CN106892922B - As the 5,8- dihydropteridine -6,7- derovatives of EGFR inhibitor and its application - Google Patents
As the 5,8- dihydropteridine -6,7- derovatives of EGFR inhibitor and its application Download PDFInfo
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Abstract
The present invention relates to as the pyrimido-pyrimidine derovatives of EGFR inhibitor and its application.Specifically, the purposes the present invention relates to compound shown in Formulas I, pharmaceutical composition containing a compound of formula I and the compound in preparation treatment EGFR related disease or the drug for inhibiting EGFR:
Description
Technical field
The present invention relates to field of medicinal chemistry；Specifically, the present invention relates to novel 5,8- dihydropteridine -6,7- diketone
Derivative, synthetic method and its application as EGFR inhibitor in the drug for preparing tumor-related illness.
Background technique
Cancer is also known as malignant tumour, is the major class disease with the characteristics of abnormal cell proliferation and transfer, has disease incidence
The high and high feature of the death rate is to threaten human health, leads to dead one of malignant disease.Data shows 2008
There are 12,700,000 cancer patients in the whole world, and wherein death toll is up to more than 700 ten thousand.And the new hair tumour patient in the whole world 20% is in
State, 24% tumor mortality patient is in China.If not adopting an effective measure prevention, or take out more preferably therapeutic scheme, it is contemplated that
To the year two thousand thirty, will occur 26,000,000 newly-increased cases of cancer in world wide every year, number of cancer deaths is up to 17,000,000.Existing
In some cancers, lung cancer is the highest malignant tumour of morbidity and mortality in current world wide, wherein non-small cell lung cancer
(NSCLC) 80% or more of patients with lung cancer is accounted for.It is predicted according to the World Health Organization (WHO), by 2025, China increased lung cancer newly every year
Case will be more than 1,000,000.Once being diagnosed as lung cancer, patient just only has remote survival prospects, and survival rate is less than 15% within 5 years.
Since the 1980s, with going deep into for oncomolecularbiology research, the molecule machine of tumorigenesis
It is increasingly clear to make.In many factors for inducing cancer, highly expressed certain albumen as caused by gene mutation swash in cancer cell
Enzyme is one of the principal element for leading to its signal transduction pathway exception.Protein tyrosine kinase is the weight in signal transduction process
Want the factor, participate in a series of cellular activities, grow, break up with cell, be proliferated it is closely related.The γ phosphate that it is catalyzed ATP turns
It moves on on the tyrosine residue of many key proteins, makes phenolic hydroxyl group phosphorylation, to transmit signal.Therefore, development selectivity
Kinases inhibitor come block or regulate and control the disease generated extremely due to these signal paths have been considered as it is antitumor
One effective research strategy of drug development.In numerous tyrosine kinase, epidermal growth factor recipient tyrosine kinase
(epidermal growth factor receptor tyrosine kinase, EGFR) is indispensable important composition portion
Point.EGFR is made of 1186 amino acid, encodes the transmembrane glycoprotein that a molecular weight is 170-kDa.EGFR can mediate more
Bars Signal Transduction Pathways, extracellular signal are transmitted to intracellular, are sent out the proliferation of normal cell and tumour cell, differentiation and apoptosis
Wave important adjustment effect (Cell, 2000,100,113-127).EGFR is many normal epithelial tissues (such as skin and hair follicle)
Constructive expression's ingredient, and in most of solid tumor, EGFR, which exists, to be overexpressed or high expression.For example, in lung cancer,
The expression rate of EGFR reaches 40~80%.Therefore selectively inhibit EGFR, the signal transduction pathway for interfering it to mediate, Ke Yida
To the purpose for the treatment of lung cancer, a practical way is opened for targeted therapy of lung cancer.
On clinical treatment, in conjunction with traditional radiotherapy, chemotherapy, with EGFR targeted drug such as Gefitinib (Iressa), E Luo
Carry out first-line drug for Buddhist nun (Tarceva) etc. is proved to be very effective in lung cancer therapy.However, clinical practice shows:
Most of Patients with Non-small-cell Lung can be occurred acquired after using Gefitinib or Tarceva treatment within the 6-12 month
Drug resistance.Wherein mutation (790 Soviet Union's ammonia of the drug resistance of about 50% case and an amino acid residue in EGFR kinase domain
Sour residue mutations are methionine, T790M) related (The New England Journal of Medicine, 2005,352,
786-792).T790M mutation cause inhibitor with EGFR ining conjunction with when generation steric hindrance or increase EGFR and ATP it is affine
Power, so that the anticancer effect for the competitive inhibitor that this kind of invertibity combines weakens significantly.The generation of drug resistance not only reduces
Patient has been greatly reduced the life quality of tumor patient to the sensibility of drug.Drug resistance caused by order to overcome T790M to be mutated
Property, a series of irreversible ATP competitive inhibitors (such as CI-1033, HKI-272, PF00299804) have entered clinical research
Stage.Irreversible inhibitor contains a michael acceptor segment, can be with a conserved amino acid of the ATP-binding site of EGFR
Residue (Cys797) forms covalent bond, to obtain EGFR binding affinity more stronger than reversible inhibitor.Nevertheless,
Since such drug is selectively poor to wild type and mutant egf R, maximal tolerance dose (MTD) is lower, clinical trial
Effect is not obvious.
Therefore, research and development selective depression T790M mutation, overcomes the third generation EGFR targeted drug of clinical drug-resistant to have
Great clinical meaning and application prospect.
Summary of the invention
The object of the present invention is to provide be capable of the compound of selective depression T790M mutation as EGFR inhibitor.
It is a further object of the present invention to provide the pharmaceutical compositions comprising above compound.
Further object of the present invention is to provide above compound in preparation treatment EGFR related disease or the medicine of inhibition EGFR
Purposes in object.
In a first aspect, the present invention provides general formula I compound represented or its pharmaceutically acceptable salt:
In formula, A is phenyl ring, five yuan or hexa-member heterocycle, C3-C8Naphthenic base；
R1It is each independently selected from hydrogen, halogen, C1-C3Alkoxy, C1-C3Alkyl, C1-C4Alkylamidoalkyl, substituted piperazinyl,
Replace high piperazine base, replaces morpholinyl, replaces thio-morpholinyl, 4-N- methyl piperazine base, 4-N- acetylpiperazinyl, 4-N, N-
Lupetidine base, substituted piperidine base, N, TMSDMA N dimethylamine base ethyl amido, N, TMSDMA N dimethylamine base oxethyl, 4- (4-N- methyl piperazine
Piperazine base) piperidyl ,-NRaRb, wherein RaAnd RbIt can be selected from alkyl and containing azanyl；
B is selected from the group:
R2It is each independently selected from following group:
R3It is selected from the group: hydrogen, C1-C10Alkyl, substituted C1-C10Alkyl, the C optionally replaced3-C8Naphthenic base optionally replaces
Benzyl, the heterocycle that optionally replaces；
M is 0-7, preferably any integer of 1-7.
In a particular embodiment, the compound is as shown in general formula II:
In formula, B, R1、R2、R3As defined in claim 1；
M is 0-5, preferably the integer of 1-5.
In a particular embodiment, the compound is as shown in general formula III:
In formula,
R2It is selected from
R3Selected from H or C1-C6Alkyl, preferably methyl or isopropyl；
R4、R5、R6、R7And R8It is independently selected from the following group:
In a particular embodiment, R3Selected from C1-C6Alkyl, preferably methyl or isopropyl；R5、R7And R8For H；R4And R6
It is independently selected from the following group:
In second aspect, the present invention provides compound selected from the group below or its pharmaceutically acceptable salt:
In the third aspect, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition contains first aspect present invention
Or compound described in second aspect or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient.
In a preferred embodiment, described pharmaceutical composition is adapted for oral dosage form, including but not limited to tablet, molten
Liquor, suspension, capsule, granule, pulvis.
In fourth aspect, the present invention provide compound described in first aspect or a second aspect of the present invention in preparation treatment or
Prevent the purposes in the disease of EGFR mediation, or the drug of inhibition EGFR.
In a particular embodiment, the disease that the EGFR is mediated is cancer.
In a particular embodiment, the cancer is selected from the group: non-small cell lung cancer, Small Cell Lung Cancer, adenocarcinoma of lung, lung
Squamous carcinoma, breast cancer, prostate cancer, neurogliocytoma, oophoroma, G. cephalantha, cervical carcinoma, the cancer of the esophagus, liver cancer, kidney
Cancer, cancer of pancreas, colon cancer, cutaneum carcinoma, leukaemia, lymthoma, gastric cancer, multiple bone marrow cancer and solid tumor.
At the 5th aspect, the present invention provides the disease method that EGFR is mediated that treats or prevents, including by first party of the present invention
Pharmaceutical composition described in compound described in face or second aspect or third aspect present invention gives the object of this needs.
In a preferred embodiment, the disease that the EGFR is mediated is cancer；Preferably, the cancer is selected from the group:
Non-small cell lung cancer, Small Cell Lung Cancer, adenocarcinoma of lung, lung squamous cancer, breast cancer, prostate cancer, neurogliocytoma, oophoroma,
It is G. cephalantha, cervical carcinoma, the cancer of the esophagus, liver cancer, kidney, cancer of pancreas, colon cancer, cutaneum carcinoma, leukaemia, lymthoma, gastric cancer, more
Hair property bone marrow cancer and solid tumor.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
Inventor after extensive and in-depth study, it was unexpectedly found that 5, the 8- dihydropteridine-that a collection of structure is completely new
6,7- derovatives, these derivatives can selective depression EGFR T790M mutation, to EGFRT790M/L858RKinase inhibition is living
The IC of property50Value reaches sub- nM rank；To cancer cell (EGFRL858R/T790MMutation) proliferation inhibitory activity IC50Value also reaches nM grades
Not.The present invention is completed on this basis.
The present inventor has synthesized the candidate compound with EGFR inhibitory activity.Structure is carried out to obtained candidate compound
Optimization, designed and synthesized it is a series of have no 5,8- dihydropteridine -6,7- cyclohexadione compounds reported in the literature, and finished
Structure characterization.The active testing that molecular level and cellular level have been carried out to this series compound, obtaining a batch has selectivity suppression
The compound of EGFR T790M mutation processed.Wherein compound 005 is to EGFRT790M/L858Kinase inhibiting activity IC50For 0.3nM,
H1975 (non-small cell lung cancer cell, EGFRL858R/T790M) cell inhibitory effect activity IC50For 18nM.It is art-recognized, inhibit
Cell comprising Wild type EGFR and the IC for inhibiting the cell comprising mutant egf R50The ratio between be greater than 100 this means that the chemical combination
Object may have very excellent difference toxicity in vivo.And the compounds of this invention for H1975 (non-small cell lung cancer cell,
EGFRL858R/T790M) cell Proliferation inhibitory activity IC50Have reached nM rank, the compounds of this invention is also equipped with outstanding above-mentioned
IC50Ratio, the wherein above-mentioned IC of compound 00550Ratio is more than 400.
Term definition
The some group definitions being referred to herein are as follows:
Herein, " alkyl " refers to that carbon chain lengths are the branched-chain or straight-chain alkyl of the saturation of 1-10 carbon atom, preferred alkane
Base includes long 2-8,1-6,1-4,3-8, the alkyl of 1-3 carbon atom not etc..The example of alkyl includes but is not limited to:
Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, heptyl etc..Alkyl can be replaced by one or more substituent groups, example
Such as replaced by halogen or halogenated alkyl.It can be for example, alkyl can be by the alkyl or alkyl that 1-4 fluorine atom replaces
The alkyl replaced by fluoro-alkyl.
Herein, " alkoxy " refers to by alkyl-substituted oxygroup.Preferred alkoxy is the alcoxyl of long 1-6 carbon atom
Base, the alkoxy of more preferably long 1-4 carbon atom.The example of alkoxy includes but is not limited to: methoxyl group, ethyoxyl, the third oxygen
Base etc..
Herein, " halogen " refers to fluorine, chlorine, bromine and iodine.
" heterocycle " used herein includes but is not limited to the heteroatomic 5- or 6-membered heterocycle that O, S or N are selected from containing 1-3
Group, including but not limited to furyl, thienyl, pyrrole radicals, pyrrolidinyl, pyrazolyl, imidazole radicals, triazolyl, oxazolyl, pyrrole
It mutters base, pyridyl group, pyrimidine radicals, pyrazinyl, piperidyl, morpholinyl etc..
Herein, " acylamino- " refers to that structural formula is the group of "-R '-NH-C (O)-R ", wherein R ' can be selected from hydrogen or alkyl,
R can be selected from alkyl, alkenyl, alkynyl, by NRcRdSubstituted alkyl, by NRcRdSubstituted alkenyl and NRcRdSubstituted alkynyl,
The alkyl being optionally substituted by halogen, the alkenyl replaced by cyano, wherein RcAnd RdIt can be selected from alkyl and alkenyl.
Herein, " optionally replace " and refer to that the substituent group that it is modified is optionally a (for example, 1,2,3,4 or 5 by 1-5
It is a) substituent group substitution selected from the following: halogen, C1-4Aldehyde radical, C1-6Linear or branched alkyl group, cyano, nitro, amino, hydroxyl, hydroxyl
Alkoxy (such as trifluoromethoxy), the carboxyl, C of alkyl (such as trifluoromethyl), halogen substitution that methyl, halogen replace1-4Alkane
Oxygroup, ethoxycarbonyl, N (CH3) and C1-4Acyl group.
The compound of the present invention
The compound of the present invention is following general formula I compound represented or its pharmaceutically acceptable salt:
In formula, A is phenyl ring, five yuan or hexa-member heterocycle, C3-C8Naphthenic base；
R1It is each independently selected from hydrogen, halogen, C1-C3Alkoxy, C1-C3Alkyl, C1-C4Alkylamidoalkyl, substituted piperazinyl,
Replace high piperazine base, replaces morpholinyl, replaces thio-morpholinyl, 4-N- methyl piperazine base, 4-N- acetylpiperazinyl, 4-N, N-
Lupetidine base, substituted piperidine base, N, N, N'- trimethyl ethylenediamine base, N, N- dimethyl ethanol amido, 1- methyl -4- (piperazine
Pyridine) piperazinyl ,-NRaRb, wherein RaAnd RbIt can be selected from alkyl and containing azanyl；
B is selected from the group:
R2It is each independently selected from following group:
R3It is selected from the group: hydrogen, C1-C10Alkyl, substituted C1-C10Alkyl, the C optionally replaced3-C8Naphthenic base optionally replaces
Benzyl, the heterocycle that optionally replaces；
M is 0-7, preferably any integer of 1-7.
In a particular embodiment, A ring is phenyl ring, so that the compound of the present invention is as shown in following general formula II:
In formula, B, R1、R2、R3As described above；It is 0-5, the preferably any integer of 1-5 with m.
In a preferred embodiment, the above-mentioned phenyl ring in the compound of the present invention can be substituted or unsubstituted, example
Such as, the compound of the present invention can be as shown in following general formula III:
In formula,
R2It is selected from
R3Selected from H or C1-C6Alkyl, preferably methyl or isopropyl；
R4、R5、R6、R7And R8It is independently selected from the following group:
In further embodiment, the above-mentioned phenyl ring in the compound of the present invention can make ortho position substitution, meta position takes
Generation and/or contraposition replace.In a preferred embodiment, the above-mentioned phenyl ring in the compound of the present invention is ortho position substitution, meta position
Replace and align substitution.R in further preferred embodiment, in formula above III3Selected from C1-C6Alkyl, preferably
Methyl or isopropyl；R5、R7And R8For H；R4And R6It is independently selected from the following group:
The present inventor, which synthesizes to have obtained a series of structures, has no 5,8- dihydropteridine -6,7- diones chemical combination reported in the literature
Object, specific compound are as follows:
In a preferred embodiment, the compound of the present invention is compound as follows:
On the basis of the compound of the present invention, the present invention provides a kind of pharmaceutical composition, and the composition, which contains treatment, to be had
The compound of the present invention of effect amount or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient.
The example of the pharmaceutically acceptable salt of the compounds of this invention includes but is not limited to inorganic and acylate, such as salt
Hydrochlorate, hydrobromate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and grass
Hydrochlorate；And it is formed with alkali such as sodium hydroxyl, three (hydroxymethyl) aminomethanes (TRIS, amine butantriol) and N-METHYL-ALPHA-L-GLUCOSAMINE
Inorganic and organic alkali salt.
Although each Man's Demands are different, those skilled in the art can determine every kind of work in pharmaceutical composition of the present invention
The optimal dose of property ingredient.Under normal circumstances, the compound of the present invention or its pharmaceutically acceptable salt, it is daily to mammal
Oral administration, dose is according to about 0.0025 to 50 mg kg of body weights.It is preferred that about 0.01 to 10 milli of per kilogram oral administration
Gram.For example, unit oral doses may include about 0.01 to 50 milligrams, preferably about 0.1 to 10 milligrams of the compounds of this invention.
Unit dose can be given one or many, be daily one or more pieces, and every contains about 0.1 to 50 milligrams, and eligibly about 0.25
To 10 milligrams of the compounds of this invention or its solvate.
Pharmaceutical composition of the invention can be formulated into the dosage form for being suitble to various administration routes, including but not limited to quilt
It is configured to for parenteral, subcutaneously, vein, muscle is intraperitoneal, transdermal, oral cavity, intrathecal, encephalic, nasal cavity or topical route administration
Form, for treating tumour and other diseases.Dosage is the dose for effectively improving or eliminating one or more illnesss.For
The treatment of specified disease, effective quantity are the doses for being enough to improve or mitigate in some manner symptom related with disease.It is such
Dose can be used as single dose application, or can be administered according to effective therapeutic scheme.Dosage also permits healing disease, still
It is administered typically to the symptom for improving disease.Repetitively administered is generally required to realize that required symptom improves.The dosage of medicine will
According to the age of patient, health and weight, the type of concurrent treatment, the frequency for the treatment of and required treatment benefit are determined.
Pharmaceutical preparation of the invention can give any mammal, as long as they can obtain the treatment of the compounds of this invention
Effect.The most importantly mankind in these mammals.
The compound of the present invention or its pharmaceutical composition can be used for treating various by epidermal growth factor receptor kinase
(EGFR) disease mediated.It herein, is various cancers by the disease that EGFR is mediated.The cancer includes but is not limited to: non-small
Cell lung cancer, Small Cell Lung Cancer, adenocarcinoma of lung, lung squamous cancer, breast cancer, prostate cancer, neurogliocytoma, oophoroma, neck
It is portion's squamous carcinoma, cervical carcinoma, the cancer of the esophagus, liver cancer, kidney, cancer of pancreas, colon cancer, cutaneum carcinoma, leukaemia, lymthoma, gastric cancer, multiple
Bone marrow cancer and solid tumor.
Pharmaceutical preparation of the invention can manufacture in a known manner.For example, by traditional mixing, granulation, ingot processed, dissolution,
Or freezing dry process manufacture.When manufacturing oral preparation, in combination with solid adjuvant material and reactive compound, selective ground and mixed
Object.After if necessary or appropriate amount of addition agent being added when necessary, granulate mixture is processed, obtains tablet or pastille core.
Suitable auxiliary material especially filler, such as carbohydrate such as lactose or sucrose, mannitol or sorbierite；Cellulose preparation or
Calcium phosphate, such as tricalcium phosphate or calcium monohydrogen phosphate；And binder, such as gelatinized corn starch, including cornstarch, wheaten starch,
Rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, or
Polyvinylpyrrolidone.If desired, can increase disintegrating agent, than starch as mentioned above and carboxymethyl starch, crosslinking is poly-
Vinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.Adjuvant especially flowing regulator and lubricant, example
Such as, silica, talcum, stearates, such as magnesium calcium stearate, stearic acid or polyethylene glycol.If desired, pastille core can be given
The suitable coating that gastric juice can be resisted is provided.For this purpose, can be using concentration saccharide solution.This solution can contain Arabic tree
Glue, talcum, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide paint solution and suitable organic solvent or solvent mixing
Object.In order to prepare the coating of resistant to gastric juice, cellulose solution appropriate, such as cellulose acetate phthalic acid or hydroxypropyl can be used
Ylmethyl cellulose phthalic acid.Dyestuff or pigment can be added to the coating of tablet or pastille core.For example, for identification or
In order to characterize the combination of active constituent dosage.
Those skilled in the art can be based on its professional knowledge and actual demand, prepared by pharmaceutical composition of the invention
At any dosage form.For example, in a particular embodiment, pharmaceutical composition of the invention is adapted for oral dosage form, including but
It is not limited to tablet, solution, suspension, capsule, granule, pulvis.
Based on above compound and pharmaceutical composition, the present invention further provides a kind of sides of disease for treating EGFR mediation
Method, this method include giving the object of needs with the compound of the present invention or pharmaceutical composition.
Medication includes but is not limited to various medications well known in the art, can be subject to according to the actual conditions of patient
It determines.These methods are including but not limited to parenteral, subcutaneous, vein, muscle, intraperitoneal, transdermal, oral cavity, intrathecal, encephalic, nasal cavity
Or topical route administration.
The present invention also includes the disease or inhibition activity of EGFR that the compounds of this invention is mediated in preparation prevention or treatment EGFR
Drug in purposes.
Advantages of the present invention:
1. compound provided by the invention is a kind of 5,8- dihydropteridine -6,7- dione compounds that structure is completely new；
2. compound provided by the invention has excellent inhibitory activity to the cancer cell that mutant egf R or EGFR are mutated；
3. compound provided by the invention is that exploitation energy selective depression T790M is mutated, clinical drug-resistant can be overcome
EGFR targeted drug is laid a good foundation, and has great industrialization and commercialization prospect and market value, remarkable in economical benefits.
Technical solution of the present invention is further described below in conjunction with specific implementation case, but following case study on implementation is not constituted
Limitation of the present invention, the various method of administration that all principles and technological means according to the present invention use, belongs to the present invention
Range.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or is built according to manufacturer
The condition of view.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Materials and methods
The synthesis of 5,8- dihydropteridine -6,7- cyclohexadione compounds of the invention is as follows:
Reagent and condition: (a) (Boc)2O,Et3N,CH3OH, room temperature, for 24 hours；(b) the chloro- 5- nitro-pyrimidine of 2,4- bis-,
Na2CO3,DMF,-70℃,1h；(c) arylamine, DIPEA, THF, room temperature, overnight；(d)H2, Pd/C, MeOH, room temperature, 10h；(e)
Diethy-aceto oxalate, triethylamine, EtOH, reflux, 30h；(f) alkyl halide, Cs2CO3, DMF, room temperature, overnight；(g) trifluoroacetic acid,
CH2Cl2, room temperature, 5h；(h) acryloyl chloride, Et3N,CH2Cl2, 0 DEG C is arrived room temperature, overnight.
Embodiment 1
The specific synthetic method of above-mentioned steps a-h is as follows:
The synthesis of (1. 3- aminophenyl) t-butyl carbamate
Weigh 1,3- phenylenediamine (10.800g, 100mmol), triethylamine (10.100g, 100mmol) is burnt in 250mL single port
Bottle is added the dissolution of 100mL methanol, stirs 15 minutes under condition of ice bath.Separately Boc- acid anhydrides (21.800g, 100mmol) is taken to be dissolved in
40mL methanol is added drop-wise in above-mentioned reaction solution, after being added dropwise to complete, is stirred at room temperature 24 hours.TLC tracks raw material conversion, and rotation is steamed
Hair removes solvent, and crude product is separated through silica gel column chromatography (petrol ether/ethyl acetate=4:1, v/v), obtains (3- aminophenyl) ammonia
Base t-butyl formate white solid 13.312g, yield 64%.1H NMR(400MHz,CDCl3) δ 7.03 (t, J=8.0Hz, 1H),
6.96 (s, 1H), 6.55 (dd, J=8.0Hz, J=1.2Hz, 1H), 6.43 (s, 1H), 6.36 (dd, J=8.0Hz, J=
1.6Hz,1H),3.54(s,2H),1.51(s,9H).LC-MS:m/z:209.1(M+H)+.
The synthesis of (2. 3- (the chloro- 5- nitro-pyrimidine -4- amino of 2-) phenyl) t-butyl carbamate
Weigh the chloro- 5- nitro-pyrimidine (1.940g, 10mmol) of 2,4- bis-, n,N-diisopropylethylamine (2.580g,
20mmol) in 100mL round-bottomed flask, 30mL DMF dissolution is added, is stirred 10 minutes under condition of ice bath.Separately take (3- aminobenzene
Base) t-butyl carbamate (2.080g, 10.0mmol) is dissolved in 20mL DMF, and it is slowly dropped in above-mentioned reaction solution, drips
Afterwards, it is stirred at room temperature 2 hours.TLC tracking raw material converts completely, and ice water is added into reaction solution, solid is precipitated, filters, washes, does
It is dry.Crude product CH2Cl2Recrystallization, obtains (3- (the chloro- 5- nitro-pyrimidine -4- amino of 2-) phenyl) t-butyl carbamate orange solids
2.950g yield 81%.1H NMR(400MHz,CDCl3)δ10.19(s,1H),9.20(s,1H),7.84(s,1H),7.36(d,
J=5.2Hz, 2H), 7.21-7.18 (m, 1H), 6.63 (s, 1H), 1.56 (s, 9H) .LC-MS:m/z:366.1 (M+H)+.
3. (3- ((2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -5- nitro-pyrimidine -4- base) amino)
Phenyl) t-butyl carbamate synthesis
Weigh (3- (the chloro- 5- nitro-pyrimidine -4- amino of 2-) phenyl) t-butyl carbamate (2.920g, 8mmol), N, N-
The dissolution of 30mL tetrahydrofuran is added in 100mL three-necked flask in diisopropylethylamine (2.064g, 16mmol).Separately take 2- methoxy
Base -4- (4- methyl piperazine base) aniline (1.768g, 8mmol) is dissolved in 15mL tetrahydrofuran, is slowly dropped under argon gas protective condition
In above-mentioned reaction solution, after dripping, temperature rising reflux is overnight.TLC tracks raw material conversion, and rotary evaporation removes partial solvent, is precipitated
Solid filters, tetrahydrofuran washing, dry.Crude product CH2Cl2Recrystallization, obtains (3- ((2- ((2- methoxyl group -4- (4- methyl piperazine
Piperazine base) phenyl) amino) -5- nitro-pyrimidine -4- base) amino) phenyl) t-butyl carbamate red brown solid 3.340g, yield
76%.1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.42(s,1H),9.19(s,1H),9.03(s,1H),7.54
(s, 1H), 7.39 (d, J=8.4Hz, 1H), 7.22 (t, J=8.8Hz, 2H), 7.09 (t, J=8.0Hz, 1H), 6.61 (d, J=
1.6Hz, 1H), 6.34 (d, J=8.8Hz, 1H), 3.76 (s, 3H), 3.15 (t, J=4.4Hz, 4H), 2.47 (t, J=4.4Hz,
4H),2.24(s,3H),1.47(s,9H).LC-MS:m/z:551.4(M+H)+.
4. (3- ((5- amino -2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) pyrimidine-4-yl) amino)
Phenyl) t-butyl carbamate synthesis
Weigh (3- ((2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -5- nitro-pyrimidine -4- base) ammonia
Base) phenyl) t-butyl carbamate (3.300g, 6mmol), palladium-carbon catalyst (0.318g, 0.3mmol, 10%Pd) is in 250mL
In heavy wall pressure bottle, the dissolution of 80mL methanol is added, is passed through hydrogen, reacts at room temperature 6 hours.TLC tracks raw material conversion, filters, filter
Liquid is spin-dried for, crude product ethyl alcohol recrystallization, obtains (3- ((5- amino -2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino)
Pyrimidine-4-yl) amino) phenyl) t-butyl carbamate white solid 2.775g, yield 89%.1H NMR(400MHz,DMSO-
d6) δ 9.32 (s, 1H), 8.17 (s, 1H), 7.99 (d, J=8.8Hz, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 7.32 (d, J
=8.0Hz, 1H), 7.16 (t, J=8.0Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 6.98 (s, 1H), 6.60 (d, J=
2.4Hz, 1H), 6.38 (dd, J=8.8Hz, J=2.4Hz, 1H), 4.39 (s, 2H), 3.82 (s, 3H), 3.07 (t, J=
4.4Hz, 4H), 2.48 (t, J=4.4Hz, 4H), 2.25 (s, 3H), 1.48 (s, 9H) .LC-MS:m/z:521.3 (M+H)+.
5. (3- (2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -6,7- dioxo -6,7- dihydro butterfly
Pyridine -8 (5H)) phenyl) t-butyl carbamate synthesis
Weigh (3- ((5- amino -2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) pyrimidine-4-yl) ammonia
Base) phenyl) t-butyl carbamate (2.600g, 5mmol), triethylamine (1.010g, 10mmol) in 100mL flask, be added
The dissolution of 40mL ethyl alcohol.Diethy-aceto oxalate (2.190g, 15mmol) is added into reaction solution, temperature rising reflux 48 hours.TLC tracking is former
Material conversion, filters, ethanol washing filter cake, dry.Obtain (3- (2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -
6,7- dioxo -6,7- dihydropteridines -8 (5H)) phenyl) t-butyl carbamate yellow solid 2.155g, yield 75%.1H
NMR(400MHz,DMSO-d6) δ 9.64 (s, 1H), 8.14 (s, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.55 (d, J=
8.0Hz, 1H), 7.43 (t, J=8.0Hz, 1H), 7.26 (d, J=8.8Hz, 1H), 6.95 (d, J=7.6Hz, 1H), 6.53 (d,
J=2.4Hz, 1H), 6.06 (d, J=8.0Hz, 1H), 3.77 (s, 3H), 3.03 (t, J=4.4Hz, 4H), 2.44 (t, J=
4.4Hz, 4H), 2.22 (s, 3H), 1.45 (s, 9H) .HRMS (ESI): calculated value C29H35N8O5(M+H)+575.2730, experiment value
575.2725.
6.N- (3- (2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -6,7- dioxo -6,7- dihydro butterfly
Pyridine -8- (5H)) phenyl) acrylamide synthesis (compound 001)
Weigh (3- (2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -6,7- dioxo -6,7- dihydro butterfly
Pyridine -8 (5H)) phenyl) for t-butyl carbamate (0.861g, 1.5mmol) in 50mL round-bottomed flask, addition 10mL methylene chloride is molten
Solution, is slowly dropped into 2mL trifluoroacetic acid, is stirred overnight at room temperature.TLC tracks raw material conversion, and saturation NaHCO is added3Solution is neutralized to
Alkalinity, methylene chloride extraction, collected organic layer, rotary evaporation remove solvent, obtain 8- (3- aminophenyl) -2- ((2- methoxyl group -
4- (4- methyl piperazine base) phenyl) amino) -5,8- dihydropteridine -6,7- diketone 491mg, yield 69%, product is not purified straight
It connects for the next step.
Weigh 8- (3- aminophenyl) -2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -5,8- dihydro butterfly
Pyridine -6,7- diketone (0.474g, 1mmol), Et3It is molten that 10mL methylene chloride is added in 25mL flask in N (0.152g, 1.5mmol)
It solves, is stirred 10 minutes under condition of ice bath.Separately acryloyl chloride (105 μ L, 1.3mmol) is taken to be dissolved in 2mL methylene chloride, is slowly added to
It states in reaction solution, drips and be stirred overnight at room temperature.TLC tracks raw material conversion, and ice water is added, and methylene chloride extraction is collected organic
Layer, rotary evaporation remove dissolution, and crude product is through silica gel column chromatography separating purification (DCM/CH3OH=15:1, v/v).Obtain N- (3- (2-
((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -6,7- dioxo -6,7- dihydropteridine -8- (5H)) phenyl) third
Acrylamide 124mg, yield 23%.1H NMR(400MHz,DMSO-d6) δ 10.69 (s, 1H), 8.22 (s, 1H), 7.51 (d, J=
8.0Hz, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.52 (t, J=8.0Hz, 1H), 7.28 (d, J=8.8Hz, 1H), 7.08
(d, J=8.0Hz, 1H), 6.59-6.52 (m, 2H), 6.26 (dd, J=16.8Hz, J=1.2Hz, 1H), 6.07 (d, J=
8.4Hz, 1H), 5.77 (dd, J=10.0Hz, J=1.2Hz, 1H), 3.78 (s, 3H), 3.31 (t, J=4.4Hz, 4H), 3.20
(t, J=4.4Hz, 4H), 2.74 (s, 3H) .HRMS (ESI): calculated value C31H39N8O5(M+H)+529.2312, experiment value
529.2312.
7. (3- (5- ethyl -2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -6,7- dioxo -6,7-
Dihydropteridine -8 (5H)) phenyl) t-butyl carbamate synthesis
Weigh (3- (2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -6,7- dioxo -6,7- dihydro butterfly
Pyridine -8 (5H)) phenyl) t-butyl carbamate (0.861g, 1.5mmol), Cs2CO3(0.587g, 1.8mmol) in 25mL flask,
10mLDMF dissolution is added, is added dropwise iodoethane (180 μ L, 2.25mmol), drips and be stirred overnight at room temperature.TLC tracks raw material and turns
Change, water is added, methylene chloride extraction, collected organic layer, rotary evaporation removing solvent, crude product is through silica gel column chromatography separating purification
(DCM/CH3OH=20:1, v/v).(3- (5- ethyl -2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -6,
7- dioxo -6,7- dihydropteridine -8 (5H)) phenyl) t-butyl carbamate 414mg, yield 46%.1H NMR(400MHz,
CDCl3) δ 8.59 (s, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.54 (d, J=8.0Hz, 1H), 7.50 (t, J=8.0Hz,
1H), 7.44 (s, 1H), 6.99 (d, J=7.2Hz, 1H), 6.72 (s, 1H), 6.45 (d, J=2.4Hz, 1H), 6.17 (d, J=
6.8Hz, 1H), 4.55 (q, J=7.2Hz, 2H), 3.83 (s, 3H), 3.14 (t, J=4.4Hz, 4H), 2.62 (t, J=4.4Hz,
4H), 2.38 (s, 3H), 1.51 (t, J=6.8Hz, 3H), 1.48 (s, 9H) .HRMS (ESI): calculated value C31H39N8O5(M+H)+
603.3043 experiment value 603.3043.
8.N- (3- (5- ethyl-2- ((2- methoxyl group-4- (4- methyl piperazine base) phenyl) amino) dioxo-6-6,7-,
7- dihydropteridine -8- (5H)) phenyl) acrylamide synthesis (compound 003)
Weigh (3- (5- ethyl-2- ((2- methoxyl group-4- (4- methyl piperazine base) phenyl) amino) dioxo-6-6,7-,
7- dihydropteridine -8 (5H)) phenyl) in 50mL round-bottomed flask, 10mL is added in t-butyl carbamate (0.400g, 0.66mmol)
Methylene chloride dissolution, is slowly dropped into 2mL trifluoroacetic acid, is stirred overnight at room temperature.TLC tracks raw material conversion, and saturation NaHCO is added3
Solution is neutralized to alkalinity, and methylene chloride extracts, collected organic layer, rotary evaporation removing solvent, crude product recrystallize with dichloromethane,
Obtain 8- (3- aminophenyl) -5- ethyl -2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -5,8- dihydropteridine -
6,7- diketone 185mg, yield 55%, product is directly used in the next step.
8- (3- aminophenyl) -5- ethyl -2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -5 is weighed,
8- dihydropteridine -6,7- diketone (0.180g, 0.36mmol), Et310mL is added in 25mL flask in N (0.055g, 0.54mmol)
Methylene chloride dissolves, and stirs 10 minutes under condition of ice bath.Separately acryloyl chloride (38 μ L, 0.47mmol) is taken to be dissolved in 1mL methylene chloride,
It is slowly added in above-mentioned reaction solution, drips and be stirred overnight at room temperature.TLC tracks raw material conversion, and ice water, methylene chloride extraction is added
It takes, collected organic layer, rotary evaporation removes dissolution, and crude product is through silica gel column chromatography separating purification (DCM/CH3OH=15:1, v/v).
Obtain N- (3- (5- ethyl -2- ((2- methoxyl group -4- (4- methyl piperazine base) phenyl) amino) -6,7- dioxo -6,7- dihydro butterfly
Pyridine -8- (5H)) phenyl) acrylamide 98mg, yield 49%.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.57
(s, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.70 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.32 (d, J=8.8Hz,
1H), 7.10 (d, J=7.6Hz, 1H), 6.53 (d, J=2.4Hz, 1H), 6.45 (dd, J=17.2Hz, J=10.4Hz, 1H),
6.26 (dd, J=16.8Hz, J=1.6Hz, 1H), 6.06-6.04 (m, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz,
1H), 4.42 (q, J=7.2Hz, 2H), 3.77 (s, 3H), 3.02 (t, J=4.4Hz, 4H), 2.45 (t, J=4.4Hz, 4H),
2.23 (s, 3H), 1.40 (t, J=7.2Hz, 3H) .HRMS (ESI): calculated value C29H33N8O4(M+H)+557.2625, experiment value
557.2615.
Following compound synthesizes to obtain according to the method for above-mentioned steps a-g:
N- (3- (2-((2- methoxyl group-4- (4- methylpiperazine-1-yl) phenyl) amino) dioxo-6-5- methyl-6,7-,
7- dihydropteridine -8- (5H)-yl) phenyl) acrylamide (compound 002)
1H NMR(400MHz,DMSO-d6) δ 10.46 (s, 1H), 8.48 (s, 1H), 7.92 (d, J=8.0Hz, 1H), 7.69
(s, 1H), 7.66 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 7.07 (d, J=8.0Hz,
1H), 6.53 (d, J=1.6Hz, 1H), 6.46 (dd, J=16.8Hz, J=10.0Hz, 1H), 6.26 (dd, J=17.2Hz, J=
1.6Hz, 1H), 6.02 (d, J=8.4Hz, 1H), 5.77 (dd, J=10.0Hz, J=1.2Hz, 1H), 3.77 (s, 3H), 3.55-
3.53 (m, 4H), 3.06-3.02 (m, 4H), 2.57 (s, 3H), 2.32 (s, 3H) .HRMS (ESI): calculated value C28H31N8O4(M+
H)+543.2468 experiment value 543.2470.
N- (3- (2-((2- methoxyl group-4- (4- methylpiperazine-1-yl) phenyl) amino) propyl-6-6,7- dioxo-5-,
7- dihydropteridine -8- (5H)-yl) phenyl) acrylamide (compound 004)
1H NMR(400MHz,DMSO-d6) δ 10.70 (s, 1H), 8.58 (s, 1H), 7.97 (s, 1H), 7.91 (d, J=
8.0Hz, 1H), 7.77 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.35 (d, J=8.8Hz, 1H), 7.11 (d, J=8.0Hz,
1H), 6.59-6.52 (m, 2H), 6.26 (dd, J=16.8Hz, J=1.2Hz, 1H), 6.11-6.09 (m, 1H), 5.77 (dd, J
=10.0Hz, J=1.6Hz, 1H), 4.32 (t, J=6.8Hz, 2H), 3.78 (s, 3H), 3.31-3.29 (m, 4H), 3.16-
3.14 (m, 4H), 2.72 (s, 3H), 1.85-1.77 (m, 2H), 1.01 (t, J=7.2Hz, 3H) .HRMS (ESI): calculated value
C30H35N8O4(M+H)+571.2781 experiment value 571.2780.
N- (3- (5- isopropyl-2-((2- methoxyl group-4- (4- methylpiperazine-1-yl) phenyl) amino)-6,7- dioxo-
6,7- dihydropteridine -8- (5H)-yl) phenyl) acrylamide (compound 005)
1H NMR(400MHz,DMSO-d6) δ 10.63 (s, 1H), 8.57 (s, 1H), 7.96 (s, 1H), 7.90 (d, J=
8.4Hz, 1H), 7.75 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.36 (d, J=8.8Hz, 1H), 7.11 (d, J=7.6Hz,
1H), 6.60 (d, J=2.0Hz, 1H), 6.54 (dd, J=16.8Hz, J=10.0Hz, 1H), 6.27 (dd, J=16.8Hz, J=
1.6Hz, 1H), 6.12-6.10 (m, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz, 1H), 5.38-5.30 (m, 1H), 3.79
(s, 3H), 3.31-3.29 (m, 4H), 3.26-3.24 (m, 4H), 2.79 (s, 3H), 1.40 (d, J=6.4Hz, 6H) .HRMS
(ESI): calculated value C30H35N8O4(M+H)+571.2781 experiment value 571.2780.
N- (3- (2- ((3- methyl-4- (4- methylpiperazine-1-yl) phenyl) amino) dioxo-6-5- isopropyl-6,7-,
7- dihydropteridine -8- (5H)-yl) phenyl) acrylamide (compound 006)
1H NMR(400MHz,DMSO-d6) δ 10.54 (s, 1H), 9.61 (s, 1H), 8.61 (s, 1H), 7.91 (d, J=
8.0Hz, 1H), 7.76 (s, 1H), 7.55 (t, J=8.0Hz, 1H), 7.20 (s, 1H), 7.13 (d, J=8.0Hz, 1H), 6.69
(d, J=8.8Hz, 1H), 6.50 (dd, J=17.2Hz, J=10.4Hz, 1H), 6.26 (dd, J=17.2Hz, J=2.0Hz,
1H), 5.76 (dd, J=10.0Hz, J=1.6Hz, 1H), 5.37-5.31 (m, 1H), 2.94-2.91 (m, 4H), 2.85-2.82
(m, 4H), 2.58 (s, 3H), 1.99 (s, 3H), 1.40 (d, J=6.0Hz, 6H) .HRMS (ESI): calculated value C30H35N8O3(M+
H)+555.2832 experiment value 555.2833.
N- (3- (2-((3- methoxyl group-4- (4- methylpiperazine-1-yl) phenyl) amino)-5- isopropyl-6,7- dioxos-
6,7- dihydropteridine -8- (5H)-yl) phenyl) acrylamide (compound 007)
1H NMR(400MHz,DMSO-d6) δ 10.59 (s, 1H), 9.57 (s, 1H), 8.62 (s, 1H), 7.90 (d, J=
8.4Hz, 1H), 7.75 (s, 1H), 7.54 (t, J=8.0Hz, 1H), 7.12 (d, J=7.6Hz, 1H), 7.04-6.99 (m, 2H),
6.55-6.49 (m, 2H), 6.27 (dd, J=17.2Hz, J=2.0Hz, 1H), 5.77 (dd, J=10.0Hz, J=1.6Hz,
1H), 5.37-5.31 (m, 1H), 3.57 (s, 3H), 3.19-3.07 (m, 8H), 2.74 (s, 3H), 1.40 (d, J=6.0Hz,
6H) .HRMS (ESI): calculated value C30H35N8O4(M+H)+571.2781 experiment value 571.2782.
((2- ((4-((2- (dimethylamino) ethyl) (methyl) amino)-2- methoxyphenyl) amino)-5- is different by 3- by N-
Propyl -6,7- dioxo -6,7- dihydropteridine -8- (5H)-yl) phenyl) acrylamide (compound 008)
1H NMR(400MHz,CDCl3) δ 8.69 (s, 1H), 8.57 (s, 1H), 7.75 (s, 1H), 7.71 (d, J=8.0Hz,
1H), 7.61 (s, 1H), 7.44 (t, J=8.0Hz, 1H), 6.98 (d, J=8.0Hz, 1H), 6.35 (dd, J=16.4Hz, J=
0.8Hz, 1H), 6.26-6.19 (m, 2H), 5.92-5.90 (m, 1H), 5.64 (dd, J=10.0Hz, J=1.2Hz, 1H),
5.49-5.43 (m, 1H), 3.80 (s, 3H), 3.40 (t, J=7.6Hz, 2H), 2.87 (s, 3H), 2.50 (t, J=7.6Hz,
2H), 2.35 (s, 6H), 1.48 (d, J=6.0Hz, 6H) .HRMS (ESI): calculated value C30H37N8O4(M+H)+573.2938, it is real
Test value 573.2939.
N- (3- (2- ((4- (2- (dimethylamino) ethyoxyl) -2- methoxyphenyl) amino) -5- isopropyl -6,7- two
Oxo -6,7- dihydropteridine -8- (5H)-yl) phenyl) acrylamide (compound 009)
1H NMR(400MHz,DMSO-d6) δ 10.64 (s, 1H), 8.57 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=
8.4Hz, 1H), 7.78 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.39 (d, J=7.2Hz, 1H), 7.11 (d, J=8.0Hz,
1H), 6.60 (d, J=2.4Hz, 1H), 6.54 (dd, J=17.2Hz, J=10.4Hz, 1H), 6.26 (dd, J=17.2Hz, J=
2.0Hz, 1H), 6.16-6.14 (m, 1H), 5.76 (dd, J=10.0Hz, J=1.6Hz, 1H), 5.37-5.31 (m, 1H), 4.21
(t, J=4.8Hz, 2H), 3.78 (s, 3H), 3.26 (t, J=4.8Hz, 2H), 2.69 (s, 6H), 1.40 (d, J=6.0Hz,
6H) .HRMS (ESI): calculated value C29H34N7O5(M+H)+560.2621 experiment value 560.2625.
N- (3- (5- isopropyl -2- ((2- methoxyl group -4- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) ammonia
Base) -8 (5H)-yl of -6,7- dioxo -6,7- dihydropteridine) phenyl) acrylamide (compound 010)
1H NMR(400MHz,DMSO-d6) δ 10.58 (s, 1H), 8.56 (s, 1H), 7.94 (d, J=8.0Hz, 1H), 7.91
(s, 1H), 7.72 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.32 (d, J=8.8Hz, 1H), 7.11 (d, J=8.4Hz,
1H), 6.55-6.48 (m, 2H), 6.27 (dd, J=17.2Hz, J=2.0Hz, 1H), 6.08-6.06 (m, 1H), 5.78 (dd, J
=10.0Hz, J=1.6Hz, 1H), 5.36-5.30 (m, 1H), 3.77 (s, 3H), 3.62-3.60 (m, 2H), 3.00-2.92 (m,
4H), 2.69-2.67 (m, 2H), 2.56 (t, J=11.6Hz, 3H), 2.42-2.39 (m, 2H), 1.82-1.81 (m, 2H),
1.54-1.49 (m, 1H), 1.39 (d, J=6.4Hz, 6H) .HRMS (ESI): calculated value C35H44N9O4(M+H)+654.3516, it is real
Test value 654.3512.
2. biological activity test of embodiment
Compound provided by the invention is following to the extracorporeal extracorporeal suppression experiment of EGFR kinase activity to carry out:
External enzyme activity assay: wild type and various saltant types (T790M, L858/T790M) EGFR are purchased from hero's public affairs
Department.It is provided with for all compounds to be tested from 5.1 × 10-11Mol/L to 1.0 × 10-610 concentration gradients of mol/L.
The concentration of different kinases is tested by optimization and is determined, corresponding concentration are as follows: EGFR (PV3872, hero company) 0.287 μ
G/ μ L, EGFR-T790M (PV4803, hero company) 0.174 μ g/ μ L, EGFR-L858R/T790M (PV4879, hero company)
0.055μg/μL.Compound is in DMSO from 5.1x10-9M to 1x10-4M dilutes three times.4 μ L compounds are dissolved in 96 μ L water, obtain
The compound solution of 4x.40 μM of ATP are dissolved in 1.33x kinase buffer liquid, and kinases/peptide mixer includes 2x kinases, 4 μM of trorsine 14s
Peptide is ready to for use.10 μ L kinase reactions include 2.5 μ L compound solutions, 5 μ L kinases/peptide mixer, 2.5 μ L ATP solution.5
μ L Phosphorylated Peptide solution replaces kinases/peptide mixer to compare as 100% phosphorylation.2.5 μ L 1.33x kinase buffer liquids replace
ATP solution is used as 100% and inhibits control, and 2.5 μ L 4%DMSO replace compound solution to inhibit control as 0%.Solution in plate
It is cultivated at room temperature after being sufficiently mixed 1.5 hours.Continue at room temperature after 5 μ L Development Solution are added in every hole
Culture 1 hour, non-phosphorylated peptide is cleaved within this time.Terminate instead finally, 5 μ L are added and terminate preparation (Stop Reagent)
It answers.Orifice plate is measured with EnVisionMultilabel Reader (Perkinelmer Inc.).Experimental data uses
GraphPad Prism version 4.0 is calculated.Experiment is repeated 3 times above every time.
Cell Proliferation and growth inhibition analysis: H1975 (non-small cell lung cancer cell, EGFRL858R/T790M), A431 it is (non-small
Cell lung cancer cell, EGFR wild type), cell is obtained from ATCC.Cell-proliferation activity is assessed using MTS analytic approach.
Cell exposure under processing conditions 72 hours, each cell line tests used cell number according to absorbance value (at 490nm every time
Absorbance value be 1.3-2.2) be adjusted.6 concentration gradients (0.1nM-10 μM) are provided with for compound to be tested, each
Concentration value at least uses 6 groups of parallel controls.
H1975, A431 cell are cultivated in corresponding culture medium, and cell at least passes on twice after recovery, are subsequently used for
Experiment uses.The cell of logarithmic phase is by trypsin acting and settling flux in the medium.H1975 (every 1000 cell of hole),
A431 (every 2000 cell of hole) is seeded in 96 orifice plates, 100 μ L of volume；6 groups of parallel and 7 column are set.Orifice plate is put in 37 DEG C 5%
In the incubator of carbon dioxide overnight.Compound is dissolved in DMSO, compound concentration is 10 μM every liter, then by compound concentration by
The compound concentration that step dilution obtains is respectively every liter 10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, 0.0001 μM.2 μ Lization
Polymer solution is added in the culture medium of 998 μ L, and mixture is adequately mixed.The mixture of 100 μ L is added in 96 orifice plates.2μL
DMSO replaces compound solution to be used as 0% inhibition control.After culture 68 hours, 20 μ L MTT (5mg/mL) are added.4 hours
It waits, abandon supernatant and 150 μ L DMSO is added.After shake 10 minutes, orifice plate is with Synergy HT (Bio TeK) (OD490)
Read data.Data are calculated using GraphPad Prism version 4.0, IC50Value is by using dose-effect curve
Nonlinear regression model (NLRM) adjust to obtain.
Test result is as follows shown in table 1.
Table 1
> 10.0 indicate weaker to the inhibiting effect of cell.
It discusses:
Inventor after extensive and in-depth study, designs and synthesizes to have obtained and a series of has no 5,8- bis- reported in the literature
Hydrogen pteridine -6,7- cyclohexadione compounds, the active testing of molecular level and cellular level has been carried out to obtained compound, has been obtained
A batch is capable of the compound of selective depression EGFR T790M mutation.Present inventors have further discovered that the compound of the present invention pair
The difference of the Proliferation Ability ability of EGFR saltant type cancer cell (H1975) and EGFR wild type cancer cell (A431) is higher than to mutation
The difference of type EGFR and Wild type EGFR kinase activity rejection ability, so that prompting the compound of the present invention in vivo has preferably
Difference toxicity, it is possible to become selective depression T790M and be mutated, overcomes the third generation EGFR targeted drug of clinical drug-resistant, or
Activity is obtained more preferably and/or the basis of difference toxicity more preferably compound as through further modification.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (9)
1. general formula III compound represented or its pharmaceutically acceptable salt:
In formula,
R2It is selected from
R3Selected from H or C1-C6Alkyl；
R4、R5、R6、R7And R8It is independently selected from the following group:
2. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that R3Selected from methyl or isopropyl
Base.
3. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that
R3Selected from C1-C6Alkyl；
R5、R7And R8For H；
R4And R6It is independently selected from the following group:
4. compound as claimed in claim 2 or its pharmaceutically acceptable salt, which is characterized in that R3Selected from methyl or isopropyl
Base.
5. compound selected from the group below or its pharmaceutically acceptable salt:
6. a kind of pharmaceutical composition, described pharmaceutical composition contains compound of any of claims 1-5 or its medicine
Acceptable salt and pharmaceutically acceptable carrier or excipient on.
7. drug or suppression that compound of any of claims 1-5 treats or prevents the disease that EGFR is mediated in preparation
Purposes in the drug of EGFR processed.
8. purposes as claimed in claim 7, which is characterized in that the disease that the EGFR is mediated is cancer.
9. purposes as claimed in claim 8, which is characterized in that the cancer is selected from the group: non-small cell lung cancer, cellule lung
Cancer, adenocarcinoma of lung, lung squamous cancer, breast cancer, prostate cancer, neurogliocytoma, oophoroma, G. cephalantha, cervical carcinoma, oesophagus
Cancer, liver cancer, kidney, cancer of pancreas, colon cancer, cutaneum carcinoma, leukaemia, lymthoma, gastric cancer, multiple bone marrow cancer and solid tumor.
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| CN201510960989.5A CN106892922B (en) | 2015-12-18 | 2015-12-18 | As the 5,8- dihydropteridine -6,7- derovatives of EGFR inhibitor and its application |
| PCT/CN2016/110437 WO2017101862A1 (en) | 2015-12-18 | 2016-12-16 | 5,8-dihydropteridine-6,7-diketone derivative as egfr inhibitor and use thereof |
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| CN201510960989.5A CN106892922B (en) | 2015-12-18 | 2015-12-18 | As the 5,8- dihydropteridine -6,7- derovatives of EGFR inhibitor and its application |
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| CN106892922B true CN106892922B (en) | 2019-04-19 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110357885A (en) * | 2019-07-24 | 2019-10-22 | 江南大学 | A kind of pteridine compounds and its application pharmaceutically |
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| CN108727382B (en) * | 2017-04-19 | 2022-07-19 | 华东理工大学 | Heterocyclic compounds as BTK inhibitors and uses thereof |
| KR20230164600A (en) * | 2022-05-25 | 2023-12-04 | 주식회사 엘지화학 | Heterocyclic compound as diacrylglycerol kinases inhibitor and use thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1373763A (en) * | 1999-09-15 | 2002-10-09 | 沃尼尔·朗伯公司 | Pteridinones and kinase inhibitors |
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| JP2008510770A (en) * | 2004-08-26 | 2008-04-10 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Novel pteridinone as a PLK inhibitor |
| JP2015501793A (en) * | 2011-11-10 | 2015-01-19 | オーエスアイ・ファーマシューティカルズ，エルエルシー | Dihydropteridinones |
| US9783504B2 (en) * | 2013-07-09 | 2017-10-10 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
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| CN1373763A (en) * | 1999-09-15 | 2002-10-09 | 沃尼尔·朗伯公司 | Pteridinones and kinase inhibitors |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357885A (en) * | 2019-07-24 | 2019-10-22 | 江南大学 | A kind of pteridine compounds and its application pharmaceutically |
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| WO2017101862A1 (en) | 2017-06-22 |
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