CN104788427B - 3 (2 pyrimdinyl-amino) phenylacryloyl amine compounds and its application - Google Patents

Abstract

The invention discloses 3 (2 pyrimdinyl-amino) the phenylacryloyl amine compounds or its salt for pharmaceutically receiving or stereoisomer or prodrugs of a kind of formula (I) structure.Compound of the present invention or its salt for pharmaceutically receiving, the growth of kinds of tumor cells can effectively be suppressed, and inhibitory action is produced to other protease of EGFR, Her family, can be used to prepare antineoplastic, and the drug resistance of the inductions such as existing medicine Gefitinib, Tarceva can be overcome.

Description

3- (2- pyrimdinyl-aminos) phenylacryloyl amine compounds and its application

Technical field

The invention belongs to antineoplastic technical field, and in particular to 3- (2- pyrimdinyl-aminos) phenylacryloyl amine chemical combination Thing and its prepare application in antineoplastic.

Background technology

In Past 30 Years, lung cancer mortality rises 465%, and the incidence of disease increases by 26.9% every year, instead of liver cancer into It is China's first place Death Cause for Malignant Tumors.A kind of this disease of death rate highest, seriously threatens the health of the mankind.Wherein Non-small cell lung cancer (non-small cell lung cancer, NSCLC) accounts for more than the 80% of all lung cancer, only three/ There is the chance of operative treatment in one NSCLC patient, about 70% patient has belonged to Locally Advanced when medical or occurred at a distance Transfer, loses operative treatment chance.In this case, drug therapy seems and is even more important.

In traditional cancer treatment procedure, chemotherapy is main treatment means；Chemotherapeutics is non-specifically blocked carefully Born of the same parents divide so that cell death, and 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 treatment because of the serious side effects of worry chemotherapy, then add The drug resistance of upper chemotherapeutics, makes the chemotherapy of NSCLC allow of no optimist, and the cycle for extending chemotherapy merely add toxic and side effect, and Without increase curative effect.The cancer cell of non-small cell lung cancer is insensitive to chemotherapy, conventional chemotherapy simultaneously, and Overall response rate also only has 25% Left and right；Limitation for these reasons, Patients with Non-small-cell Lung five year survival rate is less than 20%.

In patient NSCLC of 50%-80%, 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 class is to make For the small molecule tyrosine kinase inhibitors (TKI) of acceptor intracellular region；The another kind of monoclonal for being to act on receptor extracellular region Antibody (MAb).The first generation EGFR inhibitor such as Iressa of clinic, Erlotinib, Lapatinib etc. are applied to, they are right Very big success is achieved in the treatment of NSCLC lung cancer, Patients with Non-small-cell Lung five year survival rate is improved.Meanwhile, with chemotherapy Compare, their advantage is that will not produce bone marrow suppression, the side effect such as nausea and neurotoxicity；But they are in monotherapy When drug effect it is relatively low, and have the side effect such as obviously fash and diarrhoea, and using after 1 year, patient occurs resistance to medicine The property of medicine.Research thinks that the mutation in EGFR gene T790M sites is the main inducing of such Drug-resistant, has clinical case data to show Show, about 50% patient's acquired resistance is all originated from caused by the mutation in T790M sites.Further research confirmation, due to EGFR gene T790M is mutated, that is, the threonine for encoding 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.The mutation for yet having research display T790M sites at present is not straight Connect the compatibility of influence inhibitor and EGFR, but mutation causes the compatibility of EGFR and ATP to greatly increase so that inhibitor and The compatibility of EGFR is relative to be greatly reduced (inhibitor and ATP are competitive bindings).Second generation inhibitor such as Afatinib, Dacomitinib, they are characterised by increasing the identity of EGFR better than the first generation, can distinguish tumour cell and normal Cell, such side effect will be reduced；But these molecules are to the poor selectivity of EGFRT790M mutant, cause clinical drug resistance to Relatively low by dosage, under its maximum tolerated dose (MTD), medicine cannot in vivo reach its valid density and cause resistance to majority Medicine patient is invalid.

In a word, current EGFR-TKI can not still solve the clinical pressure caused by drug resistance, and existing medicine Thing is that it is to wild-type cell so that quinazoline or EGFR that quinoline amine is basic parent nucleus be reversible or irreversible inhibitor mostly The toxic and side effect that poor selectivity is brought is also inevitable.Therefore, exigence new type, especially novel skeleton The problems such as compound is to solve drug resistance, poor selectivity.

The content of the invention

It is an object of the present invention to provide 3- (2- pyrimdinyl-aminos) the phenylacryloyl amine compounds with formula and Its application for preparing antineoplastic.

To achieve these goals, the present invention is adopted the following technical scheme that：

3- (2- pyrimdinyl-aminos) phenylacryloyl amines compound of the invention has the structure of logical formula (I)：

Wherein, R is selected from pyrazoles, 4- fluorine pyrazoles, 1- methylpyrazoles, 1- methyl-3-trifluoromethyl pyrazols, imidazoles, the R group It is connected with pyrimidine group by the N or C on ring；

R₁Selected from H, Cl, CF₃；

R₂And R₃It is independently selected from hydrogen, alkyl, substitution alkyl, or R₂、R₃Substituted monocyclic, volution is formed together with N atoms Or bridged ring.

Preferably, described 3- (2- pyrimdinyl-aminos) phenylacryloyl amine compound is the compound of following structure：

Following is the definition of term used in this specification.Unless otherwise noted, provided herein is group or term Initially definition is applied in this specification individually or as a part for other groups.

Term " alkyl " refers to straight or branched alkyl, comprising 1-12 carbon atom, especially 1-4 carbon atom.Allusion quotation " alkyl " of type includes methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, isobutyl group etc..

" substitution alkyl " refers to that one or more positions in alkyl are substituted, especially 1-4 substitution base, can be any Replace on position.Typical substitution includes but is not limited to one or more following groups：Halogen (for example, single halogenic substituent or Many halogenic substituents), trifluoromethyl, trifluoromethoxy, cycloalkyl, OR_a, S (=O) R_a, S (=O)₂R_a, S (=O)₂OR_a,、 NR_bR_c, S (=O)₂NR_bR_c, C (=O) OR_a, C (=O) NR_bR_c, OC (=O) R_a, OC (=O) NR_bR_c、NR_dC (=O) OR_a,NR_aC (=O) NR_bR_c、NR_aS (=O)₂NR_bR_c、NR_dC (=O) R_a, wherein the R for occurring herein_a、R_dHydrogen, 1-4 carbon can independently be represented Cycloalkyl, the heterocycle of the alkyl of atom, 3-8 carbon atom；R_bAnd R_cAlkyl, the 3-8 of hydrogen, 1-4 carbon atom can independently be represented The cycloalkyl of individual carbon atom, heterocycle, in other words R_bAnd R_cHeterocycle can be formed together with N atoms；Above-mentioned typical substitution base, such as Alkyl, cycloalkyl, heterocycle can be with optionally substituted.

Term " cycloalkyl " refers to fully saturated ring-type hydro carbons compound group, including 1-4 ring, is contained in each ring 3-8 carbon atom.

Term " heterocycle " refers to fully saturated or part is undersaturated or completely undersaturated including aromatic ring (such as heteroaryl Ring) cyclic group (such as 4-7 unit monocycles, 7-11 membered bicyclics, or 8-16 membered tricyclics system), wherein at least one hetero atom is deposited Be at least one carbon atom ring in.Each contains heteroatomic heterocycle can be with 1,2,3 or 4 hetero atom, these Hetero atom is selected from nitrogen-atoms, oxygen atom or sulphur atom, and wherein nitrogen-atoms or sulphur atom can be oxidized, and nitrogen-atoms can also be by season Ammonium.(term " hetero-aromatic ring ion " refers to contain quaternary carbon, positively charged heteroaromatic group.) heterocyclic group may be coupled to On the residue of any hetero atom or carbon atom of ring or ring system molecule.Typical monocyclic heterocycles include azetidinyl, pyrroles Alkyl, pyrrole radicals, pyrazolyl, oxetanyl, pyrazolinyl, imidazole radicals, imidazolinyl, imidazolidinyl, oxazolyl, oxazoles Alkyl, isoxazole alkyl, isoxazolyl, thiazolyl, thiadiazolyl group, thiazolidinyl, isothiazolyl, isothiazole alkyl, furyl, Tetrahydrofuran base, thienyl, oxadiazolyls, piperidyl, piperazinyl, 2- oxopiperazinyls, 2- oxo-piperidine bases, 2- oxo pyrroles Alkyl, 2- oxo azepines base, azepines base, hexahydroazepine base, 4- piperidone bases, pyridine radicals, pyrazinyl, pyrimidine radicals, rattle away Piperazine base, three nitrogen piperazine bases, triazol radical, tetrazole base, THP trtrahydropyranyl, morpholine base, thio-morpholine group, thio morpholine are sub- Sulfuryl, thio morpholine sulfuryl, 1,3- alkyl dioxins and tetrahydrochysene -1,1- dioxy thiophenes etc..Typical bicyclic heterocycle includes Yin Diindyl base, isoindolyl, benzothiazolyl, benzoxazolyl, benzo oxygen di azoly, benzothienyl, benzo [d] [1,3] dioxy Alkyl, the oxyalkyl of 2,3- dihydrobenzos [b] [1,4] two, quinine base, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzo miaow Oxazolyl, benzopyranyl, indolinyl, benzofuranyl, coumaran base, Chromanyl, cumarin base, cinnolines base, (such as furans simultaneously [2,3-c] pyridine radicals, furans is simultaneously [3,2-b] for quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridyl Pyridine radicals or furans simultaneously [2,3-b] pyridine), dihydro-iso indolyl, dihydroquinazoline base (such as 3,4- dihydros -4- oxoquinazolins Base), three azepine azepines bases, tetrahydric quinoline group etc..Typical tricyclic heterocyclic include carbazyl, benzindole, phenanthroline, Acridinyl, phenanthridinyl, xanthyl etc..Term " heterocycle " potentially includes substituted heterocycle.

Term " R₂And R₃Substituted monocyclic, volution or bridged ring can be formed together with N atoms ", refer to R₂And R₃By carbon Being connected into for atom, nitrogen-atoms or sulphur atom is saturation or the monocyclic of fractional saturation, volution or bridged ring etc..

The salt that compound in the present invention is likely to form also is belonging to the scope of the present invention.Unless otherwise indicated, the present invention In compound be understood to include its esters.Term " salt " as used herein, to refer to and form acid with inorganic or organic bronsted lowry acids and bases bronsted lowry Or the salt of alkali formula.Additionally, when the compound in the present invention contains a basic moiety, it includes but is not limited to pyridine or imidazoles, During containing an acidic moiety, including but not limited to carboxylic acid, it is possible to create amphion (" inner salt ") be included in term " salt " In the range of.Pharmaceutically acceptable (i.e. nontoxic, physiologically acceptable) salt is first-selected, although other salts are also useful, for example may be used With the isolated or purified step in preparation process.Compound of the invention is likely to form salt, for example, the chemical combination of logical formula (I) Thing salts out come in media as well with a certain amount of as the acid of equivalent or alkali react, or freeze-drying gets 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.Into the typical acid of salt acetate can be included (as used acetic acid or three halogenated acetic acids, such as trifluoro second Acid), adipate, alginate, ascorbate, aspartate, benzoate, benzene sulfonate, disulfate, boric acid Salt, butyrate, citrate, camphor salt, camsilate, cyclopentane propionate, diethylene glycol (DEG) hydrochlorate, lauryl sulfate, Ethane sulfonate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, caproate, hydrochloride, hydrogen Bromate, hydriodate, isethionate (e.g., 2- isethionates), lactate, maleate, mesylate, naphthalene Sulfonate (e.g., 2- naphthalene sulfonates), nicotinate, nitrate, oxalates, pectate, persulfate, phenpropionate (such as 3- benzene Propionate), phosphate, picrate, Pivalate, propionate, salicylate, succinate, sulfate (are such as formed with sulfuric acid ), sulfonate, tartrate, rhodanate, mesylate such as tosilate, dodecanoate etc..

The acidic moiety that compound of the invention contains, including but not limited to carboxylic acid, may be with various organic or inorganics Alkali forming salt.The salt that typical alkali is formed includes ammonium salt, alkali metal salt such as sodium, lithium, sylvite, alkali salt such as calcium, magnesium salts, and The salt (such as organic amine) that organic base is formed, such as benzyl star, dicyclohexyl amine, extra large bar amine are (with N, N- bis- (dehydroabietyl) ethylenediamine shape Into salt), N- methyl-D-glucosamines, N- methyl-D-glucamides, tert-butylamine, and with amino acid such as arginine, rely ammonia The salt that acid etc. is formed.Basic nitrogen-containing groups can with halide quaternary ammonium salt, such as lower alkyl halide (such as methyl, ethyl, The chloride of propyl group and butyl, bromide and iodide), dialkyl sulfate (e.g., dimethyl suflfate, diethylester, dibutyl ester and Diamyl ester), long chain halide (such as chloride of decyl, dodecyl, myristyl and myristyl, bromide and iodate Thing), aralkyl halide (such as benzyl and pheriyl bromide).

The prodrug and solvate of compound are also within the scope of covering in the present invention.Term " prodrug " refers to one herein Kind of compound, in therapy-related disease, produced by metabolism or the chemical conversion of chemical process compound in the present invention, Salt or solvate.Compound of the invention includes solvate, such as hydrate.According to 3- in the present invention (2- pyrimdinyl-aminos) The structural formula of phenylacryloyl amine compound, with reference to the prodrug compound that the method for preparing prodrug in the prior art is obtained, Within protection scope of the present invention.

Compound, salt or solvate in the present invention, it is understood that there may be tautomeric form (such as acid amides and imines Ether).All these dynamic isomers are all a parts of the invention.

The stereoisomer of all compounds is (for example, those are due to former to various substitution asymmetric carbons that may be present Son), including its enantiomeric form and diastereomeric forms, belong to imagination scope of the invention.Compound independence in the present invention Stereoisomer may not with other isomers simultaneously exist (for example, as a pure or substantially pure optics Isomers has special activity), or be also likely to be mixture, such as raceme, or with every other stereoisomer or its In a part formed mixture.Chiral centre of the invention has two kinds of configurations of S or R, is joined with the applied chemistry world by theoretical Credit union (IUPAC) definition of suggestion in 1974.Racemic form can be solved by physical method, such as fractional crystallization, or by spreading out Raw is diastereomeric separation crystallization, or is separated by chiral column chromatography.Single optical isomer can be by suitable Method is obtained by racemic modification, including but not limited to traditional method, such as with optically active acid into recrystallization after salt.

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, being equal to or more than 95%, equal to or more than 99% (compound of " very pure "), listed in text description. " very pure " compound of the invention this herein also serves as a part of the invention.

The all of configurational isomer of compound of the invention all within the scope of covering, either mixture, it is pure or Very pure form.Cis (Z) is included in the definition of the compounds of this invention and return two kinds of olefin isomers of formula (E), and carbocyclic ring With the cis and trans isomers of heterocycle.

Throughout the specification, group and substitution base can be selected to provide the fragment and compound of stabilization.

Particular functional group and technical terms of chemistry definition are all described in detail as follows.For purposes of the invention, chemical element with Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics, It is consistent defined in 75th Ed..The definition of particular functional group is also described wherein.Additionally, the basic principle of organic chemistry and Particular functional group and reactivity are in " Organic Chemistry ", Thomas Sorrell, University Science Books,Sausalito:1999, also it is described, entire contents include the row of bibliography.

Some compounds of the invention are likely to be present in specific geometry or stereoisomer form.The present invention covers all Compound, including its cis and trans isomers, R and S enantiomters, diastereomer, (D) type isomers, (L) type isomery Body, racemic mixture and other mixtures.Other asymmetric carbon atom can represent substitution base, such as alkyl.All isomers with And their mixture, all forgive in the present invention.

According to the present invention, the ratio that the mixture of isomer contains isomers can be various.For example, for only Having two mixtures of isomers can have following combination：50:50,60:40,70:30,80:20,90:10,95:5,96:4, 97:3,98:2,99:1, or 100:0, all ratios of isomers are all within the scope of the present invention.General technology people in this specialty The similar ratio that is readily appreciated that of member, and for more complicated isomers mixture ratio also within the scope of the present invention.

Present invention additionally comprises the compound of isotope marks, it is equal to original chemical and is disclosed.It is but actually right One or more atoms is generally occurred by the atom substitution different from its atomic weight or quality ordinal number.The present invention can be classified as The example of compound isotope include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, respectively as such as²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、 ³⁵S、¹⁸F and³⁶Cl.Compound in the present invention, or enantiomer, diastereomer, isomers, or Pharmaceutically acceptable salt or solvate, wherein containing the isotope of above-claimed cpd or other isotope atoms all in this hair Within the scope of bright.Some compound isotopically labelleds in the present invention, for example³H and¹⁴The radio isotope of C also wherein, It is useful in the Tissue distribution experiment of medicine and substrate.Tritium, i.e.,³H and carbon-14, i.e.,¹⁴Appearance is compared in C, their preparation and detection Easily, it is first-selection in isotope.Additionally, higher isotope substitution such as deuterium, i.e. 2H, because its good metabolic stability is at some It is advantageous in therapy, half-life period is for example increased in vivo or consumption is reduced, therefore, can pay the utmost attention in some cases.Together The compound of position element mark can use general method, by replacing with non isotopic examination with the isotope labeling reagent being easy to get Agent.

If designing a synthesis for the specific enantiomer of compound of the invention, it can be prepared with asymmetric syntheses, Or chiral auxiliaries derivatization is used, produced mixture of diastereomers is separated, then remove chiral auxiliaries and obtain pure enantiomer. In addition, if containing a basic functionality in molecule, such as amino acid, or acidic functionality, such as carboxyl can use suitable light Acid or the formation diastereomeric salt therewith of alkali of activity are learned, then is separated by conventional meanses such as fractional crystallization or chromatograms, so Pure enantiomer has just been obtained afterwards.

As described herein, the compound in the present invention can replace base or functional group to take and expand it and forgive model with any quantity Enclose.Generally, term " substitution " includes replacing the logical of base no matter occurring in term " optional " above or below in inventive formulation Formula, refers to replace base with specified structure, instead of hydroperoxyl radical.When the multiple in ad hoc structure in position by multiple specific substitutions When base replaces, each position of substitution base can be identical or different.Term " substitution " used herein includes all fair Perhaps organic compound substitution.In broad terms, it is allowed to substitution base include non-annularity, ring-type, side chain non-branched, carbon It is ring and heterocycle, aromatic ring and non-aromatic ring organic compound.In the present invention, as hetero atom nitrogen can have hydrogen replace base or The organic compound mentioned above of any permission supplements its valence state.Additionally, the present invention be not intended to be in any way limiting it is fair Perhaps substituted organic compound.It is considered herein that substitution base and variable groups combination in stable compound form in disease It is good, such as infectious disease or proliferative disease in treatment.Term " stabilization " refers to the compound with stabilization herein, in foot Detection is enough to maintain the integrality of compound structure in the enough time long, is all being imitated preferably within the sufficiently long time, herein It is used herein to above-mentioned purpose.

Compound or its pharmaceutically acceptable salt or its prodrugs the invention also discloses the logical formula (I) is in system Application in standby antineoplastic.

In one embodiment, the compound or its pharmaceutically acceptable salt of logical formula (I) of the present invention or its before Medicine molecule can be used for treating or control non-small cell lung cancer, ED-SCLC, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast cancer, Prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, GISTs, leukaemia, histiocytic lymph cancer, nasopharyngeal carcinoma were waited Degree proliferative disease.

The metabolite of compound and its pharmaceutically acceptable salt involved by the application, and can be changed into vivo The prodrug of the structure of compound and its pharmaceutically acceptable salt involved by the application, is also contained in claims hereof In.

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 keep constant, and subsequently or simultaneously take the compound of formula (I).Work as formula (I) compound and other one or more medicines are taken simultaneously when, preferably use simultaneously containing one or more known drugs and The Pharmaceutical composition of formula (I) compound.Drug combination be also included within overlap time period take compound of formula I with other it is a kind of or Several known drugs.When formula (I) compound and other one or more medicines carry out drug combination, formula (I) compound or Know medicine dosage may than their independent medications when dosage it is low.

The medicine or active component that drug combination can be carried out with formula (I) compound include but is not limited to following material： Estrogenic agents, androgen receptor adjustment, retina receptor modulators, cytotoxin/cytostatics, antiproliferative Agent, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitors, RTI, blood vessel Formation inhibitor, cell propagation and survival signaling inhibitor, the medicine and cell death inducer of interference cell cycle check, carefully Born of the same parents' poison class medicine, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, topoisomerase Inhibitor, Histone deacetylase inhibitor, protesome inhibitors, CDK inhibitor, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitor, ATK inhibitor, Integrin retarding agent, interferon, interleukin-I2, cox 2 inhibitor, P53, P53 activator, VEGF antibody, EGF antibody 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, pacify 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, bortezomb, It is busulfan, calcitonin, A Laizuo monoclonal antibodies injection, capecitabine, carboplatin, Kang Shi get, cefesone, Celmoleukin, soft red Mycin, Chlorambucil, cis-platinum, Cladribine, chlorine bend phosphoric acid, endoxan, cytarabine, Dacarbazine, actinomycin D, Daunorubicin liposome, dexamethasone, dexamethasone phosphate, Estradiol Valerate, denileukin diftitox, Di Bomei, Deslorelin, Ground La Zuosheng, diethylstilbestrol, Fluconazole, docetaxel, doxifluridine, adriamycin, Dronabinol, -166- shitosans of admiring are answered Compound, eligrand, rasburicase, epirubicin hydrochloride, aprepitant, Epi-ADM, Epoetin Alfa, RBC acceptor garland rate Element, eptalatin, Ergamisole, estradiol inhibitor, 17-β-estradiol, estramustine phosphate sodium, female alkynol, Amifostine, hydroxyl phosphorus Acid, Etopophos, etoposide, Fadrozole, tamoxifen preparation, Filgrastim, Tamsulosin, Fei Leisi are replaced, floxuridine, fluorine health Azoles, fludarabine, 5- fluorodeoxyuridines monophosphate, 5 FU 5 fluorouracil, Fluoxymesterone, Flutamide, formestane, 1- β-D arabinofuranosylcytosine -5 '-hard acyls phosphate, Fotemustine, fluorine Wei Siqiong, gamma globulin, gemcitabine, Ji Appropriate monoclonal antibody, imatinib mesylate, carmustine wafer capsule, Ge Shelinrui, hydrochloric acid glug Ni Xi Gansu Province, Supprelin and U.S. Newly, hydrocortisone, erythro-hydroxynonyl adenine, hydroxycarbamide, for smooth different shellfish not monoclonal antibody, idarubicin, ifosfamide, Interferon-' alpha ', interferon α-2, interferon α-2 A, interferon α-2 B, Interferon α-nl, Alferon N, interferon beta, interferon γ-la, interleukin 2, intron A, Iressa, Irinotecan, Kytril, sulfuric acid lentinan, Letrozole, formyl four Hydrogen folic acid, Leuprorelin, leuprolide acetate, L-tetramisole, levo leucovorin calcium salt, levothyroxine sodium, Zuo Jiazhuan Parathyrine preparation of sodium, lomustine, Lonidamine, Dronabinol, mustargen, Mecobalamin, medroxyprogesterone acetate, tumer ground are 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- β, Octreotide, Ondansetron Hydrochloride, dehydrohydro-cortisone oral solution, oxaliplatin, taxol, metacortandracin phosphoric acid Preparation of sodium, Pegaspargase, PEG-IFN alpha-2a, Pentostatin, Picibanil, hydrochloric acid pilocarpine, adjoin it is soft than star, plicamycin, porphin Fen nurse sodium, prednimustine, Prednisolone Steaglate, metacortandracin, premarin, the third kappa navel, epoetin, thunder Carry Qu Sai, Libiee, etidronate rhenium -186, Mabthera, Redoxon-Α, Romurtide, Salagen, Octreotide, Sargramostim, Semustine, sizofiran, Sobuzoxane, bluff sodium methylprednisolone, Paphos acid, stem-cell therapy, streptozotocin, chlorination Strontium -89, levoid, TAM, YM-617, Ta Suonaming, tastolactone, taxotere, teceleukin, Temozolomide, Teniposide, testosterone propionate, thioguanine, thio-tepa, thyrotropic hormone, for Shandong phosphoric acid, TPT, support Rui meter Fen, tositumomab, Herceptin, Treosulfan, Tretinoin, methylamine dish purine tablet, trimethyl melamine, Trimetrexate, Acetic acid Triptorelin, triptorelin pamoate, excellent good fortune pyridine, uridine, valrubicin, Vesnarinone, vincaleukoblastinum, vincristine, The protein stabilized preparation of Vindesine, vinorelbine, virulizin, ADR-529, Zinostatin stimalamer, ondansetron, taxol, Aco lbifene/ interferon gammas-lb, affinitak, amino dish purine, arzoxifene, asoprisnil, atamestane, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, carat that support, cyproterone acetic acid Ester, Decitabine, DN-101/ adriamycins-MTC, dSLIM, dutasteride, edotecarin, Eflornithine, Exatecan, Suwei A amine, histamine dihydrochloric acid, Supprelin hydrogel implant, holmium -166DOTMP, ibandronic acid, interferon gamma, include Sub- PEG, ixabepilone, keyhole shape hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafamib, rice Sprinkle former times sweet smell, minot and 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, Satraplatin, seocalcitol, T-138067, tarceva, 22 carbon six Olefin(e) 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 group Close.

Present invention also offers a kind of pharmaceutical composition, the pharmaceutical composition includes the compound or its medicine of the formula (I) Acceptable salt or its prodrugs on, and solvate or pharmaceutically acceptable carrier.The pharmaceutical composition is used for Treatment or control non-small cell lung cancer, ED-SCLC, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast cancer, prostate cancer, liver cancer, The hyperproliferative diseases such as cutaneum carcinoma, cell carcinoma, GISTs, leukaemia, histiocytic lymph cancer, nasopharyngeal carcinoma.

Refer to pharmaceutically acceptable material, composition or medium, such as liquid used herein of phrase " pharmaceutically acceptable carrier " Body or solid packing, diluent, auxiliary material, solvent or encapsulating material, including from certain part of an organ or body to another Certain part of organ or body carries or transport main pharmaceutical reagent.Each carrier must be " can receive ", can it is compatible other The pharmaceutical compositions of form and patient is not damaged.Some can include as the example of pharmaceutically acceptable carrier：Sugar, Such as lactose, dextrose and saccharose sugar；Starch, such as wheaten starch and farina starch；Cellulose and its derivates, such as sodium carboxylic Methylcellulose, ethyl cellulose, cellulose acetate, powdered gum tragacanth, malt, gelatin, talcum powder；Auxiliary material, such as cocoa are yellow Oil and suppository wax；Oil, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycol, such as fourth two Alcohol；Polyalcohol, such as glycerine, sorbierite, mannitol and polyethylene glycol；Ester, such as ethyl oleate and ethyl laurate；Agar；Buffering Agent, such as magnesium hydroxide and aluminium hydroxide；Alginic acid；Apirogen water；Physiological saline；Ringer's solution；Ethanol；Phosphate buffer, And other nontoxic compatible materials applied in pharmaceutical preparation.

Wetting agent, emulsifying agent and lubricant, such as lauryl sodium sulfate, magnesium stearate, polyethylene oxide and polybutene The copolymer of oxide, and colouring agent, releasing agent, coating agent, sweetener, spices and fumigating agent, preservative and antioxidant It also is present in described pharmaceutical composition.

Pharmaceutical formulation of the invention includes those suitable oral cavities, nasal cavity, external application (including oral cavity and sublingual), rectum, the moon Road and vein treatment.The formula can easily turn into unit dosage form, and can be prepared by pharmaceutically any of method.Activity The dosage of composition can be combined with a carrier material and produce single formulation, can factor receptor therapeutic modality, specific take Pattern it is different and different.The dosage of effective ingredient can be combined with carrier material and produce single formulation, typically will be used as this Compound produces the dosage for the treatment of.In general, outside 100%, the active ingredient of this dose between about 1%-99% it Between, preferably from about 5%-70% or so, optimal is about 10%-30% or so.

The method that these formulas or chemical analysis are prepared in the present invention enters including compound and combines one or more loads The step of body and assistant agent composition.In general, formula be prepared into uniform energy, can nearly with the present invention in carrier knot Close, such as liquid-carrier, solid smalls carrier, or both have both at the same time.Then, product is fashioned into if necessary.

Suitable oral preparation of the invention can have following form, such as capsule, cachet, pill, tablet, lozenge (typically sucrose and Acacia or tragacanth, there is certain taste), pulvis, granule, or as a solution or suspension Non-aqueous liquid in water, or as Water-In-Oil or oil-in-water emulsion liquid, or as elixir or syrup, or granular (make With such as gelatin and glycerine, the inert base of sucrose and Acacia) and/or mouthwash etc, each includes chemical combination of the present invention Thing as active ingredient a predetermined close.The compounds of this invention also can be used as bolus, paste or plaster.

Invention oral solid formulation (capsule, tablet, pill, dragee, powder, particle etc.), its effective ingredient with One or more pharmaceutically acceptable carriers mix, such as sodium citrate or calcium monohydrogen phosphate, and/or any herein below：Filler Or filler, such as starch, lactose, sucrose, glucose, mannitol；And/or silicic acid, for example adhesive, sodium carboxymethylcellulose, Alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic, such as NMF, glycerine；Disintegrant, such as agar, carbon Sour calcium, potato or tapioca, alginic acid, some silicate, sodium carbonate, ethanol and sodium starch；Solution retarder, such as paraffin, Sorbefacient, such as quarternary ammonium salt compound；Wetting agent, such as hexadecanol, glyceryl monostearate and PEO, polyoxygenated are common Polymers；Absorbent, such as kaolin clay, bentonite, such as lubricant, talcum powder, calcium stearate, magnesium stearate, the poly- second two of solid Alcohol, lauryl sodium sulfate and its mixture；And colouring agent.In the case of capsule, tablet, pill, drug regimen may be also Including sustained release agent.Similar solids versions composition can be used auxiliary material to turn into soft and fill and hard filling capsule, such as lactose or milk sugar, And the filler of ultra-high molecular weight polyethylene ethylene glycol etc.

Tablet can select one or more auxiliary ingredients to compress or be molded.Compressed tablets can be prepared (such as bright with binding agent Glue or HBMC), lubricating oil, inert diluent, antistaling agent, (such as ethanol or sodium starch are crosslinked carboxylic to disintegrant Sodium carboxymethylcellulose pyce), surface-active or dispersant.Model tablet may be by powdered compounds and inert fluid dilution Mixture, being molded on a suitable injection machine.

Active component can use above-mentioned auxiliary material microencapsulation.The medicine group of tablet and other solid pharmaceutical preparations of the invention Close, such as dragee, capsule, pill, granule, selectively can be prepared or moulding with coating and shell, such as enteric coating layer, with And the coating of known other pharmaceutical forms.The preparation of the active ingredient for being likely to provide slow or control release, for example, hydroxyl Butyl methyl cellulose provides required release profiles, other polymers matrix, liposome and/or fento in different situations Dimension element.They be able to may sterilize, for example, keep off filter by filter bacteria, or merge anti-microbial agents and aseptic consolidate Body composition, they are dissolved in sterilized water, or in some sterile injectable mediums.These compositions be likely to containing opacifiers into Part, or the slowly composition of the active material of release, or preferentially form a kind of mode of delay in some parts of intestines and stomach.It is embedding The material that entering composition can use includes polymer and wax.Active component can also be prepared into micro- glue using one or more auxiliary materials Scrotiform formula.

To compound oral liquid formulation of the invention include pharmaceutically acceptable emulsion, microemulsion, solution, suspension, Syrup and elixir.Except active component, the liquid of formulation may contain pharmaceutically conventional inert diluent, for example water or other Solvent, solubilising reagent and emulsifying agent, such as ethanol, isobutanol, ethyl carbonate, ethyl acetate, phenmethylol, Ergol, butylene Ethylene glycol, 1,3-BDO, oily (particularly cottonseed oil, peanut oil, maize germ oil, olive oil, castor oil, sesame oil) is sweet Oil, tetrahydrofuran alcohol, polyethylene glycol and fatty acid ester sorbierite and its mixture.Additionally, cyclodextrin, such as hydroxyl butyl-beta- Cyclodextrin, it can also be used to the compound of dissolving.

Except inert diluent, oral composition can also be included such as wetting agent, emulsification and suspending agent, sweetener, essence, color Element, antistaling agent and preservative.

Except reactive compound, suspension may contain suspending agent, such as isostearic acid ethyl ester, polyoxyethylene sorbitol and Sorbitol ester, microcrystalline cellulose, aluminum metal hydroxide, bentonite, agar and tragacanth and its mixture.

Present invention treatment rectum or intravaginal drug composite formula can be suppository, what it can be invented by one or more Compound mixing is sponsored with one or more suitable nonirritant excipients or carrier including preparation, for example, cocoa butter, gathers Ethylene glycol, a suppository wax or salicylic acid, and be at room temperature solid, but body temperature liquid, therefore, rectum or vagina will be melted in Chamber and the invention of release active agents.

Formula of the invention is adapted for treating vagina class disease, including containing such as pessary of known carrier in pharmacy, cotton balls, Paste, gel, paste, foam or spray agent.

Include pulvis, spray, ointment, ointment, face cream, breast for the part or transdermal administration of the compounds of this invention Liquid, gel, solution, plaster and inhalant.With pharmaceutically acceptable carrier under reactive compound aseptic condition, and any anti-corrosion Agent, buffer, or mixing may be needed.

Except the active ingredient beyond the region of objective existence in the present invention, ointment, ointment may be comprising such as animal and plant in ointment and gel The auxiliary material of fat, oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, organosilicon, organobentonite is lived Property compound, silicic acid, talcum powder, zinc oxide, or their mixture.

Except the active ingredient beyond the region of objective existence in the present invention, the auxiliary material such as lactose that powder and spray can be included, talcum, silicic acid, Aluminium hydroxide, calcium-silicate and Silon, or these materials mixture.Spray may add conventional, such as fluorochlorohydrocarbon and The unsubstituted hydrocarbon of volatility, such as butane and butylene.

The patch of compound is controllable in the body to medicine in the present invention is distributed with extra benefit.This formulation can Formed by the medicament being dissolved or dispersed in buffer medium.Sorbefacient can also be used for increasing in the skin present invention The flux of medicament.Rate controlling membranes or be dispersed in polymeric matrix or gel that this rate of change can be provided by either party Compound is controlled.

Ophthalmic preparation, spongaion, powder, solution etc., fall within the scope of the present invention.

The drug regimen of suitable one or more compounds of the invention includes and one or more medicines in parenteral treatment The acceptable sterile physiological aqueous solution or non-aqueous solution, dispersant, suspending agent or emulsion on, or aseptic powdery.They may Be reassembled as aseptic injection or the preferential dispersant for using, may contain antioxidant, buffer, bacteriostatic agent, can make preparation with it is pre- The blood or suspending agent or thickener of phase acceptor are isotonic fused.

In some cases, in order to extend drug effect, medicine from the absorption subcutaneously or intramuscularly injected can be delayed.This can lead to A suspension for the bad water solubility with crystallization or amorphous substance is crossed to complete.Absorptivity to medicine then takes Certainly in its rate of dissolution, while crystallite dimension and crystal formation may be depended on.In addition, postponing an absorption for parenteral therapeutic dosage forms Realized by being dissolved or suspended in oil medium medicine.Wherein storage type injection strategy includes using polyethylene oxide Thing-polybutylene oxide thing, wherein the medium for using is flowing in room temperature, solidifies in body temperature.

Storage type injection type is such as poly- glue ester-polyglycolic acid glue in Biodegradable polymeric by host compound Microcapsules are formed under ester and be made.According to medicine and the ratio of polymer, and special polymer property, drug release rate Can be control.The poly- example of other biological degradation polymer includes POE and many condensing models.Storage type injection Type can also be prepared by the way that medicine is embedded in into liposome or microemulsion, and this is compatible with tissue.

When compound of the 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.

Compound and pharmaceutical composition in the present invention can apply to combination treatment, i.e. compound and pharmaceutical composition can Before or after simultaneously, treatment or medical procedure that the medicine needed for one or more is used.It is this to apply in the specific of rule of combination Combination treatment (treatment or program) will allow for realizing needed for treatment compatibility and/or program and preferable therapeutic effect. The application of this therapy can realize required effect (for example, compound of the invention may be anti-with another to identical disease HCV reagents work simultaneously), or be possible to reach different effects (such as controlling any harmful effect).

Compound of the invention can be by being injected intravenously, intramuscular injection, intraperitoneal injection, hypodermic injection, external application, orally, or Other acceptable methods treat disease.These compounds can be used for the condition mammal for the treatment of of arthritis (for example, people Class, domestic animal and domestic animal), birds, lizard, and it is any can be with compatible these compound other biologicals.

Present invention also offers Key works Drug packing or external member, including the packaging of one or more, 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, to produce The open method permitted in regulation is used or sale medicine or biological products, using or sell to the treatment preparation of people.

Compared with prior art, beneficial effects of the present invention are：

1, logical formula (I) compound of the present invention or its salt for pharmaceutically receiving can suppress kinds of tumor cells, especially It is can selectively acting in EGFR L858R/T790M and EGFR E745_A750/T790M lung carcinoma cells.Contrast is wild Type cancer cell, the IC50 of such compound wants 10 times high even 100 times of order of magnitude difference.Such compound is a novel class The drug resistance and selective protease inhibitors of existing EGFR-TKI can be overcome.

2, logical formula (I) compound of the present invention or its pharmaceutically acceptable salt can suppress kinds of tumor cells Growth, and to EGFR, other protease of Her families produce inhibitory action, can be used for effective suppression and prepare antineoplastic, and The resistance of the inductions such as existing medicine Gefitinib, Tarceva can be overcome.As understood by those skilled in the art, the application Involved compound and its pharmaceutically acceptable salt can be used to prepare the transition such as the treatment mankind and the tumour of other mammals Proliferative diseases.

The abbreviation concrete meaning being related in the present invention is as follows：

ACN acetonitriles

EA ethyl acetate

DMF N,N-dimethylformamides

PE petroleum ethers

DCM dichloromethane

DMF N,N-dimethylformamides

MeOH methyl alcohol

THF tetrahydrofurans

K₂CO₃Potassium carbonate

TEA triethylamines

DIPEA diisopropyl ethyl amines

DMAP N, N- dimethyl -4- amido pyridines

TFA trifluoroacetic acids

NMP 1-METHYLPYRROLIDONEs

Boc tertbutyloxycarbonyls

Tris trishydroxymethylaminomethanes

BSA bovine serum albumin(BSA)s

DTT dithiothreitol (DTT)s

ATP adenosine triphyosphates

Specific embodiment

Some aspects of the invention and embodiment can be further illustrated with by following specific embodiment.This hair The compound covered in bright can be synthesized by known conventional art.These compounds can be from readily available initiation material Advantageously synthesize.The following is the general synthetic schemes of compound of present invention synthesis.These schemes disclosed herein be it is descriptive, Being not offered as limitation those skilled in the art uses other possible methods to synthesize compound.During various methods are all this area Routine techniques.In addition, different synthesis steps can apply the synthesising target compound in different schemes.It is cited herein Among all documents are all incorporated herein by way of reference.

Compound with logical formula (I) can by scheme 1 below and scheme it is 2-in-1 into.Scheme 1 and 2 describes to synthesize this The distinct methods of a little intermediates, these methods can apply the system of the compound with formula I-IV structures in patent of the present invention It is standby upper.Those skilled in the art can complete author's similar chemical combination disclosed below by the various modifications of these methods The synthesis of thing.

The group symbol occurred in specific embodiment syntheti c route：The group symbol is to represent formula of the present invention (I) R group in structure.

R therein is selected from pyrazoles, 4- fluorine pyrazoles, 1- methylpyrazoles, 1- methyl-3-trifluoromethyl pyrazols, imidazoles, the R bases Group is connected by the N or C on ring with pyrimidine group；

R therein₁Represent H, Cl or CF₃；R₂And R₃It is independent to represent hydrogen, alkyl, substitution alkyl, or R₂、R₃With N atoms one Rise and form the monocyclic of substitution, volution or bridged ring.

Scheme 1：Compound syntheti c route with logical formula (I) is as follows：

Above-mentioned syntheti c route is comprised the following steps that：

Step 1：With THF as solvent, compound II and nitrogen heterocyclic ring in the presence of alkali NaH, by fragrant substitution reaction Obtain III.

Step 2：Intermediate III obtains IV with the fluoro- 2 methoxyl group -5- nitroanilines of 4- under p-methyl benzenesulfonic acid effect.

Step 3：With Isosorbide-5-Nitrae-dioxane as solvent, intermediate compound IV and organic amine (IIIa) react in the presence of potassium carbonate Obtain intermediate V.

Step 4：Using second alcohol and water as solvent, in the presence of ammonium chloride, with reduced iron powder as reducing agent, by intermediate V also Originally it was intermediate VI.

Step 5：With DCM as solvent, used as alkali, at low temperature, intermediate VI obtains final to pyridine with acryloyl chloride reaction Product (I) compound.

Scheme 2：It is as follows with compounds of formula I syntheti c route：

Above-mentioned syntheti c route is comprised the following steps that：

Step 1：With DMF as solvent, in the presence of p-methyl benzenesulfonic acid, the fluoro- 2 methoxyl group -5- nitroanilines of II and 4- react To intermediate VII.

Step 2：With Isosorbide-5-Nitrae-dioxane as solvent, tetra-triphenylphosphine palladium is catalyst, in simplified VII and borate (IIb) reaction obtains intermediate VIII.

Step 3：With DMF as solvent, potassium carbonate makees alkali, in simplified VIII and organic amine IIIa reaction obtain intermediate compound I X.

Step 4：Using second alcohol and water as solvent, in the presence of ammonium chloride, with reduced iron powder as reducing agent, by intermediate compound I X also Originally it was intermediate X.

Step 5：With DCM as solvent, used as alkali, at low temperature, intermediate X obtains final to pyridine with acryloyl chloride reaction Product (I) compound.

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 in originally special according to scientific and technical literature cited herein and the example of patent, and resulting various modifications and many Those skilled in the art are clear clear in the industry.It should also be appreciated that the reference of these bibliography contributes in statement herein 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

N- (5- ((the chloro- 4- of 5- (1H- pyrazol-1-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups) acrylamide

Synthetic route is as follows：

The specific synthesis step of said synthesis route is as follows：

Step 1：The synthesis of the chloro- 4- of 2,5- (1H- pyrazol-1-yls) pyrimidine (compound 3)

NaH (400mg, 16.67mmol) is suspended in anhydrous tetrahydro furan (30mL), at room temperature plus pyrazoles (340mg, 5mmol).Reaction is stirred at room temperature 10 minutes, is cooled to -30 DEG C~-40 DEG C.2,4,5- trichloropyrimidines (1.82g, 10mmol) Tetrahydrofuran (5mL) wiring solution-forming is dissolved in, it is disposable to add.Reaction is stirred 20 minutes at -30 DEG C, is poured into frozen water (50g), Ethyl acetate is extracted.Organic layer is washed with saturated common salt, anhydrous sodium sulfate drying, concentration, column chromatography (petroleum ether:Ethyl acetate (100:1~50:1) white solid product (589mg, yield are obtained：55.1%).

Step 2：The chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1H- pyrazol-1-yls) pyrimidine -2- amine (is changed Compound 5) preparation

The chloro- 4- of 2,5- (1H- pyrazol-1-yls pyrimidine (550mg, 2.57mmol), the fluoro- 2- methoxyl groups -5- nitroanilines of 4- (478mg, 2.57mmol) and p-methyl benzenesulfonic acid monohydrate (489mg, 2.57mmol) are dissolved in acetonitrile (10mL), stirring Under, reaction bulb opening is heated to 30 DEG C, after solvent evaporated, is stirred for 20 minutes.The process of being evaporated is repeated twice.Reaction solution is as cold as room Temperature, adds water (30mL), ethyl acetate extraction (30mL x 2).Organic layer successively with the dilute HCl of 0.1M (30mL x 4) and is satisfied Washed with saline solution (50mL), anhydrous sodium sulfate drying, concentrated, column chromatography (petroleum ether:Ethyl acetate=15:1~3:1) yellow is obtained Oil product (100mg, yield：58.8%).

Step 3：N1- (the chloro- 4- of 5- (1H- pyrazol-1-yls pyrimidine -2-base)-N4- (2- (dimethylamino) ethyl) -2- first The preparation of epoxide-N4- methyl-5-nitrophenyl -1,4- diamines (compound 7)

The chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1H- pyrazol-1-yls) pyrimidine -2- amine (100mg, 0.275mmol), N1, N1, N2- Trimethylethane -1,2- diamines (56mg, 0.549mmol) and potassium carbonate (114mg, 0.825mmol) it is mixed in DMF (10mL), reaction is heated to 80 DEG C and is kept for 1 hour.It is cooled to room temperature, Add water (50mL).Ethyl acetate (50mL x 2) is extracted.Organic layer saturated aqueous common salt (50mL) is washed, and anhydrous sodium sulfate is done Dry, concentration obtains yellow oily crude product (120mg), does not purify and directly throws next step.

Step 4：N4- (the chloro- 4- of 5- (1H- pyrazol-1-yls) pyrimidine -2-base)-N1- (2- (lignocaine) ethyl) -5- first The preparation of epoxide-N1- methylbenzene -1,2,4- triamines (compound 8)

N1- (the chloro- 4- of 5- (1H- pyrazol-1-yls pyrimidine -2-base)-N4- (2- (dimethylamino) ethyl) -2- methoxyl groups - N4- methyl-5-nitrophenyl -1,4- diamines (120mg, 0.269mmol), iron powder (150mg, 2.68mmol) and NH4Cl (150mg, 2.80mmol) is dissolved in EtOH/H2O=2/1 (8mL), is heated to 90 DEG C and is reacted 1 hour.Reaction is as cold as room temperature, two Chloromethanes (20mL) is added, diatomite filtering.Filtrate water dilutes, then is extracted once with 20 milliliters of dichloromethane.It is organic laminated And, saturated aqueous common salt (50mL) is washed, anhydrous sodium sulfate drying, concentration, column chromatography (petroleum ether:Ethyl acetate=1:1 arrives dichloromethane Alkane:Methyl alcohol=15:1 adds 0.2% volume triethylamine) yellow solid product (100 milligrams, yield：89.4%).LC-MS:m/z 417[M+H]⁺。

Step 5：N- (5- ((the chloro- 4- of 5- (1H- pyrazol-1-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) Ethyl) (methyl) amino) -4- methoxyl groups) and acrylamide (compound 9) preparation

N4- (the chloro- 4- of 5- (1H- pyrazol-1-yls) pyrimidine -2-base)-N1- (2- (lignocaine) ethyl) -5- methoxyl groups - N1- methylbenzene -1,2,4- triamines (100mg, 0.0240mmol) are dissolved in dichloromethane (40 milliliters), are cooled to -40 DEG C, are added Pyridine (0.2mL), acryloyl chloride (0.1mL).Reaction is stirred ten minutes at -40 DEG C, pours into 20 milliliters of water and 40 milliliters of saturations Saline solution is obtained in mixed solvent.Water layer is separated, then is extracted once with 30 milliliters of dichloromethane.Organic layer is washed with saturated common salt, Anhydrous sodium sulfate drying, concentration, column chromatography (petroleum ether:Ethyl acetate=1:1 arrives dichloromethane:Methyl alcohol=15:1 adds 0.2% body Long-pending triethylamine) not pure compound is obtained, acid efficient liquid phase (0.1% volume formic acid of addition) separates, and obtains 25mg yellow solids product Thing (yield：22.2%).

¹H-NMR(400MHz,CDCl₃)δ9.72(brs,1H),9.54(s,1H),9.10(brs,1H),8.52-8.58(m, 2H), 7.78-7.87 (m, 2H), 6.65-6.72 (m, 2H), 6.46-6.54 (m, 2H), 5.73 (dd, J=10.0,1.6Hz, 1H), 3.88 (s, 3H), 3.09 (t, J=5.2Hz, 2H), 2.75 (t, J=5.6Hz, 2H), 2.66 (s, 3H), 2.53 (s, 6H) .LC-MS:m/z 471[M+H]⁺.

Embodiment 2

N- (5- ((the chloro- 4- of 5- (4- fluorine 1H- pyrazol-1-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) second Base) (methyl) amino) -4- methoxyl groups) acrylamide

Synthetic method reference implementation example 1.

The end-product of synthesis¹H-NMR(400MHz,CDCl₃):δ9.53(s,1H),9.42(s,1H),8.49(s,1H), 7.82 (s, 1H), 7.73 (d, J=4.2Hz, 1H), 6.73 (s, 1H), 6.56 (d, J=1.4Hz, 1H), 5.75 (d, J= 11.7Hz,1H),3.90(s,3H),3.13(m,2H),2.88–2.40(m,10H).LC-MS:m/z 489[M+H]⁺.

Embodiment 3

N- (5- ((the chloro- 4- of 5- (1H- imidazoles -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (first Base) amino) -4- methoxyphenyls) acrylamide

Synthetic method reference implementation example 1.

The end-product of synthesis¹H-NMR(400MHz,CDCl₃)9.74(s,1H),δ9.70(brs, 1H),8.92(brs, 1H), 8.8.24-8.26 (m, 2H), 8.05 (s, 1H), 7.17 (s, 1H), 6.54-6.77 (m, 3H), 5.76 (d, J=8.8Hz, 1H), 3.94 (s, 3H), 3.12 (t, J=5.2Hz, 2H), 2.80 (t, J=5.2Hz, 2H), 2.68 (s, 3H), 2.56 (s, 6H) .LC-MS:m/z 471[M+H]⁺.

Embodiment 4

N- (5- ((5- trifluoromethyls -4- (1H- pyrazol-1-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) Ethyl) (methyl) amino) -4- methoxyl groups) acrylamide

The specific synthesis step of above-mentioned syntheti c route is as follows：

Step 1：The synthesis of 2- chloro- 5- trifluoromethyls -4- (1H- pyrazol-1-yls) pyrimidine

In N₂Under protection, NaH (2.35g, 58.75mmol) is dissolved in THF, is cooled to -10 DEG C, pyrazoles (1g, 14.68mmol) THF is dissolved in be added dropwise in reaction bulb.The reaction system is stirred at room temperature 10 minutes, after be cooled to -40 DEG C.2,4 ,-two chloro- 5- tri- Methyl fluoride-pyrimidine (3.49g, 16.15mmol) is dissolved in 5ml THF, is disposably added in above-mentioned reaction system.The reaction system Stirred 20 minutes at -40 DEG C.Then reaction system is poured into frozen water, EA extractions, the washing of saturation NaCl solution is anhydrous Na₂SO₄Dry, filtering is spin-dried for.Residue is through column chromatography (PE:EA=50:1) white solid product (647mg, yield are obtained: 16%).LC-MS:m/z 249[M+H]⁺.

Step 2：5- trifluoromethyls-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1H- pyrazol-1-yls) pyrimidine -2- Amine

Intermediate 2- chloro- 5- trifluoromethyls -4- (1H- pyrazol-1-yls) pyrimidine (647mg, 2.61mmol), the fluoro- 2- first of 4- Hydrations p-methyl benzenesulfonic acid of epoxide -5- nitroanilines (485.3mg, 2.61mmol) and (496.5mg, 2.61mmol) is dissolved in In 10ml acetonitriles, reactor opening is placed in oil bath, solvent volatilization is heated at 130 DEG C complete.Same operation is repeated twice. Reaction system drops to room temperature, is diluted with 30ml water, filters to obtain crude product.Crude product is through PE/EA=10：1 mashing obtains clean Yellow solid product (524mg, yield:52%).LC-MS:m/z 399[M+H]⁺.

Step 3：N1- (5- trifluoromethyls -4- (1H- pyrazol-1-yls pyrimidine -2-base)-N4- (2- (dimethylamino) second Base) -2- methoxyl group-N4- methyl-5-nitrophenyl -1,4- diamines

Intermediate 5- trifluoromethyls-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1H- pyrazol-1-yls) pyrimidine -2- Amine (524mg, 1.72mmol), N1, N1, N2- trimethyl ethylenediamine (194mg, 1.9mmol) and K₂CO₃(357mg,2.58mmol) It is dissolved in 10ml dioxane.Reaction system is stirred 1 hour at 80 DEG C.Reaction system drops to room temperature, the dilution of 50ml water, EA (50ml x 2) is extracted, the washing of organic phase saturation NaCl solution, anhydrous Na₂SO₄Dry, filtering is spin-dried for.Residue is through column chromatography (PE:EA=DCM:MeOH=40:1to 20:1) yellow oily product (500mg, yield are obtained:61%).LC-MS:m/z 481 [M+H]⁺.

Step 4：N4- (5- trifluoromethyls -4- (1H- pyrazol-1-yls) pyrimidine -2-base)-N1- (2- (lignocaine) second Base) -5- methoxyl group-N1- methylbenzene -1,2,4- triamines

Intermediate N1- (5- trifluoromethyls -4- (1H- pyrazol-1-yls pyrimidine -2-base)-N4- (2- (dimethylamino) second Base) -2- methoxyl groups-N4- methyl-5-nitrophenyls-Isosorbide-5-Nitrae-diamines (800mg, 1.67mmol), reduction Fe powder (466.5mg, 8.33mmol) 8ml EtOH/H are dissolved in NH4Cl (446mg, 8.33mmol)₂O(EtOH/H₂O=2/1 in mixed solution).Instead System is answered to be stirred 1 hour at 90 DEG C.Reaction system drops to room temperature, in 20ml DCM addition systems, is filtered by diatomite, DCM Washing.Add 20ml saturation NaCl solutions, DCM (50ml x 2) extractions, the washing of saturation NaCl solution, anhydrous Na₂SO₄Dry, rotation It is dry to obtain yellow solid product (200mg, yield：20%) it is directly used in next step.LC-MS:m/z 451[M+H]⁺.

Step 5：N- (5- ((5- trifluoromethyls -4- (1H- pyrazol-1-yls) pyrimidine -2-base) amino) -2- ((2- (dimethyl Amino) ethyl) (methyl) amino) -4- methoxyl groups) acrylamide

Under nitrogen protection, intermediate N4- (5- trifluoromethyls -4- (1H- pyrazol-1-yls) pyrimidine -2-base)-N1- (2- (lignocaine) ethyl) -5- methoxyl group-N1- methylbenzene -1,2,4- triamines (100mg, 0.0240mmol), pyridine (0.2ml) is molten In 15ml DCM, -40 DEG C are cooled to, then acryloyl chloride (0.1mL) is dissolved in 1ml DCM and is slowly added in above-mentioned mixed system. Reaction system is stirred 10 minutes at -40 DEG C, in then pouring into 20ml frozen water.DCM is extracted, the washing of saturation NaCl solution, anhydrous Na₂SO₄Dry, be spin-dried for.Residue obtains yellow solid product (15mg, yield through preparing HPLC purifying:10%).

1H-NMR(400MHz,CDCl₃):δ 9.58 (s, 1H), 9.22 (d, J=1.6Hz, 1H), 8.55 (s, 1H), 7.92 (s, 1H), 7.75 (s, 1H), 6.68 (s, 1H), 6.45 (d, J=1.7Hz, 2H), 5.74-5.66 (m, 1H), 3.86 (s, 3H), 3.17–3.07(m,2H),2.91–2.76(m,2H), 2.67(s,4H),2.63–2.48(m,6H).LC-MS:m/z(ES+): 505[M+H]⁺.

Embodiment 5

N- (5- ((the chloro- 4- of 5- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) second Base) (methyl) amino) -4- anisyls) acrylamide

The specific synthesis step of above-mentioned syntheti c route is as follows：

Step 1：The chloro- N- of 4,5- bis- (the fluoro- 2- methoxyl groups -5- nitrobenzene of 4-) pyrimidine -2- amino

By 2,4,5- trichloropyrimidines (1.5g, 8.1mmol), the fluoro- 2- methoxyl groups -5- nitroanilines of 4- (500mg, 2.7mmol) it is dissolved in DMF (45mL) with hydration p-methyl benzenesulfonic acid (616mg, 3.2mmol), is then heated to 105 DEG C of reactions 5 Hour.Then the saturated sodium bicarbonate aqueous solution of reaction solution ice is quenched, EA (30ml x 2) extractions, merges organic phase saturation Salt is washed 3 times, dry filter, concentration.Crude product obtains the chloro- N- of yellow solid 4,5- (the fluoro- 2- methoxies of 4- through silicagel column purifying Base -5- nitrobenzene) pyrimidine -2- amino (300mg, yield：34%).LC-MS:m/z 332(M+H)⁺.

Step 2：The chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzene of 4-) -4- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyrimidine -2- Amino

By the chloro- N- of 4,5- (the fluoro- 2- methoxyl groups -5- nitrobenzene of 4-) pyrimidine -2- amino (166mg, 0.5mmol), 1- methyl - 4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- bases) -1H- pyrazoles (156mg, 0.75mmol), Pd (PPh3) 4 (115.5mg,0.1mmol),Na₂CO₃(2M solution 0.8ml) and LiCl (4.3mg, 0.1mmol) is dissolved in 1,4- dioxane (15mL), is then heated to 95 DEG C and reacts 6 hours under nitrogen protection.Reaction solution adds water afterwards, DCM (30ml x 2) extractions, closes And organic phase saturated common salt water washing, dry filter, concentration.Crude product obtains the chloro- N- of yellow solid 5- through silicagel column purifying (the fluoro- 2- methoxyl groups -5- nitrobenzene of 4-) -4- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyrimidine -2- amino (110mg, yield：58%). LC-MS:m/z 379(M+H)⁺。

Step 3：N1- (the chloro- 4- of 5- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyrimidine -2-base)-N4- (2- (dimethylamino) second Base) -2- methoxyl group-N4- methyl-5-nitro benzene -1,4- diamines

By the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzene of 4-) -4- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyrimidine -2- amino (110mg, 0.29mmol), N, N, N'- trimethyl ethylenediamine (44mg, 0.44mmol) and K₂CO₃(80mg, 0.58mmol) is dissolved in DMF(5mL).Then 80 DEG C are heated under nitrogen protection to react 1 hour.Reaction solution adds water afterwards, EA (30ml x 2) extractions, closes And organic phase saturated common salt water washing, dry filter, concentration.Crude product obtains red solid N1- (5- through silicagel column purifying Chloro- 4- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyrimidine -2-base)-N4- (2- (dimethylamino) ethyl) -2- methoxyl group-N4- methyl - 5- nitrobenzene -1,4- diamines (100mg, yield：75%).LC-MS:m/z 461(M+H)⁺.

Step 4：N4- (the chloro- 4- of 5- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyrimidine -2-base)-N1- (2- (dimethylamino) second Base) -5- methoxyl group-N1- methylbenzene -1,2,4- triamines

N1- (the chloro- 4- of 5- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyrimidine -2-base)-N4- (2- (dimethylamino) ethyl) -2- first Epoxide-N4- methyl-5-nitros benzene -1,4- diamines (100mg, 0.22mmol), reduced iron powder (121mg, 2.2mmol) and NH₄Cl (115mg, 2.2mmol) is dissolved in 10ml EtOH/H₂O (v/v=1/1).80 DEG C are then heated to react 1 hour.Reaction solution afterwards Filtering, filtrate is extracted with dichloromethane (30ml x 2), merges organic phase saturated common salt water washing, dry filter, concentration.Slightly Product obtains yellow solid N4- (the chloro- 4- of 5- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyrimidine -2-base)-N1- (2- through silicagel column purifying (dimethylamino) ethyl) -5- methoxyl group-N1- methylbenzene -1,2,4- triamines (80mg, yield：80%).LC MS:m/z 454(M +H)⁺.

Step 5：N- (5- ((the chloro- 4- of 5- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyrimidine -2-base) amino) -2- ((2- (diformazans Amino) ethyl) (methyl) amino) -4- benzyloxies) acrylamide

N4- (the chloro- 4- of 5- (1- methyl isophthalic acid H- pyrazoles -4- bases) pyrimidine -2-base)-N1- (2- (dimethylamino) ethyl) -5- first Epoxide-N1- methylbenzene -1,2,4- triamines (80mg, 0.19mmol) are dissolved in DCM (50mL), are then cooled to -30 DEG C, add pyrrole Pyridine (0.2ml), is then slowly added into acryloyl chloride (51.3mg, 0.57mmol).Reaction solution reacts 15 minutes and then adds at -30 DEG C Enter frozen water to be quenched.Dichloromethane (30ml x 2) is extracted, and merges organic phase saturated common salt water washing, dry filter, concentration.Slightly Product obtain crude product through silica gel plate purifying, and crude product is through preparing HPLC isolated white solid N- (5- ((5- chloro- 4- (1- first Base -1H- pyrazoles -4- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- benzyloxies) Acrylamide (30mg, yield：32%).¹H-NMR(400MHz,DMSO-d6)δ10.05(s,1H),9.94(s,1H),9.16 (s,1H),8.29(s,1H),8.18(s,1H),8.04(s,1H),7.22(s,2H),6.69(s,1H),6.50(m,2H),5.74 (m, 2H),4.02(s,3H),3.93(s,3H),3.74(s,3H),2.97(m,2H),2.69(s,3H),2.47(m,2H), 2.48-2.37(m,6H).LC-MS:m/z 486(M+H)⁺.

Embodiment 6

N- (5- ((the chloro- 4- of 5- (1- methyl -3- (trifluoromethyl) -1H- pyrazoles -4- bases) pyrimidine -2-base) amine) -2- ((2- (dimethyl amido) ethyl) (methyl) amido) -4- anisyls) acrylamide

Synthetic method reference implementation example 5

The end-product of synthesis¹H-NMR(400MHz,CDCl₃)δ10.06(s,1H),9.79(s,1H),9.38(s,1H), 8.38 (s, 1H), 8.02 (s, 1H), 6.79 (s, 1H), 6.59 (m, 1H), 6.42 (d, J=15.2Hz, 1H), 5.72 (d, J= 8.0Hz, 1H), 4.07 (s, 3H), 3.94 (s, 3H), 3.00 (t, J=5.2Hz, 2H), 2.70 (s, 3H), 2.55 (m, 2H), 2.41(s,6H).LC-MS:m/z 553(M+H)⁺.

The biological activity test of compound prepared by above-described embodiment 1-6

The kinases IC50 tests that such compound is mutated to EGFR wild types and EGFR-T790M：

EGFR (WT) is wild-type egf acceptor, and EGFR (T790M) is by Soviet Union's ammonia with the 790th amino acids Acid mutation is the EGF-R ELISA of methionine, and RGFR (L858R) is to be mutated by leucine with the 858th amino acids It is arginic EGF-R ELISA, EGFR (L858R/T790M) is to be dashed forward by leucine simultaneous with the 858th amino acids It is changed into arginine and the 790th amino acids is sported the EGF-R ELISA of methionine by threonine.

Kinase activity is detected：This test uses Kinase-Glo Plus luminescence kinase assay kit(Promega).It remains ATP contents to detect kinase activity after quantitative analysis swashs enzymatic reaction.In test Fluorescence signal it is related to existing ATP contents.

Configure the reaction solution of 50uL, including 40mM Tris, pH 7.4,10mM MgCl₂,0.1 mg/ml BSA,1mM DTT,0.2mg/ml Poly(Glu,Tyr)substrate,10M ATP and EGFR.Testing compound is made into 10%DMSO Solution, takes during 5uL is diluted to the above-mentioned reaction solutions of 50uL and obtains the reaction solution that final DMSO concentration is 1%.All enzymic catalytic reactions All carried out at 30 DEG C 35 minutes.For the reaction of preincubation in 30 minutes, enzyme was first hatched 30 minutes with inhibitor, is subsequently adding ATP and substrate start reaction.After enzymic catalytic reaction terminates, 50uL Kinase-Glo Plus are added in reaction solution Luminescence kinase assay solution (Promega), continues in incubation at room temperature 5 minutes.During fluorescence signal by BioTek Synergy 2microplate reader are measured.IC50 be with GraphPadPrism5.00 (four parameter logistics this Meaning equation) it is calculated.Table 1 is the biological activity test data result of example 1-6

Table 1, biological activity test data

In the competition experiments of 3- (2- pyrimdinyl-aminos) phenylacryloyl amine compounds of the invention and ATP, due to existing Irreversible Michael addition reaction is formed with protein cysteine site, so all embodying inhibitory activity higher to kinases.

Embodiment described above only expresses several embodiments of the invention, and its description is more specific and detailed, but simultaneously Therefore the limitation to the scope of the claims of the present invention can not be interpreted as.It should be pointed out that for one of ordinary skill in the art For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention Shield scope.

Claims (9)

1. a kind of compound or its pharmaceutically acceptable salt, it is characterised in that the compound is：

2. application of the compound or its pharmaceutically acceptable salt described in claim 1 in antineoplastic is prepared.

3. the application of compound as claimed in claim 2 or its pharmaceutically acceptable salt in antineoplastic is prepared, its It is characterised by, the antineoplastic is the medicine of following any one tumor disease for the treatment of：Non-small cell lung cancer, cellule lung Cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, GISTs, in vain Leukemia, histiocytic lymph cancer, nasopharyngeal carcinoma.

4. the application of compound as claimed in claim 2 or its pharmaceutically acceptable salt in antineoplastic is prepared, its It is characterised by：When the compound or its pharmaceutically acceptable salt are as cancer therapy drug, can be with other anti-cancer agent in combination Medication.

5. a kind of medicine, it is characterised in that：The active component of the medicine be claim 1 described in compound or its pharmaceutically may be used The salt of receiving.

6. a kind of medicine as claimed in claim 5, it is characterised in that：The medicine is composition, and the pharmaceutical composition includes power Profit requires the compound or its pharmaceutically acceptable salt described in 1, or pharmaceutically acceptable carrier.

7. the medicine as described in claim 5 or 6, it is characterised in that：The medicine or pharmaceutical composition are used to treat or control Non-small cell lung cancer, ED-SCLC, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, epithelium Cell cancer, GISTs, leukaemia, histiocytic lymph cancer, nasopharyngeal carcinoma.

8. the medicine as described in claim 5 or 6, it is characterised in that the formulation of the medicine or pharmaceutical composition is：Capsule, Cachet, pill, tablet, pulvis, granule, spray, ointment, ointment, face cream, emulsion, gel, solution, plaster, suction Agent, or as the non-aqueous liquid being suspended in water, or as elixir or syrup or mouthwash.

9. the medicine as described in claim 5 or 6, it is characterised in that：Weight hundred of the active component of the medicine in medicine Divide than being 5%-70%.