CN108047204A - 2,4- diarylamino pyrimidine derivatives and its preparation method and application - Google Patents

2,4- diarylamino pyrimidine derivatives and its preparation method and application Download PDF

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CN108047204A
CN108047204A CN201810014443.4A CN201810014443A CN108047204A CN 108047204 A CN108047204 A CN 108047204A CN 201810014443 A CN201810014443 A CN 201810014443A CN 108047204 A CN108047204 A CN 108047204A
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amino
phenyl
base
pyrimidine
chloro
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翟鑫
左代英
宫平
王娇
郭明
王小强
类红瑞
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • 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
    • C07D239/50—Three 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • 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
    • C07D405/14—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 three or more hetero rings

Abstract

The present invention relates to 2 shown in general formula I, 4 diarylamino pyrimidine derivatives and its optical isomer, pharmaceutically acceptable salt, solvate or prodrug, compound shown in their preparation method and general formula I is the pharmaceutical composition of active ingredient, wherein substituent R1、R2、R3、R4、R5、R6, X there is the meaning that provides in the description.The invention further relates to compounds of formula I to have strong ALK and ROS1 kinase inhibitory activities, and it further relates to such compound and its optical isomer, pharmaceutically acceptable salt is preparing to treat and/or prevent due to the application in the drug of ALK and ROS1 unconventionality expression diseases caused, the particularly purposes in the drug for the treatment of and/or pre- anti-cancer is prepared.

Description

2,4- diarylamino pyrimidine derivatives and its preparation method and application
Technical field
The invention belongs to pharmaceutical technology fields, are related to 2,4- diarylaminos pyrimidine derivatives and its optical isomer, pharmacy Upper acceptable salt, solvate or prodrug, their preparation method and the pharmaceutical composition containing the compound.This hair It is bright further relate to the stronger ALK and ROS1 kinase inhibitory activities of the compound and its prepare for treat and/or prevent due to Application in the drug of ALK and ROS1 unconventionality expression diseases caused is particularly preparing the drug for the treatment of and/or pre- anti-cancer In purposes.
Background technology
The research of kinases target drug has become the important directions of current antitumor drug research and development.It is presently found to swash Protein kinases are one kind of known most study in enzyme target drug.Protein kinase can cause signal due to being mutated or resetting There is exception in conductive process obstacle, causes cell growth, differentiation, metabolism and biological behaviour abnormal, thus can induce a variety of Tumour.
Protein kinase (Protein Kinases, PKs) is a kind of terminal phosphate transesterify catalytic proteins by ATP Tyrosine, the enzyme of serine and the di in threonine residues, mainly including protein tyrosine kinase (Protein Tyrosine kinase, PTK) and serine-threonine kinase (Serine-threonine kinase, STK).Pass through signal Transduction pathway, these enzyme adjustment cell growth, differentiation and multiplication etc..PTK by with growth factor ligand binding, make growth factor Receptor is changed into activated form, the latter and the protein-interacting of cell membrane inner surface.This causes the junket of receptor and other albumen Histidine residue phosphorylation and the compound with various kinds of cell matter signaling molecule is caused to be formed in the cell, it is such as thin so as to influence Born of the same parents divide the various kinds of cell reaction such as (multiplication), cell differentiation, cell growth, metabolism.
Between be denatured lymph kinases ALK (anaplastic lymphoma kinase) be found in for the first time in 1994 between be denatured It is the single transmembrane albumen being made of 1620 amino acid in large celllymphoma AMS3 cells, a kind of tyrosine kinase, Belong to one of Insulin Receptor Family member., in embryonic development period in high expression level, subsequent expression is gradually reduced for it, Adulthood is expressed on a small quantity.The albumen is made of catalysis region in film outer portion, trans-membrane region and film, and downstream signaling pathway is Ras-ERK, JAK3-STAT3 and PI3-K/Akt etc., these accesses and cell Proliferation, survival, migration are closely related.
Morri in 1994 et al. discovery, ALK gene and the Nucleophosmin NPM on No. 5 chromosomes on No. 2 chromosomes (nucleophosmin) gene dislocation fusion, rearrangement mutator NMP-ALK have carcinogenicity.Japanese Scientists in 2007 Soda et al. is found that ALK gene is mutated in pulmonary adenocarcinoma for the first time：Occur to be inverted mutation in No. 2 the short arm of a chromosome so that 1~13 exon of echinoderm microtubule associated protein 4 (EML4) gene merges shape with 20~29 exons of ALK gene The NIH-3T3 fibroblasts that EML4-ALK fusions have transfected EML4-ALK fusions have vicious transformation ability.About Have in 3%~7% NSCLC patient that there are EML4-ALK fusions.In addition, research also shows that ALK gene mutation takes part in Kinds of tumors includes the morbidity of gradually changeable large celllymphoma, inflammatory myofibroblastic tumor, neuroblastoma.Therefore, target It can be antitumor to achieve the purpose that by inhibiting ALK downstreams coherent signal to ALK inhibitor.
It is similar with ALK, c-ros sarcoma carcinogen receptor tyrosine kinases ROS1 (ROS proto-oncogene1, Receptor tyrosine kinase) it is also haplotype receptor tyrosine kinase.The fusion of ROS1 genes is over-expressed and dashed forward The imbalance of ROS1 albumen can be caused by becoming.Abnormal ROS1 protein kinases will activate a plurality of oncogenic signals access in downstream, control Cell Proliferation, survival and the access of cell cycle.
The kinase domain of ROS1 and ALK has 49% amino acid homology sequence, and a variety of ALK inhibitor can inhibit in vitro The activity of ROS1.
The present invention has designed and synthesized a series of 2,4- diarylaminos pyrimidine derivatives.It is screened through external activity, shows this Class compound has apparent antitumor activity.
The content of the invention
The present invention relates to the 2,4- diarylaminos pyrimidine derivatives shown in general formula I and its optical isomer, can pharmaceutically connect Salt, solvate or the prodrug received,
Wherein,
X is C or N；
R1For hydroxyl, halogen, nitro, amino, cyano, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl, (C1- C6) alkoxy, (C1-C6) alkyl, (C1-C6) alkyl acyl, (C1-C6) alkyl amido, by 1-2 (C1-C6) alkyl-substituted Glycyl, (C1-C3) alkylenedioxy group；
R2For halogen, halogenated (C1-C6) alkyl, hydroxyl, cyano, amino, nitro；
R3For hydrogen, halogen, (C1-C6) alkyl, (C1-C6) alkoxy, halogen or/and hydroxyl or/and amino substitution (C1- C6) alkyl, halogen or/and hydroxyl or/and amino substitution (C1-C6) alkoxy；
R4For (C1-C6) alkyl, 3-12 members saturation or part unsaturated carbocyclic or unsubstituted comprising N, O and/or S or by The 4-7 circle heterocycles of Y substitutions；Or NHnR8R9、NHnCOR8R9、NHnCONHnR8R9、SO2(CH2)nNR8R9、SO2(CH2)nCONR8R9；
Y is H, (CH2)pR8R9、(CH2)pOR8R9、(CH2)pCO2R8R9、(CH2)pCOR8R9、(CH2)pCONRnR8R9；
R8And R9It is identical or different, it is independently selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C1-C10) alkane Oxygroup, (C2-C10) alkenyl, (C2-C10) alkynyl, cyano, they can be by R identical or different 0-37Substitution；
Or R8And R9It is described with forming 4-10 circle heterocycles base or 4-10 unit's heteroaryls together with the nitrogen-atoms connected with them Heterocycle or heteroaryl except with R8And R9Outside the nitrogen-atoms of connection, optionally containing the 0-4 hetero atoms selected from N, O and/or S, institute Heterocycle or heteroaryl are stated optionally by 0-3 identical or different R7Substitution；
R5And R6It is identical or different, it is independently selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C1-C10) alkane Oxygroup, (C2-C10) alkenyl, (C2-C10) alkynyl, hydroxyl, (C1-C4) hydroxyalkyl, cyano, 4-10 circle heterocycles base or heteroaryl, it is described Heterocycle or heteroaryl contain the hetero atom of 1-3 N, O and/or S, the R5And R6It can be by 0-3 identical or different R7It takes Generation；
Or R5And R6It is described with forming 4-10 circle heterocycles base or 4-10 unit's heteroaryls together with the nitrogen-atoms connected with them Heterocycle or heteroaryl except with R5And R6Outside the nitrogen-atoms of connection, optionally containing the 0-4 hetero atoms selected from N, O and/or S, institute Heterocycle or heteroaryl are stated optionally by 0-3 identical or different R7Substitution；
R7For (C1-C10) alkyl, (C3-C7) cycloalkyl, (C1-C10) alkoxy, hydroxyl, halogen, halogenated (C1-C10) alkyl, Halogenated (C1-C10) alkoxy, nitro；
N independences are for 0-2, and p independences are for 0-6.
2,4- diarylaminos pyrimidine derivatives and its optical isomer shown in preferred formula I of the present invention can pharmaceutically connect Salt, solvate or the prodrug received,
Wherein,
X is C or N；
R1For (C1-C6) alkyl sulphonyl, (C1-C6) alkyl amido；
R2For halogen, halogenated (C1-C4) alkyl, hydroxyl, cyano, amino, nitro；
R3For hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, halogen or/and hydroxyl or/and amino substitution (C1- C4) alkyl, halogen or/and hydroxyl or/and amino substitution (C1-C4) alkoxy；
R4For (C1-C4) alkyl, 3-12 members saturation or part unsaturated carbocyclic or unsubstituted comprising N, O and/or S or by The 5-7 circle heterocycles of Y substitutions；Or NHnR8R9、NHnCOR8R9、NHnCONHnR8R9、SO2(CH2)nNR8R9、SO2(CH2)nCONR8R9；
Y is H, (CH2)pR8R9、(CH2)pOR8R9、(CH2)pCO2R8R9、(CH2)pCOR8R9、(CH2)pCONRnR8R9；
R8And R9It is identical or different to be independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alcoxyl Base, (C2-C6) alkenyl, (C2-C6) alkynyl, cyano, they can be by R identical or different 0-37Substitution；
Or R8And R9It is described with forming 4-10 circle heterocycles base or 4-10 unit's heteroaryls together with the nitrogen-atoms connected with them Heterocycle or heteroaryl except with R8And R9Outside the nitrogen-atoms of connection, optionally containing the 0-4 hetero atoms selected from N, O and/or S, institute Heterocycle or heteroaryl are stated optionally by 0-3 identical or different R7Substitution；
R5And R6It is identical or different to be independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alcoxyl Base, (C2-C6) alkenyl, (C2-C6) alkynyl, hydroxyl, (C1-C4) hydroxyalkyl, cyano, 4-10 circle heterocycles base or heteroaryl, it is described miscellaneous Ring group or heteroaryl contain the hetero atom of 1-3 N, O and/or S, they can be by 0-3 identical or different R7Substitution；
Or R5And R6It is described with forming 4-10 circle heterocycles base or 4-10 unit's heteroaryls together with the nitrogen-atoms connected with them Heterocycle or heteroaryl except with R5And R6Outside the nitrogen-atoms of connection, optionally containing the 0-4 hetero atoms selected from N, O and/or S, institute Heterocycle or heteroaryl are stated optionally by 0-3 identical or different R7Substitution；
R7For (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alkoxy, hydroxyl, halogen, halogenated (C1-C6) alkyl, halogen Generation (C1-C6) alkoxy, nitro；
N independences are for 0-2, and p independences are for 0-4.
2,4- diarylaminos pyrimidine derivatives and its optical isomer shown in preferred formula I of the present invention can pharmaceutically connect Salt, solvate or the prodrug received,
Wherein,
X is C；
R1For (C1-C6) alkyl sulphonyl, (C1-C6) alkyl amido；
R2For halogen；
R3For (C1-C3) alkoxy；
R4For (C1-C4) alkyl, 3-12 members saturation or part unsaturated carbocyclic or unsubstituted comprising N, O and/or S or by The 5-7 circle heterocycles of Y substitutions；Or NHnR8R9、NHnCOR9R9、NHnCONHnR8R9、SO2(CH2)nNR8R9、SO2(CH2)nCONR8R9；
Y is H, (CH2)pR8R9、(CH2)pOR8R9、(CH2)pCO2R8R9、(CH2)pCOR8R9、(CH2)pCONRnR8R9；
R8And R9It is identical or different to be independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alcoxyl Base, (C2-C6) alkenyl, (C2-C6) alkynyl, cyano, they can be by R identical or different 0-37Substitution；
R5And R6It is identical or different to be independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alcoxyl Base, (C2-C6) alkenyl, (C2-C6) alkynyl, hydroxyl, (C1-C4) hydroxyalkyl, cyano, 4-10 circle heterocycles base or heteroaryl, it is described miscellaneous Ring group or heteroaryl contain the hetero atom of 1-3 N, O or S, they can be by 0-3 identical or different R7Substitution；
Or R5And R6It is described with forming 4-10 circle heterocycles base or 4-10 unit's heteroaryls together with the nitrogen-atoms connected with them Heterocycle or heteroaryl except with R5And R6Outside the nitrogen-atoms of connection, optionally containing the 0-4 hetero atoms selected from N, O and/or S, institute Heterocycle or heteroaryl are stated optionally by 0-3 identical or different R7Substitution；
R7For (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, hydroxyl, halogen, halogenated (C1-C4) alkyl, halogen Generation (C1-C4) alkoxy, nitro；
N independences are for 0-2, and p independences are for 0-4.
2,4- diarylaminos pyrimidine derivatives and its optical isomer shown in preferred formula I of the present invention can pharmaceutically connect Salt, solvate or the prodrug received,
Wherein,
X is C；
R1For (C1-C6) alkyl sulphonyl, (C1-C6) alkyl amido；
R2For halogen；
R3For (C1-C3) alkoxy；
R4For (C1-C4) alkyl, 3-12 members saturation or part unsaturated carbocyclic or the unsubstituted or Y comprising N, O and/or S Substituted 5-7 circle heterocycles；Or NHnR8R9、NHnCOR8R9、NHnCONHnR8R9、SO2(CH2)nNR8R9、SO2(CH2)nCONR8R9；
Y is H, (CH2)pR8R9、(CH2)pOR8R8、(CH2)pCO2R8R9、(CH2)pCOR8R9、(CH2)pCONRnR8R9；
R8And R9It is identical or different to be independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alcoxyl Base, cyano, they can be by 0-3 identical or different R7Substitution；
R5And R6It is identical or different, it is independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alcoxyl Base, hydroxyl, (C1-C4) hydroxyalkyl, cyano, 5-10 circle heterocycles base or heteroaryl, the heterocycle or heteroaryl contain 1-3 N, O Or the hetero atom of S, they can be by 0-3 identical or different R7Substitution；
R7For (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoro methoxy Base, nitro；
N independences are for 0-1, and p independences are for 0-2.
2,4- diarylaminos pyrimidine derivatives and its optical isomer shown in preferred formula I of the present invention can pharmaceutically connect Salt, solvate or the prodrug received,
Wherein,
X is C；
R1For isopropelsulfonyl, sulfonyloxy methyl amido, acetylamino；
R2For halogen；
R3For methoxyl group；
R4For (C1-C4) alkyl, 3-12 members saturation or part unsaturated carbocyclic or unsubstituted comprising N, O and/or S or by The 5-7 circle heterocycles of Y substitutions；Or NHnR8R9、NHnCOR8R9、NHnCONHnR8R9、SO2(CH2)nNR8R9、SO2(CH2)nCONR8R9；
Y is H, (CH2)pR8R9、(CH2)pOR8R9、(CH2)pCO2R8R9、(CH2)pCOR8R9、(CH2)pCONRnR8R9；
R8And R9It is identical or different to be independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alcoxyl Base, cyano, they can be by 0-3 identical or different R7Substitution；
R5And R6It is identical or different, it is independently selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C1-C4) alcoxyl Base, hydroxyl, (C1-C4) hydroxyalkyl, cyano, 5-10 circle heterocycles base or heteroaryl, the heterocycle or heteroaryl contain 1-3 N, O Or the hetero atom of S, they can be by 0-3 identical or different R7Substitution；
R7For (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoro methoxy Base, nitro；
N independences are for 0-1, and p independences are for 0-2；
2,4- diarylaminos pyrimidine derivatives and its optical isomer shown in preferred formula I of the present invention can pharmaceutically connect Salt, solvate or the prodrug received,
R1For isopropelsulfonyl；
R2For Cl；
R3For methoxyl group；
R4The amino that substitutes for unsubstituted or Y,
Y is one of following：
H、(CH2)2R8、(CH2)2OR8、CH2CO2R8、COR8、CH2CONHnR8；
R8Selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-64) alkoxy, cyano, they can be by 0-3 phase Same or different R7Substitution；
R5And R6It is identical or different, it is independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alcoxyl Base, cyano, hydroxyl, (C1-C4) hydroxyalkyl, The R5And R6 It can be by 0-3 identical or different R7Substitution；
R7For (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoro methoxy Base, nitro；
N independences are 0-1；
2,4- diarylaminos pyrimidine derivatives and its optical isomer shown in preferred formula I of the present invention can pharmaceutically connect Salt, solvate or the prodrug received,
R1For acetylamino；
R2For Cl；
R3For methoxyl group；
R4The amino that substitutes for unsubstituted or Y,R5And R6 It is identical or different, it is independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, (C2-C6) alkenyl, (C2-C6) alkynyl, hydroxyl, (C1-C4) hydroxyalkyl, cyano, They can be by 0-3 identical or different R7Substitution；
R7For (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoro methoxy Base, nitro；
2,4- diarylaminos pyrimidine derivatives and its optical isomer shown in preferred formula I of the present invention can pharmaceutically connect Salt, solvate or the prodrug received,
Wherein,
R1For sulfonyloxy methyl amido, acetylamino；
R2For Cl；
R3For methoxyl group；
R4For
Y is CH2NR8R9；
R8And R9It is identical or different to be independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alcoxyl Base, cyano, they can be by 0-3 identical or different R7Substitution；
R5And R6It is identical or different, it is independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alcoxyl Base,They can be by 0-3 identical or different R7Substitution；
R7For (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoro methoxy Base, nitro.
2,4- diarylaminos pyrimidine derivatives and its optical isomer shown in preferred formula I of the present invention can pharmaceutically connect Salt, solvate or the prodrug received,
Wherein,
R1For isopropelsulfonyl；
R2For Cl；
R3For methoxyl group；
R4For
R5And R6It is identical or different, it is independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alcoxyl Base,They can be by 0-3 identical or different R7Substitution；
R7For (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoro methoxy Base, nitro.
The compounds of this invention and its optical isomer, pharmaceutically acceptable salt, solvate or prodrug preferably followingization Object is closed, but these compounds are not meant to any limitation of the invention：
1- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxybenzenes Base) imidazolidinyl -2- ketone
3- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxybenzenes Base)-N, N- dimethyl -2- oxoimidazolinium -1- amides
1- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxybenzenes Base) -3- (tetrahydrochysene -2H- pyrans -4- carbonyls) imidazolidinyl -2- ketone
2- (3- (4- (the chloro- 4- of 5- (2- isopropylsulfonyls phenyl) amino) pyrimidine -2- amino) -3- anisyl -2- oxos Imidazoline -1- acetic acid
1- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxybenzenes Base) -3- (2- methoxyethyls) imidazolidinyl -2- ketone
Ethyl -2- (3- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- Methoxyphenyl) -3- methoxyphenyls) -2- imidazolidinyl -1- bases) acetic acid esters
1- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxybenzenes Base) -3- methoxyphenyls) -3- (2- morpholines ethyl) imidazolidinyl -2- ketone
2- (3- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxyl groups Phenyl) -3- methoxyphenyls) -2- oxoimidazolinium -1- bases)-N- (2- hydroxyethyls) acetamide
1- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxybenzenes Base) -3- (2- oxygen -2- (pyrrole radicals -1- bases) ethyl) imidazolidinyl -2- ketone
1- (2- (3- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- first Phenyl) -2- oxoimidazolinium -1- bases) acetyl group) piperidyl -4- ketone
N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (2- oxo-pyrrolidine -1- bases) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) acetamide
(((the chloro- 2- of 5- ((2- methoxyl groups -4- ((3- oxocyclohex -1- alkene -1- bases) amino) phenyl) amino) are phonetic by 2- by N- Pyridine -4- bases) amino) phenyl) acetamide
2- ((4- ((2- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) ammonia Base) the amyl- 1- alkene -1- carboxylic acid, ethyl esters of ring
N- (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) ring third Alkane formamide
N- (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) is thio Morpholine -4- formamides
N- (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) -4- Methyl piperidine -1- formamides
1- ((4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) ammonia Base formoxyl) piperidine-4-ethyl formate
N- (2-((the chloro- 2- of 5- ((4- (3- (4- hydroxy-cyclohexyls) urea groups)-2- methoxyphenyls) amino) pyrimidine-4-yls) Amino) phenyl) acetamide
4- (3- (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) Urea groups) piperidines -1- t-butyl formates
N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (3- (4- oxocyclohexyls) urea groups) phenyl) amino) pyrimidine-4-yl) Amino) phenyl) acetamide
N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (1H- pyrroles -1- bases) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) acetamide
N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (1H- pyrroles -1- bases) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) Methanesulfomide
N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (2- (piperidin-1-yl methyl) -1H- pyrroles -1- bases) phenyl) amino) Pyrimidine-4-yl) amino) phenyl) acetamide
N- (2- ((the chloro- 2- of 5- ((4- (2- ((diethylamine) methyl) -1H- pyrroles -1- bases) -2- methoxyphenyls) amino) Pyrimidine-4-yl) amino) phenyl) Methanesulfomide
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- ((2- (nafoxidine -1- bases) ethyl) Sulfuryl) phenyl) pyrimidine -2,4- diamines
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- ((2- (piperidin-1-yl) ethyl) sulfones Base) phenyl) pyrimidine -2,4- diamines
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- ((2- (4- methyl piperidine -1- bases) second Base) sulfuryl) phenyl) pyrimidine -2,4- diamines
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (((5- (nafoxidine -1- ylmethyls) Furans -2- bases) methyl) sulfenyl) phenyl) pyrimidine -2,4- diamines
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (((5- (piperidin-1-yl methyl) furans Mutter -2- bases) methyl) sulfenyl) phenyl) pyrimidine -2,4- diamines
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (((5- (4- methyl piperidine -1- Ji Jia Base) furans -2- bases) methyl) sulfenyl) phenyl) pyrimidine -2,4- diamines.
Moreover, according to some usual methods of the art, 2, the 4- diarylamino pyrimidines of formula of I of the present invention Derivative can generate pharmaceutically acceptable salt with acid.Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salt, under The salt of the sour addition of row is particularly preferred：Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, benzene sulphur Acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid Deng.
In addition, the prodrug present invention additionally comprises derivative of the present invention.The prodrug of derivative of the present invention is the miazines of general formula I Derivative, their own may have weaker activity even without activity, but upon administration, in physiological conditions (such as Pass through metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
" halogen " refers to fluorine, chlorine, bromine or iodine generation in the present invention；" alkyl " refers to the alkyl of linear chain or branch chain；" alkylidene " Refer to the alkylidene of linear chain or branch chain.
It has been found that the compounds of this invention has in vitro inhibits tumor cell growth activity, therefore, it may be used as making Standby treatment and/or the drug of pre- anti-cancer, as mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, Pancreas, marrow, testis, ovary, lymph, soft tissue, neck, thyroid gland, the cancer of esophagus and leukaemia, neuroblastoma etc..
By the people's primary cutaneous type cell Karpas299 and Gao Biao that inhibit high table NPM-ALK albumen in vitro Up to the HCC78 cells of SLC34A2-ROS1, the human lung adenocarcinoma cell NCI-H2228 and EGFR high tables of height expression EML4-ALK albumen The activity test of the human A549 cell lines reached, the compounds of this invention, which has lung carcinoma cell, lymphocytic cancer cell, to be significantly inhibited Effect, it is especially useful in prepare treatment and/or the drug of prevention lung cancer and lymph cancer.
By finding that the compounds of this invention has to ALK, L1196M ALK, the test of G1202R ALK and ROS1 enzymatic activity It is significant to inhibit ALK, L1196M ALK, G1202R ALK and ROS1 kinase activities, to ALK, L1196M ALK, G1202R ALK There is stronger inhibitory action with lung carcinoma cell, the lymthoma etc. of ROS1 high expression, it is especially useful in prepare treatment and/or prevention lung The drug of cancer.
The reactive compound or its officinal salt and its solvate of the present invention can be used as unique antitumor drug independent It uses or can be with the antitumor drug (such as platinum medicine cis-platinum, camptothecine Irinotecan, the Changchun that have listed Bases drug Noviburn etc.) it is used in combination.Therapeutic alliance by by each therapeutic component simultaneously, order or separate administration come reality It is existing.
Examples provided hereinafter and preparation example further elucidate and illustrate the present invention compound and its preparation side Method.It is limited the scope of the invention it should be appreciated that the scope of following embodiments and preparation example is not sufficient to any mode.
Following synthetic route is summarized and describes the preparation of I derivative of formula of the present invention, and all raw materials all pass through Mode described in these routes, prepared by organic chemistry filed method well-known to the ordinarily skilled artisan or it is commercially available. The all final derivative of the present invention is prepared by the method described in these routes or by similar method, These methods are that organic chemistry filed is well-known to the ordinarily skilled artisan.The whole variable factor following articles applied in these routes Definition in definition or such as claim.
Route 1
Route 2
Route 3
Route 4
Route 5
I derivative of formula according to the invention, all can according to route 1, route 2, route 3, route 4 and route 5 method by Intermediate 1, VII, M1、M2、M3、M4、M5、M6With corresponding HNR5R6In coordinative solvent, pass through nucleophilic displacement of fluorine or condensation reaction system .Wherein, X, Y, R in compound1、R2、R3、R5And R6As defined in the claims.
Route 6
Route 7
Route 8
Route 9
Route 10
Intermediate M1Can according to route 6 by intermediate compound IV with substitution dichloro pyrimidine be condensed, then through nucleophilic displacement of fluorine, reduction and Ring-closure reaction obtains.Wherein, X, R in compound1、R2And R3As defined in the claims.
Intermediate VII, M2、M3Can according to route 7 by intermediate compound IV with substitution dichloro pyrimidine be condensed, then through nucleophilic displacement of fluorine, Reduction, acylated and ring-closure reaction obtain.Wherein, X, R in compound1、R2And R3As defined in the claims.
Intermediate M4It can be condensed according to route 8 by intermediate compound IV and the dichloro pyrimidine of substitution, then through nucleophilic displacement of fluorine and centre Body Ⅻ is condensed to yield.In, X, R in compound1、R2And R3As defined in the claims.
Intermediate M5It can be reacted by XI and mercaptoethanol according to route 9, then reacted through chloro, oxidation, reduction and intermediate V It obtains.Wherein, X, R in compound1、R2And R3As defined in the claims.
Intermediate M6It can be reacted by XI and furfurylmercaptan according to route 10, then be obtained by the reaction through reduction and intermediate V.Wherein, X, R in compound1、R2And R3As defined in the claims.
When X be nitrogen-atoms, R1For isopropylsulfonyl, R3For methoxyl group, compound 1, M1- 1 preparation method such as route 11, Other substituent groups are as defined in the claims.
When X be nitrogen-atoms, R1For glycyl, R3For methoxyl group, compound VII -2, M2-1、M3- 1 preparation method is such as Route 12, other substituent groups are as defined in the claims.
When X be nitrogen-atoms, R1For glycyl or sulfonyloxy methyl amido, R3For methoxyl group, compound M4-1、I6- 1 Preparation method such as route 13, other substituent groups are as defined in the claims.
When X be nitrogen-atoms, R1For isopropylsulfonyl, R3For methoxyl group, compound M5- 1 and I7- 1 preparation method such as route 14, other substituent groups are as defined in the claims.
When X be nitrogen-atoms, R1For isopropylsulfonyl, R3For methoxyl group, compound M6- 1 and I8- 1 preparation method such as route 15, other substituent groups are as defined in the claims.
Route 11
Route 12
Route 13
Route 14
Route 15
Specific embodiment：
Embodiment is intended to illustrate rather than limit the scope of the invention.The nuclear magnetic resonance spectroscopy Bruker of compound ARX-400 is measured, and mass spectrum is measured with Agilent 1100LC/MSD；Agents useful for same is that analysis is pure or chemical pure.
Wherein, R4For R4’-Y；
Table one
Embodiment 1：
Step A isopropyls (2- nitrobenzophenones) thioether (II)
509.1g (3.61mol) o-fluoronitrobenzenes and 698.0g (5.06mol) Anhydrous potassium carbonate are added in 2500mL and done In dry n,N-Dimethylformamide (DMF), 301.8g (3.97mol) isopropyl mercaptan is slowly dropped into, drop finishes, and is warming up to 110 DEG C React 10h.It is cooled to room temperature, reaction solution is poured into a large amount of water, is extracted with ethyl acetate, anhydrous sodium sulfate drying is evaporated molten Agent obtains yellow liquid 604.6g, yield 85.0%.
Step B 1- isopropylsulfonyl -2- nitrobenzenes (III)
197.1g (1.00mol) isopropyl (2- nitrobenzophenones) thioether is added in into 1500mL glacial acetic acid, is slowly dropped into 35% hydrogen peroxide of 583.0g (6.00mol) is warming up to 80 DEG C, reacts 9h.It is cooled to room temperature, reaction solution is poured into a large amount of water, 30min is stirred at room temperature, filters, yellow solid 164.7g, yield 85% are obtained after biscuit is dry.
Step C 2- isopropylsulfonyls aniline (IV -1)
115.0g (0.50mol) intermediate III is added in into 500mL ethyl alcohol, add in 0.6g (0.05mol) activated carbons and 8.1g (0.05mol) anhydrous ferric trichloride, is warming up to 50 DEG C, is slowly dropped into the hydrazine hydrate of 417.2g (5.00mol) 60%, heating To 80 DEG C, 15h is reacted.It filters while hot, boils off most of solvent, residue is poured into water, 30min is stirred at room temperature, filter, filter Light yellow solid 81.62g, yield 82% are obtained after biscuit is dry.
Bis- chloro- N- of step D 2,5- (2- (isopropylsulfonyl) phenyl) pyrimidine -4- amine (V -1)
39.8g (0.20mol) intermediate IV is added in the n,N-Dimethylformamide (DMF) dried to 400mL, ice bath Under 60% hydrogen sodium of 32.0g (0.80mol) is added portionwise, stir 30min under ice bath, be slowly dropped into 73.4g (0.40mol) 2,4,5- Trichloropyrimidine reacts 10h under ice bath.Reaction solution is poured into a large amount of ammonium chloride saturated solutions, 30min is stirred at room temperature, filters, obtains Reddish brown solid.Recrystallized from acetonitrile obtains light yellow solid 27.6g, yield 40.0%.
The chloro- N of step E 5-4- (2- isopropelsulfonyls phenyl)-N2- (2- methoxyl group -4- nitrobenzophenones) pyrimidine -2,4- two Amine (VI -1)
At room temperature, by intermediate 2, bis- chloro- N- of 5- (2- isopropelsulfonyls phenyl) pyrimidine -4- amine (V) (47.5g, 0.14mol), 2- methoxyl groups -4- nitroanilines (23.5g, 0.14mol) and p-methyl benzenesulfonic acid (48.2g, 0.28mol) add in extremely In glycol monoethyl ether (400mL), 100 DEG C of stirring 20h are warming up to.Reaction is finished, and reaction solution is cooled to room temperature, and is filtered, is obtained Yellow solid 31.7g, yield 47.5%.ESI-MS[M+H](m/z):477.9.
Step F N2- (4- amino -2- methoxyphenyls) the chloro- N of -5-4- (2- isopropelsulfonyls phenyl) pyrimidine -2,4- two Amine (VII -1)
At room temperature, VI (31.5g, 0.07mol) is dissolved in 90% ethyl alcohol (150mL)/n,N-Dimethylformamide (DMF) (150mL) in the mixed solvent adds in Iron(III) chloride hexahydrate (FeCl3·6H2O) (2.8g, 0.01mol) and activated carbon (0.3g, 0.02mol), 40 DEG C are warming up to, 80% hydrazine hydrate (43.8g, 0.7mol) is added dropwise, drop finishes, and is warming up to 90 DEG C of stirring 6h.Reaction Finish, filter, after filtrate is cooled to room temperature, pour into water (600mL) while hot, stir 1h, filter, obtain faint yellow solid 21.6g, yield 68.9%.ESI-MS[M+H](m/z):447.8.
Step G 1- (4- (the chloro- 4- of 5- (2- isopropelsulfonyls phenyl) amino) pyrimidine -2- amino) -3- methoxybenzenes Base -3- (2- vinyl chloride) urea (VIII -1)
At room temperature, VII -1 (21.0g, 0.05mol) is dissolved in dry dichloromethane (200mL), at 0 DEG C, 1- is added dropwise Chloro- 2- isocyanates (10.5g, 0.1mol), drop finish, reaction solution are warming up to, 2h is stirred at room temperature.Reaction is finished, and is evaporated dichloromethane Obtained solid is dissolved in methanol (100mL) by alkane, after stirring 1h, is filtered, is obtained white solid 24.6g, yield 89.2%. ESI-MS[M+Na](m/z):575.3。
Step H 1- (4- (the chloro- 4- of 5- (2- isopropelsulfonyls phenyl) amino) pyrimidine -2- amino) -3- methoxyphenyls Imidazolidin-2-one (embodiment 1)
At 0 DEG C, intermediate VIII -1 (24.3g, 0.04mol) is dissolved in dry n,N-Dimethylformamide (DMF) In (200mL), under nitrogen protection, after adding in 60% sodium hydride (4.8g, 0.12mol), it is warming up to and 4h is stirred at room temperature.Reaction is finished, and 0 At DEG C, reaction solution is poured into saturated ammonium chloride solution (300mL), low temperature stirring 1.5h filters, obtains pale solid 9.3g, yield 45.3%.
m.p.:260.9-263.4℃；ESI-MS[M+H](m/z):516.8；1H NMR(400MHz,CDCl3)δ9.86(s, 1H), 8.50 (d, J=8.4Hz, 1H), 8.12 (s, 1H), 7.94 (dd, J=5.0,3.5Hz, 1H), 7.91 (dd, J=8.0, 1.5Hz, 1H), 7.62 (t, J=7.8Hz, 1H), 7.57 (d, J=2.1Hz, 1H), 7.30 (d, J=7.2Hz, 1H), 6.73 (d, J=7.8Hz, 1H), 4.92 (s, 1H), 3.97 (dd, J=15.1,7.6Hz, 2H), 3.89 (s, 2H), 3.64-3.54 (m, 2H), 3.23 (dt, J=13.7,6.9Hz, 1H), 1.32 (s, 3H), 1.30 (s, 3H)
According to the method for embodiment 1, nucleophilic substitution is carried out with corresponding halogenated hydrocarbons with 1 raw material of embodiment and is prepared The compound of embodiment 2-3,5-7.
2 3- of embodiment (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- Methoxyphenyl)-N, N- dimethyl -2- oxoimidazolinium -1- amides
m.p.:134-136℃；ESI-MS[M+Na](m/z)：610.3；1H NMR(400MHz,CDCl3)δ9.77(s, 1H), 8.52 (d, J=8.4Hz, 1H), 8.12 (s, 1H), 8.09 (d, J=8.7Hz, 1H), 7.92 (dd, J=8.0,1.5Hz, 1H), 7.64 (t, J=7.2Hz, 1H), 7.53 (d, J=2.3Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 6.72 (dd, J= 8.8,2.3Hz, 1H), 3.91 (s, 3H), 3.89 (s, 4H), 3.23 (dt, J=13.6,6.8Hz, 1H), 3.08 (d, J= 5.5Hz,6H),1.32(s,3H),1.31(s,3H).
3 1- of embodiment (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- Methoxyphenyl) -3- (tetrahydrochysene -2H- pyrans -4- carbonyls) imidazolidinyl -2- ketone
m.p.:234-235℃；ESI-MS[M+Na](m/z)：651.3；1H NMR(400MHz,CDCl3)δ10.44(s, 1H), 8.73 (s, 1H), 8.02-7.83 (m, 2H), 7.83 (d, J=7.3Hz, 1H), 7.73 (d, J=7.8Hz, 1H), 7.39- 7.30 (m, 2H), 7.23 (t, J=7.6Hz, 1H), 6.85 (dd, J=18.9,4.0Hz, 1H), 4.07-4.01 (m, 2H), 3.94 (d, J=8.6Hz, 2H), 3.75 (s, 3H), 3.69 (t, J=7.6Hz, 2H), 3.22 (d, J=11.0Hz, 2H), 2.92 (t, J =10.8Hz, 1H), 1.97 (d, J=8.9Hz, 2H), 1.79-1.67 (m, 2H), 1.29 (s, 3H), 1.25 (s, 3H), 0.87 (dd, J=16.6,9.8Hz, 1H)
4 2- of embodiment (3- (4- (the chloro- 4- of 5- (2- isopropylsulfonyls phenyl) amino) pyrimidine -2- amino) -3- methoxy benzene Base -2- oxoimidazolinium -1- acetic acid
At room temperature, embodiment 1 (3.0g, 5.81mmol) is dissolved in dry n,N-Dimethylformamide (DMF) (30mL) In, add in 60% sodium hydride (0.35g, 8.72mmol), stir 1h at room temperature, be added dropwise 2- bromo-acetic acid tert-butyls (1.70g, 8.72mmol), drop finishes, and 2h is stirred at room temperature.Reaction is finished, and reaction solution is poured into saturated ammonium chloride solution (100mL), is generated a large amount of Solid filters, dry, obtains 3.6g crude products.Crude product isolates and purifies (DCM with column analysis method:MeOH=100：3) in, obtaining Mesosome 2- (3- (4- (the chloro- 4- of 5- (2- isopropylsulfonyls phenyl) amino) pyrimidine -2- amino) -3- anisyl -2- oxo-imidazoles Quinoline -1- tert-butyl acetate 1.9g, yield 50.8%.ESI-MS[M+H](m/z):631.
At room temperature, by intermediate 2- (3- (4- (the chloro- 4- of 5- (2- isopropylsulfonyls phenyl) amino) pyrimidine -2- amino) -3- Anisyl -2- oxoimidazolinium -1- tert-butyl acetates (1.5g, 2.38mmol) are dissolved in dichloromethane (20mL), are slowly dripped Add trifluoroacetic acid (5mL), drop finishes, and 6h is stirred at room temperature.Reaction is finished, and after dichloromethane is evaporated, it is molten to add in dichloromethane (10mL) Dichloromethane, is evaporated, is repeated 3 times after removing unreacted trifluoroacetic acid, is evaporated dichloromethane, obtain yellow and consolidate by solution again Body 1.3g, yield 94.2%.By crude product thin layer chromatography (dichloromethane：Methanol=20：1) isolate and purify to obtain yellow Target compound embodiment 4.
m.p.:210-213℃；ESI-MS[M+Na](m/z):596.9；1H NMR(400MHz,CDCl3)δ9.81(s, 1H), 8.51 (d, J=8.1Hz, 1H), 8.09 (s, 2H), 7.97 (d, J=9.6Hz, 1H), 7.91 (d, J=7.5Hz, 1H), 7.69 (s, 1H), 7.63 (t, J=6.6Hz, 1H), 7.30 (d, J=5.6Hz, 1H), 6.69 (d, J=7.9Hz, 1H), 4.24 (d, J=4.5Hz, 3H), 4.08 (s, 2H), 3.81 (t, J=13.6Hz, 2H), 3.69-3.62 (m, 2H), 3.28-3.17 (m, 1H),1.30(s,6H).
5 1- of embodiment (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- Methoxyphenyl) -3- (2- methoxyethyls) imidazolidinyl -2- ketone
m.p.:127-130℃；ESI-MS[M+Na](m/z)：596.8；1H NMR(400MHz,CDCl3)δ9.90(s, 1H), 8.49 (d, J=8.3Hz, 1H), 8.11 (s, 1H), 7.89 (dd, J=11.6,5.8Hz, 2H), 7.71 (d, J=1.6Hz, 1H), 7.61 (t, J=7.3Hz, 1H), 7.30 (d, J=7.4Hz, 3H), 6.68 (d, J=8.2Hz, 1H), 3.89 (s, 3H), 3.87-3.78 (m, 2H), 3.64 (d, J=8.5Hz, 2H), 3.61-3.56 (m, 2H), 3.54-3.47 (m, 2H), 3.39 (d, J =4.4Hz, 3H), 3.22 (dt, J=13.6,6.8Hz, 1H), 1.32 (s, 3H), 1.30 (s, 3H)
6 ethyl -2- of embodiment (3- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) ammonia Base) -3- methoxyphenyls) -3- methoxyphenyls) -2- imidazolidinyl -1- bases) acetic acid esters
m.p.:234-236℃；ESI-MS[M+Na](m/z)：625.3；1H NMR(400MHz,CDCl3)δ9.81(s, 1H), 8.51 (d, J=8.1Hz, 1H), 8.09 (s, 2H), 7.98 (d, J=7.8Hz, 1H), 7.91 (d, J=8.9Hz, 1H), 7.69 (s, 1H), 7.62 (t, J=7.5Hz, 1H), 7.30 (d, J=5.6Hz, 4H), 6.69 (d, J=8.6Hz, 1H), 4.23 (d, J=6.7Hz, 3H), 4.08 (s, 2H), 3.90 (s, 5H), 3.73-3.52 (m, 3H), 3.35-3.10 (m, 1H), 1.30 (s, 11H),1.25(s,6H).
7 1- of embodiment (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- Methoxyphenyl) -3- methoxyphenyls) -3- (2- morpholines ethyl) imidazolidinyl -2- ketone
m.p.:234-236℃；ESI-MS[M+H](m/z)：630.2；1H NMR(400MHz,CDCl3)δ9.56(s,1H), 8.59 (d, J=8.3Hz, 1H), 8.18 (d, J=11.2Hz, 2H), 7.93 (d, J=7.8Hz, 1H), 7.67 (t, J=7.3Hz, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 7.30 (s, 1H), 6.71 (dd, J=8.8,2.0Hz, 1H), 3.98 (d, J= 15.7Hz, 4H), 3.93 (s, 3H), 3.74-3.65 (m, 4H), 3.28-3.23 (m, 1H), 2.99 (d, J=41.0Hz, 6H), 1.34(s,3H),1.32(s,3H),1.02–0.87(m,2H).
8 2- of embodiment (3- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino)- 3- methoxyphenyls) -3- methoxyphenyls) -2- oxoimidazolinium -1- bases)-N- (2- hydroxyethyls) acetamide
At room temperature, by embodiment 4 (0.15g, 0.26mmol), n,N-diisopropylethylamine (DIPEA) (0.14g, 1.05mmol) and nafoxidine (0.29mmol) is dissolved in n,N-Dimethylformamide (DMF) (2mL), adds in 2- (7- azos Benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU) (0.11g, 0.29mmol) stir 16h at room temperature. Reaction is finished, and reaction solution is poured into saturated ammonium chloride solution (10mL), is extracted with ethyl acetate 3 times, is merged organic layer, is once used Water and saturated common salt are washed 3 times, anhydrous Na2SO4After drying, solvent evaporated obtains crude product.Crude product thin layer chromatography (two Chloromethanes：Methanol=20：1) isolate and purify to obtain target compound.
m.p.:170-172℃；ESI-MS[M-H](m/z)：616.4；1H NMR(400MHz,DMSO)δ9.54(s,1H), 8.58 (d, J=6.8Hz, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 8.11 (d, J=4.3Hz, 1H), 7.80 (d, J= 7.7Hz, 1H), 7.66-7.58 (m, 1H), 7.54 (d, J=11.8Hz, 4H), 7.31 (t, J=7.2Hz, 1H), 6.93 (d, J= 8.0Hz, 1H), 4.76 (d, J=4.9Hz, 1H), 3.85 (d, J=12.8Hz, 4H), 3.76 (s, 3H), 3.53 (d, J= 7.2Hz, 8H), 3.43 (d, J=5.3Hz, 3H), 3.16 (d, J=3.2Hz, 2H), 1.17 (s, 9H), 1.15 (s, 3H)
According to 8 method of embodiment, nucleophilic substitution is carried out with corresponding small molecule amine with 4 raw material of embodiment and is prepared The compound of embodiment 9-10.
9 1- of embodiment (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- Methoxyphenyl) -3- (2- oxos -2- (pyrrole radicals -1- bases) ethyl) imidazolidinyl -2- ketone
m.p.:153-157℃；ESI-MS[M+H](m/z)：628.2；1H NMR(400MHz,CDCl3)δ10.55(s, 1H), 9.93 (d, J=39.3Hz, 1H), 8.32 (d, J=8.1Hz, 1H), 7.91 (d, J=7.2Hz, 4H), 7.69 (s, 1H), 7.57 (t, J=7.7Hz, 1H), 7.48 (d, J=8.6Hz, 1H), 7.38 (t, J=7.3Hz, 1H), 6.76 (d, J=7.8Hz, 1H), 4.06 (s, 2H), 3.93 (d, J=7.3Hz, 2H), 3.85 (s, 3H), 3.79-3.72 (m, 8H), 3.49 (dd, J=8.6, 7.6Hz, 6H), 3.23-3.15 (m, 2H), 2.01 (dd, J=12.1,5.7Hz, 5H), 1.89 (dd, J=12.6,6.1Hz, 1H),1.31(s,11H),1.30(s,3H).
10 1- of embodiment (2- (3- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) ammonia Base) -3- methoxyphenyls) -2- oxoimidazolinium -1- bases) acetyl group) piperidyl -4- ketone
m.p.:209-212℃；ESI-MS[M-H](m/z)：654.6；1H NMR(400MHz,DMSO)δ9.54(s,1H), 8.57 (d, J=6.9Hz, 1H), 8.42 (s, 1H), 8.21 (s, 1H), 7.81 (s, 1H), 7.65-7.58 (m, 1H), 7.53 (d, J =14.8Hz, 2H), 7.30 (t, J=6.5Hz, 1H), 6.92 (d, J=8.1Hz, 1H), 4.22 (s, 2H), 3.89 (t, J= 7.0Hz, 2H), 3.76 (s, 7H), 3.56 (t, J=6.5Hz, 2H), 3.48-3.41 (m, 1H), 2.69 (s, 2H), 2.39 (s, 2H),1.17(s,3H),1.15(s,3H).
Embodiment 11
Step A N- (- 4 base of 2,5- dichloro pyrimidines) -1,2- diphenylamines (V -2)
50.00g (0.46mol) o-phenylenediamines and 2,4,5- trichloropyrimidines of 84.17g (0.46mol) are added in 500mL and done In dry isopropanol (i-PrOH), 127.70g (0.93mol) n,N-diisopropylethylamine is slowly added to, is warming up to 95 DEG C of reactions 2h.It is cooled to room temperature, filters, isopropanol (10mL × 3) washing obtains white powder solid 106.56g, yield 91.20%.
Step B N- (2-((2,5- dichloro pyrimidine-4- bases) amino) phenyl) acetamide (Ⅹ-2)
Under condition of ice bath, 80.00g (0.31mol) intermediate V -2 and 63.70g (0.63mol) triethylamine are added to In the acetone of 400mL dryings, 24.72g (0.31mol) is slowly added dropwise, reacts 30 minutes, filters, acetone (10mL × 3) washing, Obtain white powder solid 87.74g, yield 94.1%.
Step C N- (2- ((the chloro- 2- of 5- ((2- methoxyl group -4- nitrobenzophenones) amino) pyrimidine-4-yl) amino) phenyl) second Amide (VI -2)
By 57.00g (0.19mol) intermediate Ⅹ -2,32.36g (0.19mol) 2- methoxyl group -4- nitroanilines and 33.12g (0.19mol) p-methyl benzenesulfonic acid is added in 300mL isopropanols, is warming up to back flow reaction.4h is reacted, is cooled to room Temperature filters, isopropanol (10mL × 2) washing, obtain pale yellow powder solid 70.69g, yield 85.76%.
Step D N- (2- ((2- ((4- amino -2- methoxyphenyls) amino) -5- chlorine pyrimidine-4-yl) amino) phenyl) second Amide (VII -2)
60.00g (0.14mol) intermediate VI -2 and 0.6g palladium carbons (Pd/C) are added in 300mL methanol, are passed through hydrogen Gas vacuumizes, and reacts at room temperature 6h.It filters, methanol (30mL × 3) washing filter cake discards filter cake, retains filtrate.It is molten to remove filtrate Agent obtains faint yellow solid crude product.Crude product passes through silicagel column (ethyl acetate：Petroleum ether=5:1) sterling 43.87g, yield are obtained 78.62%.
Step E phenyl (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxybenzenes Base) phenyl carbamate (M2-2)
Under ice bath, 10.00g (25mmol) intermediate VII -2 and 5.10g (50.44mmol) triethylamine are added to 30mL and done In dry tetrahydrofuran (THF), 4.70g (30.13mmol) phenyl chloroformate is slowly added dropwise, drop finishes, and reacts 30min, filters, THF (2mL × 3) is washed, dry, obtains pale yellow powder solid 12.54g, yield 96.39%.
Step F N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (2- oxo-pyrrolidine -1- bases) phenyl) amino) pyrimidine -4- Base) amino) phenyl) acetamide (embodiment 11)
Under ice bath, 0.40g (1.00mmol) intermediate VII -2 and 0.2g (1.98mmol) triethylamine (TEA) are added to four 0.21g (1.50mmol) chlorobutanoylchloride is slowly added dropwise in hydrogen furans (THF), and drop finishes, and reacts 10min, is warming up to 40 points of room temperature reaction Clock filters, THF (1mL × 2) washings, dry, obtains green solid intermediate A.Then in ice bath and nitrogen (N2) again will under protection Sodium hydride is added to dry 7.0mL N, N- dimethyl formyls (DMF), and the DMF solution of intermediate A is slowly added dropwise, and drop finishes, and rises Warm to room temperature reaction 6h.Reaction solution is added drop-wise in ice water, a large amount of brown solids are precipitated, stirs 1h, is filtered, it is dry, obtain brown Solid 0.28g, yield 59.57%.
ESI-MS[M+H](m/z):467.15；1H NMR(400MHz,DMSO)δ10.09(s,1H),8.52(s,1H), 8.10 (d, J=6.3Hz, 1H), 7.83-7.69 (m, 3H), 7.45 (d, J=2.2Hz, 1H), 7.34 (dd, J=7.7,1.5Hz, 2H), 7.24 (dtd, J=13.6,7.5,6.0Hz, 3H), 6.87 (dd, J=8.8,2.1Hz, 1H), 3.82 (d, J=6.9Hz, 1H), 3.79 (s, 3H), 2.47 (d, J=8.2Hz, 2H), 2.10 (s, 3H), 2.04 (dd, J=15.2,7.7Hz, 2H)
Step G N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- ((3- oxocyclohex -1- alkene -1- bases) amino) phenyl) ammonia Base) pyrimidine-4-yl) amino) phenyl) acetamide (embodiment 12)
By 0.06g (0.54mmol) 1, hydroresorcinol and 1 drop glacial acetic acid are added to 1,2- dichloroethanes, then add in 0.20g (0.50mmol) intermediate VII -2 is warming up to 80 DEG C, reacts 40 minutes.Solvent is removed, passes through silicagel column (dichloromethane： Methanol=20:1) sterling 0.16g, yield 64.78% are obtained.
ESI-MS[M+H](m/z):493.17；1H NMR(400MHz,DMSO)δ10.12(s,1H),8.79(s,1H), 8.56 (s, 1H), 8.11 (s, 1H), 7.78 (d, J=9.2Hz, 2H), 7.69 (dd, J=7.4,2.0Hz, 1H), 7.36 (dd, J =7.2,2.2Hz, 1H), 7.30-7.18 (m, 2H), 6.76 (d, J=2.0Hz, 1H), 6.55 (dd, J=8.6,1.9Hz, 1H), 5.25 (s, 1H), 3.78 (s, 3H), 2.52-2.46 (m, 5H), 2.15 (t, J=6.3Hz, 2H), 2.09 (s, 3H), 1.93- 1.83(m,2H).
According to the method for embodiment 11, condensation reaction preparation is carried out with corresponding cycloaliphatic ketone for raw material with intermediate VII -2 Obtain the compound of embodiment 13.
13 2- of embodiment ((4- ((2- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxies Base phenyl) amino) the amyl- 1- alkene -1- carboxylic acid, ethyl esters of ring
ESI-MS[M+H](m/z):537.19；1H NMR(400MHz,DMSO)δ10.05(s,1H),9.42(s,1H), 8.51 (s, 1H), 8.10 (s, 1H), 7.72 (dd, J=10.9,7.2Hz, 2H), 7.27 (ddd, J=23.1,19.3,7.5Hz, 3H), 6.79 (d, J=2.2Hz, 1H), 6.52 (d, J=8.6Hz, 1H), 4.12 (q, J=7.1Hz, 2H), 3.80 (s, 2H), 2.75 (t, J=7.4Hz, 1H), 2.09 (s, 3H), 1.81 (dd, J=14.3,7.2Hz, 2H), 1.22 (t, J=7.1Hz, 4H)
14 N- of embodiment (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyl groups Phenyl) cyclopropane carboxamide
Under condition of ice bath, by 0.20g (0.50mmol) intermediates M2- 2 and 0.08g (0.79mmol) triethylamine is added to In 2mL tetrahydrofurans (THF), 0.08g (0.79mmol) ring propionyl chloride is slowly added dropwise, drop finishes, and reacts at room temperature 30 minutes, filters, THF (0.5mL × 3) is washed, dry, obtains white powder solid 0.20g, yield 86.75%.
ESI-MS[M-H](m/z):465.18；1H NMR(400MHz,DMSO)δ10.14(s,1H),10.04(s,1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.81 (s, 1H), 7.70 (dd, J=10.7,6.4Hz, 2H), 7.44 (d, J=1.9Hz, 1H), 7.36 (dd, J=6.0,3.5Hz, 1H), 7.28-7.17 (m, 2H), 6.88 (dd, J=8.7,1.7Hz, 1H), 3.76 (s, 3H), 2.09 (s, 3H), 1.75 (td, J=7.4,3.7Hz, 1H), 0.84-0.72 (m, 4H)
15 N- of embodiment (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyl groups Phenyl) thiomorpholine -4- formamides
By 0.20g (0.39mmol) intermediate VII -2, the thio code quinolines of 0.07g (0.68mmol) and 0.10g (0.77mmol) N,N-diisopropylethylamine (DIPEA) is added in 4mL tetrahydrofurans, is warming up to back flow reaction 3h, is filtered, THF (0.5mL X 2) wash, it is dry, obtain solid 0.14g, yield 68.80%.
ESI-MS[M-H](m/z):526.14；1H NMR (400MHz, DMSO) δ 10.09 (s, 1H), 8.46 (d, J= 11.5Hz, 2H), 8.08 (s, 1H), 7.73 (d, J=6.2Hz, 1H), 7.64 (d, J=7.8Hz, 2H), 7.37-7.30 (m, 1H), 7.28-7.16 (m, 3H), 6.83 (d, J=6.9Hz, 1H), 3.75 (s, 2H), 3.74-3.70 (m, 3H), 2.64-2.56 (m,4H),2.10(s,3H).
According to the method for embodiment 15, condensation reaction preparation is carried out with corresponding aliphatic heterocycle for raw material with intermediate VII -2 Obtain the compound of embodiment 16-20.
16 N- of embodiment (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyl groups Phenyl) -4- methyl piperidine -1- formamides
ESI-MS[M-H](m/z):522.18；1H NMR(400MHz,DMSO)δ10.09(s,1H),8.47(s,1H), 8.35 (s, 1H), 8.08 (s, 1H), 7.77-7.69 (m, 1H), 7.65-7.59 (m, 2H), 7.33 (dd, J=7.4,1.9Hz, 1H), 7.29-7.11 (m, 3H), 6.84 (dd, J=8.7,1.9Hz, 1H), 4.09 (d, J=13.3Hz, 2H), 3.75 (s, 3H), 3.19 (d, J=12.5Hz, 3H), 2.10 (s, 3H), 1.71 (d, J=13.7Hz, 3H), 1.62 (d, J=12.8Hz, 3H), 1.59-1.48 (m, 1H), 0.92 (d, J=7.3Hz, 4H)
17 1- of embodiment ((4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxies Base phenyl) carbamoyl) piperidine-4-ethyl formate
ESI-MS[M+H](m/z):582.18；1H NMR(400MHz,DMSO)δ9.98(s,1H),8.45(s,1H), 8.37 (s, 1H), 8.07 (s, 1H), 7.77-7.70 (m, 1H), 7.67-7.54 (m, 2H), 7.35 (d, J=7.2Hz, 1H), 7.29-7.12 (m, 4H), 6.83 (dd, J=8.7,2.0Hz, 1H), 4.09 (q, J=7.1Hz, 2H), 4.01 (d, J= 13.4Hz, 2H), 2.91 (t, J=11.2Hz, 3H), 2.55 (td, J=11.1,5.7Hz, 1H), 2.09 (s, 4H), 1.84 (d, J =10.4Hz, 3H), 1.50 (td, J=14.9,3.8Hz, 3H), 1.26-1.13 (m, 4H)
18 N- of embodiment (2-((the chloro- 2- of 5- ((4- (3- (4- hydroxy-cyclohexyls) urea groups)-2- methoxyphenyls) amino) Pyrimidine-4-yl) amino) phenyl) acetamide
ESI-MS[M+H](m/z):540.15；1H NMR(400MHz,DMSO)δ10.32(s,1H),8.91(s,1H), 8.48 (s, 1H), 8.06 (s, 1H), 7.73 (d, J=9.1Hz, 1H), 7.65 (s, 1H), 7.56 (d, J=8.6Hz, 1H), 7.33 (d, J=6.4Hz, 1H), 7.28 (s, 1H), 7.25-7.13 (m, 1H), 6.62 (d, J=8.7Hz, 1H), 6.49 (d, J= 8.3Hz, 1H), 4.58 (s, 1H), 3.73 (s, 1H), 3.51 (s, 0H), 3.16 (s, 1H), 2.10 (s, 2H), 1.82 (d, J= 9.3Hz, 2H), 1.17 (dd, J=18.4,10.1Hz, 2H)
19 4- of embodiment (3- (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- first Phenyl) urea groups) piperidines -1- t-butyl formates
ESI-MS[M+H](m/z):625.17；1H NMR(400MHz,DMSO)δ10.12(s,1H),8.68(s,1H), 8.06 (s, 1H), 7.76-7.69 (m, 1H), 7.66 (s, 1H), 7.57 (d, J=8.6Hz, 1H), 7.35-7.29 (m, 1H), 7.27 (d, J=2.0Hz, 1H), 7.23-7.14 (m, 2H), 6.63 (d, J=8.7Hz, 1H), 6.50 (d, J=7.6Hz, 1H), 5.33 (s, 1H), 3.88-3.75 (m, 6H), 3.73 (s, 4H), 2.09 (s, 3H), 1.85-1.74 (m, 3H), 1.71 (d, J= 10.4Hz,3H),1.39(s,9H).
20 N- of embodiment (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (3- (4- oxocyclohexyls) urea groups) phenyl) amino) Pyrimidine-4-yl) amino) phenyl) acetamide
ESI-MS[M+H](m/z):538.16；1H NMR(400MHz,DMSO)δ10.00(s,1H),8.44(s,1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.77-7.69 (m, 1H), 7.66 (s, 1H), 7.60 (d, J=8.6Hz, 1H), 7.33 (dd, J=7.3,2.1Hz, 1H), 7.26 (d, J=2.1Hz, 1H), 7.25-7.15 (m, 2H), 3.96 (dd, J=10.2,6.6Hz, 1H), 3.75 (s, 3H), 2.43 (dd, J=10.7,5.2Hz, 2H), 2.31-2.19 (m, 2H), 2.09 (s, 4H), 2.07-1.99 (m, 2H), 1.69 (td, J=13.8,4.7Hz, 2H)
Embodiment 21：
Intermediate VI -2, V -2, Ⅹ -2 is synthesized according to embodiment 11 step A, B, C.
Step A 1- (3- methoxyl group -4- nitrobenzophenones) -1H- pyrroles (Ⅻ -1)
At room temperature, raw material Ⅺ -1 (20.0g, 0.12mol) is dissolved in n,N-Dimethylformamide (DMF) (200mL), stirred Lower addition potassium carbonate (33.2g, 0.24mol) and pyrroles (8.9g, 0.13mol) are mixed, is warming up to 100 DEG C of reaction 12h.Reaction is finished, Reaction solution is poured into water (1000mL), is extracted with ethyl acetate 3 times, merges organic layer, successively with water and saturated common salt washing 3 It is secondary, through anhydrous Na2SO4After drying, filtering removes solvent under reduced pressure, obtains yellow solid 22.9g, yield 87.6%.MS(ESI)m/ z：219.1[M+H]+。
Step B 2- methoxyl groups -4- (1H- pyrroles -1- bases) anilinechloride (VIII -1)
At room temperature, iron powder (20.2g, 0.36mol) is added in 95% ethyl alcohol (200mL) under stirring, is warming up to 70 DEG C of work Change reaction 30min.Ⅻ -1 (20.0g, 0.09mol) is added in reaction solution, is warming up to 80 DEG C of reaction 5h.Reaction is finished, and pads diatom Soil filters while hot, and organic layer major part solvent is evaporated off, and water (100mL), saturated sodium bicarbonate aqueous solution tune are added in into residue PH8~9 are extracted with ethyl acetate 3 times, merge organic layer, are washed 3 times with water and saturated common salt successively, through anhydrous Na2SO4It is dry Afterwards, filter, the dioxane solution (4M) of HCl to no solid is added dropwise under stirring and is precipitated, filters, dry gray solid 17.3g, yield 85.4%.
Step C N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (1H- pyrroles -1- bases) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) acetamide (embodiment 21)
Ⅹ -2 (10.0g, 0.03mol) and VIII -1 (9.0g, 0.04mol) is added in isopropanol (100mL), is stirred, is risen Temperature to 80 DEG C reaction for 24 hours.Reaction is finished, and is filtered, and filter cake is put into stirring, saturated sodium bicarbonate aqueous solution tune pH8 in water (100mL) ~9, it is extracted 2 times with dichloromethane, merges organic layer, washed 2 times, be evaporated, column chromatography (DCM with water and saturated common salt successively: MeOH=500:1~500:3) white solid 6.8g, yield 45.9% are obtained.
m.p.:201.6-204.7℃；ESI-MS[M+H](m/z):449.55；1H NMR(600MHz,DMSO)δ10.03 (s, 1H), 8.55 (s, 1H), 8.14 (s, 1H), 7.90 (d, J=8.5Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.35 (d, J=7.9Hz, 1H), 7.33-7.28 (m, 3H), 7.24 (dd, J=11.1,4.1Hz, 1H), 7.16 (d, J= 2.4Hz, 1H), 6.91 (dd, J=8.6,2.1Hz, 1H), 6.25 (t, J=2.1Hz, 2H), 3.90 (s, 3H), 2.11 (s, 3H)
According to the method for embodiment 21, nucleophilic substitution is carried out with mesyl chloride for raw material with intermediate V -2 and is prepared into To the compound of embodiment 22.
22 N- of embodiment (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (1H- pyrroles -1- bases) phenyl) amino) pyrimidine -4- Base) amino) phenyl) Methanesulfomide
m.p.:206.2-207.2℃；ESI-MS[M+H](m/z):546.12；1H NMR(600MHz,DMSO)δ9.29 (s, 1H), 8.56 (s, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.94 (d, J=7.9Hz, 1H), 7.79 (d, J=8.4Hz, 1H), 7.40 (dd, J=7.9,1.3Hz, 1H), 7.36-7.33 (m, 2H), 7.31 (d, J=7.7Hz, 1H), 7.26-7.21 (m, 1H), 7.17 (d, J=2.3Hz, 1H), 6.94 (dd, J=8.6,2.0Hz, 1H), 6.27-6.22 (m, 2H), 3.89 (s, 3H), 2.96(s,3H).
23 N- of embodiment (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (2- (piperidin-1-yl methyl) -1H- pyrroles -1- bases) Phenyl) amino) pyrimidine-4-yl) amino) phenyl) acetamide
Piperidines (0.04g), formalin (0.15mL) are dissolved in glacial acetic acid (5mL), half an hour is stirred, ice will be dissolved in Embodiment 21 (0.2g) in acetic acid (5mL) is slowly dropped into reaction solution, reacts 5h.Reaction is finished, and removes most of solvent under reduced pressure, Water (5mL), stirring are added in, saturated sodium bicarbonate aqueous solution tune pH8~9 are extracted 2 times with dichloromethane, merge organic layer, successively It is washed 2 times with water and saturated common salt, is evaporated, column chromatography, obtains white solid 60mg, yield 25.0%.
m.p.:103.4-105.6℃；ESI-MS[M+H](m/z):485.60；1H NMR(400MHz,DMSO)δ10.02 (s, 1H), 8.59 (s, 1H), 8.15 (s, 1H), 7.96 (d, J=8.6Hz, 1H), 7.78 (s, 1H), 7.71 (d, J=7.9Hz, 1H), 7.39 (d, J=7.0Hz, 1H), 7.37 (d, J=7.8Hz, 1H), 7.27 (dd, J=11.4,3.8Hz, 1H), 7.22 (t, J=6.9Hz, 1H), 6.92 (s, 1H), 6.85 (dd, J=8.6,1.8Hz, 1H), 6.14-6.08 (m, 2H), 3.86 (s, 3H), 3.22(s,2H),2.33(s,4H),2.09(s,3H),1.47(s,4H),1.39(s,2H).
According to the method for embodiment 23, Mannich reaction is carried out with diethylamine hydrochloride for raw material with embodiment 22 and is prepared into To the compound of embodiment 24.
24 N- of embodiment (2- ((the chloro- 2- of 5- ((4- (2- ((diethylamine) methyl) -1H- pyrroles -1- bases) -2- methoxybenzenes Base) amino) pyrimidine-4-yl) amino) phenyl) Methanesulfomide
ESI-MS[M+H](m/z):570.83；1H NMR(400MHz,DMSO)δ9.31(s,1H),8.63(s,1H), 8.18(s,1H),7.95(s,1H),7.91–7.86(m,2H),7.44–7.38(m,1H),7.32–7.19(m,3H),6.91– 6.86(m,2H),6.15–6.12(m,2H),3.84(s,6H),3.45(s,4H),2.94(s,6H),2.50–2.43(m,9H), 0.85 (t, J=7.1Hz, 12H)
The chloro- N of 25 5- of embodiment4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- ((2- (nafoxidine - 1- yls) ethyl) sulfuryl) phenyl) pyrimidine -2,4- diamines (I7-1)
Step A2- ((3- methoxyl group -4- nitros) sulfenyl) ethyl alcohol (XIV-1)
At room temperature, raw material Ⅺ -1 (17.1g, 0.1mol) is dissolved in n,N-Dimethylformamide (DMF) (200mL), stirred Lower addition potassium carbonate (20.7g, 0.15mol) and mercaptoethanol (9.4g, 0.12mol) are mixed, is warming up to 100 DEG C of reaction 12h.Reaction Finish, reaction solution is poured into water (1000mL), filters to obtain yellow solid 27.0g, yield 85.0%.
Step B (2- chloroethyls) (3- methoxyl group -4- nitrobenzophenones) thioether (XV-1)
At room temperature, raw material Ⅺ -1 (24.7g, 0.1mol) is dissolved in dichloromethane (DCM) (250mL), it is slow under stirring Thionyl chloride (29.0g, 0.25mol) is instilled, is warming up to reflux, reacts 5h.Reaction is finished, and solvent is evaporated off, obtains yellow oily liquid, It is directly used in next step.
Step C 4- ((2- chloroethyls) sulfuryl) -2- methoxy-nitrobenzenes (XVI-1)
At room temperature, raw material Ⅺ -1 (22.9g, 0.1mol) is dissolved in glacial acetic acid (300mL), is warming up to 70 DEG C, slowly dripped Add hydrogen peroxide 100mL, be added dropwise, react 10h.Reaction finishes, and reaction solution is poured into water (1000mL), filters white 20.9g, yield 75.0%.
4- ((2- chloroethyls) sulfuryl) -2- aminoanisoles are made according to the operation of 21 step B of embodiment in step D (XVII-1)。
The chloro- N of 5- are made according to the operation of 21 step C of embodiment in step E2- (4- ((2- chloroethyls) sulfuryl) -2- methoxyl groups Phenyl) N4- (2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamines (M5-1)
The chloro- N of step F 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- ((2- (nafoxidine -1- Base) ethyl) sulfuryl) phenyl) pyrimidine -2,4- diamines (embodiment 25)
At room temperature, raw material Ⅺ -1 (0.5g, 0.001mol) is dissolved in n,N-Dimethylformamide (DMF) (5mL), stirred Lower addition tetrahydropyridine (0.2g, 0.003mol), reacts 12h.Reaction is finished, and extraction, column chromatography obtains white solid 0.2g.ESI- MS[M+H](m/z):594.2。
According to the method for embodiment 25, embodiment 26,27 is prepared.
The chloro- N of 26 5- of embodiment4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- ((2- (piperidin-1-yl) Ethyl) sulfuryl) phenyl) pyrimidine -2,4- diamines
ESI-MS[M+H](m/z):608.2。
The chloro- N of 27 5- of embodiment4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- ((2- (4- methyl piperazines Pyridine -1- bases) ethyl) sulfuryl) phenyl) pyrimidine -2,4- diamines
ESI-MS[M+H](m/z):622.3。
The chloro- N of 28 5- of embodiment4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (((5- (nafoxidine - 1- ylmethyls) furans -2- bases) methyl) sulfenyl) phenyl) pyrimidine -2,4- diamines
Step A 2- (((3- methoxyl group -4- nitrobenzophenones) sulfenyl) methyl) furans (XVIII-1)
At room temperature, raw material Ⅺ -1 (17.1g, 0.1mol) is dissolved in n,N-Dimethylformamide (DMF) (200mL), stirred Lower addition potassium carbonate (20.7g, 0.15mol) and furfurylmercaptan (13.4g, 0.12mol) are mixed, is warming up to 100 DEG C of reaction 12h.Reaction Finish, reaction solution is poured into water (1000mL), filters to obtain yellow solid 21.4g, yield 80.0%.
4- ((furans -2- bases) methyl) sulfenyl is made according to the operation of 21 step B of embodiment in step B) -2- aminoanisoles (XIX-1)。
ESI-MS[M+H](m/z):236.1。
The chloro- N of 5- are made according to the operation of 21 step C of embodiment in step C2- 4- ((furans -2- bases) methyl) sulfenyl) -2- first Oxygroup benzene)-N4- (2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamines (M6-1)
ESI-MS[M+H](m/z):545.2。
Step D carries out Mannich reaction with nafoxidine and the chemical combination of embodiment 28 is prepared according to the operation of embodiment 23 Object.
ESI-MS[M+H](m/z):628.1。
According to the operation of embodiment 28, embodiment 29,30 is prepared through Mannich reaction.
The chloro- N of 29 5- of embodiment4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (((5- (piperidin-1-yls Methyl) furans -2- bases) methyl) sulfenyl) phenyl) pyrimidine -2,4- diamines
ESI-MS[M+H](m/z):642.1。
The chloro- N of 30 5- of embodiment4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (((5- (4- methyl piperazines Pyridine -1- ylmethyls) furans -2- bases) methyl) sulfenyl) phenyl) pyrimidine -2,4- diamines
ESI-MS[M+H](m/z):656.3。
The antitumor activity of product of the present invention
Extracorporeal anti-tumor cytoactive
The pyridine derivatives of above formula I according to the invention have been carried out with the external human world for inhibiting high table NPM-ALK albumen It is denatured the HCC78 cells of large celllymphoma cell Karpas299 and high expression SLC34A2-ROS1, height expression EML4-ALK eggs The screening active ingredients of the human A549 cell lines of white human lung adenocarcinoma cell NCI-H2228 and EGFR high expression.
(1) cell recovery and after passing on 2-3 stabilization, makes it disappear from blake bottle bottom with trypsin solution (0.25%) Change is got off.After cell dissociation buffer is poured into centrifuge tube, culture solution is added in afterwards to terminate digestion.By centrifuge tube in 800r/min Lower centrifugation 10min adds in 5mL culture solutions after abandoning supernatant, blows and beats mixing cell, draws 10 μ L cell suspensions and adds in cell It is counted in tally, adjustment cell concentration is 104A/hole.Except A1 holes are that blank well is not added with extracellularly in 96 orifice plates, remaining all adds Enter 100 μ L cell suspensions.96 orifice plates are put into incubator and are cultivated for 24 hours.
(2) with 50 μ L dmso solution given the test agent, appropriate culture solution is then added in, sample is made to be dissolved into 2mg/mL Then sample is diluted to 20,4,0.8,0.16,0.032 μ g/mL by liquid in 24 orifice plates.
Each concentration adds in 3 holes, wherein surrounding two rows, two row cell growing way is affected by environment larger, only and it is blanc cell Hole uses.96 orifice plates are put into incubator and cultivate 72h.
(3) band medicine culture solution in 96 orifice plates is discarded, is rinsed cell twice with phosphate buffer solution (PBS), in every hole Middle addition MTT (0.5mg/mL) 100 μ L are put into incubator after 4h, discard MTT solution, add in 100 μ L of dimethyl sulfoxide (DMSO).In magnetic Vibration makes survivaling cell fully be dissolved with MTT reaction products formazan on forced oscillation device, is put into measurement result in microplate reader.Pass through Drug IC can be obtained in Bliss methods50Value.
The inhibition lymphocytoma KARPAS299 and human umbilical vein endothelial cell Activity Results of compound are shown in Table 1.
Table 1
L1196M ALK and ROS1 enzymatic activity are tested
Enzyme-linked immunosorbent assay is based on for measuring the experiment of L1196M ALK enzymatic activitys.Concrete operations are：
At room temperature, on the coated plates of 0.25mg/mL PGT, by embodiment compound, 50pM L1196M ALK and 5uM ATP (25mM MOPS, Ph 7.4,1mM DTT, 5mM MgCl in buffer solution is tested2,1mM MnCl2, 0.1%NaN3) incubate 20min.By rinsing the phosphotyrosine specificity gram for removing reaction mixture and horseradish peroxidase being conjugated with 0.2ug/mL Grand antibody test phosphoric acid polymerization object substrate.After adding in 1M phosphoric acid color development stoppings, pass through spectrophotometry quantitative chromogenic at 450nm Substrate colors.
The test operation of ROS1 enzymatic activitys is the same as L1196M ALK enzymatic activity test methods.
Embodiment compound is shown in Table 2 to the inhibition data of L1196M ALK and ROS1.
Table 2
The compound of formula of I of the present invention can be administered alone, but typically be given with pharmaceutical carrier mixture, described medicinal The selection of carrier will be according to required route of administration and standard pharmaceutical practice, separately below with the various drug agent of such compound Type, such as tablet, capsule, injection, aerosol, suppository, film, pill, the preparation method of externally-applied liniment and ointment, Illustrate its new opplication in pharmaceutical field.

Claims (10)

1. 2,4- diarylaminos pyrimidine derivatives and its optical isomer, pharmaceutically acceptable salt, solvation shown in general formula I Object or prodrug,
Wherein,
X is C or N；
R1For hydroxyl, halogen, nitro, amino, cyano, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl, (C1-C6) alkane Oxygroup, (C1-C6) alkyl, (C1-C6) alkyl acyl, (C1-C6) alkyl amido, by 1-2 (C1-C6) alkyl-substituted amino Acetyl group, (C1-C3) alkylenedioxy group；
R2For halogen, halogenated (C1-C6) alkyl, hydroxyl, cyano, amino, nitro；
R3For hydrogen, halogen, (C1-C6) alkyl, (C1-C6) alkoxy, halogen or/and hydroxyl or/and amino substitution (C1-C6) alkane Base, halogen or/and hydroxyl or/and the (C of amino substitution1-C6) alkoxy；
R4For (C1-C6) alkyl, 3-12 members saturation or part unsaturated carbocyclic or unsubstituted comprising N, O and/or S or taken by Y The 4-7 circle heterocycles in generation；Or NHnR8R9、NHnCOR8R9、NHnCONHnR8R9、SO2(CH2)nNR8R9、SO2(CH2)nCONR8R9；
Y is H, (CH2)pR8R9、(CH2)pOR8R9、(CH2)pCO2R8R9、(CH2)pCOR8R9、(CH2)pCONRnR8R9；
R8And R9It is identical or different, it is independently selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C1-C10) alkoxy, (C2-C10) alkenyl, (C2-C10) alkynyl, cyano, they can be by R identical or different 0-37Substitution；
Or R8And R9With forming 4-10 circle heterocycles base or 4-10 unit's heteroaryls, the heterocycle together with the nitrogen-atoms connected with them Base or heteroaryl except with R8And R9It is described miscellaneous optionally containing the 0-4 hetero atoms selected from N, O and/or S outside the nitrogen-atoms of connection Ring group or heteroaryl are optionally by 0-3 identical or different R7Substitution；
R5And R6It is identical or different, it is independently selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C1-C10) alkoxy, (C2-C10) alkenyl, (C2-C10) alkynyl, hydroxyl, (C1-C4) hydroxyalkyl, cyano, 4-10 circle heterocycles base or heteroaryl, the heterocycle Base or heteroaryl contain the hetero atom of 1-3 N, O and/or S, the R5And R6It can be by 0-3 identical or different R7Substitution；
Or R5And R6With forming 4-10 circle heterocycles base or 4-10 unit's heteroaryls, the heterocycle together with the nitrogen-atoms connected with them Base or heteroaryl except with R5And R6It is described miscellaneous optionally containing the 0-4 hetero atoms selected from N, O and/or S outside the nitrogen-atoms of connection Ring group or heteroaryl are optionally by 0-3 identical or different R7Substitution；
R7For (C1-C10) alkyl, (C3-C7) cycloalkyl, (C1-C10) alkoxy, hydroxyl, halogen, halogenated (C1-C10) alkyl, halogenated (C1-C10) alkoxy, nitro；
N independences are for 0-2, are preferably 0-1, and p independences are for 0-6, are preferably 0-4, more preferably 0-2.
It is 2. 2,4- diarylaminos pyrimidine derivatives and its optical isomer shown in the general formula I of claim 1, pharmaceutically acceptable Salt, solvate or prodrug,
Wherein,
R1For (C1-C6) alkyl sulphonyl, (C1-C6) alkyl amido.
3. 2,4- diarylaminos pyrimidine derivatives and its optical isomer shown in the general formula I of claim 1 or 2 pharmaceutically may be used Salt, solvate or the prodrug of receiving,
Wherein,
R4For (C1-C4) alkyl, 3-12 members saturation or part unsaturated carbocyclic or unsubstituted comprising N, O and/or S or taken by Y The 5-7 circle heterocycles in generation；Or NHnR8R9、NHnCOR8R9、NHnCONHnR8R9、SO2(CH2)nNR8R9、SO2(CH2)nCONR8R9；
Y is H, (CH2)pR8R9、(CH2)pOR8R9、(CH2)pCO2R8R9、(CH2)pCOR8R9、(CH2)pCONRnR8R9；
R8And R9It is identical or different to be independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alkoxy, (C2-C6) alkenyl, (C2-C6) alkynyl, cyano, they can be by R identical or different 0-37Substitution；
Or R8And R9With forming 4-10 circle heterocycles base or 4-10 unit's heteroaryls, the heterocycle together with the nitrogen-atoms connected with them Base or heteroaryl except with R8And R9It is described miscellaneous optionally containing the 0-4 hetero atoms selected from N, O and/or S outside the nitrogen-atoms of connection Ring group or heteroaryl are optionally by 0-3 identical or different R7Substitution；
Preferably,
R4For (C1-C4) alkyl, 3-12 members saturation or part unsaturated carbocyclic or unsubstituted comprising N, O and/or S or taken by Y The 5-7 circle heterocycles in generation；Or NHnR8R9、NHnCOR9R9、NHnCONHnR8R9、SO2(CH2)nNR8R9、SO2(CH2)nCONR8R9；
Y is H, (CH2)pR8R9、(CH2)pOR8R9、(CH2)pCO2R8R9、(CH2)pCOR8R9、(CH2)pCONRnR8R9；
R8And R9It is identical or different to be independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, (C2-C6) alkenyl, (C2-C6) alkynyl, cyano, they can be by R identical or different 0-37Substitution；
It is highly preferred that
R4The amino that substitutes for unsubstituted or Y,
Y is one of following：
H、(CH2)2R8、(CH2)2OR8、CH2CO2R8、COR8、CH2CONHnR8；
R8Selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-64) alkoxy, cyano, they can it is identical by 0-3 or Different R7Substitution.
4. 2,4- diarylaminos pyrimidine derivatives and its optical isomer, medicine shown in the general formula I of claim 1-3 any one Acceptable salt, solvate or prodrug on,
Wherein,
R5And R6It is identical or different to be independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alkoxy, (C2-C6) alkenyl, (C2-C6) alkynyl, hydroxyl, (C1-C4) hydroxyalkyl, cyano, 4-10 circle heterocycles base or heteroaryl, the heterocycle Or heteroaryl contains the hetero atom of 1-3 N, O and/or S, they can be by 0-3 identical or different R7Substitution；
Or R5And R6With forming 4-10 circle heterocycles base or 4-10 unit's heteroaryls, the heterocycle together with the nitrogen-atoms connected with them Base or heteroaryl except with R5And R6It is described miscellaneous optionally containing the 0-4 hetero atoms selected from N, O and/or S outside the nitrogen-atoms of connection Ring group or heteroaryl are optionally by 0-3 identical or different R7Substitution；
Preferably,
R5And R6It is identical or different, it is independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, hydroxyl Base, (C1-C4) hydroxyalkyl, cyano, 5-10 circle heterocycles base or heteroaryl, the heterocycle or heteroaryl contain 1-3 N, O or S Hetero atom, they can be by 0-3 identical or different R7Substitution；
It is highly preferred that
R5And R6It is identical or different, it is independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, cyanogen Base, hydroxyl, (C1-C4) hydroxyalkyl, The R5And R6It can be by 0-3 identical or different R7 It takes.
5. 2,4- diarylaminos pyrimidine derivatives and its optical isomer, medicine shown in the general formula I of claim 1-4 any one Acceptable salt, solvate or prodrug on,
Wherein,
R2For halogen, halogenated (C1-C4) alkyl, hydroxyl, cyano, amino, nitro；
R3For hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, halogen or/and hydroxyl or/and amino substitution (C1-C4) alkane Base, halogen or/and hydroxyl or/and the (C of amino substitution1-C4) alkoxy.
6. 2,4- diarylaminos pyrimidine derivatives and its optical isomer shown in general formula I described in claim 1 pharmaceutically may be used Salt, solvate or the prodrug of receiving,
1- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxyphenyls) miaow Oxazolidinyl -2- ketone
3- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxyphenyls) - N, N- dimethyl -2- oxoimidazolinium -1- amides
1- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxyphenyls) - 3- (tetrahydrochysene -2H- pyrans -4- carbonyls) imidazolidinyl -2- ketone
2- (3- (4- (the chloro- 4- of 5- (2- isopropylsulfonyls phenyl) amino) pyrimidine -2- amino) -3- anisyl -2- oxo-imidazoles Quinoline -1- acetic acid
1- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxyphenyls) - 3- (2- methoxyethyls) imidazolidinyl -2- ketone
Ethyl -2- (3- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxies Base phenyl) -3- methoxyphenyls) -2- imidazolidinyl -1- bases) acetic acid esters
1- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxyphenyls) - 3- methoxyphenyls) -3- (2- morpholines ethyl) imidazolidinyl -2- ketone
2- (3- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxybenzenes Base) -3- methoxyphenyls) -2- oxoimidazolinium -1- bases)-N- (2- hydroxyethyls) acetamide
1- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxyphenyls) - 3- (2- oxygen -2- (pyrrole radicals -1- bases) ethyl) imidazolidinyl -2- ketone
1- (2- (3- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxyl groups Phenyl) -2- oxoimidazolinium -1- bases) acetyl group) piperidyl -4- ketone
N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (2- oxo-pyrrolidine -1- bases) phenyl) amino) pyrimidine-4-yl) amino) benzene Base) acetamide
N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- ((3- oxocyclohex -1- alkene -1- bases) amino) phenyl) amino) pyrimidine -4- Base) amino) phenyl) acetamide
2- ((4- ((2- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) amino) ring Amyl- 1- alkene -1- carboxylic acid, ethyl esters
N- (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) cyclopropane first Amide
N- (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) is thio Quinoline -4- formamides
N- (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) -4- methyl Piperidines -1- formamides
1- ((4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) amino first Acyl group) piperidine-4-ethyl formate
N- (2-((the chloro- 2- of 5- ((4- (3- (4- hydroxy-cyclohexyls) urea groups)-2- methoxyphenyls) amino) pyrimidine-4-yl) ammonia Base) phenyl) acetamide
4- (3- (4- ((4- ((2- acetylamino phenyls) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyls) urea groups) Piperidines -1- t-butyl formates
N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (3- (4- oxocyclohexyls) urea groups) phenyl) amino) pyrimidine-4-yl) ammonia Base) phenyl) acetamide
N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (1H- pyrroles -1- bases) phenyl) amino) pyrimidine-4-yl) amino) phenyl) second Amide
N- (2- ((the chloro- 2- of 5- ((2- methoxyl groups -4- (1H- pyrroles -1- bases) phenyl) amino) pyrimidine-4-yl) amino) phenyl) first Sulfonamide
(((the chloro- 2- of 5- ((2- methoxyl groups -4- (2- (piperidin-1-yl methyl) -1H- pyrroles -1- bases) phenyl) amino) are phonetic by 2- by N- Pyridine -4- bases) amino) phenyl) acetamide
N- (2- ((the chloro- 2- of 5- ((4- (2- ((diethylamine) methyl) -1H- pyrroles -1- bases) -2- methoxyphenyls) amino) pyrimidine - 4- yls) amino) phenyl) Methanesulfomide
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- ((2- (nafoxidine -1- bases) ethyl) sulfones Base) phenyl) pyrimidine -2,4- diamines
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- ((2- (piperidin-1-yl) ethyl) sulfuryl) benzene Base) pyrimidine -2,4- diamines
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- ((2- (4- methyl piperidine -1- bases) ethyl) sulfones Base) phenyl) pyrimidine -2,4- diamines
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (((5- (nafoxidine -1- ylmethyls) furans Mutter -2- bases) methyl) sulfenyl) phenyl) pyrimidine -2,4- diamines
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (((5- (piperidin-1-yl methyl) furans -2- Base) methyl) sulfenyl) phenyl) pyrimidine -2,4- diamines
The chloro- N of 5-4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (((5- (4- methyl piperidine -1- ylmethyls) furans Mutter -2- bases) methyl) sulfenyl) phenyl) pyrimidine -2,4- diamines.
7. a kind of pharmaceutical composition, comprising 2, the 4- diarylaminos pyrimidine derivatives described in claim 1-6 any one and its Optical isomer, pharmaceutically acceptable salt, solvate or prodrug and pharmaceutically acceptable carrier.
8. 2,4- diarylaminos pyrimidine derivatives and its optical isomer described in claim 1-6 any one pharmaceutically may be used Pharmaceutical composition described in salt, solvate or the prodrug or claim 7 of receiving is in ALK and ROS1 kinase inhibitors are prepared Application.
9. claims requirement 1-6 any one described in 2,4- diarylaminos pyrimidine derivatives and its optical isomer, Pharmaceutical composition described in pharmaceutically acceptable salt, solvate or prodrug or claim 7 is in antitumor drug is prepared Application.
10. application as claimed in claim 9, which is characterized in that the tumour is lymph cancer or lung cancer.
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