CN107840847A - Deuterated 3 (4,5 substituted-amino pyrimidine) phenyl derivatives and its application - Google Patents
Deuterated 3 (4,5 substituted-amino pyrimidine) phenyl derivatives and its application Download PDFInfo
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- CN107840847A CN107840847A CN201610833361.3A CN201610833361A CN107840847A CN 107840847 A CN107840847 A CN 107840847A CN 201610833361 A CN201610833361 A CN 201610833361A CN 107840847 A CN107840847 A CN 107840847A
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- AZWYVTAQBOKVTA-UHFFFAOYSA-N CC(C)(C)OC(NCCN(C)Cc1ccccc1)=O Chemical compound CC(C)(C)OC(NCCN(C)Cc1ccccc1)=O AZWYVTAQBOKVTA-UHFFFAOYSA-N 0.000 description 1
- 0 CN(C)CCN(*)c(c(N)c1)cc(OC)c1Nc1nccc(-c2c[n](CCC3)c4c3cccc24)n1 Chemical compound CN(C)CCN(*)c(c(N)c1)cc(OC)c1Nc1nccc(-c2c[n](CCC3)c4c3cccc24)n1 0.000 description 1
- LIUGRXFEJOSPIA-UHFFFAOYSA-N CN(CCN)Cc1ccccc1 Chemical compound CN(CCN)Cc1ccccc1 LIUGRXFEJOSPIA-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
Abstract
The invention discloses one kind deuterated 3 (4,5 substituted-amino pyrimidines) phenyl derivatives and its application, it is compound or its pharmaceutically acceptable salt with formula (I) structure, these compound or its salts can be used for the treatment or prevention of disease or the patient's condition by the EGF-R ELISA of some mutant forms, the growth of kinds of tumor cells can effectively be suppressed, and inhibitory action is produced to EGFR, Her family other protease, available for preparing antineoplastic.
Description
Technical field
The invention belongs to antineoplastic technical field, and in particular to deuterated 3- (4,5- substituted-amino pyrimidine) phenyl derivative
Thing and its application in antineoplastic is prepared.
Background technology
In traditional cancer treatment procedure, chemotherapy is main treatment means；Chemotherapeutics non-specifically blocks carefully
Born of the same parents divide so that cell death, they also destroy the growth of human normal cell significantly while tumour cell is killed,
Bring many adverse reactions.Many people make mood pessimistic or even abandon treating because of the serious side effects of worry chemotherapy, then add
The drug resistance of upper chemotherapeutics, the chemotherapy of non-small cell lung cancer (NSCLC) is set to allow of no optimist, and the cycle for extending chemotherapy only increases
Toxic side effect, does not increase curative effect.The cancer cell of non-small cell lung cancer is insensitive to chemotherapy, conventional chemotherapy simultaneously, total slow
Solution rate also only has 25% or so；Limitation for these reasons, Patients with Non-small-cell Lung five year survival rate are less than 20%.
In 50%-80% patient NSCLC, their EGF-R ELISA (epidermal growth
Factor receptor, EGFR) all over-express, so as to cause canceration.Targeting EGFR medicine mainly has two classes：One kind is to make
Small molecule tyrosine kinase inhibitors (TKI) for acceptor intracellular region；Another kind of is the monoclonal for acting on receptor extracellular region
Antibody (MAb).It is applied to clinical first generation EGFR inhibitor such as Iressa, Erlotinib, Lapatinib etc., they are right
Very big success is achieved in the treatment of NSCLC lung cancer, improves the Patients with Non-small-cell Lung survival rate of 5 years.Meanwhile with
Chemotherapy is compared, and their advantage is that bone marrow suppression, the side effect such as nausea and neurotoxicity will not be produced；But they are individually being controlled
Drug effect is relatively low during treatment, and has the side effect such as obviously fash and diarrhoea, and after using 1 year, patient occurs to medicine
Drug resistance.Research thinks that the mutation in EGFR gene T790M sites is the main inducing of such Drug-resistant, there is clinical case data
It has been shown that, about 50% patient's acquired resistance are all originated from caused by the mutation in T790M sites.Further research confirms, due to
EGFR gene T790M is mutated, that is, the threonine encoded is changed into methionine, inhibitor is hindered so as to cause steric hindrance
Combined with ATP-binding domain and ultimately resulted in inhibitor activity forfeiture.Also there is research to show that the mutation in T790M sites is not straight at present
Connecing influences inhibitor and EGFR compatibility, but mutation causes EGFR and ATP compatibility to greatly increase so that inhibitor with
EGFR compatibility is relative to be greatly reduced (inhibitor and ATP are competitive bindings).Second generation inhibitor such as Afatinib,
Dacomitinib, they are characterised by the increase of EGFR identity better than the first generation, can distinguish tumour cell and normal
Cell, such side effect will be reduced.But these molecules cause clinical drug to the poor selectivity of EGFR T790M mutant
Tolerance dose is relatively low, and under its maximum tolerated dose (MTD), medicine can not reach its valid density in vivo and cause to majority
Resistance patient is invalid.
In a word, current EGFR-TKI can not still solve the clinical demand caused by drug resistance, and existing medicine
Thing is that it is to wild-type cell using quinazoline or quinoline amine as the EGFR of basic parent nucleus is reversible or irreversible inhibitor mostly
The toxic side effect that poor selectivity is brought is also inevitable.Therefore, clinically there is an urgent need to new type, especially novel skeleton
Compound solve the problems such as drug resistance, poor selectivity.
The content of the invention
It is an object of the invention to provide a kind of deuterated 3- (4,5- substituted-aminos pyrimidine) phenyl derivatives.
The purpose of the present invention can be reached by following measures：
The present invention deuterated 3- (4,5- substituted-aminos pyrimidine) phenyl derivatives for formula (I) structure compound or its
Pharmaceutically acceptable salt,
Wherein, R1,R2,R3And R4Independently selected from-CH3Or-CD3, and R1,R2,R3And R4At least one is-CD3。
Further, the described compound with formula (I) structure, preferably R1For-CH3。
The compound or its pharmaceutically acceptable salt, some of particular compounds of the present invention is selected from：
Compound syntheti c route with logical formula (I) is as follows：
Above-mentioned syntheti c route comprises the following steps that：
Step 1：With dimethyl ether (DME) for solvent, compound II and 2,4- dichloro pyrimidine are in lewis acids such as alchlors
In the presence of, III is obtained by nucleophilic substitution.
Step 2：Intermediate III obtains IV with the fluoro- 2- methoxyl groups -5- nitroanilines of 4- under p-methyl benzenesulfonic acid effect.
Step 3：Using Isosorbide-5-Nitrae-dioxane as solvent, intermediate compound IV and deuterated organic amine react in the presence of DIPEA
To intermediate V.
Step 4：Using methanol or ethanol as solvent, using Pd/C as reducing agent, intermediate V is reduced to intermediate VI.
Step 5：With THF/H2O is solvent, and intermediate VI reacts to obtain intermediate compound, do not separated, directly with chlorpromazine chloride
Hydrogenation sodium oxide molybdena is connect to continue reaction and obtain final products compound of formula I.
The salt that compound in the present invention is likely to form is also to belong to the scope of the present invention.Unless otherwise indicated, it is of the invention
In compound be understood to include its esters.For example, the compound of logical formula (I) and a certain amount of acid or alkali such as equivalent are anti-
Should, salt out come in media as well, or freeze-drying is got in aqueous.The basic moiety that compound in the present invention contains,
Including but not limited to amine or pyridine or imidazole ring, may be with organic or inorganic acid forming salt.Can be into the typical acid bag of salt
Include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzene sulfonate, p-methyl benzenesulfonic acid
Salt, disulfate, borate, butyrate, citrate, camphor salt, camsilate, cyclopentane propionate, diethylene glycol (DEG) hydrochlorate,
Lauryl sulfate, ethane sulfonate, fumarate, gluceptate, glycerophosphate, enanthate, caproate, hydrochloric acid
Salt, hydrobromate, hydriodate, isethionate, lactate, maleate, mesylate, naphthalene sulfonate, nicotinate, nitre
Hydrochlorate, oxalates, pectate, persulfate, phenpropionate, phosphate, picrate, Pivalate, propionate, salicylic acid
Salt, succinate, sulfate, sulfonate, tartrate, rhodanate.
Compound in the present invention, pass sequentially through preparation, isolate and purify the compound of acquisition its weight content be equal to or
More than 90%, for example, equal to or more than 95%, equal to or more than 99% (compound of " very pure "), listed in text description.
The compound of " very pure " present invention this herein also serves as the part of the present invention.
The invention also discloses the compound of the logical formula (I) or its pharmaceutically acceptable salt in preparation or pre- preventing tumor
Application in medicine.
The tumour is selected from non-small cell lung cancer, ED-SCLC, cancer of pancreas, breast cancer, prostate cancer, liver cancer, skin
Cancer, cell carcinoma, GISTs, leukaemia, histiocytic lymph cancer, nasopharyngeal carcinoma.
One aspect of the present invention provide formula (I) compound, for treat or prevent by EGFR mediation or by activating
Disease, obstacle, disorder or the patient's condition of the EGFR of mutant or resistant mutant forms mediations.
By disease that is EGFR mediations or being mediated by the EGFR of activated mutant body or resistant mutant forms, obstacle, disorder
Or the patient's condition is selected from non-small cell lung cancer, ED-SCLC, cancer of pancreas, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, epithelial cell
Cancer, GISTs, leukaemia, histiocytic lymph cancer or nasopharyngeal carcinoma.
The EGFR of the activated mutant body or resistant mutant forms is selected from L858R activated mutants body, Exon19 missings swash
Mutant and T790M resistant mutants living.
The compound of the logical formula (I) of the present invention can be combined to the known other drugs for treating or improving similar symptom.Connection
When closing administration, originally the administering mode of medicine and dosage are kept constant, and subsequently or simultaneously take formula (I) compound.Work as formula
(I) compound and other one or more of medicines are taken simultaneously when, preferably using simultaneously containing one or more of known drugs and
The Pharmaceutical composition of formula (I) compound.Drug combination is also included within the overlapping period and takes formula (I) compound and other one kind
Or several known drugs.When formula (I) compound carries out drug combination with other one or more of medicines, formula (I) compound or
The dosage when dosage of known drug may be than their independent medications is low.The medicine of drug combination can be carried out with formula (I) compound
Thing or active component include but is not limited to following material：
Estrogenic agents, androgen receptor adjustment, retina receptor modulators, cytotoxin/cytostatics,
Antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitors, reverse transcriptase suppress
Agent, angiogenesis inhibitors, cell propagation and survival signaling inhibitor, the medicine of interference cell cycle check and Apoptosis lure
Lead agent, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine protein suppression
Preparation, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, topology are different
Structure enzyme inhibitor, Histone deacetylase inhibitor, protesome inhibitors, CDK inhibitor, Bcl-2 family proteins suppress
Agent, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitor, ATK suppress
Agent, integrin retarding agent, interferon, IL-12, cox 2 inhibitor, P53, P53 activator, VEGF antibody and EGF resist
Body etc..
In one embodiment, can with formula (I) compound carry out drug combination medicine or active component include but
It is not limited to following material：Aldesleukin, alendronic acid, interferon, Ah Qu Nuoying, Allopurinol, allopurinol sodium, Pa Luonuosi
Fine jade hydrochloride, hemel, amino glutethimide, peace phosphorus spit of fland, peace it is soft than star, SN-11841, arimidex, Dolasetron,
Aranesp, arglabin, arsenic trioxide, A Nuoxin, U-18496, imuran, BCG vaccine or tice BCG vaccines, Beta
Fixed, betamethasone acetate, betamethasone sodium phosphate inhibitor, bexarotene, Bleomycin Sulphate, broxuridine, bortezomib, card
Luxuriant and rich with fragrance left rice, busulfan, calcitonin, A Laizuo monoclonal antibodies injection, capecitabine, carboplatin, Kang Shi get, cefesone, Xi Mobai are situated between
Element, daunorubicin, Chlorambucil, cis-platinum, Cladribine, chlorine bend phosphoric acid, endoxan, cytarabine, Dacarbazine, unwrapping wire
Rhzomorph D, daunorubicin liposome, dexamethasone, dexamethasone phosphate, Estradiol Valerate, denileukin diftitox, Di Bomei, Lip river
Rayleigh, La Zuosheng, diethylstilbestrol, Fluconazole, docetaxel, doxifluridine, adriamycin, Dronabinol, admire -166- shells gather
Saccharide complex, eligrand, rasburicase, epirubicin hydrochloride, aprepitant, Epi-ADM, Epoetin Alfa, red blood cell life
Cheng Su, eptalatin, Ergamisole, estradiol inhibitor, 17- stand enzyme estradiol, estramustine phosphate sodium, female alkynol, Amifostine,
Hydroxyl phosphoric acid, Etopophos, etoposide, Fadrozole, tamoxifen preparation, Filgrastim, Tamsulosin, Fei Leisi are replaced, floxuridine,
Fluconazole, fludarabine, 5- fluorodeoxyuridines monophosphate, 5 FU 5 fluorouracil, Fluoxymesterone, Flutamide, good fortune Mace
Smooth, 1- pyrimidines, the furans hard acyl of arabinofuranosylcytosine -5 phosphate, Fotemustine, fluorine Wei Siqiong, gamma globulin, Ji
His shore, WAY-CMA 676, imatinib mesylate, carmustine wafer capsule, Ge Shelinrui, hydrochloric acid glug Ni Xi Gansu Province, histamine of west
Rayleigh and U.S. are new, hydrocortisone, erythro-hydroxynonyl adenine, hydroxycarbamide, for smooth different shellfish not monoclonal antibody, idarubicin, different
Endoxan, interleukin 2, intron A, Iressa, Irinotecan, Kytril, sulfuric acid lentinan, Letrozole, formyl
Tetrahydrofolic acid, Leuprorelin, leuprolide acetate, L-tetramisole, levo leucovorin calcium salt, levothyroxine sodium, Zuo Jia
Shape parathyrine preparation of sodium, lomustine, Lonidamine, Dronabinol, mustargen, Mecobalamin, medroxyprogesterone acetate, tumer it is pregnant
Ketone, melphalan, esterified estriol, Ismipur, mesna, methotrexate, amino-laevulic acid methyl esters, replace the good fortune new, beautiful
Pleomycin, mitomycin C, mitotane, rice support green onion quinone, Trilostane, citric acid Evacet, Nedaplatin, polyethylene glycol
Change Filgrastim, oprelvekin, neupogen, Nilutamide, TAM, NSC-631570, combining human interleukins
Plain 1- groups, Octreotide, Ondansetron Hydrochloride, dehydrohydro-cortisone oral solution, oxaliplatin, taxol, metacortandracin phosphorus
Sour preparation of sodium, Pegaspargase, PEG-IFN alpha-2a, Pentostatin, Picibanil, hydrochloric acid pilocarpine, adjoin it is soft than star, plicamycin,
Porfimer Sodium, prednimustine, Prednisolone Steaglate, metacortandracin, premarin, the third kappa navel, epoetin,
Thunder carries Qu Sai, Libiee, etidronate rhenium -186, Mabthera, Redoxon-U.S., Romurtide, Salagen, song difficult to understand
Peptide, sargramostim, Semustine, sizofiran, Sobuzoxane, bluff sodium methylprednisolone, Paphos acid, stem-cell therapy, streptozotocin, chlorine
Change strontium -89, levoid, TAM, YM-617, Ta Suonaming, tastolactone, taxotere, for western sulphur
Tianjin, Temozolomide, Teniposide, testosterone propionate, thioguanine, thio-tepa, thyrotropic hormone, for Shandong phosphoric acid, TPT,
Toremifene, tositumomab, Herceptin, Treosulfan, Tretinoin, methylamine dish purine tablet, trimethyl melamine, front three are bent
Sand, acetic acid Triptorelin, triptorelin pamoate, excellent good fortune pyridine, uridine, valrubicin, Vesnarinone, vincaleukoblastinum, Changchun are new
The protein stabilized system of alkali, Vindesine, vinorelbine, virulizin, dextropine imine, Zinostatin stimalamer, ondansetron, taxol
Agent, acolbifene, affinitak, amino dish purine, arzoxifene, asoprisnil, atamestane, BAY43-9006, A Wa
This fourth, CCI-779, CDC-501, Celebrex, Cetuximab, carat that support, cyproterone acetate, Decitabine, DN-
101/ adriamycin-MTC, dSLIM, dutasteride, edotecarin, Eflornithine, Exatecan, Suwei A amine, histamine disalt
Hydrochlorate, Supprelin hydrogel implant, holmium -166DOTMP, ibandronic acid, ixabepilone, keyhole shape hemocyanin, L-
651582nd, lanreotide, lasofoxifene, libra, lonafamib, Miproxifene, minot bend acid esters, MS-209, liposome MEP-
PE, MX-6, nafarelin, Nemorubicin, Neovastat, Nola Qu Te, oblimersen, onco-TCS, osidem, taxol
Polyglutamic acid esters, pamidronate disodium injection, PN-401, OS-21, overstate the West, R-1549, Raloxifene, ranpirnase, isotretinoin, sand
Platinum, seocalcitol, T-138067, tarceva, docosahexaenoic acid taxol, extrasin alpha, loud, high-pitched sound azoles furan woods,
Tipifarnib, for pulling eye is bright, TLK-286, Toremifene, trans MID-lo7R, valspodar, Vapreotide, vatalanob,
Verteporfin, vinflunine, Z-100 and Zoledronate or their combination.
Present invention also offers a kind of pharmaceutical composition, the pharmaceutical composition includes the compound or its medicine of the formula (I)
Acceptable salt and pharmaceutically acceptable auxiliary material or carrier on.Used herein of phrase " pharmaceutically acceptable auxiliary material or
Carrier " refers to pharmaceutically acceptable material, composition or medium, such as liquid or solid filler, diluent, auxiliary material, solvent or package material
Material, including main pharmaceutical examination is carried or transported from certain part of an organ or body to certain part of another organ or body
Agent.Each carrier must be " can receive ", can compatible other forms pharmaceutical compositions and patient is not damaged.Some can
Example as pharmaceutically acceptable carrier includes：Sugar, such as lactose, dextrose and saccharose sugar；Starch, such as wheaten starch and
Farina starch；Cellulose and its derivates, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, powdery west
Bassora gum, malt, gelatin, talcum powder；Auxiliary material, such as cocoa butter and suppository wax；Oil, such as peanut oil, cottonseed oil, safflower oil, sesame
Sesame oil, olive oil, corn oil and soya-bean oil；Glycol, such as butanediol；Polyalcohol, such as glycerine, sorbierite, mannitol and polyethylene glycol；
Ester, such as ethyl oleate and ethyl laurate；Agar；Buffer, such as magnesium hydroxide and aluminium hydroxide；Alginic acid；Apirogen water；It is raw
Manage salt solution；Ringer's solution；Ethanol；Phosphate buffer, and other nontoxic compatible materials applied in pharmaceutical preparation.
When the compound of the present invention is treated as medicament to human and animal, they can be in itself or as medicine
Composition and be administered.For example, the active component comprising 0.1%-99.5% (preferably 0.5%-90%) and pharmaceutically acceptable
Carrier.
The compound of the present invention intramuscular injection, can be injected intraperitoneally, be subcutaneously injected, external application by intravenous injection, orally, or
Other acceptable methods treat disease.
Present invention also offers Key works Drug packing or external member, including one or more packagings, wherein containing in the present invention
The drug regimen of one or more compositions.Optional such packaging is produced in the form of announcing by government organs' specification, with production
The open method permitted in regulation uses or sale medicine or biological products, the treatment preparation of use or sale to people.
Compared with prior art, beneficial effects of the present invention are：
The deuterated compound of the present invention, with AZD9291 similar in enzyme and cellular level bioactivity and with lower
Cardiac toxic.The deuterated compound of the present invention provides more choices for new type antineoplastic medicine, has good medicine
Application prospect.
Embodiment
Representational example is intended to help and illustrates the present invention below, rather than also should not be construed as limited to this intentionally
The scope of invention.In fact, in addition to those occur and be described herein, the full content of file in the present invention, including according to
It is further change according to the example of scientific and technical literature cited herein and patent, and resulting various modifications and many to originally special
Those skilled in the art are clearly clear in the industry.It should also be appreciated that the reference of these bibliography helps to state in this paper
Hold.Following example contains important side information, example and guidance, is adaptable to various change and similar feelings in the present invention
Condition.
Embodiment 1
Synthetic route is as follows：
Compound 1
Take 250mL single-necked flasks, be separately added into N- methylethanolamines (10g, 133.1mmol), TEA (26.9g,
266.3mmol), acetonitrile (100mL), benzyl chloride (23.9g, 139.8mmmol) is slowly then added drop-wise to reaction solution at 0 DEG C
In, and continue to stir 1h at room temperature, TLC monitorings are evaporated under reduced pressure without starting material left and remove solvent, column chromatography purifies to obtain 21g
Colourless liquid is compound 1, yield 95.5%.
Compound 2
250mL eggplant type bottles are taken, add compound 1 (21g, 127.1mmol), TEA (25.7g, 254.2mmol) and DCM
(100ml), MsCl (14.6g, 127.1mmol) is then added dropwise at 0 DEG C.Reaction solution is stirred at room temperature 3h, TLC monitorings without
Starting material left, is evaporated under reduced pressure and removes solvent, and column chromatography purifies to obtain 20g weak yellow liquids i.e. compound 2, yield 85.6%.
Compound 3
Take 500mL tube sealings, add compound 2 (20g, 108.9mmol), ammoniacal liquor 215mL, mixed liquor is stirred at 40 DEG C
Night, TLC are monitored without starting material left, and column chromatography purifies to obtain 15g colourless liquids i.e. compound 3, yield 84%.
Compound 4
500mL eggplant type bottles are taken, compound 3 (15g, 91.3mmol), DCM (200mL) is added, is slowly added dropwise at room temperature
Boc2O (19.9g, 91.3mmol), rear mixed liquor is added dropwise and continues to stir 3h at room temperature, TLC is monitored without starting material left, subtracted
Solvent is distilled off in pressure, and column chromatography purifies to obtain 21g compounds 4, is white solid, yield 87%.
Compound 5
100mL eggplant type bottles are taken, compound 4 (10g, 37.8mmol), DMF (40mL) is added, NaH is then added portionwise
(2.3g, 56.7mmol), 30mins is stirred, add TsOCD3DMF (10mL) solution of (7.9g, 41.6mmol), then room temperature
Lower stirring 3h, TLC monitoring add 150mL H without starting material left2O is quenched, and EA (50mL*3) extractions, merges organic phase, brine
Wash, anhydrous Na2SO4Dry, be evaporated under reduced pressure away solvent, column chromatography purifies to obtain 8.5g i.e. compound 5, is white solid, yield
For 80%.
Compound 6
250mL eggplant type bottles are taken, compound 5 (8.5g, 30.18mmol), THF (80ml) is added, is added portionwise under ice bath
LiAlH4(3.4g, 90.59mmol), it is then heated to 60 DEG C overnight, TLC is monitored without starting material left, is slowly added to Na2SO4·
10H2O is quenched, and is removed by filtration solid, collects filtrate, is evaporated under reduced pressure and removes solvent, and column chromatography purifies to obtain 4.5g colourless liquids i.e.
Compound 6, yield 76.3%.
Compound 7
100mL eggplant type bottles are taken, are separately added into compound 6 (4.5g, 23mmol), MeOH (50mL), Pd (OH)2/C
(200mg), vacuumize and change hydrogen 3 times, be stirred overnight at room temperature, TLC is monitored without starting material left, is removed by filtration Pd (OH)2/ C,
Then reacting liquid pH value is transferred to acidity, is evaporated under reduced pressure removing solvent and obtains 2.8g white solids i.e. compound 7, yield
85.9%.
Compound 8
250mL eggplant type bottles are taken, are separately added into 2,4- dichloro pyrimidines (11.37g, 76.33mmol), AlCl3(10.18g,
76.33mmol) and 100mLDME, stir 20 minutes at room temperature.Then be added portionwise compound 8-01 (10.00g,
63.61mmol), 80 degree of reaction 6h are risen to.Stop reaction and be cooled to room temperature, add 100 milliliters of water, stir 2h, filtering, solid is used
Ethanol washs, and is dried in vacuo to obtain the red i.e. compound 8-02 of 15.46 grams of crude product, yield 90.1%.
Take 300mL1,4- dioxane in 500mL eggplant type bottles, be separately added into compound 8-02 (20.00g,
82.07mmol), compound 8-03 (16.80g, 90.28mmol) and p-methyl benzenesulfonic acid (17.17g, 90.28mmol).Rise to 85
Degree reaction 8h, is cooled to room temperature, adds water to stir, and 40% sodium hydroxide solution is added dropwise and is filtered to pH=9., and solid is washed with ethanol
Wash, after vacuum drying yellow solid 30.00g is compound 8, yield 92.9%.
Compound 9
Take 120mL tube sealings, add compound 8 (2g, 4.77mmol), 7 (810mg, 5.72mmol), DIPEA (1.23g,
9.54mmol)、DMA(10mL).Then 140 DEG C of tube sealing reacts 6h, and TLC is monitored without starting material left, and reaction solution is cooled into room temperature,
20mL water is added, separates out solid, then filtering adds filter cake adding the mashing washing of 2mL methanol, filtering, drying obtain 1.7g
Red solid is compound 9, yield 70.6%.
Compound 10
250mL single-necked flasks are taken, compound 9 (1.7g, 3.37mmol), Pd/C (200mg), MeOH (100mL) is added, takes out
Vacuum changes hydrogen 3 times, is stirred overnight at room temperature, and TLC monitorings without starting material left, are removed by filtration Pd/C, and it is molten to be evaporated under reduced pressure removing
Agent obtains greenish yellow solid, column chromatography purifying, eluant, eluent (DCM：MeOH：NH3H2O=20:1:0.1) elute, it is yellowish green to obtain 1.2g
Color solid is compound 10, yield 75%.
Compound 11
20mL single-necked flasks are taken, compound 10 (500mg, 1.05mmol), DCM (30mL) are added, then by 3- chlorine propionyl
Chlorine (133.7mg, 1.05mmol), is slowly added drop-wise in reaction solution at 0 DEG C, and continues to stir 30min, TLC prisons at room temperature
Survey without starting material left, then add NaOH (168mg, 4.2mmol), be warming up to 65 DEG C and be stirred overnight, HPLC monitorings remain without raw material
It is remaining, it is evaporated under reduced pressure and removes solvent, column chromatography purifying, eluant, eluent (DCM：MeOH=10:1) 280mg faint yellow solids are afforded
That is compound 11, yield 50.4%.
1H NMR (400MHz, CDCl3) δ 10.19 (s, 1H), 9.88 (s, 1H), 9.12 (s, 1H), 8.39 (d, J=
5.3Hz, 1H), 7.85 (d, J=8.0Hz, 1H), 7.74 (s, 1H), 7.26-7.14 (m, 2H), 7.00 (d, J=7.0Hz, 1H),
6.82 (s, 1H), 6.49 (dd, J=16.9,2.2Hz, 1H), 6.39 (dd, J=16.9,9.8Hz, 1H), 5.73 (dd, J=
9.8,2.2Hz, 1H), 4.49-4.32 (m, 2H), 3.91 (s, 3H), 3.05 (t, J=6.0Hz, 2H), 2.95-2.87 (m, 2H),
2.73(s,3H),2.39–2.23(m,7H),1.82(s,3H).LC-MS[M+H]+528.7
Embodiment 2
Synthetic route is as follows：
Compound 12
Take 120mL tube sealings, add compound 8 (500mg, 1.19mmol), N- methylethanolamines (107.26mg,
1.42mmol), DIPEA (307.59mg, 2.38mmol), DMA (5mL).Then 140 DEG C of reaction 6h, TLC monitorings of tube sealing are without raw material
Residue, reaction solution is cooled to room temperature, adds 20mL water, separated out solid, filtering, then add and beat filter cake addition 2mL methanol
Plasm scouring, filtering, drying obtain 480mg red brown solids i.e. compound 12, yield 85%.
Compound 13
20mL eggplant type bottles are taken, add compound 12 (450mg, 1.05mmol), TEA (159.39mg, 1.57mmol) and DCM
(5ml).MsCl (120.28mg, 1.05mmol) is slowly added dropwise at 0 DEG C, is stirred at such a temperature after being added dropwise, TLC is supervised after 1h
Survey without starting material left, be evaporated under reduced pressure and remove solvent, column chromatography purifies to obtain 320mg red solids i.e. compound 13, yield
55.15%.
Compound 14
Take 5mL tube sealings, add compound 13 (220mg, 0.40mmol), deuterated dimethylamine (175.16mmg, 2mmol),
DIPEA (103.39mg, 0.8mmol), THF (2mL), it is stirred overnight at 80 DEG C, TLC monitorings without starting material left, are evaporated under reduced pressure
Remove solvent and obtain red solid, column chromatography purifying, eluant, eluent (DCM：MeOH：NH3H2O=40:1:0.1) elute, obtain 90mg
Red solid is compound 14, yield 44.32%.
Compound 15
250mL single-necked flasks are taken, compound 14 (90mg, 0.18mmol), Pd/C (30mg), MeOH (10mL) is added, takes out
Vacuum changes hydrogen 3 times, is stirred overnight at room temperature, and TLC monitorings without starting material left, are removed by filtration Pd/C, and it is molten to be evaporated under reduced pressure removing
Agent obtains greenish yellow solid, column chromatography purifying, eluant, eluent (DCM：MeOH：NH3H2O=20:1:0.1) elute, it is yellowish green to obtain 40mg
Color solid is compound 15, yield 46.53%.
Compound 16
10mL single-necked flasks are taken, compound 15 (40mg, 0.08mmol), DCM (4mL) are added, then by 3- chlorpromazine chlorides
(10.63mg, 0.08mmol) is slowly added drop-wise in reaction solution at 0 DEG C, and continues to stir 30min, TLC monitoring nothings at room temperature
Starting material left, NaOH (16mg, 0.4mmol) is then added, 65 DEG C is warming up to and is stirred overnight, HPLC is monitored without starting material left, is subtracted
Solvent, column chromatography purifying, eluant, eluent (DCM is distilled off in pressure：MeOH：NH3H2O=40:1:0.1) it is faint yellow to afford 38mg
Solid is compound 16, yield 89.34%.
1H NMR (400MHz, CDCl3) δ 10.12 (s, 1H), 9.88 (s, 1H), 9.10 (s, 1H), 8.39 (d, J=
5.2Hz, 1H), 7.86 (d, J=8.0Hz, 1H), 7.74 (s, 1H), 7.19 (dd, J=17.1,6.5Hz, 2H), 7.00 (d, J=
6.9Hz, 1H), 6.81 (s, 1H), 6.46 (d, J=8.4Hz, 2H), 5.73 (dd, J=8.6,3.1Hz, 1H), 4.51-4.28
(m, 2H), 3.90 (s, 3H), 3.05 (t, J=5.6Hz, 2H), 2.98-2.87 (m, 2H), 2.72 (s, 3H), 2.31 (dd, J=
16.4,11.2Hz,4H).LC-MS[M+H]+531.7
Embodiment 3
Synthetic route is as follows：
Compound 17
2L three-necked bottles are taken, are separately added into CD3OH (15g, 415.8mmol), THF (600mL).Then at -40 DEG C slowly
N-BuLi (174.6mL, 436.6mmol) is added dropwise.The tetrahydrofuran that TsCl (79.3g, 415.8mmol) is added dropwise after stirring 1h is molten
Liquid, continue to stir 3h after being added dropwise, TLC is monitored without starting material left.Add 600mLH2O is quenched, EA extractions (200mL*3),
Brine is washed, anhydrous Na2SO4Dry, merge organic phase, vacuum distillation removes solvent and obtains crude compound, and column chromatography purifies
It is compound 17 to 73 grams of white solids, yield 92.7%.
Compound 18
Take 250mL eggplant type bottles, be separately added into compound 17 (8g, 42.3mmol), N- benzyl ethyl alcohols amine (5.3g,
35.2mmol), triethylamine (9.8ml, 70.4mmol), tetrahydrofuran (100mL).Mixed liquor reacts 8h, TLC monitorings under reflux
Without starting material left, it is evaporated under reduced pressure and removes solvent, column chromatography purifies to obtain 5g colourless viscous liquids i.e. compound 18, yield
84.4%.
Compound 19
50mL eggplant type bottles are taken, are separately added into compound 18 (3g, 15.87mmol), triethylamine (3.2g, 31.74mmol), two
Chloromethanes (20mL), methane sulfonyl chloride (2.18g, 19.05mmol) is then slowly added dropwise at 0 DEG C, reaction solution stirs at room temperature
3h is mixed, TLC monitorings are evaporated under reduced pressure removing solvent and obtain light yellow viscous liquid, column chromatography purifies to obtain 2.8g without starting material left
Weak yellow liquid is compound 19, yield 71.6%.
Compound 20
10mL tube sealings are taken, are separately added into compound 19 (2.8g, 11.37mmol), dimethylamine solution (1.5mL), THF
(3mL).Mixed liquor stirs 5h at 80 DEG C, and TLC is monitored without starting material left.The dilution of 5mL water is added, ethyl acetate (5mL*3), is closed
And organic phase, saturated common salt water washing, anhydrous Na2SO4Dry, be evaporated under reduced pressure and remove solvent, it is colourless that the middle standby purifying of compacting obtains 2g
Liquid is compound 20, yield 75%.
Compound 21
100mL eggplant type bottles are taken, are separately added into compound 20 (2g, 10.2mmol), 10% palladium carbon (500mg), methanol
(30mL), 35 DEG C of stirring under hydrogen are stayed overnight, and TLC monitorings filter solid, HCl (in EA) is added dropwise extremely in filtrate without starting material left
PH is acidity, is evaporated under reduced pressure removing solvent and obtains 900mg white solids i.e. compound 21, yield 62.3%.
Compound 22
120mL tube sealings are taken, add compound 8 (965mg, 2.3mmol), 21 (467mg, 2.76mmol), diisopropyl second
Amine (1.18g, 9.2mmol), DMA (5mL).Then 140 DEG C of reaction 6h, TLC monitorings of tube sealing cool down reaction solution without starting material left
To room temperature, 20mL water is added, solid is separated out, filtering, then adds and filter cake is added into the mashing washing of 2mL methanol, filter, dry
It is compound 22 to 900mg red solids, yield 77.5%.
Compound 23
250mL single-necked flasks are taken, add compound 22 (900mg, 1.78mmol), Pd/C (300mg), MeOH (100mL),
Vacuumize and change hydrogen 3 times, be stirred overnight at room temperature, TLC monitorings without starting material left, are removed by filtration Pd/C, are evaporated under reduced pressure and remove
Solvent obtains greenish yellow solid, column chromatography purifying, eluant, eluent (DCM：MeOH：NH3H2O=20:1:0.1) elute, obtain 600mg
Greenish yellow solid is compound 23, yield 71%.
Compound 24
20mL single-necked flasks are taken, add compound 23 (300mg, 0.63mmol), THF (6mL) and H2O (1mL), then will
3- chlorpromazine chlorides (80.36mg, 0.63mmol) are slowly added drop-wise in reaction solution at 0 DEG C, and continue to stir at room temperature
30min, TLC are monitored without starting material left, are then added NaOH (100.8mg, 2.52mmol), are warming up to 65 DEG C and are stirred overnight,
HPLC monitorings are evaporated under reduced pressure without starting material left and remove solvent, column chromatography purifies, eluant, eluent (DCM：MeOH=10:1), elute
It is compound 24 to 170mg faint yellow solids, yield 51%.
1H NMR (400MHz, CDCl3) δ 10.07 (s, 1H), 9.87 (s, 1H), 9.10 (s, 1H), 8.39 (d, J=
5.3Hz, 1H), 7.85 (d, J=8.0Hz, 1H), 7.75 (s, 1H), 7.25-7.14 (m, 2H), 7.00 (d, J=7.0Hz, 1H),
6.80 (s, 1H), 6.57-6.38 (m, 2H), 5.74 (dd, J=8.2,3.8Hz, 1H), 4.49-4.30 (m, 2H), 3.91 (s,
3H), 3.05 (t, J=6.0Hz, 2H), 2.98-2.89 (m, 2H), 2.42-2.21 (m, 13H) .LC-MS [M+H]+528.7
Embodiment 4：The biological activity test of the compound of preparation
Such compound is to EGFR wild types, EGFR (T790M, L858R) double-mutants and EGFR (L858R) single mutation
The kinase activity IC of type50Test.Above-mentioned kinases is purchased in Invitrogen (Shanghai) Trading Co., Ltd..
It is double prominent that EGFR wild types, EGFR (T790M, L858R) are established using the method for homogeneous phase time discrimination fluorescence (HTRF)
Modification and the kinase activity detection method of EGFR (L858R) single mutation type, determine the inhibitory activity of compound.Configure 8uL's
Reaction solution, including 1 × enzymatic buffer (Cisbio, HTRF KinEASETM- TK), 5mM MgCl2, 1mM MnCl2,
1mM DTT, 0.5 μM of TK substrate-biotin (Cisbio, HTRF KinEASETM-TK), 10 μM of ATP, gradient concentration
Compound and 0.04ng/ μ L EGFR or 0.025ng/ μ L EGFR (T790M, L858R) or EGFR (L858R).Chemical combination
Thing reaction density is that 1000nM plays 3 times of dilutions, 9 concentration.DMSO concentration is 2% in reaction system.Enzyme and compound preincubate 15
Minute, then add ATP and substrate starts to react.All enzymic catalytic reactions are carried out 60 minutes all at 25 DEG C.Enzymic catalytic reaction
4 μ L TK antibody-cryptate and 4 μ L streptavidin-XL665 (reaction densities are added after end, in reaction solution
For 62.5nM), continue to be incubated 60 minutes at 25 DEG C.Incubation detects HTRF after terminating on CLARIOstar (BMG LABTECH)
Fluorescent value, and calculate IC using GraphPad Prism 5.050。
The external zymetology active testing data (IC of table 150, nM)
The present invention deuterated compound, have with AZD9291 similar in enzyme bioactivity.
EGFR wild types, EGFR Exon19 missing (activation single mutant) and EGFR (T790M, L858R) double-mutants
Cells phosphorylation is tested
Test 1：EGFR wild-type cells phosphorylation is test
Application on human skin squamous cell carcinoma line A431 expresses Wild type EGFR, from Chinese Academy of Sciences's cell bank purchase.Will
A431 is maintained in the EMEM culture mediums containing 10% hyclone.Cell is set to have 5%CO2Humidified incubator in 37 DEG C
Growth.According to the scheme described in Phospho-EGFR HTRF kit (Cisbio, article No. #64HR1PEG), detection cell cracking
Endogenous p-EGFR in liquid.100 μ L cells are inoculated in 96 orifice plates (50000 cells/well), in 37 DEG C, 5%CO2Cell is trained
Support overnight incubation in case.The compound of continuous 4 times dilutions is added in cell, reaction maximum concentration is 10 μM.It is small to continue culture 2
Shi Hou, the EGF for adding 100ng/ holes are cultivated 10 minutes in 37 DEG C, then discard nutrient solution, and add 25 μ L/ porous dehiscence solutions immediately
Liquid, in lysis at room temperature cell 10 minutes, then take 12 μ L/ holes to add in the orifice plate of Greiner whites low volume 384, add detection
Antibody (Anti-phospho EGFR-d2 and Anti-EGFR-Tb), it is incubated 60 minutes at 25 DEG C.Incubation terminate after
HTRF fluorescent values are detected on CLARIOstar (BMG LABTECH), and IC is calculated using GraphPad Prism 5.050。
Test 2：Exon19 missing EGFR (activation single mutant) cells phosphorylation tests
Non-small cell lung carcinoma cell line HCC827 (Exon19 lacks EGFR, activates single mutant) is thin from the Chinese Academy of Sciences
Buy in born of the same parents storehouse.HCC827 is maintained containing in 10% hyclone RPMI1640 culture mediums.Cell is set to have 5%CO2Plus
In 37 DEG C of growths in wet incubator.Described in Phospho-EGFR HTRF kit (Cisbio, article No. #64HR1PEG)
Scheme, detect endogenous p-EGFR in cell pyrolysis liquid.100 μ L cells are inoculated in 96 orifice plates (50000 cells/well), in
37 DEG C, 5%CO2Overnight incubation in cell culture incubator.The compound of continuous 4 times dilutions is added in cell, reacts maximum concentration
For 10 μM.Nutrient solution is discarded after continuing culture 2 hours, and adds 25 μ L/ holes lysates immediately, is divided in lysis at room temperature cell 10
Clock, then take 12 μ L/ holes to add in the orifice plate of Greiner whites low volume 384, add detection antibody (Anti-phospho
EGFR-d2 and Anti-EGFR-Tb), it is incubated 60 minutes at 25 DEG C.Incubation terminate after at CLARIOstar (BMG LABTECH)
Upper detection HTRF fluorescent values, and calculate IC using GraphPad Prism 5.050。
Test 3：EGFR (T790M, L858R) double-mutants cells phosphorylation is test
Non-small cell lung carcinoma cell line NCI-H1975 expresses EGFR (T790M, L858R) double-mutant, from Chinese science
Institute's cell bank purchase.NCI-H1975 is maintained containing in 10% hyclone RPMI1640 culture mediums.Cell is set to have 5%
CO2Humidified incubator in 37 DEG C growth.According in Phospho-EGFR HTRF kit (Cisbio, article No. #64HR1PEG)
The scheme of description, detect endogenous p-EGFR in cell pyrolysis liquid.100 μ L cells are inoculated in 96 orifice plates (50000 cells/
Hole), in 37 DEG C, 5%CO2Overnight incubation in cell culture incubator.The compound of continuous 4 times dilutions is added in cell, reaction is most
High concentration is 10 μM.Nutrient solution is discarded after continuing culture 2 hours, and adds 25 μ L/ holes lysates immediately, in lysis at room temperature cell
10 minutes, then take 12 μ L/ holes to add in the orifice plate of Greiner whites low volume 384, add detection antibody (Anti-phospho
EGFR-d2 and Anti-EGFR-Tb), it is incubated 60 minutes at 25 DEG C.Incubation terminate after at CLARIOstar (BMG LABTECH)
Upper detection HTRF fluorescent values, and calculate IC using GraphPad Prism 5.050。
The cellular level EGFR of table 2 is wild and mutant phosphorylation tests (IC50, nM)
The present invention deuterated compound, have with AZD9291 similar in cellular level bioactivity.
Embodiment 9：The test that the compound of preparation is acted on hERG potassium-channels
The HEK293 cell culture of stable expression hERG passages is in 35mm culture dishes, in 37 DEG C/5%CO2In incubator
It is used to test after placing at least 24 hours.Cell culture medium is the DMEM containing 10% hyclone and 250 μ g/mL G418.
The composition of extracellular fluid is (mM) used in whole-cell patch-clamp experiment：NaCl,137；KCl,4；CaCl2,1.8；
MgCl2,1；HEPES,10；glucose 10；PH 7.4 (NaOH titration).All test compounds and control compound solution are equal
Containing 0.3%DMSO.Intracellular fluid (mM) is：K Aspartate,130；MgCl2,5；EGTA 5；HEPES,10；Tris-ATP
4；PH 7.2 (KOH titration).
A culture dish is taken out in experiment every time, is cleaned twice, is positioned on inverted microscope objective table with extracellular fluid.Entirely
Membrane elastic property experiment is carried out at room temperature, and Pyrex microelectrode tip resistance used is 3~5M Ω.Whole-cell recording technique pattern
Afterwards, film potential is clamped down in -80mV, every 30s give cell+50mV depolarizing voltages stimulate, continue 2s after repolarization to -
50mV, continue 3s, you can draw hERG tail currents.Before depolarizing voltage stimulates, cell 50ms, -50mV repolarization electricity are first given
Press, the electric current recorded under the voltage is as the baseline for calculating hERG tail currents.Before adding compound, hERG tail currents are extracellular
At least stable recording 3 minutes in liquid.When the change of hERG tail currents amplitude is less than after perfusion administration<When 5%, it is considered as medicine effect
Reach stable state.Data acquisition and issuance uses the software programs of pCLAMP 10.1.Choose electric current before adding compound and be in stable state
4~5 sweep, peak average value is calculated, as control current amplitude.Choose add compound after electric current be in stable state 4~
5 sweep, peak average value is calculated, the remaining amplitude after being suppressed as electric current.Suppression of the testing compound to hERG electric currents
Rate is calculated according to below equation：
% inhibiting rates={ 1- (electric current residue amplitude)/(control current amplitudes) } × 100
Inhibiting rate (average value ± standard of the multiple concentration of testing compound to hERG electric currents is obtained according to above-mentioned computational methods
Difference) after, data are fitted using logistic equations, obtain IC50Value.
The IC that the compound of table 3 suppresses in cellular level to hERG potassium-channels50(μM)
| Compound ID | IC50 |
| AZD9291 | 0.37 |
| Compound 11 | 1.85 |
| Compound 16 | 2.67 |
| Compound 24 | 1.97 |
The deuterated compound of the present invention, has lower cardiac toxic relative to AZD9291.
Claims (10)
1. compound or its pharmaceutically acceptable salt with formula (I) structure,
Wherein,
R1,R2,R3And R4Independently selected from-CH3Or-CD3, and R1,R2,R3And R4At least one is-CD3。
2. the compound according to claim 1 with formula (I) structure, it is characterised in that R1For-CH3。
3. compound or its pharmaceutically acceptable salt, wherein compound are selected from：
4. according to the compound according to any one of claims 1 to 3 with formula (I) structure or its is pharmaceutically acceptable
Salt, wherein the pharmaceutically acceptable salt is selected from acetate, adipate, alginate, ascorbate, aspartic acid
Salt, benzoate, benzene sulfonate, tosilate, disulfate, borate, butyrate, citrate, camphor salt, camphor
Sulfonate, cyclopentane propionate, diethylene glycol (DEG) hydrochlorate, lauryl sulfate, ethane sulfonate, fumarate, glucoheptonic acid
Salt, glycerophosphate, enanthate, caproate, hydrochloride, hydrobromate, hydriodate, isethionate, lactate, Malaysia
Hydrochlorate, mesylate, naphthalene sulfonate, nicotinate, nitrate, oxalates, pectate, persulfate, phenpropionate, phosphoric acid
Salt, picrate, Pivalate, propionate, salicylate, succinate, sulfate, sulfonate, tartrate, thiocyanic acid
Salt.
5. a kind of pharmaceutical composition, it includes such as the compound according to any one of claims 1 to 4 with formula (I) structure
Or its pharmaceutically acceptable salt, and pharmaceutically acceptable auxiliary material.
6. the compound with formula (I) structure or its pharmaceutically acceptable salt in Claims 1 to 4 described in any one exist
Prepare the purposes in terms for the treatment of or prevention tumour medicine.
7. purposes according to claim 6, wherein the tumour be selected from non-small cell lung cancer, ED-SCLC, cancer of pancreas,
Breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, GISTs, leukaemia, histiocytic lymph cancer or nose
Pharynx cancer.
8. the compound according to any one of claims 1 to 4 with formula (I) structure or its pharmaceutically acceptable salt are being made
It is ready for use on and treats or prevents by EGFR mediations or by the EGFR of activated mutant body or resistant mutant forms mediations disease, barrier
Hinder, the purposes of disorderly or the patient's condition medicine.
9. purposes according to claim 8, wherein it is described by EGFR mediations or by activated mutant body or resistant mutants
Disease, obstacle, disorder or the patient's condition of the EGFR mediations of form are selected from non-small cell lung cancer, ED-SCLC, cancer of pancreas, mammary gland
Cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, GISTs, leukaemia, histiocytic lymph cancer or nasopharynx
Cancer.
10. purposes according to claim 8, wherein the EGFR of the activated mutant body or resistant mutant forms is selected from
L858R activated mutants body, Exon19 missing activated mutant bodies and T790M resistant mutants.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610833361.3A CN107840847A (en) | 2016-09-19 | 2016-09-19 | Deuterated 3 (4,5 substituted-amino pyrimidine) phenyl derivatives and its application |
| EP17850310.8A EP3498708B1 (en) | 2016-09-19 | 2017-09-18 | Deuterated 3-(4,5-substituted pyrimidinamine) phenyl derivatives and applications thereof |
| CA3037097A CA3037097C (en) | 2016-09-19 | 2017-09-18 | Deuterated 3-(4,5-substituted aminopyrimidine) phenyl derivatives and use thereof |
| AU2017326029A AU2017326029B2 (en) | 2016-09-19 | 2017-09-18 | Deuterated 3-(4,5-substituted pyrimidinamine) phenyl derivatives and applications thereof |
| JP2019536634A JP6746794B2 (en) | 2016-09-19 | 2017-09-18 | Deuterated 3-(4,5-substituted aminopyrimidine)phenyl derivatives and uses thereof |
| KR1020197007580A KR102245280B1 (en) | 2016-09-19 | 2017-09-18 | Deuterated 3-(4,5-substituted aminopyrimidine) phenyl derivatives and applications thereof |
| ES17850310T ES2863925T3 (en) | 2016-09-19 | 2017-09-18 | Deuterated 3- (4,5-substituted pyrimidinamine) phenyl derivatives and applications thereof |
| US16/333,700 US10654851B2 (en) | 2016-09-19 | 2017-09-18 | Deuterated 3-(4,5-substituted aminopyrimidine)phenyl derivatives and use thereof |
| PCT/CN2017/102027 WO2018050108A1 (en) | 2016-09-19 | 2017-09-18 | Deuterated 3-(4,5-substituted pyrimidinamine) phenyl derivatives and applications thereof |
| CN201780056474.XA CN109689657B (en) | 2016-09-19 | 2017-09-18 | Deuterated 3- (4, 5-substituted aminopyrimidine) phenyl derivative and application thereof |
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| WO2019174623A1 (en) * | 2018-03-16 | 2019-09-19 | 南京创特医药科技有限公司 | Crystal form of monomethanesulfonate of deuterated 3-(4,5-substituted aminopyrimidine)phenyl compound, and preparation method therefor |
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| WO2019174623A1 (en) * | 2018-03-16 | 2019-09-19 | 南京创特医药科技有限公司 | Crystal form of monomethanesulfonate of deuterated 3-(4,5-substituted aminopyrimidine)phenyl compound, and preparation method therefor |
| US11629144B2 (en) | 2018-03-16 | 2023-04-18 | Nanjing Chuangte Pharmaceutical Technology Co., Ltd | Crystal form of monomethanesulfonate of deuterated 3-(4,5-substituted aminopyrimidine)phenyl compound and preparation method therefor |
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