liquid (50mL) is extracted with methylene chloride (100mL), and organic phase is dry with anhydrous sodium sulfate, is spin-dried for, pillar layer separation (dichloromethane Alkane: methanol=10:1) obtain product as white solid (3.82g, yield 83.8%).
(2) preparation of N- Acetylpiperazine
4- Acetylpiperazine -1- carboxylic acid tert-butyl ester (3.82g, 16.8mmol) is dissolved in methylene chloride (10mL) and trifluoro second In the mixed solution of sour (10mL), 25 DEG C are stirred 30 minutes, are depressurized and are spin-dried for solvent, pillar layer separation (methylene chloride: methanol= 10:1) obtain yellow oil (1.91g, yield 88.8%).
(3) preparation of N- acetyl group-N- (3- methoxyl group -4- nitrobenzophenone) piperazine
By the fluoro- 2- methoxyl group -1- nitrobenzene (2.55g, 14.9mmol) of 4-, N- Acetylpiperazine (1.91g, 14.9mmol), potassium carbonate (2.47g, 17.9mmol) is added in n,N-dimethylacetamide (25mL).It is heated to 120 DEG C instead It answers 5 hours.It is added ethyl acetate (50mL), is washed with saturated salt solution (50mL), organic phase is dry, is spin-dried for, column chromatography (petroleum Ether: ethyl acetate=5:1) obtain product as white admittedly (body 1.87g, yield 45.0%).
(4) preparation of 1- (4- (4- amino -3- methoxyphenyl) piperazine -1- base) ethyl ketone
N- acetyl group-N- (3- methoxyl group -4- nitrobenzophenone) piperazine (1.87g, 6.7mmol) is dissolved in methanol (25mL) In, it is added palladium-carbon catalyst (187mg), replacing hydrogen, 25 DEG C are stirred 2 hours, are filtered, are washed, be spin-dried for a small amount of methanol (5mL) Solvent, pillar layer separation (methylene chloride: methanol=10:1) obtain brown solid (1.4g, yield 83.9%).
(5) preparation of the chloro- N- of 2- (the fluoro- 3- nitrobenzophenone of 4-) -5- (trifluoromethyl) pyridine -4- amine
By 2- chlorine-4-iodine -5- (trifluoromethyl) pyridine (2.36g, 7.68mmol), the fluoro- 3- nitroaniline of 4- (1.0g, 6.41mmol), cesium carbonate (4.2g, 12.9mmol), tris(dibenzylideneacetone) dipalladium (236mg) and 4, the bis- diphenylphosphines-of 5- 9,9- xanthphos (236mg) are added in 1,4- dioxane (30mL).It is small to be heated to 100 DEG C of reactions 6 for nitrogen protection When.Evaporated under reduced pressure solvent after completion of the reaction, column chromatography (petroleum ether: ethyl acetate=10:1) separate faint yellow solid (1.0g, Yield 46.5%).
(6) 1- (4- (4- ((6- ((the fluoro- 3- nitrobenzophenone of 4-) amino) -5- (trifluoromethyl) pyridine -2- base) amino) -3- Methoxyphenyl) piperazine -1- base) ethyl ketone preparation
By the chloro- N- of 2- (the fluoro- 3- nitrobenzophenone of 4-) -5- (trifluoromethyl) pyridyl group -4- amine (671mg, 2.0mmol), 1- (4- (4- amino -3- methoxyphenyl) piperazine -1- base) ethyl ketone (498mg, 2.0mmol), cesium carbonate (652mg, 2.0mmol), Tris(dibenzylideneacetone) dipalladium (67mg) and 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl (67mg) are added to 1,4- bis- In six ring of oxygen (30mL).Nitrogen protection is heated to 100 DEG C and reacts 6 hours.Evaporated under reduced pressure solvent after completion of the reaction, column chromatography (stone Oily ether: ethyl acetate=10:1-4:1) separate to obtain faint yellow solid (275mg, yield 25.1%).
(7) 1- (4- (4- ((6- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- nitrobenzophenone) amino) - 5- (trifluoromethyl) pyridine -2- base) amino) -3- methoxyphenyl) piperazine -1- base) ethyl ketone preparation
By 1- (4- (4- ((6- ((the fluoro- 3- nitrobenzophenone of 4-) amino) -5- (trifluoromethyl) pyridine -2- base) amino) -3- Methoxyphenyl) piperazine -1- base) ethyl ketone (275mg, 0.50mmol), N, N, N- trimethyl ethylenediamine (51mg, 0.50mmol), N,N-diisopropylethylamine (65mg, 0.50mmol) is added in n,N-Dimethylformamide (5mL), is heated to 100 DEG C of reactions 5 Hour.It being added sodium chloride saturated solution (30mL), is extracted with methylene chloride (50mL), (50mL) three times is washed with water in organic phase, Anhydrous sodium sulfate is dry, is spin-dried for, and pillar layer separation (methylene chloride: methanol=10:1) obtains product pale yellow oily liquid (238mg, yield 75.4%).
(8) 1- (4- (4- ((6- ((3- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) - 5- (trifluoromethyl) pyridine -2- base) amino) -3- methoxyphenyl) piperazine -1- base) ethyl ketone preparation
By 1- (4- (4- ((6- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3- nitrobenzophenone) amino) - 5- (trifluoromethyl) pyridine -2- base) amino base) -3- methoxyphenyl) piperazine -1- base) ethyl ketone (238mg, 0.38mmol) is dissolved in It in methanol (10mL), is added palladium-carbon catalyst (24mg), replacing hydrogen, 25 DEG C are stirred 2 hours, are filtered, with a small amount of methanol (5mL) Washing, is spin-dried for solvent, obtains faint yellow oil product (183mg, yield 80.7%).
(9) N- (5- ((6- ((4- (4- Acetylpiperazine -1- base) -2- methoxyphenyl) amino) -3- (trifluoromethyl) pyrrole Pyridine -2- base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) and -3- chlorine propionamide preparation
By 1- (4- (4- ((6- ((3- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) - 5- (trifluoromethyl) pyridine -2- base) amino) -3- methoxyphenyl) piperazine -1- base) ethyl ketone (183mg, 0.304mmol), three second Amine (31mg, 0.307mmol) is dissolved in methylene chloride (10mL), and 3- chlorpromazine chloride (39mg, 0.307mmol) is added under ice bath, 25 DEG C are risen to after adding to stir 30 minutes, is spin-dried for solvent, are added saturated solution of sodium bicarbonate (10mL), are used methylene chloride (30mL) extraction, organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and pillar layer separation (methylene chloride: methanol=10:1) obtains yellowish Color oil product (139mg, yield 66.2%).
(10) N- (5- ((6- ((4- (4- Acetylpiperazine -1- base) -2- methoxyphenyl) amino) -3- (trifluoromethyl) Pyridine -2- base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) and acrylamide preparation
By N- (5- ((6- ((4- (4- Acetylpiperazine -1- base) -2- methoxyphenyl) amino) -3- (trifluoromethyl) pyrrole Pyridine -2- base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -3- chlorine propionamide (139mg, It 0.20mmol) is dissolved in tetrahydrofuran (10mL), is added sodium hydrate aqueous solution (1.0mol/L, 0.20mL, 0.20mol), rise Temperature to 60 DEG C stir 1 hour.It is cooled to 25 DEG C, is added sodium chloride saturated solution (20mL), is extracted with methylene chloride (30mL), it is organic It is mutually dry with anhydrous sodium sulfate, it is spin-dried for, reversed phase chromatography separation (water: acetonitrile=10:1-3:2) obtains product as white solid, and (85mg is produced Rate 64.5%).
1H-NMR(400MHz,CDCl3)δ:8.03(s,1H),7.81(s,1H),7.27-7.29(m,2H),7.07(dd, 1H,J 1=8.4Hz, J2=2.0Hz), 6.72-6.79 (m, 1H), 6.60 (d, 1H, J=1.6Hz), 6.41-6.46 (m, 2H), 6.15(s,1H),5.86(dd,1H,J 1=6.4Hz, J2=1.6Hz), 3.80 (s, 3H), 3.56-3.65 (m, 4H), 3.25- 3.28(m,2H),2.76(s,3H),3.12-3.15(m,2H),3.05-3.12(m,4H),2.74(s,6H),2.68(s,3H), 2.16(s,3H)。

Claims (7)

  1. General formula 1. (I) compound represented, its pharmaceutically acceptable salt or its stereoisomer:
    Wherein,
    Y is selected from C or N；
    W, Q is separately selected from NH or O；
    M is selected from 2；
    L is selected from and is not present；
    R3Selected from hydrogen atom, halogen atom, hydroxyl, amino, C1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alcoxyl Base or C1-4Alkyl sulphonyl；
    R4Selected from hydrogen atom, 6 circle heterocyclic ring bases being optionally substituted with a substituent, the substituent group is selected from halogen atom, C1-4Alkyl, C1-4Alkyl-carbonyl or C1-4Alkyl sulphonyl；
    R1、R2、R5、R6Separately it is selected from hydrogen atom, halogen atom, C1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkoxy or halogen For C1-4Alkoxy；
    R7、R7' it is selected from hydrogen atom；
    R8Selected from hydrogen atom, methyl or ethyl.
  2. 2. compound described in claim 1, its pharmaceutically acceptable salt or its stereoisomer:
    Wherein,
    R3Selected from hydrogen atom, chlorine atom, hydroxyl, amino, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, methyl sulphonyl, Sulfonyl propyl base or isopropelsulfonyl；
    R4Selected from hydrogen atom, the THP trtrahydropyranyl, tetrahydropyridine ketone group, the dihydropyridine ketone group, piperidones that are optionally substituted with a substituent Base, piperidyl, piperazinyl or morpholinyl, the substituent group are selected from chlorine atom, fluorine atom, methyl, ethyl, acetyl group, methylsulfonyl Base or the third sulfonyl；
    R1、R2、R5、R6Separately it is selected from hydrogen atom, chlorine atom, fluorine atom, methyl, trifluoromethyl, methoxyl group or fluoroform Oxygroup；
    R7、R7' it is selected from hydrogen atom；
    R8Selected from hydrogen atom, methyl or ethyl.
  3. 3. compound as stated in claim 2, its pharmaceutically acceptable salt or its stereoisomer, the compound choosing From:
  4. General formula 4. (I) compound represented, its pharmaceutically acceptable salt or its stereoisomer:
    Wherein,
    Y is selected from N；
    W, Q is separately selected from NH；
    M is selected from 2；
    L is selected from O or NH；
    R3Selected from methyl, ethyl, trifluoromethyl, methoxyl group, ethyoxyl or trifluoromethoxy；
    R4Selected from methyl, ethyl, propyl, isopropyl, pyrrolidinyl, tetrahydrofuran base, the thiophane being optionally substituted with a substituent Base, piperidyl, piperazinyl or morpholinyl, the substituent group be selected from acetyl group, acetylamino, mesyl or methanesulfonamido,；
    R1、R2、R5、R6Separately it is selected from hydrogen atom, chlorine atom, fluorine atom, methyl, ethyl, trifluoromethyl, methoxyl group or three Fluorine methoxyl group；
    R7、R7' it is selected from hydrogen atom；
    R8Selected from hydrogen atom, methyl or ethyl.
  5. 5. compound as claimed in claim 4, its pharmaceutically acceptable salt or its stereoisomer, the compound are selected from:
  6. 6. pharmaceutical composition contains compound described in claim 1 or 4 or its pharmaceutically acceptable salt or its solid Isomers and one or more pharmaceutical carriers and/or diluent.
  7. 7. compound described in claim 1 or 4, its pharmaceutically acceptable salt or its stereoisomer preparation treatment and/ Or the purposes in the prevention EGFR mutation Cancerous disease caused and the drug of the caused drug resistance disease of EGFR T790M mutation, institute State cancer be selected from non-small cell lung cancer, head and neck cancer, breast cancer, kidney, cancer of pancreas, cancer of the esophagus, prostate cancer, oophoroma or they Any combination.
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