CN106608868A - 5-(thioether)pyrimidine compound, pharmaceutical composition and applications thereof - Google Patents
5-(thioether)pyrimidine compound, pharmaceutical composition and applications thereof Download PDFInfo
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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
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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- 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
Abstract
The present invention belongs to the field of chemical drugs, and relates to a 5-(thioether)pyrimidine compound, a pharmaceutical composition and applications thereof. The present invention discloses a 5-(thioether)pyrimidine compound having a structure represented by a formula (I) or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, wherein the substituents in the formula (I) are defined in the specification. According to the present invention, the compound and the pharmaceutically acceptable salt thereof can effectively inhibit the growth of a variety of tumor cells, can inhibit the other proteases in EGFR and Her family, can be used for preparing antitumor drugs, and can overcome the drug resistance induced by the existing drugs such as gefitinib, erlotinib, and the like. The formula (I) is defined in the specification.
Description
Technical field
The invention belongs to chemical medicine field, and in particular to 5- (thioether group) pyrimidines and its Pharmaceutical composition and
Using.
Background technology
It is reported that, the mortality rate that current mankind's evil tumor causes has surmounted head of the every other disease positioned at mortality
Position, China are died from the total population of cancer every year and are close to 2,000,000 people.According to Ministry of Public Health statistical yearbook data display in 2013,
Malignant tumor occupies first in China cities in 2012 and rural area main vital disease, in disease Disease structure
Respectively reach 26.81% and 22.96%.
At present, the primary treatment medicine in clinical practice for tumor patient is divided into two big class, wherein, a class is traditional
Chemotherapeutics, including alkylating agent, antimetabolite, antitumor antibiotic, plant parhormone etc., they have very to tumor cell
Strong lethal effect, is referred to as cytotoxic drug；In recent years, the targeted drug treatment of tumor is the main of oncotherapy
Direction, which mainly (includes gene, enzyme, signal using the difference on molecular biology between tumor cell and normal cell
Transduction etc.), optionally suppress the growth of tumor cell, ultimately result in which dead；Relative to traditional cytotoxic drug
Thing, targeting anti-tumor medical instrument for specificity it is high, selectivity is strong, toxic and side effects are lighter the advantages of, when being used in combination, manifest
Go out to strengthen the curative effect of classic chemotherapy, radiotherapy, and the effect of reduction postoperative recurrence, at present, anti-tumor drugs targeting is with her
Imatinib mesylate (STI571) (Novartis, 2001), gefitinib (ZD1839) (AstraZeneca, 2003),
Erlotinib (OSI774) (Genetechand OSIP, 2004), Sorafenib tosilate (Bay 43-9006)
(Bayer and Onyx, 2005), sunitinib malate (SU11248) (Pfizer, 2006) and Dasatinib
(BMS-354825) (2006) Bristol-Myers Squibb are representative.
In the research and development of molecular targeted agents, family tyrosine kinase is to study one of field the most deep.It includes 90
Multiple family members, are divided into receptor type and non-receptor type.They are participated in by the phosphorylation to target protein L-Tyrosine site
The regulation and control of intracellular various signal paths, such as cell transfer, cell cycle, propagation, apoptosis and differentiation.Kinase activity
Exception directly results in the imbalance of unlike signal path, plays an important role in tumor development.
EGFR belongs to a member of receptor tyrosine kinase family ErbB (also known as EGFR families), it with ErbB2 (HER2),
ErbB3 (HER3) and ErbB4 (HER4) belong to the family together.EGFR is predominantly located at surface of cell membrane, after ligand binding
There is homologous or Heterodimerization in conformational change, receptor, further by allosteric activation effect, its intracellular region occurs from phosphorus
Acidifying, activates its kinase activity, and then activates a plurality of downstream signaling pathway, such as Ras/Raf/MEK/ERK/MAPK
Path, PI3K/PDK1/Akt (PKB) path, PLC- γ paths, JAK/STAT paths etc..The activation of blocking EGFR
It has been that leading method carrys out targeting therapy on tumor by clinical verification.
EGFR has had multi-medicament to be applied to clinic as the important target spot of antineoplastic at present, including 6 kinds of cheese
Histidine kinase micromolecular inhibitor (Gefitinib, Erlotinib, Lapatinib, Vandetanib, Icotinib, Afatinib) and
2 kinds of monoclonal antibodies (Cetuximab, Panitumumab) for ectodomain.
Gefitinib was approved for clinic respectively at 2003,2004 with Erlotinib.The II phase clinical research table of early stage
Bright gefitinib and Erlotinib are used for unselected patient as first-line treatment, and its best curative effect is only that symptom is moderately slow
Solution, responsiveness (response rate, RR) only 4-23%, progression free survival phase (progress free survival, PFS)
For 1.6-3.5 month, Overall survival was 5-13 month, and compared with placebo group, its curative effect is faint.But subsequently for taking
The subgroup for obtaining good therapeutic effect carries out retrospective analysiss, it is found that such crowd's responsiveness reaches 13-43%, progression free survival phase
Reach 4-5.6 month, comparing other patient's curative effects has significance to improve.Such crowd mainly includes East Asia Region non-smoking
Women non-small cell patient.The analysis shows of molecular level, benefit most patients to gefitinib and Erlotinib and deposit
In EGFR sensitizing mutations, most common of which is the deletion mutation E746-750 (19del) and 21 extras of 19 exons
Show the point mutation L858R of son, they account for reporting the 85% of all mutation.The discontinuity height of EGFR kinase domains
Activation kinases so that the existence of tumor cell has dependency to mutant kinase.Subsequently clinical research shows EGFR
The patient of sensitizing mutation is significantly higher than EGFR wild type NSCLC patients to the response rate of EGFR-TKI, and get nowhere life
Deposit the phase and Overall survival also significantly extends.Although gefitinib and Erlotinib treat the NSCLC of EGFR sensitizing mutations
Patient outcome is obvious, but the PFS of most of patient there occurs drug resistance to TKI less than 12-14 month.Drug resistance
Problem becomes the threat for restricting such inhibitor clinical practice most serious.
There is research to show, the resistance mechanism of EGFR is mainly primary drug resistance and acquired drug-resistance, and primary drug resistance is not
It is mutated by the drug resistance induced using EGFR inhibitor, including EGFR primary drug resistance, KRAS, PI3K/AKT
The activation of signal path, IGF-1 1 (IGF1R) height is expressed and NF- κ B signal paths are extremely living
Change；Acquired drug-resistance refers to the drug resistance that long-time is induced using EGFR inhibitor, such as EGFR medicament-resistant mutations, and liver is thin
Intracellular growth factor acceptor (MET) is expanded, high with hepatocyte growth factor (HGF) to express, morphocytology transformation,
High expression of IGF1R and VEGF (VEGF) etc., and patient its EGFR of 60% TKI acquired drug-resistances
There is medicament-resistant mutation such as T790M, L747S, D761Y, T854A, wherein T790M accounts for the overwhelming majority, up to total drug resistance
The 50% of number.
Studies have found that T790M mutation can make EGFR substantially increase the affinity of ATP so that the TKI of the first generation
It is less competitive than ATP and fails；In order to overcome the defect, covalently bound secondary inhibitor can be formed with target and be developed,
They can form irreversible fixation with target relative to generation inhibitor, so as to effectively overcome after EGFR T790M mutation
The impact brought by ATP affinity increases, while effect is more longlasting.It is currently in the EGFR bis- of clinical investigation phase
It is as shown in table 1 for inhibitor.
The secondary inhibitor of table 1.EGFR
Disc.:discontinued；MBC:Metastatic breast cancer
It is approved by the FDA in the United States listing within Afatinib and 2013 year, but infective use shows, such inhibitor is not
Irreversible combination is only capable of on the EGFR that T790M mutation occur, the EGFR of wild type can be also acted on.Due to
People's epidermis and gastric mucosa are distributed the EGFR of a large amount of wild types, can bring serious without selective irreversible persistently suppression
The 3-4 level untoward reaction such as erythra diarrhoea.The medicine is only used for the treatment of the NSCLC containing EGFR sensitizing mutations at present, its
In the selectivity that do not have become the bottleneck factor of restriction such inhibitor development.
Based on the present situation of prior art, present inventor intends the TKI for providing a new generation with high selectivity, to solve
The selective problems of certainly secondary inhibitor.
The content of the invention
The purpose of the present invention is the defect to overcome prior art to exist, based on the clinical practice present situation of EGFR inhibitor,
A kind of 5- (thioether group) pyrimidines, more particularly to 5- (thioether group) miazines of formula I structure are provided
Compound or its pharmaceutically acceptable salt or stereoisomer or its prodrugs：
Wherein,
M represents 0,1,2；
N represents that 0,1,2, m is 0 when different with n；
X represents N or CH,
L represents covalent bond or C1-3Alkyl, NH, O, S ,-C (O)-or-SO2-；
R1Represent C1-4Alkyl or-L1-R5,
L1Expression-(C1-4Alkyl)-,
R5Represent 3-7 units cycloalkyl, phenyl or 5-6 unit's heteroaryls；
The C1-4Moieties, cycloalkyl, phenyl, heteroaryl can further by 1-4 Q1Replace,
Q1Represent hydrogen atom, halogen atom ,-CN ,-CF3,-NH2,-NH (C1-3Alkyl) ,-OH ,-O (C1-3Alkyl),
-C(0)-(C1-3Alkyl) ,-S (C1-3Alkyl) or-SO2(C1-3Alkyl), wherein Q1Can be with identical or different；
Carbon atom in the cycloalkyl can be by 1-4 identical or different N, NH, N (C1-3Alkyl), O, C (O) or
SO2Replace；
R2Represent hydrogen, halogen or-O (C1-4Alkyl),
The C1-4Moieties further can be replaced by 1-4 fluorine atom；
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl-OH,
-SO2-C1-4Alkyl-OH or NH2,
Wherein, C1-4Moieties further can be replaced by 1-4 fluorine；
R4Represent hydrogen, halogen, amino, hydroxyl, cyano group, nitro, C1-4Alkyl, C3-7Cycloalkyl, aryl, or
Selected from following structure：
W represents CH2, CH2CH2, O, S, NH or NR7；R7Represent alkyl or aryl；
R6Represent hydrogen, halogen, C1-4Alkyl, C3-7Cycloalkyl or aryl.
In some embodiments of the invention, described 5- (thioether group) pyrimidines or which is pharmaceutically acceptable
Salt or stereoisomer or its prodrugs, which has formula II structure：
R1,R2,R3, L, X are as claimed in claim 1；
R8,R9,R10Represent hydrogen, CH3, CH2CH3；
In some embodiments of the invention, described 5- (thioether group) pyrimidines or which is pharmaceutically acceptable
Salt or stereoisomer or its prodrugs, which has formula III structure：
M represents 0,1,2；
N represents that 0,1,2, m is 0 when different with n；
X represents N or CH；
L represents covalent bond or C1-3Alkyl, NH, O, S ,-C (O)-,-SO2-；
R2Represent hydrogen, halogen ,-O (C1-4Alkyl),
The C1-4Moieties further can be replaced by 1-4 fluorine atom；
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl-OH,
-SO2-C1-4Alkyl-OH or NH2,
Wherein, C1-4Moieties further can be replaced by 1-4 fluorine；
R8,R9,R10Represent hydrogen, CH3, CH2CH3；
In some embodiments of the invention, described 5- (thioether group) pyrimidines or which is pharmaceutically acceptable
Salt or stereoisomer or its prodrugs, which has formula IV structure：
M represents 0,1,2；
N represents that 0,1,2, m is 0 when different with n；
X represents N or CH；
L represents covalent bond or C1-3Alkyl, NH, O, S ,-C (O)-,-SO2-；
R2Represent hydrogen, halogen ,-O (C1-4Alkyl),
The C1-4Moieties further can be replaced by 1-4 fluorine atom；
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl
-OH,-SO2-C1-4Alkyl-OH or NH2。
Wherein, C1-4Moieties further can be replaced by 1-4 fluorine.
In some embodiments of the invention, described 5- (thioether group) pyrimidines or which is pharmaceutically acceptable
Salt or stereoisomer or its prodrugs, which has formula (V) structure：
R2Represent hydrogen, halogen ,-O (C1-4Alkyl),
The C1-4Moieties further can be replaced by 1-4 fluorine atom.
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl-OH,
-SO2-C1-4Alkyl-OH or NH2。
Wherein, C1-4Moieties further can be replaced by 1-4 fluorine.
In some embodiments of the invention, described 5- (thioether group) pyrimidines or which is pharmaceutically acceptable
Salt or stereoisomer or its prodrugs, which has formula VI structure：
R2Represent hydrogen, halogen ,-O (C1-4Alkyl),
The C1-4Moieties further can be replaced by 1-4 fluorine atom.
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl-OH,
-SO2-C1-4Alkyl-OH or NH2。
Wherein, C1-4Moieties further can be replaced by 1-4 fluorine.
In some embodiments of the invention, described 5- (thioether group) pyrimidines or which is pharmaceutically acceptable
Salt or stereoisomer or its prodrugs, which has formula (VII) structure：
R2Represent hydrogen, halogen ,-O (C1-4Alkyl),
The C1-4Moieties further can be replaced by 1-4 fluorine atom.
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl-OH,
-SO2-C1-4Alkyl-OH or NH2。
Wherein, C1-4Moieties further can be replaced by 1-4 fluorine.
In some embodiments of the invention, described 5- (thioether group) pyrimidines or which is pharmaceutically acceptable
Salt or stereoisomer or its prodrugs, the compound be selected from following molecule：
In some embodiments of the invention, described 5- (thioether group) pyrimidines or which is pharmaceutically acceptable
Salt or stereoisomer or its prodrugs, the compound be selected from following molecule：
A further object of the present invention is to provide a kind of Pharmaceutical composition for treating tumor.
The Pharmaceutical composition of the treatment tumor, its by the 5- (thioether group) pyrimidines or its can pharmaceutically connect
The salt received or stereoisomer or its prodrugs are constituted with pharmaceutically acceptable carrier.
A further object of the present invention is to provide the purposes in pharmacy of the 5- (thioether group) pyrimidines；Especially
It is the 5- (thioether group) pyrimidines and its pharmaceutically acceptable salt or stereoisomer or its before
Purposes of the medicine molecule in the medicine for preparing treatment tumor；
In the present invention, the tumor is nonsmall-cell lung cancer, and small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas are newborn
Adenocarcinoma, carcinoma of prostate, hepatocarcinoma, skin carcinoma, cell carcinoma, gastrointestinal stromal tumors (GISTs), leukemia, histiocytic lymph
Cancer, any one in nasopharyngeal carcinoma.
Jing rows of the present invention test cell line, as a result shows, 5- (thioether group) miazines of described logical formula I structure
Compound, can suppress kinds of tumor cells, especially can selectively acting in EGFR L858R/T790M and EGFR
E745A750/T790M lung carcinoma cells；Relative to wild type cancerous cell, the IC50 of such compound wants high ten times even
Tens times of difference, further, such compound can be used to preparing and new can overcome existing EGFR-TKI drug resistances
And selective kinases inhibitor.
Compound of the present invention and its pharmaceutically acceptable salt, can effectively suppress the growth of kinds of tumor cells,
And to EGFR, other protease of Her families produce inhibitory action；Further, can be used for preparing antitumor drug, and
Overcome the drug resistance of the inductions such as existing medicine gefitinib, Erlotinib.As understood by those skilled in the art, the application
Described compound and its pharmaceutically acceptable salt can be used to prepare the treatment mankind and the tumor of other mammals was waited
Degree proliferative disease.
In compound of the present invention, as any variable (such as R1, R etc.) occur more than in any component once,
The definition that the definition that then which occurs every time occurs every time independently of other.Equally, it is allowed to the combination of substituent group and its variable,
As long as this combination is stability of compounds.It is appreciated that those of ordinary skill in the art may be selected the substituent group of the compounds of this invention
And replacement form and provide chemically stable and the allowing from can be readily available of art technology and following proposition can be passed through
The compound that is readily synthesized of raw material.If instead of base itself more than a substituent group, it should be understood that these groups can be
In identical carbon atoms or on different carbon atoms, as long as making Stability Analysis of Structures.
In the present invention, term " alkyl " used means the saturated fat for including the side chain and straight chain with particular carbon atom number
Fat alkyl.For example, " C1-4" C in alkyl "1-4" definition include with straight or branched arrange with 1,2,3 or 4
The group of individual carbon atom.For example, " C1-4Alkyl " specifically includes methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl,
Isobutyl group, the tert-butyl group.Term " cycloalkyl " refers to the monocyclic saturated fat alkyl with particular carbon atom number.Such as " ring
Alkyl " includes cyclopropyl, methyl-cyclopropyl, 2,2- dimethyl-cyclobutyls, 2- ethyI-cyclopentyls, cyclohexyl etc..
In the present invention, term " heteroaryl " used is represented in stable monocyclic or each rings of up to 6 atoms in ring up to
6 atom bicyclic carbocyclics, wherein at least one ring is for aromatic rings and containing the 1-4 hetero atom selected from O, N and S.
Heteroaryl as defined in the range of this is included but is not limited to：Imidazole radicals, triazolyl, pyrazolyl, furyl, thienyl are disliked
Oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals.For the definition of following heteroaryl,
" heteroaryl " also is understood as the N- oxide derivatives for including any heteroaryl containing nitrogen.It is bicyclic in heteroaryl substituent
And have a ring nonaro-maticity or not contain in heteroatomic example, it should be understood that respectively hang oneself aromatic rings or Jing contain hetero atom
Ring connects.
As will be appreciated by a person skilled in the art, in the present invention, " halogen " or " halogen " used means to include fluorine, chlorine, bromine
And iodine.
The present invention includes the free form of-VII compound of formula I and XQ-1～XQ-9 compounds, also pharmaceutically may be used including which
The salt and stereoisomer of acceptance.In the present invention, some specific exemplary compounds are the protonated of aminated compoundss
Salt.Term " free form " refers to the aminated compoundss with salt-independent shape, and the pharmaceutically-acceptable salts being included include owning
The typical pharmaceutically acceptable salt of the free form of-VII compound of formula I and XQ-1～XQ-9 compounds.Can make
The free form of the compound specific salts is separated with techniques known in the art, for example, appropriate alkali dilute aqueous solution can be passed through
Such as sodium hydroxide dilute aqueous solution, potassium carbonate dilute aqueous solution, weak ammonia and sodium bicarbonate dilute aqueous solution process the salt and make to dissociate
Form regenerates；Free form some physical propertys for example in polar solvent on dissolubility with its each salt form it is how rare
It is a little to distinguish, but in order to invention this hydrochlorate of purpose and alkali salt in terms of other pharmacy with its respective free form phase
When.
Conventional chemical processes can be passed through from the pharmacy of the synthesis present invention of the compounds of this invention containing basic moiety or acidic moiety
Upper acceptable salt.Generally, by example exchange chromatography or by free alkali and the required salt shape of stoichiometric amount or excess
The reaction in the combination of appropriate solvent or multi-solvents of the inorganic or organic acid of formula prepares the salt of alkali compoundss, similar,
By the salt that acid compound is formed with appropriate inorganic or organic alkali reaction.
The pharmaceutically acceptable salt of the compounds of this invention includes anti-by the alkali compoundss and organic or inorganic acid of the present invention
The conventional non-toxic salts of the compounds of this invention that should be formed, for example, conventional nontoxic salts are included from mineral acid such as hydrochloric acid, hydrogen
The salt of bromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid etc., also includes from organic acid such as acetic acid, propanoic acid, succinic acid,
Glycolic, stearic acid do not have lactic acid, and malic acid, tartaric acid, citric acid, anti-deteriorated blood acid flutter acid, maleic acid, hydroxyl
Maleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, 2- acetoxy-benzoics, rich horse
The salt of the preparations such as acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyethylsulfonic acid., trifluoroacetic acid.
If the compounds of this invention is acid, appropriate " pharmaceutically acceptable salt " refers to by pharmaceutically acceptable
Nontoxic alkali includes salt prepared by inorganic base and organic base, and the salt for deriving from inorganic base includes aluminium salt, ammonium salt, calcium salt, mantoquita,
Iron salt, ferrous salt, lithium salts, magnesium salt, sodium salt, zinc salt etc..Particularly preferred ammonium salt, calcium salt, magnesium salt, potassium salt and sodium salt.
The salt of pharmaceutically acceptable organic nontoxic alkali is derived from, the alkali includes primary amine, secondary amine, the salt of tertiary amine, substituted amine bag
Include naturally occurring replacement amine, cyclic amine and deacidite such as arginine, glycine betaine, caffeine, choline,
N, N- dibenzyl-ethylenediamin, diethylamine, DMAE, ethylaminoethanol, ethanolamine, ethylenediamine, N- ethyls
Morpholine, N- acetyl piperidines, glucamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, first
Base glucamine, morpholine, piperazine, piperidines, croak smack one's lips, many polyimide resins, procaine, purine, theobromine, triethylamine,
Trimethylamine, tripropyl amine (TPA), tromethane etc..
Berg etc., " Pharmaceutical Salts, " J.Pharm.Sci.1997:66:1-19 is described in more detail the above
Its content is introduced the present invention by the preparation of pharmaceutically acceptable salt and other typical pharmaceutically acceptable salts, here
In.
As the acidic moiety such as carboxyl of compound deprotonation in physiological conditions can be anion, and this carry
Then electric charge can be carried the basic moiety such as quaternary nitrogen atom of the protonated or alkylation of cation and be put down by inside
Weighing apparatus is offset, it is noted that potential inner salt or amphion during the compounds of this invention.
In addition to known in the literature or the illustration in experimental arrangement standard method, can be using as shown in following embodiment
The reaction shown prepares the compounds of this invention.Therefore, following illustrative embodiment is for the purpose of illustration rather than is confined to institute
Row compound or any specific substituent group.The substituent group number shown in embodiment not necessarily meets in claim
Number used, and for clarity, showing that monosubstituted base is connected to has allowed multi-substituent under the definition of formula I above
Compound on.
Specific embodiment
- VII compound of the formula I and XQ-1～XQ-9 compounds are invented such as, those skilled in the art can be according to existing
There are technology and the general knowledge for possessing, can be that initiation material is closed by the reaction of several steps by 2,4-, bis- chloro- 5- (methyl mercapto) pyrimidines
Into (concrete synthesis step is shown in embodiment 1).
In one embodiment, this application provides a kind of using with-VII compound of formula I and XQ-1～XQ-9ization
Compound, and its pharmaceutically acceptable salt treatment the excess proliferative disease such as people or other mammal tumors or symptom should
With.
In one embodiment, the compound and its pharmaceutically acceptable salt involved by the application can be used for treatment or
Person controls nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, liver
Cancer, skin carcinoma, cell carcinoma, gastrointestinal stromal tumors (GISTs), leukemia, histiocytic lymphatic cancer, nasopharyngeal carcinoma etc. excessively increase
Growing property disease.
The metabolite of compound and its pharmaceutically acceptable salt involved by the application, and can be changed in vivo
The prodrug of the structure of compound and its pharmaceutically acceptable salt involved by the application, the right for being also contained in the application will
In asking.
The present invention will be further described for following examples, only express the present invention several embodiments, its description compared with
For concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for
For one of ordinary skill in the art, without departing from the inventive concept of the premise, some deformations can also be made and is changed
Enter, these belong to protection scope of the present invention.
Embodiment 1
N- (3- ((2- ((4- (4- methylpiperazine-1-yls) -2- methoxyphenyls) amino) -5- (methyl mercapto) pyrimidine -4-
Base) epoxide) phenyl) acrylamide (XQ-1)
Step 1 tert-butyl group (3- ((2- chloro- 5- (methyl mercapto) pyrimidine-4-yls) epoxide) phenyl) t-butyl carbamate
(1)
It is pre-loaded with the round-bottomed flask of magnetic stirring apparatuss in 50mL bottoms, adds the tert-butyl group (3- hydroxy phenyls) amino
T-butyl formate (1.88g, 9.0mmol) and isopropanol (18.0mL).Reactant mixture is cooled to 0 DEG C.2,4- bis-
Chloro- 5- (methyl mercapto) pyrimidine (1.75g, 9.0mmol) is added drop-wise in above-mentioned reactant mixture at 0 DEG C.Again by DIPEA
(1.9mL, 10.8mmol) is added dropwise in above-mentioned reactant mixture, and reactant mixture is stirred in 90 DEG C of oil baths
Mix 4 hours.After the completion of TLC monitoring reactions.Solid precipitation is leached and filter cake is washed with isopropanol (6mL).
Gained white solid is dried 1 hour under 40 DEG C of decompressions.(1.3g, yield：40%).
1H NMR(400MHz,CDCl3) δ 8.22 (s, 1H), 7.44 (brs., 1H), 7.32 (t, J=8.1Hz, 1H), 7.10
(d, J=7.9Hz, 1H), 6.84 (d, J=6.8Hz, 1H), 6.57 (s, 1H), 2.53 (s, 3H), 1.51 (s, 9H) .ES/MS
(M+H)+=367.9
Step 2 1- (4- (3- methoxyl group -4- nitrobenzophenones) piperazine -1- bases) second -1- ketone (2)
By 1- (piperazine -1- bases) second -1- ketone (3.59g, 28mmol)) and potassium carbonate (3.88g, 28mmol) addition N,
In dinethylformamide (40mL), then add in the suspension the fluoro- 2- methoxyl groups -1- Nitrobenzol of 4- (4.09g,
23mmol) and at 80 DEG C it is stirred overnight.Mixture is poured in water, solid precipitation is leached.Gained solid is at 50 DEG C
It is dried in vacuum, obtains yellow solid (3.5g, yield：45%)
1H NMR (400MHz, DMSO) δ 7.92 (d, J=9.4Hz, 1H), 6.60 (dd, J=9.4,2.4Hz, 1H),
6.54 (d, J=2.3Hz, 1H), 3.92 (s, 3H), 3.60-3.58 (m, 4H), 3.55-3.53 (m, 2H), 3.49-3.47
(m, 2H), 2.06 (s, 3H) .ES/MS (M+H) +=280.1
Step 3 1- (4- (4- amino -3- methoxyphenyls) piperazine -1- bases) second -1- ketone (3)
1- (4- (3- methoxyl group -4- nitrobenzophenones) piperazine -1- bases) second -1- ketone (3.5g, 12.5mmol) is dissolved in into 50
In mL ethanol, 10% palladium carbon (350mg) is added under nitrogen protection.The balloon that will be filled with hydrogen is mounted on reaction bulb,
And evacuation 3 times, until hydrogen is full of in reaction system.It is stirred overnight under room temperature.Filtered off in reaction system with kieselguhr
Insoluble matter, and washed with methanol.Filtrate decompression concentrated by rotary evaporation, obtains dark oil thing.(3.1g, Quantitative yield)
1H NMR (400MHz, DMSO) δ 6.54 (d, J=1.9Hz, 1H), 6.53 (d, J=7.9Hz, 1H), 6.32
(dd, J=8.4,2.3Hz, 1H), 4.34 (brs., 2H), 3.75 (s, 3H), 3.58-3.50 (m, 4H), 2.97-2.91 (m,
2H), 2.90-2.84 (m, 2H), 2.03 (s, 3H) .ES/MS (M+H) +=250.2
Step 4 tert-butyl group (3- ((2- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- (first
Sulfenyl) pyrimidine-4-yl) epoxide) phenyl) t-butyl carbamate (4)
By the tert-butyl group (3- ((2- chloro- 5- (methyl mercapto) pyrimidine-4-yls) epoxide) phenyl) t-butyl carbamate (550mg, 1.5
) and 1- (4- (4- amino -3- methoxyphenyls) piperazine -1- bases) second -1- ketone (250mg, 1.0mmol) is dissolved in dioxy mmol
In six rings (10mL), the trifluoroacetic acid of catalytic amount is subsequently adding.Reaction system is placed in 90 DEG C of oil bath and is stirred overnight.
Pass through column chromatography purification (dichloromethane after reactant liquor vacuum rotary steam is concentrated：Methanol 20:1 used as eluant) obtain Fructus Citri tangerinae
Yellow solid.(174mg, yield:34%)
1H NMR(400MHz,CDCl3)δ8.31(s,1H),7.67(s,1H),7.55(s,1H),7.34(s,1H),7.29
(s, 1H), 6.95-6.84 (m, 1H), 6.63 (s, 1H), 6.46 (d, J=1.7Hz, 1H), 6.21 (d, J=8.2Hz, 1H),
3.82(s,3H),3.81–3.65(m,2H),3.70–3.50(m,2H),3.22–2.93(m,4H),2.44(s,3H),2.14
(s, 1H), 1.49 (s, 9H) .ES/MS (M+H) +=580.9
Step 5 1- (4- (4- ((4- (3- amino-benzene oxygens) -5- (methyl mercapto) pyrimidine -2-base) amino) -3- methoxies
Base phenyl) piperazine -1- bases) second -1- ketone (5)
By the tert-butyl group (3- ((2- ((4- (4- Acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- (first sulfur
Base) pyrimidine-4-yl) epoxide) phenyl) t-butyl carbamate (174mg, 0.3mmol) is dissolved in dichloromethane 4mL,
Under condition of ice bath, 5mL trifluoroacetic acids are added thereto to.Reaction system moves to room temperature, and stirs at ambient temperature
1 hour.Reactant liquor is depressurized concentrated by rotary evaporation, is then dissolved with dichloromethane again, and with the sodium carbonate of 1mol/L
Solution is washed, and then uses salt water washing, which floor has be concentrated to give crocus solid with vacuum rotary steam after anhydrous sodium sulfate drying.
(96mg, Quantitative yield)
1H NMR (400MHz, DMSO) δ 8.26 (s, 1H), 7.88 (s, 1H), 7.48 (d, J=8.8Hz, 1H), 7.08 (t,
J=8.0Hz, 1H), 6.61 (d, J=2.5Hz, 1H), 6.49 (dd, J=8.1,1.3Hz, 1H), 6.36 (t, J=2.1Hz,
1H),6.33–6.28(m,2H),5.29(brs.,2H),3.78(s,3H),3.59–3.56(m,4H),3.12–3.04(m,
2H), 3.05-2.98 (m, 2H), 2.40 (s, 3H), 2.05 (s, 3H) .ES/MS (M+H) +=481.0
Step 6 N- (3- ((2- ((4- (4- methylpiperazine-1-yls) -2- methoxyphenyls) amino) -5- (methyl mercapto)
Pyrimidine-4-yl) epoxide) phenyl) acrylamide (XQ-1)
Under condition of ice bath, acryloyl chloride (9 μ L, 0.11mmol) is added drop-wise to 1- (4- (4- ((4- (3- amino-benzene oxygens)
- 5- (methyl mercapto) pyrimidine -2-base) amino) -3- methoxyphenyls) piperazine -1- bases) second -1- ketone (48mg, 0.10mmol)
In dichloromethane (2mL) solution of diisopropylethylamine (26 μ L, 0.15mmol).Then continue to stir under condition of ice bath
Mix 1 hour, reactant liquor vacuum rotary steam is concentrated, and priority saturated sodium bicarbonate aqueous solution and saturated nacl aqueous solution are washed
Wash, vacuum rotary steam concentration, column chromatography purification (dichloromethane after organic layer anhydrous sodium sulfate drying：Methanol 20:1 does
For mobile phase) obtain white solid (35mg, yield:65%)
1H NMR(600MHz,DMSO)δ10.31(s,1H),8.30(s,1H),7.96(s,1H),7.59(s,1H),
7.57 (d, J=8.0Hz, 1H), 7.41 (t, J=8.0Hz, 1H), 7.33 (d, J=8.1Hz, 1H), 6.94 (d, J=7.6Hz,
1H), 6.57 (s, 1H), 6.43 (dd, J=16.7,10.1Hz, 1H), 6.27 (d, J=16.9Hz, 1H), 6.19 (brs., 1H),
5.78 (d, J=10.1Hz, 1H), 3.75 (s, 3H), 3.56-3.54 (m, 4H), 3.06-3.04 (m, 2H), 2.99-2.97
(m, 2H), 2.42 (s, 3H), 2.04 (s, 3H) .ES/MS (M+H) +=535.3.
Embodiment 2
N- (3- ((2- ((2- methoxyl group -4- (4- (methyl sulphonyl) piperazine -1- bases) phenyl) amino) -5- (first
Sulfenyl) pyrimidine-4-yl) epoxide) phenyl) acrylamide (XQ-2)
Synthetic method such as embodiment 1；
1H NMR(600MHz,DMSO)δ10.31(s,1H),8.30(s,1H),7.98(s,1H),7.60(s,1H),
7.56 (d, J=8.0Hz, 1H), 7.41 (t, J=8.1Hz, 1H), 7.34 (d, J=8.5Hz, 1H), 6.94 (d, J=7.9Hz,
1H), 6.58 (s, 1H), 6.43 (dd, J=16.9,10.1Hz, 1H), 6.27 (d, J=16.9Hz, 1H), 6.22 (brs., 1H),
5.78 (d, J=10.2Hz, 1H), 3.75 (s, 3H), 3.23-3.21 (m, 4H), 3.16-3.14 (m, 4H), 2.93 (s, 3H),
2.42 (s, 3H) .ES/MS (M+H) +=571.2.
Embodiment 3
N- (3- ((2- ((4- (4- acetyl group -1,4- Diazesuberane -1- bases) -2- methoxyphenyls) amino) -5-
(methyl mercapto) pyrimidine-4-yl) epoxide) phenyl) acrylamide (XQ-3)
Synthetic method such as embodiment 1；
1H NMR(400MHz,CDCl3) δ 8.30 (s, 1H), 8.02 (brs., 1H), 7.60 (t, J=9.6Hz, 1H), 7.49
(s, 1H), 7.41-7.34 (m, 3H), 6.97 (d, J=8.1Hz, 1H), 6.43 (dd, J=17.0,2.3Hz, 1H), 6.30
(dd, J=16.8,10.0,1H), 6.19 (s, 1H), 5.92 (brs., 1H), 5.74 (dd, J=10.0,2.5Hz, 1H), 3.78 (s,
3H), 3.74 (t, J=5.3Hz, 1H), 3.63-3.61 (m, 1H), 3.57 (d, J=4.6Hz, 1H), 3.53-3.51 (m,
2H), 3.51-3.44 (m, 2H), 3.36 (t, J=6.1Hz, 1H), 2.44 (s, 3H), 2.04 (s, 3H), 1.98-1.93 (m,
1H), 1.92-1.87 (m, 1H) .ES/MS (M+H) +=549.2.
Embodiment 4
N- (3- ((2- ((4- ((1- Acetylpiperidin -4- bases) amino) -2- methoxyphenyls) amino) -5- (first
Sulfenyl) pyrimidine-4-yl) epoxide) phenyl) acrylamide (XQ-4)
Synthetic method such as embodiment 1；
1H NMR(400MHz,CDCl3) δ 8.35 (s, 1H), 7.77 (brs., 1H), 7.39 (t, J=8.1Hz, 1H), 6.99
(dd, J=7.8,1.8Hz, 1H), 6.40-6.36 (m, 4H), 6.34 (dd, J=17.0,2.3Hz, 1H), 5.86 (dd, J=
16.8,10.3Hz, 1H), 5.79-5.65 (m, 1H), 5.46 (dd, J=10.4,2.3Hz, 1H), 5.00-4.59 (m, 2H),
3.80(s,3H),3.81–3.79(m,1H),3.25–3.14(m,1H),2.68–2.55(m,1H),1.99(s,3H),1.88
- 1.74 (m, 2H), 1.21-1.07 (m, 2H) .ES/MS (M+H) +=549.3.
Embodiment 5
N- (3- ((2- ((2- methoxyl group -4- (4- propiono piperazine -1- bases) phenyl) amino) -5- (methyl mercapto)
Pyrimidine-4-yl) epoxide) phenyl) acrylamide (XQ-5)
Synthetic method such as embodiment 1；
1H NMR(400MHz,CDCl3) δ 8.31 (s, 1H), 7.70 (d, J=8.0Hz, 1H), 7.65 (brs., 1H),
7.56 (s, 1H), 7.49 (s, 1H), 7.43 (t, J=8Hz, 1H), 7.42 (s, 1H), 6.98 (dd, J=8.1,1.5Hz, 1H),
6.44 (dd, J=16.8,1.2Hz, 1H), 6.43 (d, J=2.4Hz, 1H), 6.23 (dd, J=16.8,10.2Hz, 1H),
6.17 (s, 1H), 5.77 (dd, J=10.2,1.1Hz, 1H), 3.80 (s, 3H), 3.75-3.73 (m, 2H), 3.60-3.58 (m,
2H), 3.03-3.00 (m, 4H), 2.44 (s, 3H), 2.39 (dd, J=14.9,7.4Hz, 2H), 1.17 (t, J=7.4Hz,
3H) .ES/MS (M+H) +=549.0.
Embodiment 6
(((2- ((4- (4- isobutyryl piperazine -1- bases) -2- methoxyphenyls) amino) -5- (methyl mercapto) is phonetic for 3- for N-
Pyridine -4- bases) epoxide) phenyl) acrylamide (XQ-6)
Synthetic method such as embodiment 1；
1H NMR(400MHz,CDCl3) δ 8.32 (s, 1H), 7.70 (d, J=8.0Hz, 1H), 7.65 (brs., 1H),
7.56 (s, 1H), 7.49 (s, 1H), 7.43 (t, J=8Hz, 1H), 7.42 (s, 1H), 6.98 (dd, J=8.1,1.5Hz, 1H),
6.44 (dd, J=16.8,1.2Hz, 1H), 6.43 (d, J=2.4Hz, 1H), 6.23 (dd, J=16.8,10.2Hz, 1H),
6.17 (s, 1H), 5.77 (dd, J=10.2,1.1Hz, 1H), 3.81 (s, 3H), 3.76-3.74 (m, 2H), 3.65-3.63 (m,
2H), 3.04-3.00 (m, 4H), 2.90-2.73 (m, 1H), 2.44 (s, 3H), 1.15 (d, J=6.8Hz, 6H) .ES/MS
(M+H) +=563.0.
Embodiment 7
(((2- ((2- methoxyl group -4- (4- pivaloyl piperazine -1- bases) phenyl) amino) -5- (methyl mercapto) is phonetic for 3- for N-
Pyridine -4- bases) epoxide) phenyl) acrylamide (XQ-7)
Synthetic method such as embodiment 1；
1H NMR(400MHz,DMSO)δ10.29(brs.,1H),8.26(s,1H),7.94(s,1H),7.55(s,1H),
7.54 (d, J=8.9Hz, 1H), 7.38 (t, J=7.8Hz, 1H), 7.29 (d, J=8.5Hz, 1H), 6.91 (d, J=7.6Hz,
1H), 6.53 (s, 1H), 6.39 (dd, J=16.6,10.0Hz, 1H), 6.22 (d, J=15.9Hz, 1H), 6.15 (d, J=7.8
Hz, 1H), 5.74 (d, J=11.0Hz, 1H), 3.71 (s, 3H), 3.68-3.59 (m, 4H), 3.04-2.91 (m, 4H),
2.39 (s, 3H), 1.19 (s, 9H) .ES/MS (M+H) +=577.3.
Embodiment 8
N- (3- ((2- ((2- methoxyl group -4- (4- (2,2,2- trifluoroacetyl groups) piperazine -1- bases) phenyl) amino) -5-
(methyl mercapto) pyrimidine-4-yl) epoxide) phenyl) acrylamide (XQ-8)
Synthetic method such as embodiment 1；
1H NMR(400MHz,CDCl3) δ 8.33 (s, 1H), 7.69 (m, 2H), 7.51 (brs., 1H), 7.44 (t, J=8.2
Hz, 1H), 7.40 (s, 1H), 7.37 (s, 1H), 6.99 (dd, J=7.7,1.8Hz, 1H), 6.44 (dd, J=16.8,1.2Hz,
1H), 6.43 (d, J=2.4Hz, 1H), 6.22 (dd, J=16.8,10.2Hz, 1H), 6.20 (s, 1H), 5.79 (dd, J=
10.2,1.0Hz,1H),3.82(s,3H),3.83-3.80(m,2H),3.78–3.71(m,2H),3.14–3.06(m,4H),
2.44 (s, 3H) .ES/MS (M+H) +=589.0.
Embodiment 9
N- (3- ((2- ((4- (4- Acetylpiperazine -1- bases) -2- (difluoro-methoxy) phenyl) amino) -5- (first
Sulfenyl) pyrimidine-4-yl) epoxide) phenyl) acrylamide (XQ-9)
Synthetic method such as embodiment 1；
1H NMR(400MHz,CDCl3) δ 8.32 (s, 1H), 7.71 (d, J=8.9Hz, 1H), 7.64 (d, J=7.8Hz,
1H), 7.49 (s, 1H), 7.45 (s, 1H), 7.41 (d, J=8.2Hz, 1H), 7.22 (s, 1H), 6.97 (dd, J=8.1,1.6Hz,
1H), 6.63 (d, J=2.7Hz, 1H), 6.44 (dd, J=16.8,1.2Hz, 1H), 6.44 (t, J=79.6Hz, 1H), 6.25
(dd, J=16.8,10.2Hz, 1H), 5.79 (dd, J=10.2,1.1Hz, 1H), 3.77-3.70 (m, 2H), 3.66-3.52
(m, 2H), 3.11-2.97 (m, 4H), 2.45 (s, 3H), 2.13 (s, 3H) .ES/MS (M+H) +=571.0.
Embodiment 10
5- (thioether group) pyrimidines are to EGFR wild types and the kinases IC50 of the double mutation of EGFR L858R/T790M
Test,
EGFR WT are wild-type egf receptor, and EGFR L858R/T790M are with the 858th bit amino
Acid has leucine to be mutated into arginine and 790 amino acids has threonine to be mutated into the epidermal growth factor receptor of methionine
Body,
Kinase activity is detected：
Tyrosine phosphorylation is detected with enzyme linked immunosorbent assay (Enzyme-Linked Immunosorbent Assay, ELISA)
The ability of substrate, calculates inhibitory action of the compound to kinase activity, using Bac-to-BacTMBaculovirus expression system
(Invitrogen, Carlsbad, CA, USA) carries out the kinases area of Wild type EGFR and EGFR T790M/L858R mutation
Expression, Jing nickel posts (QIAGEN Inc., Valencia, CA, USA) purification.ELISA key steps are as follows：Enzyme reaction bottom
Thing Poly (Glu,Tyr)4:1 with the PBS without potassium ion (10mM sodium phosphate buffers, 150mM NaCl, pH 7.2-7.4)
20 μ g/mL are diluted to, 12-16h coated elisa plates are reacted in 37 DEG C, then with the PBS containing 0.1%Tween-20
(T-PBS) board-washing, adds with reaction buffer (50mM HEPES pH 7.4,50mM MgCl per hole2,0.5mM
MnCl2,0.2mM Na3VO4, 1mM DTT) and ATP (5 μM of the final concentration) solution that dilutes, add variable concentrations
Testing compound or solvent control, be then respectively adding respective kinase and start reaction, 37 DEG C of shaking tables react 1h, T-PBS
Board-washing three times, adds antibody PY99100 μ L/ holes (being diluted with the T-PBS containing BSA) in 37 DEG C of shaking table reaction 0.5h,
After T-PBS board-washings, the 100 μ L/ holes of IgG of the sheep anti mouse of horseradish peroxidase-labeled are added (with the T-PBS containing BSA
Dilution), 37 DEG C of shaking tables react 0.5h, again after board-washing, the 100 μ L/ holes of OPD nitrite ions of addition 2mg/mL, 25 DEG C
Lucifuge reacts 1-10min, adds 2M H2SO4Terminating reaction, with wavelengthtunable microwell plate microplate reader SPECTRA
190 readings of MAX, wavelength are 492nm, IC50Value is obtained by suppression curve.Table 2 shows compound kinase activity.
Table 2
The cellular level test of embodiment 11EGFR activity
Using Sulforhodamine B (sulforodamine B, SRB) method detection compound cell proliferation inhibitory action,
From EGFR dependent cells strains：Human epidermal cell cancer A431 cell strain and Non-small cell lung carcinoma NCI-H1975 cells
Strain (being purchased from ATCC).Cell is inoculated in 96 orifice plates with certain density, it is adherent overnight, add variable concentrations compound
Effect 72h, with 10% trichloroacetic acid of pre-cooling in 4 DEG C of fixed 1h, distilled water washes away fixative post-drying, uses 4
SRB solution (the being dissolved in 1% acetic acid) room temperature of mg/mL is dyeed 15 minutes, washes away excess stain liquid, and room temperature is dried,
Before using microplate reader detection, add 100 μ L of 10mmol/L Tris per hole, after about 15 minutes, SRB is completely dissolved,
The absorbing wavelength of 515nm, suppression ratio meter are determined using multi-function microplate reader (VERSAmax, Molecular Devices)
Calculating formula is：[1–(A515treated/A515control)] × 100%.Table 3 shows Compound cellular activity.
Table 3
Claims (12)
1. there are 5- (thioether group) pyrimidines or its pharmaceutically acceptable salt or solid of formula I structure
Isomer or its prodrugs：
Wherein,
M represents 0,1,2；
N represents that 0,1,2, m is 0 when different with n；
X represents N or CH；
L represents covalent bond or C1-3Alkyl, NH, O, S ,-C (O)-,-SO2-；
R1Represent C1-4Alkyl or-L1-R5,
L1Expression-(C1-4Alkyl)-,
R5Represent 3-7 units cycloalkyl, phenyl or 5-6 unit's heteroaryls；
The C1-4Moieties, cycloalkyl, phenyl, heteroaryl can further by 1-4 Q1Replace,
Q1Represent hydrogen atom, halogen atom ,-CN ,-CF3,-NH2,-NH (C1-3Alkyl) ,-OH ,-O (C1-3Alkyl),
-C(0)-(C1-3Alkyl) ,-S (C1-3Alkyl) or-SO2(C1-3Alkyl), wherein Q1Can be with identical or different；
Carbon atom in the cycloalkyl can be by 1-4 identical or different N, NH, N (C1-3Alkyl), O, C (O)
Or SO2Replace；
R2Represent hydrogen, halogen or-O (C1-4Alkyl),
The C1-4Moieties further can be replaced by 1-4 fluorine atom,
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl-OH,
-SO2-C1-4Alkyl-OH or NH2,
Wherein, C1-4Moieties further can be replaced by 1-4 fluorine；
R4Represent hydrogen, halogen, amino, hydroxyl, cyano group, nitro, C1-4Alkyl, C3-7Cycloalkyl, aryl, or
Selected from following structure：
W represents CH2,CH2CH2,O,S,NH,NR7；R7Represent alkyl or aryl；
R6Represent hydrogen, halogen, C1-4Alkyl, C3-7Cycloalkyl or aryl.
2. 5- (thioether group) pyrimidines according to claim 1 or its pharmaceutically acceptable salt or
Stereoisomer or its prodrugs, it is characterised in which has formula II structure：
Wherein, R1,R2,R3, L, X are as claimed in claim 1；
R8,R9,R10Represent hydrogen, CH3,CH2CH3。
3. 5- (thioether group) pyrimidines according to claim 1 or its pharmaceutically acceptable salt or
Stereoisomer or its prodrugs, it is characterised in which has formula III structure:
M represents 0,1,2；
N represents that 0,1,2, m is 0 when different with n；
X represents N or CH；
L represents covalent bond or C1-3Alkyl, NH, O, S ,-C (O)-or-SO2-；
R2Represent hydrogen, halogen or-O (C1-4Alkyl)；
The C1-4Moieties are replaced by 1-4 fluorine atom；
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl-OH,
-SO2-C1-4Alkyl-OH or NH2；
Wherein, C1-4Moieties are replaced by 1-4 fluorine；
R8,R9,R10Represent hydrogen, CH3, CH2CH3。
4. 5- (thioether group) pyrimidines according to claim 3 or its pharmaceutically acceptable salt or
Stereoisomer or its prodrugs, it is characterised in which has formula IV structure
M represents 0,1,2；
N represents that 0,1,2, m is 0 when different with n；
X represents N or CH,
L represents covalent bond or C1-3Alkyl, NH, O, S ,-C (O)-or-SO2-；
R2Represent hydrogen, halogen or-O (C1-4Alkyl),
The C1-4Moieties are replaced by 1-4 fluorine atom；
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl-OH ,-SO2-C1-4
Alkyl-OH or NH2,
Wherein, C1-4Moieties are replaced by 1-4 fluorine.
5. 5- (thioether group) pyrimidines according to claim 4 or its pharmaceutically acceptable salt or
Stereoisomer or its prodrugs, it is characterised in which has formula (V) structure
R2Represent hydrogen, halogen or-O (C1-4Alkyl),
The C1-4Moieties are replaced by 1-4 fluorine atom；
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl
-OH,-SO2-C1-4Alkyl-OH or NH2,
Wherein, C1-4Moieties are replaced by 1-4 fluorine.
6. 5- (thioether group) pyrimidines according to claim 4 or its pharmaceutically acceptable salt or
Stereoisomer or its prodrugs, it is characterised in which has formula VI structure
R2Represent hydrogen, halogen or-O (C1-4Alkyl),
The C1-4Moieties are replaced by 1-4 fluorine atom；
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl-OH,
-SO2-C1-4Alkyl-OH or NH2,
Wherein, C1-4Moieties are replaced by 1-4 fluorine.
7. 5- (thioether group) pyrimidines according to claim 4 or its pharmaceutically acceptable salt or
Stereoisomer or its prodrugs, it is characterised in which has formula (VII) structure：
R2Represent hydrogen, halogen or-O (C1-4Alkyl),
The C1-4Moieties are replaced by 1-4 fluorine atom；
R3Represent-C (O)-C1-4Alkyl ,-SO2-C1-4Alkyl ,-C (O) NH2,-SO2NH2,-C (O)-C1-4Alkyl
-OH,-SO2-C1-4Alkyl-OH or NH2,
Wherein, C1-4Moieties are replaced by 1-4 fluorine.
8. 5- (thioether group) pyrimidines according to claim 1 or its pharmaceutically acceptable salt or
Stereoisomer or its prodrugs, it is characterised in that the compound is selected from following molecule：
9. 5- (thioether group) pyrimidines according to claim 8 or its pharmaceutically acceptable salt or vertical
Body isomer or its prodrugs, it is characterised in that the compound is selected from following molecule：
10. a kind of Pharmaceutical composition for treating tumor, it is characterised in which is included in claim 1-9 of therapeutically effective amount
5- (thioether group) pyrimidines or its pharmaceutically acceptable salt or stereoisomer described in any one or its before
Medicine molecule, and pharmaceutically acceptable carrier.
5- (thioether group) pyrimidines or its pharmaceutically acceptable salt described in 11. any one of claim 1-9
Or the purposes of stereoisomer or its prodrugs in the medicine for preparing treatment tumor.
12. purposes as described in claim 11, it is characterised in that the tumor be nonsmall-cell lung cancer, minicell lung
Cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, hepatocarcinoma, skin carcinoma, cell carcinoma, gastrointestinal
Mesenchymoma, leukemia, any one in histiocytic lymphatic cancer or nasopharyngeal carcinoma.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103269704A (en) * | 2010-11-01 | 2013-08-28 | 西建阿维拉米斯研究公司 | Heterocyclic compounds and uses thereof |
| WO2014040555A1 (en) * | 2012-09-12 | 2014-03-20 | 山东亨利医药科技有限责任公司 | Nitrogen-containing heteroaromatic ring derivative as tyrosine kinase inhibitor |
| WO2015006754A2 (en) * | 2013-07-11 | 2015-01-15 | Acea Biosciences Inc. | Heterocyclic compounds and uses thereof |
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2015
- 2015-10-21 CN CN201510688060.1A patent/CN106608868A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103269704A (en) * | 2010-11-01 | 2013-08-28 | 西建阿维拉米斯研究公司 | Heterocyclic compounds and uses thereof |
| WO2014040555A1 (en) * | 2012-09-12 | 2014-03-20 | 山东亨利医药科技有限责任公司 | Nitrogen-containing heteroaromatic ring derivative as tyrosine kinase inhibitor |
| WO2015006754A2 (en) * | 2013-07-11 | 2015-01-15 | Acea Biosciences Inc. | Heterocyclic compounds and uses thereof |
Non-Patent Citations (1)
| Title |
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| 尤启东主编: "《药物化学》", 31 January 2014 * |
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Application publication date: 20170503 |