CN105254615B - Phenylaminopyrimidine derivatives and their use in preparation of drugs for resisting cancers - Google Patents
Phenylaminopyrimidine derivatives and their use in preparation of drugs for resisting cancers Download PDFInfo
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- CN105254615B CN105254615B CN201510405448.6A CN201510405448A CN105254615B CN 105254615 B CN105254615 B CN 105254615B CN 201510405448 A CN201510405448 A CN 201510405448A CN 105254615 B CN105254615 B CN 105254615B
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- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to phenylaminopyrimidine derivatives and their use in preparation of drugs for preventing and/or treating cancers. The phenylaminopyrimidine derivatives are ideal high-efficiency non-reversible EGFR kinase inhibitors and can be used for treating or preventing lung cancer, stomach and intestine cancer, breast cancer, pancreas cancer, ovarian cancer, esophagus cancer, head and neck squamous carcinoma, epidermal squamous carcinoma, prostate cancer, glioma and nasopharyngeal carcinoma.
Description
Technical field
The present invention relates to aniline pyrimidine derivative and its purposes in preparation prevention, treatment malignant tumor medicine.
Background technology
EGFR (epidermal growth factor receptor, EGF-R ELISA) is that a kind of cross-film is subject to
Body, EGFR is incorporated into ectodomain and forms receptor dimer and activate intracellular tyrosine kinase domain, causes kinases certainly
Body phosphorylation and the phosphorylation of downstream molecules, various kinds of cell function including propagation and survival for the activation.Nearly 80%～85%
NSCLC patient can detect that EGFR, its expression is widely different in a continuous scope.The mutation of adenocarcinoma of lung EGFR
Incidence rate reaches 50% in asian population, and in non-smoker, women and non-myxomous tumour, incidence rate is higher.
Modal EGFR sports exons 19 and lacks (E19del sees 45% patient) and exon 2 1L858R
Mutation (seeing 40% patient), the two all can lead to tyrosine kinase domain to activate, and all with tumor to small molecule TKIs
The sensitivity of (tyrosine kinase inhibitor, tyrosine kinase inhibitor) is related.The mutation of these drug susceptibilities is shown in
White people NSCLC patient in nearly 10% and up to 50% asian patients.EGFR gene is that Asia patients with lung adenocarcinoma mutation is general
Rate is maximum, most patients can be made to treat the target spot benefiting.Other drug susceptibility mutation types include exon 21 (L861Q)
With exons 18 (G719X) point mutation.T790M mutation may result in TKI class Drug-resistant, and relevant report shows that this mutation type is shown in
In about 50% tumour progression patient.
Content of the invention
The technical problem to be solved be provide a kind of new aniline pyrimidine derivative, its be preferably non-can
Inverse property EGFR kinase inhibitor, can be used for effectively preventing or treat pulmonary carcinoma, human primary gastrointestinal cancers, breast carcinoma, cancer of pancreas, ovarian cancer, esophaguses
The Several Kinds of Malignancy diseases such as cancer, G. cephalantha, epidermis scale cancer, carcinoma of prostate, glioma and nasopharyngeal carcinoma.
For solving above technical problem, the present invention adopts the following technical scheme that：
There is the compound of logical formula I, its officinal salt, hydrate, or the metabolite that metabolism is formed in any form,
Wherein：
R1For CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, C2～C3Fluoro alkyl, C2～C3Chloro alkyl；Or, R1
For OCkH2k+1, wherein k is the integer between 1～3；
R2And R3For having straight chain or the branched chain hydrocarbon chain of at least one double bond, and R2And R3One or two is other sub-
Methyl group unit optionally and independently through-NHC (O)-,-C (O) NH- ,-N (H) SO2- or-SO2N (H)-displacement；Or, R2And R3
For-NHCH2CH2N(H)CH3、-NHCH2CH2N(CH3)2、-N(CH3)CH2CH2N(H)CH3、-N(CH3)CH2CH2N(CH3)2, 4- first
Base piperazine -1- base, 4- ethyl piperazidine -1- base, wherein, R2And R3It can not be identical group；
R4For
Wherein, R5For H, CH3、CH2CH3；
X is N or CH；
The described compound with logical formula I, its officinal salt, hydrate, or the metabolism that metabolism is formed in any form
In product, the hydrogen of commutativity is unsubstituted, or is partly or entirely replaced by deuterium.
According to an aspect of the present invention, in formula (I), R1It is selected from CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, with
And OCH3One of；R2、R3、R4、R5And X is defined as above.
According to another aspect of the invention, in formula I, R2For-NHC (O) CH=CH2,-NHC (O) CH=CHCH2N
(CH3)2、-NHSO2CH=CH2、-NHSO2CH=CHCH2N(CH3)2；R3For-NHCH2CH2N(H)CH3、-NHCH2CH2N
(CH3)2、-N(CH3)CH2CH2N(H)CH3、-N(CH3)CH2CH2N(CH3)2, 4- methylpiperazine-1-yl, 4- ethyl piperazidine -1- base；
R1、R4、R5And X is defined as above.
According to another aspect of the invention, in formula I, R3For-NHC (O) CH=CHCH2N(CH3)2、-NHSO2CH=
CH2、-NHSO2CH=CHCH2N(CH3)2；R2For-NHCH2CH2N(H)CH3、-NHCH2CH2N(CH3)2、-N(CH3)CH2CH2N(H)
CH3、-N(CH3)CH2CH2N(CH3)2, 4- methylpiperazine-1-yl, 4- ethyl piperazidine -1- base；R1、R4、R5And the definition of X is same
On.
One according to the present invention concrete and preferred aspect, in formula (I), R5For H or CH3, R1、R2、R3、R4And the determining of X
Justice is ibid.
According to a specific aspect, X is CH.
According to a preferred aspect of the present invention, in formula (I), R1It is selected from OCH2F, OCHF2, OCF3, OCH3And OCH2CH3
One of；R3For-NHC (O) CH=CHCH2N(CH3)2、-NHSO2CH=CH2、-NHSO2CH=CHCH2N(CH3)2；R2For-
NHCH2CH2N(H)CH3、-NHCH2CH2N(CH3)2、-N(CH3)CH2CH2N(H)CH3、-N(CH3)CH2CH2N(CH3)2, 4- methyl
Piperazine -1- base, 4- ethyl piperazidine -1- base；X is CH, R4、R5It is defined as above.
According to the present invention, representational compound is as follows：
According to the present invention, described compound, it not only includes certain single compound form, also includes various structures
Meet the form of mixtures of the compound that logical formula I requires, and the different isomer form such as raceme of same compound
Body, enantiomer, diastereomer etc..Described officinal salt include but is not limited to hydrochlorate, phosphate, sulfate,
Acetate, maleate, mesylate, benzene sulfonate, benzoic acid salt, toluenesulfonate, succinate, fumarate, richness
Horse hydrochlorate, tartrate, gallate, citrate etc..It is described that " prodrug with the compound of logical formula I " refers to one kind
Material, after being applied using suitable method, can be carried out metabolism or chemical reaction in subject and be transformed into structure formula I
At least one compound or its salt.
The preparation of the compounds of this invention can pass through the route of synthesis of chemical field those similar methods well-known,
Synthesize the compound of the present invention in particular according to the description comprising herein.Reagent typically obtains or easy to use from commercial source
Prepared by the well-known method of skilled person.
The invention still further relates to a kind of intermediate preparing the above-mentioned compound with logical formula (I), this intermediate such as formula
(II) shown in：
In logical formula (II), R1, R2, R4It is defined as above.
Further, in above-mentioned logical formula (II), R2For-NHCH2CH2N(H)CH3、-NHCH2CH2N(CH3)2、-N(CH3)
CH2CH2N(H)CH3、-N(CH3)CH2CH2N(CH3)2, 4- methylpiperazine-1-yl or 4- ethyl piperazidine -1- base.
Further, in above-mentioned logical formula (II), R1For OCH2F, OCHF2, OCF3Or OCH3.
Representational logical formula (II) intermediate has for example：
Using above-mentioned intermediate, can get via a step amidation process and lead to formula (I) compound accordingly.
Due to the enforcement of above technical scheme, the present invention compared with prior art has the advantage that：
The compound that the present invention provides is new aniline pyrimidine derivative, and it is preferable efficient non reversibility EGFR cheese
Histidine kinase inhibitor, by acting on EGFR intracellular portion and ATP competitive binding, the activity of suppression kinases and phosphoric acid
Change, and close EGFR SRCA TP binding site thus reaching the purpose that specificity suppresses EGFR.Chemical combination therefore of the present invention
Thing can be used for preparation treatment or prevent the various indications relevant with EGFR kinase function, including but not limited to pulmonary carcinoma, human primary gastrointestinal cancers,
Breast carcinoma, cancer of pancreas, ovarian cancer, the esophageal carcinoma, G. cephalantha, epidermis scale cancer, carcinoma of prostate, glioma and nasopharyngeal carcinoma etc.
Several Kinds of Malignancy disease.More specifically the compounds of this invention can specifically act on the EGFR with T790M mutation and swash
Enzyme, and the inhibitory action only weaker to Wild type EGFR kinases, this selective inhibitory action obtains to band T790M mutation
Obtain property drug-resistant tumor and there is therapeutic potential, and toxicity is less.
Specific embodiment
With reference to specific embodiment, the present invention will be further described in detail, but the present invention is not limited to following enforcement
Example.
Embodiment 1
Formulas I a compound, its chemical constitution is as follows：
Formulas I a compound can be obtained by following synthetic route：
The preparation method of Formulas I a compound specifically includes following steps：
(1), prepare intermediate 3：To 2,4- dichloro pyrimidine (4.83g, 32.4mmol) and dimethoxy-ethane (50mL) 60
DEG C about add ferric chloride (5.5g, 33.9mmol) and 1- methylindole (5.0g, 38mmol) in agitating solution.Gained is mixed
Compound stirs 60 DEG C about overnight.After cooling, by adding methanol (50mL) and water (100mL) solid precipitation.By gained slurry
Stirring 3 hours.Solid by filtration is collected, is rinsed with methanol (100mL), 50 DEG C are dried overnight, obtain intermediate 3 (6g,
77%), it is violet solid.
(2), prepare intermediate 5：By toluenesulfonic acid hydrate (772.82mg, 4.1mmol) be added to intermediate 3 (1g,
4.1mmol) and in 2- amylalcohol (10mL) mixture of intermediate 4 (763mg, 4.1mmol).By the 105 DEG C of stirrings of gained mixture
2.5 hour.It is subsequently cooled to room temperature, gained sediment is collected by filtration, is rinsed with 2- amylalcohol (20mL), be dried under vacuum,
Obtain intermediate 5 (1.2g, 75%), be yellow solid.
(3), prepare intermediate 7：Intermediate 5 (500mg, 1.27mmol) and intermediate 6 (155.8mg, 1.53mmol)
85 DEG C of stirring 5-6 hours of DMA (50mL) solution, are subsequently cooled to room temperature.Add water (50mL), then stir the mixture for 3-4
Hour.Solid matter is collected by filtration, and is washed with water (30mL), 50 DEG C of dryings 12 hours, obtain intermediate 7 (400mg,
96%), it is orange solids.
(4), prepare intermediate 8：By intermediate 7 (400mg, 0.84mmol), ferrum (281.84mg, 5.04mmol), chlorination
Ammonium (31.5 milligrams, 0.588mmol), ethanol (30mL) and water (10mL) mixture are heated to reflux 2 hours.Required product 7M first
Alcohol ammonia eluting post merges, and is concentrated in vacuo on silica gel.Intermediate 8 is obtained by column chromatography purification, is beige color foam, it is direct
For next step reaction.
(5), formula Ia compound：In adding in intermediate 8 (300mg, 0.67mmol) DMF solution (12mL) solution
Mesosome 9 (222mg, 1.34mmol), HATU (255mg, 0.67mmol) and TEA (135mg, 1.34mmol).Under mixture room temperature
Stirring 2 hours.This mixture passes through preparation HPLC purification, directly obtains crude product (300mg), is burgundy grease.Will
Crude product is further purified with TLC chromatography and obtains Ia compound, is luteotestaceous semisolid.
Hydrogen nuclear magnetic resonance has been carried out to the target product Ia obtaining1H-NMR (400MHz, MeOD) and mass spectrometric measurement, result
As follows：
1Absworption peak in H-NMR spectrum：δ=8.88 (s, 1H) 8.33 (m, 1H) 8.27 (m, 2H) 7.47 (m, 1H) 7.24 (m,
3H)6.99(m,2H)6.83(d,1H)4.01(s,3H)3.92(s,3H)3.46(t,2H)3.33(m,2H)3.29(m,2H)2.89
(s,6H)2.72(m,9H).
m/z[MH]+:557.3.Calculate product and there is molecular formula C31H40N8O2, accurate molecular quality (exact
Mass it is) 556.33.
Embodiment 2
Formulas I b compound, its chemical constitution is as follows：
Formulas I b compound can be obtained by following synthetic route：
The preparation method of Formulas I b compound specifically includes following steps：
(1), prepare intermediate 12：Add to suspension in DMA (10mL) for the intermediate 5 (340mg, 0.86mmol)
DIPEA (144mg, 1.12mmol), intermediate 11 (117mg, 1.03mmol), heat the mixture to 80 DEG C 16 hours.To mix
Compound is poured in water (40mL), and stirring 5 minutes is simultaneously filtered, and obtains intermediate 12 (290mg, 69%), is orange solids, m/z
[MH]+For 488.
(2), prepare intermediate 13：To add in intermediate 12 (290mg, 0.59mmol) EtOH (12mL)/water (4mL) solution
Enter ferrum (200mg, 3.57mmol) and ammonium chloride (22mg, 0.41mmol).It is heated to reflux 2 hours.By mixture ethanol
(100mL) extract with water (80mL), kieselguhr filters, be dried and intermediate 13 (250mg, 93%) is obtained by chromatography, be
Secretly semi-solid.
(3), formula Ib compound：In adding in intermediate 13 (200mg, 0.44mmol) DMF solution (8mL) solution
Mesosome 9 (145mg, 0.88mmol), HATU (168mg, 0.44mmol) and TEA (88mg, 0.88mmol).Under this mixture room temperature
Stirring 2 hours.Ib compound (140mg, 56%) is obtained by preparation HPLC purification, is green solid.
Hydrogen nuclear magnetic resonance has been carried out to the target product Ib obtaining1H-NMR (400MHz, MeOD) and mass spectrometric measurement, result
As follows：
1Absworption peak in H-NMR spectrum：δ=8.65 (s, 1H) 6.58 (s, 1H) 8.29 (m, 1H) 8.05 (m, 1H) 7.52 (d,
J=8.0Hz, 1H) 7.34 (m, 2H) 7.24 (m, 1H) 7.05 (s, 1H) 6.85 (m, 2H) 4.01 (m, 2H) 3.97 (s, 3H) 3.95
(s,3H)3.72(m,2H)3.46(m,2H)3.37(m,2H)3.33(m,4H)2.94(s,6H)1.44(m,3H).
m/s:[MH]+:569.4.Calculate product and there is molecular formula C32H40N8O2, accurate molecular quality (exact
Mass it is) 568.33.
Embodiment 3
Formulas I c compound, its chemical constitution is as follows：
Formulas I c compound can be obtained by following synthetic route：
The preparation method of Formulas I c compound specifically includes following steps：
(1), prepare intermediate 15：To DMF solution (500 milliliters) solution of intermediate 14 (25g, 159mmol) under room temperature
Middle addition sodium carbonate (100g, 943mmol).Then, reactant is heated to 90 DEG C, compound A (71.5g, 550mmol) is added
Enter in this solution.Reactant is stirred 2 hours.Mixture is poured in frozen water (300mL), and is extracted with MTBE.To merge
Organic phases washed with brine, anhydrous sodium sulfate drying is simultaneously concentrated in vacuo.Thick material is obtained centre through Silica gel chromatography
Body 15 (31g, 94%), is yellow oil.
(2), prepare intermediate 16：Under room temperature, Pd/C (3g, 3.0mmol) is added to intermediate 15 (31g, 150mmol)
The agitating solution of EtOH (80mL) in.Reactant mixture is reacted overnight under 40psi hydrogen.By mixture mistake under reduced pressure
Filter is concentrated to intermediate 16 (22g, 82%), is brown oil.
(3), prepare intermediate 17：At DEG C, intermediate 16 (11.0g, 62mmol) is added drop-wise in concentrated sulphuric acid.Then, will
KNO3(6.2g, 62mmol) is dividedly in some parts.Stir 30 minutes at DEG C.Solution is poured in frozen water, by pH regulator to 7-8, saturation
NaHCO3With ethanol extraction.Use salt water washing, and be vacuum dried and be concentrated to give intermediate 17 (9.6g, 70%), be yellow solid.
(4), prepare intermediate 18：Add intermediate 3 to intermediate 17 (2.0g, 9.0mmol) 2- amylalcohol (15mL) solution
(2.2g, 9.0mmol) and p-methyl benzenesulfonic acid (2.1 grams, 10.8mmol).Reactant mixture is stirred overnight at 120 DEG C.Will be molten
Agent is evaporated under reduced pressure, and obtains intermediate 18 (2.9g, 75%), is brown solid.
(5), prepare intermediate 19：Intermediate 6 is added in intermediate 18 (2.9g, 6.7mmol) DMA (20mL) solution
(0.8g, 8.1mmol) and DIPEA (1.1 grams, 8.7mmol).Mixture is stirred 2 hours at 85 DEG C.Mixture is poured into ice
In water and stir half an hour.Then, filter lower for mixture decompression.By filter cake washing with alcohol obtain intermediate 19 (2.0g,
65%), it is yellow solid.
(6), prepare intermediate 20：Ammonium chloride is added in intermediate 19 (2.0g, 3.9mmol) ethanol solution (25mL)
(150mg, 2.7mmol) and ferrum (1.3g, 23.4mmol).Mixture is stirred 2 hours at 75 DEG C.Mixture was reduced pressure
Filter.Filtrate extract is concentrated in vacuo with the drying of salt water washing.Thick material is obtained intermediate 20 through Silica gel chromatography
(800mg, 41%), is gray solid.
(7), formula Ic compound：To in intermediate 20 (300mg, 0.63mmol) DMF agitating solution (10mL) solution
Add intermediate 9 (165mg, 1.26mmol), HATU (237mg, 0.63mmol) and TEA (126mg, 1.26mmol).To react
It is stirred at room temperature 2 hours.This mixture obtains Ic compound (20mg, 5.3%) by preparation HPLC purification, is that yellow is solid
Body.
Hydrogen nuclear magnetic resonance has been carried out to the target product Ic obtaining1H-NMR (400MHz, MeOD) and mass spectrometric measurement, result
As follows：
1Absworption peak in H-NMR spectrum：δ=8.88 (s, 1H), 8.32 (t, J=4.0Hz, 1H), 8.28 (s, 1H), 7.48
(d, J=8.0Hz, 1H), 7.21 (d, J=12.0Hz, 1H), 7.20-7.14 (m, 4H), 7.10-6.96 (m, 2H), 6.74 (t, J
=12.0Hz, 1H), 3.94 (s, 3H), 3.70 (d, J=4.0Hz, 2H), 3.44 (t, J=8.0Hz, 2H), 3.28 (t, J=
8.0Hz,2H),2.89(s,6H),2.75(s,3H),2.70(s,6H).
m/s:[MH]+:536.3.Calculate product and there is molecular formula C28H31F2N7O2, accurate molecular quality (exact
Mass it is) 535.25.
Embodiment 4
Formulas I d compound, its chemical constitution is as follows：
This compound can be reacted acquisitions by making the intermediate 20 described in embodiment 3 and intermediate 9, concrete preparation
Process can be found in embodiment 3.
Hydrogen nuclear magnetic resonance has been carried out to the target product Id obtaining1H-NMR (400MHz, MeOD) and mass spectrometric measurement, result
As follows：
1Absworption peak in H-NMR spectrum：δ=8.97 (s, 1H), 8.31 (t, J=4.0Hz, 2H), 8.27 (d, J=8.0Hz,
1H), 7.47 (d, J=8.0Hz, 1H), 7.28-7.13 (m, 4H), 6.94 (t, J=76.0Hz, 1H), 6.61-6.51 (m, 1H),
6.47 (d, J=4.0Hz, 1H), 3.92 (s, 3H), 3.05 (t, J=4.0Hz, 2H), 3.01-2.88 (m, 2H), 2.74 (s,
3H),2.72(s,6H).
m/s:[MH]+:593.3.Calculate product and there is molecular formula C31H38F2N8O2, accurate molecular quality (exact
Mass it is) 592.31.
Embodiment 5
Formulas I e compound, its chemical constitution is as follows：
This compound can be by making the intermediate 8 described in embodiment 1 and intermediate 8a【ClS(O2)CH2CH2Cl】Occur
Reaction obtains, and concrete preparation process can be found in embodiment 1.
Hydrogen nuclear magnetic resonance has been carried out to the target product Ie obtaining1H-NMR (400MHz, CDCl3) and mass spectrometric measurement, result
As follows：
1Absworption peak in H-NMR spectrum：δ=9.0 (s, 1H) 8.72 (s, 1H) 8.32 (m, 1H) 8.08 (m, 1H) 7.70 (s,
1H) 7.41 (m, 1H) 7.30 (m, 2H) 7.21 (m, 1H) 6.77 (s, 1H) 6.55 (m, 1H) 6.15 (m, 1H) 5.72 (d, J=
10Hz,1H)3.96(s,3H)3.89(s,3H)2.85(m,2H)2.71(s,3H)2.33(s,6H)2.25(m,2H).
m/s:[MH]+:536.3.Calculate product and there is molecular formula C27H33N7O3S, accurate molecular quality (exact
Mass it is) 535.24.
Embodiment 6
Formulas I f compound, its chemical constitution is as follows：
This compound can be by making the intermediate 16 described in embodiment 3 and intermediate 8a【ClS(O2)CH2CH2Cl】Occur
Reaction obtains, and concrete preparation process can be found in embodiment 3.
Hydrogen nuclear magnetic resonance has been carried out to the target product If obtaining1H-NMR (400MHz, CDCl3) and mass spectrometric measurement, result
As follows：
1Absworption peak in H-NMR spectrum：δ=9.0 (s, 1H) 8.63 (s, 1H) 8.38 (d, J=5.2Hz, 1H) 8.08 (d, J
=8.0Hz, 1H) 7.41 (m, 2H) 7.28 (m, 3H) 7.03 (s, 1H) 6.55 (m, 1H) 6.21 (m, 1H) 5.76 (d, J=10Hz,
1H)3.93(s,3H)2.81(m,2H)2.70(s,3H)2.35(s,6H)2.33(m,2H).
m/s:[MH]+:572.1.Calculate product and there is molecular formula C27H31F2N7O3S, accurate molecular quality (exact
Mass it is) 571.22.
Embodiment 7
Formulas I g compound, its chemical constitution is as follows：
Formulas I g compound can be obtained by following synthetic route：
The preparation method of Formulas I g compound specifically includes following steps：
(1), prepare intermediate 21：By CH at 0 DEG C3MgBr (in THF, 35mL, 105mol) dropped to indole in 10 minutes
In the THF solution (45mL) of (11.50g, 98.16mmol).Then solution is stirred 0.5 hour at 0-5 DEG C.Will be chloro- for 2,4- bis-
THF solution (25mL) solution of 5- methylpyrimidine (8g, 49.08mmol) is added drop-wise in this solution.Then remove ice bath, this is molten
Stir under liquid room temperature 1 hour, then 18 hours at 60 DEG C.Add acetic acid (6mL) solution, be subsequently added into water (80mL).By gained
Suspension stirs 0.5 hour at 60 DEG C.Gained solid by filtration is collected, and is washed with water and methanol, and vacuum drying obtains centre
Body 21 (2.8 grams, 23.4%), is white solid.
(2), prepare intermediate 22：Add in THF solution (100mL) solution of intermediate 21 (8.7g, 35.8mmol)
NaH (945mg, 39.4 moles).Stir half an hour at 0 DEG C.It is subsequently adding MeI (6.1g, 43mmol) to be added in mixture.Will
Reaction is stirred at room temperature 3 hours.Mixture is filtered under reduced pressure, obtains intermediate 22 (6.0g, 65%), solid for white
Body.
(2), prepare intermediate 23：Intermediate 4 is added in intermediate 22 (2.9g, 11mmol) 2- amylalcohol (30mL) solution
(2.5g, 244mmol) and p-methyl benzenesulfonic acid (2.3g, 13mmol).Reaction is stirred overnight at 120 DEG C.Mixture is being subtracted
Pressure is filtered, and obtains intermediate 23 (4.3 grams, 88%), is brown solid.
(2), prepare intermediate 24：Intermediate 6 is added in intermediate 23 (4.3g, 9.6mmol) DMA (30mL) solution
(1.2g, 12mmol) and DIPEA (1.6g, 13mmol).Reactant mixture is stirred 2 hours at 85 DEG C.Mixture is poured into
In frozen water and stir half an hour.Then, mixture is filtered under reduced pressure.By filter cake washing with alcohol, obtain intermediate 24
(2.3g, 45%), is yellow solid.
(2), prepare intermediate 25：Add ammonium chloride to intermediate 24 (2.3g, 4.3mmol) ethanol solution (25mL)
(115mg, 2.1mmol) and ferrum (1.2g, 21.4mmol).Reactant mixture is stirred 2 hours at 75 DEG C.Mixture is passed through
Filtration under diminished pressure.Filtrate extracts, salt water washing, and vacuum drying concentrates.By thick material through Silica gel chromatography, obtain intermediate
25 (1.2g, 56%), are gray solid.
(3), formula Ig compound：Cobaltous chloride is added in intermediate 9 (64mg, 0.4mmol) DCM (5mL) solution
1mL) He DMF.Reactant is stirred at room temperature 1 hour.It is evaporated under reduced pressure and removes cobaltous chloride, residue is dissolved in DCM
(5mL) in.Compound 5 (100mg, 0.3mmol) is added in this mixture.Reaction is stirred 30 minutes at 0 DEG C.By mixture
Concentrated in vacuo.Crude product is passed through to prepare TLC purification, obtains Ig compound (26mg, 10%), be yellow solid.
Hydrogen nuclear magnetic resonance has been carried out to the target product Ig obtaining1H-NMR (400MHz, MeOD) and mass spectrometric measurement, result
As follows：
1Absworption peak in H-NMR spectrum：δ=8.71 (s, 1H), 8.33 (d, J=8.0Hz, 1H), 8.15-8.10 (m, 2H),
7.49 (d, J=8.0Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.23 (s, 1H), 7.15-6.74 (m, 5H), 6.32-6.28
(m, 1H), 4.04 (d, J=8.0Hz, 2H), 3.95 (s, 3H), 3.44 (d, J=8.0Hz, 2H), 2.94 (s, 12H), 2.77 (s,
3H),2.47(s,3H).
m/s:[MH]+:607.2.Calculate product and there is molecular formula C32H40F2N8O2, accurate molecular quality (exact
Mass it is) 606.32.
Embodiment 8
Formulas I h compound, its chemical constitution is as follows：
This compound can be reacted by making the intermediate 21 described in embodiment 7 and intermediate 4, and 3 step below
Same reaction step obtains, and concrete preparation process can be found in embodiment 7.
Hydrogen nuclear magnetic resonance has been carried out to the target product Ih obtaining1H-NMR (400MHz, MeOD) and mass spectrometric measurement, result
As follows：
1Absworption peak in H-NMR spectrum：δ=9.02 (s, 1H), 8.26-8.23 (m, 2H), 7.93 (s, 1H), 7.43 (d, J
=8.0Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 7.14 (s, 1H), 7.03 (d, J=8.0Hz, 1H), 6.87-6.82 (m,
1H), 6.77 (d, J=76Hz, 1H), 6.43-6.39 (m, 1H), 3.21 (d, J=8.0Hz, 2H), 3.05 (t, J=4.0Hz,
2H), 2.70 (s, 3H), 2.52 (t, J=8.0Hz, 2H), 2.44 (s, 3H), 2.34 (s, 6H), 2.31 (s, 6H).
m/s:[MH]+:593.2.Calculate product and there is molecular formula C31H38F2N8O2, accurate molecular quality (exact
Mass it is) 592.31.
The test of pesticide effectiveness
First, compound enzymatic activity test：
1st, test method
The 503nhibiting concentration IC of compound50(the concentration of inhibition of enzyme activity to required compound when 50%) is with fixation
Enzyme mix the testing compound of specific substrates and variable concentrations to measure.Assay method used is slide calliper rule migration variation point
Analysis (Caliper Mobility Shift Assay), the kinases being measured is EGFRWTAnd EGFR790M/L858R, the mark applied
Quasi- reference compound is D-82041 DEISENHOFEN (staurosporine).
2nd, result of the test
Table 1 summarizes compound inhibition of enzyme activity experimental result.Result display target compound (Ia, Ib, Ic, Id, Ie,
If, Ig and Ih) to two kinds of EGFR kinases, there is very strong inhibitory action, meanwhile, result display target compound (Ia, Ib,
Ic, Id, Ie and If) selective inhibitory activity preferable.This selective inhibitory action to carry T790M mutation acquired
Drug-resistant tumor has important therapeutic potential.
Table 1 compound inhibition of enzyme activity experimental result
2nd, inhibiting tumour cells test：
1st, test method
(1), compound：First test compound is dissolved in 100%DMSO in vitro study, then is diluted to desired concn,
Final concentration of the 0.1% of DMSO.The DMSO of 0.1% (v/v) is added culture medium as solvent control, totally 9 Concentraton gradient, weight
Repetition measurement examination is secondary.
(2), tumor cell line：Surveyed tumor cell ties up in the RPMI10 culture medium containing 10% hyclone, in 5%
CO2, cultivate in 37 DEG C of incubators.Surveyed tumor cell line is：A431, Calu-3, H1975, H1650 and HCC827.
(3), MTS method：Cell is inoculated in 96 orifice plates, 3000 cells in every hole, and in 5%CO2, 37 DEG C of humidification cultures
Overnight incubation in case.Test compound is added after in the hole, then is incubated 72 hours within second day.Detect the activity of cell using MTS.
Calculate IC50(cell growth is made to be subject to the drug level needed for 50% suppression, using GraphPad compared with DMSO matched group
The nonlinear regression analyses of Prism software are calculated).
2nd, result of the test
Target compound Id exists to A431, Calu-3, H1975, H1650 and HCC827 inhibiting tumour cells Activity Summary
In table 2.
Table 2 inhibiting tumour cells result of the test
As seen from Table 2, the compounds of this invention Id is all demonstrated by inhibitory activity to various test tumor cells.
3rd, pharmacokinetic experiment
1st, experimental technique：
Laboratory animal：Nude mice, female, 6～7 weeks；Body weight：20～25g；
Test sample is prepared：It (is oral that test compound is configured to 0.2mg/mL (for intravenously administrable use) and 1.0mg/mL
Administrable), stand-by.Route of administration：Oral/vein.Administration capacity and frequency：5mL/kg, single-dose.
Sample collecting：Gather blood, 3 animals of each time point according to following time point, take whole blood about 0.5-1.0mL.
After administration, 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h take blood.All animals are all implemented peaceful and comfortable after completing test
Extremely.
2nd, sample analysis and result
Sample analysis：Using LC-MS/MS method, collection sample is detected.Using INSTRUMENT MODEL it is
SHIMADZU20A-API4000.
Pharmacokinetic data Analysis：Gained plasma drug concentration data is carried out according to non-compartment model method using WinNolin
Matching and calculating, partial results are summarized in table 3.
The target compound pharmacokinetic parameter that table 3 calculates according to non-compartment model method
Result of the test in nude mice shows that the compounds of this invention has good pharmacokinetic characteristic.
In addition, also experimental test has been carried out to the toxic and side effects of the compounds of this invention.To nude mice successive administration once a day
21 days, to rat successive administration 14 days once a day, result showed that the compounds of this invention has less toxic and side effects, in animal
In toleration good, the maximum dose level of test is 100mg/kg/ days.
Above example is only representational.Visible by above-described embodiment, the compound of the present invention is preferably efficient
Dual non reversibility tyrosine kinase inhibitor is it may be desirable to be used for treating or prevent pulmonary carcinoma, human primary gastrointestinal cancers, breast carcinoma, cancer of pancreas, ovum
The Several Kinds of Malignancy diseases such as nest cancer, the esophageal carcinoma, G. cephalantha, epidermis scale cancer, carcinoma of prostate, glioma and nasopharyngeal carcinoma
And obtaining extraordinary effect, it can also combine with different types of pharmaceutical salts and make oral formulations (tablet or capsule
Deng).The tablet made with the compounds of this invention or capsule can be taken one or more times daily.The compounds of this invention also can and its
His its medicine combines makes compound preparation.
Above-described embodiment only technology design to illustrate the invention and feature, its object is to allow person skilled in the art
Scholar will appreciate that present disclosure and implements according to this, can not be limited the scope of the invention with this.All according to the present invention
Equivalence changes or modification that spirit is made, all should be included within the scope of the present invention.
Claims (8)
1. there is the compound or pharmaceutically acceptable salt thereof of logical formula I：
Wherein：
R1For CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, C2～C3Fluoro alkyl, C2～C3Chloro alkyl；Or, R1For
OCkH2k+1, wherein k is the integer between 1～3；
R2For-NHCH2CH2N(H)CH3、-NHCH2CH2N(CH3)2、-N(CH3)CH2CH2N(H)CH3、-N(CH3)CH2CH2N
(CH3)2；
R3For-NHC (O) CH=CHCH2N(CH3)2、-NHSO2CH=CH2、-NHSO2CH=CHCH2N(CH3)2；R4For
Wherein, R5For H, CH3、CH2CH3；
X is CH.
2. the compound or pharmaceutically acceptable salt thereof with logical formula I according to claim 1 it is characterised in that：In formula (I), R1
It is selected from CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, OCH3And OCH2CH3One of.
3. the compound or pharmaceutically acceptable salt thereof with logical formula I according to claim 1 it is characterised in that：In formula (I), R5
For H or CH3.
4. the compound or pharmaceutically acceptable salt thereof with logical formula I according to claim 1 it is characterised in that：In formula (I), R1
It is selected from OCH2F, OCHF2, OCF3, OCH3And OCH2CH3One of；R3For-NHC (O) CH=CHCH2N(CH3)2、-NHSO2CH
=CH2、-NHSO2CH=CHCH2N(CH3)2；R2For-NHCH2CH2N(H)CH3、-NHCH2CH2N(CH3)2、-N(CH3)CH2CH2N
(H)CH3、-N(CH3)CH2CH2N(CH3)2；X is CH.
5. the compound or pharmaceutically acceptable salt thereof with logical formula I according to claim 1 it is characterised in that：Described chemical combination
Thing is one of compound that following structural formula represents：
6. the compound or pharmaceutically acceptable salt thereof representing as Formulas I c,
7. the compound or pharmaceutically acceptable salt thereof as described in any one of claim 1 to 6 claim in preparation prevention and/or is controlled
Treat the purposes in the medicine of indication relevant with EGFR kinase function.
8. purposes according to claim 7 it is characterised in that：The described indication related to EGFR kinase function is mammary gland
Cancer, ovarian cancer, human primary gastrointestinal cancers, the esophageal carcinoma, pulmonary carcinoma, G. cephalantha, cancer of pancreas, epidermis scale cancer, carcinoma of prostate, glioma and
Nasopharyngeal carcinoma.
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| AU2017269335B2 (en) | 2016-05-26 | 2021-07-01 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
| CN107840846B (en) * | 2016-09-19 | 2020-11-24 | 郑州泰基鸿诺医药股份有限公司 | Pyrimidine ring-containing compound, EGFR inhibitor and application thereof |
| WO2019010619A1 (en) * | 2017-07-10 | 2019-01-17 | 焦玉奇 | 2-(2,4,5-substituted aniline) pyrimidine derivative |
| CN108558832B (en) * | 2018-01-17 | 2021-04-30 | 浙江树人学院 | Novel antitumor drug oxitinib derivative and preparation method thereof |
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| CN110857292A (en) * | 2018-08-22 | 2020-03-03 | 上海艾力斯医药科技有限公司 | EGFR kinase inhibitor and preparation method and application thereof |
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