CN106543143B

CN106543143B - A kind of novel FLT3 kinase inhibitor and application thereof

Info

Publication number: CN106543143B
Application number: CN201510608850.4A
Authority: CN
Inventors: 刘青松; 刘静; 李滨华; 王傲莉; 吴宏; 陈程; 王文超; 胡晨; 赵铮; 余凯琳; 王蓓蕾; 王黎
Original assignee: Hefei Zhongke Bio Pharmaceutical Technology Co Ltd
Current assignee: Hefei Zhongke Bio Pharmaceutical Technology Co Ltd
Priority date: 2015-09-22
Filing date: 2015-09-22
Publication date: 2019-03-22
Anticipated expiration: 2035-09-22
Also published as: CN106543143A

Abstract

The present invention provides a kind of Azaindole kinase inhibitors comprising the compound of formula (I) or its pharmaceutically acceptable salt, solvate, isomers, ester, acid, metabolin or prodrug.The present invention also provides the pharmaceutical composition for including formula (I) compound and it is used to prevent or treat cell proliferative disorders and/or the purposes and method of FLT3, c-Kit associated disease, and in response to the illness of FLT3 kinases (especially FLT3/ITD is mutated type kinase) inhibition.

Description

A kind of novel FLT3 kinase inhibitor and application thereof

Technical field

The present invention relates to a kind of novel FLT3 kinase inhibitor compounds, the pharmaceutical composition including the compound and Cell or FLT3, c-Kit kinases and/or saltant type FLT3 of subject are reduced or inhibited using these compounds and composition Kinase activity and prevent in subject or treat cell proliferative disorders and/or FLT3, c-Kit associated disease purposes and Method.

Background technique

Protein kinase is the enzyme component of signal transduction pathway, is catalyzed the terminal phosphate transesterify of ATP to the junket of protein The hydroxyl of propylhomoserin, serine and/or threonine residues.The overexpression of normal in mammals or mutation protein kinase or Improper expression has become the theme studied extensively, and it is verified play an important role in the development of many diseases, institute Stating disease includes diabetes, angiogenesis, psoriasis, restenosis, eye disease, schizophrenia, rheumatoid arthritis, artery congee Sample hardening, cardiovascular disease and cancer.In short, the inhibitor of protein kinase has special answer in treatment human and animal's disease With.

FLT3 (Fms-like tyrosine kinase 3) i.e. FMS sample tyrosine kinase 3, with c-Kit, c-FMS and PDGFR belongs to type III receptor tyrosine kinase (receptor tyrosine kinase III, RTK III) family member, Extracellular region of its protein structure including 5 immunoglobulin (Ig) spline structure domains composition, 1 transmembrane region, 1 membrane-proximal region (JM), And it is intracellular be separated by kinase insert 2 tyrosine kinase (TK) areas (S.D.Lyman etc., Oncogene, 1993, 8,815-822).Have found within 1996 that FLT3 is mutated in AML cell first, mutation type is that internal series-connection repeats (FLT3/ ITD).In recent years, many researchs have confirmed the activated mutant of FLT3 in acute myeloblastic leukemia or acute myeloid leukaemia Highly important pathological effect is played in the generation of (Acute Myeloblastic Leukemia, AML) and the progress of disease. AML patient with FLT3/ITD activated mutant usually has leukocyte counts high, and clinical prognosis is poor, easy to recur etc. Unique Clinical symptoms, and since the detection method of FLT3 activated mutant is simple and easy, therefore more and more researchers endeavour In FLT3 is developed into AML conventional detection means be used to instruct AML patient treatment and prognosis judgement and as micro- The detection means of small residual leukemia, and as the another new target spot of leukaemic's chemotherapeutics.

Haematological malignancies are that the blood of body is formed and immune system, the cancer of marrow and lymphoid tissue.Although In normal marrow, FLT3 expression is only limited to early progenitor cell, but in haematological malignancies, FLT3 be expressed at high levels or Person FLT3 mutation causes uncontrolled FLT3 receptor and the induction of downstream molecules channel, possible RAS activation.Hematological malignancy is swollen Tumor includes leukaemia, lymthoma (non-Hodgkin lymphoma), Hodgkin's disease (also referred to as Hodgkin lymphoma) and myeloma --- For example, acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia or acute myeloid leukaemia (AML), acute early young grain Chronic myeloid leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (Chronic Myelogenous Leukemia, CML), chronic neutrophilic chronic myeloid leukemia (CNL), acute undifferentiated cell leukemia (AUL), anaplastic Macrocytic lymthoma (ALCL), human adult T cell ALL, with the AML of three pedigrees (trilineage) myelodysplasia (AML/TMDS), mixed type pedigree leukaemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disorder (MPD), Huppert's disease (MM) and spinal cord sarcoma (Kottaridis, P.D., R.E.Gale et al., FLT3mutations and leukaemia,British Journal of Haematology,2003,122(4):523-38；Ansari-Lari, Ali etc. People, FLT3mutations in myeloid sarcoma, British Journal of Haematology, 2004,126 (6):785-91)。

There are mainly two types of the activated mutants for having confirmed FLT3: internal series-connection repeats (internal tandem Duplication, ITD) and activation ring in point mutation (point mutation in the activation loop, TKD Point mutation).Both activated mutants of FLT3 are responsible for FLT3 and autophosphorylation occur and then causes FLT3 generation ligand non- The constitutively activated of dependence further activates signal transduction abnormal downstream, to play promotion proliferation and inhibit apoptosis Effect so that with this mutant phenotype leukaemic's clinical prognosis it is poor.

Research hotspot is become to the targeted inhibition of FLT3 and saltant type FLT3 at present, predominantly exploitation small molecule tyrosine swashs Enzyme inhibitor inhibits its activity and competing ATP-binding site with FLT3 tyrosine kinase.Clinical suppression is come at present The kinase inhibitor of FLT3 processed has AC220 etc..

Receptor tyrosine kinase c-Kit (also known as CD117) is a kind of tool encoded by retrovirus proto-oncogene protein c-kit There is the transmembrane receptor protein of tyrosine kinase activity, is pierced with platelet derived growth factor receptor (PDGFR), macrophage colony Swash -1 receptor of the factor (CSF-1R) and Fms sample tyrosine kinase receptor 3 (FLT3) collectively constitutes III receptor tyrosine kinase and surpasses Family plays a very important role during tumor development.Therefore, c-Kit is that current tumor cells targeting is controlled One of popular target for the treatment of.C-Kit is one of the important member of tyrosine kinase receptor protein family, is used as stem cell factor Receptor, can pass through a series of signal access participate in hemopoietic stem cell proliferation differentiation regulation.Recent study discovery, c- There is mutation in kit gene, especially activity mutation and morbidity, treatment and prognosis in acute leukemia etc. is closely related.

Gastrointestinal stromal tumor (Gastrointestinal Stromal Tumors, GIST) is alimentary canal most common Leaf source property tumour.The GIST of the overwhelming majority expresses the Kit albumen (CD117) of c-kit gene coding.On molecular level, greatly There is c-kit gene mutation in partial GIST, so as to cause Kit albumen activation do not need ligand SCF participation can stimulate The continuous proliferation of tumour cell and anti-apoptotic signal it is out of control.Gastrointestinal stromal tumor accounts for the 1~3% of gastrointestinal cancer, estimates Counting annual morbidity is about 10-20/100 ten thousand, is mainly in middle-older patient, patient is rare within 40 years old or less, and men and women's disease incidence is without obvious Difference.GIST largely betides stomach (50~70%) and small intestine (20~30%), and Colon and rectum accounts for about 10~20%, and esophagus accounts for 0 ~6%, it is rare behind mesenterium, nethike embrane and abdominal cavity.Patient GIST 20-30% be it is pernicious, when medical for the first time there are about 11~ 47% has transfer, shifts mainly in liver and abdominal cavity.2001, Joensuu etc. reported the first advanced GIST subject and receives Molecular targeted agents imatinib mesylate (abbreviation Imatinib) treatment is effective, U.S. Food and Drug Administration in 2002 (FDA) Standard dose of the official approval Imatinib as GIST has started the molecular targeted therapy new era of GIST.c-Kit Success of the kinase inhibitor in tumor cells targeted therapy makes us filled with exultation really, and Unfortunately, Partial tumors are suffered from Person will appear drug resistance using such drug afterwards for a period of time, and mechanism is sufficiently complex, main secondary including kinase domain Point mutation, the amplification of target gene and overexpression or epigenetic regulation activation, the up-regulation of redundancy/downstream signaling pathway swash Living and overexpression of abc transport albumen etc..Therefore, it is imperative to develop new c-Kit inhibitor.

Summary of the invention

The present invention provides a kind of novel FLT3 kinase inhibitors comprising the compound of formula (I) or its is pharmaceutically acceptable Salt, solvate, isomers, ester, acid, metabolin or prodrug:

Wherein:

Ar₁And Ar₂It is each independently aryl or heteroaryl；

X be selected from Linking group；

R₁And R₂It is each independently selected from hydrogen, halogen, alkyl and halogenated alkyl；

R₃It is selected from:

R₄It is selected from

R₅Selected from alkyl；Alkenyl；Alkynyl；Halogenated alkyl；Naphthenic base；Aminoalkyl；Alkylaminoalkyl group；Alkyl amino alkene Base；Heterocyclylalkyl is optionally optionally taken by alkyl by alkyl, alkyl-carbonyl, naphthene base carbonyl, amino protecting group or hetero atom The Heterocyclylalkyl in generation replaces；Cycloalkenyl；Heteroaryl；Optionally by alkyl-substituted hetercycloalkylalkyl；Optionally taken by alkyl The heteroaryl in generation；Alkyl is optionally by amino replaces and nitrogen is optionally replaced by amino protecting group aminoacyl alkyl；Alkyl is optional Ground is replaced by amino and nitrogen is optionally by amino protecting group replaces and/or aryl is optionally optionally substituted by a hydroxyl group aryl alkyl；And alkane Base is optionally replaced by amino and nitrogen is optionally by amino protecting group replaces and/or heteroaryl is optionally optionally substituted by a hydroxyl group heteroaryl alkane Base.Wherein, amino protecting group is independently selected from tertbutyloxycarbonyl, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl, benzyl and to methoxy benzene Base.

On the other hand, the present invention provides a kind of pharmaceutical composition comprising at least one of therapeutically effective amount mentions herein The compound of confession or its pharmaceutically acceptable salt, solvate, isomers, ester, acid, metabolin or prodrug and pharmacy can connect The carrier or excipient received, and optional other therapeutic agents.

It yet still another aspect, the present invention provides a kind of formula of the invention (I) compound or its pharmaceutically acceptable salt, solvation The preparation method of object, isomers, ester, acid, metabolin or prodrug.

It yet still another aspect, the present invention relates to formula (I) compound or its pharmaceutically acceptable salt, solvate, isomers, Ester, acid, metabolin or prodrug reduce or inhibit in vivo or in vitro tyrosine kinase FLT3, c-KIT, ABL, EGFR, BMX, The active purposes of BLK, VEGFR, RET, PDGFR, MEK, BCR/ABL, JAK, BRAF, especially FLT3 kinases and/or saltant type FLT3 kinases and c-Kit kinases.

It yet still another aspect, the present invention relates to formula (I) compound or its pharmaceutically acceptable salt, solvate, isomers, Ester, acid, metabolin or prodrug or pharmaceutical composition including formula (I) compound are in preparation for treating cell proliferative disorders And/or the purposes in the drug of FLT3, c-Kit associated disease.

Particularly, the illness presses down in response to FLT3 or saltant type FLT3 kinase inhibition, or in response to c-Kit kinases System.FLT3 mutation includes ITD mutation and TKD point mutation, especially FLT3/ITD mutation.

Detailed description of the invention

Fig. 1 a to 1h be shown respectively the compound of the present invention 2-3, compound 2-1 and compound 2-33 MV-4-11, To the influence of opposite with FLT3 closely related albumen and associated signal paths in MOLM-14 and MOLM-13 cell.

The compound of the present invention 2-1 and compound 2-33 is shown respectively in MV-4-11, MOLM-14 and MOLM- in Fig. 2 a to 2e To the influence of Apoptosis in 13 cells.

The compound of the present invention 2-1 and compound 2-33 is shown respectively to MV-4-11 and MOLM-14 cell strain in Fig. 3 a to 3c Cell cycle distribution influence.

Specific embodiment

Term

Unless otherwise defined, all scientific and technical terminologies used herein all have the skill with claimed theme fields Art personnel are commonly understood by identical meaning.

Unless otherwise indicated, the present invention is using mass spectrum, the NMR, HPLC, protein chemistry, life within the scope of art technology The conventional methods such as object chemistry, recombinant DNA technology and pharmacology.Unless provide specific definition, otherwise with analysis described herein The chemically relevant name of chemistry, synthetic organic chemistry and medicine and pharmaceutical chemistry etc. and laboratory operation and technology, are these Known to the technical staff of field.In general, aforementioned techniques and step can be by well-known in the art and various one As conventional method described in document and more specific document implement, these documents are cited in the present specification and discuss.

Terms used herein " alkyl " refer to the linear chain or branched chain alkyl containing 1 to 12 carbon atom.Term " lower alkyl Base " refers to C1~C6 alkyl chain.Alkyl can be optionally substituted by one or more substituents.In the present invention, alkyl is preferred For C1-C8 alkyl, more preferably C1-C6 alkyl.Typical alkyl includes but is not limited to methyl, ethyl, propyl, isopropyl, fourth Base, isobutyl group, tert-butyl, amyl, hexyl etc..It should be understood that " alkyl " that is mentioned herein include all configurations that may be present and The alkyl of conformation, such as " butyl " that is mentioned herein includes normal-butyl, isobutyl group and tert-butyl.

Term " alkenyl " refers to the aliphatic unsaturated hydrocarbon that can be linear chain or branched chain, contains 2 to 12 carbon atoms and at least One carbon-to-carbon double bond.Alkenyl can be optionally substituted by one or more substituents.In the present invention, alkenyl is preferably C2-C8 Alkenyl, more preferably C2-C6 alkenyl, more preferably C2-C4 alkenyl.

Term " alkynyl " refers to the aliphatic unsaturated hydrocarbon that can be linear chain or branched chain, contains 2 to 12 carbon atoms and at least One carbon-carbon triple bond.Alkynyl can be optionally substituted by one or more substituents.In the present invention, alkynyl is preferably C2-C8 Alkynyl, more preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl.

The sp of alkenyl and alkynyl²Or sp carbon can be optionally the tie point of alkenyl or alkynyl respectively.

Term " amino " refers to group-NH₂.Term " aminoacyl " refers to-CO-NH₂.Term " amide groups " or " acylamino- " Refer to-NR-CO-R ', wherein R and R ' are each independently hydrogen or alkyl.

Term " alkyl amino " refers to further by one or two alkyl-substituted amino-substituent, in particular to base Group-NRR ', wherein R and R ' is each independently selected from hydrogen or low alkyl group, and condition is that-NRR ' is not-NH₂.Term " amino alkane Base " refers to the alkyl substituent further replaced by one or more amino.Term " hydroxyalkyl " or " hydroxy alkyl " are fingering The alkyl substituent that one step is replaced by one or more hydroxyls.Term " cyanoalkyl " refers to further by one or more cyano Substituted alkyl substituent.Term " alkanoyl " or " alkyl-carbonyl " refer to further by an alkyl-substituted carbonyl.Term " Alkylcarbonylalkyl " refers to the alkyl further replaced by an alkyl-carbonyl.Term " alkoxy carbonyl " refer to further by The carbonyl that one alkoxy replaces.Term " alkylaminoalkyl group " refers to alkyl defined herein by alkyl amino defined herein Replace.Alkyl amino, aminoalkyl, hydroxy alkyl, cyanoalkyl, alkyl-carbonyl, Alkylcarbonylalkyl, alkoxy carbonyl, with And the moieties in alkylaminoalkyl group can be optionally substituted by one or more substituents.

Term " aromatic radical " refers to that planar rings have the pi-electron system of delocalization and contain 4n+2 pi-electron, and wherein n is Integer.Fragrant basic ring can be by five, six, seven, eight, nine or more than nine atomic buildings.Aromatic radical, which can be, optionally to be replaced.Art Language " aromatic radical " includes isocyclic aryl (such as phenyl) and heterocyclic aryl (or " heteroaryl " or " heteroaryl perfume base ") group (such as pyrrole Pyridine).The term includes monocycle or polycyclic (sharing the ring of the adjacent carbon atom pair) group of condensed ring.

The atom that terms used herein " aryl " refer to that each in fragrant basic ring constitutes ring is carbon atom.Aryl rings By five, six, seven, eight, nine or nine atomic buildings can be more than.Aryl, which can be, optionally to be replaced.The example of aryl include but It is not limited to phenyl, naphthalene, phenanthryl, anthryl, fluorenyl and indenyl.According to structure, aryl can be monoradical or bivalent radical (i.e. Arlydene).

" alkyl (aryl) " or " aralkyl " refer to that alkyl defined herein is replaced by aryl defined herein.It is non-limiting Alkyl (aryl) include benzyl, phenethyl etc..

Term " naphthenic base " refers to monocycle or polycyclic group, only contains carbon and hydrogen.Naphthenic base includes having 3-8 annular atom Group.According to structure, naphthenic base can be monoradical or bivalent radical (such as cycloalkylidene).In the present invention, cycloalkanes Base is preferably the naphthenic base with 3-8 carbon atom, more preferably with " low-grade cycloalkyl " of 3-6 carbon atom.

" alkyl (naphthenic base) " or " cycloalkyl-alkyl " refer to that alkyl defined herein is replaced by naphthenic base defined herein. Unrestricted alkyl (naphthenic base) includes Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl etc..

Terms used herein " miscellaneous alkyl " refer to that one or more skeletal chain atoms in alkyl defined herein are miscellaneous Atom, such as oxygen, nitrogen, sulphur, silicon, phosphorus or their combination.The hetero atom (one or more) can be located inside miscellaneous alkyl Any position or in the position that miscellaneous alkyl is connected with the rest part of molecule.

Term " heteroaryl " refers to include one or more ring hetero atoms selected from nitrogen, oxygen and sulphur in aryl.Containing N " heteroaryl Base " partially refers to that at least one skeletal atom is nitrogen-atoms in aromatic radical middle ring.According to structure, heteroaryl can be monovalent radical Group or bivalent radical (i.e. inferior heteroaryl).The example of heteroaryl include but is not limited to pyridyl group, imidazole radicals, pyrimidine radicals, pyrazolyl, Triazolyl, pyrazinyl, tetrazole radical, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrole radicals, quinoline Quinoline base, isoquinolyl, indyl, benzimidazolyl, benzofuranyl, indazolyl, indolizine base, phthalazinyl, pyridazinyl, iso-indoles Base, pteridyl, purine radicals, oxadiazoles base, thiadiazolyl group, furyl, benzofuranyl, benzothienyl, benzothiazolyl, benzene And oxazolyl, quinazolyl, naphthyridines base and furopyridyl etc..

Terms used herein " Heterocyclylalkyl " refer to that one or more atoms for constituting ring are to be selected from non-aromatic basic ring The hetero atom of nitrogen, oxygen and sulphur.Heterocycloalkyl ring can be by three, four, five, six, seven, eight, nine or more than nine atomic buildings.Heterocycle Alkyl ring, which can be, optionally to be replaced.The example of Heterocyclylalkyl includes but is not limited to lactams, lactone, ring Asia glue, epithio generation Asia Amine, cyclic carbramates, tetrahydric thiapyran, 4H- pyrans, oxinane, piperidines, 1,3- dioxin, 1,3- dioxanes, 1,4- bis- are disliked English, 1,4- dioxanes, piperazine, 1,3- thioxane, 1,4- oxathiin, 1,4- thioxane, tetrahydro- 1,4- thiazine, 2H-1,2- oxazines, maleimide, succinimide, barbiturates, thiobarbituricacidα-, dioxopiperazine, Hydantoins, dihydrouracil, azepineHigh piperidines, morpholine, trioxane, hexahydro -1,3,5- triazine, thiophane, tetrahydro furan It mutters, pyrrolin, pyrrolidines, imidazolidine, pyrrolidones, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3- dioxane penta Alkene, 1,3- dioxolane, 1,3- dithiole, 1,3- dithiolane, isoxazoline, isoxazole alkane, oxazole Quinoline, oxazolidine, oxazolidone, thiazoline, thiazolidine and 1,3- oxathiolane.According to structure, Heterocyclylalkyl can be list Valence group or bivalent radical (i.e. sub- Heterocyclylalkyl).

Term " alkyl (heteroaryl) " or " heteroaryl alkyl " refer to alkyl defined herein by heteroaryl defined herein Replace.

Term " alkyl (Heterocyclylalkyl) " or " hetercycloalkylalkyl " refer to alkyl defined herein by defined herein miscellaneous Naphthenic base replaces.

Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.

Term " halogenated alkyl ", " alkoxy that halogen replaces " and " miscellaneous alkyl that halogen replaces " include alkyl, alkoxy or miscellaneous The structure of alkyl, wherein at least one hydrogen are replaced by halogen atom.In some embodiments, if two or more hydrogen atom quilts Halogen atom displacement, the halogen atom are same or different to each other.

Term " acyl group " refers to remaining monovalent radical after organic or inorganic oxyacid removes hydroxyl, general formula R-M (O)-, wherein M is usually C.

Term " carbonyl " is the organo-functional group (C=O) being formed by connecting by two kinds of atoms of carbon and oxygen by double bond.

Term " substituted " refers to that mentioned group can be replaced by one or more additional groups, it is described additionally Group is respectively and independently selected from alkyl, naphthenic base, aryl, heteroaryl, hydroxyl, alkoxy, cyano, halogen, amide groups, nitre Base, halogenated alkyl, amino, alkoxy carbonyl, alkyl (heteroaryl), alkyl (Heterocyclylalkyl) etc..

Any group is (for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, naphthenic base, heterocycle Alkyl) it can optionally be substituted by one or more substituents, and substituent group can be on the arbitrary atom of the group, wherein can Substituted any group can optionally be replaced by one or more substituent groups (it can be same or different), respectively Replace a hydrogen atom.The example of substituent group appropriate includes, but are not limited to alkyl, alkenyl, alkynyl, naphthenic base, heterocycle alkane Base, aralkyl, heteroarylalkyl, aryl, heteroaryl, halogen, halogenated alkyl, cyano, nitro, alkoxy, halogenated alkoxy, fragrant oxygen Base, hydroxyl, hydroxy alkyl, oxygen (that is, carbonyl), carboxyl, formoxyl, alkyl-carbonyl, Alkylcarbonylalkyl, alkoxy carbonyl, alkane Base carbonyl oxygroup, aryloxycarbonyl, heteroaryloxy, Heteroaryloxycarbonyl, sulfenyl, sulfydryl, mercaptoalkyl, aryl sulfonyl, ammonia Base, aminoalkyl, dialkyl amido, alkyl-carbonyl-amino, alkyl amino-carbonyl, alkoxycarbonyl amino, alkyl amino, aryl The aryl that amino, ammonia diaryl base, alkyl-carbonyl or arylamino replace；Aryl-alkyl amino, Aralkylaminocarbonyl, acyl Amino, alkyl amino sulfonyl, n-aryl sulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, aryl sulfonyl Amino, imino group, urea groups, carbamoyl, ghiourea group, thiocyano, sulfonamido, Sulfonylalkyl, sulfonyl aryl, sulfydryl Alkoxy, N- hydroxyl amidino groups or N '-aryl, N "-hydroxyl amidino groups, thio alkoxy, cycloalkyloxy, the fluoro containing 1~5 fluorine Alkoxy, formamido group, the aryl optionally replaced or the heteroaryl optionally replaced.

" inhibition ", " inhibition " or " inhibitor " of terms used herein kinases, refers to that phosphate transferase activity is pressed down System.

" metabolin " of compound disclosed herein is the derivative of the compound formed when the compound is metabolized.Art Language " active metabolite " refers to the biologically active derivatives of the compound formed when the compound is metabolized.Art used herein Language " is metabolized ", refers to the process of predetermined substance by organism transform summation (including but not limited to hydrolysis and by enzymatic Reaction, such as oxidation reaction).Therefore, enzyme can produce specific structure and be changed into compound.For example, Cytochrome P450 It is catalyzed various oxidations and reduction reaction, while the glucuronic acid molecule of diphosphate glucose sweet acid based transferase catalytic activation is extremely The conversion of aromatic alcohol, aliphatic alcohol, carboxylic acid, amine and free sulfydryl.The further information of metabolism can be from " The Pharmacological Basis of Therapeutics ", the 9th edition, McGraw-Hill (1996) is obtained.It is disclosed herein The metabolin of compound can be by giving compound to host and analyzing tissue sample from the host or by that will change Object is closed to be incubated in vitro with liver cell and analyze gained compound to identify.Both methods is all known in the art.? In some embodiments, the metabolin of compound be by oxidation process formed and it is corresponding with corresponding hydroxy-containing compounds.? In some embodiments, compound is metabolized as pharmaceutical active metabolite.Terms used herein " adjusting ", refer to directly or It connects and interacts with target, to change the activity of target, for example only, activity, suppression target including enhancing target Activity, limit target target activity or the activity for extending target.

Term " prodrug " includes the compound with the part that can be metabolized in vivo.In general, prodrug is by esterase or leads to It crosses other mechanism and is metabolized active drugs in vivo.The example of prodrug and application thereof is known (see, for example, Berge in the art Et al. (1977) " Pharmaceutical Salts ", J.Pharm.Sci.66:1-19).Can compound be finally recovered and Prodrug is prepared in situ during purifying, or by individually making the compound of purifying with its free acid form or hydroxyl and suitably Esterifying agent reacts to prepare.Hydroxyl can handle through carboxylic acid and be converted into ester.The example of prodrug moiety includes replacing and not taken Generation, branch or unbranched lower alkyl ester moieties (such as propionic ester), low-grade alkenyl ester, two-lower alkyl-amino lowers Arrcostab (such as dimethyl aminoethyl ester), acyl amino lower alkyl esters (such as acetoxy-methyl ester), acyloxy are low Grade Arrcostab (such as oxy acid methyl neopentyl ester), aromatic yl elementary alkyl ester (such as benzyl ester), replaces aryl ester (phenylester) (such as being replaced by methyl, halogen or methoxy substitution base) aryl and aromatic yl elementary alkyl ester, amide, low alkyl group acyl Amine, two lower alkyls and hydroxy amide.Preferred prodrug moiety is propionic ester and acyl ester.It is also included within and passes through it in vivo Its mechanism is converted to the prodrug of active form.In some respects, the compound of the present invention is the prodrug of any this paper general formula.

Term " isomers " refers to that chemical composition is identical but compound that atom or group are different on space arrangement, meaning Include diastereoisomer, enantiomter, region isomer (regioisomers), constitutional isomer, rotational isomer, Tautomer etc..For the compound containing one or more Stereocenters (stereogenic center), such as hand Property compound, can be used enantiomeric enrichment compound, racemic modification or non-enantiomer mixture to implement the present invention Method.

Terms used herein " target protein " refer to the protein molecule that can be combined by selective binding compounds or portion Divide protein.In some embodiments, target protein is FLT3.

Drug concentration needed for GI50 used herein refers to 50% growth inhibition of cell, i.e. drug make 50% cancer cell Growth is inhibited or controls, drug concentration at this time.

IC used herein₅₀Refer to that the 50% of ceiling effect is obtained in the analysis for measuring such effect inhibits specific Test amount, concentration or the dosage of compound.

EC used herein₅₀Dosage, concentration or the amount for referring to measurement compound, particular assay compound is caused to induce, The dose-dependant reaction of 50% maximum expression of stimulation or the specific reaction reinforced.

The novel kinase inhibitor of the present invention

Wherein:

Ar₁And Ar₂It is each independently aryl or heteroaryl, such as phenyl, thiazolyl, quinazolyl, benzoxazolyl；

X be selected from Linking group；

R₁And R₂It is each independently selected from hydrogen；Halogen；Alkyl, such as methyl；And halogenated alkyl, such as trifluoromethyl；

R₃It is selected from:

R₄It is selected from

R₅Selected from alkyl, such as methyl, ethyl, propyl, neopentyl, nonyl；Alkenyl, such as vinyl, acrylic；Alkynes Base, such as acetenyl；Halogenated alkyl, such as chloric ethane base；Naphthenic base, such as cyclopropyl；Aminoalkyl, such as amino first Base, amino-ethyl；Alkylaminoalkyl group, such as N, N- dimethylaminomethyl, N, N- dipropylamino ethyl；Alkyl amino alkene Base, such as N, N- Dimethylamino-propenoyl base；Heterocyclylalkyl (such as piperidyl, pyranose), optionally by alkyl (such as first Base, ethyl), alkyl-carbonyl (such as methyl carbonyl, ethylcarbonyl group), naphthene base carbonyl (such as cyclopropyl carbonyl), amido protecting Base (such as Boc) or hetero atom are optionally replaced by the Heterocyclylalkyl that alkyl (such as methyl) replaces；Cycloalkenyl, preferably five yuan or Hexa-atomic cycloalkenyl, such as cyclopentenyl, cyclohexenyl group；Heteroaryl, such as pyridyl group；Optionally by alkyl-substituted Heterocyclylalkyl Alkyl；Optionally by alkyl-substituted heteroaryl (such as pyridyl group, isoxazolyl)；Alkyl is optionally replaced by amino and nitrogen is appointed Select the aminoacyl alkyl replaced by amino protecting group；Alkyl is optionally replaced by amino and nitrogen is optionally replaced by amino protecting group And/or the aryl alkyl that aryl is optionally optionally substituted by a hydroxyl group；And alkyl is optionally replaced by amino and nitrogen is optionally by amido protecting The heteroaryl alkyl that base replaces and/or heteroaryl is optionally optionally substituted by a hydroxyl group.Wherein, amino protecting group is independently selected from tertiary butyloxycarbonyl Base (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl (FMOC), benzyl (Bn) and p-methoxyphenyl (PMP).

Compound involved in the present invention with chirality, configuration can be arbitrary configuration or mixed racemic modification.

For each variable, any combination of above-mentioned group also among considering herein.It is to be understood that being mentioned herein Substituent group and substitute mode on the compound of confession can be selected by those skilled in the art, in order to provide chemically stable And can be used techniques known in the art and technology set forth herein synthesis compound.

Described herein is novel kinase inhibitor.The pharmaceutically acceptable salt, molten of this compound has been also described herein Agent compound, isomers, ester, acid, pharmaceutical active metabolite and prodrug.

In other or further embodiment, by compound described herein give after organism in need Its metabolism in vivo generates metabolin, and generated metabolin is subsequently used for generating desired effect, including desired therapeutic effect.

Compound described herein can be made into and/or be used as pharmaceutically acceptable salt.Pharmaceutically acceptable salt Type includes but is not limited to: (1) acid-addition salts, by by the free alkali form of compound and pharmaceutically acceptable inorganic acid reaction It is formed, described inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc.；Or formed with organic acid reaction, it is described Organic acid for example acetic acid, propionic acid, caproic acid, pentamethylene propionic acid, hydroxyacetic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, Succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3- (4- hydroxy benzoyl) benzoic acid, cortex cinnamomi Acid, mandelic acid, Loprazolam, ethane sulfonic acid, 1,2- ethionic acid, 2- ethylenehydrinsulfonic acid, benzene sulfonic acid, toluenesulfonic acid, 4- methyl Bicyclic-[2.2.2] oct-2-ene -1- formic acid, 2- naphthalene sulfonic acids, butylacetic acid, glucoheptonic acid, 4,4' methylene bis-(3- hydroxyl Base -2- alkene -1- formic acid), 3- phenylpropionic acid, trimethylace tonitric, dodecyl sulphate, gluconic acid, glutamic acid, salicylic acid, hydroxyl Naphthoic acid, stearic acid, muconic acid etc.；(2) base addition salts, the shape when acid proton in parent compound is replaced by metal ion At, such as alkali metal ion (such as lithium, sodium, potassium), alkaline-earth metal ions (such as magnesium or calcium) or aluminium ion；Or match with organic base Position.Acceptable organic base includes ethanol amine, diethanol amine, triethanolamine, trimethylamine, N- methyl glucose osamine, etc..It can connect The inorganic base received includes aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc..

Various method analyses and identification can be used in the corresponding ion balance of pharmaceutically acceptable salt, the method includes But be not limited to ion-exchange chromatography, ion chromatography, Capillary Electrophoresis, inductively coupled plasma body, atomic absorption spectrum, mass spectrum or Any combination of them.

Recycle the salt using at least one of following technology: filtering is then filtered, solvent evaporation with non-solvent precipitation, Or desivac is used in the case where aqueous solution.

Screening and characterize pharmaceutically acceptable salt, polymorphic and/or solvate can be used multiple technologies completion, described Technology includes but is not limited to heat analysis, X-ray diffraction, spectrum, microscopy, elemental analysis.The various spectral techniques used Including but not limited to Raman, FTIR, UVIS and NMR (liquid and solid state).Various microscopies include but is not limited to IR Microscopy and Raman (Raman) microscopy.

Medical composition and its use of the invention

The present invention also relates to pharmaceutical compositions, they include formula (I) compound or its pharmaceutically acceptable salt, solvation Object, isomers, ester, acid, metabolin or prodrug are as active constituent and pharmaceutically acceptable carrier or excipient, Yi Jiren Other therapeutic agents of choosing.

Formula (I) compound or its pharmaceutically acceptable salt, solvate, isomers, ester, acid, metabolin or prodrug and Pharmaceutical composition including it is hereinafter also known as " substance of the invention ".

Substance of the invention can be used to treat or prevent cell proliferative disorders and/or FLT3, c-Kit associated disease, special It is not in response to the disease inhibited in protein tyrosine kinase inhibition, especially FLT3 or saltant type FLT3 kinase inhibition or c-Kit. FLT3 mutation includes ITD mutation and TKD point mutation, especially ITD mutation." treatment " of the invention can be it is therapeutic (such as Symptomatic treatment) and/or it is preventative.Substance of the invention can preferably treat or prevent illness relevant to FLT3 or c-Kit, special Other preferred therapeutic or prevention illness relevant to saltant type FLT3/ITD.

Over the course for the treatment of, substance of the invention can according to circumstances individually or with one or more other therapeutic agent groups It closes and uses.Can by injecting, taking orally, suck, at least one of rectum and transdermal administration will be comprising comprising at least one formula (I) medicament administration of compound is to the patient needed.Other therapeutic agents can be selected from following drug: immunosuppressor (example Such as tacrolimus, encircle rhzomorph, rapamycin, Methylaminopterin, cyclophosphamide, imuran, mercaptopurine, mycophenolate or FTY720), glucocorticoids medicine (such as prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, times he Meter Song, triamcinolone, hydrogen hydroxyl prednisolone, beclomethasone, fludrocortisone acetate, percorten, aldosterone), it is non- Steroidal anti-inflammatory medicine (such as salicylate, aryl alkanoic acid, 2- arylpropionic acid, N- aryl-anthranilic acid, former times health class, examine former times class Or sulphonanilid), allergic reaction bacterin, antihistamine, anti-leukotriene medicine, beta-2-agonists, theophylline, anticholinergic agent or other choosings Selecting property kinase inhibitor (such as mTOR inhibitors, c-Met inhibitor) or Her2 antibody-drug.It other is controlled in addition, mentioned Treating agent can also be rapamycin (Rapamycin), gram azoles for Buddhist nun (Crizotinib), tamoxifen, Raloxifene, Ah Nagqu Azoles, Exemestane, Letrozole, Trastuzumab^TM(Herceptin), Gleevec^TM(Imatinib), taxol^TM(taxol), ring Phosphamide, Lovastatin, U.S. promise tetracycline (Minosine), cytarabine, 5 FU 5 fluorouracil (5-FU), methotrexate (MTX) (MTX), Taxotere^TM(docetaxel), Zoladex^TM(Goserelin), vincristine, vincaleukoblastinum, nocodazole, Teniposide, support Moor glycosides, gemzar^TM(gemcitabine), Epothilones (Epothilone), promise only sheet, camptothecine, daunorubicin (Daunonibicin), dactinomycin D, mitoxantrone, amsacrine, Doxorubicin (adriamycin), epirubicin or Yi Da Compare star.Alternatively, other therapeutic agents are also possible to cell factor such as G-CSF (granulocyte colony stimulating factor).Alternatively, other control It treats agent to be also possible to be such as, but not limited to, CMF (cyclophosphamide, methotrexate (MTX) and 5 FU 5 fluorouracil), CAF (cyclophosphamide, Asia Baudrillard mycin and 5 FU 5 fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5 FU 5 fluorouracil, epirubicin and Cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide and taxol) or CMFP (cyclophosphamide, methotrexate (MTX), 5- Fluorouracil and prednisone).

Other therapeutic agents further include, for example, cytostatics, other antiproliferatives.

This kind of antiproliferative includes but is not limited to aromatization enzyme inhibitor, antiestrogenic, topoisomerase I inhibitor, opens up Flutter isomerase II inhibitor, microtubule active agent, alkylating agent, inhibitors of histone deacetylase, farnesyl transferase inhibitor, Cox 2 inhibitor, mTOR inhibitors, anti-tumor formative antimetabolite, platinum compounds, reduces protein kinase activity at MMP inhibitor Compound and further anti-angiogenic compounds, GnRF agonist, antiandrogen, Bengamide, bis-phosphonic acids compounds, steroids, anti proliferative antibody, 17- (allyl amido) -17- de-methoxy Ge Erde Mycin (17-AAG) and Temozolomide (TMEMODAL).

Terms used herein " aromatization enzyme inhibitor " is related to inhibiting estrogen production, namely substrates androstenedione and female The compound of diketone conversion.The term includes but is not limited to steroids, especially Exemestane and formestane, and is especially non-class Sterol, especially aminoglutethimide, R 83842, Fadrozole, Anastrozole, very especially Letrozole.Exemestane for example can be with The administration of its commercial form, such as trade mark are AROMASIN^TM.Formestane can be for example administered with its commercial form, such as trade mark is LENTARON^TM.Fadrozole can be for example administered with its commercial form, such as trade mark is AFEMA^TM.Aminoglutethimide for example can be with The administration of its commercial form, such as trade mark are ORIMETEN^TM。

It is particularly useful for treating hormone receptor as the present composition of anti-tumor form agent comprising aromatization enzyme inhibitor Positive breast tumors.

The term as used herein " antiestrogenic " is related to the compound of the antagonising oestrogen effect on Estrogen Receptor. The term includes but is not limited to tamoxifen, fulvestrant, Raloxifene and RALOXIFENE HCL.Tamoxifen for example may be used To be administered with its commercial form, such as trade mark is NOLVADEX^TM.RALOXIFENE HCL can be for example administered with its commercial form, Such as trade mark is EVISTA^TM.Fulvestrant can be prepared as described in US4659516, such as can be with its commercial form Administration, such as trade mark are FASLODEX^TM。

The term as used herein " topoisomerase I inhibitor " includes but is not limited to topotecan, Irinotecan, 9- nitro Camptothecin conjugate PNU-166148 (the compound A1 in WO99/17804).Irinotecan can for example be given with its commercial form Medicine, such as trade mark are CAMPTOSAR^TM.Topotecan can be for example administered with its commercial form, such as trade mark is HYCAMTIN^TM。

The term as used herein " Topoisomerase II inhibitors " includes but is not limited to anthracyclines (antracycline) Adriamycin (including Liposomal formulation, such as CAELYX^TM), epirubicin, idarubicin and Nai Mo be than star (nemorubin), anthracene Quinones mitoxantrone and Lip river element anthraquinone and podophillotoxines etoposide and Teniposide.Etoposide for example can the city Yi Qi Sell form administration, such as trade mark ETOPOPHOS^TM.Teniposide can be for example administered with its commercially available formula, such as trade mark is VM 26- BRISTOL^TM.Adriamycin can be for example administered with its commercial form, such as trade mark is ADRIBLASTIN^TM.Idarubicin is for example It can be administered with its commercial form, such as trade mark is ZAVEDOS^TM.Mitoxantrone can be for example administered with its commercial form, such as Trade mark is NOVANTRON^TM。

Term " microtubule active agent " is related to microtubule stabilization agent, including but not limited to taxane taxol (paclitaxel) and Docetaxel (docetaxel), catharanthus alkaloid, such as vincaleukoblastinum, especially vinblastine sulfate, discodermolide , such as epothilone B and D (discodermolide) and Epothilones (epothilone).Docetaxel for example can be with it Commercial form administration, such as trade mark are TAXOTERE^TM.Vinblastine sulfate can be administered with its commercial form, such as trade mark is VINBLASTIN R.P.^TM.Vincristine sulphate can be for example administered with its commercial form, such as trade mark is FARMISTION^TM。 Discodermolide can for example be obtained as described in US 5010099.

The term as used herein " alkylating agent " includes but is not limited to ring phosphamidon, ifosfamide and melphalan.Ring phosphinylidyne Amine can be for example administered with its commercial form, such as trade mark is CYCLOSTIN^TM.Ifosfamide for example can be with its commercially available shape Formula administration, such as trade mark are HOLOXAN^TM。

Term " inhibitors of histone deacetylase " is related to inhibition of histone deacetylase and has antiproliferative activity Compound.This includes compound disclosed in WO 02/22577, especially N- hydroxyl -3- [[(2- hydroxyethyl) [2- (1H- indoles - 3- yl) ethyl]-amino] methyl] phenyl] -2E-2- acrylamide, N- hydroxyl -3- [[(2- hydroxyethyl) [2- (1H- indoles - 3- yl) ethyl]-amino] methyl] phenyl] -2E-2- acrylamide and its pharmaceutically acceptable salt.It further especially include pungent Two anilide hydroxamic acid (SAHA).

Term " farnesyl transferase inhibitor " is related to inhibiting farnesyl transferase and has the chemical combination of antiproliferative activity Object.

Term " cox 2 inhibitor " is related to inhibiting cyclooxygenase 2 type enzyme (COX-2) and has the chemical combination of antiproliferative activity (COX189) is examined former times in object, such as celecoxib (Celebrex), profenoxib (Vioxx) and Rumi drawing.

Term " MMP inhibitor " is related to inhibiting matrix metalloproteinase (MMP) and has the compound of antiproliferative activity.

Term " mTOR inhibitors " is related to inhibiting mammal rapamycin target (mTOR) and has antiproliferative activity Compound, such as sirolimus (Rapamune), everolimus (Certican^TM), CCI-779 and ABT578.

Term " anti-tumor formative antimetabolite " include but is not limited to 5 FU 5 fluorouracil, Tegafur, capecitabine, carat bend Shore, cytarabine, fludarabine phosphate, fluridine (fluorouridine), gemcitabine, Ismipur, hydroxycarbamide, first The salt of ammonia petrin, Edatrexate and this kind of compound, in addition there are ZD1694 (RALTITREXED^TM)、LY231514 (ALIMTA^TM)、LY264618(LOMOTREXOL^TM) and OGT719.

The term as used herein " platinum compounds " includes but is not limited to carboplatin, cis-platinum and oxaliplatin.Carboplatin for example can be with With the administration of its commercial form, such as trade mark is CARBOPLAT^TM.Oxaliplatin can be for example administered with its commercial form, such as quotient It is designated as ELOXATIN^TM。

The term as used herein " compound and further anti-angiogenic compounds that reduce protein kinase activity " packet Include but be not limited to reduce following active compound, for example, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), C-Src, protein kinase C, platelet derived growth factor (PDGF), Bcr-Abl, c-Kit, FLT3, insulin-like growth factor I Receptor (IGF-IR) and cell cycle protein dependent kinase (CDK) have the function of being different from reducing protein kinase activity machine The anti-angiogenic compounds of reason.

Reduce the tyrosine kinase activity that VEGF active compound especially inhibits vegf receptor, especially vegf receptor Compound and the compound in conjunction with VEGF, especially general and specific those disclosed compound, albumen in the following documents Matter and monoclonal antibody: WQ98/35958 (description compound of formula I), WO00/09495, WO00/27820, WO00/59509, WO98/11223, WO00/27819, WO01/55114, WO01/58899 and EP0769947；M.Prewett et al. is in Cancer In Research 59 (1999) 5209-5218, Z.Zhu et al. in Cancer Res.58,1998,3209-3214 and J.Mordenti et al. is in Toxicologic Pathology, vol.27, those of described in no.1,14-21,1999； WO00/37502 and WO94/10202；Angiostatin^TM, such as M.S.O ' Reilly et al., Cell 79,1994,315-328 institute It states.

Reduce the active compound of EGF especially inhibits EGF combination compound, especially in the following documents generally with Those specifically disclosed compounds: WO97/02266 (description formula IV compound), EP0564409, WO99/03854, EP0520722、EP0566226、EP0787722、EP0837063、WO98/10767、WO97/30034、WO97/49688、 WOWO97/38983 and especially WO96/33980.

Reducing the active compound of c-Src includes but is not limited to inhibition c-Src protein tyrosine kinase as defined below Those of active compound and SH2 interaction inhibitor, such as be disclosed in WO97/07131 and WO97/08193.

The compound for inhibiting c-Src protein tyrosine kinase activity includes but is not limited to the chemical combination for belonging to having structure type Object: Pyrrolopyrimidine, especially pyrrolo- [2,3-d] pyrimidine；Purines；Pyrazolopyrimidines type, especially pyrrolo- [3,4-d] are phonetic Pyridine；Pyrazolopyrimidines type, especially pyrazolo pyrrolo- [3,4-d] pyrimidine and Pyridopyrimidine class, especially pyrido pyrrolo- [2, 3-d] pyrimidine.Preferably, which is related to being disclosed in WO96/10028, WO97/28161, WO97/32879 and WO97/49706 In those of compound.

It reduces the active compound of IGF-IR and those of is especially disclosed in WO02/92599 compound.

It reduces protein kinase activity and the further particular compound that can also be used in combination with the compounds of this invention has Imatinib(Gleevec/Glivec)、PKC412、Iressac^TM(ZD1839), AEE788 and its pharmaceutically acceptable salt be (see also WO03/13541), PTK787 and its pharmaceutically acceptable salt (see also WO98/35958), ZD6474, GW2016, CHIR- 200131, CEP-7055/CEP-5214, CP-547632, KRN-633 and SU5416.

Anti-angiogenic compounds with the mechanism of action for being different from reducing protein kinase activity include but is not limited to example Such as Thalidomide (THALOMID), celecoxib (Celebrex) and ZD6126.

The term as used herein " GnRF agonist " include but is not limited to abarelix, Coserelin and Goserelin acetate.Coserelin is disclosed in US4100274, such as can be administered with its commercial form, such as trade mark is ZOLADEX^TM.Abarelix can for example be prepared as described in US5843901.

The term as used herein " antiandrogen " includes but is not limited to Bicalutamide (CASODEX^TM), it for example can be as It is prepared described in US4636505.

Term " bengamide " is related to bengamide and its derivative with anti proliferative properties.

The term as used herein " bis-phosphonic acids compounds " include but is not limited to according to bent phosphonic acids (pamidronic acid), Alendronic acid (alendronic acid).It can be for example administered according to bent phosphonic acids with its commercial form, such as trade mark is DIDRINEL^TM.Clodronate can be for example administered with its commercial form, such as trade mark is BONEFOS^TM.Tiludronic Acid for example can be with With the administration of its commercial form, such as trade mark is SKELID^TM.Pamidronic acid can be for example administered with its commercial form, such as trade mark For AREDIA^TM.Alendronic acid can be for example administered with its commercial form, such as trade mark is FOSAMAX^TM.Ibandronic acid for example may be used To be administered with its commercial form, such as trade mark is BONDRANAT^TM.Risedronic Acid can be for example administered with its commercial form, such as Trade mark is ACTONEL^TM.Zoledronic acid can be for example administered with its commercial form, such as trade mark is ZOMETA^TM。

Term " steroids " includes hydrocortisone, dexamethasone (Decadron), hydrogenated methyl Bo Nisong and Bo Nisong.

The term as used herein " anti proliferative antibody " includes but is not limited to Herceptin (Trastuzumab) (Herceptin^TM), Herceptin-DM1, erlotinib (Terceva^TM)、bevacizumab(Avastin^TM), the appropriate uncommon Ma of benefit (Rituxan), PRO64553 (anti-CD 40) and 2C4 antibody.

It yet still another aspect, the present invention relates to Substance treatment of the invention or prevention cell proliferative disorders and/or FLT3, The method of c-Kit associated disease.Over the course for the treatment of, can by injecting, taking orally, suck, rectum or the sheet that will percutaneously provide The substance of invention is administered to patient.It can also be according to circumstances by a effective amount of compound or drug comprising at least one formula (I) Composition individually or with one or more other therapeutic agents is applied in combination.Mentioned other therapeutic agents as limited above It is fixed.Over the course for the treatment of, the chemotherapy of the compound comprising at least one formula (I) or pharmaceutical composition can also be combined and is put Therapy is penetrated to be administered.

Specifically, substance of the invention can be used to treat or prevent cell proliferative disorders, selected from benign or malignant swollen Tumor, including but not limited to: solid tumor (including benign or especially malignant class), sarcoma, gastrointestinal stromal tumor (Gastrointestinal Stromal Tumors, GIST), acute myeloblastic leukemia (Acute Myeloblastic Leukemia, AML), chronic myelogenous leukemia (Chronic Myelogenous Leukemia, CML), to ABL and BCR/ABL Tyrosine kinase activity inhibits have influential leukaemia, B- cell lymphom, lymthoma, diffusivity large B cell lymphoid tumor, filter Bubble property lymthoma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, B born of the same parents' pre-lymphocytic leukemia, lymph-plasma Cell lymphoma/macroglobulinemia Waldenstron, splenic marginal zone lymthoma, plasma cell myeloma, plasmacytoma, knot Outer edge area B cell lymphoma, lymphoma nodal marginal zone B cell, lymphoma mantle cell, the leaching of mediastinum (thymus gland) large B cell Bar tumor, intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma, leukaemia, lymthoma sample granulation Swollen disease, mesenchymoma, systemic mast cell disease, hypereosinophilia syndrome (HES), fibre modification, rheumatoid close Save inflammation, panarthritis, chorionitis, lupus erythematosus, graft versus host disease(GVH disease) (graft-versus-host disease, GVHD), Neurofibroma, pulmonary hypertension, breast ductal cancer, lobular carcinoma, gland cancer, melanoma, B cell proliferative disease, the cancer of the brain, kidney, Liver cancer, adrenal, bladder cancer, breast cancer, lymph cancer, gastric cancer, gastrointestinal stromal tumor, stomach neoplasm, cancer of the esophagus, oophoroma, knot are straight Intestinal cancer, prostate cancer, cancer of pancreas, lung cancer, carcinoma of vagina, film gland cancer, thyroid cancer, neck cancer, the cancer of CNS, glioblastoma, bone Marrow hyperplasia disease, spongioblastoma, Huppert's disease, human primary gastrointestinal cancers, colorectal cancer, H/N tumors, brain tumor, epidermis excessively increase Life, psoriasis, hyperplasia of prostate, the tumor formation of epithelial character, carcinoma of vagina, cervical carcinoma, carcinoma of endometrium, Huppert's disease, Neck and head tumor, Alzheimer disease, seminoma, dysgerminoma, mast cell tumor, bronchiolar carcinoma, on testis Intradermal tumor formation, breast cancer, neuroblastoma, mamillary/follicular thyroid cancer, malignant lymphoma, non-Hodgkin lymphoma, 2 type Multiple Endocrine tumor formation, pheochromocytoma, parathyroid hyperplasia/adenoma, colon cancer, colorectal adenomas, pernicious chest Film celiothelioma, hemangioblastoma, hemangioma, the carcinoma of the rectum, tumor formation and other Hypertrophic or proliferative diseases or combinations thereof.

Substance of the invention can also be used to treat or prevent c-Kit associated disease, especially gastrointestinal stromal tumor (Gastrointestinal Stromal tumors, GIST) or similar disease or combination.

Substance of the invention can also be used to treat or prevent FLT3 associated disease, especially saltant type FLT3/ITD related diseases Disease, including but not limited to: haematological malignancies include leukaemia, lymthoma (non-Hodgkin lymphoma), Hodgkin's disease (also referred to as For Hodgkin lymphoma) and myeloma --- for example, acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), chronic neutrophilic chronic myeloid leukemia (CNL), acute undifferentiated cell leukemia (AUL), anaplastic macrocytic Lymthoma (ALCL), human adult T cell ALL, with three pedigrees (trilineage) myelodysplasia AML (AML/TMDS), Mixed type pedigree leukaemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disorder (MPD), Huppert's disease (MM) and spinal cord sarcoma, chronic lymphocytic leukemia, diffusivity large B cell lymphoid tumor (DLBCL), follicular lymphoma or slow Property lymphocytic leukemia, lymphoma mantle cell (mantle cell lymphoma), mediastinum (thymus gland) large B cell lymphoid tumor, Intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma (Burkitt lymphoma) or similar Disease, or combinations thereof.

It is preferred that warm-blooded animal, especially mankind's enteral administration for example nose, oral cavity, rectum or especially the composition that is administered orally and Parenteral administration is for example intravenous, intramuscular or subcutaneous administration composition.The dose-dependant of active constituent is in institute's disease to be treated With kind, its age, weight and individual condition, individual pharmacokinetic data available and administration mode.

Described pharmaceutical composition can optionally be used in combination with known treatment methods, such as the application of hormone or radiation.

For example, formula (I) compound can join with standard leukemia therapies for the treatment of acute myeloid leukaemia AML It closes and uses, particularly for treating the therapy of AML.Specifically, formula (I) compound can be with such as farnesyl transferase inhibitor And/or other can be used for treating the administered in combination of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, replace Ni Bo Glycosides, mitoxantrone, idarubicin, carboplatin and PKC412.

The structure of the active constituent determined by code, adopted name or product name can come from classic " Merck The current edition of index " comes from database, such as Patents International (such as IMS World Publications)。

The above-mentioned compound that can be used in combination with formula (I) compound can be such as this field such as documents cited above institute State preparation and administration.

In embodiments of the present invention, when treating according to the present invention to patient, the amount of given drug is depended on Factors, such as specific dosage regimen, disease or implant treatment and its seriousness, subject in need for the treatment of or host Unique (such as weight), still, according to specific ambient conditions, including for example used specific drug, administration route, control The illness for the treatment of and the subject or host for the treatment of, administration dosage can routinely be determined by methods known in the art.In general, For the dosage that adult treatment uses, administration dosage is typically at 0.02-5000mg/ days, for example, about 1-1500mg/ days models It encloses.The required dosage is expressed as (or in a short time) one or be administered simultaneously or at interval appropriate in which can be convenient Divided dose, such as daily two, three, four doses or more divided agent.It will be appreciated by persons skilled in the art that although giving Dosage range is stated, but specific effective quantity can suitably be adjusted according to the case where patient and in conjunction with doctor diagnosed.

The preparation of compound

Using Standard synthetic techniques well known by persons skilled in the art or using methods known in the art be described herein Method combination, the compound of formula (I) can be synthesized.In addition, solvent given herein, temperature and other reaction conditions can roots Change according to art technology.

In some embodiments, it provided herein is the preparation method of kinase inhibitor compounds described herein and its Application method.In some embodiments, the scheme synthesis of following synthesis can be used in compound described herein.It can be used Compound is synthesized by using selectable starting material appropriate with following similar methods.

Starting material for synthesizing compound described herein can be synthesized or can obtain from commercial source.Herein Technology well known by persons skilled in the art can be used to other related compounds with different substituents in the compound of description And Material synthesis.The reaction for preparing compound disclosed herein can be by the reagent be deemed appropriate by those skilled in the art It is modified with condition, to be incorporated herein the various parts in the molecule of offer.

If desired, routine techniques separation and purifying can be used in reaction product, including but not limited to filters, distills, knot The methods of brilliant, chromatography.Conventional method characterization, including physical constant and spectrum data can be used in these products.

Using synthetic method described herein, compound disclosed herein is obtained with good yield and purity.According to herein The compound of disclosed method preparation is purified by conventional method known in the art, such as filtering, recrystallization, chromatography, distillation And combinations thereof.

Site on the aromatic moiety of the compound of formula (I) may be easy to that various metabolic responses occur, therefore appropriate Substituent group be introduced on aromatic ring structure, for example, only for example, halogen can restore, reduce or eliminate this metabolism Approach.

Embodiment

Non-limiting embodiment in detail below is to be interpreted as being merely illustrative, not limit in any way originally It is open.Although without being described in further detail, it is believed that those skilled in the art can be based on description herein, completely benefit Use the disclosure.

Preferred compounds of the invention is as follows:

Embodiment 1

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) phenyl) piperidin-4-yl) The synthesis of propionamide 1-1

The synthesis of 3- ((6,7- dimethoxy-quinoline -4- base)-oxygroup) aniline A

Step 1: potassium tert-butoxide (1.2 equivalent) is slowly added to sub- equipped with 3- amino-phenol (1.2 equivalent) and dimethyl In the reaction flask of sulfone (3mL), chloro- 6, the 7- dimethoxy quinoline of 4- is added into reaction flask again after stirring 2 hours under room temperature Quinoline (2.2mmol) and potassium carbonate (0.6 equivalent).Heating reaction is to 110 DEG C, and reaction is overnight.Mass Spectrometer Method is without the chloro- 6,7- diformazan of 4- Phenoxyl quinoline is remaining, stops reaction, is cooled to room temperature, it is molten that reaction solution adds saturated sodium bicarbonate after being diluted with ethyl acetate Liquid, after liquid separation, ethyl acetate phase uses diluted sodium hydroxide solution, saturated common salt water washing respectively again, and anhydrous magnesium sulfate is dry, mistake Filter, concentration rear pillar chromatograph to obtain compound A (400mg), yield 61%.Exact Mass (calculated value): 296.1161；MS(ESI) m/e(M+1)⁺:297.1201；¹H-NMR (400MHz, DMSO-d6) 8.49 (d, J=4.2Hz, 1H), 7.46 (s, 1H), 7.39 (s, 1H), 7.14~7.10 (m, 1H), 6.53 (d, J=4.2Hz, 1H), 6.51 (d, J=8.0Hz, 1H), 6.37~6.34 (m, 2H),5.39(s,2H),4.04(s,3H),3.94(s,3H).

The synthesis of tert-butyl (1- (4- nitrobenzophenone) piperidin-4-yl) carbamate B

Step 2: 4- chloronitrobenzene (12.69mmol) and 4-Boc amino piperidine (1.0 equivalent) are dissolved in N, N- dimethyl It in formamide (60mL), adds potassium carbonate (3.0 equivalent), heating is reacted to 100 DEG C and reacted 10 hours.Mass Spectrometer Method is without raw material Residue stops reaction.It is cooled to room temperature, reaction solution is diluted with sodium bicarbonate solution, is extracted with ethyl acetate three times, combined second Acetoacetic ester phase is dried, filtered with saturated common salt water washing, and compound B crude product (3.9g) is obtained after concentration.Exact Mass (meter Calculation value): 321.1689；MS(ESI)m/e(M+1)⁺:321.1601；¹H-NMR (400MHz, DMSO-d6) 8.04 (d, J= 8.0Hz, 2H), 7.02 (d, J=8.0Hz, 2H), 4.02~3.96 (m, 2H), 3.56~3.53 (m, 1H), 3.11~3.05 (m, 2H), 2.51~2.50 (m, 2H), 1.82~1.80 (m, 2H), 1.39 (s, 9H)

The synthesis of tert-butyl (1- (4- aminophenyl) piperidin-4-yl) carbamate C

Step 3: compound B (12.96mmol) is dissolved in methanol (500mL), is added palladium carbon (2.0g), and reaction is mixed Liquid is closed to react under atmosphere of hydrogen 7 hours.Mass Spectrometer Method stops reaction without starting material left.Rear pillar chromatography is concentrated in reaction mixture It obtains compound C (1.2g), two step yields are 32%.Exact Mass (calculated value): 291.1947；MS(ESI)m/e(M+1)⁺: 292.2011；¹H-NMR (400MHz, DMSO-d6) 6.83 (s, 1H), 6.69~6.67 (m, 2H), 6.49~6.47 (m, 2H), 4.62 (br., 2H), 3.33~3.27 (m, 3H), 2.54~2.51 (m, 2H), 1.78~1.75 (m, 2H), 1.50~1.47 (m, 2H),1.39(s,9H).

Tert-butyl (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) phenyl) piperidines -4- The synthesis of aminocarbamic acid ester D

Step 4: under argon atmosphere, triphosgene (0.4 equivalent) being dissolved in methylene chloride (20mL), and ice-water bath is cooling, so Afterwards by compound A (1.34mmol), 4-dimethylaminopyridine (0.1 equivalent), triethylamine (1.0 equivalent) and methylene chloride (5mL) Mixed liquor slowly instilled in the mixed liquor of triphosgene by the low liquid funnel of constant pressure, reacted 30 minutes after dripping off, then at ice-water bath Under the conditions of by compound C (1.34mmol), 4-dimethylaminopyridine (0.1 equivalent), triethylamine (1.0 equivalent) and methylene chloride The mixed liquor of (5mL) is slowly instilled in above-mentioned mixed reaction solution by the low liquid funnel of constant pressure, and reaction is stayed overnight at room temperature.Mass spectrum inspection It surveys, raw material reacts totally, stops reaction.Reaction mixture concentration rear pillar chromatographs to obtain compound D (206mg), yield 25%. Exact Mass (calculated value): 613.2900；MS(ESI)m/e(M+1)⁺:614.2907；¹H-NMR(400MHz,DMSO-d6) 9.46 (s, 1H), 8.99 (s, 1H), 8.52 (d, J=4.0Hz, 1H), 7.55~7.52 (m, 2H), 7.42~7.38 (m, 2H), 7.27~7.25 (m, 3H), 6.87~6.83 (m, 4H), 6.57 (d, J=4.0Hz, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.52~3.49 (m, 2H), 3.36 (br, 1H), 2.66~2.61 (m, 2H), 1.79~1.77 (m, 2H), 1.49~1.42 (m, 2H),1.39(s,9H).

1- (4- (4- amino piperidine -1- base) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea The synthesis of E

Step 5: Hydrochloride/ethyl acetate (15mL) is slowly instilled to the reaction equipped with compound D (0.33mmol) In bottle, react 4 hours at room temperature.Mass Spectrometer Method, raw material react totally, stop reaction.By reaction solution filter off-white color is consolidated Body, the hydrochloride (170mg) of as compound E.Exact Mass (calculated value): 513.2376；MS(ESI)m/e(M+1)⁺: 514.2402；¹H-NMR (400MHz, DMSO-d6) 8.47 (d, J=4.0Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.35 ~7.30 (m, 3H), 7.21~7.19 (m, 2H), 6.88~6.83 (m, 3H), 6.52 (d, J=4.0Hz, 1H), 4.15 (s, 3H), 4.13 (s, 3H), 3.59~3.56 (m, 2H), 2.82~2.71 (m, 3H), 1.92~1.90 (m, 2H), 1.47~1.44 (m,2H).

Step 6: compound E (0.078mmol) is dissolved in n,N-Dimethylformamide (0.5mL), triethylamine is added (0.04mL) is cooled to -50 DEG C, then propionyl chloride (1.2 equivalent) is slowly added in reaction solution.Mass Spectrometer Method after five minutes is reacted, Raw material reacts totally.Saturated sodium bicarbonate solution is added into reaction solution, chloroform extracts three times, and chloroform layer again wash by saturated common salt It washs, dries, filters, concentration rear pillar chromatographs to obtain compound 1-1 (34mg), yield 79%.Exact Mass (calculated value): 569.2638；MS(ESI)m/e(M+1)⁺:570.2599；¹H-NMR (400MHz, DMSO-d6) 9.25 (s, 1H), 8.87 (s, 1H), 8.50 (d, J=5.2Hz, 1H), 7.73 (d, J=7.6Hz, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 7.41~7.37 (m, 2H), 7.29~7.25 (m, 3H), 6.87~6.83 (m, 3H), 6.55 (d, J=5.2Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.67~3.65 (m, 1H), 3.53~3.50 (m, 2H), 2.72~2.66 (m, 2H), 2.07 (q, J=7.6Hz 14.8Hz, 2H), 1.80~1.77 (m, 2H), 1.51~1.45 (m, 2H), 0.99 (t, J=8.0Hz 15.2Hz, 3H).

Embodiment 2

The chloro- N- of 2- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) phenyl) piperidines - 4- yl) acetamide 1-2 synthesis

The synthesis of compound 1-2 is completed by using the step of being similar to described in embodiment 1, only in step 6 chlorine Chloroacetic chloride replaces propionyl chloride.Exact Mass (calculated value): 590.0770；MS(ESI)m/e(M+1)⁺:591.0807。

Embodiment 3

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) phenyl) piperidin-4-yl third The synthesis of acrylamide 1-3

The synthesis of compound 1-3 is completed by using the step of being similar to described in embodiment 1, only in step 6 with third Alkene chloride for propionyl chloride.Exact Mass (calculated value): 567.2482；MS(ESI)m/e(M+1)⁺:568.2479。

Embodiment 4

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) propionamide 2-1 synthesis

The synthesis of compound 2-1 is completed by using the step of being similar to described in embodiment 1, is only used in step 2 The chloro- 5- nitro-trifluoromethyl toluene of 2- replaces 4- chloronitrobenzene.Exact Mass (calculated value): 637.2512；MS(ESI)m/e(M+1)⁺: 638.2481。

Embodiment 5

The chloro- N- of 2- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (fluoroform Base) phenyl) piperidin-4-yl) and acetamide 2-2 synthesis

The synthesis of compound 2-2 is completed by using the step of being similar to described in embodiment 4, only in step 6 chlorine Chloroacetic chloride replaces propionyl chloride.Exact Mass (calculated value): 657.1966；MS(ESI)m/e(M+1)⁺:658.1999。

Embodiment 6

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) acrylamide 2-3 synthesis

The synthesis of compound 2-3 is completed by using the step of being similar to described in embodiment 4, only in step 6 chlorine Chloroacetic chloride replaces propionyl chloride.Exact Mass (calculated value): 635.2356；MS(ESI)m/e(M+1)⁺:636.2401。

Embodiment 7

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) propine amide 2-4 synthesis

According to 1-5 step synthesis compound 1- (4- (4- amino piperidine -1- base) -3- trifluoromethyl)-of embodiment 6 3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea.

Step 6: by compound 1- (4- (4- amino piperidine -1- base) -3- trifluoromethyl) -3- (3- ((6,7- diformazan Phenoxyl quinoline -4- base) oxygroup) phenyl) urea (0.085mmol) is dissolved in n,N-Dimethylformamide (0.5mL), then is separately added into three Ethamine (0.05mL), 4-dimethylaminopyridine (0.5 equivalent), 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea Hexafluorophosphoric acid ester (HATU, 1.5 equivalents) and propiolic acid (1.2 equivalent).Room temperature reaction 5 hours, Mass Spectrometer Method, no starting material left, Stop reaction.Reaction solution is diluted with chloroform, then successively washing, saturated common salt washing, and anhydrous magnesium sulfate dries, filters, after concentration Column chromatographs to obtain compound 2-4 (6.3mg), yield 12%.Exact Mass (calculated value): 633.2199；MS(ESI)m/e(M+1)⁺: 634.2226。

Embodiment 8

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) -2- (trifluoro Methyl) phenyl) piperidin-4-yl) and propionamide 3-1 synthesis

The synthesis of compound 3-1 is completed by using the step of being similar to described in embodiment 1, is only used in step 1 2- methyl -5- amino-phenol replaces 3- amino-phenol, replaces 4- chlorine nitro with the chloro- 5- nitro-trifluoromethyl toluene of 2- in step 2 Benzene.Exact Mass (calculated value): 651.2669；MS(ESI)m/e(M+1)⁺:652.2678。

Embodiment 9

The chloro- N- of 2- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) -2- (trifluoromethyl) phenyl) piperidin-4-yl) acetamide 3-2 synthesis

The synthesis of compound 3-2 is completed by using the step of being similar to described in embodiment 8, is only used in step 6 Chloracetyl chloride replaces propionyl chloride.Exact Mass (calculated value): 671.2122；MS(ESI)m/e(M+1)⁺:672.2098。

Embodiment 10

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) -2- (trifluoro Methyl) phenyl) piperidin-4-yl) and acrylamide 3-3 synthesis

The synthesis of compound 3-3 is completed by using the step of being similar to described in embodiment 8, is only used in step 6 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 649.2512；MS(ESI)m/e(M+1)⁺:650.2488。

Embodiment 11

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) piperazine Pyridine -4- base) propionamide 4-1 synthesis

The synthesis of compound 4-1 is completed by using the step of being similar to described in embodiment 1, is only used in step 1 2- methyl -5- amino-phenol replaces 3- amino-phenol.Exact Mass (calculated value): 583.2795；MS(ESI)m/e(M+1)⁺: 584.2799。

Embodiment 12

The chloro- N- of 2- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) benzene Base) piperidin-4-yl) acetamide 4-2 synthesis

The synthesis of compound 4-2 is completed by using the step of being similar to described in embodiment 11, only in step 6 Propionyl chloride is replaced with chlorpromazine chloride.Exact Mass (calculated value): 603.2248；MS(ESI)m/e(M+1)⁺:604.2301。

Embodiment 13

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) piperazine Pyridine -4- base) acrylamide 4-3 synthesis

The synthesis of compound 4-3 is completed by using the step of being similar to described in embodiment 11, only in step 6 Propionyl chloride is replaced with acryloyl chloride.Exact Mass (calculated value): 581.2638；MS(ESI)m/e(M+1)⁺:582.2630。

Embodiment 14

1- (3- ((6,7- dimethoxy-quinoline -4- base) -4 aminomethyl phenyls) -3- (4- ((1- propionyl piperidin-4-yl) oxygroup) Phenyl) urea 5-1 synthesis

The synthesis of compound 5-1 is completed by using the step of being similar to described in embodiment 11, only in step 2 4-Boc amino piperidine is replaced with 4- hydroxyl -1-Boc piperidines.Exact Mass (calculated value): 584.2635；MS(ESI)m/e(M+ 1)⁺:585.2660。

Embodiment 15

1- (4- ((2- chloracetyl) piperidin-4-yl) oxygroup) phenyl) -3- (3- ((6,7- dimethoxy-4 '-yl) oxygen Base) -4- aminomethyl phenyl) urea 5-2 synthesis

The synthesis of compound 5-2 is completed by using the step of implementing described in 14 is similar to, only in step 6 chlorine Chloroacetic chloride replaces propionyl chloride.Exact Mass (calculated value): 604.2089；MS(ESI)m/e(M+1)⁺:605.2103。

Embodiment 16

1- (4- ((2- acryloylpiperidine -4- base) oxygroup) phenyl) -3- (3- ((6,7- dimethoxy-4 '-yl) oxygroup) - 4- aminomethyl phenyl) urea 5-3 synthesis

The synthesis of compound 5-3 is completed by using the step of being similar to described in embodiment 14, is only used in step 6 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 582.2478；MS(ESI)m/e(M+1)⁺:583.2461。

Embodiment 17

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) pyrroles Quinoline -3- base) propionamide 6-1 synthesis

The synthesis of compound 6-1 is completed by using the step of being similar to described in embodiment 14, is only used in step 2 3-Boc amino pyrroline replaces 4- hydroxyl -1-Boc piperidines.Exact Mass (calculated value): 569.2638；MS(ESI)m/e(M+ 1)⁺:570.2709。

Embodiment 18

The chloro- N- of 2- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) benzene Base) pyrrolin -3- base) acetamide 6-2 synthesis

The synthesis of compound 6-2 is completed by using the step of being similar to described in embodiment 17, is only used in step 6 Chloracetyl chloride replaces propionyl chloride.Exact Mass (calculated value): 589.2092；MS(ESI)m/e(M+1)⁺:590.2111。

Embodiment 19

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) pyrroles Quinoline -3- base) acrylamide 6-3 synthesis

The synthesis of compound 6-3 is completed by using the step of being similar to described in embodiment 17, is only used in step 6 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 567.2483；MS(ESI)m/e(M+1)⁺:568.2561。

Embodiment 20

1- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) -3- (4- (4- propiono piperazine -1- Base) phenyl) urea 7-1 synthesis

The synthesis of compound 7-1 is completed by using the step of being similar to described in embodiment 14, is only used in step 2 4-Boc piperazine replaces 4- hydroxyl -1-Boc piperidines.Exact Mass (calculated value): 569.2638；MS(ESI)m/e(M+1)⁺: 570.2600。

Embodiment 21

1- (4- (4- (2- chloracetyl) piperazine -1- base) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygen Base) -4- aminomethyl phenyl) urea 7-2 synthesis

The synthesis of compound 7-2 is completed by using the step of being similar to described in embodiment 20, is only used in step 6 Chloracetyl chloride replaces propionyl chloride.Exact Mass (calculated value): 589.2092；MS(ESI)m/e(M+1)⁺:590.2116。

Embodiment 22

1- (4- (4- acryloylpiperazines -1- base) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- Aminomethyl phenyl) urea 7-3 synthesis

The synthesis of compound 7-3 is completed by using the step of being similar to described in embodiment 20, is only used in step 6 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 567.2482；MS(ESI)m/e(M+1)⁺:568.2417。

Embodiment 23

1- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) -3- (4 ((1- propiono pyrrolins - 3- yl) oxygroup) phenyl) and urea 8-1 synthesis

The synthesis of compound 8-1 is completed by using the step of being similar to described in embodiment 14, is only used in step 2 3- hydroxyl -1- pyrrolin replaces 4- hydroxyl -1-Boc piperidines.Exact Mass (calculated value): 570.2478；MS(ESI)m/e(M+ 1)⁺:571.2399。

Embodiment 24

1- (4- ((2- chloracetyl) pyrrolin -3- base) oxygroup) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- Base) oxygroup) -4- aminomethyl phenyl) and urea 8-2 synthesis

The synthesis of compound 8-2 is completed by using the step of being similar to described in embodiment 23, is only used in step 6 Chloracetyl chloride replaces propionyl chloride.Exact Mass (calculated value): 590.1932；MS(ESI)m/e(M+1)⁺:591.2010。

Embodiment 25

1- (4- ((1- acryloyl group pyrrolin -3- base) oxygroup) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- base) Oxygroup) -4- aminomethyl phenyl) urea 8-3 synthesis

The synthesis of compound 8-3 is completed by using the step of being similar to described in embodiment 23, is only used in step 6 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 568.2322；MS(ESI)m/e(M+1)⁺:569.2331。

Embodiment 26

1- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) -3- (4- ((1- propionyl phenylpiperidines -4- Base) amino) phenyl) and urea 9-1 synthesis

The synthesis of compound 9-1 is completed by using the step of being similar to described in embodiment 14, is only used in step 2 4- amino -1-Boc piperidines replaces 4- hydroxyl -1-Boc piperidines.Exact Mass (calculated value): 583.2795；MS(ESI)m/e(M +1)⁺:584.2799。

Embodiment 27

1- (4- ((2- chloracetyl) piperidin-4-yl) amino) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- base) Oxygroup) -4- aminomethyl phenyl) urea 9-2 synthesis

The synthesis of compound 9-2 is completed by using the step of being similar to described in embodiment 26, is only used in step 6 Chloracetyl chloride replaces propionyl chloride.Exact Mass (calculated value): 603.2248；MS(ESI)m/e(M+1)⁺:604.2250。

Embodiment 28

1- (4- ((1- acryloylpiperidine -4- base) amino) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygen Base) -4- aminomethyl phenyl) urea 9-3 synthesis

The synthesis of compound 9-3 is completed by using the step of being similar to described in embodiment 26, is only used in step 6 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 581.2638；MS(ESI)m/e(M+1)⁺:582.2661。

Embodiment 29

1- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) -3- (4- ((1- propiono pyrrolin - 3- yl) amino) phenyl) and urea 10-1 synthesis

The synthesis of compound 10-1 is completed by using the step of being similar to described in embodiment 14, is only used in step 2 3- amino -1-Boc pyrrolin replaces 4- hydroxyl -1-Boc piperidines.Exact Mass (calculated value): 569.2638；MS(ESI)m/e (M+1)⁺:570.2707。

Embodiment 30

1- (4- ((2- chloracetyl) pyrrolin -3- base) amino) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- Base) oxygroup) -4- aminomethyl phenyl) and urea 10-2 synthesis

The synthesis of compound 10-2 is completed by using the step of being similar to described in embodiment 29, is only used in step 6 Chloracetyl chloride replaces propionyl chloride.Exact Mass (calculated value): 589.2902；MS(ESI)m/e(M+1)⁺:590.2112。

Embodiment 31

1- (4- ((1- acryloyl group pyrrolin -3- base) amino) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- base) Oxygroup) -4- aminomethyl phenyl) urea 10-3 synthesis

The synthesis of compound 10-3 is completed by using the step of being similar to described in embodiment 29, is only used in step 6 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 567.2482；MS(ESI)m/e(M+1)⁺:568.2409。

Embodiment 32

N- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) propionamide 11-1 Synthesis

Step 1: the synthesis of compound F is completed by using the step of being similar to described in embodiment 1 one, only anti- Ying Zhongyong 2- methyl -5- amino-phenol replaces 3- amino-phenol.Exact Mass (calculated value): 310.3530；MS(ESI)m/e (M+1)⁺:311.2350。

Step 2: the synthesis of compound G is completed by using the step of being similar to described in embodiment 1 four, only anti- Ying Zhongyong 3- nitroaniline replaces compound C.Exact Mass (calculated value): 474.4730；MS(ESI)m/e(M+1)⁺: 478.5112。

Step 3: the synthesis of compound H is completed by using the step of being similar to described in embodiment 1 three, only anti- Ying Zhongyong compound G replaces compound B.Exact Mass (calculated value): 444.4910；MS(ESI)m/e(M+1)⁺: 445.5609。

Step 4: the synthesis of compound 11-1 is completed by using the step of being similar to described in embodiment 1 six, is only existed Compound E is replaced with compound H in reaction.Exact Mass (calculated value): 500.2060；MS(ESI)m/e(M+1)⁺: 501.5550。

Embodiment 33

The chloro- N- of 2- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) acetyl The synthesis of amine 11-2

The synthesis of compound 11-2 is completed by using the step of being similar to described in embodiment 32, is only used in step 4 Chloracetyl chloride replaces propionyl chloride.Exact Mass (calculated value): 520.1513；MS(ESI)m/e(M+1)⁺:521.2106。

Embodiment 34

N- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) acrylamide The synthesis of 11-3

The synthesis of compound 11-3 is completed by using the step of being similar to described in embodiment 32, is only used in step 4 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 498.1903；MS(ESI)m/e(M+1)⁺:499.2607。

Embodiment 35

(E)-N- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) -4- (two Methylamino) butyl -2- eneamide 11-4 synthesis

The synthesis of compound 11-4 is completed by using the step of being similar to described in embodiment 32, is only used in step 4 4- dimethylamino -2- alkene butyl chloride replaces propionyl chloride.Exact Mass (calculated value): 555.2482；MS(ESI)m/e(M+1)⁺: 556.6350。

Embodiment 36

(E)-N- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) butyl - The synthesis of 2- eneamide 11-5

The synthesis of compound 11-5 is completed by using the step of being similar to described in embodiment 32, is only used in step 4 2- alkene butyl chloride replaces propionyl chloride.Exact Mass (calculated value): 512.2060；MS(ESI)m/e(M+1)⁺:513.3099。

Embodiment 37

N- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) propionamide The synthesis of 12-1

The synthesis of compound 12-1 is completed by using the step of being similar to described in embodiment 32, is only used in step 2 Paranitroanilinum replaces 3- nitroaniline.Exact Mass (calculated value): 500.2060；MS(ESI)m/e(M+1)⁺: 501.3001。

Embodiment 38

The chloro- N- of 2- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) second The synthesis of amide 12-2

The synthesis of compound 12-2 is completed by using the step of being similar to described in embodiment 37, is only used in step 4 Chloracetyl chloride replaces propionyl chloride.Exact Mass (calculated value): 520.1513；MS(ESI)m/e(M+1)⁺:521.3101。

Embodiment 39

N- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) acryloyl The synthesis of amine 12-3

The synthesis of compound 12-3 is completed by using the step of being similar to described in embodiment 37, is only used in step 4 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 498.1503；MS(ESI)m/e(M+1)⁺:499.5390。

Embodiment 40

(E)-N- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) fourth The synthesis of base -2- acrylamide 12-4

The synthesis of compound 12-4 is completed by using the step of being similar to described in embodiment 37, is only used in step 4 2- alkene butyl chloride replaces propionyl chloride.Exact Mass (calculated value): 512.2060；MS(ESI)m/e(M+1)⁺:513.5330。

Embodiment 41

(E)-N- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) -4- aminomethyl phenyl) urea groups) phenyl) -4- The synthesis of (dimethylamino) butyl -2- acrylamide 12-5

The synthesis of compound 12-5 is completed by using the step of being similar to described in embodiment 37, is only used in step 4 4- dimethylamino -2- alkene butyl chloride replaces propionyl chloride.Exact Mass (calculated value): 555.2482；MS(ESI)m/e(M+1)⁺: 556.6350。

Embodiment 42

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) phenyl) piperidines -3- base) The synthesis of propionamide 13-1

The synthesis of compound 13-1 is completed by using the step of being similar to described in embodiment 1, is only used in step 2 3-Boc amino piperidine replaces 4-Boc amino piperidine.Exact Mass (calculated value): 569.2638；MS(ESI)m/e(M+1)⁺: 570.6620。

Embodiment 43

The chloro- N- of 2- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) phenyl) piperidines - 3- yl) acetamide 13-2 synthesis

The synthesis of compound 13-2 is completed by using the step of being similar to described in embodiment 42, is only used in step 6 Chloracetyl chloride replaces propionyl chloride.Exact Mass (calculated value): 589.2092；MS(ESI)m/e(M+1)⁺:590.0770。

Embodiment 44

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) phenyl) piperidines -3- base) The synthesis of acrylamide 13-3

The synthesis of compound 13-3 is completed by using the step of being similar to described in embodiment 42, is only used in step 6 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 567.2482；MS(ESI)m/e(M+1)⁺:568.6460。

Embodiment 45

(E)-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) phenyl) piperidines -3- Base) butyl -2- acrylamide 13-4 synthesis

The synthesis of compound 13-4 is completed by using the step of being similar to described in embodiment 42, is only used in step 6 2- alkene butyl chloride replaces propionyl chloride.Exact Mass (calculated value): 581.2638；MS(ESI)m/e(M+1)⁺:582.6730。

Embodiment 46

(E)-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) phenyl) piperidines -3- Base) -4- (dimethylamino) butyl -2- acrylamide 13-5 synthesis

The synthesis of compound 13-5 is completed by using the step of being similar to described in embodiment 42, is only used in step 6 4- dimethylamino -2- alkene butyl chloride replaces propionyl chloride.Exact Mass (calculated value): 624.3020；MS(ESI)m/e(M+1)⁺: 625.7420。

Embodiment 47

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) phenyl) piperidines -3- base) The synthesis of cyclohexyl -3- alkene -1- carbamide 13-6

The synthesis of compound 13-6 is completed by using the step of being similar to described in embodiment 42, is only used in step 6 3- alkene -1- Cyclohexanoyl chloride replaces propionyl chloride.Exact Mass (calculated value): 621.2951；MS(ESI)m/e(M+1)⁺: 622.7380。

Embodiment 48

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) phenyl) piperidines -3- base) The synthesis of cyclopenta -2- alkene -1- carbamide 13-7

The synthesis of compound 13-7 is completed by using the step of being similar to described in embodiment 42, is only used in step 6 2- alkene -1- ring valeric chloride replaces propionyl chloride.Exact Mass (calculated value): 607.2795；MS(ESI)m/e(M+1)⁺: 608.7111。

Embodiment 49

(R)-(1- ((1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (fluoroform Base) phenyl) piperidin-4-yl) amino) -3- (4- hydroxy phenyl) -1- Ethylene Oxide -2- base) and carbamic acid tert-butyl alcohol ester 2-5 conjunction At

The synthesis of compound 2-5 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 Boc amino tyrosine replaces propiolic acid.Exact Mass (calculated value): 844.3407；MS(ESI)m/e(M+1)⁺: 845.8892。

Embodiment 50

(S) -2- amino-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) phenyl) piperidin-4-yl) -3- (- 3 base of 1 hydrogen-indoles) propionamide hydrochloride 2-6 synthesis

The synthesis of compound 2-6: solid is obtained by using the step of being similar to described in embodiment 7 first, is only existed Step 6 replaces propiolic acid with Boc amino tryptophan.Then resulting solid is dissolved in the ethyl acetate solution of hydrochloric acid, reaction 2 Volatile substances, obtained solid, that is, compound 2-6 hydrochloride is removed in vacuum after hour.Exact Mass (calculated value): 767.3403；MS(ESI)m/e(M+1)⁺:768.8102。

Embodiment 51

(S) -2- amino-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) phenyl) piperidin-4-yl) pentane diamides 2-7 synthesis

The synthesis of compound 2-7 is completed by using the step of being similar to described in embodiment 49, is only used in step 6 Glutamine replaces Boc amino tryptophan.Exact Mass (calculated value): 709.2836；MS(ESI)m/e(M+1)⁺: 710.7272。

Embodiment 52

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) cyclohexyl -1- alkene -1- formamide 2-8 synthesis

The synthesis of compound 2-8 is completed by using the step of being similar to described in embodiment 7, only in step 6 1- Alkene hexahydrobenzoid acid replaces propiolic acid.Exact Mass (calculated value): 689.2825；MS(ESI)m/e(M+1)⁺:690.7362。

Embodiment 53

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) Methanesulfomide 2-9 synthesis

The synthesis of compound 2-9 is completed by using the step of being similar to described in embodiment 7, only in step 6 first Sulfonic acid replaces propiolic acid.Exact Mass (calculated value): 659.2625；MS(ESI)m/e(M+1)⁺:660.6812。

Embodiment 54

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) piperidines -4- formamide 2-10 synthesis

The synthesis of compound 2-10 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 4- carboxylic acid piperidin replaces propiolic acid.Exact Mass (calculated value): 692.2934；MS(ESI)m/e(M+1)⁺:693.7402。

Embodiment 55

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) tetrahydro -2H- pyrans -4- formamide 2-11 synthesis

The synthesis of compound 2-11 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 4- formic acid pyrans replaces propiolic acid.Exact Mass (calculated value): 693.2774；MS(ESI)m/e(M+1)⁺:694.2669。

Embodiment 56

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) acetamide 2-12 synthesis

The synthesis of compound 2-12 is completed by using the step of being similar to described in embodiment 4, is only used in step 6 Chloroacetic chloride replaces propionyl chloride.Exact Mass (calculated value): 623.2356；MS(ESI)m/e(M+1)⁺:624.2426。

Embodiment 57

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) cyclopropylsulfonamide 2-13 synthesis

The synthesis of compound 2-13 is completed by using the step of being similar to described in embodiment 4, is only used in step 6 Cyclopropyl sulfonic acid replaces propionyl chloride.Exact Mass (calculated value): 685.2182；MS(ESI)m/e(M+1)⁺:686.2229。

Embodiment 58

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) -3,3- amide dimethyl butyrate 2-14 synthesis

The synthesis of compound 2-14 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 3,3- acid dimethyl replaces propiolic acid.Exact Mass (calculated value): 679.2982；MS(ESI)m/e(M+1)⁺: 680.3001。

Embodiment 59

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) -1- methyl piperidine -4- formamide 2-15 synthesis

The synthesis of compound 2-15 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 4- formic acid -1- methyl piperidine replaces propiolic acid.Exact Mass (calculated value): 706.3091；MS(ESI)m/e(M+1)⁺: 707.4291。

Embodiment 60

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) -1- ethyl piperidine -4- formamide 2-16 synthesis

The synthesis of compound 2-16 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 4- formic acid -1- ethyl piperidine replaces propiolic acid.Exact Mass (calculated value): 720.3247；MS(ESI)m/e(M+1)⁺: 721.4433。

Embodiment 61

1- acetyl-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoro Methyl) phenyl) piperidin-4-yl) and piperidines -4- formamide 2-17 synthesis

The synthesis of compound 2-17 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 4- formic acid -1- Acetylpiperidin replaces propiolic acid.Exact Mass (calculated value): 734.3040；MS(ESI)m/e(M+1)⁺: 735.4262。

Embodiment 62

Tert-butyl 4- ((1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoro Methyl) phenyl) piperidin-4-yl) amine formyl) piperidines -1- carboxylate 2-18 synthesis

The synthesis of compound 2-18 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 4- formic acid -1-Boc piperidines replaces propiolic acid.Exact Mass (calculated value): 792.3458；MS(ESI)m/e(M+1)⁺: 793.3691。

Embodiment 63

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) piperidines -4- carboxamide hydrochloride 2-19 synthesis

The synthesis of compound 2-19 is completed by using the step of being similar to described in embodiment 50, is only used in the reaction 4- carboxylic acid piperidin replaces Boc- amino tryptophan.Exact Mass (calculated value): 728.2701；MS(ESI)m/e(M+1)⁺: 729.2881。

Embodiment 64

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) ethyl sulfonamide 2-20 synthesis

The synthesis of compound 2-20 is completed by using the step of being similar to described in embodiment 4, is only used in step 6 Ethyl sulfonic chloride replaces propionyl chloride.Exact Mass (calculated value): 673.2182；MS(ESI)m/e(M+1)⁺:674.2275。

Embodiment 65

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) propyl -1- sulfonamide 2-21 synthesis

The synthesis of compound 2-21 is completed by using the step of being similar to described in embodiment 4, is only used in step 6 Third sulfonic acid chloride replaces propionyl chloride.Exact Mass (calculated value): 687.2338；MS(ESI)m/e(M+1)⁺:688.3026。

Embodiment 66

(R) -2- amino-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) phenyl) piperidin-4-yl) propionamide hydrochloride 2-22 synthesis

The synthesis of compound 2-22 is completed by using the step of being similar to described in embodiment 50, is only used in the reaction Boc alanine replaces Boc- amino tryptophan.Exact Mass (calculated value): 688.2388；MS(ESI)m/e(M+1)⁺: 689.2403。

Embodiment 67

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) -2- (dimethylamino) acetamide 2-23 synthesis

The synthesis of compound 2-23 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 N, N- dimethylglycine replace propiolic acid.Exact Mass (calculated value): 666.2788；MS(ESI)m/e(M+1)⁺: 667.7022。

Embodiment 68

2- amino-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoro Methyl) phenyl) piperidin-4-yl) and acetamide hydrochloride 2-24 synthesis

The synthesis of compound 2-24 is completed by using the step of being similar to described in embodiment 50, is only used in the reaction Boc glycine replaces Boc- amino tryptophan.Exact Mass (calculated value): 674.2231；MS(ESI)m/e(M+1)⁺: 675.1022。

Embodiment 69

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) -2- (trifluoromethyl) benzene Base) piperidin-4-yl) niacinamide 2-25 synthesis

The synthesis of compound 2-25 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 Niacin replaces propiolic acid.Exact Mass (calculated value): 686.3465；MS(ESI)m/e(M+1)⁺:687.4004。

Embodiment 70

Tert-butyl -3- ((1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (trifluoro Methyl) phenyl) piperidin-4-yl) carbamyl) piperidines -1- carboxylate 2-26 synthesis

The synthesis of compound 2-26 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 3- formic acid -1-Boc piperidines replaces propiolic acid.Exact Mass (calculated value): 792.8572；MS(ESI)m/e(M+1)⁺: 793.7271。

Embodiment 71

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (trifluoromethyl) benzene Base) piperidin-4-yl) carbamyl) and piperidines -1- carboxamide hydrochloride 2-27 synthesis

The synthesis of compound 2-27 is completed by using the step of being similar to described in embodiment 50, is only used in the reaction 3- formic acid -1-Boc piperidines replaces Boc- amino tryptophan.Exact Mass (calculated value): 729.1289；MS(ESI)m/e(M+ 1)⁺:730.0109。

Embodiment 72

(S)-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (trifluoromethyl) Phenyl) piperidin-4-yl) -2- (dipropylamino) propionamide 2-28 synthesis

The synthesis of compound 2-28 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 N, N- dipropyl propionic acid replace propiolic acid.Exact Mass (calculated value): 736.8372；MS(ESI)m/e(M+1)⁺: 737.8377。

Embodiment 73

1- (cyclopropyl carbonyl)-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups - 2- (trifluoromethyl) phenyl) piperidin-4-yl) piperidines -4- formamide 2-29 synthesis

The synthesis of compound 2-29 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 4- formic acid -1- cyclopropane carbonyl piperidines replaces propiolic acid.Exact Mass (calculated value): 760.8152；MS(ESI)m/e(M+1)⁺: 761.8222。

Embodiment 74

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (trifluoromethyl) benzene Base) piperidin-4-yl) -1 '-methyl-[1,4 '-two piperidines] -4- formamide 2-30 synthesis

The synthesis of compound 2-30 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 4- formic acid -1- (1- methyl -4- piperidyl) piperidines replaces propiolic acid.Exact Mass (calculated value): 789.8052；MS(ESI) m/e(M+1)⁺:790.1624。

Embodiment 75

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (trifluoromethyl) benzene Base) piperidin-4-yl) -2- (piperidin-1-yl) acetamide 2-31 synthesis

The synthesis of compound 2-31 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 1- acetic acid phenylpiperidines replace propiolic acid.Exact Mass (calculated value): 706.7672；MS(ESI)m/e(M+1)⁺:707.3124。

Embodiment 76

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (trifluoromethyl) benzene Base) piperidin-4-yl) -2- (3- methyl piperidine -1- base) acetamide 2-32 synthesis

The synthesis of compound 2-32 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 3- methyl-1-acetic acid phenylpiperidines replace propiolic acid.Exact Mass (calculated value): 720.7942；MS(ESI)m/e(M+1)⁺: 721.3281。

Embodiment 77

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (trifluoromethyl) benzene Base) piperidin-4-yl) -3- (1- methyl piperidine -2- base) propionamide 2-33 synthesis

The synthesis of compound 2-33 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 3- (1- methyl -2- piperidyl) propionic acid replaces propiolic acid.Exact Mass (calculated value): 734.3404；MS(ESI)m/e(M+1)⁺: 735.3437。

Embodiment 78

2- (high piperidin-1-yl)-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups - 2- (trifluoromethyl) phenyl) piperidin-4-yl) -3- (1- methyl piperidine -2- base) acetamide 2-34 synthesis

The synthesis of compound 2-34 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 2- (1- homopiperidinyl) acetic acid replaces propiolic acid.Exact Mass (calculated value): 720.7942；MS(ESI)m/e(M+1)⁺: 721.3281。

Embodiment 79

Tert-butyl -4- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (fluoroform Base) phenyl) piperidin-4-yl) carbamyl)-pipecoline -1- carboxylate 2-35 synthesis

The synthesis of compound 2-35 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 4- formic acid-2- methyl-1-Boc piperidines replaces propiolic acid.Exact Mass (calculated value): 806.8842；MS(ESI)m/e(M+1)⁺: 807.3648。

Embodiment 80

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (trifluoromethyl) benzene Base) piperidin-4-yl)-pipecoline -4- carboxamide hydrochloride 2-36 synthesis

The synthesis of compound 2-36 is completed by using the step of being similar to described in embodiment 50, is only used in the reaction 4- formic acid-2- methyl-1-Boc piperidines replaces Boc- amino tryptophan.Exact Mass (calculated value): 743.2252；MS(ESI) m/e(M+1)⁺:743.2891。

Embodiment 81

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (trifluoromethyl) benzene Base) piperidin-4-yl) -3- (piperidin-1-yl) propionamide 2-37 synthesis

The synthesis of compound 2-37 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 3- (piperidin-1-yl) propionic acid replaces propiolic acid.Exact Mass (calculated value): 720.7942；MS(ESI)m/e(M+1)⁺: 721.3281。

Embodiment 82

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (trifluoromethyl) benzene Base) piperidin-4-yl) -3- morpholine acetamide 2-38 synthesis

The synthesis of compound 2-38 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 Morpholinyl propionic acid replaces propiolic acid.Exact Mass (calculated value): 722.7662；MS(ESI)m/e(M+1)⁺:723.3703。

Embodiment 83

3- tert-butyl-n-(1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups -2- (trifluoro Methyl) phenyl) piperidin-4-yl) and isoxazole -5- formamide 2-39 synthesis

The synthesis of compound 2-39 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 3- tert-butyl isoxazole -5- formic acid replaces propiolic acid.Exact Mass (calculated value): 732.7612；MS(ESI)m/e(M+1)⁺: 733.7617。

Embodiment 84

N- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) -4- (4- propionamido- piperidin-1-yl) -3- three The synthesis of methyl fluoride benzamide 14-1

The synthesis of 3- ((6,7- dimethoxy-quinoline -4- base)-oxygroup) aniline A

The synthesis of methyl -4- (4- ((tertbutyloxycarbonyl) amino) piperidin-1-yl) -3- trifluoro methyl benzoate I

Step 2: by the chloro- 3- trifluoromethyl benzoic acid methyl ester (12.69mmol) of 4- and 4- carbamic acid tert-butyl alcohol ester (1.0 Equivalent) it is dissolved in n,N-Dimethylformamide (60mL), it adds potassium carbonate (3.0 equivalent), heating reaction to 100 DEG C of reactions 10 Hour.Mass Spectrometer Method stops reaction without starting material left.It is cooled to room temperature, reaction solution is diluted with sodium bicarbonate solution, with acetic acid second Ester extracts three times, and combined ethyl acetate phase saturated common salt water washing dries, filters, and compound I crude product is obtained after concentration (3.9g).Exact Mass (calculated value): 402.4142；MS(ESI)m/e(M+1)⁺:403.1801；

The synthesis of 4- (4- ((tertbutyloxycarbonyl) amino) piperidin-1-yl) -3- trifluoromethylbenzoic acid J

Step 3: compound I (12.96mmol) is dissolved in methanol (500mL), then by sodium hydroxide (12.96mmol) It is dissolved in the solution in water (13mL) to be added in above-mentioned mixed liquor, reactant is heated to back flow reaction 2 hours.Mass Spectrometer Method is without raw material Residue stops reaction.Compound J crude product (1.2g) is directly concentrated to give after being cooled to room temperature.Exact Mass (calculated value): 388.3872；MS(ESI)m/e(M+1)⁺:389.1643；

Tert-butyl-(1- (4- ((3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) carbamyl) -2- (trifluoro Methyl) phenyl) piperidin-4-yl) and carbamate K synthesis

Step 4: by compound A (1.34mmol), compound J (1.34mmol), HATU (1.89mmol), triethylamine (3.01mmol) is dissolved in DMF (5mL).It reacts at room temperature.Mass Spectrometer Method, raw material react totally, stop reaction.Reaction mixing Liquid is diluted with ethyl acetate, is washed with water three times, and saturated common salt washing is primary, and gained ethyl acetate phase is dry with anhydrous magnesium sulfate Dry, filtering and concentrating object column chromatographs to obtain compound K (206mg).Exact Mass (calculated value): 666.6982；MS(ESI)m/e(M+ 1)⁺:667.2689。

4- (4- amino piperidine -1- base)-N- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) -3- (fluoroform Base) phenyl) benzamide L synthesis

Step 5: Hydrochloride/ethyl acetate (15mL) is slowly instilled to the reaction equipped with compound K (0.33mmol) In bottle, react 4 hours at room temperature.Mass Spectrometer Method, raw material react totally, stop reaction.By reaction solution filter off-white color is consolidated Body, the as hydrochloride (170mg) of compound L.Exact Mass (calculated value): 566.5812；MS(ESI)m/e(M+1)⁺: 567.2173。

Step 6: the synthesis of compound 14-1 is finally by complete the step of use similar to described in 1 step 6 of embodiment At only replacing compound E with compound L.Exact Mass (calculated value): 622.6452；MS(ESI)m/e(M+1)⁺: 623.2437。

Embodiment 85

4- (4- (2- chloracetyl amido) piperidin-1-yl)-N- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) benzene Base) -3- trifluoromethyl benzamide 14-2 synthesis

The synthesis of compound 14-2 is completed by using the step of being similar to described in embodiment 84, only in step 6 Propionyl chloride is replaced with chloracetyl chloride.Exact Mass (calculated value): 643.0602；MS(ESI)m/e(M+1)⁺:643.1890。

Embodiment 86

4- (4- acrylamido piperidin-1-yl)-N- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) -3- The synthesis of trifluoromethyl benzamide 14-3

The synthesis of compound 14-3 is completed by using the step of being similar to described in embodiment 84, only in step 6 Propionyl chloride is replaced with acryloyl chloride.Exact Mass (calculated value): 620.6292；MS(ESI)m/e(M+1)⁺:621.2280。

Embodiment 87

N- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) -4- (4- (4- propionamido- piperidin-1-yl) benzene Base) cyclopropyl -1,1- diformamide 15-1 synthesis

Step 2: by compound A (12.69mmol), 1- (methoxycarbonyl group) cyclopropyl -1- formic acid (12.69mmol), HATU The mixing of (15.00mmol) and triethylamine (15.00mmol) is dissolved in DMF (15mL).It is reacted at room temperature to Mass Spectrometer Method without original Material is remaining, stops reaction.It is diluted with ethyl acetate, mixed liquor is washed with water three times, and saturated common salt washing is primary, and organic phase is with anhydrous Magnesium sulfate dries, filters concentration rear pillar and chromatographs to obtain compound M.Exact Mass (calculated value): 422.4370；MS(ESI)m/e(M +1)⁺:423.1511。

Step 3: compound M (6.66mmol) is dissolved in methanol (10mL), then sodium hydroxide (6.66mmol) is dissolved in Solution in water (7mL) is added in above-mentioned mixed liquor, and reactant is heated to back flow reaction 2 hours.Mass Spectrometer Method without starting material left, Stop reaction.Compound N crude product is directly concentrated to give after being cooled to room temperature.Exact Mass (calculated value): 408.4100；MS (ESI)m/e(M+1)⁺:409.1355。

Step 4: 4- chloronitrobenzene (12.69mmol) and 4- carbamic acid tert-butyl alcohol ester (1.0 equivalent) are dissolved in N, N- bis- It in methylformamide (60mL), adds potassium carbonate (3.0 equivalent), heating is reacted to 100 DEG C and reacted 10 hours.Mass Spectrometer Method without Starting material left stops reaction.It is cooled to room temperature, reaction solution is diluted with sodium bicarbonate solution, is extracted with ethyl acetate three times, is merged Ethyl acetate phase dried, filtered with saturated common salt water washing, after concentration compound B crude product (3.9g).Exact Mass (calculated value): 321.1689；MS(ESI)m/e(M+1)⁺:321.1601；¹H-NMR(400MHz,DMSO-d6)8.04(d,J =8.0Hz, 2H), 7.02 (d, J=8.0Hz, 2H), 4.02~3.96 (m, 2H), 3.56~3.53 (m, 1H), 3.11~3.05 (m, 2H), 2.51~2.50 (m, 2H), 1.82~1.80 (m, 2H), 1.39 (s, 9H)

Step 5: compound B (12.96mmol) is dissolved in methanol (500mL), is added palladium carbon (2.0g), and reaction is mixed Liquid is closed to react under atmosphere of hydrogen 7 hours.Mass Spectrometer Method stops reaction without starting material left.Rear pillar chromatography is concentrated in reaction mixture It obtains compound C (1.2g), two step yields are 32%.Exact Mass (calculated value): 291.1947；MS(ESI)m/e(M+1)⁺: 292.2011；¹H-NMR (400MHz, DMSO-d6) 6.83 (s, 1H), 6.69~6.67 (m, 2H), 6.49~6.47 (m, 2H), 4.62 (br., 2H), 3.33~3.27 (m, 3H), 2.54~2.51 (m, 2H), 1.78~1.75 (m, 2H), 1.50~1.47 (m, 2H),1.39(s,9H).

Step 6: compound N, compound C, HATU (15.00mmol) and triethylamine (15.00mmol) are mixed and are dissolved in In DMF (15mL).It is reacted at room temperature to Mass Spectrometer Method without starting material left, stops reaction.It is diluted with ethyl acetate, mixed liquor is used Three times, saturated common salt washing is primary for washing, and organic phase dries, filters concentration rear pillar with anhydrous magnesium sulfate and chromatographs to obtain compound O. Exact Mass (calculated value): 681.7900；MS(ESI)m/e(M+1)⁺:682.3196。

Step 7: Hydrochloride/ethyl acetate (15mL) is slowly instilled to the reaction equipped with compound O (0.33mmol) In bottle, react 4 hours at room temperature.Mass Spectrometer Method, raw material react totally, stop reaction.By reaction solution filter off-white color is consolidated Body, the hydrochloride (170mg) of as compound P.Exact Mass (calculated value): 581.6730；MS(ESI)m/e(M+1)⁺: 582.6732。

Step 8: the synthesis of compound 15-1 is finally by complete the step of use similar to described in 1 step 6 of embodiment At only replacing compound E with compound P.Exact Mass (calculated value): 637.7370；MS(ESI)m/e(M+1)⁺: 638.6931。

Embodiment 88

N- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) -4- (4- (4- propionamido- piperidin-1-yl) -3- Trifluoromethyl) cyclopropyl -1,1- diformamide 16-1 synthesis.

The synthesis of compound 16-1 is completed by using the step of being similar to described in embodiment 87, is only used in step 4 The chloro- 5- nitro-trifluoromethyl toluene of 2- replaces 4- chloronitrobenzene.Exact Mass (calculated value): 705.7352；MS(ESI)m/e(M+1)⁺: 706.2808。

Embodiment 89

N- (4- (4- (2- chloracetyl amido) piperidin-1-yl) -3- trifluoromethyl)-N- (3- ((6,7- dimethoxy Quinolyl-4) oxygroup) phenyl) and cyclopropyl -1,1- diformamide 16-2 synthesis

The synthesis of compound 16-2 is completed by using the step of being similar to described in embodiment 88, is only used in step 8 Chloracetyl chloride replaces propionyl chloride.Exact Mass (calculated value): 726.1502；MS(ESI)m/e(M+1)⁺:726.2262。

Embodiment 90

N- (4- (4- acrylamido piperidin-1-yl) -3- trifluoromethyl)-N- (3- ((6,7- dimethoxy-quinoline - 4- yl) oxygroup) phenyl) and cyclopropyl -1,1- diformamide 16-3 synthesis

The synthesis of compound 16-3 is completed by using the step of being similar to described in embodiment 88, is only used in step 8 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 703.7192；MS(ESI)m/e(M+1)⁺:704.2651。

Embodiment 91

N- (4- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl)-N- (4- (4- propionamido- piperidin-1-yl) -3- Trifluoromethyl) cyclopropyl -1,1- diformamide 17-1 synthesis.

The synthesis of compound 17-1 is completed by using the step of being similar to described in embodiment 88, is only used in step 1 Para-aminophenol replaces 3- amino-phenol.Exact Mass (calculated value): 705.7352；MS(ESI)m/e(M+1)⁺: 706.2810。

Embodiment 92

N- (4- (4- chloroacetamide phenylpiperidines -1- base) -3- trifluoromethyl)-N- (4- ((6,7- dimethoxy-quinoline - 4- yl) oxygroup) phenyl) and cyclopropyl -1,1- diformamide 17-2 synthesis.

The synthesis of compound 17-2 is completed by using the step of being similar to described in embodiment 91, is only used in step 8 Acryloyl chloride replaces propionyl chloride.Exact Mass (calculated value): 703.7200；MS(ESI)m/e(M+1)⁺:704.1099。

Embodiment 93

N- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl)-N '-(4- (4- propionamido- piperidin-1-yl) - 3- trifluoromethyl) malonamide 18-1 synthesis.

The synthesis of compound 18-1 is completed by using the step of being similar to described in embodiment 88, is only used in step 2 3- methoxycarbonyl group propionic acid replaces 1- (methoxycarbonyl group) cyclopropyl -1- formic acid.Exact Mass (calculated value): 679.6972；MS (ESI)m/e(M+1)⁺:680.3162。

Embodiment 94

N- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) -2- methyl-N- (4- (4- propionamido- piperidines - 1- yl) -3- trifluoromethyl) malonamide 19-1 synthesis.

The synthesis of compound 19-1 is completed by using the step of being similar to described in embodiment 88, is only used in step 2 3- methoxyl group -2- methyl -3- carbonyl propionic acid replaces 1- (methoxycarbonyl group) cyclopropyl -1- formic acid.Exact Mass (calculated value): 693.7242；MS(ESI)m/e(M+1)⁺:694.6610。

Embodiment 95

N- (4- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) piperidin-1-yl) -3- three Trifluoromethylphenyl) propionamide 20-1 synthesis

Step 1: it carries out and same steps described in 87 step 1 of embodiment.

Step 2: it carries out being similar to step described in 87 step 4 of embodiment, only uses 2- chloro- 5- nitro-trifluoromethyl toluene generation For 4- chloronitrobenzene.Obtained solid is AD, Exact Mass (calculated value): 389.1562；MS(ESI)m/e(M+1)⁺: 390.1077。

Step 3: it carries out being similar to step described in 87 step 7 of embodiment, only replaces compound O with AD.Gained is solid Body be compound AE, Exact Mass (calculated value): 289.2582；MS(ESI)m/e(M+1)⁺:290.1072。

Step 4: it carries out being similar to step described in 1 step 4 of embodiment, only replaces compound C with AE.Obtained solid For AF, Exact Mass (calculated value): 611.5782；MS(ESI)m/e(M+1)⁺:612.2025。

Step 5: it carries out being similar to step described in 1 step 3 of embodiment, only replaces compound B with AF.Obtained solid For AG, Exact Mass (calculated value): 581.5962；MS(ESI)m/e(M+1)⁺:582.2283。

Step 6: the synthesis of compound 20-1 is finally by complete the step of use similar to described in 1 step 6 of embodiment At only replacing compound E with AG.Exact Mass (calculated value): 637.6602；MS(ESI)m/e(M+1)⁺:638.6736。

Embodiment 96

N- (4- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) urea groups) piperidin-1-yl) -3- three Trifluoromethylphenyl) -1- (1- methyl piperidine -2- base) propionamide 20-3 synthesis

The synthesis of compound 20-3 is completed by using the step of being similar to described in embodiment 7, is only used in step 6 AG replaces compound E, while replacing propiolic acid with 3- (1- methyl piperidine -2- base) propionic acid.Exact Mass (calculated value): 734.8212；MS(ESI)m/e(M+1)⁺:735.6736。

Embodiment 97

N- (1- (4- (2- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) acetamido) -2- trifluoromethyl Phenyl) piperidin-4-yl) -3- (1- methyl piperidine -2- base) propionamide 21-1 synthesis

Step 1: it carries out being similar to 1 step of embodiment using 3- hydroxyphenylacetic acid methyl ester and the chloro- 6,7- dimethyl quinoline of 4- Step described in one.Gained compound be AH, Exact Mass (calculated value): 353.3771；MS(ESI)m/e(M+1)⁺: 354.1201。

Step 2: it carries out being similar to step described in 87 step 3 of embodiment, only replaces compound M with AH.Gained Conjunction object be AI, Exact Mass (calculated value): 339.3445；MS(ESI)m/e(M+1)⁺:340.2025。

Step 3: it carries out being similar to step described in 87 step 5 of embodiment, only replaces compound B with AD.Gained Conjunction object be AJ, Exact Mass (calculated value): 359.3932；MS(ESI)m/e(M+1)⁺:360.4001。

Step 4: it carries out being similar to step described in 87 step 2 of embodiment, only replaces compound A with AI.Gained Conjunction object be AK, Exact Mass (calculated value): 680.7522；MS(ESI)m/e(M+1)⁺:681.2225。

Step 5: it carries out being similar to step described in 87 step 7 of embodiment, only replaces compound O with AK.Gained Conjunction object be AL, Exact Mass (calculated value): 580.6082；MS(ESI)m/e(M+1)⁺:581.2333。

Step 6: the synthesis of compound 21-1 is finally by the step of being similar to described in embodiment 7 completion is used, only Compound E is replaced with AL, while replacing propiolic acid with compound 3- (1- methyl piperidine -2- base) propionic acid.Exact Mass (is calculated Value): 733.8212；MS(ESI)m/e(M+1)⁺:734.8332。

Embodiment 98

N- (1- (4- (2- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) acetamido) -2- trifluoromethyl Phenyl) piperidin-4-yl) propionamide 21-2 synthesis

The synthesis of compound 21-2 is completed by using the step of being similar to described in embodiment 97, is only used in step 6 Propionyl chloride replaces 3- (1- methyl piperidine -2- base) propionic acid.Exact Mass (calculated value): 636.6322；MS(ESI)m/e(M+1)⁺: 637.2559。

Embodiment 99

N- (1- (4- (7- ((6,7- dimethoxy-quinoline -4- base) oxygroup) quinazoline -2- base) amido) -2- trifluoromethyl Phenyl) piperidin-4-yl) propionamide 22-1 synthesis

Step 1: the chloro- 7- bromine quinazoline (8.11mmol) of 2- is dissolved in n,N-Dimethylformamide (10mL), in argon gas Cuprous bromide (10.16mmol), sodium methoxide (40.54mmol, 5.4M are in MeOH) are sequentially added into above-mentioned solution again under atmosphere In.Reflux Mass Spectrometer Method is heated to no starting material left, stops reaction.It is cooled to room temperature, after solvent is removed in vacuum, residue is used Ethyl acetate dissolution, gained organic phase, which is washed with water, is light blue color to solution three times, and saturated common salt washing is primary, and anhydrous magnesium sulfate is dry Dry, filtering and concentrating rear pillar chromatographs to obtain target compound Q.Exact Mass (calculated value): 194.6186；MS(ESI)m/e(M+1)⁺: 196.0017。

Step 2: above compound Q (7.98mmol) is dissolved in methylene chloride (100mL), will after being cooled to -78 DEG C The dichloromethane solution (1.0M, 25mL) of boron chloride is slowly added into above-mentioned reaction solution, and reaction to Mass Spectrometer Method is surplus without raw material Yu Hou stops reaction.With saturated ammonium chloride solution quenching reaction liquid, separatory filtration process, gained methylene chloride mutually uses saturated salt solution It washes, gained crude product R is directly used in reaction in next step after anhydrous magnesium sulfate dries, filters concentration.Exact Mass (calculated value): 180.5898；MS(ESI)m/e(M+1)⁺:181.1067。

Step 3: be similar to described in 1 step 1 of embodiment using compound R and the chloro- 6,7- dimethoxy-quinoline of 4- The step of, obtain compound S.Exact Mass (calculated value): 367.7681；MS(ESI)m/e(M+1)⁺:368.7211。

Step 4: by compound S (7.01mmol) and tert-butyl-(1- (4- amino -2- trifluoromethyl) piperidines -4- Base) carbamate (7.33mmol) is dissolved in n-butanol (20mL), adds p-methyl benzenesulfonic acid (0.7mmol), and heating is mixed Liquid is closed to 80 DEG C of reactions to Mass Spectrometer Method without starting material left.Stop reaction, is cooled to room temperature.N-butanol is removed in vacuum, residual is solid Body is washed once after being dissolved with ethyl acetate with saturated sodium bicarbonate solution, is washed once with saturated common salt, dry with anhydrous magnesium sulfate It is dry, filtering and concentrating rear pillar chromatograph target compound T, Exact Mass (calculated value): 690.7244；MS(ESI)m/e(M+1)⁺: 691.6631。

Step 5: it carries out being similar to step described in 1 step 5 of embodiment, only replaces compound D with compound T, obtain To compound U.Exact Mass (calculated value): 590.6970；MS(ESI)m/e(M+1)⁺:591.3262。

Step 6: the synthesis of compound 22-1 is finally by complete the step of use similar to described in 1 step 6 of embodiment At only replacing compound E with compound U.Exact Mass (calculated value): 646.6712；MS(ESI)m/e(M+1)⁺: 647.2579。

Embodiment 100

N- (1- (4- (7- ((6,7- dimethoxy-quinoline -4- base) oxygroup) quinazoline -2- base) amido) -2- trifluoromethyl Phenyl) piperidin-4-yl) -3- (1- methyl piperidine -2- base) propionamide 22-3 synthesis

The synthesis of compound 22-3 is completed by using the step of being similar to described in embodiment 99, is only used in step 6 3- (1- methyl piperidine -2- base) propionic acid replaces propionyl chloride.Exact Mass (calculated value): 743.8122；MS(ESI)m/e(M+1)⁺: 744.3441。

Embodiment 101

N- (1- (4- (6- ((6,7- dimethoxy-quinoline -4- base) oxygroup) quinazoline -2- base) amido) -2- trifluoromethyl Phenyl) piperidin-4-yl) propionamide 23-1 synthesis

The synthesis of compound 23-1 is completed by using the step of being similar to described in embodiment 99, is only used in step 1 The chloro- 6- bromine quinazoline of 2- replaces the chloro- 7- bromine quinazoline of 2-.Exact Mass (calculated value): 646.6723；MS(ESI)m/e(M+ 1)⁺:647.2556。

Embodiment 102

N- (1- (4- (6- ((6,7- dimethoxy-quinoline -4- base) oxygroup) quinazoline -2- base) amido) -2- trifluoromethyl Phenyl) piperidin-4-yl) -3- (1- methyl piperidine -2- base) propionamide 23-3 synthesis

The synthesis of compound 23-3 is completed by using the step of being similar to described in embodiment 101, only in step 6 Propionyl chloride is replaced with 3- (1- methyl piperidine -2- base) propionic acid.Exact Mass (calculated value): 743.8322；MS(ESI)m/e(M+ 1)⁺:744.3671。

Embodiment 103

N- (1- (4- (5- ((6,7- dimethoxy-quinoline -4- base) oxygroup) benzo [d] oxazole -2- base) amido) -2- trifluoro Aminomethyl phenyl) piperidin-4-yl) propionamide 24-1 synthesis

The synthesis of compound 24-1 is completed by using the step of being similar to described in embodiment 99, is only used in step 1 The chloro- 5- bromine benzoxazoles of 2- replaces the chloro- 7- bromine quinazoline of 2-.Exact Mass (calculated value): 635.6442；MS(ESI)m/e(M +1)⁺:636.6389。

Embodiment 104

N- (1- (4- (6- ((6,7- dimethoxy-quinoline -4- base) oxygroup) benzo [d] oxazole -2- base) amido) -2- trifluoro Aminomethyl phenyl) piperidin-4-yl) -3- (1- methyl piperidine -2- base) propionamide 24-3 synthesis

The synthesis of compound 24-3 is completed by using the step of being similar to described in embodiment 103, only in step 6 Propionyl chloride is replaced with 3- (1- methyl piperidine -2- base) propionic acid.Exact Mass (calculated value): 732.8352；MS(ESI)m/e(M+ 1)⁺:733.3971。

Embodiment 105

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) -2- carbonyl tetrahydropyrimidine -1- (2H)-yl) -2- trifluoromethyl) piperidin-4-yl) and propionamide 25-1 synthesis

Step 1: compound 3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) aniline (2.11mmol) is dissolved in anhydrous In methylene chloride (10mL), sodium hydride (3.15mmol) is slowly added into after stirring 30 minutes at room temperature, then by compound 1,3- Dibromopropane (2.11mmol) is added in above-mentioned mixed liquor, and being heated to back flow reaction to Mass Spectrometer Method is not having starting material left, stops Only react.It is cooled to room temperature, is diluted with methylene chloride, then washed with saturated sodium bicarbonate solution, washed, saturated common salt washing, nothing Water magnesium sulfate dries, filters concentration rear pillar and chromatographs to obtain compound V.Exact Mass (calculated value): 417.3022；MS(ESI)m/e (M+1)⁺:418.0755。

Step 2: compound V, triphosgene, tert-butyl-(1- (4- amino -2- trifluoromethyl) piperidin-4-yl) are used Carbamate carries out the step of being similar to described in 1 step 4 of embodiment, and obtaining compound is W.Exact Mass (is calculated Value): 732.8352；MS(ESI)m/e(M+1)⁺:733.3971。

Step 3: compound W (0.88mmol) is dissolved in tetrahydrofuran (10mL), and sodium hydride (1.34mmol) is added In above-mentioned mixed liquor, back flow reaction is heated to Mass Spectrometer Method without starting material left, stops reaction.It is cooled to room temperature, is removed in vacuum Solvent, residue with Ethyl acetate dissolution are washed with water, saturated common salt washing, and anhydrous magnesium sulfate dries, filters concentration rear pillar chromatography Obtain compound X.Exact Mass (calculated value): 721.7282；MS(ESI)m/e(M+1)⁺:723.3971。

Step 4: the step of being similar to described in 1 step 5 of embodiment is carried out using compound X, obtains compound Y. Exact Mass (calculated value): 621.6612；MS(ESI)m/e(M+1)⁺:622.7156。

Step 5: the synthesis of compound 25-1 is finally by complete the step of use similar to described in 1 step 6 of embodiment At only replacing compound E with compound Y.Exact Mass (calculated value): 677.7652；MS(ESI)m/e(M+1)⁺: 678.6752。

Embodiment 106

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) -2- carbonyl tetrahydropyrimidine -1- (2H)-yl) -2- trifluoromethyl) piperidin-4-yl) and -3- (1- methyl piperidine -2- base) propionamide 25-3 synthesis

The synthesis of compound 25-3 is completed by using the step of being similar to described in embodiment 105, only in step 5 Propionyl chloride is replaced with 3- (1- methyl piperidine -2- base) propionic acid.Exact Mass (calculated value): 774.8662；MS(ESI)m/e(M+ 1)⁺:775.7551。

Embodiment 107

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) -2- carbonylic imidazole quinoline -1- base) - 2- trifluoromethyl) piperidin-4-yl) propionamide 26-1 synthesis

The synthesis of compound 26-1 is completed by using the step of being similar to described in embodiment 105, only in step 1 1,3- dibromopropane is replaced with glycol dibromide.Exact Mass (calculated value): 663.6982；MS(ESI)m/e(M+1)⁺: 664.6702。

Embodiment 108

N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) -2- carbonylic imidazole quinoline -1- base) - 2- trifluoromethyl) piperidin-4-yl) -3- (1- methyl piperidine -2- base) propionamide 26-3 synthesis

The synthesis of compound 26-3 is completed by using the step of being similar to described in embodiment 107, only in step 5 Propionyl chloride is replaced with 3- (1- methyl piperidine -2- base) propionic acid.Exact Mass (calculated value): 760.8592；MS(ESI)m/e(M+ 1)⁺:761.8593。

Embodiment 109

N- (1- (2- (2- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) acetylamino) thiazole -4- carbonyl) Piperidin-4-yl) propionamide 27-1 synthesis

Step 1: compound thiazolamine -4- Ethyl formate (0.71mmol) is dissolved in methanol (10mL), will be prepared Sodium hydroxide (1.0M, 0.71mmol) solution be added in above-mentioned mixed liquor, be heated to flowing back, reaction to Mass Spectrometer Method is without original Material is remaining, stops reaction.It is cold to go to room temperature, mixed liquor is concentrated in vacuo, gained residue is the mixture of compound Z, directly It connects for reacting in next step.Exact Mass (calculated value): 144.1841；MS(ESI)m/e(M+1)⁺:145.9901。

Step 2: carrying out the step of being similar to described in 87 step 2 of embodiment using mixture Z, 4-Boc amino piperidine, Gained compound is AA.Exact Mass (calculated value): 326.4150；MS(ESI)m/e(M+1)⁺:327.1687。

Step 3: class is carried out using compound AA, 2- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) acetic acid The step of being similar to described in 87 step 2 of embodiment, gained compound are AB.Exact Mass (calculated value): 647.7472；MS (ESI)m/e(M+1)⁺:648.2613。

Step 4: the step of being similar to described in 1 step 5 of embodiment is carried out using compound AB, obtains compound AC. Exact Mass (calculated value): 547.5391；MS(ESI)m/e(M+1)⁺:548.2670。

Step 5: the synthesis of compound 27-1 is finally by complete the step of use similar to described in 1 step 6 of embodiment At only replacing compound E with compound AC.Exact Mass (calculated value): 603.6940；MS(ESI)m/e(M+1)⁺: 604.6938。

Embodiment 110

N- (1- (2- (2- (3- ((6,7- dimethoxy-quinoline -4- base) oxygroup) phenyl) acetylamino) thiazole -4- carbonyl) Piperidin-4-yl) -3- (1- methyl piperidine -2- base) propionamide 27-3 synthesis

The synthesis of compound 27-3 is completed by using the step of being similar to described in embodiment 109, only in step 5 Propionyl chloride is replaced with 3- (1- methyl piperidine -2- base) propionic acid.Exact Mass (calculated value): 700.8511；MS(ESI)m/e(M+ 1)⁺:701.3781。

Embodiment 111: the influence to cancer cell multiplication

Pass through compound 2-1, compound 2-2, compound 2-3, compound 2-9, compound 2-8, compound in test text 2-5, compound 2-10, compound 2-11, compound 2-12, compound 2-13, compound 2-14, compound 2-15, compound 2-16, compound 2-17, compound 2-18, compound 2-19, compound 2-20, compound 2-21, compound 2-22, compound 2-23, compound 2-24, compound 2-25, compound 2-26, compound 2-27, compound 2-28, compound 2-29, compound 2-30, compound 2-31, compound 2-32, compound 2-33, compound 2-34, compound 2-35, compound 2-36, compound 2-37, compound 14-1, compound 14-2, compound 14-3, compound 16-1, compound 16-2, compound 16-3, compound The influence (table 1) of 17-1, compound 17-2 to growth of cancer cells, further inhibition of the compound to cancer cell multiplication in assessment text Effect, and its to the selectivity for inhibiting cancer cell multiplication.People's acute monocytic leukemia cell has been selected in the present embodiment Strain MV-4-11 (expression FLT3/ITD mutated genes), human muscle creatine kinase cell strain MOLM-13 (expression FLT3/ITD Mutated genes and wild type FLT3 gene), Non-small cell lung carcinoma cell H1975 (expression EGFR L858R/T790M it is bis- dash forward Modification gene), blood cell K562, human A549 cell lines (expression Wild type EGFR gene), prostate cancer C4-2, diffuse Property large B cell lymphoid tumor cell line TMD8, prostate cancer RV-1, people's Burkitt's lymphoma cell Namalwa, human B cell are slow Property lymphoblastic leukemia cell lines MEC-2, MEG-01, chronic myelogenous leukemia KU812, human muscle creatine kinase cell strain MOLM-14 (expression FLT3/ITD mutated genes and wild type FLT3 gene), human muscle creatine kinase cell strain U937 (table Up to wild type FLT3 gene), acute myeloid leukemia cells in children HL-60 (expression wild type FLT3 gene), Non-small cell lung carcinoma Cell NCI-H460 (EGFR WT), human muscle creatine kinase cell strain OCI-AML-3 (expression FLT3 A680V saltant type base Cause), human T cell lymphoma cell PF-382, human lung adenocarcinoma cell PC-9, human breast cancer cell MDA-MB-468, human breast carcinoma Cell T47D, human bladder cancer cell Hb-c, Non-small cell lung carcinoma cell HCC827, Non-small cell lung carcinoma cell NCI-H23, CHL cells CHL, Chinese hamster ovary cell (Chinese hamster ovary) CHO, mouse pro B lymphocyte BaF3, The above cell is purchased from ATCC.Also selected mouse BaF3-FLT3-ITD (stablize expression FLT3-ITD mutation activated protein kinase), Mouse BaF3-FLT3-D835Y (activated protein kinase for stablizing expression FLT3 D835Y mutation), mouse BaF3-FLT3-D835V are (steady Surely expression FLT3 D835V mutation activated protein kinase), mouse BaF3-FLT3-D835H (stablize expression FLT3 D835H mutation Activated protein kinase), mouse BaF3-FLT3-K663Q (stablize expression FLT3 K663Q mutation activated protein kinase), mouse TEL-BMX- BaF3 (stablizing expression BMX kinases), mouse BaF3-TEL-PDGFRa (stablizing PDGF-B expression Ra kinases), mouse BaF3-TEL- VEGFR2 (stablizing VEGF expression R2 kinases), mouse TEL-FLT3-BaF3 (stablizing expression FLT3 kinases), mouse BaF3-FLT3- ITD-D835Y (activated protein kinase for stablizing expression FLT3/ITD D835Y mutation), mouse BaF3-FLT3-ITD-F691L (stablize Express the activated protein kinase of FLT3/ITD F691L mutation), mouse TEL-c-KIT-BaF3 (stablize expression cKIT kinases), mouse TEL-c-KIT-N822K-BaF3 (activated protein kinase for stablizing expression cKIT N882K mutation), mouse TEL-c-KIT-D816V- BaF3 (activated protein kinase for stablizing expression cKIT D816V mutation), mouse TEL-c-KIT-T670I-BaF3 (stablize expression cKIT The activated protein kinase of T670I mutation), mouse TPR-MET-BaF3 (stablize expression MET kinases), mouse TEL-ABL-BaF3 (stablize Express ABL kinases), mouse TEL-ABL-T315I-BaF3 (stablize expression ABL T315I kinases), mouse BaF3-p210 (stablize Express ABL p210 kinases), mouse TEL-ALK-BaF3 (stablize expression ALK kinases),.Above-mentioned cell strain is by this laboratory structure Build, construction method are as follows: PCR expand respectively mankind FLT3/ITD, FLT3 D835Y, FLT3 D835V, FLT3 D835H, BMX, FLT3、FLT3/ITD D835Y、FLT3/ITD F691L、cKIT、cKIT N882K、cKIT D816V、cKIT T670I、MET、 EGFR, EGFR L858R, BLK, PDGFRa, JAK1 kinases region sequence, and be inserted respectively into N-terminal TEL or TPR segment MSCV-Puro carrier (Clontech), by retrovirus method, stabilization is transferred to mouse BaF3 cell, and removes IL-3 Growth factor, finally obtain rely on FLT3/ITD, FLT3 D835Y, FLT3 D835V, FLT3 D835H, FLT3 K663Q, BMX、ABL、ABL T315I、ALK、FLT3、FLT3/ITD D835Y、FLT3/ITD F691L、cKIT、cKIT N882K、cKIT D816V, cKIT T670I, MET, EGFR, VEGFR2, PDGFRa, EGFR L858R, BLK, JAK1 are transferred to the cell line of albumen.

In embodiment by various concentration (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μ M, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM in DMSO) above compound be added separately to above-mentioned cell In, and be incubated for 72 hours, use Cell(Promega, the U.S.) chemistry self-luminous method cell viability detection reagent Box detects number of viable cells by being quantitative determined to the ATP in living cells.Experimental result is shown in Table 1.

The influence of 1 cell proliferation of table

Continued 1

Embodiment 112: external inhibitory activity (enzyme activity) detection

Compound 2-1, compound 2-2, compound 2-3, compound 2-11, compound 2- are measured in enzyme activity experiment in vitro 12, compound 2-13, compound 2-14, compound 2-15, compound 2-16, compound 2-32, compound 2-33, compound 2- 34, IC50 value of the compound 2-37 to protein kinase FLT3, FLT3-ITD and cKIT.By protein kinase FLT3, FLT3-ITD and The intracellular section of regional cloning of cKIT utilizes insect expression system BaculoGold into insect expression vector pAcG2T^TM Baculovirus Expression System (BD Pharmingen, the U.S.) carries out protein expression, and with GST or Histag label.The carrier built is transfected to SF9 packaging virus, expresses albumen with virus infection SF9.

Take the 9 μ L of FLT3, FLT3-ITD and cKIT protein kinase (6ng/ μ L) of purifying upper with three times gradient dilution respectively State 1 μ L of compound react at room temperature 4 hours (drug is 10 μM final concentration of, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003μM)；

2 μ L ATP and 3 μ L substrate Poly (4:1Glu, Tyr) Peptide (Promega, the U.S.) (final concentration difference are added For 10 μM and 0.2 μ g/ μ L), 37 DEG C are reacted 1 hour；

5 μ L ADP-Glo are added in kinase solution after taking 5 μ L to react^TM(Promega, the U.S.) reagent reacts at room temperature 40min To terminate kinase reaction and run out of remaining ATP；

10 μ L kinase assay reagents are added, ADP is converted to ATP, uses luciferase/luciferin reaction detection of coupling Newly synthesized ATP is mapped after being read using Envision, is calculated IC50 value (table 2).

Experimental result is as shown in table 2: above-mentioned example compound of the invention swashs FLT3, FLT3-ITD and cKIT albumen Enzyme has strong inhibiting effect.These results illustrate that the compounds of this invention is the inhibitor of FLT3 kinases, while to FLT3- ITD and cKIT kinases also has inhibiting effect.

2 Enzyme activity assay result of table

Embodiment 113: compound 2-1, compound 2-3 and compound 2-33 are in cell to FLT3 upstream and downstream signal path Influence

In the human muscle creatine kinase cell MV-4-11 (table for carrying FLT3 gene and/or FLT3-ITD mutated genes Up to FLT3-ITD mutated genes) cell strain, human muscle creatine kinase cell strain MOLM-13 (expression FLT3-ITD saltant type Gene and wild type FLT3 gene) cell strain and human muscle creatine kinase cell strain MOLM-14 (expression FLT3-ITD saltant type Gene and wild type FLT3 gene) in cell strain, by measuring many cellular biochemistry terminals and functional terminal, test Compound 2-1, compound 2-3, compound 2-33 and control compound FLT3 kinase inhibitor AC220 (are purchased from Hao Yuan Chemexpress company, Shanghai) to the phosphorylation of the FLT3 and/or FLT3-ITD protein kinase in cell and its closely related Signal path downstream STAT5 protein phosphorylation influence and other relevant Protein kinase ERKs, AKT phosphorylation influence, We also have detected the influence (Fig. 1) of PROTEIN C-Myc and transcription factor NF-KB subunit p65 phosphorylation simultaneously.It is dense with difference Spend 0nM, 3nM, 10nM, 30nM, 100nM, 300nM, 1000nM (in DMSO) compound 2-1, compound 2-3 and 0 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM (in DMSO) of compound 2-33 and the suppression of 0.1 μM (in DMSO) of FLT3 kinases Preparation AC220 handles acute myeloid leukemia cells in children MV-4-11, the MOLM- for carrying FLT3 and/or FLT3-ITD gene respectively 13, sample is collected in MOLM-14 cell strain 4 hours.Measure FLT3, the STAT5, C-Myc, ERK, NF- κ B in compound on intracellular The influence (Fig. 1) of the protein phosphorylations such as p65, AKT.

Experimental result is as shown in Figure 1: in human muscle creatine kinase cell MV-4-11 (expression FLT3-ITD saltant type base Cause) in cell strain, compound 2-1, compound 2-3 and compound 2-33 can very strongly inhibit protein kinase FLT3's Phosphorylation (its IC50 is less than 10nM).Meanwhile compound 2-1, compound 2-3 and compound 2-33 are under FLT3-ITD in cell The phosphorylation of trip Protein S TAT5 also has inhibiting effect strongly, has apparent inhibition to the phosphorylation of Protein kinase ERK Effect.In addition, compound 2-1, compound 2-3 and 2-33 couples of the compound PROTEIN C-Myc closely related with FLT3 protein kinase There is strong degradation.In same experiment, control compound FLT3 kinase inhibitor AC220 is also able to observe that similarly Experimental phenomena.

In human muscle creatine kinase cell strain MOLM-13 (expression FLT3-ITD mutated genes and wild type FLT3 base Cause) cell strain and human muscle creatine kinase cell strain MOLM-14 (expression FLT3-ITD mutated genes and wild type FLT3 base Cause) in cell strain, compound 2-1, compound 2-3 and compound 2-33 also can very strongly inhibit protein kinase FLT3 Phosphorylation (its IC50 be less than 10nM).Compound 2-1, compound 2-3 and compound 2-33 are to the downstream FLT3-ITD in cell The phosphorylation of Protein S TAT5 equally also has inhibiting effect strongly.In addition, compound 2-1, compound 2-3 and chemical combination Object 2-33 has apparent inhibiting effect to the phosphorylation of Protein kinase ERK, to the PROTEIN C-closely related with FLT3 protein kinase Myc has strong degradation.In same experiment, control compound FLT3 kinase inhibitor AC220 is also able to observe that together The experimental phenomena of sample.

Embodiment 113 shows that compound 2-1, compound 2-3 and compound 2-33 can not only consumingly inhibit albumen to swash The phosphorylation of enzyme FLT3, and have to the phosphorylation of the signal path downstream albumen STAT5 of protein kinase FLT3 in cell strong Inhibiting effect has strong degradation to the PROTEIN C-Myc closely related with FLT3 protein kinase, and then inhibits to carry FLT3 And/or the cell Proliferation of the acute myeloid leukemia cells in children strain of FLT3-ITD gene.

Embodiment 114: compound 2-1 and compound 2-33 is on cell to the influence of Apoptosis

In order to prove that the death of cell after medication is to carry FLT3 gene and/or FLT3- by apoptosis or necrosis Human muscle creatine kinase cell MV-4-11 (expression FLT3-ITD mutated genes) cell strain of ITD mutated genes, people are anxious Property marrow leukaemia cell strain MOLM-13 (expression FLT3-ITD mutated genes and wild type FLT3 gene) cell strain and people it is anxious Property marrow leukaemia cell strain MOLM-14 (expression FLT3-ITD mutated genes and wild type FLT3 gene) cell strain in, inspection Compound 2-1, compound 2-33 have been surveyed in cell to the DNA repair enzyme poly- adenosine diphosphate-closely related with Apoptosis The influence of ribose polymerase PARP, 3 protein cleavage of aspartic acid proteolytic enzyme Caspase containing cysteine.It is dense with difference 0 μM of degree, 0.3 μM, 1 μM, 3 μM (in DMSO) of compound 2-1 and 1 μM (in DMSO) of FLT3 kinase inhibitor AC220 MOLM-13, MOLM-14 and MV-4-11 cell strain are handled respectively, with 0 μM of various concentration, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM compound 2-33 of (in DMSO) and 0.1 μM (in DMSO) of FLT3 kinase inhibitor AC220 handles MOLM- respectively 14, MV-4-11 cell strain collected cell after 24 hours.With the medicine of Western Blot detection various concentration in different time sections Adenosine diphosphate-ribose polymerase PARP poly- to DNA repair enzyme and aspartic acid proteolytic enzyme Caspase containing cysteine The influence (Fig. 2) of 3 shear protein.

Experimental result is as shown in Figure 2: for carrying the acute myelogenous white of FLT3 gene and/or FLT3-ITD mutated genes Blood disease cell line MOLM-13, MOLM-14 and MV-4-11 cell strain, when the Drug level of compound 2-1 is 0.3 μM, effect Just it can be seen that the poly- adenosine diphosphate of particularly apparent DNA repair enzyme-ribose polymerase PARP shearing, Yi Jite after 24 hours The not significantly shearing of the aspartic acid proteolytic enzyme Caspase 3 containing cysteine, is used in the same manner 1 μM of control chemical combination Object FLT3 kinase inhibitor AC220 can also observe same phenomenon.

For carry FLT3 gene and/or FLT3-ITD mutated genes acute myeloid leukemia cells in children MOLM-14 and MV-4-11 cell strain, when the Drug level of compound 2-33 is 0.1 μM, after effect 24 hours, it can be seen that particularly apparent The poly- adenosine diphosphate of DNA repair enzyme-ribose polymerase PARP shearing, can also see the aspartic acid albumen water containing cysteine Solve the shearing of enzyme Caspase 3.Embodiment 114, which demonstrates compound 2-1 and compound 2-33, can cause to carry FLT3 gene And/or the apoptosis of the acute myeloid leukemia cells in children of FLT3-ITD mutated genes.

Embodiment 115: the influence of compound 2-1 and compound the 2-33 cell cycle on cell

It is prominent in carrying FLT3 gene and/or FLT3-ITD in order to study which growth cycle cell after medication is stopped in Acute myeloid leukemia cells in children MOLM-14 and the MV-4-11 cell strain of modification gene, tests compound 2-1 and compound 2- The influence of the cell cycle distribution of 33 pairs of these cell strains.With 0.5 μM, 1 μM (in DMSO) of compound 2-1 of various concentration And the FLT3 kinase inhibitor AC220 of 10nM (in DMSO) is acted on and is carried FLT3 gene and/or FLT3-ITD saltant type base Acute myeloid leukemia cells in children MOLM-14 and the MV-4-11 cell strain of cause, with 0 μM of various concentration, 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM (in DMSO) of compound 2-33 and 0.1 μM (in DMSO) of FLT3 kinase inhibitor AC220 make In acute myeloid leukemia cells in children MV-4-11 cell strain for only carrying FLT3-ITD mutated gene, after effect 24 hours, receive Collecting cell, 1XPBS buffer washes twice, and 75% ethyl alcohol fixes 24 hours in -20 DEG C, and 1XPBS buffer washes twice again, The PI dyeing liquor (purchased from U.S. BD Bioscience) of 0.5mL 1XPBS buffer and 0.5mL is added to put into cell and by cell It is placed in dark and is protected from light 37 DEG C of dyeing 15 minutes, with flow cytometer (BD FACS Calibur) detection cell cycle distribution (figure 3)。

Experimental result is as shown in Figure 3: in the acute myeloid leukemia cells in children strain MV-4- for carrying FLT3/ITD mutated genes In 11 cell strains, as the drug concentration of compound 2-1 increases to 1 μM from 0 μM, the cell of the G0-G1 phase of capture also from 53.38% increases to 88.53%；In same experiment, the stronger FLT3 kinase inhibitor AC220 of selectivity is captured in 10nM The G0-G1 phase cell be 85.31%；And as the drug concentration of compound 2-33 increases to 1 μM from 0 μM, the G0-G1 of capture The cell of phase also increases to 91.93% from 57.57%；With the stronger FLT3 kinase inhibitor AC220 of selectivity in experiment 0.1 μM when the cell of G0-G1 phase that captures be 88.66%.In the urgency of expression FLT3-ITD mutated genes and wild type FLT3 gene In property marrow leukaemia cell MOLM-14 cell strain, as the drug concentration of compound 2-1 increases to 1 μM from 0 μM, capture The cell of G0-G1 phase also increases to 85.63% from 48.92%；And with the stronger FLT3 kinase inhibitor of selectivity in testing The cell for the G0-G1 phase that AC220 is captured in 10nM is 87.29%；

Embodiment 115, which demonstrates compound 2-1 and compound 2-33 and can will carry FLT3 gene and/or FLT3-ITD, dashes forward Acute myeloid leukemia cells in children MOLM-14 and the MV-4-11 cell strain of modification gene was prevented in the G0-G1 phase, and to cell week Strong influence (Fig. 3) is distributed in phase.

Claims

1. the compound or its pharmaceutically acceptable salt of a kind of formula (I), have a structure that

Wherein:

Ar₁And Ar₂For phenyl；

X be selected from Linking group；

R₃It is selected from:

R₄It is selected from

R₅Selected from alkyl；Alkenyl；Alkynyl；Halogenated alkyl；Naphthenic base；Aminoalkyl；Alkylaminoalkyl group；Alkyl amino alkenyl；It is miscellaneous Naphthenic base, optionally by alkyl, alkyl-carbonyl, naphthene base carbonyl, amino protecting group or hetero atom optionally by alkyl-substituted miscellaneous Naphthenic base replaces；Cycloalkenyl；Heteroaryl；Optionally by alkyl-substituted hetercycloalkylalkyl；Optionally by alkyl-substituted miscellaneous Aryl；Alkyl is optionally by amino replaces and nitrogen is optionally replaced by amino protecting group aminoacyl alkyl；Alkyl is optionally by ammonia Base replaces and nitrogen is optionally by amino protecting group replaces and/or aryl is optionally optionally substituted by a hydroxyl group aryl alkyl；Alkyl optionally by Amino replaces and nitrogen is optionally by amino protecting group replaces and/or heteroaryl is optionally optionally substituted by a hydroxyl group heteroaryl alkyl.

2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein amino protecting group be tertbutyloxycarbonyl, Benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl, benzyl or p-methoxyphenyl.

3. compound according to claim 1 or its pharmaceutically acceptable salt, wherein X is

4. compound according to claim 1 or its pharmaceutically acceptable salt, wherein R₁For hydrogen, and/or R₂For fluoroform Base.

5. compound according to claim 1 or its pharmaceutically acceptable salt, wherein R₃ForAnd R₄For

6. compound according to any one of claims 1-5 or its pharmaceutically acceptable salt are selected from following compound:

7. a kind of pharmaceutical composition, including such as compound of any of claims 1-6 or its pharmaceutically acceptable salt, Pharmaceutically acceptable carrier or excipient, and optional other therapeutic agents.

8. compound according to claim 1 to 6 preparation for reducing or inhibit tyrosine kinase FLT3, Purposes in the active drug of cKIT, ABL, EGFR, BMX, BLK, VEGFR, RET, PDGFR, MEK, BCR/ABL, JAK, BRAF.

9. compound according to claim 1 to 6 is in preparation for treating proliferative disorders and/or FLT3, c- Purposes in the drug of KIT associated disease.

10. purposes according to claim 9, wherein the illness presses down in response to FLT3 kinases or saltant type FLT3 kinases System.

11. purposes according to claim 9, wherein the illness is in response to Kit kinase inhibition.

12. purposes according to claim 10, wherein the saltant type FLT3 kinases is FLT3/ITD mutation type kinase.

13. purposes according to claim 9, wherein the proliferative disorders are selected from: benign or malignant solid tumor, sarcoma, Gastrointestinal stromal tumor, acute myeloblastic leukemia (AML), chronic myelogenous leukemia (CML), to ABL and BCR/ABL tyrosine-kinase Inhibition of enzyme activity has influential leukaemia, B- cell lymphom, diffusivity large B cell lymphoid tumor, follicular lymphoma, chronic Lymphocytic lympboma, chronic lymphocytic leukemia, B born of the same parents' pre-lymphocytic leukemia, lymphoplasmacytic lymphoma/Wa Er Deng Sitelun macroglobulinemia, splenic marginal zone lymthoma, plasma cell myeloma, plasmacytoma, knot outer edge area B cell leaching Bar tumor, lymphoma nodal marginal zone B cell, lymphoma mantle cell, mediastinum (thymus gland) large B cell lymphoid tumor, intravascular big B are thin Born of the same parents' lymthoma, lymphoma primary effusion, Burkitt lymphoma, lymphomatoid granulomatosis, mesenchymoma, systemic mast are thin Born of the same parents' disease, hypereosinophilia syndrome (HES), fibre modification, rheumatoid arthritis, panarthritis, chorionitis, erythema Lupus, graft versus host disease(GVH disease), neurofibroma, pulmonary hypertension, breast ductal cancer, lobular carcinoma, gland cancer, melanoma, B cell increase Natural disposition disease, the cancer of the brain, kidney, liver cancer, adrenal, bladder cancer, breast cancer, lymph cancer, gastric cancer, gastrointestinal stromal tumor, stomach neoplasm, Cancer of the esophagus, oophoroma, colorectal cancer, prostate cancer, cancer of pancreas, lung cancer, carcinoma of vagina, film gland cancer, thyroid cancer, neck cancer, CNS Cancer, glioblastoma, myeloproliferative disease, spongioblastoma, Huppert's disease, human primary gastrointestinal cancers, colorectal cancer, neck are swollen Tumor, brain tumor, epidermal hyper-proliferative, psoriasis, hyperplasia of prostate, the tumor formation of epithelial character, carcinoma of vagina, cervical carcinoma, intrauterine Film cancer, Huppert's disease, neck and head tumor, Alzheimer disease, seminoma, dysgerminoma, mast cell are swollen Tumor, bronchiolar carcinoma, the formation of testis intraepithelial neoplasia, breast cancer, neuroblastoma, mamillary/follicular thyroid cancer, malignant lymphatic Tumor, non-Hodgkin lymphoma, 2 type Multiple Endocrine tumor formation, pheochromocytoma, parathyroid hyperplasia/adenoma, colon cancer, Colorectal adenomas, malignant pleural mesothelioma, hemangioblastoma, hemangioma, the carcinoma of the rectum, tumor formed and other it is Hypertrophic or Proliferative diseases or combinations thereof.

14. purposes according to claim 9, wherein the FLT3 associated disease is selected from: Hodgkin's disease, myeloma, acute It is lymphocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic Granulocytic leukemia, chronic neutrophilic chronic myeloid leukemia, acute undifferentiated cell leukemia, anaplastic macrocytic lymph Tumor, human adult T cell ALL, it is integrated with the AML of three pedigree myelodysplasias, mixed type pedigree leukaemia, myelodysplasia Sign, myeloproliferative disorder, Huppert's disease and spinal cord sarcoma, chronic lymphocytic leukemia, diffusivity large B cell lymph Tumor, follicular lymphoma or chronic lymphocytic leukemia, lymphoma mantle cell, mediastinum (thymus gland) large B cell lymphoid tumor, blood vessel Interior large B cell lymphoid tumor, lymphoma primary effusion, Burkitt lymphoma, and combinations thereof.

15. purposes according to claim 9, wherein the proliferative disorders or the FLT3 associated disease are leukaemia.

16. purposes according to claim 9, wherein the proliferative disorders or the FLT3 associated disease are lymthoma.