CN106543143A - New FLT3 kinase inhibitors of one class and application thereof - Google Patents

New FLT3 kinase inhibitors of one class and application thereof Download PDF

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CN106543143A
CN106543143A CN201510608850.4A CN201510608850A CN106543143A CN 106543143 A CN106543143 A CN 106543143A CN 201510608850 A CN201510608850 A CN 201510608850A CN 106543143 A CN106543143 A CN 106543143A
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compound
synthesis
flt3
cell
alkyl
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CN106543143B (en
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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
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Hefei Zhongke Bio Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention provides a kind of Azaindole kinase inhibitors, which includes the compound of formula (I) or its pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug.The present invention is also provided includes the pharmaceutical composition and its purposes and method for preventing or treating cell proliferative disorders and/or FLT3, c-Kit associated conditions of formula (I) compound, and in response to disease that FLT3 kinases (especially FLT3/ITD is mutated type kinase) suppresses.

Description

New FLT3 kinase inhibitors of one class and application thereof
Technical field
The present invention relates to a kind of new FLT3 kinase inhibitor compounds, including the medicine of the compound Compositions and using these compounds and compositionss reducing or suppress cell or experimenter FLT3, c-Kit kinases and/or saltant type FLT3 kinase activity and in experimenter prevention or The purposes and method for the treatment of cell proliferative disorders and/or FLT3, c-Kit associated conditions.
Background technology
Protein kinase is the enzyme component of signal transduction pathway, and the terminal phosphate ester of its catalysis ATP turns Move on to the hydroxyl of L-Tyrosine, serine and/or the threonine residues of protein.In mammal The overexpression of the protein kinase of normal or mutation or improper expression have become widely studied master Topic, and it is verified play an important role in the development of numerous disease, the disease includes Diabetes, angiogenesis, psoriasises, restenosiss, oculopathy, schizophrenia, rheumatoid Arthritis, atherosclerosiss, cardiovascular disease and cancer.In a word, the suppression of protein kinase Agent has special application in treatment human and animal's disease.
FLT3 (Fms-like tyrosine kinase 3) i.e. FMS samples tyrosine kinase 3, with c-Kit, C-FMS and PDGFR belong to type III receptor tyrosine kinase (receptor tyrosine kinase III, RTK III) family member, its protein structure include 5 The extracellular region of immunoglobulin (Ig) spline structure domain composition, 1 transmembrane region, 1 membrane-proximal region (JM), And 2 tyrosine kinase (TK) area (S.D. that intracellular is separated by kinase insert Lyman etc., Oncogene, 1993,8,815-822).Send out first in AML cells within 1996 FLT3 mutation are showed, its mutation type is that internal series-connection repeats (FLT3/ITD).In recent years, Many activated mutants for having confirmed FLT3 of studying are in acute myeloblastic leukemia or acute myelogenous Rise in the generation of leukemia (Acute Myeloblastic Leukemia, AML) and the progress of disease To highly important pathological effect.AML patient with FLT3/ITD activated mutants generally has There are leukocyte counts high, clinical prognosis are poor, easily unique Clinical symptoms such as recurrence, And as the detection method of FLT3 activated mutants is simple, therefore increasing researcher is caused Power is in FLT3 to be developed into the conventional sense means of AML for instructing controlling for AML patient The judgement with prognosis and the detection meanss as minimal residual leukemia are treated, and as white The another new target spot of disorders of blood Chemotherapy in Patients medicine.
Haematological malignancies is that the blood of body is formed and immune system, bone marrow and lymphoid tissue Cancer.Although in normal bone marrow, FLT3 expression is only limited to early progenitor cell, in blood In liquid malignant tumor, FLT3 is expressed at high levels or FLT3 mutation cause uncontrolled FLT3 receptors and the induction of downstream molecules passage, possible RAS activation.Haematological malignancies Including leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin, (also referred to as Huo Qijin drenches Bar tumor) and myeloma --- for example, acute lymphoblastic leukemia (ALL), acute myelogenous Leukemia or acute myeloid leukaemia (AML), acute promyelocytic leukemia (APL), Chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (Chronic Myelogenous Leukemia, CML), chronic neutrophilic chronic myeloid leukemia (CNL), acute undifferentiated cell it is white Disorders of blood (AUL), anaplastic macrocytic lymphoma (ALCL), human adult T cell ALL, With the AML (AML/TMDS) of three pedigrees (trilineage) myelodysplasia, mixing Type spectrum system leukemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disorder (MPD), multiple myeloma (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 et al., FLT3mutations in myeloid sarcoma,British Journal of Haematology,2004,126(6):785-91)。
Confirm that the activated mutant of FLT3 mainly there are two kinds：Internal series-connection repeats Point mutation in (internal tandem duplication, ITD) and activation ring (point mutation in the activation loop, TKD point mutation).Both of FLT3 swash Mutation living is responsible for FLT3 be there is autophosphorylation and then causes FLT3 that part non-dependent occurs Property constitutively activate, further activate downstream abnormal signal transduction, so as to play promotion The effect of propagation and suppression apoptosis so that the leukaemic's clinical prognosis with this mutant phenotype It is poor.
Study hotspot is become to the targeted inhibition of FLT3 and saltant type FLT3 at present, is predominantly opened Small molecule tyrosine kinase inhibitors are sent out, and are combined by ATP being competed with FLT3 tyrosine kinase Site and suppress its activity.The kinase inhibitor for coming into the suppression FLT3 of clinic at present has AC220 etc..
Receptor tyrosine kinase c-Kit (also known as CD117) is by retrovirus proto-oncogene protein c-kit One class of coding has the transmembrane receptor protein of tyrosine kinase activity, with platelet derived growth Factor acceptor (PDGFR), macrophage colony-stimulating factor receptor (CSF-1R) and Fms Sample tyrosine kinase receptor 3 (FLT3) collectively constitutes III receptor tyrosine kinase superfamily, Which is played a very important role during tumor development.Therefore, c-Kit is swollen at present One of popular target of tumor molecular targeted therapy.C-Kit is tyrosine kinase receptor protein family One of important member, its receptor as stem cell factor can pass through a series of signal path Participate in the regulation and control of hemopoietic stem cell proliferation differentiation.Recent study finds that c-kit genes exist prominent Become, particularly activity is mutated and the close phase such as the morbidity in acute leukemia, treatment and prognosis Close.
Gastrointestinal stromal tumor (Gastrointestinal Stromal Tumors, GIST) be digestive tract most Property tumor in leaf source between common.The GIST of the overwhelming majority expresses the Kit of c-kit gene codes Albumen (CD117).On molecular level, there is c-kit gene mutation in most GIST, So as to the activation for causing Kit albumen does not need ligand SCF to participate in just stimulating holding for tumor cell Continuous propagation is out of control with anti-apoptotic signal.Gastrointestinal stromal tumor account for gastrointestinal cancer 1～ 3%, estimate that annual morbidity is about 10-20/100 ten thousand, be mainly in middle-older patient, less than 40 years old Patient is rare, men and women's sickness rate no significant difference.GIST major parts betide stomach (50～70%) With small intestinal (20～30%), Colon and rectum accounts for 10～20%, and esophagus accounts for 0～6%, mesentery, It is rare after nethike embrane and abdominal cavity.Patient GIST 20-30% is pernicious, be there are about when medical for the first time 11～47% have shifted, and shift mainly in liver and abdominal cavity.Calendar year 2001, Joensuu etc. are reported The first advanced GIST experimenter receives molecular targeted agents imatinib mesylate, and (referred to as her horse is replaced Buddhist nun) treatment is effective, FDA (FDA) official approval in 2002 her horse For Buddhist nun as the Standard dose of GIST, the molecular targeted therapy New Times of GIST has been started. Success of the c-Kit kinase inhibitors in tumor cells targeted therapy makes us filled with exultation really, so And unfortunately, Partial tumors patient drug resistance occurs for a period of time afterwards using such medicine, Its mechanism is sufficiently complex, the main secondary point mutation for including kinase domain, the amplification of target gene With overexpression or epigenetic regulation activation, the rise of redundancy/downstream signaling pathway or activation And the overexpression of abc transport albumen etc..Therefore, develop new c-Kit inhibitor gesture to exist Must go.
The content of the invention
The invention provides a kind of new FLT3 kinase inhibitors, which includes the chemical combination of formula (I) Thing or its pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or front Medicine：
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 haloalkyl；
R3It is selected from：
R4It is selected from
R5Selected from alkyl；Thiazolinyl；Alkynyl；Haloalkyl；Cycloalkyl；Aminoalkyl；Alkyl Aminoalkyl；Alkyl amino thiazolinyl；Heterocyclylalkyl, optionally by alkyl, alkyl-carbonyl, ring Alkyl-carbonyl, amino protecting group or hetero atom are optionally replaced by alkyl-substituted Heterocyclylalkyl； Cycloalkenyl group；Heteroaryl；Optionally by alkyl-substituted hetercycloalkylalkyl；Optionally by alkyl Substituted heteroaryl；Alkyl is optionally replaced by amino and nitrogen is optionally by amino protecting group replacement Aminoacyl alkyl；Alkyl optionally by amino replace and nitrogen optionally by amino protecting group replace 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 appointed Select the heteroaryl alkyl being optionally optionally substituted by a hydroxyl group by amino protecting group replacement and/or heteroaryl.Wherein, Amino protecting group independently selected from tertbutyloxycarbonyl, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl, benzyl and P-methoxyphenyl.
On the other hand, the present invention provides a kind of pharmaceutical composition, and which includes therapeutically effective amount It is at least one provided herein is compound or its pharmaceutically acceptable salt, solvate, isomer, Ester, acid, metabolite or prodrug, and pharmaceutically acceptable carrier or excipient, and optionally Other therapeutic agents.
It yet still another aspect, formula (I) compound or its pharmacy that the present invention provides a kind of present invention can The preparation method of the salt of acceptance, solvate, isomer, ester, acid, metabolite or prodrug.
It yet still another aspect, the present invention relates to formula (I) compound or its pharmaceutically acceptable salt, molten Agent compound, isomer, ester, acid, metabolite or prodrug are reduced in vivo or in vitro or suppress cheese Histidine kinase FLT3, c-KIT, ABL, EGFR, BMX, BLK, VEGFR, RET, The purposes of PDGFR, MEK, BCR/ABL, JAK, BRAF activity, particularly 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, molten Agent compound, isomer, ester, acid, metabolite or prodrug or the medicine including formula (I) compound Compositions are being prepared for treating cell proliferative disorders and/or FLT3, c-Kit associated conditions Medicine in purposes.
Especially, the disease is in response to FLT3 or saltant type FLT3 kinase inhibition or loud Should be in c-Kit kinase inhibition.FLT3 mutation include ITD mutation and TKD point mutation, especially FLT3/ITD is mutated.
Description of the drawings
Fig. 1 a to 1h are shown respectively compound 2-3, the compound 2-1 and compound 2-33 of the present invention To relative with FLT3 closely related in MV-4-11, MOLM-14 and MOLM-13 cell Albumen and associated signal paths impact.
Fig. 2 a to 2e be shown respectively the present invention compound 2-1 and compound 2-33 MV-4-11, On apoptotic impact in MOLM-14 and MOLM-13 cells.
Fig. 3 a to 3c are shown respectively the compound 2-1 and compound 2-33 of the present invention to MV-4-11 With the impact of the cell cycle distribution of MOLM-14 cell strains.
Specific embodiment
Term
Unless otherwise defined, all scientific and technical terminologies used herein all with claimed master Topic those skilled in the art is commonly understood by identical implication.
Unless otherwise stated, the present invention using the mass spectrum in the range of art technology, NMR, The conventional methods such as HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology. Unless provide it is specific define, otherwise with analytical chemistry described herein, synthetic organic chemistry, And chemically related name and laboratory operation and the technology such as medical science and pharmaceutical chemistry, it is this Known to art personnel.In general, aforementioned techniques and step can be many by this area Well known and described in various general literatures and more specific document conventional method implementing, These documents are cited in this manual and discuss.
Terms used herein " alkyl " refers to the straight or branched containing 1 to 12 carbon atom Alkyl.Term " low alkyl group " refers to C1～C6 alkyl chains.Alkyl can optionally by one Or multiple substituent groups replace.In the present invention, alkyl is preferably C1-C8 alkyl, more preferably C1-C6 alkyl.Typical alkyl include but is not limited to methyl, ethyl, propyl group, isopropyl, Butyl, isobutyl group, the tert-butyl group, amyl group, hexyl etc..It should be understood that " alkyl " that be mentioned herein Including all configurations that may be present and the alkyl of conformation, such as " butyl " being mentioned herein Including normal-butyl, isobutyl group and the tert-butyl group.
Term " thiazolinyl " refer to can be straight or branched aliphatic unsaturated hydrocarbon, its contain 2 to 12 carbon atoms and at least one carbon-to-carbon double bond.Thiazolinyl optionally can be replaced by one or more Base replaces.In the present invention, thiazolinyl is preferably C2-C8 thiazolinyls, more preferably C2-C6 thiazolinyls, More preferably C2-C4 thiazolinyls.
Term " alkynyl " refer to can be straight or branched aliphatic unsaturated hydrocarbon, its contain 2 to 12 carbon atoms and at least one carbon-to-carbon triple bond.Alkynyl optionally can be replaced by one or more Base replaces.In the present invention, alkynyl is preferably C2-C8 alkynyls, more preferably C2-C6 alkynyls, More preferably C2-C4 alkynyls.
The sp of thiazolinyl and alkynyl2Or sp carbon can be optionally the junction point of alkenyl or alkynyl respectively.
Term " amino " refers to group-NH2.Term " aminoacyl " refers to-CO-NH2.Art Language " amide groups " or " acylamino- " refer to-NR-CO-R ', and wherein R and R ' is independently of one another For hydrogen or alkyl.
Term " alkyl amino " is referred to Base, specifically refers to group-NRR ', and wherein R and R ' is each independently selected from hydrogen or low alkyl group, It is not -NH that condition is-NRR '2.Term " aminoalkyl " is referred to further by one or more ammonia The alkyl substituent that base replaces.Term " hydroxyalkyl " or " hydroxy alkyl " refer to further by The alkyl substituent that one or more hydroxyls replace.Term " cyanoalkyl " refer to further by The alkyl substituent that one or more cyano group replace.Term " alkanoyl " or " alkyl-carbonyl " Refer to further by an alkyl-substituted carbonyl.Term " Alkylcarbonylalkyl " is fingering one Walk the alkyl replaced by an alkyl-carbonyl.Term " alkoxy carbonyl " is referred to further by one The carbonyl that individual alkoxyl replaces.Term " alkylaminoalkyl group " refers to alkyl quilt defined herein Alkyl amino defined herein replaces.Alkyl amino, aminoalkyl, hydroxy alkyl, cyano group alkane In base, alkyl-carbonyl, Alkylcarbonylalkyl, alkoxy carbonyl and alkylaminoalkyl group Moieties optionally can be 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 Individual pi-electron, wherein n are integers.Fragrant basic ring can be by five, six, seven, eight, nine or many In nine atomic buildings.Aromatic radical can be optionally substituted.Term " aromatic radical " is including carbon Group is (for example for cyclophane base (such as phenyl) and heterocyclic aryl (or " heteroaryl " or " heteroaryl perfume base ") Pyridine).The term includes multi-ring (sharing the ring of the adjacent carbon atom pair) group of monocyclic or condensed ring.
Terms used herein " aryl " refers to the atom of each composition ring in fragrant basic ring It is carbon atom.Aryl rings can be by five, six, seven, eight, nine or more than nine atomic buildings. Aryl can be optionally substituted.The example of aryl include but is not limited to phenyl, naphthyl, phenanthryl, Anthryl, fluorenyl and indenyl.According to structure, aryl can be that monoradical or bivalent radical are (i.e. sub- Aryl).
" alkyl (aryl) " or " aralkyl " refer to alkyl defined herein by virtue defined herein Base replaces.Nonrestrictive alkyl (aryl) is including benzyl, phenethyl etc..
Term " cycloalkyl " refers to monocyclic or many ring groups, and which only contains carbon and hydrogen.Cycloalkyl bag Include the group with 3-8 annular atom.According to structure, cycloalkyl can be monoradical or bivalent Group (such as cycloalkylidene).In the present invention, cycloalkyl preferably has 3-8 carbon atom Cycloalkyl, " low-grade cycloalkyl " more preferably with 3-6 carbon atom.
" alkyl (cycloalkyl) " or " cycloalkyl-alkyl " refer to alkyl defined herein by fixed herein The cycloalkyl substituted of justice.Nonrestrictive alkyl (cycloalkyl) is including Cvclopropvlmethvl, cyclobutylmethyl Base, cyclopentyl-methyl, cyclohexyl methyl etc..
Terms used herein " miscellaneous alkyl " refers to one or more in alkyl defined herein Skeletal chain atoms are hetero atoms, for example oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof.It is described Hetero atom (one or more) may be located at the optional position inside miscellaneous alkyl or miscellaneous alkyl with point The position that the remainder of son is connected.
Term " heteroaryl " refers to that aryl includes one or more rings selected from nitrogen, oxygen and sulfur Hetero atom." heteroaryl " containing N partly refers at least one skeletal atom on aromatic radical medium ring It is nitrogen-atoms.According to structure, heteroaryl can be monoradical or bivalent radical (i.e. inferior heteroaryl). The example of heteroaryl includes but is not limited to pyridine radicals, imidazole radicals, pyrimidine radicals, pyrazolyl, triazole Base, pyrazinyl, tetrazole radical, furyl, thienyl, isoxazolyls, thiazolyl, oxazolyls, Isothiazolyl, pyrrole radicals, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzo It is furyl, indazolyl, indolizine base, phthalazinyl, pyridazinyl, isoindolyl, pteridyl, fast Purine Ji, oxadiazolyls, thiadiazolyl group, furyl, benzofuranyl, benzothienyl, benzene Benzothiazolyl, benzoxazolyl, quinazolyl, naphthyridinyl and furopyridyl etc..
Terms used herein " Heterocyclylalkyl " refers to one or more compositions in non-aromatic basic ring The atom of ring is the hetero atom selected from nitrogen, oxygen and sulfur.Heterocycloalkyl ring can by three, four, five, 6th, seven, eight, nine or be more than nine atomic buildings.Heterocycloalkyl ring can be optionally substituted. The example of Heterocyclylalkyl include but is not limited to lactams, lactone, ring Asia glue, ring thioimines, Cyclic carbramates, tetrahydric thiapyran, 4H- pyrans, Pentamethylene oxide., piperidines, 1,3- bioxin, 1,3- dioxs, 1,4- bioxin, 1,4- dioxs, piperazine, 1,3- thioxane, 1,4- Oxathiin, 1,4- thioxane, tetrahydrochysene -1,4- thiazines, 2H-1,2- oxazines, Maleimide, butanimide, barbituratess, thiobarbituricacidα-, dioxopiperazine, Hydantoin, dihydrouracil, azepineHigh piperidines, morpholine, trioxanes, hexahydro -1,3,5- Triazine, Tetramethylene sulfide, tetrahydrofuran, pyrrolin, pyrrolidine, imidazolidine, ketopyrrolidine, Pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3- dioxole, 1,3- dioxanes Pentane, 1,3- dithioles, 1,3- dithiolane, isoxazoline, isoxazole alkyls, Oxazoline, oxazolidine, oxazolidones, thiazoline, Thiazolidine and 1,3- oxathiolanes.Root According to structure, Heterocyclylalkyl can be monoradical or bivalent radical (i.e. sub- Heterocyclylalkyl).
Term " alkyl (heteroaryl) " or " heteroaryl alkyl " refer to alkyl defined herein by this The heteroaryl of text definition replaces.
Term " alkyl (Heterocyclylalkyl) " or " hetercycloalkylalkyl " refer to alkyl defined herein Replaced by Heterocyclylalkyl defined herein.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Term " haloalkyl ", " alkoxyl that halogen replaces " and " miscellaneous alkyl that halogen replaces " bag The structure of alkyl, alkoxyl or miscellaneous alkyl is included, wherein at least one hydrogen is replaced by halogen atom. In some embodiments, if two or more hydrogen atoms are replaced by halogen atom, the halogen atom It is same to each other or different to each other.
Term " acyl group " refers to that organic or inorganic oxyacid removes remaining monovalent atom after hydroxyl Group, formula be R-M (O)-, wherein M is usually C.
Term " carbonyl " is the organic functional being formed by connecting by double bond by two kinds of atoms of carbon and oxygen Group (C=O).
Term " substituted " refers to that mentioned group can be by one or more extra groups Replace, the extra group is each and independently selected from alkyl, cycloalkyl, aryl, miscellaneous Aryl, hydroxyl, alkoxyl, cyano group, halogen, amide groups, nitro, haloalkyl, amino, Alkoxy carbonyl, alkyl (heteroaryl), alkyl (Heterocyclylalkyl) etc..
Any group (for example, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, Heteroarylalkyl, cycloalkyl, Heterocyclylalkyl) optionally can be substituted by one or more substituents, And substituent group can be on the arbitrary atom of the group, wherein any group that can be substituted can be with Optionally replaced by one or more substituent groups (which can be same or different), each Replace a hydrogen atom.The example of appropriate substituent group include, but not limited to alkyl, thiazolinyl, Alkynyl, cycloalkyl, Heterocyclylalkyl, aralkyl, heteroarylalkyl, aryl, heteroaryl, halogen, Haloalkyl, cyano group, nitro, alkoxyl, halogenated alkoxy, aryloxy group, hydroxyl, hydroxyl Alkyl, oxygen (that is, carbonyl), carboxyl, formoxyl, alkyl-carbonyl, Alkylcarbonylalkyl, alkane Epoxide carbonyl, alkyl carbonyl epoxide, aryloxycarbonyl, heteroaryloxy, Heteroaryloxycarbonyl, Sulfenyl, sulfydryl, mercaptoalkyl, aryl sulfonyl, amino, aminoalkyl, dialkyl amido, Alkyl-carbonyl-amino, alkyl amino-carbonyl, alkoxycarbonyl amino, alkyl amino, aryl ammonia The aryl that base, ammonia diaryl base, alkyl-carbonyl or arylamino replace；Aryl-alkyl amino, Aralkylaminocarbonyl, acylamino-, alkyl amino sulfonyl, n-aryl sulfonyl, dioxane Base amino-sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, imino group, urea groups, Carbamoyl, ghiourea group, thiocyano, sulfonamido, Sulfonylalkyl, sulfonyl aryl, Sulfydryl alkoxyl, N- hydroxyls amidino groups or N '-aryl, N "-hydroxyl amidino groups, thio alkoxy, Cycloalkyloxy, the fluoroalkyl containing 1～5 fluorine, formamido group, optionally substituted aryl, Or optionally substituted heteroaryl.
" suppression ", " suppression " or " inhibitor " of terms used herein kinases, refers to phosphorus Sour transferase active is suppressed.
" metabolite " of compound disclosed herein is the change formed when the compound is metabolized The derivant of compound.Term " active metabolite " refers to what is formed when the compound is metabolized The biologically active derivatives of compound.Terms used herein " is metabolized ", refers to predetermined substance By organism transform process summation (including but not limited to hydrolysis and by enzymatic reaction, Such as oxidation reaction).Therefore, enzyme can produce specific structural transformation for compound.For example, Cytochrome P450 is catalyzed various oxidations and reduction reaction, while diphosphate glucose sweet acid base turns The glucal acid molecule of enzyme catalysiss activation is moved to aromatic alcohol, aliphatic alcohol, carboxylic acid, amine and trip From sulfydryl conversion.Metabolic further information can be from《The Pharmacological Basis of Therapeutics》, the 9th edition, McGraw-Hill (1996) is obtained .The metabolite of compound disclosed herein can by by compound give host and analyze come From the tissue sample of the host or by compound is incubated in vitro and be analyzed with hepatocyte Gained compound is differentiating.Both approaches are all known in the art.In some embodiments In, the metabolite of compound be formed by oxidizing process and with corresponding hydroxy-containing compounds pair Should.In some embodiments, compound is metabolized as pharmaceutical active metabolite.Use herein Term " regulation ", refer to directly or indirectly with target interact, to change the activity of target, Only for example, including intensifier target target activity, the activity of suppression target, limit target target The activity of activity or prolongation target.
Term " prodrug " include with can the part of metabolism in vivo compound.Generally, Prodrug passes through esterase or passes through other mechanism metabolism active drugs in vivo.Prodrug and application thereof Example known in the art (see, for example, Berge et al. (1977) " Pharmaceutical Salts”,J.Pharm.Sci.66:1-19).Can be former during compound is finally recovered with purification Position prepares prodrug, or by individually making the compound of purification with its free acid form or hydroxyl React to prepare with suitable esterifying agent.Hydroxyl can be converted into ester with the process of Jing carboxylic acids.Prodrug Partial example includes replacing and unsubstituted, side chain or unbranched lower alkyl ester moieties (such as propionic ester), low-grade alkenyl ester, two-lower alkyl-amino lower Arrcostab (such as two Methylaminoethyl ester), acyl amino lower alkyl esters (such as acetoxy-methyl ester), acyl Epoxide lower alkyl esters (such as oxy acid methyl neopentyl ester), aryl ester (phenylester), aryl Lower alkyl esters (such as benzyl ester), replace (such as by methyl, halogen or methoxy substitution What base replaced) aryl and aromatic yl elementary alkyl ester, amide, lower alkyl, two lower alkyl Base amide and hydroxy amide.Preferred prodrug moiety is propionic ester and acyl ester.It is also included within body The interior prodrug that activity form is changed into by other mechanism.In some respects, chemical combination of the invention Thing is the prodrug of any this paper formulas.
Term " isomer " but refer to the identical atom of chemical composition or group in spatial arrangements Different compound, it is intended that including diastereomer, enantiomer, regional isomer (regioisomers), constitutional isomer, rotamer, tautomer etc..For containing There are the compound of one or more Stereocenters (stereogenic center), such as chiral compound Thing, it is possible to use enantiomeric enrichment compound, racemic modification or diastereomer mixing Thing is implementing the method for the present invention.
Terms used herein " target protein " refers to what is can combined by selectivity binding compounds Protein molecule or partially protein.In some embodiments, target protein is FLT3.
GI50 used herein refers to the drug level needed for 50% growth inhibited of cell, i.e. medicine The growth of 50% cancerous cell is made to be inhibited or control, drug level now.
IC used herein50Refer to and ceiling effect is obtained in the analysis of effect as measurement 50% amount of fc-specific test FC compound for suppressing, concentration or dosage.
EC used herein50Dosage, concentration or the amount for determining compound is referred to, which causes specific Determine compound induction, stimulate or strengthen the 50% of specific reaction maximum expression dosage according to Rely reaction.
The new kinase inhibitor of the present invention
The invention provides a kind of new FLT3 kinase inhibitors, which includes the chemical combination of formula (I) Thing or its pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or front Medicine：
Wherein：
Ar1And Ar2It is each independently aryl or heteroaryl, such as phenyl, thiazolyl, quinoline azoles Quinoline base, benzoxazolyl；
X be selected from Linking group；
R1And R2It is each independently selected from hydrogen；Halogen；Alkyl, such as methyl；And alkyl halide Base, such as trifluoromethyl；
R3It is selected from：
R4It is selected from
R5Selected from alkyl, such as methyl, ethyl, propyl group, neopentyl, nonyl；Thiazolinyl, example Such as vinyl, acrylic；Alkynyl, such as acetenyl；Haloalkyl, such as chloric ethane base； Cycloalkyl, such as cyclopropyl；Aminoalkyl, such as amino methyl, amino-ethyl；Alkyl ammonia Base alkyl, such as N, N- dimethylaminomethyls, N, N- dipropylamino ethyls；Alkyl amino Thiazolinyl, such as N, N- Dimethylamino-propenoyl bases；Heterocyclylalkyl (such as piperidyl, pyranose), Optionally by alkyl (such as methyl, ethyl), alkyl-carbonyl (such as methyl carbonyl, ethyl Carbonyl), naphthene base carbonyl (such as cyclopropyl carbonyl), amino protecting group (such as Boc), or The Heterocyclylalkyl that hetero atom is optionally replaced by alkyl (such as methyl) replaces；Cycloalkenyl group, preferably Five yuan or hexa-atomic cycloalkenyl group, such as cyclopentenyl, cyclohexenyl group；Heteroaryl, such as pyridine radicals； Optionally by alkyl-substituted hetercycloalkylalkyl；Optionally by alkyl-substituted heteroaryl (example Such as pyridine radicals, isoxazolyls)；Alkyl is optionally replaced by amino and nitrogen is optionally by amino protecting group Substituted aminoacyl alkyl；Alkyl is optionally replaced by amino and nitrogen is optionally taken by amino protecting group The aryl alkyl that generation and/or aryl are optionally optionally substituted by a hydroxyl group；And alkyl is optionally replaced by amino And the heteroaryl alkane that nitrogen is optionally optionally optionally substituted by a hydroxyl group by amino protecting group replacement and/or heteroaryl Base.Wherein, amino protecting group independently selected from tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl (FMOC), benzyl (Bn) and p-methoxyphenyl (PMP).
Compound with chirality involved in the present invention, its configuration can be arbitrary configurations or mixed The racemic modification of conjunction.
For each variable, the combination in any of above-mentioned group is also among considering herein.Can manage Solution be：Substituent group and substitute mode on compound provided in this article can be by this area skill Art personnel selected, to provide chemically stable and can to use skill known in the art Art and the compound of technology set forth herein synthesis.
Described herein is new kinase inhibitor.The pharmacy of this compound has been also described herein Acceptable salt, solvate, isomer, ester, acid, pharmaceutical active metabolite and prodrug.
In other or further embodiment, compound described herein has been given to be needed Metabolite is produced in its internal metabolism after the organism wanted, produced metabolite is subsequently used for producing Raw intended effect, including desired therapeutic effect.
Compound described herein can be made into and/or be used as pharmaceutically acceptable salt.Pharmacy The type of acceptable salt is included but is not limited to：(1) acid-addition salts, by dissociating compound Alkali form is formed with pharmaceutically acceptable inorganic acid reaction, the mineral acid for example hydrochloric acid, hydrobromic acid, Sulphuric acid, nitric acid, phosphoric acid, Metaphosphoric acid etc.；Or formed with organic acid reaction, the organic acid is such as Acetic acid, propanoic acid, caproic acid, Pentamethylene. propanoic acid, hydroxyacetic acid, acetone acid, lactic acid, malonic acid, Malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, Benzoic acid, 3- (4- hydroxy benzoyls) benzoic acid, cinnamic acid, mandelic acid, Loprazolam, second Alkyl sulfonic acid, 1,2- ethionic acids, 2- ethylenehydrinsulfonic acids, benzenesulfonic acid, toluenesulfonic acid, 4- methyl are double Ring-[2.2.2] oct-2-ene -1- formic acid, 2- LOMAR PWA EINECS 246-676-2, butylacetic acid, glucoheptonic acid, 4,4'- are sub- Methyl pair-(3- hydroxyl -2- alkene -1- formic acid), 3- phenylpropionic acids, trimethylace tonitric, dodecyl sulfur Acid, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid etc.；(2) alkali Addition salts, its acid proton in parent compound are formed when being replaced by metal ion, for example Alkali metal ion (such as lithium, sodium, potassium), alkaline-earth metal ions (such as magnesium or calcium) or aluminium ion； Or be coordinated with organic base.Acceptable organic base include ethanolamine, diethanolamine, triethanolamine, Trimethylamine, N- methyl glucose osamines, etc..Acceptable inorganic base includes aluminium hydroxide, hydrogen Calcium oxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc..
The corresponding ion balance of pharmaceutically acceptable salt can be analyzed and be reflected using various methods It is fixed, methods described include but is not limited to ion exchange chromatography, chromatography of ions, capillary electrophoresis, Inductively coupled plasma, atomic absorption spectrum, mass spectrum or any combination of them.
The salt is reclaimed using at least one of following technology：Filter, with non-solvent precipitation then Filter, solvent evaporates, or in the case of aqueous solution, use lyophilization.
Screening and characterize pharmaceutically acceptable salt, polymorphic and/or solvate can use it is various Technology is completed, and the technology includes but is not limited to heat analysis, X-ray diffraction, spectrum, micro- Mirror method, elementary analysiss.The various spectral techniques for using include but is not limited to Raman, FTIR, UVIS and NMR (liquid and solid state).Various microscopies include but is not limited to IR and show Micro- microscopy and Raman (Raman) microscopy.
The medical composition and its use of the present invention
The present invention also relates to pharmaceutical composition, they include formula (I) compound or its pharmacy can connect Salt, solvate, isomer, ester, acid, metabolite or the prodrug received as active component, And pharmaceutically acceptable carrier or excipient, and other optional therapeutic agent.
Formula (I) compound or its pharmaceutically acceptable salt, solvate, isomer, ester, acid, Metabolite or prodrug and the " thing of the present invention is hereinafter also called including its pharmaceutical composition Matter ".
The material of the present invention can be used to treating or preventing cell proliferative disorders and/or FLT3, c-Kit Associated conditions, particularly in response to protein tyrosine kinase suppression, especially FLT3 or saltant type The disease that FLT3 kinase inhibition or c-Kit suppress.FLT3 mutation include ITD mutation and TKD Point mutation, especially ITD mutation." treatment " of the present invention can be curative (as right Disease is treated) and/or it is preventative.The present invention material can preferably treat or prevent and FLT3 or C-Kit related disease, the particularly preferably treatment or prevention disease related to saltant type FLT3/ITD Disease.
Over the course for the treatment of, material of the invention can according to circumstances individually or with one or more Other therapeutic combinations are used.Can be applied by injection, oral, suction, rectum and percutaneous At least one with will be comprising the medicament administration of the compound comprising at least one formula (I) to needs Patient.Other therapeutic agents can be selected from following medicine：Immunosuppressant (such as Ta Kemo Department, encircle rhzomorph, rapamycin, Methylaminopterin, cyclophosphamide, azathioprine, mercaptopurine, Mycophenolate or FTY720), glucocorticoidss medicine (for example prednisone, cortisone acetate, Prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, hydrogen hydroxyl prednisone Dragon, beclometasone, fludrocortisone acetate, percorten, aldosterone), non-steroidal Anti-inflammatory agent (such as salicylate, aryl alkanoic acid, 2- arylpropionic acids, N- aryl-anthranilics Acid, former times health class, examine former times class or sulphonanilid), it is allergic reaction bacterin, antihistaminic, anti-white Triolefin medicine, beta-2-agonists, theophylline, anticholinergic agent or other selective kinase inhibitors are (for example MTOR inhibitors, c-Met inhibitor) or Her2 antibody-drugs.In addition, its mentioned Its therapeutic agent can also be rapamycin (Rapamycin), gram azoles for Buddhist nun (Crizotinib), he Not former times sweet smell, raloxifene, Anastrozole, exemestane, letrozole, TrastuzumabTM(toltrazuril Monoclonal antibody), GlivecTM(imatinib), paclitaxelTMHim is cut down in (paclitaxel), cyclophosphamide, Lip river Spit of fland, U.S. promise tetracycline (Minosine), cytosine arabinoside, 5-fluorouracil (5-FU), first ammonia butterfly Purine (MTX), taxotereTM(docetaxel), ZoladexTM(goserelin), vincristine, Vinblastine, nocodazole, teniposide, etoposide, GemzarTM(gemcitabine), Ai Bo Mycin (Epothilone), promise only sheet, camptothecine, daunorubicin (Daunonibicin), more raw Mycin, mitoxantrone, amsacrine, doxorubicin (adriamycin), epirubicin or she Up to than star.Or, other therapeutic agents can also be cytokine such as G-CSF (granulocyte collection G-CSF).Or, other therapeutic agents can also be, such as but not limited to, CMF (rings Phosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, Epirubicin and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide and purple China fir alcohol) or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).
Described other therapeutic agents also include, for example, cytostatics, other antiproliferatives.
It is different that this kind of antiproliferative includes but is not limited to aromatization enzyme inhibitor, estrogen antagonist, topology Structure enzyme I inhibitor, Topoisomerase II inhibitors, microtubule active agent, alkylating agent, group egg White deacetylase inhibitor, farnesyl transferase inhibitor, cox 2 inhibitor, MMP suppress Agent, mTOR inhibitors, neoplasia resisting antimetabolite, platinum compounds, reduction protein kinase The compound of activity is swashed with further anti-angiogenic compounds, GnRF Dynamic agent, androgen antagonist, bengamide, bis-phosphonic acids compounds, steroid, anti proliferative resist Body, 17- (allyl amido) -17-AAG (17-AAG) and temozolomide (TMEMODAL)。
Terms used herein " aromatization enzyme inhibitor " be related to suppress estrogen produce, namely Substrates androstenedione and the compound of estradione conversion.The term includes but is not limited to steroid, Especially exemestane and formestane, and particularly on-steroidal, especially aminoglutethimide, Fu Luo Azoles, fadrozole, Anastrozole, very especially letrozole.Exemestane for example can be with which Commercial form is administered, and such as trade mark is AROMASINTM.Formestane for example can be commercially available with which Form is administered, and such as trade mark is LENTARONTM.Fadrozole for example can be with its commercial form Administration, such as trade mark are AFEMATM.Aminoglutethimide for example can be administered with its commercial form, Such as trade mark is ORIMETENTM。
It is particularly useful for comprising the present composition of the aromatization enzyme inhibitor as anti-tumor form agent Treatment hormone receptor positive breast tumor.
It is female sharp that term " estrogen antagonist " used herein is related to the antagonism on Estrogen Receptor The compound of plain effect.The term includes but is not limited to tamoxifen, fulvestrant, Lei Luoxi Fragrant and RALOXIFENE HCL.Tamoxifen for example can be administered with its commercial form, such as trade mark For NOLVADEXTM.RALOXIFENE HCL for example can be administered with its commercial form, such as business It is designated as EVISTATM.Fulvestrant can be prepared as described in US4659516, or for example may be used To be administered with its commercial form, such as trade mark is FASLODEXTM。
Term " topoisomerase I inhibitor " used herein include but is not limited to topotecan, Irinotecan, the 9-nitrocamptothecin conjugate PNU-166148 (chemical combination in WO99/17804 Thing A1).Irinotecan for example can be administered with its commercial form, and for example trade mark is CAMPTOSARTM.Topotecan for example can be administered with its commercial form, and for example trade mark is HYCAMTINTM。
Term " Topoisomerase II inhibitors " used herein includes but is not limited to anthracyclines (antracycline) amycin (includes Liposomal formulation, such as CAELYXTM), the soft ratio of table Star, idarubicin and Nai Mo than star (nemorubin), anthraquinones mitoxantrone and Lip river element anthraquinone, With podophillotoxines etoposide and teniposide.Etoposide for example can be with its commercial form Administration, such as trade mark ETOPOPHOSTM.Teniposide for example can be administered with its commercially available formula, Such as trade mark is VM 26-BRISTOLTM.Amycin for example can be administered with its commercial form, Such as trade mark is ADRIBLASTINTM.Idarubicin for example can be administered with its commercial form, Such as trade mark is ZAVEDOSTM.Mitoxantrone for example can be administered with its commercial form, for example Trade mark is NOVANTRONTM。
Term " microtubule active agent " is related to microtubule stabilization agent, and including but not limited to taxane is safe Plain (paclitaxel) and docetaxel (docetaxel), such as catharanthus alkaloid, Changchun Alkali, especially vinblastine sulfate, discodermolide (discodermolide) and Epothilones (epothilone), such as epothilone B and D.Docetaxel for example can be with its commercial form Administration, such as trade mark are TAXOTERETM.Vinblastine sulfate can be administered with its commercial form, Such as trade mark is VINBLASTIN R.P.TM.Vincristine sulfate for example can be with its commercially available shape Formula is administered, and such as trade mark is FARMISTIONTM.Discodermolide for example can be such as US 5010099 It is described to obtain.
Term " alkylating agent " used herein includes but is not limited to ring phosphamidon, ifosfamide And melphalan.Cyclophosphamide for example can be administered with its commercial form, and for example trade mark is CYCLOSTINTM.Ifosfamide for example can be administered with its commercial form, and for example trade mark is HOLOXANTM。
Term " inhibitors of histone deacetylase " is related to inhibition of histone deacetylase and has The compound of standby antiproliferative activity.This includes compound disclosed in WO 02/22577, especially N- Hydroxyl -3- [[(2- hydroxyethyls) [2- (1H- indol-3-yls) ethyl]-amino] methyl] phenyl] -2E-2- third Acrylamide, N- hydroxyl -3- [[(2- hydroxyethyls) [2- (1H- indol-3-yls) ethyl]-amino] methyl] benzene Base] -2E-2- acrylamides and its pharmaceutically acceptable salt.Further especially include suberoyl benzene Amine hydroxamic acid (SAHA).
Term " farnesyl transferase inhibitor " is related to suppress farnesyl transferase and possess anti- The compound of proliferation activity.
Term " cox 2 inhibitor " be related to suppress COX-2 type enzyme (COX-2) and Possess the compound of antiproliferative activity, such as Celecoxib (Celebrex), VIOXX (Vioxx) Draw with Rumi and examine former times (COX189).
Term " MMP inhibitor " is related to suppress matrix metalloproteinase (MMP) and have The compound of standby antiproliferative activity.
Term " mTOR inhibitors " be related to suppress mammal rapamycin target (mTOR) and And possess the compound of antiproliferative activity, such as sirolimuss (Rapamune), everolimus (CerticanTM), CCI-779 and ABT578.
Term " neoplasia resisting antimetabolite " include but is not limited to 5-fluorouracil, ftorafur, Capecitabine, cladribine, cytosine arabinoside, Fludarabine Phosphate, floxuridine (fluorouridine), Gemcitabine, Ismipur, hydroxyurea, methotrexate, edatrexate and this kind of compound Salt, in addition with ZD1694 (RALTITREXEDTM)、LY231514(ALIMTATM)、 LY264618(LOMOTREXOLTM) and OGT719.
Term " platinum compounds " used herein includes but is not limited to carboplatin, cisplatin and Ao Shali Platinum.Carboplatin for example can be administered with its commercial form, and such as trade mark is CARBOPLATTM。 Oxaliplatin for example can be administered with its commercial form, and such as trade mark is ELOXATINTM。
" compound for reducing protein kinase activity is anti-angiogenic with further for term used herein Generate compound " including but not limited to reduce following active compound, such as blood vessel endothelium life The long factor (VEGF), epidermal growth factor (EGF), c-Src, Protein kinase C, platelet Derivative growth factor (PDGF), Bcr-Abl, c-Kit, FLT3, insulin-like growth factor I Receptor (IGF-IR) and cell cycle protein dependent kinase (CDK), with different from reducing The anti-angiogenic compounds of the mechanism of action of protein kinase activity.
The compound for reducing VEGF activity especially suppresses vegf receptor, especially VEGF to receive The compound of the tyrosine kinase activity of body and the compound combined with VEGF, particularly under General and specific those disclosed compound, protein and monoclonal antibody in row document： 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 59 (1999) 5209-5218 of Cancer Research In, Z.Zhu et al. is in Cancer Res.58,1998,3209-3214 and J.Mordenti etc. People is in Toxicologic Pathology, vol.27, those described in no.1,14-21,1999； WO00/37502 and WO94/10202；AngiostatinTM, such as M.S.O ' Reilly et al., Described in Cell 79,1994,315-328.
The compound for reducing EGF activity especially suppresses the compound of EGF combinations, particularly exists In following documents typically with specifically disclosed those compounds：WO97/02266 (description formula IVs Compound), EP0564409, WO99/03854, EP0520722, EP0566226, EP0787722、EP0837063、WO98/10767、WO97/30034、WO97/49688、 WOWO97/38983 and especially WO96/33980.
The compound for reducing c-Src activity includes but is not limited to suppression c-Src eggs as defined below The compound and SH2 interaction inhibitors of white tyrosine kinase activity, for example, be disclosed in Those in WO97/07131 and WO97/08193.
The compound of c-Src protein tyrosine kinase activities is suppressed including but not limited to belong to following knot The compound of structure species：Pyrrolopyrimidine, especially pyrrolo- [2,3-d] pyrimidine；Purines；Pyrrole Azoles miazines, especially pyrrolo- [3,4-d] pyrimidine；Pyrazolopyrimidines type, especially pyrazolo pyrroles And [3,4-d] pyrimidine and Pyridopyrimidine class, especially pyrido pyrrolo- [2,3-d] pyrimidine.Preferably, The term be related to be disclosed in WO96/10028, WO97/28161, WO97/32879 and Those compounds in WO97/49706.
The compound for reducing IGF-IR activity is especially disclosed in those changes in WO02/92599 Compound.
Reduce protein kinase activity and can also be further with what the compounds of this invention was used in combination Particular compound has Imatinib (Gleevec/Glivec), PKC412, IressacTM(ZD1839)、 AEE788 and its pharmaceutically acceptable salt (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 bag with the mechanism of action different from reducing protein kinase activity Include but be not limited to such as Thalidomide (THALOMID), Celecoxib (Celebrex) and ZD6126。
Term " GnRF agonist " used herein is including but not limited to Abarelix, Coserelin and goserelin acetate.Coserelin is disclosed in US4100274, for example may be used To be administered with its commercial form, such as trade mark is ZOLADEXTM.Abarelix for example can be as Prepare described in US5843901.
Term " androgen antagonist " used herein includes but is not limited to bicalutamide (CASODEXTM), it for example can be prepared as described in US4636505.
Term " bengamide " is related to bengamide and which has the derivant of anti proliferative properties.
Term " bis-phosphonic acids compounds " used herein is included but is not limited to according to bent phosphonic acids (pamidronic acid), alendronic Acid (alendronic acid).For example can be with according to bent phosphonic acids Its commercial form is administered, and such as trade mark is DIDRINELTM.Clodronic acid for example can Yi Qi cities Form administration is sold, such as trade mark is BONEFOSTM.Tiludronic acid for example can be with its commercially available shape Formula is administered, and such as trade mark is SKELIDTM.Pamidronic acid for example can be administered with its commercial form, Such as trade mark is AREDIATM.Alendronic Acid for example can be administered with its commercial form, for example Trade mark is FOSAMAXTM.Ibandronic acid for example can be administered with its commercial form, such as business It is designated as BONDRANATTM.Risedronic acid for example can be administered with its commercial form, such as business It is designated as ACTONELTM.Zoledronic acid for example can be administered with its commercial form, and for example trade mark is ZOMETATM。
Term " steroid " includes hydrocortisone, dexamethasone (Decadron), methyl hydrogen Change Bo Nisong and Bo Nisong.
Term " anti proliferative antibody " used herein includes but is not limited to Herceptin (Trastuzumab)(HerceptinTM), Herceptin-DM1, erlotinib (TercevaTM)、 bevacizumab(AvastinTM), the appropriate uncommon agate (Rituxan) of profit, PRO64553 (anti-CD 40) With 2C4 antibody.
It yet still another aspect, the present invention relates to the Substance treatment of the present invention or prevention cell proliferative The method of disease and/or FLT3, c-Kit associated conditions.Over the course for the treatment of, can be by note Penetrate, orally, suction, rectum or percutaneous the material of the present invention of offer is administered to into patient.Also Can according to circumstances by the compound comprising at least one formula (I) or pharmaceutical composition list of effective dose Solely or with one or more other therapeutic combination use.Mentioned other therapeutic agents are such as Limited above.Over the course for the treatment of, can also by the compound comprising at least one formula (I) or The chemotherapy joint X-ray therapy of pharmaceutical composition is administered.
Specifically, material of the invention can be used to treating or preventing cell proliferative disorders, select From benign or malignant tumor, including but not limited to：Solid tumor (includes benign or especially pernicious Type), sarcoma, gastrointestinal stromal tumor (Gastrointestinal Stromal Tumors, GIST), Acute myeloblastic leukemia (Acute Myeloblastic Leukemia, AML), chronic Myelogenous are white Disorders of blood (Chronic Myelogenous Leukemia, CML), to ABL and BCR/ABL cheese Histidine kinase activity suppression has influential leukemia, B- cell lymphoms, lymphoma, diffuses Property large B cell lymphoid tumor, follicular lymphoma, chronic lymphocytic leukemia, chronic lymphatic Chronic myeloid leukemia, B born of the same parents' PL, lymphoplasmacytic lymphoma/Walden this Special human relations macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmocytoma, Extranodal marginal zone B cell lymphoma, lymphoma nodal marginal zone B cell, jacket cell lymph Tumor, mediastinum (thymus) large B cell lymphoid tumor, intravascular large B cell lymphoma, constitutional ooze Going out property lymphoma, Burkitt lymphoma, leukemia, lymphomatoid granulomatosises, mesenchymoma, Systemic mast cell disease, hypereosinophilia syndrome (HES), fibre modifications, class Rheumatic arthritis, polyarthritis, scleroderma, lupus erythematosus, graft versus host disease (graft-versus-host disease, GVHD), neurofibroma, pulmonary hypertension, breast duct Cancer, lobular carcinoma, adenocarcinoma, melanoma, B cell proliferative disease, the brain cancer, renal carcinoma, liver Cancer, adrenal carcinoma, bladder cancer, breast carcinoma, lymphatic cancer, gastric cancer, gastrointestinal stromal tumors (GISTs), stomach swell Tumor, esophageal carcinoma, ovarian cancer, colorectal cancer, carcinoma of prostate, cancer of pancreas, pulmonary carcinoma, cancer of vagina, Film adenocarcinoma, thyroid carcinoma, neck cancer, the cancer of CNS, glioblastoma, myeloproliferative disease, Glioblastoma, multiple myeloma, human primary gastrointestinal cancers, colorectal carcinoma, H/N tumors, brain Tumor, epidermal hyper-proliferative, psoriasises, prostatic hyperplasia, the neoplasia of epithelial character, vagina Cancer, cervical cancer, carcinoma of endometrium, multiple myeloma, neck and head tumor, alzheimer ' On silent disease, spermocytoma, dysgerminoma, mast cell tumor, bronchogenic carcinoma, testis Intradermal neoplasia, breast carcinoma, neuroblastoma, mamillary/follicular thyroid carcinoma, pernicious pouring Bar tumor, non-Hodgkin lymphoma, 2 type Multiple Endocrine neoplasia, pheochromocytoma, first shape It is other gland hypertrophy/adenoma, colon cancer, colorectal adenomas, malignant pleural mesothelioma, thin into blood vessel Born of the same parents' tumor, hemangioma, rectal cancer, neoplasia and other Hypertrophic or proliferative diseasees or its group Close.
The material of the present invention can be additionally used in treating or prevent c-Kit associated conditions, especially between gastrointestinal Matter tumor (Gastrointestinal Stromal tumors, GIST) or similar disease or combination.
The material of the present invention can be additionally used in treating or prevent FLT3 associated conditions, especially saltant type FLT3/ITD associated conditions, including but not limited to：Haematological malignancies includes leukemia, drenches Bar tumor (non-Hodgkin lymphoma), Hodgkin (also referred to as Hodgkin lymphoma) and myeloma --- for example, acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), Acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic grain It is chronic myeloid leukemia (CML), chronic neutrophilic chronic myeloid leukemia (CNL), acute undifferentiated thin Born of the same parents' leukemia (AUL), anaplastic macrocytic lymphoma (ALCL), human adult T cell ALL, the AML (AML/TMDS) with three pedigrees (trilineage) myelodysplasia, Mixed type pedigree leukemia (MLL), myelodysplastic syndrome (MDSs), myelosises Abnormal (MPD), multiple myeloma (MM) and spinal cord sarcoma, chronic lymphocytic lymph Tumor, diffusivity large B cell lymphoid tumor (DLBCL), follicular lymphoma or chronic lymphocytic Big B is thin for leukemia, lymphoma mantle cell (mantle cell lymphoma), mediastinum (thymus) Born of the same parents' lymphoma, intravascular large B cell lymphoma, lymphoma primary effusion, Hugh Burkitt drench Bar tumor (Burkitt lymphoma), similar disease or its combination.
Preferred pair homoiothermic animal, especially mankind's enteral administration such as nose, oral cavity, rectum or especially mouth The compositionss of the compositionss and parenteral such as intravenouss, intramuscular or subcutaneous administration of clothes administration. The dose-dependant of active component is in disease to be treated and kind, its age, body weight and individuality Condition, individual pharmacokinetic data available and administering mode.
Described pharmaceutical composition optionally can be used in combination with known treatment methods, for example hormone Or the administration of radiation.
For example, for the treatment of acute myeloid leukaemia AML, formula (I) compound can be with It is used in combination with standard leukemia therapies, is particularly useful for treating the therapy of AML.Specifically, Formula (I) compound can with such as farnesyl transferase inhibitor and/or other can be used to treat The administered in combination of AML, such as daunorubicin, amycin, Ara-C, VP-16, for Buddhist nun Pool glycosides, mitoxantrone, idarubicin, carboplatin and PKC412.
Determined by code, adopted name or trade name, the structure of active component can come from The current edition of classic " Merck index " or from data base, 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 for example gone up such as this area Prepare described in the document that face is quoted and be administered.
In embodiments of the present invention, when being treated to patient according to the present invention, give The amount of medicine depends on factors, such as specific dosage regimen, disease or implant treatment and its The uniqueness (such as body weight) of seriousness, subject in need for the treatment of or host, but, root According to specific ambient conditionss, including the concrete medicine, route of administration, treatment for for example having adopted Disease and the subject or host for the treatment of, application dosage can be by methods known in the art It is conventional to determine.Generally, for the dosage that adult treatment is used, application dosage typically exists 0.02-5000mg/ days, the e.g., from about scope of 1-1500mg/ days.The required dosage can be easily Be expressed as it is one, (or at short notice) that be administered simultaneously or appropriate interval point Dosage, such as daily two, three, four doses or more points of agent.It will be appreciated by those skilled in the art that Although giving above-mentioned dosage range, specific effective dose can be according to the situation of patient And combine doctor diagnosed and suitably adjust.
The preparation of compound
Using Standard synthetic techniques well known by persons skilled in the art or using side known in the art Method is combined with method described herein, can synthesize the compound of formula (I).In addition, giving herein Solvent, temperature and other reaction conditions for going out can change according to art technology.
In some embodiments, it provided herein is kinase inhibitor compounds described herein Preparation method and its using method.In some embodiments, compound described herein can Synthesized with the scheme using following synthesis.Can use and following similar methods, by using Appropriate selectable initiation material, synthesizes compound.
Initiation material for synthesizing compound described herein can be synthesized or can be from business Source obtains.The compound described herein compound with different substituents related to other can With using technology well known by persons skilled in the art and Material synthesis.Prepare chemical combination disclosed herein The reaction of thing can by the reagent thought fit by those skilled in the art and condition modification, With the various parts being incorporated herein in the molecule of offer.
If desired, product can using routine techniquess separate and purification, including but do not limit In methods such as filtration, distillation, crystallization, chromatographs.These products can be characterized using conventional method, Including physical constant and spectrum data.
Using synthetic method described herein, disclosed hereinization is obtained with good yield and purity Compound.According to the compound of method disclosed herein preparation by conventional method known in the art Purification, such as filtration, recrystallization, chromatograph, distillation and combinations thereof.
Site on the aromatic moiety of the compound of formula (I), may be easy to various generations Thank to reaction, therefore appropriate substituent group is introduced on aromatic ring structure, for example, is only illustrated Illustrate, halogen can reduce, this metabolic pathway is reduced or eliminated.
Embodiment
Non-limiting example in detail below is to be interpreted as being merely illustrative, not with Any mode limits the disclosure.Although need not describe in further detail, it is believed that ability Field technique personnel can be based on description herein, completely using the disclosure.
Preferred compounds of the invention is as follows：
Embodiment 1
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) phenyl) piperidines - 4- bases) propionic acid amide. 1-1 synthesis
The synthesis of 3- ((6,7- dimethoxy-quinoline -4- bases)-epoxide) aniline A
Step one：Potassium tert-butoxide (1.2 equivalent) is slowly added to equipped with 3- amino-phenols (1.2 Equivalent) and the reaction bulb of dimethyl sulfoxide (3mL) in, under room temperature condition stir 2 hours Add the chloro- 6,7- dimethoxy-quinolines (2.2mmol) of 4- and potassium carbonate (0.6 afterwards again toward reaction bulb Equivalent)., to 110 DEG C, reaction is overnight for reacting by heating.Mass Spectrometer Method is without the chloro- 6,7- dimethoxys of 4- Quinoline is remaining, and stopped reaction is cooled to room temperature, adds after reactant liquor diluted ethyl acetate After saturated sodium bicarbonate solution, point liquid, ethyl acetate phase again respectively with diluted sodium hydroxide solution, Saturated common salt water washing, anhydrous magnesium sulfate are dried, and filter, and after concentration, column chromatography obtains compound A (400mg), yield 61%.Exact Mass (value of calculation):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 the tert-butyl group (1- (4- nitrobenzophenones) piperidin-4-yl) carbamate B
Step 2：By 4- chloronitrobenzenes (12.69mmol) and 4-Boc amino piperidines, (1.0 work as Amount) it is dissolved in DMF (60mL), potassium carbonate (3.0 equivalent) is added, Reacting by heating is reacted 10 hours to 100 DEG C.Mass Spectrometer Method is without starting material left, stopped reaction.It is cold But to room temperature, reactant liquor is diluted with sodium bicarbonate solution, is extracted with ethyl acetate three times, is merged Ethyl acetate phase, use saturated common salt water washing, be dried, filter, after concentration compound B Crude product (3.9g).Exact Mass (value of calculation):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 the tert-butyl group (1- (4- aminophenyls) piperidin-4-yl) carbamate C
Step 3：Compound B (12.96mmol) is dissolved in methanol (500mL), then Palladium carbon (2.0g), reaction mixture is added to react under atmosphere of hydrogen 7 hours.Mass Spectrometer Method without Starting material left, stopped reaction.After reaction mixture concentration, column chromatography obtains compound C (1.2g), Two step yields are 32%.Exact Mass (value of calculation):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).
The tert-butyl group (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) phenyl) The synthesis of piperidin-4-yl carbamate D
Step 4：Under argon atmosphere, triphosgene (0.4 equivalent) is dissolved in into dichloromethane (20mL) In, ice-water bath cooling, then by compound A (1.34mmol), DMAP (0.1 Equivalent), the mixed liquor of triethylamine (1.0 equivalent) and dichloromethane (5mL) is low by constant pressure Liquid funnel is slowly instilled in the mixed liquor of triphosgene, is reacted 30 minutes, then at frozen water after dripping off By compound C (1.34mmol) under the conditions of bath, DMAP (0.1 equivalent), three second The mixed liquor of amine (1.0 equivalent) and dichloromethane (5mL) is slowly dripped by the low liquid funnel of constant pressure Enter in above-mentioned mixed reaction solution, react overnight under room temperature.Mass Spectrometer Method, raw material reaction totally, Stopped reaction.After reaction mixture concentration, column chromatography obtains compound D (206mg), yield 25%. Exact Mass (value of calculation):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- bases) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) Phenyl) urea E synthesis
Step 5：Hydrochloride/ethyl acetate (15mL) is slowly instilled equipped with compound D (0.33mmol), in reaction bulb, react 4 hours at room temperature.Mass Spectrometer Method, raw material are anti- Should totally, stopped reaction.Reacting liquid filtering is obtained into off-white powder, the as salt of compound E Hydrochlorate (170mg).Exact Mass (value of calculation):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 into N,N-dimethylformamide (0.5mL) In, triethylamine (0.04mL) is added, -50 DEG C are cooled to, then by propionyl chloride (1.2 equivalent) It is slowly added in reactant liquor.Mass Spectrometer Method after reacting 5 minutes, raw material reaction is totally.Toward reaction Saturated sodium bicarbonate solution, chloroform extraction three times, chloroform layer saturated common salt washing again are added in liquid Wash, be dried, filter, column chromatography obtains compound 1-1 (34mg), yield 79% after concentration.Exact Mass (value of calculation):569.2638；MS(ESI)m/e(M+1)+:570.2599；1H-NMR(400 MHz, 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- bases) epoxide) phenyl) urea groups) phenyl) Piperidin-4-yl) acetamide 1-2 synthesis
The step of synthesis of compound 1-2 is by using similar to described in embodiment 1 is completed, only It is to replace propionyl chloride with chloracetyl chloride in step 6.Exact Mass (value of calculation):590.0770； MS(ESI)m/e(M+1)+:591.0807。
Embodiment 3
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) phenyl) piperidines The synthesis of -4- base acrylamide 1-3
The step of synthesis of compound 1-3 is by using similar to described in embodiment 1 is completed, only It is to replace propionyl chloride with acryloyl chloride in step 6.Exact Mass (value of calculation):567.2482； MS(ESI)m/e(M+1)+:568.2479。
Embodiment 4
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and propionic acid amide. 2-1 synthesis
The step of synthesis of compound 2-1 is by using similar to described in embodiment 1 is completed, only It is in step 2 to replace 4- chloronitrobenzenes with the chloro- 5- nitro-trifluoromethyl toluenes of 2-.Exact Mass (meters Calculation 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- bases) epoxide) phenyl) urea groups) -2- (three Methyl fluoride) phenyl) piperidin-4-yl) and acetamide 2-2 synthesis
The step of synthesis of compound 2-2 is by using similar to described in embodiment 4 is completed, only It is to replace propionyl chloride with chloracetyl chloride in step 6.Exact Mass (value of calculation):657.1966； MS(ESI)m/e(M+1)+:658.1999。
Embodiment 6
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and acrylamide 2-3 synthesis
The step of synthesis of compound 2-3 is by using similar to described in embodiment 4 is completed, only It is to replace propionyl chloride with chloracetyl chloride in step 6.Exact Mass (value of calculation):635.2356； MS(ESI)m/e(M+1)+:636.2401。
Embodiment 7
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and propine amide 2-4 synthesis
According to 1-5 step synthesis compound 1- (4- (4- amino piperidine -1- the bases) -3- three of embodiment 6 Trifluoromethylphenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea.
6th step：By compound 1- (4- (4- amino piperidine -1- bases) -3- trifluoromethylbenzenes Base) -3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea (0.085mmol) is dissolved in N, N- Dimethylformamide (0.5mL), then it is separately added into triethylamine (0.05mL), 4- dimethylaminos Pyridine (0.5 equivalent), 2- (7- azo BTAs)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid Ester (HATU, 1.5 equivalents) and acetylenecarboxylic acid (1.2 equivalent).Room temperature reaction 5 hours, mass spectrum Detection, without starting material left, stopped reaction.Reactant liquor is diluted with chloroform, then is washed successively, satisfied Wash with Sal, anhydrous magnesium sulfate is dried, filter, column chromatography obtains compound 2-4 (6.3 after concentration Mg), yield 12%.Exact Mass (value of calculation):633.2199；MS(ESI)m/e(M+1)+: 634.2226。
Embodiment 8
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) ureas Base) -2- (trifluoromethyl) phenyl) piperidin-4-yl) and propionic acid amide. 3-1 synthesis
The step of synthesis of compound 3-1 is by using similar to described in embodiment 1 is completed, only It is in step one to replace 3- amino-phenols with 2- methyl -5- amino-phenols, 2- is used in step 2 Chloro- 5- nitro-trifluoromethyl toluenes replace 4- chloronitrobenzenes.Exact Mass (value of calculation):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- bases) epoxide) -4- aminomethyl phenyls) ureas Base) -2- (trifluoromethyl) phenyl) piperidin-4-yl) and acetamide 3-2 synthesis
The step of synthesis of compound 3-2 is by using similar to described in embodiment 8 is completed, only It is in step 6 to replace propionyl chloride with chloracetyl chloride.Exact Mass (value of calculation):671.2122； MS(ESI)m/e(M+1)+:672.2098。
Embodiment 10
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) ureas Base) -2- (trifluoromethyl) phenyl) piperidin-4-yl) and acrylamide 3-3 synthesis
The step of synthesis of compound 3-3 is by using similar to described in embodiment 8 is completed, only It is in step 6 to replace propionyl chloride with acryloyl chloride.Exact Mass (value of calculation):649.2512； MS(ESI)m/e(M+1)+:650.2488。
Embodiment 11
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) benzene Base) piperidin-4-yl) propionic acid amide. 4-1 synthesis
The step of synthesis of compound 4-1 is by using similar to described in embodiment 1 is completed, only It is in step one to replace 3- amino-phenols with 2- methyl -5- amino-phenols.Exact Mass (are 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- bases) epoxide) -4- aminomethyl phenyls) ureas Base) phenyl) piperidin-4-yl) and acetamide 4-2 synthesis
The step of synthesis of compound 4-2 is by using similar to described in embodiment 11 is completed, Simply replace propionyl chloride with chlorpromazine chloride in step 6.Exact Mass (value of calculation): 603.2248；MS(ESI)m/e(M+1)+:604.2301。
Embodiment 13
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) benzene Base) piperidin-4-yl) acrylamide 4-3 synthesis
The step of synthesis of compound 4-3 is by using similar to described in embodiment 11 is completed, Simply replace propionyl chloride with acryloyl chloride in step 6.Exact Mass (value of calculation): 581.2638；MS(ESI)m/e(M+1)+:582.2630。
Embodiment 14
1- (3- ((6,7- dimethoxy-quinoline -4- bases) -4 aminomethyl phenyls) -3- (4- ((1- propionyl piperidin-4-yls) Epoxide) phenyl) urea 5-1 synthesis
The step of synthesis of compound 5-1 is by using similar to described in embodiment 11 is completed, Simply replace 4-Boc amino piperidines with 4- hydroxyl -1-Boc piperidines in step 2.Exact Mass (value of calculation):584.2635；MS(ESI)m/e(M+1)+:585.2660。
Embodiment 15
1- (4- ((2- chloracetyls) piperidin-4-yl) epoxide) phenyl) -3- (3- ((6,7- dimethoxy-4 's-yl) Epoxide) -4- aminomethyl phenyls) urea 5-2 synthesis
The step of synthesis of compound 5-2 is by using similar to described in enforcement 14 is completed, only It is to replace propionyl chloride with chloracetyl chloride in step 6.Exact Mass (value of calculation):604.2089； MS(ESI)m/e(M+1)+:605.2103。
Embodiment 16
1- (4- ((2- acryloylpiperidine -4- bases) epoxide) phenyl) -3- (3- ((6,7- dimethoxy-4 's-yl) Epoxide) -4- aminomethyl phenyls) urea 5-3 synthesis
The step of synthesis of compound 5-3 is by using similar to described in embodiment 14 is completed, Simply replace propionyl chloride with acryloyl chloride in step 6.Exact Mass (value of calculation):582.2478； MS(ESI)m/e(M+1)+:583.2461。
Embodiment 17
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) benzene Base) pyrrolin -3- bases) propionic acid amide. 6-1 synthesis
The step of synthesis of compound 6-1 is by using similar to described in embodiment 14 is completed, Simply replace 4- hydroxyl -1-Boc piperidines with 3-Boc amino pyrrolines in step 2.Exact Mass (value of calculation):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- bases) epoxide) -4- aminomethyl phenyls) ureas Base) phenyl) pyrrolin -3- bases) and acetamide 6-2 synthesis
The step of synthesis of compound 6-2 is by using similar to described in embodiment 17 is completed, Simply replace propionyl chloride with chloracetyl chloride in step 6.Exact Mass (value of calculation):589.2092； MS(ESI)m/e(M+1)+:590.2111。
Embodiment 19
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) benzene Base) pyrrolin -3- bases) acrylamide 6-3 synthesis
The step of synthesis of compound 6-3 is by using similar to described in embodiment 17 is completed, Simply replace propionyl chloride with acryloyl chloride in step 6.Exact Mass (value of calculation):567.2483； MS(ESI)m/e(M+1)+:568.2561。
Embodiment 20
1- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) -3- (4- (4- propiono piperazines Piperazine -1- bases) phenyl) urea 7-1 synthesis
The step of synthesis of compound 7-1 is by using similar to described in embodiment 14 is completed, Simply replace 4- hydroxyl -1-Boc piperidines with 4-Boc piperazines in step 2.Exact Mass (are calculated Value):569.2638；MS(ESI)m/e(M+1)+:570.2600。
Embodiment 21
1- (4- (4- (2- chloracetyls) piperazine -1- bases) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- bases) Epoxide) -4- aminomethyl phenyls) urea 7-2 synthesis
The step of synthesis of compound 7-2 is by using similar to described in embodiment 20 is completed, Simply replace propionyl chloride with chloracetyl chloride in step 6.Exact Mass (value of calculation):589.2092； MS(ESI)m/e(M+1)+:590.2116。
Embodiment 22
1- (4- (4- acryloylpiperazines -1- bases) phenyl) -3- (3- ((6,7- dimethoxy-quinoline -4- bases) oxygen Base) -4- aminomethyl phenyls) urea 7-3 synthesis
The step of synthesis of compound 7-3 is by using similar to described in embodiment 20 is completed, Simply replace propionyl chloride with acryloyl chloride in step 6.Exact Mass (value of calculation):567.2482； MS(ESI)m/e(M+1)+:568.2417。
Embodiment 23
1- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) -3- (4 ((1- propiono pyrroles Cough up quinoline -3- bases) epoxide) phenyl) and urea 8-1 synthesis
The step of synthesis of compound 8-1 is by using similar to described in embodiment 14 is completed, Simply replace 4- hydroxyl -1-Boc piperidines with 3- hydroxyl -1- pyrrolins in step 2.Exact Mass (value of calculation):570.2478；MS(ESI)m/e(M+1)+:571.2399。
Embodiment 24
1- (4- ((2- chloracetyls) pyrrolin -3- bases) epoxide) phenyl) -3- (3- ((6,7- dimethoxy quinolines Quinoline -4- bases) epoxide) -4- aminomethyl phenyls) and urea 8-2 synthesis
The step of synthesis of compound 8-2 is by using similar to described in embodiment 23 is completed, Simply replace propionyl chloride with chloracetyl chloride in step 6.Exact Mass (value of calculation):590.1932； MS(ESI)m/e(M+1)+:591.2010。
Embodiment 25
1- (4- ((1- acryloyl group pyrrolin -3- bases) epoxide) phenyl) -3- (3- ((6,7- dimethoxy-quinolines - 4- bases) epoxide) -4- aminomethyl phenyls) and urea 8-3 synthesis
The step of synthesis of compound 8-3 is by using similar to described in embodiment 23 is completed, Simply replace propionyl chloride with acryloyl chloride in step 6.Exact Mass (value of calculation):568.2322； MS(ESI)m/e(M+1)+:569.2331。
Embodiment 26
1- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) -3- (4- ((1- propionos Piperidin-4-yl) amino) phenyl) and urea 9-1 synthesis
The step of synthesis of compound 9-1 is by using similar to described in embodiment 14 is completed, Simply replace 4- hydroxyl -1-Boc piperidines with 4- amino -1-Boc piperidines in step 2.Exact Mass (value of calculation):583.2795；MS(ESI)m/e(M+1)+:584.2799。
Embodiment 27
1- (4- ((2- chloracetyls) piperidin-4-yl) amino) phenyl) -3- (3- ((6,7- dimethoxy-quinolines - 4- bases) epoxide) -4- aminomethyl phenyls) and urea 9-2 synthesis
The step of synthesis of compound 9-2 is by using similar to described in embodiment 26 is completed, Simply replace propionyl chloride with chloracetyl chloride in step 6.Exact Mass (value of calculation):603.2248； MS(ESI)m/e(M+1)+:604.2250。
Embodiment 28
1- (4- ((1- acryloylpiperidine -4- bases) amino) phenyl) -3- (3- ((6,7- dimethoxy-quinolines - 4- bases) epoxide) -4- aminomethyl phenyls) and urea 9-3 synthesis
The step of synthesis of compound 9-3 is by using similar to described in embodiment 26 is completed, Simply replace propionyl chloride with acryloyl chloride in step 6.Exact Mass (value of calculation):581.2638； MS(ESI)m/e(M+1)+:582.2661。
Embodiment 29
1- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) -3- (4- ((1- propionos Pyrrolin -3- bases) amino) phenyl) and urea 10-1 synthesis
The step of synthesis of compound 10-1 is by using similar to described in embodiment 14 is completed, Simply replace 4- hydroxyl -1-Boc piperidines with 3- amino -1-Boc pyrrolins in step 2.Exact Mass (value of calculation):569.2638；MS(ESI)m/e(M+1)+:570.2707。
Embodiment 30
1- (4- ((2- chloracetyls) pyrrolin -3- bases) amino) phenyl) -3- (3- ((6,7- dimethoxy quinolines Quinoline -4- bases) epoxide) -4- aminomethyl phenyls) and urea 10-2 synthesis
The step of synthesis of compound 10-2 is by using similar to described in embodiment 29 is completed, Simply replace propionyl chloride with chloracetyl chloride in step 6.Exact Mass (value of calculation):589.2902； MS(ESI)m/e(M+1)+:590.2112。
Embodiment 31
1- (4- ((1- acryloyl group pyrrolin -3- bases) amino) phenyl) -3- (3- ((6,7- dimethoxy-quinolines - 4- bases) epoxide) -4- aminomethyl phenyls) and urea 10-3 synthesis
The step of synthesis of compound 10-3 is by using similar to described in embodiment 29 is completed, Simply replace propionyl chloride with acryloyl chloride in step 6.Exact Mass (value of calculation):567.2482； MS(ESI)m/e(M+1)+:568.2409。
Embodiment 32
N- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) phenyl) third The synthesis of amide 11-1
Step one：The step of synthesis of compound F is by using similar to described in embodiment 1 One completes, and simply replaces 3- amino-phenols with 2- methyl -5- amino-phenols in the reaction.Exact Mass (value of calculation):310.3530；MS(ESI)m/e(M+1)+:311.2350。
Step 2：The step of synthesis of compound G is by using similar to described in embodiment 1 Four complete, and simply replace compound C with 3- nitroanilines in the reaction.Exact Mass (are calculated Value):474.4730；MS(ESI)m/e(M+1)+:478.5112。
Step 3：The step of synthesis of compound H is by using similar to described in embodiment 1 Three complete, and simply replace compound B with compound G in the reaction.Exact Mass (value of calculation): 444.4910；MS(ESI)m/e(M+1)+:445.5609。
Step 4：The synthesis of compound 11-1 is by using similar to the step described in embodiment 1 Rapid six complete, and simply replace compound E with compound H in the reaction.Exact Mass (are 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- bases) epoxide) -4- aminomethyl phenyls) urea groups) benzene Base) acetamide 11-2 synthesis
The step of synthesis of compound 11-2 is by using similar to described in embodiment 32 is completed, Simply replace propionyl chloride with chloracetyl chloride in step 4.Exact Mass (value of calculation):520.1513； MS(ESI)m/e(M+1)+:521.2106。
Embodiment 34
N- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) phenyl) third The synthesis of acrylamide 11-3
The step of synthesis of compound 11-3 is by using similar to described in embodiment 32 is completed, Simply replace propionyl chloride with acryloyl chloride in step 4.Exact Mass (value of calculation):498.1903； MS(ESI)m/e(M+1)+:499.2607。
Embodiment 35
(E)-N- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) benzene Base) -4- (dimethylamino) butyl -2- eneamide 11-4 synthesis
The step of synthesis of compound 11-4 is by using similar to described in embodiment 32 is completed, Simply replace propionyl chloride with 4- dimethylamino -2- alkene butyl chlorides in step 4.Exact Mass (are calculated Value):555.2482；MS(ESI)m/e(M+1)+:556.6350。
Embodiment 36
(E)-N- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) phenyl) The synthesis of butyl -2- eneamide 11-5
The step of synthesis of compound 11-5 is by using similar to described in embodiment 32 is completed, Simply replace propionyl chloride with 2- alkene butyl chlorides in step 4.Exact Mass (value of calculation): 512.2060；MS(ESI)m/e(M+1)+:513.3099。
Embodiment 37
N- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) phenyl) The synthesis of propionic acid amide. 12-1
The step of synthesis of compound 12-1 is by using similar to described in embodiment 32 is completed, Simply replace 3- nitroanilines with paranitroanilinum in step 2.Exact Mass (value of calculation): 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- bases) epoxide) -4- aminomethyl phenyls) urea groups) Phenyl) acetamide 12-2 synthesis
The step of synthesis of compound 12-2 is by using similar to described in embodiment 37 is completed, Simply replace propionyl chloride with chloracetyl chloride in step 4.Exact Mass (value of calculation):520.1513； MS(ESI)m/e(M+1)+:521.3101。
Embodiment 39
N- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) phenyl) The synthesis of acrylamide 12-3
The step of synthesis of compound 12-3 is by using similar to described in embodiment 37 is completed, Simply replace propionyl chloride with acryloyl chloride in step 4.Exact Mass (value of calculation):498.1503； MS(ESI)m/e(M+1)+:499.5390。
Embodiment 40
(E)-N- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) benzene Base) butyl -2- acrylamides 12-4 synthesis
The step of synthesis of compound 12-4 is by using similar to described in embodiment 37 is completed, Simply replace propionyl chloride with 2- alkene butyl chlorides in step 4.Exact Mass (value of calculation): 512.2060；MS(ESI)m/e(M+1)+:513.5330。
Embodiment 41
(E)-N- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -4- aminomethyl phenyls) urea groups) benzene Base) -4- (dimethylamino) butyl -2- acrylamides 12-5 synthesis
The step of synthesis of compound 12-5 is by using similar to described in embodiment 37 is completed, Simply replace propionyl chloride with 4- dimethylamino -2- alkene butyl chlorides in step 4.Exact Mass (are calculated Value):555.2482；MS(ESI)m/e(M+1)+:556.6350。
Embodiment 42
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) phenyl) piperidines - 3- bases) propionic acid amide. 13-1 synthesis
The step of synthesis of compound 13-1 is by using similar to described in embodiment 1 is completed, Simply replace 4-Boc amino piperidine with 3-Boc amino piperidines in step 2.Exact Mass (are 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- bases) epoxide) phenyl) urea groups) phenyl) Piperidines -3- bases) acetamide 13-2 synthesis
The step of synthesis of compound 13-2 is by using similar to described in embodiment 42 is completed, Simply replace propionyl chloride with chloracetyl chloride in step 6.Exact Mass (value of calculation):589.2092； MS(ESI)m/e(M+1)+:590.0770。
Embodiment 44
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) phenyl) piperidines - 3- bases) acrylamide 13-3 synthesis
The step of synthesis of compound 13-3 is by using similar to described in embodiment 42 is completed, Simply replace propionyl chloride with acryloyl chloride in step 6.Exact Mass (value of calculation):567.2482； MS(ESI)m/e(M+1)+:568.6460。
Embodiment 45
(E)-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) phenyl) Piperidines -3- bases) butyl -2- acrylamides 13-4 synthesis
The step of synthesis of compound 13-4 is by using similar to described in embodiment 42 is completed, Simply replace propionyl chloride with 2- alkene butyl chlorides in step 6.Exact Mass (value of calculation): 581.2638；MS(ESI)m/e(M+1)+:582.6730。
Embodiment 46
(E)-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) phenyl) Piperidines -3- bases) -4- (dimethylamino) butyl -2- acrylamides 13-5 synthesis
The step of synthesis of compound 13-5 is by using similar to described in embodiment 42 is completed, Simply replace propionyl chloride with 4- dimethylamino -2- alkene butyl chlorides in step 6.Exact Mass (are calculated Value):624.3020；MS(ESI)m/e(M+1)+:625.7420。
Embodiment 47
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) phenyl) piperidines - 3- bases) cyclohexyl -3- alkene -1- phosphoamide 13-6 synthesis
The step of synthesis of compound 13-6 is by using similar to described in embodiment 42 is completed, Simply replace propionyl chloride with 3- alkene -1- Cyclohexanoyl chlorides in step 6.Exact Mass (value of calculation): 621.2951；MS(ESI)m/e(M+1)+:622.7380。
Embodiment 48
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) phenyl) piperidines - 3- bases) cyclopenta -2- alkene -1- phosphoamide 13-7 synthesis
The step of synthesis of compound 13-7 is by using similar to described in embodiment 42 is completed, Simply replace propionyl chloride with 2- alkene -1- ring valeric chlorides in step 6.Exact Mass (value of calculation): 607.2795；MS(ESI)m/e(M+1)+:608.7111。
Embodiment 49
(R)-(1- ((1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (three Methyl fluoride) phenyl) piperidin-4-yl) amino) -3- (4- hydroxy phenyls) -1- Ethylene Oxide -2- bases) carbamic acid The synthesis of tert-butyl alcohol ester 2-5
The step of synthesis of compound 2-5 is by using similar to described in embodiment 7 is completed, only It is to replace acetylenecarboxylic acid with Boc amino L-Tyrosine in step 6.Exact Mass (value of calculation): 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- bases) epoxide) phenyl) ureas Base) -2- (trifluoromethyl) phenyl) piperidin-4-yl) -3- (- 3 base of 1 hydrogen-indole) propionamide hydrochloride 2-6 Synthesis
The synthesis of compound 2-6：First by using similar to described in embodiment 7 the step of, obtains To solid, simply replace acetylenecarboxylic acid with Boc amino tryptophans in step 6.Then by gained Solid is dissolved in the ethyl acetate solution of hydrochloric acid, and reaction was removed in vacuum volatile substances after 2 hours, Gained solid is the hydrochlorate of compound 2-6.Exact Mass (value of calculation):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- bases) epoxide) phenyl) ureas Base) -2- (trifluoromethyl) phenyl) piperidin-4-yl) and pentane diamides 2-7 synthesis
The step of synthesis of compound 2-7 is by using similar to described in embodiment 49 is completed, Simply replace Boc amino tryptophans with glutamine in step 6.Exact Mass (value of calculation): 709.2836；MS(ESI)m/e(M+1)+:710.7272。
Embodiment 52
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and cyclohexyl -1- alkene -1- Methanamide 2-8 synthesis
The step of synthesis of compound 2-8 is by using similar to described in embodiment 7 is completed, only It is to replace acetylenecarboxylic acid with 1- alkene hexahydrobenzoid acids in step 6.Exact Mass (value of calculation): 689.2825；MS(ESI)m/e(M+1)+:690.7362。
Embodiment 53
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and Methanesulfomide 2-9 synthesis
The step of synthesis of compound 2-9 is by using similar to described in embodiment 7 is completed, only It is to replace acetylenecarboxylic acid with methanesulfonic acid in step 6.Exact Mass (value of calculation):659.2625； MS(ESI)m/e(M+1)+:660.6812。
Embodiment 54
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and piperidines -4- Methanamide 2-10 synthesis
The step of synthesis of compound 2-10 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 4- carboxylic acid piperidins in step 6.Exact Mass (value of calculation): 692.2934；MS(ESI)m/e(M+1)+:693.7402。
Embodiment 55
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and tetrahydrochysene -2H- pyrans -4- Methanamide 2-11 synthesis
The step of synthesis of compound 2-11 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 4- formic acid pyrans in step 6.Exact Mass (value of calculation): 693.2774；MS(ESI)m/e(M+1)+:694.2669。
Embodiment 56
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and acetamide 2-12 synthesis
The step of synthesis of compound 2-12 is by using similar to described in embodiment 4 is completed, Simply replace propionyl chloride with chloroacetic chloride in step 6.Exact Mass (value of calculation):623.2356； MS(ESI)m/e(M+1)+:624.2426。
Embodiment 57
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and cyclopropylsulfonamide 2-13 synthesis
The step of synthesis of compound 2-13 is by using similar to described in embodiment 4 is completed, Simply replace propionyl chloride with ring propane sulfonic acid in step 6.Exact Mass (value of calculation):685.2182； MS(ESI)m/e(M+1)+:686.2229。
Embodiment 58
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and -3,3- amide dimethyl butyrate 2-14 synthesis
The step of synthesis of compound 2-14 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 3,3- acid dimethyls in step 6.Exact Mass (value of calculation): 679.2982；MS(ESI)m/e(M+1)+:680.3001。
Embodiment 59
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and -1- methyl piperidine -4- Methanamide 2-15 synthesis
The step of synthesis of compound 2-15 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 4- formic acid -1- methyl piperidines in step 6.Exact Mass (value of calculation): 706.3091；MS(ESI)m/e(M+1)+:707.4291。
Embodiment 60
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and -1- ethyl piperidine -4- Methanamide 2-16 synthesis
The step of synthesis of compound 2-16 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 4- formic acid -1- ethyl piperidines in step 6.Exact Mass (value of calculation): 720.3247；MS(ESI)m/e(M+1)+:721.4433。
Embodiment 61
1- acetyl-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) ureas Base) -2- (trifluoromethyl) phenyl) piperidin-4-yl) and piperidines -4- Methanamide 2-17 synthesis
The step of synthesis of compound 2-17 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 4- formic acid -1- Acetylpiperidins in step 6.Exact Mass (value of calculation): 734.3040；MS(ESI)m/e(M+1)+:735.4262。
Embodiment 62
Tert-butyl group 4- ((1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) ureas Base) -2- (trifluoromethyl) phenyl) piperidin-4-yl) amine formyl) piperidines -1- carboxylate 2-18 synthesis
The step of synthesis of compound 2-18 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 4- formic acid -1-Boc piperidines in step 6.Exact Mass (value of calculation): 792.3458；MS(ESI)m/e(M+1)+:793.3691。
Embodiment 63
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and piperidines -4- carboxamide hydrochloride 2-19 synthesis
The step of synthesis of compound 2-19 is by using similar to described in embodiment 50 is completed, Simply replace Boc- amino tryptophans in the reaction with 4- carboxylic acid piperidins.Exact Mass (value of calculation): 728.2701；MS(ESI)m/e(M+1)+:729.2881。
Embodiment 64
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and ethyl sulfonamide 2-20 synthesis
The step of synthesis of compound 2-20 is by using similar to described in embodiment 4 is completed, Simply replace propionyl chloride with ethyl sulfonic chloride in step 6.Exact Mass (value of calculation):673.2182； MS(ESI)m/e(M+1)+:674.2275。
Embodiment 65
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and propyl group -1- sulfonamide 2-21 synthesis
The step of synthesis of compound 2-21 is by using similar to described in embodiment 4 is completed, Simply replace propionyl chloride with the third sulfonic acid chloride in step 6.Exact Mass (value of calculation):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- bases) epoxide) phenyl) ureas Base) -2- (trifluoromethyl) phenyl) piperidin-4-yl) and propionamide hydrochloride 2-22 synthesis
The step of synthesis of compound 2-22 is by using similar to described in embodiment 50 is completed, Simply replace Boc- amino tryptophans in the reaction with Boc alanine.Exact Mass (value of calculation): 688.2388；MS(ESI)m/e(M+1)+:689.2403。
Embodiment 67
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and -2- (dimethylamino) acetamide 2-23 synthesis
The step of synthesis of compound 2-23 is by using similar to described in embodiment 7 is completed, Simply in step 6 N, N- dimethylglycines replace acetylenecarboxylic acid.Exact Mass (value of calculation): 666.2788；MS(ESI)m/e(M+1)+:667.7022。
Embodiment 68
2- amino-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) ureas Base) -2- (trifluoromethyl) phenyl) piperidin-4-yl) and acetamide hydrochloride 2-24 synthesis
The step of synthesis of compound 2-24 is by using similar to described in embodiment 50 is completed, Simply replace Boc- amino tryptophans in the reaction with Boc glycine.Exact Mass (value of calculation): 674.2231；MS(ESI)m/e(M+1)+:675.1022。
Embodiment 69
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) -2- (fluoroforms Base) phenyl) piperidin-4-yl) and nicotiamide 2-25 synthesis
The step of synthesis of compound 2-25 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with nicotinic acid in step 6.Exact Mass (value of calculation):686.3465； MS(ESI)m/e(M+1)+:687.4004。
Embodiment 70
The tert-butyl group -3- ((1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups - 2- (trifluoromethyl) phenyl) piperidin-4-yl) carbamyl) and piperidines -1- carboxylate 2-26 synthesis
The step of synthesis of compound 2-26 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 3- formic acid -1-Boc piperidines in step 6.Exact Mass (value of calculation): 792.8572；MS(ESI)m/e(M+1)+:793.7271。
Embodiment 71
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups -2- (fluoroforms Base) phenyl) piperidin-4-yl) carbamyl) piperidines -1- carboxamide hydrochloride 2-27 synthesis
The step of synthesis of compound 2-27 is by using similar to described in embodiment 50 is completed, Simply replace Boc- amino tryptophans with 3- formic acid -1-Boc piperidines in the reaction.Exact Mass (value of calculation):729.1289；MS(ESI)m/e(M+1)+:730.0109。
Embodiment 72
(S)-N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups -2- (trifluoros Methyl) phenyl) piperidin-4-yl) and -2- (dipropylamino) propionic acid amide. 2-28 synthesis
The step of synthesis of compound 2-28 is by using similar to described in embodiment 7 is completed, Simply in step 6 N, N- dipropyl propanoic acid replaces acetylenecarboxylic acid.Exact Mass (value of calculation): 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- bases) epoxide) phenyl) Urea groups -2- (trifluoromethyl) phenyl) piperidin-4-yl) piperidines -4- Methanamide 2-29 synthesis
The step of synthesis of compound 2-29 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 4- formic acid -1- cyclopropane carbonyl piperidines in step 6.Exact Mass (meters Calculation value):760.8152；MS(ESI)m/e(M+1)+:761.8222。
Embodiment 74
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups -2- (fluoroforms Base) phenyl) piperidin-4-yl) and -1 '-methyl-[1,4 '-two piperidines] -4- Methanamide 2-30 synthesis
The step of synthesis of compound 2-30 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 4- formic acid -1- (1- methyl -4- piperidyls) piperidines in step 6.Exact Mass (value of calculation):789.8052；MS(ESI)m/e(M+1)+:790.1624。
Embodiment 75
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups -2- (fluoroforms Base) phenyl) piperidin-4-yl) and -2- (piperidin-1-yl) acetamide 2-31 synthesis
The step of synthesis of compound 2-31 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 1- acetic acid phenylpiperidines in step 6.Exact Mass (value of calculation): 706.7672；MS(ESI)m/e(M+1)+:707.3124。
Embodiment 76
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups -2- (fluoroforms Base) phenyl) piperidin-4-yl) and -2- (3- methyl piperidine -1- bases) acetamide 2-32 synthesis
The step of synthesis of compound 2-32 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 3- methyl isophthalic acids-acetic acid phenylpiperidines in step 6.Exact Mass (value of calculation): 720.7942；MS(ESI)m/e(M+1)+:721.3281。
Embodiment 77
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups -2- (fluoroforms Base) phenyl) piperidin-4-yl) and -3- (1- methyl piperidine -2- bases) propionic acid amide. 2-33 synthesis
The step of synthesis of compound 2-33 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 3- (1- methyl -2- piperidyls) propanoic acid in step 6.Exact Mass (are 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- bases) epoxide) phenyl) Urea groups -2- (trifluoromethyl) phenyl) piperidin-4-yl) -3- (1- methyl piperidine -2- bases) acetamide 2-34 Synthesis
The step of synthesis of compound 2-34 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 2- (1- homopiperidinyls) acetic acid in step 6.Exact Mass (value of calculation): 720.7942；MS(ESI)m/e(M+1)+:721.3281。
Embodiment 79
The tert-butyl group -4- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups - 2- (trifluoromethyl) phenyl) piperidin-4-yl) carbamyl)-pipecoline -1- carboxylate 2-35 Synthesis
The step of synthesis of compound 2-35 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 4- formic acid -2- methyl isophthalic acid-Boc piperidines in step 6.Exact Mass (meters Calculation value):806.8842；MS(ESI)m/e(M+1)+:807.3648。
Embodiment 80
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups -2- (fluoroforms Base) phenyl) piperidin-4-yl) and-pipecoline -4- carboxamide hydrochloride 2-36 synthesis
The step of synthesis of compound 2-36 is by using similar to described in embodiment 50 is completed, Simply replace Boc- amino tryptophans with 4- formic acid -2- methyl isophthalic acid-Boc piperidines in the reaction.Exact Mass (value of calculation):743.2252；MS(ESI)m/e(M+1)+:743.2891。
Embodiment 81
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups -2- (fluoroforms Base) phenyl) piperidin-4-yl) and -3- (piperidin-1-yl) propionic acid amide. 2-37 synthesis
The step of synthesis of compound 2-37 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with 3- (piperidin-1-yl) propanoic acid in step 6.Exact Mass (value of calculation): 720.7942；MS(ESI)m/e(M+1)+:721.3281。
Embodiment 82
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups -2- (fluoroforms Base) phenyl) piperidin-4-yl) and -3- morpholine acetamide 2-38 synthesis
The step of synthesis of compound 2-38 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with morpholinyl propanoic acid in step 6.Exact Mass (value of calculation): 722.7662；MS(ESI)m/e(M+1)+:723.3703。
Embodiment 83
3- tert-butyl-n -s (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups - 2- (trifluoromethyl) phenyl) piperidin-4-yl) isoxazole -5- Methanamide 2-39 synthesis
The step of synthesis of compound 2-39 is by using similar to described in embodiment 7 is completed, Simply replace acetylenecarboxylic acid with the tertiary Ding isoxazoles -5- formic acid of 3- in step 6.Exact Mass (are calculated Value):732.7612；MS(ESI)m/e(M+1)+:733.7617。
Embodiment 84
N- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) -4- (4- propionamido- piperidines -1- Base) -3- trifluoromethyl benzamide 14-1 synthesis
The synthesis of 3- ((6,7- dimethoxy-quinoline -4- bases)-epoxide) aniline A
Step one：Potassium tert-butoxide (1.2 equivalent) is slowly added to equipped with 3- amino-phenols (1.2 Equivalent) and the reaction bulb of dimethyl sulfoxide (3mL) in, under room temperature condition stir 2 hours Add the chloro- 6,7- dimethoxy-quinolines (2.2mmol) of 4- and potassium carbonate (0.6 afterwards again toward reaction bulb Equivalent)., to 110 DEG C, reaction is overnight for reacting by heating.Mass Spectrometer Method is without the chloro- 6,7- dimethoxys of 4- Quinoline is remaining, and stopped reaction is cooled to room temperature, adds after reactant liquor diluted ethyl acetate After saturated sodium bicarbonate solution, point liquid, ethyl acetate phase again respectively with diluted sodium hydroxide solution, Saturated common salt water washing, anhydrous magnesium sulfate are dried, and filter, and after concentration, column chromatography obtains compound A (400mg), yield 61%.Exact Mass (value of calculation):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).
Methyl -4- (4- ((tertbutyloxycarbonyl) amino) piperidin-1-yl) -3- trifluoro methyl benzoate I's Synthesis
Step 2：By 4- chloro- 3- trifluoromethyl benzoic acid methyl esters (12.69mmol) and 4- amino Formic acid tert-butyl alcohol ester (1.0 equivalent) is dissolved in DMF (60mL), then plus Enter potassium carbonate (3.0 equivalent), reacting by heating is reacted 10 hours to 100 DEG C.Mass Spectrometer Method is without original Material is remaining, stopped reaction.Room temperature is cooled to, reactant liquor is diluted with sodium bicarbonate solution, uses second Acetoacetic ester is extracted three times, the ethyl acetate phase saturated common salt water washing of merging, is dried, and is filtered, Compound I crude products (3.9g) is obtained after concentration.Exact Mass (value of calculation):402.4142； MS(ESI)m/e(M+1)+:403.1801；
The synthesis of 4- (4- ((tertbutyloxycarbonyl) amino) piperidin-1-yl) -3- (Trifluoromethyl)benzoic acid. J
Step 3：Compound I (12.96mmol) is dissolved in methanol (500mL), then will Sodium hydroxide (12.96mmol) is dissolved in the above-mentioned mixed liquor of the addition of the solution in water (13mL), Reactant is heated to back flow reaction 2 hours.Mass Spectrometer Method is without starting material left, stopped reaction.It is cold But compound J crude products (1.2g) is directly concentrated to give to room temperature.Exact Mass (value of calculation): 388.3872；MS(ESI)m/e(M+1)+:389.1643；
The tert-butyl group-(1- (4- ((3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) carbamyls Base) -2- (trifluoromethyl) 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).At room temperature Reaction.Mass Spectrometer Method, raw material reaction totally, stopped reaction.Reaction mixture ethyl acetate Dilution, is washed with water three times, and saturated common salt is washed once, the anhydrous sulfur of gained ethyl acetate phase Sour magnesium is dried, and filtering and concentrating thing column chromatography obtains compound K (206mg).Exact Mass (are calculated Value):666.6982；MS(ESI)m/e(M+1)+:667.2689。
4- (4- amino piperidine -1- bases)-N- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) benzene Base) -3- (trifluoromethyl) phenyl) Benzoylamide L synthesis
Step 5：Hydrochloride/ethyl acetate (15mL) is slowly instilled equipped with compound K (0.33mmol), in reaction bulb, react 4 hours at room temperature.Mass Spectrometer Method, raw material are anti- Should totally, stopped reaction.Reacting liquid filtering is obtained into off-white powder, the as salt of compound L Hydrochlorate (170mg).Exact Mass (value of calculation):566.5812；MS(ESI)m/e(M+1)+: 567.2173。
Step 6：The synthesis of compound 14-1 is finally by use similar to 1 step 6 of embodiment Described in the step of complete, simply replace compound E with compound L.Exact Mass (are calculated Value):622.6452；MS(ESI)m/e(M+1)+:623.2437。
Embodiment 85
4- (4- (2- chloracetyl amidos) piperidin-1-yl)-N- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) Phenyl) -3- trifluoromethyl benzamide 14-2 synthesis
The step of synthesis of compound 14-2 is by using similar to described in embodiment 84 is completed, Simply replace propionyl chloride with chloracetyl chloride in step 6.Exact Mass (value of calculation): 643.0602；MS(ESI)m/e(M+1)+:643.1890。
Embodiment 86
4- (4- acrylamido piperidin-1-yls)-N- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) benzene Base) -3- trifluoromethyl benzamide 14-3 synthesis
The step of synthesis of compound 14-3 is by using similar to described in embodiment 84 is completed, Simply replace propionyl chloride with acryloyl chloride in step 6.Exact Mass (value of calculation): 620.6292；MS(ESI)m/e(M+1)+:621.2280。
Embodiment 87
N- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) -4- (4- (4- propionamido- piperidines -1- Base) phenyl) cyclopropyl -1,1- diformamide 15-1 synthesis
Step one：Potassium tert-butoxide (1.2 equivalent) is slowly added to equipped with 3- amino-phenols (1.2 Equivalent) and the reaction bulb of dimethyl sulfoxide (3mL) in, under room temperature condition stir 2 hours Add the chloro- 6,7- dimethoxy-quinolines (2.2mmol) of 4- and potassium carbonate (0.6 afterwards again toward reaction bulb Equivalent)., to 110 DEG C, reaction is overnight for reacting by heating.Mass Spectrometer Method is without the chloro- 6,7- dimethoxys of 4- Quinoline is remaining, and stopped reaction is cooled to room temperature, adds after reactant liquor diluted ethyl acetate After saturated sodium bicarbonate solution, point liquid, ethyl acetate phase again respectively with diluted sodium hydroxide solution, Saturated common salt water washing, anhydrous magnesium sulfate are dried, and filter, and after concentration, column chromatography obtains compound A (400mg), yield 61%.Exact Mass (value of calculation):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).
Step 2：By compound A (12.69mmol), 1- (methoxycarbonyl group) cyclopropyl -1- formic acid (12.69mmol), HATU (15.00mmol) and triethylamine (15.00mmol) mix molten In DMF (15mL).Reacted to Mass Spectrometer Method at room temperature without starting material left, stopped anti- Should.With diluted ethyl acetate, mixed liquor is washed with water three times, and saturated common salt is washed once, organic It is dried with anhydrous magnesium sulfate, after filtering and concentrating, column chromatography obtains compound M.Exact Mass (meters Calculation value):422.4370；MS(ESI)m/e(M+1)+:423.1511。
Step 3：Compound M (6.66mmol) is dissolved in methanol (10mL), then will Sodium hydroxide (6.66mmol) is dissolved in the above-mentioned mixed liquor of the addition of the solution in water (7mL), Reactant is heated to back flow reaction 2 hours.Mass Spectrometer Method is without starting material left, stopped reaction.It is cold But compound N crude product is directly concentrated to give to room temperature.Exact Mass (value of calculation): 408.4100；MS(ESI)m/e(M+1)+:409.1355。
Step 4：By 4- chloronitrobenzenes (12.69mmol) and 4- carbamic acid tert-butyl alcohols ester (1.0 Equivalent) it is dissolved in DMF (60mL), potassium carbonate (3.0 equivalent) is added, Reacting by heating is reacted 10 hours to 100 DEG C.Mass Spectrometer Method is without starting material left, stopped reaction.It is cold But to room temperature, reactant liquor is diluted with sodium bicarbonate solution, is extracted with ethyl acetate three times, is merged Ethyl acetate phase, use saturated common salt water washing, be dried, filter, after concentration compound B Crude product (3.9g).Exact Mass (value of calculation):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), then Palladium carbon (2.0g), reaction mixture is added to react under atmosphere of hydrogen 7 hours.Mass Spectrometer Method without Starting material left, stopped reaction.After reaction mixture concentration, column chromatography obtains compound C (1.2g), Two step yields are 32%.Exact Mass (value of calculation):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：By compound N, compound C, HATU (15.00mmol) and triethylamine (15.00mmol) mixing is dissolved in DMF (15mL).Reacted to mass spectrum at room temperature and examined Survey without starting material left, stopped reaction.With diluted ethyl acetate, mixed liquor is washed with water three times, full Wash once with Sal, organic faciess are dried with anhydrous magnesium sulfate, and after filtering and concentrating, column chromatography must be changed Compound O.Exact Mass (value of calculation):681.7900；MS(ESI)m/e(M+1)+:682.3196。
Step 7：Hydrochloride/ethyl acetate (15mL) is slowly instilled equipped with compound O (0.33mmol), in reaction bulb, react 4 hours at room temperature.Mass Spectrometer Method, raw material are anti- Should totally, stopped reaction.Reacting liquid filtering is obtained into off-white powder, the as salt of compound P Hydrochlorate (170mg).Exact Mass (value of calculation):581.6730；MS(ESI)m/e(M+1)+: 582.6732。
Step 8：The synthesis of compound 15-1 is finally by use similar to 1 step 6 of embodiment Described in the step of complete, simply replace compound E with compound P.Exact Mass (are calculated Value):637.7370；MS(ESI)m/e(M+1)+:638.6931。
Embodiment 88
N- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) -4- (4- (4- propionamido- piperidines -1- Base) -3- trifluoromethyls) cyclopropyl -1,1- diformamide 16-1 synthesis.
The step of synthesis of compound 16-1 is by using similar to described in embodiment 87 is completed, Simply replace 4- chloronitrobenzene with the chloro- 5- nitro-trifluoromethyl toluenes of 2- in step 4.Exact Mass (meters Calculation value):705.7352；MS(ESI)m/e(M+1)+:706.2808。
Embodiment 89
N- (4- (4- (2- chloracetyl amidos) piperidin-1-yl) -3- trifluoromethyls)-N- (3- ((6,7- bis- Methoxy quinoline -4- bases) epoxide) phenyl) and cyclopropyl -1,1- diformamide 16-2 synthesis
The step of synthesis of compound 16-2 is by using similar to described in embodiment 88 is completed, Simply replace propionyl chloride with chloracetyl chloride in step 8.Exact Mass (value of calculation):726.1502； MS(ESI)m/e(M+1)+:726.2262。
Embodiment 90
N- (4- (4- acrylamido piperidin-1-yls) -3- trifluoromethyls)-N- (3- ((6,7- dimethoxies Base quinolyl-4) epoxide) phenyl) and cyclopropyl -1,1- diformamide 16-3 synthesis
The step of synthesis of compound 16-3 is by using similar to described in embodiment 88 is completed, Simply replace propionyl chloride with acryloyl chloride in step 8.Exact Mass (value of calculation):703.7192； MS(ESI)m/e(M+1)+:704.2651。
Embodiment 91
N- (4- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl)-N- (4- (4- propionamido- piperidines - 1- bases) -3- trifluoromethyls) cyclopropyl -1,1- diformamide 17-1 synthesis.
The step of synthesis of compound 17-1 is by using similar to described in embodiment 88 is completed, Simply replace 3- amino-phenols with para-aminophenol in step one.Exact Mass (are calculated Value):705.7352；MS(ESI)m/e(M+1)+:706.2810。
Embodiment 92
N- (4- (4- chloroacetamide phenylpiperidines -1- bases) -3- trifluoromethyls)-N- (4- ((6,7- dimethoxies Base quinolyl-4) epoxide) phenyl) and cyclopropyl -1,1- diformamide 17-2 synthesis.
The step of synthesis of compound 17-2 is by using similar to described in embodiment 91 is completed, Simply replace propionyl chloride with acryloyl chloride in step 8.Exact Mass (value of calculation):703.7200； MS(ESI)m/e(M+1)+:704.1099。
Embodiment 93
N- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl)-N '-(4- (4- propionamido- piperidines - 1- bases) -3- trifluoromethyls) Malondiamide 18-1 synthesis.
The step of synthesis of compound 18-1 is by using similar to described in embodiment 88 is completed, Simply replace 1- (methoxycarbonyl group) cyclopropyl -1- formic acid with 3- methoxycarbonyl group propanoic acid in step 2. Exact Mass (value of calculation):679.6972；MS(ESI)m/e(M+1)+:680.3162。
Embodiment 94
N- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) -2- methyl-N- (4- (4- propionic acid amide .s Phenylpiperidines -1- bases) -3- trifluoromethyls) Malondiamide 19-1 synthesis.
The step of synthesis of compound 19-1 is by using similar to described in embodiment 88 is completed, Simply replace 1- (methoxycarbonyl group) cyclopropyl with 3- methoxyl group -2- methyl -3- carbonyl propionic acids in step 2 - 1- formic acid.Exact Mass (value of calculation):693.7242；MS(ESI)m/e(M+1)+:694.6610。
Embodiment 95
N- (4- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) piperidines -1- Base) -3- trifluoromethyls) propionic acid amide. 20-1 synthesis
Step one：Carry out and the same steps described in 87 step one of embodiment.
Step 2：Carry out similar to the step described in 87 step 4 of embodiment, simply with the chloro- 5- of 2- Nitro-trifluoromethyl toluene replaces 4- chloronitrobenzenes.Gained solid be AD, Exact Mass (calculate Value):389.1562；MS(ESI)m/e(M+1)+:390.1077。
Step 3：Carry out, similar to the step described in 87 step 7 of embodiment, simply using AD generations Alternative compound O.Gained solid is compound AE, Exact Mass (value of calculation):289.2582； MS(ESI)m/e(M+1)+:290.1072。
Step 4：Carry out, similar to the step described in 1 step 4 of embodiment, simply using AE generations Alternative compound C.Gained solid is AF, Exact Mass (value of calculation):611.5782；MS(ESI) m/e(M+1)+:612.2025。
Step 5：Carry out, similar to the step described in 1 step 3 of embodiment, simply being replaced with AF Compound B.Gained solid is AG, Exact Mass (value of calculation):581.5962；MS(ESI) m/e(M+1)+:582.2283。
Step 6：The synthesis of compound 20-1 is finally by use similar to 1 step 6 of embodiment Described in the step of complete, simply replace compound E with AG.Exact Mass (are calculated Value):637.6602；MS(ESI)m/e(M+1)+:638.6736。
Embodiment 96
N- (4- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) urea groups) piperidines -1- Base) -3- trifluoromethyls) -1- (1- methyl piperidine -2- bases) propionic acid amide. 20-3 synthesis
The step of synthesis of compound 20-3 is by using similar to described in embodiment 7 is completed, Simply replace compound E with AG in step 6, while with 3- (1- methyl piperidine -2- bases) propanoic acid generations For acetylenecarboxylic acid.Exact Mass (value of calculation):734.8212；MS(ESI)m/e(M+1)+: 735.6736。
Embodiment 97
N- (1- (4- (2- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) acetamido) -2- three Trifluoromethylphenyl) piperidin-4-yl) -3- (1- methyl piperidine -2- bases) propionic acid amide. 21-1 synthesis
Step one：Carried out using 3- hydroxyphenylacetic acid methyl esters 6,7- dimethyl quinolines chloro- with 4- similar In the step described in 1 step one of embodiment.Gained compound is AH, Exact Mass (value of calculation): 353.3771；MS(ESI)m/e(M+1)+:354.1201。
Step 2：Carry out, similar to the step described in 87 step 3 of embodiment, simply using AH generations Alternative compound M.Gained compound is AI, Exact Mass (value of calculation):339.3445；MS(ESI) m/e(M+1)+:340.2025。
Step 3：Carry out, similar to the step described in 87 step 5 of embodiment, simply using AD generations Alternative compound B.Gained compound is AJ, Exact Mass (value of calculation):359.3932；MS(ESI) m/e(M+1)+:360.4001。
Step 4：Carry out, similar to the step described in 87 step 2 of embodiment, simply using AI generations Alternative compound A.Gained compound is AK, Exact Mass (value of calculation):680.7522；MS(ESI) m/e(M+1)+:681.2225。
Step 5：Carry out, similar to the step described in 87 step 7 of embodiment, simply using AK generations Alternative compound O.Gained compound is AL, Exact Mass (value of calculation):580.6082；MS(ESI) m/e(M+1)+:581.2333。
Step 6：The synthesis of compound 21-1 is finally by use similar to described in embodiment 7 The step of complete, simply replace compound E with AL, while with compound 3- (1- methyl piperidine -2- Base) propanoic acid replacement acetylenecarboxylic acid.Exact Mass (value of calculation):733.8212；MS(ESI)m/e(M+1)+: 734.8332。
Embodiment 98
N- (1- (4- (2- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) acetamido) -2- three Trifluoromethylphenyl) piperidin-4-yl) propionic acid amide. 21-2 synthesis
The step of synthesis of compound 21-2 is by using similar to described in embodiment 97 is completed, Simply replace 3- (1- methyl piperidine -2- bases) propanoic acid with propionyl chloride in step 6.Exact Mass (are calculated Value):636.6322；MS(ESI)m/e(M+1)+:637.2559。
Embodiment 99
N- (1- (4- (7- ((6,7- dimethoxy-quinoline -4- bases) epoxide) quinazoline -2- bases) amido) -2- three Trifluoromethylphenyl) piperidin-4-yl) propionic acid amide. 22-1 synthesis
Step one：2- chloro- 7- bromine quinazolines (8.11mmol) are dissolved in into N,N-dimethylformamide (10mL) in, again by cuprous bromide (10.16mmol), Feldalat NM (40.54 under argon atmosphere Mmol, 5.4M are in MeOH) sequentially add in above-mentioned solution.It is heated to the mass spectrum inspection that flows back Survey to without starting material left, stopped reaction.Room temperature is cooled to, after solvent removed in vacuo, residue Dissolved with ethyl acetate, gained organic phases washed with water is light blue color, saturated common salt to solution three times Once, anhydrous magnesium sulfate is dried, and after filtering and concentrating, column chromatography obtains target compound Q for washing.Exact Mass (value of calculation):194.6186；MS(ESI)m/e(M+1)+:196.0017。
Step 2：Above-claimed cpd Q (7.98mmol) is dissolved in into dichloromethane (100mL) In, it is after being cooled to -78 DEG C, the dichloromethane solution (1.0M, 25mL) of boron chloride is slow Slowly in adding above-mentioned reactant liquor, react to Mass Spectrometer Method without starting material left after, stopped reaction.With Saturated ammonium chloride solution is quenched reactant liquor, and separatory filtration process, gained dichloromethane mutually use saturated common salt Washing, anhydrous magnesium sulfate are dried, and it is anti-that crude product R obtained by after filtering and concentrating is directly used in next step Should.Exact Mass (value of calculation):180.5898；MS(ESI)m/e(M+1)+:181.1067。
Step 3：Carried out similar to enforcement using compound R and the chloro- 6,7- dimethoxy-quinolines of 4- Step described in 1 step one of example, obtains compound S.Exact Mass (value of calculation):367.7681； MS(ESI)m/e(M+1)+:368.7211。
Step 4：By compound S (7.01mmol) and the tert-butyl group-(1- (4- amino -2- fluoroforms Base phenyl) piperidin-4-yl) carbamate (7.33mmol) is dissolved in n-butyl alcohol (20mL), P-methyl benzenesulfonic acid (0.7mmol) is added, heating mixed liquor is reacted to Mass Spectrometer Method to 80 DEG C Without starting material left.Stopped reaction, is cooled to room temperature.N-butyl alcohol is removed in vacuum, residual solids are used Washed once with saturated sodium bicarbonate solution after ethyl acetate dissolving, washed once with saturated common salt, It is dried with anhydrous magnesium sulfate, after filtering and concentrating, column chromatography obtains target compound T, Exact Mass (meters Calculation value):690.7244；MS(ESI)m/e(M+1)+:691.6631。
Step 5：Carry out, similar to the step described in 1 step 5 of embodiment, simply using compound T Replace compound D, obtain compound U.Exact Mass (value of calculation):590.6970；MS(ESI) m/e(M+1)+:591.3262。
Step 6：The synthesis of compound 22-1 is finally by use similar to 1 step 6 of embodiment Described in the step of complete, simply replace compound E with compound U.Exact Mass (are calculated Value):646.6712；MS(ESI)m/e(M+1)+:647.2579。
Embodiment 100
N- (1- (4- (7- ((6,7- dimethoxy-quinoline -4- bases) epoxide) quinazoline -2- bases) amido) -2- three Trifluoromethylphenyl) piperidin-4-yl) -3- (1- methyl piperidine -2- bases) propionic acid amide. 22-3 synthesis
The step of synthesis of compound 22-3 is by using similar to described in embodiment 99 is completed, Simply replace propionyl chloride with 3- (1- methyl piperidine -2- bases) propanoic acid in step 6.Exact Mass (are calculated Value):743.8122；MS(ESI)m/e(M+1)+:744.3441。
Embodiment 101
N- (1- (4- (6- ((6,7- dimethoxy-quinoline -4- bases) epoxide) quinazoline -2- bases) amido) -2- three Trifluoromethylphenyl) piperidin-4-yl) propionic acid amide. 23-1 synthesis
The step of synthesis of compound 23-1 is by using similar to described in embodiment 99 is completed, Simply replace 2- chloro- 7- bromine quinazoline with the chloro- 6- bromines quinazolines of 2- in step one.Exact Mass (meters Calculation value):646.6723；MS(ESI)m/e(M+1)+:647.2556。
Embodiment 102
N- (1- (4- (6- ((6,7- dimethoxy-quinoline -4- bases) epoxide) quinazoline -2- bases) amido) -2- three Trifluoromethylphenyl) piperidin-4-yl) -3- (1- methyl piperidine -2- bases) propionic acid amide. 23-3 synthesis
The step of synthesis of compound 23-3 is by using similar to described in embodiment 101 is completed, Simply replace propionyl chloride with 3- (1- methyl piperidine -2- bases) propanoic acid in step 6.Exact Mass (are calculated Value):743.8322；MS(ESI)m/e(M+1)+:744.3671。
Embodiment 103
N- (1- (4- (5- ((6,7- dimethoxy-quinoline -4- bases) epoxide) benzo [d] oxazole -2- bases) amine Base) -2- trifluoromethyls) piperidin-4-yl) and propionic acid amide. 24-1 synthesis
The step of synthesis of compound 24-1 is by using similar to described in embodiment 99 is completed, Simply replace 2- chloro- 7- bromine quinazoline with the chloro- 5- bromoxynil oxazolines of 2- in step one.Exact Mass (value of calculation):635.6442；MS(ESI)m/e(M+1)+:636.6389。
Embodiment 104
N- (1- (4- (6- ((6,7- dimethoxy-quinoline -4- bases) epoxide) benzo [d] oxazole -2- bases) amine Base) -2- trifluoromethyls) piperidin-4-yl) and -3- (1- methyl piperidine -2- bases) propionic acid amide. 24-3 synthesis
The step of synthesis of compound 24-3 is by using similar to described in embodiment 103 is completed, Simply replace propionyl chloride with 3- (1- methyl piperidine -2- bases) propanoic acid in step 6.Exact Mass (are calculated Value):732.8352；MS(ESI)m/e(M+1)+:733.3971。
Embodiment 105
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) -2- carbonyl tetrahydropyrimidines - 1- (2H)-yl) -2- trifluoromethyls) piperidin-4-yl) and propionic acid amide. 25-1 synthesis
Step one：By compound 3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) aniline (2.11 Mmol) it is dissolved in anhydrous methylene chloride (10mL), by sodium hydride (3.15mmol) slowly Add after stirring 30 minutes under room temperature, then by compound 1,3- dibromopropanes (2.11mmol) add Enter in above-mentioned mixed liquor, being heated to back flow reaction is not having starting material left to Mass Spectrometer Method, stops Reaction.Room temperature is cooled to, with dchloromethane, then is washed with saturated sodium bicarbonate solution, water Wash, saturated common salt washing, anhydrous magnesium sulfate are dried, and after filtering and concentrating, column chromatography obtains compound V. Exact Mass (value of calculation):417.3022；MS(ESI)m/e(M+1)+:418.0755。
Step 2：Using compound V, triphosgene, the tert-butyl group-(1- (4- amino -2- trifluoromethylbenzenes Base) piperidin-4-yl) carbamate the step of carry out similar to described in 1 step 4 of embodiment, obtains It is W to compound.Exact Mass (value of calculation):732.8352；MS(ESI)m/e(M+1)+: 733.3971。
Step 3：Compound W (0.88mmol) is dissolved in tetrahydrofuran (10mL), Sodium hydride (1.34mmol) is added in above-mentioned mixed liquor, back flow reaction is heated to and is examined to mass spectrum Survey without starting material left, stopped reaction.It is cooled to room temperature, solvent removed in vacuo, residue second Acetoacetic ester dissolve, wash with water, saturated common salt washing, anhydrous magnesium sulfate be dried, after filtering and concentrating Column chromatography obtains compounds X.Exact Mass (value of calculation):721.7282；MS(ESI)m/e(M+1)+: 723.3971。
Step 4：The step of being carried out similar to described in 1 step 5 of embodiment using compounds X, Obtain compound Y.Exact Mass (value of calculation):621.6612；MS(ESI)m/e(M+1)+: 622.7156。
Step 5：The synthesis of compound 25-1 is finally by use similar to 1 step 6 of embodiment Described in the step of complete, simply replace compound E with compound Y.Exact Mass (are calculated Value):677.7652；MS(ESI)m/e(M+1)+:678.6752。
Embodiment 106
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) -2- carbonyl tetrahydropyrimidines - 1- (2H)-yl) -2- trifluoromethyls) piperidin-4-yl) -3- (1- methyl piperidine -2- bases) propionic acid amide. The synthesis of 25-3
The step of synthesis of compound 25-3 is by using similar to described in embodiment 105 is completed, Simply replace propionyl chloride with 3- (1- methyl piperidine -2- bases) propanoic acid in step 5.Exact Mass (are calculated Value):774.8662；MS(ESI)m/e(M+1)+:775.7551。
Embodiment 107
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) -2- carbonylic imidazole quinolines - 1- bases) -2- trifluoromethyls) piperidin-4-yl) and propionic acid amide. 26-1 synthesis
The step of synthesis of compound 26-1 is by using similar to described in embodiment 105 is completed, Simply replace 1,3- dibromopropanes with glycol dibromide in step one.Exact Mass (are calculated Value):663.6982；MS(ESI)m/e(M+1)+:664.6702。
Embodiment 108
N- (1- (4- (3- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) -2- carbonylic imidazole quinolines - 1- bases) -2- trifluoromethyls) piperidin-4-yl) -3- (1- methyl piperidine -2- bases) propionic acid amide. 26-3 Synthesis
The step of synthesis of compound 26-3 is by using similar to described in embodiment 107 is completed, Simply replace propionyl chloride with 3- (1- methyl piperidine -2- bases) propanoic acid in step 5.Exact Mass (are calculated Value):760.8592；MS(ESI)m/e(M+1)+:761.8593。
Embodiment 109
N- (1- (2- (2- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) acetylamino) thiazoles - 4- carbonyls) piperidin-4-yl) propionic acid amide. 27-1 synthesis
Step one：Compound thiazolamine -4- Ethyl formates (0.71mmol) is dissolved in into methanol (10mL), in, the sodium hydroxide for preparing (1.0M, 0.71mmol) solution is added above-mentioned In mixed liquor, backflow is heated to, reacting to Mass Spectrometer Method does not have starting material left, stopped reaction. Cold to go to room temperature, mixed liquor is concentrated in vacuo, and gained residue is the mixture of compound Z, It is directly used in next step reaction.Exact Mass (value of calculation):144.1841；MS(ESI) m/e(M+1)+:145.9901。
Step 2：Carried out similar to 87 step of embodiment using mixture Z, 4-Boc amino piperidine The step of described in rapid two, gained compound are AA.Exact Mass (value of calculation):326.4150； MS(ESI)m/e(M+1)+:327.1687。
Step 3：Using compound AA, 2- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) The step of acetic acid is carried out similar to described in 87 step 2 of embodiment, gained compound are AB. Exact Mass (value of calculation):647.7472；MS(ESI)m/e(M+1)+:648.2613。
Step 4：Carried out similar to the step described in 1 step 5 of embodiment using compound AB Suddenly, obtain compound AC.Exact Mass (value of calculation):547.5391；MS(ESI)m/e(M+1)+: 548.2670。
Step 5：The synthesis of compound 27-1 is finally by use similar to 1 step 6 of embodiment Described in the step of complete, simply replace compound E with compound AC.Exact Mass (are calculated Value):603.6940；MS(ESI)m/e(M+1)+:604.6938。
Embodiment 110
N- (1- (2- (2- (3- ((6,7- dimethoxy-quinoline -4- bases) epoxide) phenyl) acetylamino) thiazoles - 4- carbonyls) piperidin-4-yl) -3- (1- methyl piperidine -2- bases) propionic acid amide. 27-3 synthesis
The step of synthesis of compound 27-3 is by using similar to described in embodiment 109 is completed, Simply replace propionyl chloride with 3- (1- methyl piperidine -2- bases) propanoic acid in step 5.Exact Mass (are calculated Value):700.8511；MS(ESI)m/e(M+1)+:701.3781。
Embodiment 111：Impact to cancer cell multiplication
By test text in compound 2-1, compound 2-2, compound 2-3, compound 2-9, Compound 2-8, compound 2-5, compound 2-10, compound 2-11, compound 2-12, change Compound 2-13, compound 2-14, compound 2-15, compound 2-16, compound 2-17, change Compound 2-18, compound 2-19, compound 2-20, compound 2-21, compound 2-22, change Compound 2-23, compound 2-24, compound 2-25, compound 2-26, compound 2-27, change Compound 2-28, compound 2-29, compound 2-30, compound 2-31, compound 2-32, change Compound 2-33, compound 2-34, compound 2-35, compound 2-36, compound 2-37, change Compound 14-1, compound 14-2, compound 14-3, compound 16-1, compound 16-2, change The impact (table 1) of compound 16-3, compound 17-1, compound 17-2 to growth of cancer cells, enters Inhibitory action of the compound to cancer cell multiplication in one step assessment text, and its anticancer is increased The selectivity grown.People's acute monocytic leukemia cell strain has been selected in the present embodiment 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 genes), people are non-little Cell lung cancer cell H1975 (expression EGFR L858R/T790M double-mutant genes), leukemia Cell K562, human A549 cell lines (expression Wild type EGFR gene), carcinoma of prostate C4-2, diffusivity large B cell lymphoid tumor cell line TMD8, carcinoma of prostate RV-1, people Burkitt's Lymphoma cell Namalwa, human B cell chronic lymphocytic leukemia cell strain 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 genes), human muscle creatine kinase Cell strain U937 (expression wild type FLT3 genes), acute myeloid leukemia cells in children HL-60 (tables Up to wild type FLT3 genes), Non-small cell lung carcinoma cell NCI-H460 (EGFR WT), Human muscle creatine kinase cell strain OCI-AML-3 (expression FLT3 A680V mutated genes), HTL cell PF-382, human lung adenocarcinoma cell PC-9, human breast cancer cell MDA-MB-468, human breast cancer cell T47D, human bladder cancer cell Hb-c, people are non-little thin Born of the same parents lung carcinoma cell HCC827, Non-small cell lung carcinoma cell NCI-H23, CHL cells CHL, Chinese hamster ovary cell (Chinese hamster ovary) CHO, mice pro B lymphocyte BaF3, above cell are purchased from ATCC.Also select mice BaF3-FLT3-ITD (stable The activated protein kinase of expression FLT3-ITD mutation), mice BaF3-FLT3-D835Y (stable tables Up to the activated protein kinase of FLT3 D835Y mutation), mice BaF3-FLT3-D835V (stable tables Up to the activated protein kinase of FLT3 D835V mutation), mice BaF3-FLT3-D835H (stable tables Up to the activated protein kinase of FLT3 D835H mutation), mice BaF3-FLT3-K663Q (stable tables Up to the activated protein kinase of FLT3 K663Q mutation), mice TEL-BMX-BaF3 it is (stable to express BMX kinases), it is mice BaF3-TEL-PDGFRa (stable PDGF-B expression Ra kinases), little Mus BaF3-TEL-VEGFR2 (stable VEGF expression R2 kinases), mice TEL-FLT3-BaF3 (stably expressing FLT3 kinases), mice BaF3-FLT3-ITD-D835Y are (stable to express The activated protein kinase of FLT3/ITD D835Y mutation), mice BaF3-FLT3-ITD-F691L it is (steady Surely express the activated protein kinase of FLT3/ITD F691L mutation), mice TEL-c-KIT-BaF3 it is (steady Surely express cKIT kinases), mice TEL-c-KIT-N822K-BaF3 (stably express cKIT N882K mutation activated protein kinase), mice TEL-c-KIT-D816V-BaF3 (stably express cKIT D816V mutation activated protein kinase), mice TEL-c-KIT-T670I-BaF3 (stably express cKIT The activated protein kinase of T670I mutation), mice TPR-MET-BaF3 (stably express MET kinases), Mice TEL-ABL-BaF3 (stably expressing ABL kinases), mice TEL-ABL-T315I-BaF3 (stably expressing ABL T315I kinases), mice BaF3-p210 (stably express ABL p210 Kinases), mice TEL-ALK-BaF3 (stably express ALK kinases),.Above-mentioned cell strain is equal Built by this laboratory, construction method is：PCR expands the mankind FLT3/ITD, FLT3 respectively 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 it is inserted respectively into the MSCV-Puro carriers with N-terminal TEL or TPR fragment (Clontech), by retrovirus method, mice BaF3 cells are stably proceeded to, and is removed Except IL-3 somatomedin, finally give dependence 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 proceeds to the cell line of albumen.
In embodiment by variable concentrations (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137μM、0.0411μM、0.123μM、0.370μM、1.11μM、3.33μM、10 μM in DMSO) above-claimed cpd be added separately in above-mentioned cell, and it is little to be incubated 72 When, use CellThe cell viability detection of (Promega, the U.S.) chemistry self-luminous method Test kit, detects number of viable cells by carrying out quantitative determination to the ATP in living cells.It is real Test and the results are shown in Table 1.
The impact of 1 cell proliferation of table
Continued 1
Continued 1
Continued 1
Continued 1
Continued 1
Embodiment 112：Vitro inhibition activity (enzyme activity) detection
Compound 2-1, compound 2-2, compound 2-3, change are determined in enzyme activity experiment in vitro Compound 2-11, compound 2-12, compound 2-13, compound 2-14, compound 2-15, Compound 2-16, compound 2-32, compound 2-33, compound 2-34, compound 2-37 IC50 values to protein kinase FLT3, FLT3-ITD and cKIT.By protein kinase FLT3, The intracellular section regional cloning of FLT3-ITD and cKIT is in insect expression vector pAcG2T, sharp With insecticide expression system BaculoGoldTM Baculovirus Expression System(BD Pharmingen, the U.S.) protein expression is carried out, and carry GST or histag labels.By structure The carrier built up is transfected to SF9 packaging virus, with virus infection SF9 expressing proteins.
Take the 9 μ L of FLT3, FLT3-ITD and cKIT protein kinase (6ng/ μ L) of purification respectively (medicine is final concentration of within 4 hours with the 1 μ L room temperature reactions of above-claimed cpd of three times gradient dilution 10μM、3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM)；
Add 2 μ L ATP and 3 μ L substrates Poly (4:1Glu, Tyr) Peptide (Promega, The U.S.) (final concentration is respectively 10 μM and 0.2 μ g/ μ L), 37 DEG C are reacted 1 hour；
The reacted kinase solutions of 5 μ L are taken, 5 μ L ADP-Glo are addedTM(Promega, it is beautiful State) reagent room temperature reaction 40min to be terminating kinase reaction and run out of remaining ATP；
Add 10 μ L kinase assay reagents that ADP is changed into ATP, using the luciferin being coupled The ATP of enzyme/luciferin reaction detection newly synthesis, maps using after Envision readings, calculates IC50 Value (table 2).
Experimental result is as shown in table 2：The present invention above-mentioned example compound to FLT3, FLT3-ITD and cKIT protein kinases have strong inhibitory action.These results illustrate this Bright compound is the inhibitor of FLT3 kinases, while also having to FLT3-ITD and cKIT kinases Inhibitory action.
2 Enzyme activity assay result of table
Embodiment 113：Compound 2-1, compound 2-3 and compound 2-33 are in cell to FLT3 The impact of upstream and downstream signal path
In the human muscle creatine kinase for carrying FLT3 genes and/or FLT3-ITD mutated genes Cell MV-4-11 (expression FLT3-ITD mutated genes) cell strain, the acute myelogenous white blood of people Disease cell line MOLM-13 (expression FLT3-ITD mutated genes and wild type FLT3 genes) Cell strain and human muscle creatine kinase cell strain MOLM-14 (expression FLT3-ITD saltant types Gene and wild type FLT3 genes) in cell strain, by determining many cellular biochemistry terminals With feature terminal, compound 2-1, compound 2-3, compound 2-33 and controlization are tested Compound FLT3 kinase inhibitor AC220 (Hao Yuan Chemexpress companies are purchased from, on Sea) to the phosphorylation of the FLT3 and/or FLT3-ITD protein kinases in cell and its closely related Signal path downstream STAT5 protein phosphorylations impact and other related protein kinases The impact of ERK, AKT phosphorylation, at the same we also have detected PROTEIN C-Myc and transcription because The impact (Fig. 1) of sub- NF- κ B subunit p65 phosphorylations.With variable concentrations 0nM, 3nM, The compound of 10nM, 30nM, 100nM, 300nM, 1000nM (in DMSO) 2-1, compound 2-3 and 0 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM (in In DMSO) compound 2-33 and 0.1 μM (in DMSO) FLT3 kinase inhibition Agent AC220 processes the acute myeloid leukaemia for carrying FLT3 and/or FLT3-ITD genes respectively Cell MV-4-11, MOLM-13, MOLM-14 cell strain 4 hours, collects sample.Survey Determine FLT3, STAT5, C-Myc, ERK, NF- κ B p65, the AKT in compound on intracellular Deng the impact (Fig. 1) of protein phosphorylation.
Experimental result is as shown in Figure 1：In human muscle creatine kinase cell MV-4-11 (expression FLT3-ITD mutated genes) in cell strain, compound 2-1, compound 2-3 and compound 2-33 very strongly can suppress protein kinase FLT3 phosphorylation (its IC50 be less than 10 nM).Meanwhile, compound 2-1, compound 2-3 and compound 2-33 are to FLT3-ITD in cell The phosphorylation of downstream albumen STAT5 also has inhibitory action strongly, to protein kinase The phosphorylation of ERK has obvious inhibitory action.Additionally, compound 2-1, compound 2-3 and change PROTEIN C-the Myc closely related with FLT3 protein kinases of compound 2-33 pair has strong degraded to make With.In same experiment, control compound FLT3 kinase inhibitors AC220 can also be observed To same experimental phenomena.
In human muscle creatine kinase cell strain MOLM-13 (expression FLT3-ITD saltant type bases Because and wild type FLT3 genes) cell strain and human muscle creatine kinase cell strain MOLM-14 In (expression FLT3-ITD mutated genes and wild type FLT3 genes) cell strain, compound 2-1, compound 2-3 and compound 2-33 also can very strongly suppress protein kinase FLT3 Phosphorylation (its IC50 be less than 10nM).Compound 2-1, compound 2-3 and compound 2-33 The phosphorylation of FLT3-ITD downstreams albumen STAT5 in cell is equally also had strongly Inhibitory action.Additionally, compound 2-1, compound 2-3 and compound 2-33 are to protein kinase The phosphorylation of ERK has obvious inhibitory action, to the egg closely related with FLT3 protein kinases White C-Myc has strong Degradation.In same experiment, control compound FLT3 kinases Inhibitor AC 220 is also able to observe that same experimental phenomena.
Embodiment 113 shows that compound 2-1, compound 2-3 and compound 2-33 can not only be strong Suppress the phosphorylation of protein kinase FLT3, and the signal to protein kinase FLT3 in cell strongly The phosphorylation of passage downstream Protein S TAT5 has strong inhibitory action, to swashing with FLT3 albumen Closely related PROTEIN C-the Myc of enzyme has a strong Degradation, so suppress to carry FLT3 and/ Or the cell propagation of the acute myeloid leukemia cells in children strain of FLT3-ITD genes.
Embodiment 114：Compound 2-1 and compound 2-33 are on cell to apoptotic shadow Ring
In order to prove that the death of cell is, by apoptosis or necrosis, to carry FLT3 for medication later The human muscle creatine kinase cell MV-4-11 (tables of 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 mutated genes and wild type FLT3 genes) cell strain and the acute marrow of people Property leukemia cell line MOLM-14 (expression FLT3-ITD mutated genes and wild type FLT3 Gene) in cell strain, have detected compound 2-1, compound 2-33 in cell to cell Poly- adenosine diphosphate-ribose polymerase PARP of the closely related DNA repair enzymes of apoptosis, containing half Guang The impact of 3 protein cleavages of aspartic acid proteolytic enzyme Caspase of propylhomoserin.With variable concentrations 0 μM, 0.3 μM, the compound 2-1 of 1 μM, 3 μM (in DMSO) and 1 μM (in In DMSO) FLT3 kinase inhibitors AC220 process MOLM-13, MOLM-14 respectively And MV-4-11 cell strains, with 0 μM of variable concentrations, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, The FLT3 of the compound 2-33 of 3 μM (in DMSO) and 0.1 μM (in DMSO) Kinase inhibitor AC220 processes MOLM-14, MV-4-11 cell strain respectively, after 24 hours Collect cell.Detect that with Western Blot the medicine of variable concentrations is repaiied to DNA in different time sections Multiple poly- adenosine diphosphate-ribose polymerase PARP of enzyme and the aspartic acid albumen water containing cysteine The impact (Fig. 2) of the shear protein of solution enzyme Caspase 3.
Experimental result is as shown in Figure 2：For carrying FLT3 genes and/or FLT3-ITD saltant types Acute myeloid leukemia cells in children strain MOLM-13, MOLM-14 and MV-4-11 cell of gene Strain, when the Drug level of compound 2-1 is 0.3 μM, after effect 24 hours just it can be seen that The shearing of poly- adenosine diphosphate-ribose polymerase PARP of particularly apparent DNA repair enzymes, with And the shearing of the particularly apparent aspartic acid proteolytic enzyme Caspase 3 containing cysteine, together Can also be observed equally using 1 μM of control compound FLT3 kinase inhibitors AC220 sample Phenomenon.
For the acute myeloid leukaemia for carrying FLT3 genes and/or FLT3-ITD mutated genes Cell MOLM-14 and MV-4-11 cell strain, when the Drug level of compound 2-33 is 0.1 μM When, after effect 24 hours, it can be seen that the poly- adenosine diphosphate of particularly apparent DNA repair enzymes- The shearing of ribose polymerase PARP, can also see the aspartic acid Proteolytic enzyme containing cysteine The shearing of enzyme Caspase 3.Embodiment 114 demonstrates compound 2-1 and compound 2-33 can Cause the acute myeloid leukemia cells in children for carrying FLT3 genes and/or FLT3-ITD mutated genes Apoptosis.
Embodiment 115：The shadow of the compound 2-1 and compound 2-33 cell cycle on cell Ring
In order to study which growth cycle cell after medication is stopped in, carry FLT3 genes and / or FLT3-ITD mutated genes acute myeloid leukemia cells in children MOLM-14 and MV-4-11 Cell strain, tests the cell cycle point of compound 2-1 and compound 2-33 to these cell strains The impact of cloth.With the compound 2-1 of 0.5 μM, 1 μM (in DMSO) of variable concentrations And the FLT3 kinase inhibitor AC220 of 10nM (in DMSO) act on carrying FLT3 The acute myeloid leukemia cells in children MOLM-14 of gene and/or FLT3-ITD mutated genes and MV-4-11 cell strains, with 0 μM of variable concentrations, 0.01 μM, 0.03 μM, 0.1 μM, The compound 2-33 of 0.3 μM, 1 μM (in DMSO) and 0.1 μM (in DMSO) FLT3 kinase inhibitor AC220 act on only carry FLT3-ITD mutant genes acute marrow Property leukaemia's MV-4-11 cell strains in, effect 24 hours after, collect cell, 1XPBS Twice, 75% ethanol fixes 24 hours to buffer solution in -20 DEG C, and 1XPBS buffer is again Wash twice, plus the PI dyeing liquors of 0.5mL 1XPBS buffer and 0.5mL (are purchased from the U.S. BD Bioscience) in cell and cell is positioned over into 37 DEG C of dark lucifuge dyes 15 minutes, With flow cytometer (BD FACS Calibur) detection cell cycle distribution (Fig. 3).
Experimental result is as shown in Figure 3：Carrying the acute myelogenous white of FLT3/ITD mutated genes In disorders of blood cell strain MV-4-11 cell strains, as the drug level of compound 2-1 increases from 0 μM 1 μM is added to, the cell of the G0-G1 phases of capture also increases to 88.53% from 53.38%；Equally Experiment in, the stronger FLT3 kinase inhibitors AC220 of selectivity is captured in 10nM The cell of G0-G1 phases is 85.31%；And as the drug level of compound 2-33 increases from 0 μM 1 μM is added to, the cell of the G0-G1 phases of capture also increases to 91.93% from 57.57%；With real Test the G0-G1 that the stronger FLT3 kinase inhibitors AC220 of middle selectivity is captured at 0.1 μM The cell of phase is 88.66%.In expression FLT3-ITD mutated genes and wild type FLT3 bases In the acute myeloid leukemia cells in children MOLM-14 cell strains of cause, with the medicine of compound 2-1 Concentration increases to 1 μM from 0 μM, and the cell of the G0-G1 phases of capture also increases from 48.92% To 85.63%；And with the stronger FLT3 kinase inhibitor AC220 of selectivity in testing in 10nM When the cell of G0-G1 phases that captures be 87.29%；
Embodiment 115 demonstrates compound 2-1 and compound 2-33 and can will carry FLT3 genes And/or FLT3-ITD mutated genes acute myeloid leukemia cells in children MOLM-14 and MV-4-11 cell strains are prevented in the G0-G1 phases, and cell cycle is distributed with very strong shadow Ring (Fig. 3).

Claims (15)

1. the compound or its pharmaceutically acceptable salt of a kind of formula (I), solvate, isomer, Ester, acid, metabolite or prodrug, which has following structure：
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 haloalkyl；
R3It is selected from：
R4It is selected from
R5Selected from alkyl；Thiazolinyl；Alkynyl；Haloalkyl；Cycloalkyl；Aminoalkyl；Alkyl Aminoalkyl；Alkyl amino thiazolinyl；Heterocyclylalkyl, optionally by alkyl, alkyl-carbonyl, ring Alkyl-carbonyl, amino protecting group or hetero atom are optionally replaced by alkyl-substituted Heterocyclylalkyl； Cycloalkenyl group；Heteroaryl；Optionally by alkyl-substituted hetercycloalkylalkyl；Optionally by alkyl Substituted heteroaryl；Alkyl is optionally replaced by amino and nitrogen is optionally by amino protecting group replacement Aminoacyl alkyl；Alkyl optionally by amino replace and nitrogen optionally by amino protecting group replace and/or The aryl alkyl that aryl is optionally optionally substituted by a hydroxyl group；Alkyl is optionally replaced and nitrogen optionally quilt by amino The heteroaryl alkyl that amino protecting group replaces and/or heteroaryl is optionally optionally substituted by a hydroxyl group.
2. compound according to claim 1 or its pharmaceutically acceptable salt, solvate, Isomer, ester, acid, metabolite or prodrug, wherein amino protecting group are tertbutyloxycarbonyl, benzyl Oxygen carbonyl, 9-fluorenylmethyloxycarbonyl, benzyl or p-methoxyphenyl.
3. compound according to claim 1 or its pharmaceutically acceptable salt, solvate, Isomer, ester, acid, metabolite or prodrug, wherein Ar1And/or Ar2For phenyl.
4. compound according to claim 1 or its pharmaceutically acceptable salt, solvate, Isomer, ester, acid, metabolite or prodrug, wherein X are
5. compound according to claim 1 or its pharmaceutically acceptable salt, solvate, Isomer, ester, acid, metabolite or prodrug, wherein R1For hydrogen, and/or R2For trifluoromethyl.
6. compound according to claim 1 or its pharmaceutically acceptable salt, solvate, Isomer, ester, acid, metabolite or prodrug, wherein R3ForAnd R4For
Compound 7. according to any one of claim 1-6 or its pharmaceutically acceptable salt, Solvate, isomer, ester, acid, metabolite or prodrug, which is selected from following compound：
8. a kind of pharmaceutical composition, including the compound as any one of claim 1-7 Or its pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug, Pharmaceutically acceptable carrier or excipient, and other optional therapeutic agent.
9. the compound according to any one of claim 1-7 is being prepared for reducing or pressing down Tyrosine kinase FLT3, cKIT processed, ABL, EGFR, BMX, BLK, VEGFR, RET, Purposes in the medicine of PDGFR, MEK, BCR/ABL, JAK, BRAF activity.
10. the compound according to any one of claim 1-7 is being prepared for treating propagation Purposes in the medicine of sexually transmitted disease (STD) disease and/or FLT3, c-KIT associated conditions.
11. purposes according to claim 10, wherein the disease is swashed in response to FLT3 Enzyme or saltant type FLT3 kinase inhibition.
12. purposes according to claim 10, wherein the disease is in response to Kit kinases Suppress.
13. purposes according to claim 11, wherein the saltant type FLT3 kinases is FLT3/ITD is mutated type kinase.
14. purposes according to claim 10, wherein the proliferative disorders are selected from：It is good Property or malignant solid tumor, sarcoma, gastrointestinal stromal tumor, acute myeloblastic leukemia (AML), Chronic myelogenous leukemia (CML), to ABL and BCR/ABL tyrosine kinase activities suppress Have influential leukemia, B- cell lymphoms, lymphoma, diffusivity large B cell lymphoid tumor, Follicular lymphoma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, before B born of the same parents Lymphocytic leukemia, lymphoplasmacytic lymphoma/macroglobulinemia Waldenstron, Splenic marginal zone lymphoma, plasma cell myeloma, plasmocytoma, knot outer edge area B cell are drenched Bar tumor, lymphoma nodal marginal zone B cell, lymphoma mantle cell, the big B of mediastinum (thymus) Cell lymphoma, intravascular large B cell lymphoma, lymphoma primary effusion, Hugh Burkitt Lymphoma, leukemia, lymphomatoid granulomatosises, mesenchymoma, systemic mast cell disease, Hypereosinophilia syndrome (HES), fibre modifications, rheumatoid arthritiss, many passes Section inflammation, scleroderma, lupus erythematosus, graft versus host disease, neurofibroma, pulmonary hypertension, Breast ductal cancer, lobular carcinoma, adenocarcinoma, melanoma, B cell proliferative disease, the brain cancer, Renal carcinoma, hepatocarcinoma, adrenal carcinoma, bladder cancer, breast carcinoma, lymphatic cancer, gastric cancer, gastro-intestinal stromal Tumor, gastric tumor, esophageal carcinoma, ovarian cancer, colorectal cancer, carcinoma of prostate, cancer of pancreas, pulmonary carcinoma, Cancer of vagina, film adenocarcinoma, thyroid carcinoma, neck cancer, the cancer of CNS, glioblastoma, bone marrow Hypertrophy disease, glioblastoma, multiple myeloma, human primary gastrointestinal cancers, colorectal carcinoma, head and neck Tumor, cerebroma, epidermal hyper-proliferative, psoriasises, prostatic hyperplasia, the tumor shape of epithelial character Into, cancer of vagina, cervical cancer, carcinoma of endometrium, multiple myeloma, neck and head tumor, Alzheimer, spermocytoma, dysgerminoma, mast cell tumor, bronchogenic carcinoma, The formation of testis intraepithelial neoplasia, breast carcinoma, neuroblastoma, mamillary/follicular thyroid carcinoma, Malignant lymphoma, non-Hodgkin lymphoma, 2 type Multiple Endocrine neoplasia, pheochromocytoma, Parathyroid hyperplasia/adenoma, colon cancer, colorectal adenomas, malignant pleural mesothelioma, into blood Solencyte tumor, hemangioma, rectal cancer, neoplasia and other Hypertrophic or proliferative diseasees or Its combination.
15. purposes according to claim 10, wherein the FLT3 associated conditions are selected from： Leukemia, lymphoma, Hodgkin, myeloma, acute lymphoblastic leukemia, acute grain Chronic myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic grain Chronic myeloid leukemia, chronic neutrophilic chronic myeloid leukemia, acute undifferentiated cell leukemia, regression Developmental character macrocytic lymphoma, human adult T cell ALL, with three pedigree myelodysplasias AML, mixed type pedigree leukemia, myelodysplastic syndrome, myeloproliferative disorder, Multiple myeloma and spinal cord sarcoma, chronic lymphocytic leukemia, diffusivity large B cell drench Bar tumor, follicular lymphoma or chronic lymphocytic leukemia, lymphoma mantle cell, mediastinum (breast Gland) large B cell lymphoid tumor, intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma, and combinations thereof.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110833553A (en) * 2018-08-15 2020-02-25 广西梧州制药（集团）股份有限公司 Use of pyrazolopyrimidine derivatives for the treatment of Arthus response
CN112867493A (en) * 2018-10-16 2021-05-28 达纳-法伯癌症研究所有限公司 Azaindole inhibitors of wild type and mutant LRRK2

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030140A2 (en) * 2003-09-26 2005-04-07 Exelixis, Inc. C-met modulators and methods of use
WO2005073224A2 (en) * 2004-01-23 2005-08-11 Amgen Inc Quinoline quinazoline pyridine and pyrimidine counds and their use in the treatment of inflammation angiogenesis and cancer
CN101558055A (en) * 2007-03-14 2009-10-14 美国爱德程实验室有限公司 Spiro substituted compounds as angiogenesis inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030140A2 (en) * 2003-09-26 2005-04-07 Exelixis, Inc. C-met modulators and methods of use
WO2005073224A2 (en) * 2004-01-23 2005-08-11 Amgen Inc Quinoline quinazoline pyridine and pyrimidine counds and their use in the treatment of inflammation angiogenesis and cancer
CN101558055A (en) * 2007-03-14 2009-10-14 美国爱德程实验室有限公司 Spiro substituted compounds as angiogenesis inhibitors

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110833553A (en) * 2018-08-15 2020-02-25 广西梧州制药（集团）股份有限公司 Use of pyrazolopyrimidine derivatives for the treatment of Arthus response
CN112867493A (en) * 2018-10-16 2021-05-28 达纳-法伯癌症研究所有限公司 Azaindole inhibitors of wild type and mutant LRRK2

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