CN101300249A

CN101300249A - Aminoquinoline and aminoquinazoline kinase modulators

Info

Publication number: CN101300249A
Application number: CNA2006800289532A
Authority: CN
Inventors: N·拜因杜尔; M·D·高尔; K·D·克罗伊特尔; C·A·鲍曼; 徐国章; 金柱龙; 赵保平
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 2005-06-10
Filing date: 2006-06-07
Publication date: 2008-11-05
Also published as: ZA200800271B

Abstract

The invention is directed to aminoquinoline and aminoquinazoline compounds of Formula I: where R1, R2, R3, B, Z, Q, p, q and X are as defined herein, the use of such compounds as protein tyrosine kinase modulators, particularly inhibitors of FLT3 and/or TrkB, the use of such compounds to reduce or inhibit kinase activity of FLT3 and/or TrkB in a cell or a subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to FLT3 and/or TrkB. The present invention is further directed to pharmaceutical compositions comprising the compounds of the present invention and to methods for treating conditions such as cancers and other cell proliferative disorders.

Description

Quinolylamine and amido quinazoline kinase modulator

CROSS-REFERENCE TO RELATED APPLICATIONS

The right of priority of the U.S. Provisional Patent Application that the application requires to submit on June 10th, 2005 U.S. Provisional Patent Application is submitted to number on May 16th, 60/689,382 and 2006 number 60/747,321, all disclosures by reference and integral body is attached to herein.

Invention field

The present invention relates to new compound with protein tyrosine kinase conditioning agent function.More particularly, the present invention relates to new compound with FLT3 and/or TrkB inhibitor function.

Background of invention

The present invention relates to quinoline and quinazoline as tyrosine kinase inhibitor, Tyrosylprotein kinase comprises FLT3 and TrkB.It is reported that quinazoline has useful therapeutic property: U.S. Patent number 4,001, the quinazoline as cardiant has been set forth in 422 (DE 2530894) and 4,542,132 (EP 135318), U.S. Patent number 3,517,005 discloses the quinazoline with ypotension and bronchiectasis activity.The report that also has the cardiac stimulant quinazoline is referring to Chemical ﹠amp; Pharmaceutical Bulletin (1990), 38 (11), 3014-19.It is reported that quinoline has the effect that suppresses the FLT3 autophosphorylation, referring to PCT International Application No. WO 2004039782; With treatment amnesia and apoplexy, and multiple other illness, referring to U.S. Patent number 5,300,515 (EP497303) and 5,866,562; PCT International Application No. WO 2004/002960 and WO2002/088107.At WO2004058727 (3 of replacement, 5-dihydro-4H-imidazol-4-one treatment of obesity); WO 2000013681 (as the 4-quinoline methanol derivative of purinoceptor antagonist); DE 19756388 (US 6613772) (the 2-aryl-4-amino-quinazolines of replacement); JP59076082 (piperidine derivative); WO 1999031086 (quinoline piperazine and quinoline piperidine derivative and they are as the purposes of 5-HT1A, 5-HT1B and 5-HT1D mixing receptor antagonist); United States Patent (USP) 5948786 (piperidinyl pyrimidine tumor necrosis factor inhibitors); WO 1997038992 (piperidinyl pyrimidine derivatives that can be used for tumor necrosis factor inhibitors); Ivan, Marius G. etc., Photochemistry and Photobiology (2003), 78 (4), 416-419; Sadykov, T. etc., Khimiya Geterotsiklicheskikh Soedinenii (1985), (4), 563; Erzhanov, K.B. etc., Zhurnal Organicheskoi Khimii (1989), 25 (8), 1729-32; Fujiwara, Norio etc., Bioorganic ﹠amp; Medicinal Chemistry Letters (2000), 10 (12), 1317-1320; Takai, Haruki etc., Chemical ﹠amp; Pharmaceutical Bulletin (1986), 34 (5), 1907-16; WO 2002069972 ((triazolyl piperazinyl) isoquinoline 99.9 of treatment neurodegenerative disease, brain injury and cerebral ischemia); With among the GB 2295387 (as the quinazoline derivant of adrenergic 1C receptor antagonist) relevant report is arranged also.

Protein kinase is the enzyme element of signal transduction path, and under this kinase whose catalysis, the end phosphoric acid ester of ATP is converted into the hydroxyl of proteinic tyrosine, Serine and/or threonine residues.Therefore, the compound of arrestin kinase function is a valuable instrument of estimating protein kinase activated physiology result.The overexpression or express the problem that has become broad research irrelevantly in Mammals of normal or mutain kinases; and confirmed that this type of is expressed in multiple disease and plays an important role in taking place, these diseases comprise diabetes, vasculogenesis, psoriatic, restenosis, eye illness, schizophrenia, rheumatoid arthritis, atherosclerosis, cardiovascular disorder and cancer.Also have suppressing the research that kinases produces the cardiac stimulant benefit.In a word, kinases inhibitor especially has the effect of treatment humans and animals disease.

Trk family receptors Tyrosylprotein kinase TrkA, TrkB and TrkC are the frizzled receptors of the biological action of peptide hormone in the mediation neurotrophin family.This growth factor family comprises nerve growth factor (NGF), neurotrophic factor derived from brain (BDNF) and two kinds of neurotrophin (NT) NT-3 and NT-4.TrkB is as the acceptor of BDNF and NT-4.BDNF impels normal neurons part for example retina cell and neurogliocyte propagation, differentiation and survival.

Recently, report is (referring to Nature 2004 Aug 26; 430 (7003); 973-4; Claim that 1034-40) it is the effective and specific inhibitor of anchorage-independent cell death (anoikis) that TrkB activates.The survival of anchorage-independent cell makes tumour cell move by systemic circulation, grows in the far-end organ.This transfer process causes the cancer therapy failure usually, and is the reason of cancer mortality.Other research is (referring to Cancer Lett.2003 Apr 10; 193 (1): 109-14) also propose the necrocytosis that can stop cis-platinum to cause with BDNF antagonism TrkB.Be summarized in together, these results suggest, it is optimum and malignant proliferation disease, the especially valuable target of tumor disease of treatment that TrkB regulates.

Fms sample Tyrosylprotein kinase 3 (FLT3) part (FLT3L) is a kind of in the many hematopoietic cell lineages of the influence cytokine of growing.These effects combine generation by FLT3L with the FLT3 acceptor and the STK-1 that are called tire liver kinases-2 (flk-2) again, and STK-1 is the receptor tyrosine kinase (RTK) of expressing on hemopoietic stem cell and progenitor cell.FLT3 genes encoding film is in conjunction with RTK, and during normal plasma cell generated, film played an important role in cell proliferation, differentiation and apoptosis in conjunction with RTK.The FLT3 gene is mainly expressed by early stage marrow and lymph progenitor cell.Referring to McKenna, Hilary J. etc., Mice lacking flt3 ligand have deficienthematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells (lack the hemoposieis deficiency of the mouse of flt3 part, influence hematopoiesis progenitor cell, dendritic cell and natural killer cell) .Blood.Jun 2000; 95:3489-3497; Drexler, H.G.and H.Quentmeier (2004). " FLT3:receptor andligand. " (FLT3: acceptor and part) Growth Factors 22 (2): 71-3.

The part of FLT3 is by marrow stromal cell and other cell expressing, and collaborative other factors stimulated growth stem cell, progenitor cell, dendritic cell and proliferating natural killer cells.

Hematopoietic disorders is an illness before these system's cancerations, and comprise that for example myeloproliferative disorder, for example thrombocythemia, spy are sent out property thrombocythemia (ET), special property myeloid metaplasia, myelofibrosis (MF), myelofibrosis merge the preceding myelodysplastic syndrome of myeloid metaplasia (MMM), chronic idiopathic myelofibrosis (IMF) and polycythemia vera (PV), cytopenia and canceration.Referring to Stirewalt, D.L and J.P.Radich (2003). " The role of FLT3in haematopoietic malignancies. " (effect of FLT3 in leukemia) Nat RevCancer 3 (9): 650-65; Scheijen, B.and J.D.Griffin (2002). " Tyrosinekinase oncogenes in normal hematopoiesis and hematological disease. " (the Tyrosylprotein kinase oncogene in normal plasma cell generation and hemopathy) Oncogene 21 (21): 3314-33.

Leukemia is the formation of health blood and immunity system, marrow and adenoid cancer.Yet in normal bone marrow, FLT3 expresses and is limited to early stage progenitor cell; In leukemia, the expression level height of FLT3, or FLT3 sudden change to cause FLT3 acceptor and downstream molecules approach to bring out out of control, may activate Ras.Leukemia comprises leukemia, lymphoma (Fei Huoqijinshi lymphatic cancer), the acute lymphoblastic leukemia (ALL) of Hodgkin's disease (being called the Huo Qijin lymphatic cancer again) and myelomatosis-for example, acute myelocytic leukemia (AML), acute promyelocytic leukemia (APL), lymphocytic leukemia (CLL), chronic granulocytic leukemia (CML), chronic neutrophilic leukemia (CNL), acute nondifferentiated leukemia (AUL), retrogressive development large celllymphoma (ALCL), prolymphocytic leukemia (PML), teenager's myelomonocytic leukemia (JMML), adult T cell ALL, AML merges three pedigrees (trilineage) myelodysplasias (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), multiple myeloma (MM) and medullary sarcoma.Referring to Kottaridis, P.D., R.E.Gale etc., (2003). " Flt3 mutations andleukaemia. " (Flt3 sudden change and leukemia) Br J Haematol 122 (4): 523-38.Medullary sarcoma is also relevant with the FLT3 sudden change.Referring to Ansari-Lari, Ali etc., FLT3 mutations inmyeloid sarcoma. (FLT3 sudden change in the medullary sarcoma) British Journal ofHaematology.2004 Sep.126 (6): 785-91.

Record about 30% acute myelocytic leukemia patient and minority acute lymphoblastic leukemia or marrow the more unusual syndrome patient of hyperplasia FLT3 sudden change takes place.The patient of FLT3 sudden change has poor prognosis, alleviates the trend of number of times minimizing and fatal disease.The activated mutant type that two kinds of known FLT3 are arranged.A kind of is that 4-40 amino acid duplicates (ITD sudden change) (25-30% patient) in the nearly film territory of acceptor, and another kind is the point mutation (5-7% patient) in the kinases territory.The amino acid repetition of connecting on a small quantity produces tyrosine kinase activity in the most normal nearly film territory that relates to acceptor of this type of sudden change.The sudden change FLT3 acceptor of expressing in the mouse medullary cell causes the unusual syndrome of mortality bone marrow proliferation, preliminary study (Blood.2002; 100:1532-42) prompting, sudden change FLT3 unites other leukemia oncogene and produces more aggressive phenotype.

Be summarized in together, the specific inhibitor of the single kinases FLT3 of these results suggest can provide the attractive target of treatment hematopoietic disorders and leukemia.

FLT3 kinase inhibitor as known in the art comprises AG 1295 and AG 1296; Lestaurtinib (be called CEP 701 again, preceding title KT-5555, Kyowa Hakko, Cephalon is given in permission); CEP-5214 and CEP-7055 (Cephalon); CHIR-258 (ChironCorp.); EB-10 and IMC-EB 10 (ImClone Systems Inc.); GTP 14564 (MerkBiosciences UK); Midostaurin (being called PKC 412 Novartis AG again); MLN 608 (Millennium USA); MLN-518 (Millennium Pharmaceuticals Inc. is given in permission for preceding title CT53518, COR Therapeutics Inc.); MLN-608 (MillenniumPharmaceuticals Inc.); SU-11248 (Pfizer USA); SU-11657 (Pfizer USA); SU-5416 and SU 5614; THRX-165724 (Theravance Inc.); AMI-10706 (Theravance Inc.); VX-528 and VX-680 (Vertex Pharmaceuticals USA, Novartis (Switzerland), Merck ﹠amp are given in permission; Co USA); With XL 999 (ExelixisUSA).Following PCT international application and U.S. Patent Application Publication comprise other kinase modulator of the conditioning agent of FLT3: WO 2002032861, WO 2002092599, WO2003035009, WO 2003024931, WO 2003037347, WO 2003057690, WO 2003099771, WO 2004005281, WO 2004016597, WO 2004018419, WO 2004039782, WO 2004043389, WO2004046120, WO 2004058749, WO 2004058749, WO 2003024969 and Application No. 20040049032.

In addition referring to Levis, M., K.F.Tse etc., 2001 " A FL T3 tyrosine kinaseinhibitor is selectively cytotoxic to acute myeloid leukemia blastsharboring FLT3 internal tandem duplication mutations. " (the FLT3 tyrosine kinase inhibitor has selecting cell toxicity for the acute myelocytic leukemia protoblast that series connection in the potential FLT3 repeats to suddenly change) Blood 98 (3): 885-7; Tse KF etc., Inhibition ofFLT3-mediated trahsformation by use of a tyrosine kinase inhibitor. (suppressing the conversion of FLT3 mediation) Leukemia.2001 Jul by using tyrosine kinase inhibitor; 15 (7): 1001-10; Smith, B.Douglas etc., Single-agent CEP-701, a novelFLT3 inhibitor, shows biologic and clinical activity in patients withrelapsed or refractorY acute myeloid leukemia (the FLT3 inhibitor that single medicine CEP-701-is new, recurrent and intractable acute myelocytic leukemia patient are had biology and clinical activity) Blood, May 2004; 103:3669-3676; Griswold, Ian J. etc., Effects of ML N518, A Dual FLT3 and KIT Inhibitor, on Normal andMalignant Hematopoiesis. (a kind of FLT3 and KIT double inhibitor MLN518 are to the effect of normal and pernicious hemopoietic) Blood, Jul 2004; [Epub ahead of print]; Yee, Kevin W.H. etc., SU5416 and SU5614 inhibit kinase activity ofwild-type and mutant FLT3 receptor tyrosine kinase. (SU5416 and SU5614 suppress the kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase) Blood, Sep2002; 100:2941-294; O ' Farrell, Anne-Marie etc., SU11248 is a novelFLT3 tyrosine kinase inhibitor with potent activity in vitro and invivo. (SU11248 be new have in the body, the FLT3 tyrosine kinase inhibitor of external activity) Blood, May 2003; 101:3597-3605; Stone, R.M. etc., PKC 412 FLT3inhibitor therapy in AML:results of a phase II trial. (PKC 412 FLT3 inhibitor for treating AML:II phase test-results) Ann Hematol.2004; 83Suppl 1:S89-90; And Murata, K. etc., Selective cytotoxic mechanism of GTP-14564, a noveltyrosine kinase inhibitor in leukemia cells expressing a constitutivelyactive Fms-like tyrosine kinase 3 (FL T3). (the selecting cell toxic mechanism of the GTP-14564-new tyrosine kinase inhibitor in the leukemia cell who expresses constitutive activity Fms sample Tyrosylprotein kinase 3 (FLT3)) J Biol Chem.2003 Aug 29; 278 (35): 32892-8; Levis, Mark etc., Novel FLT3 tyrosine kinase inhibitors. (new FLT3 tyrosine kinase inhibitor) Expert Opin.Investing.Drugs (2003) 12 (12) 1951-1962; Levis, Mark etc., Small Molecule FLT3 Tyrosine KinaseInhibitors. (small molecules FLT3 tyrosine kinase inhibitor) Current PharmaceuticalDesign, 2004,10,1183-1193.

Summary of the invention

The invention provides new for the protein tyrosine kinase conditioning agent, the aminopyrimidine of FLT3 and/or TrkB inhibitor (formula I compound) especially; Purposes with FLT3 and/or TrkB kinase activity among this compounds minimizing or inhibition cell or the patient; Purposes with the prevention of this compounds or treatment patient's cell proliferative disorders and/or the illness relevant with FLT3 and/or TrkB.

An example of the present invention is the medicinal compositions that contains formula I compound and pharmaceutically acceptable carrier.Another example of the present invention is the medicinal compositions that is mixed with by with any formula I compound and pharmaceutically acceptable carrier.

According to following detailed description of the present invention and claim, other features and advantages of the present invention will be conspicuous.

Detailed Description Of The Invention

Definition

Following term used herein has following connotation (in this specification, can provide other definition if desired):

No matter separately or the term " thiazolinyl " that uses as a substituting group part " C for example _1-4Thiazolinyl (aryl) " be meant undersaturated side chain of the part with at least one carbon-to-carbon double bond or straight chain univalence hydrocarbyl; and wherein each removes a hydrogen atom two keys of deriving by two adjacent carbon atoms from the parent alkyl molecule, by remove a hydrogen atom this group of deriving from a carbon atom.Atom about two keys can be by being orientated along (Z) or anti-(E) conformation.Typical thiazolinyl includes but not limited to vinyl, propenyl, allyl group (2-propenyl), butenyl etc.Example comprises C _2-8Thiazolinyl or C _2-4Thiazolinyl.

Term " C _A-b" (wherein carbonatoms purpose integer is specified in a and b representative) is meant alkyl, thiazolinyl, alkynyl, alkoxyl group or cycloalkyl, or refers to the moieties of group, and wherein alkyl occurs as the prefix root that contains a-b carbon atom (comprising a and b).For example, C _1-4Representative contains the group of 1,2,3 or 4 carbon atom.

No matter separately or the term " alkyl " that uses as a substituting group part be meant saturated side chain or straight chain univalence hydrocarbyl, wherein by remove a hydrogen atom this group of deriving from a carbon atom.

(for example by using limited term for example " end carbon atom ") except as expressly stated, the substituting group variable can be positioned on any carbochain atom.Typical alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl etc.Example comprises C _1-8Alkyl, C _1-6Alkyl and C _1-4Alkyl.

Term " alkylamino " be meant by from alkylamine for example the nitrogen of butylamine remove the group that hydrogen atom forms, term " dialkyl amido " be meant by from secondary amine for example the nitrogen of dibutylamine remove the group that a hydrogen atom forms.In two kinds of situations, expectation is a nitrogen-atoms with the tie point of molecule rest part.

No matter be meant undersaturated side chain of the part with at least one carbon-to-carbon triple bond or straight chain univalence hydrocarbyl separately or as a part of term " alkynyl " that uses of substituting group, wherein each removes two hydrogen atoms triple bond of deriving by two adjacent carbon atoms from the parent alkyl molecule, by remove a hydrogen atom this group of deriving from a carbon atom.Typical alkynyl comprises ethynyl, proyl, butynyl etc.Example comprises C _2-8Alkynyl or C _2-4Alkynyl.

Term " alkoxyl group " is meant saturated or undersaturated side chain of part or straight chain monovalent hydrocarbon alcohol radical, removes hydrogen atom this group of deriving by the oxyhydroxide oxygen substituting group on parent alkane, alkene or alkynes.Wherein should have concrete saturation levels, the definition of usage and alkyl, thiazolinyl and the alkynyl of term " alkoxyl group ", " alkene oxygen base " and " alkynyloxy group " is identical.Example comprises C _1-8Alkoxyl group or C _1-4Alkoxyl group.

Term " alkoxyl group ether " is meant saturated side chain or straight chain monovalent hydrocarbon alcohol radical, removes hydrogen atom this group of deriving by oxyhydroxide oxygen substituting group from hydroxy ethers.Example comprises 1-hydroxyl-2-methoxyl group-ethane and 1-(2-hydroxyl-oxyethyl group)-2-methoxyl group-ethane group.

Term " aralkyl " is meant the C that contains aryl substituent _1-6Alkyl.Example comprises benzyl, styroyl or 2-menaphthyl.Should be alkyl with the tie point of molecule rest part.

Term " aromatics " is meant the cyclic hydrocarbon loop systems with unsaturated conjugated πDian Zi system.

Term " aryl " is meant by remove a hydrogen atom deutero-aromatic ring hydrocarbon cyclic base group from a carbon atom of loop systems.Typical aryl comprises phenyl, naphthyl, fluorenyl, indenyl, camomile cyclic group, anthryl etc.

Term " arylamino " is meant by the aryl amino that replaces of phenyl ammonia for example for example.The tie point of expectation and molecule rest part should pass through nitrogen-atoms.

Term " benzo-fused cycloalkyl " is meant bicyclic condensed loop systems group, and one of them ring is a phenyl, and another ring is cycloalkyl or cyclenes basic ring.Typical benzo-fused cycloalkyl comprises indanyl, 1,2,3,4-tetralin base, 6,7,8,9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl, 5,6,7,8,9,10-six hydrogen-benzo cyclooctene base etc.Benzo-fused cycloalkyl ring system is the subclass of aryl.

Term " benzo-fused heteroaryl " is meant bicyclic condensed loop systems group, and wherein a ring in the system is a phenyl, and another is a hetero-aromatic ring.Typical benzo-fused heteroaryl comprises indyl, indolinyl, pseudoindoyl, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, 2 base, quinazolyl etc.Benzo-fused hetero-aromatic ring is the subclass of heteroaryl.

Term " benzo-fused heterocycle base " is meant bicyclic condensed loop systems group, and wherein a ring in the system is a phenyl, and another is a heterocyclic ring.Typical benzo-fused heterocycle group comprises 1,3-benzo dioxolyl (is called 1 again, the 3-methylenedioxyphenyl), 2,3-dihydro-1,4-benzo dioxine base (being called 1 again, 4-ethylenedioxy phenyl), benzo-dihydrofuran base, benzo-THP trtrahydropyranyl, benzo-dihydro-thiophene base etc.

Term " carboxyalkyl " is meant for example tert-butoxycarbonyl of alkanisation carboxyl, and wherein the tie point with the molecule rest part is a carbonyl.

Term " the assorted diketo of ring " is meant the heterogeneous ring compound with two carbonyl substituted bases.Example comprises thiazolidyl diketone, oxazolidinyl diketone and pyrrolidyl diketone.

Term " cycloalkenyl group " is meant that this hydrocarbon loop systems contains at least one carbon-to-carbon double bond by removing a undersaturated cycloalkyl of hydrogen atom deutero-part in the dealkylation loop systems.Example comprises cyclohexenyl, cyclopentenyl and 1,2,5,6-cyclooctadiene base.

Term " cycloalkyl " is meant by removing a hydrogen atom deutero-saturated or undersaturated monocycle of part or the dicyclic hydrocarbon cyclic group on the ring carbon atom.Typical cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, suberyl and ring octyl group.Other example comprises C _3-8Cycloalkyl, C _5-8Cycloalkyl, C _3-12Cycloalkyl, C _3-20Cycloalkyl, naphthane base and 2,3,4,5,6,7-six hydrogen-1H-indenyl.

Term " condensed ring system " is meant that wherein two adjacent atoms are present in two loop sections the bicyclic molecule of each.Can choose wantonly and have heteroatoms.Example comprises benzothiazole, 1,3-benzo dioxole and naphthane.

" mix " as the term of loop systems prefix and to be meant that at least one ring carbon atom is with the one or more atomic substitutions that independently are selected from N, S, O or P.Example comprises that wherein 1,2,3 or 4 ring members is a nitrogen-atoms; Or 0,1,2 or 3 ring members is nitrogen-atoms and 1 ring that the member is oxygen or sulphur atom.

Term " heteroaralkyl " is meant and contains the substituent C of heteroaryl _1-6Alkyl.Example comprises furyl methyl and pyridyl propyl group.Should be alkyl with the tie point of molecule rest part.

Term " heteroaryl " is meant by removing a hydrogen atom deutero-group on the ring carbon atom in the heteroaromatic ring system.Typical heteroaryl comprises furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolizine base, indyl, pseudoindoyl, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzimidazolyl-, benzothiazolyl, purine radicals, 4H-quinolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalzinyl, quinazolyl, quinoxalinyl, 1,8-phthalazinyl, pteridyl etc.

Term " heteroaryl-fused rings alkyl " is meant bicyclic condensed loop systems group, and one of them ring is a cycloalkyl, and another ring is a heteroaryl.Typical heteroaryl-fused rings alkyl comprises 5,6,7,8-tetrahydrochysene-4H-cyclohepta (b) thienyl, 5,6, oneself (cyclohexa) (b) thienyl, 5 also of 7-three hydrogen-4H-virtue, 6-dihydro-4H-cyclopenta (b) thienyl etc.

Term " heterocyclic radical " is meant by removing the saturated or undersaturated monocycle cyclic group of part of a hydrogen atom deutero-on carbon or the azo-cycle atom.Typical heterocyclic radical comprises 2H-pyrryl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidyl, 1,3-dioxolanyl, 2-imidazolinyl (are called 4 again, 5-dihydro-1H-imidazolyl), imidazolidyl, 2-pyrazolinyl, pyrazolidyl, tetrazyl, piperidyl, 1,4-alkyl dioxin, morpholinyl, 1,4-dithiane base, thio-morpholinyl, piperazinyl, azepan base, six hydrogen-1, the 4-diaza Base etc.

Term " square acyl group (squaryl) " is meant cyclobutene base-1,2-diketone group.

Term " replacement " is meant that wherein one or more hydrogen atoms are by one or more functional moieties metathetical parent nucleus molecules.Replacement is not limited to the parent nucleus molecule, also can occur on the substituting group, so this substituting group becomes linking group.

Term " independently is selected from " and is meant and is selected from one group of substituent one or more substituting group, and wherein these substituting groups can be identical or different.

The substituting group name of using during the present invention is open obtains by the following method: describes atom earlier, describes the linking group atom from left to right along the direction of end chain atom then with tie point, as follows basically:

(C _1-6) alkyl C (O) NH (C _1-6) alkyl (Ph)

Or, along the direction of atom the linking group atom is described then with tie point by describing the end chain atom earlier, as follows basically:

Ph (C _1-6) alkyl amido (C _1-6) alkyl

Wherein any all refers to the following formula group:

Introduce line the loop systems from substituting group and represent the key that can be connected with any suitable annular atoms.

At any variable (R for example ₄) when appearance was once above in any formula I embodiment, each definition should be independent.

In this article, by their opening, indefiniteness connotation use that term " comprises ", " comprising " and " containing ".

Name

Unless otherwise indicated, by standard I UPAC nomenclature reference Nomenclature of Organic Chemistry for example, Sections A, B, C, D, E, F and H, (Pergamon Press, Oxford, 1979, Copyright 1979 IUPAC) and A Guide toIUPAC Nomenclature of Organic Compounds (recommending 1993), (BlackwellScientific Publications, 1993, Copyright 1993 IUPAC); Or the commercial software bag Autonom (ChemDraw that CambridgeSoft.com sells for example The name software trade mark that provides in the office software); With ACD/Index Name ^TM(Advanced ChemistryDevelopment, Inc., Toronto, the business name software trade mark that Ontario sells) obtains the compound title with naming rule well known in the art.

Abbreviation

Following abbreviation used herein should have following connotation (in this specification, also providing other abbreviation if desired):

The Boc tert-butoxycarbonyl

The DCM methylene dichloride

The DMF dimethyl formamide

The DMSO dimethyl sulfoxide (DMSO)

The DIEA diisopropylethylamine

The EDTA ethylenediamine tetraacetic acid (EDTA)

EDC hydrochloric acid 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide

The EtOAc ethyl acetate

HOBT I-hydroxybenzotriazole hydrate

HBTU O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea

Hexafluorophosphate

The i-PrOH Virahol

LC/MS (ESI) liquid chromatography/mass spectrometry (electro-spray ionization)

MeOH methyl alcohol

The NMM N-methylmorpholine

The NMR nucleus magnetic resonance

The PS polystyrene

The RT room temperature

NaHMDS hexamethyldisilane yl amino sodium

The TEA triethylamine

The TFA trifluoroacetic acid

The THF tetrahydrofuran (THF)

The TLC thin-layer chromatography

Formula I

The present invention includes formula I compound and N-oxide compound, pharmacy acceptable salt and three-dimensional chemical isomer:

Formula I

Wherein:

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or straight key;

X is N or C-CN or CH, and condition is R _BbBe not heteroaryl or halogen;

Z is NH, N (alkyl) or CH ₂

B is selected from: (wherein said cycloalkyl is preferably the pentamethylene base to cycloalkyl, cyclohexyl, cyclopentenyl or cyclohexenyl), (wherein said 9 yuan of-10 yuan of benzo-fused heteroaryls are preferably benzothiazolyl benzoxazolyl to 9 yuan of-10 yuan of benzo-fused heteroaryls, benzimidazolyl-, benzofuryl, indyl, quinolyl, isoquinolyl or benzo [b] thienyl), or 9 yuan of-10 yuan of benzo-fused heterocycle bases (wherein said 9 yuan of-10 yuan of benzo-fused heterocycle bases are preferably 2,3-dihydro-benzothiazolyl, 2,3-dihydro-benzoxazolyls, 2,3-dihydro-benzimidazolyl-, 1,2,3,4-tetrahydrochysene-quinolyl, 1,2,3,4-tetrahydrochysene-isoquinolyl, the isochroman base, 2, the 3-dihydro-indolyl, 2,3-dihydro-benzofuryl or 2,3-dihydro-benzo [b] thienyl, most preferably 2, the 3-dihydro-indolyl, 2,3-dihydro-benzofuryl or 2,3-dihydro-benzo [b] thienyl), if or have a R ₃Then be selected from phenyl or heteroaryl, condition is that B is not the thiadiazine base, (wherein said heteroaryl is preferably pyrryl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiapyran base, pyridyl, pyrimidyl, pyrazinyl, pyridyl-N-oxide compound or pyrryl-N-oxide compound, and most preferably pyrryl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl or pyrazinyl);

R ₁And R ₂Independently be selected from following group:

Wherein n is 1,2,3 or 4;

Y is straight key, O, S, NH or N (alkyl);

R _aBe alkoxyl group, phenoxy group, optional by R ₅The heteroaryl (wherein said heteroaryl is preferably pyrryl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiapyran base, pyridyl, pyrimidyl, triazolyl, pyrazinyl, pyridyl-N-oxide compound or pyrryl-N-oxide compound, most preferably pyrryl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, triazolyl or pyrazinyl) that replaces, hydroxyl, alkylamino, dialkyl amido, optional by R ₅The oxazolidine ketone group that replaces, optional by R ₅The pyrrolidone-base that replaces, optional by R ₅The piperidone base that replaces, optional by R ₅The assorted diketo of the ring that replaces, optional by R ₅The heterocyclic radical (wherein said heterocyclic radical is preferably pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, imidazolidyl, thiazolidyl, oxazolidinyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, thio-morpholinyl, thio-morpholinyl 1,1-dioxide, morpholinyl or piperazinyl) that replaces, square acyl group ,-COOR _y,-CONR _wR _x,-N (R _w) CON (R _y) (R _x) ,-N (R _y) CON (R _w) (R _x) ,-N (R _w) C (O) OR _x,-N (R _w) COR _y,-SR _y,-SOR _y,-SO ₂R _y,-NR _wSO ₂R _y,-NR _wSO ₂R _x,-SO ₃R _y,-OSO ₂NR _wR _xOr-SO ₂NR _wR _x

R _BbBe hydrogen, halogen, alkoxyl group, phenyl, (wherein said heteroaryl is preferably pyrryl to heteroaryl, furyl, thienyl, imidazolyl, thiazolyl oxazolyl, pyranyl, the thiapyran base, pyridyl, pyrimidyl, triazolyl, pyrazinyl, pyridyl-N-oxide compound or pyrryl-N-oxide compound, pyrryl most preferably, furyl, thienyl, imidazolyl, thiazolyl oxazolyl, pyridyl, pyrimidyl, triazolyl or pyrazinyl) or heterocyclic radical (wherein said heterocyclic radical is preferably pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, imidazolidyl, thiazolidyl oxazolidinyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, thio-morpholinyl, thio-morpholinyl 1, the 1-dioxide, morpholinyl or piperazinyl);

R ₅For independently being selected from 1,2 or 3 following substituting group: halogen, cyano group, trifluoromethyl, amino, hydroxyl, alkoxyl group ,-C (O) alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl ,-C ( _1-4) alkyl-OH or alkylamino;

R _wAnd R _xIndependently be selected from following group: (heteroaryl moieties of wherein said heteroaralkyl is preferably pyrryl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiapyran base, pyridyl, pyrimidyl, pyrazinyl, pyridyl-N-oxide compound or pyrryl-N-oxide compound for hydrogen, alkyl, thiazolinyl, aralkyl (aryl moiety of wherein said aralkyl is preferably phenyl) or heteroaralkyl, most preferably pyrryl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl or pyrazinyl), or R _wAnd R _xCan choose wantonly and be combined together to form 5 yuan of-7 yuan of rings, optional containing is selected from following hetero moiety (heteromoiety): O, NH, N (alkyl), SO, SO ₂Or S, be preferably selected from:

R _yBe selected from hydrogen, alkyl, thiazolinyl, cycloalkyl (wherein said cycloalkyl is preferably pentamethylene base or cyclohexyl), phenyl, aralkyl (aryl moiety of wherein said aralkyl is preferably phenyl), (heteroaryl moieties of wherein said heteroaralkyl is preferably pyrryl to heteroaralkyl, furyl, thienyl, imidazolyl, thiazolyl oxazolyl, pyranyl, the thiapyran base, pyridyl, pyrimidyl, pyrazinyl, pyridyl-N-oxide compound or pyrryl-N-oxide compound, pyrryl most preferably, furyl, thienyl, imidazolyl, thiazolyl oxazolyl, pyridyl, pyrimidyl or pyrazinyl) or heteroaryl (wherein said heteroaryl is preferably pyrryl, furyl, thienyl, imidazolyl, thiazolyl oxazolyl, pyranyl, the thiapyran base, pyridyl, pyrimidyl, pyrazinyl, pyridyl-N-oxide compound or pyrryl-N-oxide compound, most preferably pyrryl, furyl, thienyl, imidazolyl, thiazolyl oxazolyl, pyridyl, pyrimidyl or pyrazinyl); And

R ₃Be the optional one or more substituting groups that exist, and described substituting group independently is selected from following group: alkyl, alkoxyl group, halogen, nitro, optional by R ₄The cycloalkyl (wherein said cycloalkyl is preferably pentamethylene base or cyclohexyl) that replaces, optional by R ₄The heteroaryl (wherein said heteroaryl is preferably pyrryl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiapyran base, pyridyl, pyrimidyl, triazolyl, pyrazinyl, pyridyl-N-oxide compound or pyrryl-N-oxide compound, most preferably pyrryl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, triazolyl or pyrazinyl) that replaces, alkylamino, optional by R ₄The heterocyclic radical (wherein said heterocyclic radical is preferably azepine base (azepenyl), pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, imidazolidyl, thiazolidyl, oxazolidinyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, thio-morpholinyl, morpholinyl or piperazinyl tetrahydro pyridyl, tetrahydrochysene pyrazinyl, dihydrofuran base, Er Qing oxazinyl, pyrrolin base or glyoxalidine base) that replaces, alkoxyl group ether ,-O (cycloalkyl), optional by R ₄The pyrrolidone-base that replaces, optional by R ₄The phenoxy group that replaces ,-CN ,-OCHF ₂,-OCF ₃,-CF ₃, haloalkyl, optional by R ₄The heteroaryloxy that replaces, dialkyl amido ,-NHSO ₂Alkyl or-SO ₂Alkyl; R wherein ₄Independently be selected from following group: halogen, cyano group, trifluoromethyl, amino, hydroxyl, alkoxyl group ,-C (O) alkyl ,-CO ₂Alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or alkylamino.

Hereinafter the term of Shi Yonging " formula I compound " will also comprise its N-oxide compound, pharmacy acceptable salt and three-dimensional chemical isomer.

The embodiment of formula I

In one embodiment of the invention: the N-oxide compound is optional be present in one of following atom and a plurality of on: N-1 or N-3 (when X is N) (referring to Fig. 1 of following ring numbering).

Fig. 1

Fig. 1 explanation is used for the annular atoms of the numbering 1-8 of this specification sheets.

Preferred embodiment of the present invention is a formula I compound, wherein has one or more following restricted conditions:

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or straight key;

X is N or C-CN or CH, and condition is R _BbBe not heteroaryl or halogen;

Z is NH, N (alkyl) or CH ₂

B is selected from: 9 yuan of-10 yuan of benzo-fused heteroaryls, if or have a R ₃, then being selected from phenyl or heteroaryl, condition is that B is not the thiadiazine base;

R ₁And R ₂Independently be selected from following group:

Wherein n is 1,2,3 or 4;

Y is straight key, O, S, NH or N (alkyl);

R _aBe alkoxyl group, phenoxy group, optional by R ₅The heteroaryl that replaces, hydroxyl, alkylamino, dialkyl amido, optional by R ₅The oxazolidine ketone group that replaces, optional by R ₅The pyrrolidone-base that replaces, optional by R ₅The piperidone base that replaces, optional by R ₅The assorted diketo of the ring that replaces, optional by R ₅The heterocyclic radical that replaces, square acyl group ,-COOR _y,-CONR _wR _x,-N (R _w) CON (R _y) (R _x) ,-N (R _y) CON (R _w) (R _x) ,-N (R _w) C (O) OR _x,-N (R _w) COR _y,-SR _y,-SOR _y,-SO ₂R _y,-NR _wSO ₂R _y,-NR _wSO ₂R _x,-SO ₃R _y,-OSO ₂NR _wR _xOr-SO ₂NR _wR _x

R _BbBe hydrogen, halogen, alkoxyl group, phenyl, heteroaryl or heterocyclic radical;

R _wAnd R _xIndependently be selected from following group: hydrogen, alkyl, thiazolinyl, aralkyl or heteroaralkyl, or R _wAnd R _xCan choose wantonly and be combined together to form 5 yuan of-7 yuan of rings, described ring is chosen wantonly to contain and is selected from following hetero moiety: O, NH, N (alkyl), SO, SO ₂Or S;

R _yBe selected from: hydrogen, alkyl, thiazolinyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl or heteroaryl; With

R ₃For independently being selected from following one or more substituting groups: alkyl, alkoxyl group, halogen, nitro, optional by R ₄The cycloalkyl that replaces, optional by R ₄The heteroaryl that replaces, alkylamino, optional by R ₄The heterocyclic radical that replaces, alkoxyl group ether ,-O (cycloalkyl), optional by R ₄The pyrrolidone-base that replaces, optional by R ₄The phenoxy group that replaces ,-CN ,-OCHF ₂,-OCF ₃,-CF ₃, haloalkyl, optional by R ₄The heteroaryloxy that replaces, dialkyl amido ,-NHSO ₂Alkyl or-SO ₂Alkyl; R wherein ₄Independently be selected from following group: halogen, cyano group, trifluoromethyl, amino, hydroxyl, alkoxyl group ,-C (O) alkyl ,-CO ₂Alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or alkylamino.

Other preferred embodiment of the present invention is a formula I compound, wherein has one or more following restricted conditions:

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or straight key;

X is N or C-CN or CH, and condition is R _BbBe not heteroaryl or halogen;

Z is NH, N (alkyl) or CH ₂

B is selected from: phenyl or heteroaryl, condition are that B is not the thiadiazine base;

R ₁And R ₂Independently be selected from following group:

Wherein n is 1,2,3 or 4;

Y is straight key, O, S, NH or N (alkyl);

R _yBe selected from: hydrogen, alkyl, thiazolinyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl or heteroaryl; And

R ₃For independently being selected from following one or more substituting groups: alkyl, alkoxyl group, halogen, optional by R ₄The cycloalkyl that replaces, optional by R ₄The heteroaryl that replaces, alkylamino, optional by R ₄The heterocyclic radical that replaces, alkoxyl group ether ,-O (cycloalkyl), optional by R ₄The phenoxy group or the dialkyl amido that replace; R wherein ₄Independently be selected from following group: halogen, cyano group, trifluoromethyl, amino, hydroxyl, alkoxyl group ,-C (O) alkyl ,-CO ₂Alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or alkylamino.

Also other preferred embodiment of the present invention is a formula I compound, wherein has one or more following restricted conditions:

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or straight key;

X is N or C-CN or CH, and condition is R _BbBe not heteroaryl or halogen;

Z is NH, N (alkyl) or CH ₂

R ₁And R ₂Independently be selected from following group:

Wherein n is 1,2,3 or 4;

Y is straight key, O, NH or N (alkyl);

R _aBe alkoxyl group, optional by R ₅The heteroaryl that replaces, hydroxyl, alkylamino, dialkyl amido, optional by R ₅The oxazolidine ketone group that replaces, optional by R ₅The pyrrolidone-base that replaces, optional by R ₅The piperidone base that replaces, optional by R ₅The heterocyclic radical that replaces ,-CONR _wR _x,-N (R _y) CON (R _w) (R _x) ,-N (R _w) COR _y,-SR _y,-SOR _y,-SO ₂R _yOr-NR _wSO ₂R _y

R _BbBe hydrogen, halogen or alkoxyl group;

Especially preferred embodiment of the present invention is a formula I compound, wherein has one or more following restricted conditions:

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or straight key;

Z is NH or CH ₂

X is N or C-CN or CH, and condition is R _BbBe not heteroaryl or halogen;

R ₁And R ₂Independently be selected from following group:

Wherein n is 1,2 or 3;

Y is O;

R _aBe alkoxyl group, hydroxyl, optional by R ₅The heteroaryl that replaces, alkylamino, dialkyl amido, optional by R ₅The pyrrolidone-base that replaces, optional by R ₅The heterocyclic radical that replaces ,-CONR _wR _x,-N (R _y) CON (R _w) (R _x) ,-SO ₂R _yOr-NR _wSO ₂R _y

R _BbBe hydrogen, halogen or alkoxyl group;

R ₅Be one independently be selected from following substituting group :-C (O) alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or-C ( _1-4) alkyl-OH;

R ₃Be one and be selected from following substituting group: alkyl, alkoxyl group, cycloalkyl, heterocyclic radical ,-O (cycloalkyl), phenoxy group or dialkyl amido.

The most especially preferred embodiment of the present invention is a formula I compound, wherein has one or more following restricted conditions:

Q is 1 or 2;

P is 0 or 1;

Q is NH, O or straight key;

X is N;

Z is NH;

B is selected from: phenyl and pyridyl;

R ₁And R ₂Independently be selected from following group:

Wherein n is 1,2 or 3;

Y is O;

R _aBe alkoxyl group, hydroxyl, alkylamino, dialkyl amido, optional by R ₅The pyrrolidone-base that replaces, optional by R ₅The heterocyclic radical that replaces or-NR _wSO ₂R _y

R _BbBe hydrogen or alkoxyl group;

R ₃Be one and be selected from following substituting group: alkyl, alkoxyl group, heterocyclic radical ,-O (cycloalkyl) or dialkyl amido.

Preferred embodiment of the present invention also comprises formula I compound, wherein has one or more following restricted conditions:

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or straight key;

X is N or C-CN or CH, and condition is R _BbBe not heteroaryl or halogen;

Z is NH, N (alkyl) or CH ₂

B is selected from: 9 yuan of-10 yuan of benzo-fused heteroaryls; If or have a R ₃, then being selected from phenyl or heteroaryl, condition is that B is not the thiadiazine base;

R ₁And R ₂In one be H, another independently is selected from following group:

Wherein n is 1,2,3 or 4;

Y is straight key, O, S, NH or N (alkyl);

Other embodiment preferred of the present invention also comprises formula I compound, wherein has one or more following restricted conditions:

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or straight key;

X is N or C-CN or CH, and condition is R _BbBe not heteroaryl or halogen;

Z is NH, N (alkyl) or CH ₂

Wherein n is 1,2,3 or 4;

Y is straight key, O, S, NH or N (alkyl);

Also other preferred embodiment of the present invention also comprise formula I compound, wherein have one or more following restricted conditions:

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or straight key;

X is N or C-CN or CH, and condition is R _BbBe not heteroaryl or halogen;

Z is NH, N (alkyl) or CH ₂

Wherein n is 1,2,3 or 4;

Y is straight key, O, NH or N (alkyl);

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or straight key;

Z is NH or CH ₂

X is N or C-CN or CH, and condition is R _BbBe not heteroaryl or halogen;

Wherein n is 1,2 or 3;

Y is O;

The most especially preferred embodiment of the present invention also comprises formula I compound, wherein has one or more following restricted conditions:

Q is 1 or 2;

P is 0 or 1;

Q is NH, O or straight key;

X is N;

Z is NH;

B is selected from: phenyl and pyridyl;

Wherein n is 1,2 or 3;

Y is O;

Pharmacy acceptable salt

Also can there be the pharmacy acceptable salt form in The compounds of this invention.

For medicinal, the salt of The compounds of this invention is meant nontoxic " pharmacy acceptable salt ".The pharmacy acceptable salt form of FDA approval is (referring to International J.Pharm.1986,33,201-217; J.Pharm.Sci, 1977, Jan, 66 (1), p1) comprise pharmaceutically acceptable acidity/negatively charged ion or basic/cationic salts.

Pharmaceutically acceptable acidity/anion salt includes but not limited to acetate, benzene sulfonate, benzoate, supercarbonate, bitartrate, bromide, Ca-EDTA, camsilate, carbonate, muriate, Citrate trianion, dihydrochloride, edetate, ethanedisulphonate, estolate, esilate, fumarate, glyceptate, gluconate, glutaminate, bismuth glycolyl arsanilate salt, Sucrets salt, Hydrabamine Peniccilin G (hydrabamine), hydrobromate, hydrochloride, Hydroxynaphthoate, iodide, isethionate, lactic acid salt, Lactobionate, malate, maleate, mandelate, mesylate, MB, methyl nitrate, Methylsulfate, mucate, naphthalenesulfonate, nitrate, pamoate, pantothenate, phosphoric acid salt/diphosphate, Polygalacturonate, salicylate, stearate, subacetate, succinate, vitriol, tannate, tartrate, the teoclate, tosylate and triethyl iodate thing (triethiodide).Organic or inorganic acid also includes but not limited to hydroiodic acid HI, perchloric acid, sulfuric acid, phosphoric acid, propionic acid, oxyacetic acid (glycolic), methylsulfonic acid, isethionic acid, oxalic acid, 2-naphthene sulfonic acid, tosic acid, cyclohexane sulfamic acid, saccharinic acid or trifluoroacetic acid.

Pharmaceutically acceptable basic/cationic salts includes but not limited to aluminium, 2-amino-2-hydroxymethyl-the third-1,3-glycol (being called three (methylol) aminomethane, Tutofusin tris (tromethane) or " TRIS " again), ammonia, Benzathini Benzylpenicilinum, TERTIARY BUTYL AMINE, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, Choline Bicarbonate, choline chloride 60, hexahydroaniline, diethanolamine, quadrol, lithium, LiOMe, L-Methionin, magnesium, meglumine, NH ₃, NH ₄The salt of OH, N-methyl D-glycosamine, piperidines, potassium, potassium tert.-butoxide, potassium hydroxide (aqueous solution), PROCAINE HCL, PHARMA GRADE, quinine, sodium, yellow soda ash, 2 ethyl hexanoic acid sodium (SEH), sodium hydroxide, trolamine (TEA) or zinc.

Prodrug

The present invention comprises the prodrug of The compounds of this invention in its scope.Generally speaking, this type of prodrug is the functional group derivant of these compounds, and they are easy to be converted into active compound in vivo.Therefore, in methods of treatment of the present invention, term " administration " or " giving " should comprise with concrete disclosed compound or compound, or the method for its prodrug treatment, alleviation or prevention described herein syndrome, illness or disease, although clearly do not disclose some The compounds of this invention, obviously they are included in the scope of the invention.The ordinary method of selecting and preparing suitable prodrug derivant is at for example " Design of Prodrugs ", ed.H.Bundgaard, and Elsevier has description in 1985.

Three-dimensional chemical isomer

Those of skill in the art will recognize that formula I compound can have one and a plurality of unsymmetrical carbons in their structure.Wherein there is enantiomeric excess in the present invention at the mixture that its scope planted agent comprises single enantiomer, racemic mixture and the enantiomorph of these compounds.

Term used herein " single enantiomer " is defined as all possible homochiral form that formula I compound and N-oxide compound, additive salt, quaternary amine or physiological functional deriv may have.

Can obtain stereochemistry pure isomer form by the technology of using known principle.Can separate diastereomer by physical separation method for example fractional crystallization and chromatographic technique, can be by optionally making the diastereoisomeric salt crystallization with opticity acid or alkali, or enantiomorph is separated from each other by the chirality chromatography.Also can be by by the pure raw material of suitable stereochemistry or use stereospecific reaction, the synthetic pure stereoisomers for preparing.

Term " isomer " is meant to have same composition with molecular weight but the different compound of physics and/or chemical property.This type of material has the atom of similar number and kind but structure is different.Textural difference can be because of forming (geometrical isomer) or making due to the ability (enantiomorph) of polarized light flat rotation.

Term " steric isomer " is meant the isomer of the same composition that the atom spatial disposition is different.Enantiomorph and diastereomer are the examples of steric isomer.

Term " chirality " is meant the structural performance of molecule, and this characteristic can't be superimposed upon on its mirror image it.

Term " enantiomorph " is meant mirror image each other but in can not synergetic a pair of molecule one.

Term " diastereomer " is meant and is not the steric isomer of mirror image.

Substituent configuration around symbol " R " and the one or more chiral carbon atoms of " S " representative.

Term " racemic modification " or " racemic mixture " are meant that wherein said composition does not have the optics activity by two compositions that enantiomorph is formed of equimolar amount.

Term " homochiral " is meant the state of enantiomer-pure.

Term " optical activity " is meant that the non-racemic mixture of homochiral molecule or chiral molecules makes the degree of polarized light flat rotation.

Term " geometrical isomer " is meant the orientation different isomer of substituting group atom about carbon-to-carbon double bond, cycloalkyl ring or bridge bicyclic system.Substituting group atom (non-H) in the every side of carbon-to-carbon double bond can be E or Z configuration.In " E " (offside) configuration, substituting group is positioned at the offside of carbon-to-carbon double bond, and in " Z " (homonymy) configuration, substituting group is about the same side orientation of carbon-to-carbon double bond.The substituting group atom (non-hydrogen) that is connected with carbocyclic ring can be suitable or transconfiguration.In " cis " configuration, substituting group is at the homonymy of plane of a loop; In " trans " configuration, substituting group is at the offside of plane of a loop.Compound with " suitable " and negation formula molecule mixture is called " suitable/anti-".

It is commercially available to be appreciated that the various substituting group steric isomers that are used to prepare The compounds of this invention, geometrical isomer and composition thereof have; Can maybe can be prepared as isomer mixture by the synthetic preparation of marketable material, the technology fractionation isomer of knowing with those of ordinary skills obtains then.

As describing herein, isomer indications " R ", " S ", " E ", " Z ", " suitable " and negation are used to illustrate the one or more atomic configurations with respect to the parent nucleus molecule, should be by document (IUPACRecommendations for Fundamental Stereochemistry (E part), Pure Appl.Chem., 1976, the 45:13-30) use of middle definition.

Can be by the isomer specificity synthetic or by splitting isomer mixture, the individual isomer of preparation The compounds of this invention.Conventional disassemble technique comprises with each right isomer free alkali of opticity salt formation isomer (fractional crystallization with free alkali is lived again) then; Form the ester of each right isomer of isomer or acid amides (chromatographic separation and remove chiral auxiliary(reagent)) then, or with the isomer mixture of preparation TLC (thin-layer chromatography) or chirality HPLC post fractionation raw material or end product.

Polymorphic

In addition, The compounds of this invention can have one or more polymorphics or imperfect crystal formation form, and therefore they will be included in the scope of the present invention.In addition, some compound can form solvate (being hydrate) with ordinary organic solvents or water, and therefore they be also included within the scope of the invention.

The N-oxide compound

Can formula I compound be converted into corresponding N-oxide form according to the known technology method that trivalent nitrogen is converted into its N-oxide form.Usually can carry out described N-oxidizing reaction by making formula I raw material and suitable organic or inorganic peroxide reactions.Suitable inorganic peroxide comprises for example hydrogen peroxide; Basic metal or alkaline earth metal peroxide be sodium peroxide, Potassium peroxide for example; Suitable organo-peroxide can comprise peroxy acid for example benzoyl hydroperoxide or halo benzoyl hydroperoxide, for example 3-chloroperoxybenzoic acid; The peroxide bond alkanoic acid is Peracetic Acid for example; Alkyl hydroperoxide is tert-butyl hydroperoxide for example.Suitable solvent is a water for example; Lower alcohol is ethanol etc. for example; Hydrocarbon is toluene for example; Ketone is 2-butanone for example; Halohydrocarbon is the mixture of methylene dichloride and this kind solvent for example.

Tautomeric forms

Also can there be its tautomeric forms in some formula I compound.Although do not offer some clarification in this application, this type of form should be included in the scope of the present invention.

The preparation of The compounds of this invention

In any process of preparation The compounds of this invention, sensitivity or active group on any relevant molecule that may must and/or need protection.Can be by the GPF (General Protection False group for example at ProtectingGroups, P.Kocienski, Thieme Medical Publishers, 2000; And T.W.Greene﹠amp; P.G.M Wuts, Protective Groups in Organic Synthesis, the 3rd edition, WileyInterscience, those of setting forth in 1999 are finished this protection.Can remove blocking group with methods known in the art in follow-up phase easily.

General reaction process

Can pass through the method known to those skilled in the art preparation I compound.Following reaction process only is used to represent example of the present invention, does not represent limitation of the present invention.

Can be by synthetic compound of formula i shown in the general synthetic route of explanation in the flow process 1, wherein Q is O, and p, q, B, X, Z, R ₁, R ₂And R ₃Definition cotype I.Can be under 50 ℃-150 ℃, for example in the Virahol, handle suitable 4-chloro-quinazoline or quinoline II at solvent with suitable hydroxyl cyclammonium III, obtain intermediate compound IV.At solvent for example in the tetrahydrofuran (THF) (THF), with alkali for example sodium hydride handle intermediate compound IV, add suitable acidylate group V then, wherein Z is NH or N (alkyl), LG can be chlorine, p-nitrophenyl oxygen base or imidazoles, or is CH at Z ₂The time, for example 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) or I-hydroxybenzotriazole (HOBT) of available standards coupler then, by with suitable R ₃BCH ₂CO ₂The H coupling obtains end product I.4-chloro-quinazoline or quinoline II have commercially available, or can prepare according to method shown in flow process 6 or 7; Hydroxyl cyclammonium III has commercially available, or can be by currently known methods (JOC, 1961,26,1519; EP314362) derive and obtain.Acylating agent V has commercially available, or can prepare according to method shown in the flow process 1.Alkali for example triethylamine in the presence of, for example carbonyl dimidazoles or p-nitrophenyl chloroformate ester are handled suitable R with suitable acylating agent ₃BZH, wherein Z is NH or N (alkyl), obtains V.Multiple R ₃BZH reagent has commercially available, and (for example Tet Lett 1995,36,2411-2414) can to pass through multiple currently known methods preparation.

Flow process 1

Perhaps, can be by method shown in the general synthetic route of flow process 2 illustrated, synthetic compound of formula i, wherein Q is O, Z is NH or N (alkyl), and p, q, B, X, R ₁, R ₂And R ₃Definition cotype I.Available acylating agent for example carbonyl dimidazoles or p-nitrophenyl chloroformate ester is handled alcohol intermediate IV by preparation described in the flow process 1, and wherein LG can be chlorine, imidazoles or p-nitrophenyl oxygen base, obtains acidylate intermediate VI.Be the R of NH or N (alkyl) then with suitable wherein Z ₃BZH handles VI, can obtain end product I.Acylating agent has commercially available, and multiple R ₃BZH reagent also has commercially available, and (for example Tet Lett 1995,36,2411-2414) preparation maybe can to pass through multiple currently known methods.

Flow process 2

Wherein LG is a leavings group

The alternative approach of preparation I compound is in flow process 3 illustrated, and wherein Q is O, and Z is NH, and p, q, B, X, R ₁, R ₂And R ₃Definition cotype I.Alkali for example triethylamine in the presence of, handle alcohol intermediate IV with suitable isocyanic ester by preparation described in the flow process 1, can obtain end product I.Isocyanic ester has commercially available, maybe can pass through currently known methods (J.Org Chem, 1985,50,5879-5881) preparation.

Flow process 3

The method of preparation I compound, wherein Q is NH or N (alkyl), and p, q, B, X, Z, R ₁, R ₂And R ₃Definition cotype I sees shown in the general synthetic route of flow process 4 illustrated.Under 50 ℃-150 ℃, at solvent for example in the Virahol, handle suitable chloro-quinazoline or quinoline II with the amino cyclammonium VII of N-protected, wherein PG is an amido protecting group well known by persons skilled in the art, can obtain intermediate VIII.Under the standard conditions that are known in the art, deaminize blocking group (PG) can obtain Compound I X, uses suitable reagent V with its acidylate then, and wherein Z is NH or N (alkyl), and LG can be chlorine, p-nitrophenyl oxygen base or imidazoles, or is CH at Z ₂The time, the available standards coupler is 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) or I-hydroxybenzotriazole (HOBT) for example, by with suitable R ₃BCH ₂CO ₂H coupling acidylate obtains end product I.4-chloro-quinazoline or quinoline II have commercially available, maybe can prepare by method shown in flow process 6 or 7; Amino cyclammonium has commercially available, maybe can be by currently known methods (US4822895; EP401623) derive and obtain; R ₃Acylating agent V has commercially available, maybe can prepare by method shown in the flow process 1.In addition, also can obtain formula I compound by handling intermediate compound I X with suitable isocyanic ester, wherein Z is NH.

Flow process 4

The method of preparation I compound, wherein Q is straight key, Z is NH or N (alkyl), and p, q, B, X, R ₁, R ₂And R ₃Definition cotype I sees shown in the general synthetic route of flow process 5 illustrated.Under 50 ℃-150 ℃, for example in the Virahol, X handles suitable 4-chloro-quinazoline or quinoline II with the ring amino ester, by basic hydrolysis ester functional group, can obtain intermediate X I then at solvent.With standard coupler 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) or carbonyl dimidazoles for example, making suitable wherein Z is the R of NH or N (alkyl) ₃BZH and XI coupling can obtain end product I.

Flow process 5

Can be by the reaction sequence of flow process 6 illustrated, preparation chloro-quinazoline II.For example in the ethanol, is raw material with corresponding anthranilic acid XII at solvent, with reagent for example carbonamidine handle, can obtain quinazolone XIII.Then at solvent for example in the ethylene dichloride,, can obtain the chloro-quinazoline II that needs with chlorizating agent dimethyl formamide (DMF) the solution-treated XIII of phosphorus oxychloride or oxalyl chloride for example.Anthranilic acid has commercially available currently known methods (WO9728118) preparation of maybe can passing through.

Flow process 6

Can prepare suitable 4-chloro-3-cyano quinolines II by the reaction sequence of flow process 7 illustrated.Under 100 ℃-150 ℃, for example in the toluene, be raw material at solvent with aniline XIV, XV handles with the cyano group ester, at solvent for example 1, in the 2-dichlorobenzene, 200 ℃-250 ℃ heating down, can obtain quinolone XVI then.Then at solvent for example in the ethylene dichloride,, can obtain the chloroquinoline II that needs with the chlorizating agent DMF solution-treated XVI of phosphorus oxychloride or oxalyl chloride for example.The aniline raw material has commercially available, and (for example Tet Lett 1995,36,2411-2414) preparation maybe can to pass through multiple currently known methods.

Flow process 7

Can be according to order shown in the flow process 8 preparation I compound, wherein R ₁For-CC (CH ₂) _nR _a, and n, p, q, B, X, Z, Q, R _a, R ₂And R ₃Definition cotype I.Under 25 ℃-150 ℃, at palladium catalyst two (triphenylphosphine) palladium chloride for example; Copper catalyst is cuprous iodide (I) for example; Alkali is diethylamine and solvent for example under the existence of dimethyl formamide for example, handles suitable 6-iodine heteroaromatics XVII by the preparation of method shown in the flow process 1-5 with suitable alkynyl alcohol, can obtain alkynyl alcohol XVIII.Pure XVIII is converted into for example methanesulfonates of suitable leavings group well known by persons skilled in the art, carries out SN with suitable nucleophilicity heterocycle, heteroaryl, amine, alcohol or mercaptan then ₂Replacement(metathesis)reaction can obtain whole Compound I.If R _aNucleophilic reagent is a mercaptan, also the further oxidation of this mercaptan can be able to be obtained corresponding sulfoxide and sulfone.If R _aNucleophilic reagent is amino, and then available suitable acylating agent or sulfonyl agent can obtain corresponding amide, carbamate, urea and sulphonamide with nitrogen acylation.R if desired _aBe COOR _yOr CONR _wR _x, then they can be derived by corresponding hydroxyl and obtain.Under the condition that is known in the art, be acid, form ester or acid amides then, can obtain wherein R hydroxyl oxidize _aBe COOR _yOr CONR _wR _xExample.Can be according to identical reaction sequence, the 7-iodine aryl intermediate with suitable prepares wherein R ₂For-CC (CH ₂) _nR _aCompound.

Flow process 8

Wherein:

LG is a leavings group

Nuc is a nucleophilic reagent

Can be according to order shown in the flow process 9 preparation I compound, wherein R ₁For-CHCH (CH ₂) _nR _a, and n, p, q, B, X, Z, Q, R _a, R ₂And R ₃Definition cotype I.Under 25 ℃-150 ℃, can palladium catalyst for example two (triphenylphosphine) palladium chlorides and solvent for example dimethyl formamide in the presence of, handle the suitable 6-iodine heteroaromatics XVII for preparing by method shown in the flow process 1-5 with suitable vinyl stannane XX, obtain alkenyl alcohol XXI.Pure XXI is converted into for example methanesulfonates of suitable leavings group well known by persons skilled in the art, carries out SN with suitable nucleophilicity heterocycle, heteroaryl, amine, alcohol, sulphonamide or mercaptan then ₂Replacement(metathesis)reaction can obtain whole Compound I.If R _aNucleophilic reagent is a mercaptan, also the further oxidation of this mercaptan can be able to be obtained corresponding sulfoxide and sulfone.If R _aNucleophilic reagent is amino, and then available suitable acylating agent or sulfonyl agent can obtain corresponding amide, carbamate, urea and sulphonamide with nitrogen acylation.R if desired _aBe COOR _yOr CONR _wR _x, then they can be derived by corresponding hydroxyl and obtain.Under the condition that is known in the art, be acid, form ester or acid amides then, can obtain wherein R hydroxyl oxidize _aBe COOR _yOr CONR _wR _xExample.Can be by identical method, with the suitable corresponding formula I cis-form olefin of cis vinyl stannane reagent preparation isomer.Under known conditions,, can obtain saturated compound, wherein R with the alkene partial reduction ₁For-CH ₂CH ₂(CH ₂) _nR _aCan prepare wherein R with suitable 7-iodine quinazoline or quinoline according to identical reaction sequence ₂For-CHCH (CH ₂) _nR _aCompound.

Flow process 9

Wherein

LG is a leavings group

Nuc is a nucleophilic reagent

Can be according to method preparation I compound, wherein R shown in the flow process 10 ₁Be phenyl or heteroaryl, and p, q, B, X, Z, Q, R ₂And R ₃Definition cotype I.Can be under 50 ℃-200 ℃, at palladium catalyst for example in the presence of two (triphenylphosphine) palladium chloride, at solvent for example in the toluene, with suitable aryl boric acid or aryl-boric acid ester ArB (OR) ₂, wherein R is H or alkyl, processing can obtain whole Compound I by the compounds X VII for preparing described in the flow process 1-5.Boric acid/boric acid ester has commercially available, maybe can (Synthesis 2003,4,469-483 by currently known methods; Organicletters 2001,3,1435-1437) preparation.Can prepare wherein R with suitable 7-iodine quinazoline or quinoline according to identical reaction sequence ₂Compound for phenyl or heteroaryl.

Flow process 10

Ar is aryl or heteroaryl

R is H or alkyl

Can be by order shown in the flow process 11 preparation I compound, wherein R ₂For-Y (CH ₂) _nR _a, Q is NH, N (alkyl) or O, and n, p, q, B, X, Z, R ₁And R ₃Definition cotype I.Under 25 ℃-150 ℃, in suitable R _a(CH ₂) _nYH exists down, at solvent for example among the THF, with alkali for example hydroxide ion or potassium tert.-butoxide handle can be by the XXIII compound of preparation described in flow process 1 or 4, the XXIV that can obtain replacing.Under standard conditions, slough amine well known by persons skilled in the art or pure blocking group, can obtain intermediate X XV.Alkali for example diisopropylethylamine in the presence of, with the XXV acidylate, wherein Z is NH or N (alkyl) with suitable reagent V, LG is for example chlorine, imidazoles or a p-nitrophenyl oxygen base of suitable leavings group, or when Z be CH ₂The time, the available standards coupler is 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) or I-hydroxybenzotriazole (HOBT) for example, by with suitable R ₃BCH ₂CO ₂The H coupling can obtain whole Compound I.Can prepare wherein R with suitable 6-halo quinazoline or quinoline according to identical reaction sequence ₁For-Y (CH ₂) _nR _aCompound.

Flow process 11

Perhaps, can be according to shown in the general synthetic route of flow process 12 illustrated, synthetic compound of formula i, wherein Q is O, NH or N (alkyl), and p, q, B, X, Z, R ₁, R ₂And R ₃Definition cotype I.The acylating agent V that can be chlorine, imidazoles or p-nitrophenyl oxygen base with LG wherein handles the cyclammonium XXVI of suitable N-protected, and wherein PG is an amido protecting group well known by persons skilled in the art, can obtain acidylate intermediate X XVII.Under standard conditions known in the art, slough the amido protecting group (PG) of XXVII, then under 50 ℃-150 ℃, for example in the Virahol, handle with suitable chloro-quinazoline or quinoline II at solvent, can obtain end product I.

Flow process 12

Wherein

LG is a leavings group

PG is a blocking group

Perhaps, can be by shown in the general synthetic route of flow process 13 illustrated, synthetic compound of formula i, wherein Q is straight key, Z is NH or N (alkyl), and p, q, B, X, R ₁, R ₂And R ₃Definition cotype I.With standard coupler 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) or carbonyl dimidazoles for example, make the cyclic amino acids XXVIII of suitable N-protected, wherein PG is an amido protecting group well known by persons skilled in the art, with suitable R ₃BZH, wherein Z is NH or N (alkyl) coupling, can obtain acidylate intermediate X XIX.Under the standard conditions that are known in the art, slough the amido protecting group (PG) of XXIX, then under 50 ℃-150 ℃, for example in the Virahol, handle, can obtain end product I with suitable chloro-quinazoline or quinoline II at solvent.

Flow process 13

Wherein PG is a blocking group

Representation compound

Below list by preceding method synthetic representation compound of the present invention.Provide the embodiment of synthetic particular compound hereinafter.Preferred compound is 5,12,14,17,64,66,70,71,74 and No. 75 compounds; Especially preferred 66,70,71,74 and No. 75 compounds.

Embodiment 1

(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester (No. 1 compound)

In bottle, add 1-(6, the 7-dimethoxy-quinazoline-4-yl)-piperidines-4-alcohol press embodiment 3a and to prepare (29mg, 0.1mmol), isocyanic acid 4-isopropyl phenyl ester (20mg, 0.12mmol) and ethylene dichloride (1mL).Descend stirring after 16 hours at 60 ℃ in mixture, content obtains the product of needs, yield 65% through water aftertreatment and TLC purifying.

¹H NMR(300MHz，CDCl ₃)δ8.67(s，1H)，7.33-7.25(m，3H)，7.18(d，J＝7.6Hz，2H)，7.09(s，1H)，6.64(s，1H)，5.08(m，1H)，4.02(s，3H)，3.99(s，3H)，3.95-3.89(m，2H)，3.55-3.48(m，2H)，2.88(sept，J＝6.1Hz，1H)，2.22-2.14(m，2H)，2.04-1.91(m，2H)，1.23(d，J＝6.1Hz，6H)；

LC/MS (ESI): Theoretical Mass 450.2, actual measurement 451.6 (M+H) ⁺

Embodiment 2

(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester (No. 2 compounds)

A. (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester

Stir down, under of short duration ice bath cooling, in～30 seconds, to the 4-isopropyl aniline (3.02g, add in DCM 22.3mmol) (40mL) and pyridine (10mL) solution in batches chloroformic acid 4-nitro phenyl ester (4.09g, 20.3mmol).After at room temperature stirring 1h, with homogeneous phase solution with DCM (100mL) dilution, and with 0.6M HCl (1 * 250mL), 0025M HCl (1 * 400mL), water (1 * 100mL) with 1M NaHCO ₃(1 * 100mL) washing.With organic layer drying (Na ₂SO ₄), concentrate, obtain title compound, be pale pink look solid (5.80g, 95%).

¹H NMR(300MHz，CDCl ₃)δ8.28(m，2H)，7.42-7.32(m，4H)，7.23(m，2H)，6.93(br s，1H)，2.90(h，J＝6.9Hz，1H)，1.24(d，J＝6.9Hz，6H).

LC/MS (ESI): Theoretical Mass 300.1, actual measurement 601.3 (2MH) ⁺

B. (4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester

To racemize 3-pyrrolidinol (141mg, 1.62mmol), 4-chloro-6,7-dimethoxyquinazoline (Oakwood Products, Inc) (372mg, 1.65mmol) and DIEA (300 μ L add DMSO (1.0mL) in mixture 1.82mmol), mixture is stirred down 20min at 100 ℃.After being cooled to room temperature, (646mg 2.15mmol), stirs 1min with the crude reaction thing down at 100 ℃, makes substance dissolves to add (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester of pressing the described preparation of previous step.Then reactant is cooled off on ice bath, and disposable adding NaH (57mg, 2.4mmol).Reaction mixture is stirred 1-2min on ice bath, until a large amount of H ₂Emit and stop, afterwards, reactant is stirred 20min down at 80 ℃.After being cooled to room temperature, with solution and 2M K ₂CO ₃(9mL) jolting together is with DCM (2 * 10mL) extractions.Organic layer is merged dry (Na ₂SO ₄), concentrate, after dodging chromatography (1: 2 → 1: 4 hexane/acetone) purifying, obtain title compound (446mg, 62%).With this material at hot CH ₃Recrystallization among the CN (30mL) obtains title compound, is canescence rose emblem shape thing (363mg, 50%).

¹H NMR(300MHz，CDCl ₃)δ8.52(s，1H)，7.38(s，1H)，7.29(m，2H)，7.21(s，1H)，7.16(m，2H)，6.87(br s，1H)，5.52(m，1H)，4.25-3.98(m，4H)，4.00(s，3H)，3.97(s，3H)，2.86(heptet，J＝6.9Hz，1H)，2.42-2.17(m，2H)，1.22(d，J＝6.9Hz，6H).

LC/MS (ESI): Theoretical Mass 436.2, actual measurement 437.3 (MH) ⁺C ₂₄H ₂₈N ₄O ₄Ultimate analysis: C, 66.04; H, 6.47; N, 12.84.Actual measurement: C, 65.84; H, 6.34; N, 12.86.

Embodiment 3

(4-isopropoxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester (No. 3 compounds)

A.1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-alcohol

(40.4mg, (89.9mg 0.401mmol) handles Virahol 0.400mmol) (1mL) solution with 4-chloro-6,7-dimethoxy-quinazoline with the 4-hydroxy piperidine.After 100 ℃ stirring is spent the night down, reactant is cooled to room temperature, make it at DCM (10mL) and H ₂Distribute between the O (10mL).Organic layer is through Na ₂SO ₄Drying, vacuum concentration obtains title compound, is solid (60mg, 52%).

B. (4-isopropoxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester

In bottle, add the 1-(6 that presses embodiment 3a preparation basically, 7-dimethoxy-quinazoline-4-yl)-piperidines-4-alcohol (29mg, 0.1mmol), p-nitrophenyl chloroformate ester (24mg, 0.12mmol), triethylamine (20mg, 0.2mmol) and ethylene dichloride (1mL).Descend stirring after 16 hours at 60 ℃ in mixture, and adding 4-isopropoxy aniline (18mg, 0.12mmol).Content 60 ℃ of following stirrings 12 hours, through water aftertreatment and TLC purifying, is obtained the product of needs, yield 45%.

¹H NMR(300MHz，CDC1 ₃)δ8.67(s，1H)，7.31-7.24(m，3H)，7.09(s，1H)，6.85(m，2H)，6.65(brs，1H)，5.07(m，1H)，4.48(sept，J＝6.1Hz，1H)，4.02(s，3H)，3.99(s，3H)，3.94-3.88(m，2H)，3.54-3.46(m，2H)，2.21-2.14(m，2H)，1.99-1.91(m，2H)，1.31(d，J＝6.1Hz，6H)；

LC/MS (ESI): Theoretical Mass 466.2, actual measurement 467.6 (M+H) ⁺

Embodiment 4

(4-sec.-propyl-phenyl)-carboxylamine 1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-base methyl esters (No. 4 compounds)

Press preparation described in the embodiment 34, difference is that the 7-dimethoxyquinazoline replaces racemize 3-pyrrolidinol and 4-chloroquinoline respectively with racemize piperidines-3-methyl alcohol and 4-chloro-6.And replace (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester with isocyanic acid 4-sec.-propyl phenyl ester, do not add NaHMDS, replace THF, mixture is stirred 3h down at 100 ℃ with diox.Through dodging column chromatography (silica gel; 1-2% methyl alcohol (MeOH)/DCM) purifying obtains pure (4-sec.-propyl-phenyl)-carboxylamine 1-[1-of 17.1mg (35%) (6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-base methyl esters.

¹H NMR(300MHz，CDCl ₃)：δ8.66(s，1H)，7.31-7.24(m，3H)，7.19-7.09(m，3H)，6.71(bs，1H)，4.29-4.18(m，2H)，4.15-3.92(m，8H)，3.17-3.04(m，1H)，2.98-2.82(m，2H)，2.27(m，1H)，2.18-1.78(m，4H)，1.22(d，6H).

LC/MS (ESI): Theoretical Mass 464.2, actual measurement 465.3 (MH) ⁺

Embodiment 5

2-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-N-(4-sec.-propyl-phenyl)-ethanamide (No. 5 compounds)

(73mg adds PS-carbodiimide (0.4mmol) in anhydrous DCM solution 0.3mmol), with mixture jolting 15min at room temperature to 4-carboxymethyl-piperidines-1-t-butyl formate.(27mg 0.2mmol) adds mixture, and jolting is at room temperature spent the night with the 4-isopropyl aniline then.Filter then,, filtrate merged,, obtain thick 4-[(4-sec.-propyl-phenyl amino formyl radical the washings vacuum concentration with resin DCM washed twice)-methyl]-piperidines-1-t-butyl formate (5a), its unprocessed next step that promptly is used for.

Thick 5a (0.2mmol) is dissolved in 2mL 3M HCl/MeOH solution, at room temperature stirs 1h.Vacuum concentration obtains thick N-(4-sec.-propyl-phenyl)-2-piperidin-4-yl-ethanamide (5b) then, is HCl salt, its unprocessed next step that promptly is used for.

In the anhydrous isopropyl alcohol solution of 5b (0.1mmol), add 4-chloro-6 successively, and the 7-dimethoxyquinazoline (23mg, 0.1mmol), (35 μ L 0.2mmol), down stir mixture at 100 ℃ and to spend the night DIEA.Be cooled to room temperature then, vacuum concentration.Crude product through the preparation TLC (silica gel, 5%MeOH/DCM) purifying obtain the pure 2-[1-of 16.4mg (37%) (6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-N-(4-sec.-propyl-phenyl)-ethanamide.

¹H NMR(300MHz，CDCl ₃)：δ8.63(s，1H)，7.45(d，2H)，7.35(s，1H)，7.25(s，1H)，7.18(d，2H)，7.07(s，1H)，4.22(d，2H)，3.99(d，6H)，3.13(m，2H)，2.88(m，1H)，2.40-2.22(m，3H)，2.04-1.82(m，2H)，1.62-1.45(m，2H)，1.22(d，6H).

LC/MS (ESI): Theoretical Mass 448.3, actual measurement 449.3 (MH) ⁺

Embodiment 6

2-[11-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-N-(4-sec.-propyl-phenyl)-ethanamide (No. 6 compounds)

Except that replacing 4-carboxymethyl-piperidines-1-t-butyl formate, all by preparation described in the embodiment 5 with racemize 3-carboxymethyl-tetramethyleneimine-1-t-butyl formate.Through dodging column chromatography (silica gel; 1-2%MeOH/DCM) purifying obtains the pure 2-[11-of 15.3mg (35%) (6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-N-(4-sec.-propyl-phenyl)-ethanamide.

¹H NMR(300MHz，CDCl ₃)：δ8.44(s，1H)，7.84(s，1H)，7.43(m，3H)，7.17(m，3H)，4.15-4.05(m，1H)，4.05-3.90(m，8H)，3.79-3.69(m，1H)，2.95-2.80(m，2H)，2.63-2.47(m，2H)，2.38-2.25(m，1H)，1.87-1.73(m，1H)，1.22(d，6H).

LC/MS (ESI): Theoretical Mass 434.2, actual measurement 435.3 (MH) ⁺

Embodiment 7

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-urea (No. 7 compounds)

To by the 1-(6 for preparing described in the embodiment 35b, 7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base amine trifluoroacetate (30mg, 0.08mmol) and triethylamine (20mg, and adding isocyanic acid 4-sec.-propyl phenyl ester in DCM 0.2mmol) (1mL) solution (35mg, 0.21mmol).Mixture at room temperature stirred spend the night,, obtain the product (21mg, 62%) that needs through standard aftertreatment and preparation TLC purifying.

¹H NMR(300MHz，CDCl ₃)δ8.22(s，1H)，7.40(s，1H)，7.28-7.04(m，6H)，6.63(s，1H)，4.62(m，1H)，4.09-3.90(m，10H)，2.88(m，J＝6.9Hz，1H)，2.20(m，2H)，1.2(d，J＝6.9Hz，6H).

LC/MS (ESI) Theoretical Mass 435.2, actual measurement 436.2 (MH) ⁺

Embodiment 8

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-isopropoxy-phenyl)-urea (No. 8 compounds)

According to the synthetic method of embodiment 29, use 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base amine trifluoroacetate of pressing embodiment 35b preparation.

¹H NMR(300MHz，CDCl ₃)δ8.30(s，1H)，7.41(s，1H)，7.21-7.01(m，4H)，6.80(d，J＝8.9Hz，2H)，6.21(s，1H)，4.51(m，1H)，4.45(m，J＝6.1Hz，1H)，4.15-3.81(m，4H)，3.94(s，3H)，3.92(s，3H)，2.17(m，2H)，1.29(d，J＝6.1Hz，6H).

LC/MS (ESI) Theoretical Mass 451.2, actual measurement 452.2 (MH) ⁺

Embodiment 9

(4-sec.-propyl-phenyl)-carboxylamine 1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-2-base methyl esters (No. 9 compounds)

Press preparation described in the embodiment 34, difference is that the 7-dimethoxyquinazoline replaces racemize 3-pyrrolidinol and 4-chloroquinoline respectively with racemize piperidines-2-methyl alcohol and 4-chloro-6.And replace (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester with isocyanic acid 4-sec.-propyl phenyl ester, do not add NaHMDS, replace THF, mixture is stirred 3h down at 100 ℃ with diox.Through dodging column chromatography (silica gel; 1-2%MeOH/DCM) purifying obtains pure (4-sec.-propyl-phenyl)-carboxylamine 1-[1-of 5.2mg (12%) (6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-2-base methyl esters.

¹H NMR(300MHz，CDCl ₃)：δ8.41(s，1H)，7.30(s，1H)，7.25-7.05(m，6H)，4.95(m，1H)，4.39(d，2H)，4.08-3.84(m，8H)，2.88-2.74(m，1H)，2.24-1.82(m，4H)，1.16(d，6H).

LC/MS (ESI): Theoretical Mass 450.2, actual measurement 451.3 (MH) ⁺

Embodiment 10

(4-sec.-propyl-phenyl)-carboxylamine 1-quinolyl-4)-piperidin-4-yl ester (No. 10 compounds)

Press preparation described in the embodiment 34, difference is to replace tetramethyleneimine-3-alcohol with the 4-hydroxy piperidine.Through preparation TLC (silica gel; 5%MeOH/DCM) purifying obtains pure (4-sec.-propyl-phenyl)-carboxylamine 1-of 8.8mg (23%) quinolyl-4)-the piperidin-4-yl ester.

¹H NMR(300MHz，CDCl ₃)：δ8.73(d，1H)，8.08(d，1H)，8.00(d，1H)，7.67(m，1H)，7.50(m，1H)，7.33(d，2H)，7.19(d，2H)，6.86(d，1H)，6.74(m，1H)，5.11-5.00(m，1H)，3.60-3.35(m，2H)，3.15(m，2H)，2.95-2.82(m，1H)，2.30-2.15(m，2H)，2.10-1.95(m，2H)，1.24(d，6H).

LC/MS (ESI): Theoretical Mass 389.2, actual measurement 390.3 (MH) ⁺

Embodiment 11

(6-cyclobutoxy group-pyridin-3-yl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester (No. 11 compounds)

A.1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-alcohol

To 4-chloro-6,7-dimethoxy-quinazoline (96.5mg, and adding 4-hydroxy piperidine in i-PrOH 0.43mmol) (2mL) solution (56.5mg, 0.56mmol).Stir down, mixture is heated 2h down at 95 ℃, be cooled to room temperature.Behind the 14h, with sedimentation and filtration.(3 * 1mL) washings, vacuum-drying obtains title compound, is white solid (60mg, 48.2%) with EtOAc.

¹H NMR(300MHz，CDCl ₃)δ8.65(s，1H)，7.28(s，1H)，7.10(s，1H)，4.06(m，1H)，4.03(s，3H)，3.99(s，3H)，3.37(m，2H)，2.10(m，2H)，1.70-1.79(m，4H).

LC/MS (ESI): Theoretical Mass 289.1; Actual measurement 290.2 (MH ⁺).

B.2-cyclobutoxy group-5-nitro-pyridine

Under 0 ℃, with 2-chloro-5-nitropyridine (7.12g, 45.0mmol) and cyclobutanol (3.40g, 47.2mmol) mixture vigorous stirring in THF (30mL), simultaneously in～10-20s, under ventilating, (1.18g 46.7mmol) (notes: produce a large amount of gases) to add NaH in three batches.Reaction residues is washed with other THF (5mL), then under positive Ar Pressure, in ice bath restir 1-2 minute.Remove ice bath then, brown homogeneous phase solution is at room temperature stirred 1h.Reactant at 80 ℃ of following concentrating under reduced pressure, is dissolved in 0.75M EDTA (tetra-na salt) (150mL), with DCM (1 * 100mL, 1 * 50mL) extraction.With the organic layer drying (Na that merges ₂SO ₄), concentrate, be dissolved in MeOH (2 * 100mL), at 60 ℃ of following concentrating under reduced pressure, obtain title compound, for the dark amber oily thing of consistence, obtain crystallization (7.01g, 80%) after leaving standstill.

¹H NMR (300MHz, CDCl ₃) δ 9.04 (dd, J=2.84 and 0.40Hz, 1H), 8.33 (dd, J=9.11 and 2.85Hz, 1H), 6.77 (dd, J=9.11 and 0.50Hz, 1H), 5.28 (m, 1H), 2.48 (m, 2H), 2.17 (m, 2H), 1.87 (m, 1H), 1.72 (m, 1H).

C.6-cyclobutoxy group-pyridin-3-yl amine

The flask that contains 10%w/w Pd/C (485mg) slowly purges with argon gas, simultaneously slowly add MeOH (50mL) along flask walls, press～press the adding of 5mL part 2-cyclobutoxy group-5-nitro-pyridine (4.85g of previous step preparation then, MeOH 25mmol) (30mL) solution (noting: in the presence of air, add a large amount of volatile organic matters to Pd/C and can cause burning).Then once, at H with the flask emptying ₂Under the ball pressure, at room temperature stir 2h.Then reactant is filtered, it is concentrated clarify amber filtrate, be dissolved in toluene (2 * 50mL), remove remaining MeOH, concentrating under reduced pressure obtains thick title compound, is translucent dark-brown oily matter, has faint toluene smell (4.41g, " 108% " crude product yield).

¹H MR (300MHz, CDCl ₃) δ 7.65 (d, J=3.0Hz, 1H), 7.04 (dd, J=8.71 and 2.96Hz, 1H), 6.55 (d, J=8.74Hz, 1H), 5.04 (m, 1H), 2.42 (m, 2H), 2.10 (m, 2H), 1.80 (m, 1H), 1.66 (m, 1H).

LC-MS (ESI): Theoretical Mass 164.1, actual measurement 165.2 (MH ⁺).

D. (6-cyclobutoxy group-pyridin-3-yl)-carboxylamine 4-nitro-phenyl ester

At room temperature, will be by the 6-cyclobutoxy group-pyridin-3-yl amine (4.41g supposes 25mmol) and the CaCO of previous step preparation ₃(3.25g, 32.5mmol) ((react spontaneous intensification) and stir 2h under " room temperature " by 5.54g, the disposable processing of toluene 27.5mmol) (28mL) homogeneous phase solution with chloroformic acid 4-nitro phenyl ester for the mixture of (10 microns powder).Then reaction mixture directly is loaded into and dodges on the silicagel column (95: 5 DCM/MeOH → 9: 1 DCM/MeOH), obtain the 5.65g material, by (1 * 200mL) grinds, and it is further purified, and obtains title compound (4.45g, 54%) with hot toluene.

¹H NMR(400MHz，CDCl ₃)δ8.32-8.25(m，2H)，8.12(d，1H)，7.81(m，1H)，7.42-7.36(m，2H)，6.85(br s，1H)，6.72(d，1H)，5.19-5.10(m，1H)，2.50-2.40(m，2H)，2.19-2.07(m，2H)，1.89-1.79(m，1H)，1.75-1.61(m，1H).

LC-MS (ESI): Theoretical Mass 329.1, actual measurement 330.1 (MH ⁺).

E. (6-cyclobutoxy group-pyridin-3-yl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester

To the 1-(6 that presses embodiment 11a preparation, 7-dimethoxy-quinazoline-4-yl)-piperidines-4-alcohol (30.7mg, 0.11mmol) anhydrous THF (2mL) solution in add successively 60%NaH (10mg), by (6-cyclobutoxy group-pyridin-3-yl)-carboxylamine 4-nitro-phenyl ester of previous step preparation (35mg, 0.11mmol).Mixture is stirred 0.5h down at 80 ℃, concentrate then.Residue obtains title compound through preparation TLC (5%MeOH/EtOAc) purifying, is light brown solid (17.8mg, 35%).

¹H NMR(300MHz，CD ₃OD)δ8.49(s，1H)，8.14(s，1H)，7.79(d，J＝7.93Hz，1H)，7.17(d，J＝5.78Hz，1H)，7.16(s，1H)，6.69(dd，J＝8.91 and 0.64Hz，1H)，5.05(m，2H)，3.98(s，3H)，3.96(s，3H)，3.93(m，2H)，3.62(m，2H)，2.43(m，2H)，2.04-2.22(m，4H)，1.64-2.00(m，4H).

LC/MS (ESI): Theoretical Mass 4792, actual measurement 480.2 (MH ⁺).

Embodiment 12

(6-cyclobutoxy group-pyridin-3-yl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester (No. 12 compounds)

A.1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-alcohol

It is described to press embodiment 11a, with the preparation of 3-pyrrolidinol.

¹H NMR(300MHz，DMSO-d ₆)δ8.70(s，1H)，7.68(s，1H)，7.27(s，1H)，4.48(m，1H)，4.10-4.25(m，3H)，3.96(s，6H)，3.90(m，1H)，2.05(m，2H).

LC/MS (ESI): Theoretical Mass 274.1, actual measurement 275.2 (MH ⁺).

B. (6-cyclobutoxy group-pyridin-3-yl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester

In sealed tube, add 4-chloro-6, the 7-dimethoxyquinazoline (0.30g, 1.34mmo1), piperidine-4-ethyl formate (0.236g, 1.5mmol) and 2-propyl alcohol (5mL).Mixture was heated 16 hours down at 100 ℃.After being cooled to room temperature, in content impouring water, the aqueous solution is extracted with DCM.With the organic layer drying, concentrate, obtain pure ester products, with its saponification, obtain the acid of needs, yield 90%.

¹H NMR(d ₆-DMSO)δ8.76(s，1H)，7.31(s，2H)，4.55-4.51(m，2H)，3.97(s，3H)，3.95(s，3H)，3.65(m，2H)，2.76(m，1H)，2.05(m，2H)，1.80(m，2H).

B.N-(4-sec.-propyl-phenyl)-1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-methane amide

To 1-(6 by the previous step preparation, 7-dimethoxyquinazoline (quinazalin)-4-yl)-piperidines-4-formic acid (32mg, 0.1mmol) and 4-isopropyl aniline (15mg, 0.11mmol) mixture in DMF (1mL) adds EDC (30mg, 0.15mmol), HOBT (2mg) and triethylamine (20mg, 0.2mmol).After at room temperature stirring 16 hours, content obtains the product of needs, yield 82% through water aftertreatment and TLC purifying.

¹HNMR(300MHz，CDCl ₃)δ8.68(s，1H)，7.46(m，2H)，7.26(s，1H)，7.21(m，3H)，7.12(s，1H)，4.25-4.21(m，2H)，4.03(s，3H)，4.00(s，3H)，3.12(m，2H)，2.89(sept，J.＝6.9Hz，1H)，2.55(m，1H)，2.24-2.12(m，4H)，1.31(d，J＝6.9Hz，6H)；

LC/MS (ESI): Theoretical Mass 434.2, actual measurement 435.5 (M+H) ⁺

Embodiment 14

(4-sec.-propyl-phenyl)-carboxylamine 1-[6-(3-hydroxyl-third-1-alkynyl)-quinazoline-4-yl]-tetramethyleneimine-3-base ester (No. 14 compounds)

Utilize method described in the embodiment 11e, with 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-alcohol preparation.

¹H NMR(300MHz，CD ₃OD)δ8.31(s，1H)，8.12(m，1H)，7.76(m，1H)，7.57(s，1H)，7.11(s，1H)，6.67(d，J＝9.30Hz，1H)，5.47(m，1H)，5.02(m，1H)，4.29(dd，J＝12.60 and 3.90Hz，1H)，4.04-4.21(m，3H)，3.97(s，3H)，3.96(s，3H)，2.30-2.48(m，4H)，2.02-2.12(m，2H)，1.82(m，1H)，1.67(m，1H).

LC/MS (ESI): Theoretical Mass 465.2, actual measurement 466.2 (MH ⁺).

Embodiment 13

N-(4-sec.-propyl-phenyl)-1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-methane amide (No. 13 compounds)

A.1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-formic acid

Purge (4-sec.-propyl-phenyl)-carboxylamine 1-(6-iodo-quinazoline-4-yl)-tetramethyleneimine-3-base ester (63mg, 125 μ mol), the CuI (1.7mg, 8.9 μ mol), trans-PdCl that presses preparation described in the embodiment 20 with argon gas stream ₂[P (C ₆H ₅) ₃] ₂Mixture～the 15s of (3.0mg, 4.3 μ mol), propargyl alcohol (19.2 μ L, 325 μ mol) and diethylamine (800 μ L), sealing rapidly under argon gas, is at room temperature stirred 2h then.With the translucent light amber solution that obtains concentrating under reduced pressure at room temperature, use DCM (5mL) and 0.75M EDTA (tetra-na salt) to distribute then.With organic layer drying (Na ₂SO ₄), concentrate, through dodging the chromatography (purifying of 1: 9 hexane/EtOAc).Obtain title compound, be little yellow solid (40.2mg, 75%).

¹H NMR(400MHz，CDCl ₃)δ8.59(s，1H)，8.05(s，1H)，7.75(d，1H)，7.60(dd，1H)，7.30(m，2H)，7.20-7.13(m，3H)，5.51(m，1H)，4.53(s，2H)，4.17(m，1H)，4.11-3.97(m，3H)，2.86(heptet，1H)，2.40-2.31(m，1H)，2.29-2.17(m，1H)，1.22(d，6H).

LC/MS (ESI): Theoretical Mass 430.2, actual measurement 431.2 (MH) ⁺

Embodiment 15

(4-isopropoxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester (No. 15 compounds)

According to the synthetic method of embodiment 3b, use and press 1-(6, the 7-dimethoxy-quinazoline 4-yl)-tetramethyleneimine-3-alcohol for preparing with pyrrolidinol described in the embodiment 3a basically.

¹H NMR(300MHz，CDCl ₃)δ8.52(s，1H)，7.38(s，1H)，7.38-7.21(m，3H)，6.84-6.81(m，3H)，5.51(br s，1H)，4.47(m，J＝6.1Hz，1H)，4.25-4.05(m，4H)，4.00(s，3H)，3.97(s，3H)，2.39-2.23(m，2H)，1.30(d，J＝6.1Hz，6H).

LC/MS (ESI) Theoretical Mass 452.2, actual measurement 453.5 (MH) ⁺

Embodiment 16

1-(4-sec.-propyl-phenyl)-3-(1-quinazoline-4-base-tetramethyleneimine-3-yl) urea (No. 16 compounds)

The mixture of 4-chloro-quinazoline (30.0mg, 182 μ mol), 3-(tert-butoxycarbonyl amino) tetramethyleneimine (32.8mg, 176 μ mol), DIEA (33 μ L, 200 μ mol) and DMSO (121 μ L) is stirred 20min down at 100 ℃.After being cooled to room temperature, (270 μ L 3.6mmol) add the homogeneous phase yellow solution that obtains, and solution is stirred 5min down at 100 ℃ with TFA.After being cooled to room temperature, reactant with DCM (2mL) dilution, is used 2.5M NaOH (1 * 2mL) washing.Organic layer is collected, concentrated, be dissolved in CH ₃CN (100 μ L) adds (4-isopropyl phenyl)-carboxylamine 4-nitro phenyl ester (62.5mg, 208 μ mol) of pressing embodiment 2a preparation.Reactant is stirred 20min down at 100 ℃, be cooled to room temperature, with 2M K ₂CO ₃(2mL) jolting together is with DCM (2 * 2mL) extractions.Organic layer is merged dry (Na ₂SO ₄), concentrating, residue dodges chromatography (3: 4 hexane/acetone → 3: 4 toluene/acetone) purifying through silica gel, obtains title compound, is pale powder (26.2mg, 40%).

¹H NMR(300MHz，CDCl ₃)δ8.33(s，1H)，7.89(dd，1H)，7.72(dd，1H)，7.62(m，1H)，7.36(br s，1H)，7.28(m，1H)，7.22(m，2H)，7.10(m，2H)，6.86(br d，1H)，4.65(m，1H)，4.07(dd，1H)，3.96-3.80(m，3H)，2.83(heptet，1H)，2.26-2.16(m，2H)，1.19(d，6H).

LC/MS (ESI): Theoretical Mass 375.2, actual measurement 376.3 (MH) ⁺

Embodiment 17

(4-sec.-propyl-phenyl)-3-carboxylamine 1-[6-(3-diethylamino-third-1-alkynyl)-quinazoline-4-yl]-tetramethyleneimine-3-base ester (No. 17 compounds)

Methylsulfonic acid 3-{4-[3-(4-sec.-propyl-phenyl amino formyl radical oxygen base)-tetramethyleneimine-1-yl]-quinazoline-6-yl }-the Propargyl ester

At room temperature, stir down, in～5s, by dripping methylsulfonyl chloride (6.4 μ L, 82.4 μ mol), handle (4-sec.-propyl-phenyl)-carboxylamine 1-[6-(3-hydroxyl-third-1-alkynyl)-quinazoline-4-yl press embodiment 14 preparations]-DCM (500 μ L) and TEA (12.5 μ L, the 89.9 μ mol) solution of the basic ester of tetramethyleneimine-3-(32.2mg, 74.9 μ mol).The homogeneous phase yellow solution is at room temperature stirred 35min, directly be loaded into silica gel then and dodge on the post that (purifying of 1: 9 hexane/EtOAc) obtains title compound, is canescence foam (30.9mg, 81%).

¹H NMR(400MHz，CDCl ₃)δ8.63(s，1H)，8.25(s，1H)，7.80(d，1H)，7.72(m，1H)，7.29-7.24(m，2H)，7.19-7.14(m，2H)，6.61(br s，1H)，5.56-5.52(m，1H)，5.12(s，2H)，4.28-4.22(m，1H)，4.20-4.05(m，3H)，3.16(s，3H)，2.86(heptet，1H)，2.44-2.36(m，1H)，2.35-2.23(m，1H)，1.27(d，6H).

LC/MS (ESI): Theoretical Mass 508.2, actual measurement 509.2 (MH) ⁺

B. (4-sec.-propyl-phenyl)-3-carboxylamine 1-[6-(3-diethylamino-third-1-alkynyl)-quinazoline-4-yl]-tetramethyleneimine-3-base ester

At room temperature, stir down, will be by methylsulfonic acid 3-{4-[3-(4-sec.-propyl-phenyl amino formyl radical oxygen base)-tetramethyleneimine-1-yl of previous step preparation]-quinazoline-6-yl }-CH of Propargyl ester (30.9mg, 60.8 μ mol) ₃CN (100 μ L) the solution disposable fast processing of diethylamine (13.9 μ L, 134 μ mol).After at room temperature stirring 20min, opaque yellow pulpous state reactant directly is added on the sudden strain of a muscle chromatography column (3: 5 hexane/acetone), obtains title compound (3.7mg, 13%).

¹H NMR(400MHz，CDCl ₃)δ8.60(s，1H)，8.17(d，1H)，7.75(d，1H)，7.70(dd，1H)，7.30-7.23(m，2H)，7.16(m，2H)，6.61(br s，1H)，5.54(m，1H)，4.27-4.03(m，4H)，3.67(s，2H)，2.86(heptet，1H)，2.65(q，4H)，2.42-2.34(m，1H)，2.32-2.21(m，1H)，1.22(d，6H)，1.14(t，6H).

LC/MS (ESI): Theoretical Mass 485.3, actual measurement 486.3 (MH) ⁺

Embodiment 18

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl methyl]-3-(4-sec.-propyl-phenyl)-urea (No. 18 compounds)

A.C-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-methylamine

(145mg, (152mg 0.679mmol) handles Virahol 0.678mmol) (2mL) solution with 4-chloro-6,7-dimethoxy-quinazoline with N-(4-piperidino methyl) t-butyl carbamate.After 100 ℃ stirring is spent the night down, reactant is cooled to room temperature, with the sedimentation and filtration that obtains in the organic layer, obtain thick solid.In thick solid, add TFA (20mL) and DCM (20mL), stir 30min,, obtain title compound, be solid (102mg, 50%) the solvent concentrating under reduced pressure.

¹H NMR(300MHz，CDCl ₃)δ8.66(s，1H)，7.23(s，1H)，7.10(s，1H)，4.22(m，2H)，4.02(s，3H)，3.99(s，3H)，3.07(m，2H)，2.72(m，2H)，1.96-1.92(m，2H)，1.55-1.45(m，3H)；

LC/MS (ESI): Theoretical Mass 302.2, actual measurement 303.3, [M+1] ⁺

B.1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl methyl]-3-(4-sec.-propyl-phenyl)-urea

Will be by the C-[1-(6 of previous step preparation, 7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-methylamine (47.9mg, 0.159mmol) acetonitrile (1mL) solution with (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester of press embodiment 2a preparation (47.6mg, 0.159mmol) processing.After stirring 2h under 100 ℃, reactant is cooled to room temperature, the solvent vacuum is removed, obtain thick solid.Through preparation TLC (1: 9 MeOH/DCM) purifying, obtain title compound, be yellow solid (19.3mg, 26%).

¹H NMR(300MHz，CDCl ₃)δ8.62(s，1H)，7.22-7.12(m，6H)，7.04-7.02(m，2H)，4.16(m，2H)，3.98(s，3H)，3.95(s，3H)，3.20(m，2H)，3.00(m，2H)，2.84(m，1H)，1.85-1.82(m，3H)，1.44(m，2H)，1.19(d，6H)；

LC/MS (ESI): Theoretical Mass 463.3, actual measurement 464.3[M+1] ⁺

Embodiment 19

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-1-methyl-urea (No. 19 compounds)

A.[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-the methylamine trifluoroacetate

To basically by [1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-t-butyl carbamate for preparing described in the embodiment 35a (200mg, add in DMF 0.54mmol) (1mL) solution NaH (90%, 30mg).After mixture at room temperature stirred 30 minutes, add methyl-sulfate (101mg, 0.80mmol).Content was at room temperature stirred 2 hours, be heated to 80 ℃, restir 3 hours.Through standard aftertreatment and silicagel column purifying, obtain the product (152mg, 73%) of N-Boc protection, it is used 50%TFA/CH ₂Cl ₂(5mL) handle.After at room temperature stirring 3h,, obtain title compound, be trifluoroacetate solution evaporation.The Theoretical Mass 288.2 of LC/MS (ESI) free alkali, actual measurement 289.3 (MH) ⁺

B.1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-1-methyl-urea

According to the synthetic method of embodiment 7, use [1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-methylamine trifluoroacetate by the previous step preparation.

¹H NMR(300MHz，CDCl ₃)δ8.54(s，1H)，7.41(s，1H)，7.30-7.04(m，5H)，6.38(s，1H)，5.22(m，1H)，4.10-3.90(m，10H)，3.07(s，3H)，2.86(m，J＝6.9Hz，1H)，2.31(m，2H)，1.21(d，J＝6.9Hz，6H).

LC/MS (ESI) Theoretical Mass 449.2, actual measurement 450.2 (MH) ⁺

Embodiment 20

(4-sec.-propyl-phenyl)-carboxylamine 1-(6-iodo-quinazoline-4-yl)-tetramethyleneimine-3-base ester (No. 20 compounds)

Basically press described in the embodiment 2b, use 4-chloro-6-iodine quinazoline (WO2004046101) preparation, difference is to use 1.2 equivalent carboxylamine nitro phenyl esters and 1.2 equivalent NaH.(1: 1 hexane/EtOAc → 1: 3 hexane/EtOAc), obtain title compound is light yellow solid (70.7mg, 6.9%) through dodging chromatography.

¹H NMR(400MHz，CDCl ₃)δ8.62(s，1H)，8.43(d，1H)，7.93(dd，1H)，7.58(d，1H)，7.28(m，2H)，7.16(m，2H)，6.71(br s，1H)，5.53(m，1H)，4.24-4.00(m，4H)，2.87(heptet，1H)，2.43-2.35(m，1H)，2.32-2.21(m，1H)，1.22(d，6H).

LC/MS (ESI): Theoretical Mass 502.1, actual measurement 503.1 (MH) ⁺

Embodiment 21

N-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-2-(4-sec.-propyl-phenyl)-ethanamide (No. 21 compounds)

A.[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-t-butyl carbamate

To 4-chloro-6,7-dimethoxy-quinazoline (44.8mg, add successively in i-PrOH 0.20mmol) (2mL) solution 4-(N-Boc amino)-piperidines (43.9mg, 0.22mmol), DIEA (51.4mg, 0.4mmol).Stir down, mixture is heated down at 100 ℃.After stirring 1h,, residue is distributed between EtOAc and water with the homogeneous phase solution concentrating under reduced pressure.Organic layer is merged, dry (through Na ₂SO ₄), concentrate, obtain title compound, be white solid (60mg, 78%).

¹H NMR(300MHz，CD ₃OD)δ8.58(s，1H)，7.34(s，1H)，7.18(s，1H)，4.72(m，2H)，4.04(s，3H)，4.00(s，3H)，3.80(m，1H)，3.68(m，2H)，2.12(m，2H)，1.65(m，2H)，1.45(s，9H).

LC/MS (ESI): Theoretical Mass 388.2, actual measurement 389.3 (MH ⁺).

B.1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl amine trifluoroacetate

To by previous step preparation [1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-(20mg adds TFA (1.5mL) in DCM 0.052mmol) (1.5mL) solution to t-butyl carbamate.With mixture continuously stirring 3h, concentrating under reduced pressure obtains title compound, is pale solid (21mg, 100%).

¹H NMR(300MHz，CD ₃OD)δ8.65(s，1H)，7.34(s，1H)，7.23(s，1H)，4.05(s，3H)，4.01(s，3H)，3.63(m，5H)，2.25(m，2H)，1.79(m，2H).

LC/MS (ESI): the Theoretical Mass 288.2 of free alkali, actual measurement 289.2 (MH ⁺).

C.N-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-2-(4-sec.-propyl-phenyl)-ethanamide

To 1-(6 by the previous step preparation, 7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl amine trifluoroacetate (21mg, 0.052mmol) and (4-sec.-propyl-phenyl)-acetate (10.1mg, 0.052mmol) add HOBT (10.3mg successively in the mixture in anhydrous THF (2mL), 0.067mmol), HBTU (25.4mg, 0.067mmol) and DIEA (33.3mg, 0.26mmol).Suspension is at room temperature stirred 14h, concentrating under reduced pressure.Residue dodges column chromatography (4%MeOH/EtOAc makes elutriant) purifying through silica gel, obtains title compound, is white solid (15.5mg, 67.1%).

¹H NMR (300MHz, CDCl ₃) δ 8.61 (s, 1H), 7.23 (s, 1H), 7.19 (m, 4H), 7.03 (s, 1H), 5.38 (d, J=6.69Hz, 1H), 4.12 (m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.55 (s, 2H), 3.24 (td, J=12.65 and 2.30Hz, 2H), 2.90 (m, 1H), 2.06 (m, 2H), 1.46-1.61 (m, 3H), 1.24 (d, J=6.92Hz, 6H).

LC/MS (ESI): Theoretical Mass 448.3, actual measurement 449.2 (MH ⁺).

Embodiment 22

(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl methyl esters (No. 22 compounds)

A.4-(imidazoles-1-ketonic oxygen ylmethyl)-piperidines-]-t-butyl formate

To 1,1 '-carbonyl dimidazoles (145mg, and adding 4-hydroxymethyl-piperidines-1-t-butyl formate in DCM 0.894mmol) (5mL) solution (192mg, 0.894mmol).After 0 ℃ stirring is spent the night down, the solvent vacuum is removed, obtain thick solid.(purifying of 1: 1 hexane/EtOAc) obtains title compound, is solid (167mg, 61%) through preparation TLC.

B. (4-sec.-propyl-phenyl)-carboxylamine piperidin-4-yl methyl esters

To by 4-(imidazoles-1-ketonic oxygen ylmethyl)-piperidines-1-t-butyl formate of previous step preparation (167mg, add in DMF 0.540mmol) (2mL) solution 4-isopropyl aniline (0.75mL, 5.61mmol).After stirring 24h under 80 ℃, (0.75mL 5.61mmol), stirs 22h down at 80 ℃ to add another part 4-isopropyl aniline.Reactant is cooled to room temperature,, obtains thick solid the sedimentation and filtration that obtains.Add TFA (10mL) and DCM (10mL) to thick solid, stir 30min,, obtain title compound, be solid (70mg, 47%) the solvent concentrating under reduced pressure.

¹H NMR(300MHz，CDCl ₃)δ7.30-7.26(m，2H)，7.18-7.15(m，2H)，4.00(m，2H)，3.50(m，1H)，3.15(m，2H)，2.90(m，1H)，2.66(m，2H)，2.02(m，2H)，1.76(m，3H)，1.24(s，3H)，1.21(s，3H)；

LC/MS (ESI): Theoretical Mass 276.2, actual measurement 318.2[M+41+1] ⁺

C. (4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl methyl esters

Will be by (4-sec.-propyl-phenyl)-carboxylamine piperidin-4-yl methyl esters (38.9mg, Virahol 0.141mmol) (1mL) solution 4-chloro-6,7-dimethoxy-quinazoline (31.6mg, 0.141mmol) processing of previous step preparation.After stirring 5h under 100 ℃, reactant is cooled to room temperature, by rotary evaporation solvent is removed, obtain thick solid.(purifying of 3: 7 hexanes/EtOAc) obtains title compound, is solid (1.5mg, 2.3%) through silicagel column.

¹H NMR(300MHz，CDCl ₃)δ8.65(s，1H)，7.32-7.29(m，3H)，7.19-7.16(m，2H)，7.09(m，1H)，6.57(br s，NH)，4.26(m，2H)，4.12(m，2H)，4.03(s，3H)，3.99(s，3H)，3.12(m，2H)，2.88(m，1H)，1.98(m，2H)，1.58(m，3H)，1.24(s，3H)，1.22(s，3H)；

LC/MS (ESI): Theoretical Mass 464.2, actual measurement 465.4[M+1] ⁺

Embodiment 23

N-(4-isopropoxy-phenyl)-1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-methane amide (No. 23 compounds)

According to the synthetic method of embodiment 13b, use the 4-isopropoxy aniline.

¹H NMR(300MHz，CDCl ₃)δ8.67(s，1H)，7.42(d，J＝9.0Hz，2H)，7.35(s，1H)，7.23(s，1H)，7.11(s，1H)，6.85(d，J＝9.0Hz，2H)，4.50(sept，J＝6.1Hz，1H)，4.24-4.19(m，2H)，4.01(s，3H)，3.99(s，3H)，3.10(m，2H)，2.574H)，1.31(d，J＝6.1Hz，6H)；

LC/MS (ESI): Theoretical Mass 450.2, actual measurement 451.5 (M+H) ⁺

Embodiment 24

(4-sec.-propyl-phenyl)-carboxylamine 1-quinazoline-4-base-tetramethyleneimine-3-base ester (No. 24 compounds)

A.4-chloro-quinazoline

With 4-hydroxyl quinazoline (2.56g, 17.5mmol) and POCl ₃(8.0mL, mixture 88mmol) under 140 ℃ (oil bath) stir 10min.Then the light amber homogeneous phase solution is cooled to room temperature, then at 70 ℃ of following concentrating under reduced pressure.Translucent residue is dissolved in DCM (25mL), with yellow homogeneous phase solution ice and 1M NaHCO ₃Distribute, to pH～6 (test paper) (～20mL water layer).With organic layer drying (Na ₂SO ₄) twice, filtering by 0.22 micron filter, concentrating under reduced pressure (bath temperature＜40 ℃) obtains title compound, is yellow solid (2.53g, 88%).

¹H NMR(300MHz，CDCl ₃)δ9.07(s，1H)，8.30(ddd，1H)，8.11(m，1H)，8.00(m，1H)，7.77(m，1H).

B. (4-sec.-propyl-phenyl)-carboxylamine 1-quinazoline-4-base-tetramethyleneimine-3-base ester

Basically press described in the embodiment 2b, use the 4-chloro-quinazoline preparation of the described preparation of previous step, difference is to form use～1.5 equivalent NaH in the step at carbamate, and this second step is carried out 20min under 100 ℃.Through dodging chromatography (6: 5 hexane/acetone), obtain title compound, be translucent white membranoid substance (13.5mg, 20%).

¹H NMR(300MHz，CDCl ₃)δ8.63(s，1H)，8.11(dd，1H)，7.86(dd，1H)，7.71(m，1H)，7.41(m，1H)，7.31-7.22(m，2H)，7.15(m，2H)，6.69(br s，1H)，5.52(m，1H)，4.29-4.02(m，4H)，2.86(heptet，1H)，2.42-2.20(m，2H)，1.22(d，6H).

LC/MS (ESI): Theoretical Mass 3762, actual measurement 377.3 (MH) ⁺

Embodiment 25

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-azetidine-3-ylmethyl]-3-(4-isopropoxy-phenyl)-urea (No. 25 compounds)

A.C-[1-(6,7-dimethoxy-quinazoline-4-yl)-azetidine-3-yl]-methylamine

(76.2mg, (89.6mg 0.400mmol) handles Virahol 0.409mmol) (1mL) solution with 4-chloro-6,7-dimethoxy-quinazoline with azetidine-3-ylmethyl-t-butyl carbamate.After 100 ℃ stirring is spent the night down, reactant is cooled to room temperature, the solvent vacuum is removed, obtain thick solid.Add TFA (10mL) and DCM (10mL) to thick solid, stir 1h,, obtain title compound, be solid (42mg, 38%) the solvent concentrating under reduced pressure.

B.1-[1-(6,7-dimethoxy-quinazoline-4-yl)-azetidine-3-ylmethyl]-3-(4-isopropoxy-phenyl)-urea

To 1,1 '-carbonyl dimidazoles (20.6mg, add in DCM 0.127mmol) (1mL) solution 4-isopropoxy aniline (19.4mg, 0.128mmol).After stirring 2h under 0 ℃, add C-[1-(6, the 7-dimethoxy-quinazoline-4-yl)-azetidine-3-yl of previous step preparation]-(35.2mg 0.128mmol), at room temperature stirs and spends the night methylamine.Make reactant at DCM (10mL) and H then ₂Distribute between the O (10mL).Organic phase is through Na ₂SO ₄Drying, vacuum concentration.Through preparation TLC (1: 9 MeOH/DCM) purifying, obtain title compound, be brown solid (18.1mg, 31.6%).

¹H NMR(300MHz，CD ₃OD)δ8.33(s，1H)，7.29(s，1H)，7.19-7.15(m，2H)，7.09(s，1H)，6.80-6.77(m，2H)，4.71(m，2H)，4.50-4.40(m，3H)，3.97(s，3H)，3.94(s，3H)，3.52(m，2H)，3.07(m，1H)，1.27(d，6H)；

LC/MS (ESI): Theoretical Mass 451.2, actual measurement 452.2[M+1] ⁺

Embodiment 26

1-[1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-urea (No. 26 compounds)

A.2-cyano group-3-(3,4-dimethoxy-phenyl amino)-ethyl propenoate

To 3, the 4-dimethoxyaniline (153mg, and adding (oxyethyl group methylene radical) ethyl cyanacetate in toluene 1mmol) (5mL) solution (169mg, 1mmol).Solution is stirred 1h down at 100 ℃, stir 15min down at 125 ℃ then.Then reactant is cooled to room temperature, with the sedimentation and filtration that obtains in the organic layer.With the solid hexane wash, obtain title compound, be solid.

¹H NMR(300MHz，CDCl ₃)δ7.77(d，1H)，6.85(d，1H)，6.70-6.60(m，2H)，4.29(m，2H)，3.91(s，3H)，3.90(s，3H)，1.58(s，NH)，1.37(m，3H)；

LC/MS (ESI): Theoretical Mass 276.1, actual measurement 277.1[M+1] ⁺

B.6,7-dimethoxy-4 '-oxo-1,4-dihydro-quinoline-3-formonitrile HCN

Under 250 ℃, with 2-cyano group-3-(3,4-dimethoxy-phenyl amino)-ethyl propenoate of previous step preparation (176mg, 0.638mmol) and 1, the mixture microwave exposure 1h of 2--dichlorobenzene (3mL).Then reactant is cooled to room temperature.Hexane is added in the mixture, with the sedimentation and filtration that obtains in the organic layer.With solid with hexane (2 * 10mL) and DCM (2 * 10mL) wash, and drying under reduced pressure obtains title compound then, is solid (20.8mg, 14%).

¹H NMR(300MHz，DMSO-d ₆)δ8.60(s，1H)，7.46(s，1H)，7.05(s，1H)，3.89(s，3H)，3.86(s，3H)；

LC/MS (ESI): Theoretical Mass 230.1, actual measurement 231.1[M+1] ⁺

C.4-chloro-6,7-dimethoxy yl-quinoline-3-formonitrile HCN

With 6 of previous step preparation, 7-dimethoxy-4 '-oxo-1,4-dihydro-quinoline-3-formonitrile HCN and phosphoryl chloride stir down at 150 ℃ and spend the night.Then reactant is cooled to room temperature, the phosphoryl chloride vacuum is removed, obtain thick oily matter.Oily matter is distributed between ether and frozen water, and organic phase is through Na ₂SO ₄Drying, concentrating under reduced pressure obtains title compound, is solid.Also can pass through J.Med.Chem.43:3244, method described in 2000 prepares 4-chloro-6,7-dimethoxy yl-quinoline-3-formonitrile HCN.

¹H NMR(300MHz，DMSO-d ₆)δ9.00(s，1H)，7.56(s，1H)，7.46(s，1H)，4.02(s，6H)；

LC/MS (ESI): Theoretical Mass 248.0, actual measurement 290.1[M+41+1] ⁺

D.4-(3-amino-tetramethyleneimine-1-yl)-6,7-dimethoxy yl-quinoline-3-formonitrile HCN

With the 4-chloro-6 of previous step preparation, (125mg, (93.5mg 0.502mmol) handles Virahol 0.502mmol) (1mL) solution 7-dimethoxy yl-quinoline-3-formonitrile HCN with tetramethyleneimine-3-base-t-butyl carbamate.After 100 ℃ stirring is spent the night down, reactant is cooled to room temperature, solvent is removed by rotary evaporation, obtain thick solid.Add TFA (1mL) then, stir 1h,, add CHCl the TFA concentrating under reduced pressure ₃(1mL) and ice.Be added dropwise to K ₂CO ₃The aqueous solution is until pH 10.Organic phase is through Na ₂SO ₄Drying, vacuum concentration obtains title compound, is solid (110mg, 74%).

E.1-[1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-urea

To 1,1 '-carbonyl dimidazoles (27.0mg adds the 4-(3-amino-tetramethyleneimine-1-yl)-6 of previous step preparation in DCM 0.166mmol) (1mL) solution, and 7-dimethoxy yl-quinoline-3-formonitrile HCN (49.6mg, 0.166mmol).After stirring 30min under 0 ℃, (22.5mg 0.166mmol), at room temperature stirs and spends the night to add the 4-isopropyl aniline.Make reactant at DCM (10mL) and H then ₂Distribute between the O (10mL).Organic phase is through Na ₂SO ₄Drying, vacuum concentration.(purifying of 1: 1 hexane/EtOAc) obtains title compound, is light brown solid (13.4mg, 18%) through preparation TLC.

¹H NMR(300MHz，CDCl ₃)δ8.32(s，1H)，7.36-7.03(m，6H)，5.99(m，1H)，4.62(m，1H)，4.32-4.23(m，2H)，4.04-3.88(m，8H)，2.83(m，1H)，2.32(m，1H)，2.14(m，2H)，1.19(d，6H)；

LC/MS (ESI): Theoretical Mass 459.2, actual measurement 460.2[M+1] ⁺

Embodiment 27

(4-sec.-propyl-phenyl)-3-(1-quinolyl-4)-tetramethyleneimine-3-base-urea (No. 27 compounds)

To racemize tetramethyleneimine-3-base-t-butyl carbamate (102mg, 0.55mmol), (Sigma-Aldrich, Inc) (82mg adds Virahol (2.5mL) to the 4-chloroquinoline in mixture 0.5mmol), mixture is stirred down at 100 ℃ spend the night.After being cooled to room temperature, vacuum concentration.Make residue at K ₂CO ₃Distribute between the aqueous solution and the DCM.Organic layer is emitted, use the salt water washing, through anhydrous MgSO ₄Drying is filtered, and vacuum concentration obtains thick (1-quinolyl-4-tetramethyleneimine-3-the yl)-t-butyl carbamate (27a) of 155mg (100%), its unprocessed next step that promptly is used for.LC/MS(ESI)：314(MH) ⁺。

(78mg 0.25mmol) is suspended in 5mL 50%TFA/DCM, at room temperature stirs 1h with thick 27a.With the mixture vacuum concentration, residue is washed with anhydrous diethyl ether then, discard washings.This process is repeated twice again,, obtain the thick 1-quinolyl-4-tetramethyleneimine of 97mg (90%)-3-base amine (27b) residue solid vacuum-drying, for yellow semi-solid, its unprocessed next step that promptly is used for.LC/MS(ESI)：214(MH) ⁺。

With thick 27b (22mg, 0.05mmol) be dissolved in anhydrous THF, add successively triethylamine (20mg, 0.2mmol), by (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester (30mg for preparing described in the embodiment 2a, 0.1mmol), mixture is stirred 1h down at 70 ℃.With the mixture vacuum concentration, make residue then at K ₂CO ₃Distribute between the aqueous solution and the EtOAc.Organic layer is emitted, use the salt water washing, through anhydrous MgSO ₄Drying is filtered, and vacuum concentration obtains crude product, through dodging column chromatography (silica gel; 1-2%MeOH/DCM, 90: 9: 1 DCM: MeOH: NH then ₃) purifying, obtain pure (4-sec.-propyl-phenyl)-3-of 10mg (54%) (1-quinolyl-4)-tetramethyleneimine-3-base-urea.

¹H NMR(300MHz，CDCl ₃)：δ8.07-7.97(m，2H)，7.94-7.84(m，2H)，7.62-7.5(m，2H)，7.31-7.23(m，3H)，7.11-7.05(m，2H)，5.81(d，1H)，4.74-4.64(m，1H)，4.09-4.00(dd，1H)，3.66-3.38(m，3H)，2.88-2.74(heptet，1H)，2.34-1.90(m，2H)，1.18(d，6H).

LC/MS (ESI): Theoretical Mass 374.2, actual measurement 375.2 (MH) ⁺

Embodiment 28

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-yl]-3-(4-sec.-propyl-phenyl)-urea (No. 28 compounds)

Press preparation described in the embodiment 27, difference is that the 7-dimethoxyquinazoline replaces racemize tetramethyleneimine-3-base-t-butyl carbamate and 4-chloroquinoline respectively with racemize piperidines-3-base-t-butyl carbamate and 4-chloro-6.And replace (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester with isocyanic acid 4-sec.-propyl phenyl ester, replace THF, mixture is stirred 3h down at 100 ℃ with diox.Through dodging column chromatography (silica gel; 2-3%MeOH/DCM) purifying obtains the pure 1-[1-of 30mg (67%) (6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-yl]-3-(4-sec.-propyl-phenyl)-urea.

¹H NMR(300MHz，CDCl ₃)：δ8.32(s，1H)，7.21(s，1H)，7.17(d，2H)，7.02(m，3H)，4.09(m，1H)，4.00-3.78(m，9H)，3.60(m，1H)，2.79(m，1H)，2.12-1.91(m，2H)，1.82-1.65(m，2H)，1.16(d，6H).

LC/MS (ESI): Theoretical Mass 449.2, actual measurement 450.4 (MH) ⁺

Embodiment 29

1-[1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-yl]-3-(4-isopropoxy-phenyl)-urea (No. 29 compounds)

To 1,1 '-carbonyl dimidazoles (29.0mg adds in DCM 0.179mmol) (1mL) solution and press the 4-(3-amino-tetramethyleneimine-1-yl)-6 that embodiment 26d prepares, and 7-dimethoxy yl-quinoline-3-formonitrile HCN (53.3mg, 0.179mmol).After stirring 30min under 0 ℃, (27.0mg 0.179mmol), at room temperature stirs and spends the night to add the 4-isopropoxy aniline.Make reactant at DCM (10mL) and H then ₂Distribute between the O (10mL).Organic phase is through Na ₂SO ₄Drying, vacuum concentration.(purifying of 1: 1 hexane/EtOAc) obtains title compound, is light brown solid (13.9mg, 16%) through preparation TLC.

¹H NMR(300MHz，CDCl ₃)δ8.34(s，1H)，7.28-7.24(m，iH)，7.15(d，2H)，6.93(s，1H)，6.78(d，2H)，5.73(br s，NH)，4.56(br s，NH)，4.43(m，1H)，4.20(m，2H)，3.96(s，3H)，3.94(s，3H)，3.84(m，2H)，2.30-2.04(m，3H)，1.28(d，6H)；

LC/MS (ESI): Theoretical Mass 475.2, actual measurement 476.2[M+1] ⁺

Embodiment 30

N-(3-isopropoxy-phenyl)-1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-methane amide (No. 30 compounds)

According to the synthetic method of embodiment 13b, use the 3-isopropoxy aniline.

¹H NMR(300MHz，CDCl ₃)δ8.68(s，1H)，7.39-7.35(m，2H)，7.24(s，1H)，7.20(t，J＝8.1Hz，1H)，7.10(s，1H)，6.95(d，J＝8.6Hz，1H)，6.66(dd，J＝8.1Hz，2.3Hz，1H)，4.56(sept，J＝6.1Hz，1H)，4.24-4.19(m，2H)，4.01(s，3H)，3.99(s，3H)，3.10(m，2H)，2.57(m，1H)，2.23-2.10(m，4H)，1.33(d，J＝6.1Hz，6H)；

LC/MS (ESI): Theoretical Mass 450.2, actual measurement 451.5 (M+H) ⁺

Embodiment 31

(4-sec.-propyl-phenyl)-carboxylamine 1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-yl] ester (No. 31 compounds)

(15mg, 0.115mmol) with 4-chloro-6, (23mg 0.1mmol) is dissolved in no Shui diox to the 7-dimethoxyquinazoline with racemize piperidines-3-alcohol.(Argonaut, Inc.) (100mg 0.3mmol), stirs 3h with mixture down at 100 ℃, is cooled to room temperature then to add PS-NMM.Add then the PS-isocyanic ester (Argonaut, Inc.) (100mg, 0.3mmol), with mixture jolting 3h at room temperature.Filter then, resin Yong diox is washed.In filtrate that merges and washings, add isocyanic acid 4-sec.-propyl phenyl ester (0.15mmol), mixture is stirred 3h down at 100 ℃, be cooled to room temperature then, vacuum concentration.Residue through dodge column chromatography (silica gel, 0-1%MeOH/DCM) purifying obtain pure (4-sec.-propyl-phenyl)-carboxylamine 1-[1-of 31mg (70%) (6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-yl] ester.

¹H NMR(300MHz，CDCl ₃+CD ₃OD)：δ8.50(s，1H)，7.22(s，1H)，7.18-7.00(m，5H)，4.98(m，1H)，4.14-3.80(m，8H)，3.75-3.45(m，3H)，2.79(m，1H)，2.15-1.70(m，3H)，1.16(d，6H).

LC/MS (ESI): Theoretical Mass 450.2, actual measurement 451.4 (MH) ⁺

Embodiment 32

(4-isopropoxy-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-base ester (No. 32 compounds)

A. (4-isopropoxy-phenyl)-carboxylamine 4-nitro-phenyl ester

Basically press described in the embodiment 2a, with the preparation of 4-isopropoxy aniline, difference is not water and 1M NaHCO ₃Washing.Obtain title compound, be grey violet-white solid (16.64g, 98%).

¹H NMR(300MHz，CDCl ₃)δ8.26(m，2H)，7.40-7.28(m，4H)，6.98(br s，1H)，6.87(m，2H)，4.50(heptet，J＝6.0Hz，1H)，1.33(d，J＝6.0Hz，6H).

LC/MS (ESI): Theoretical Mass 316.1, actual measurement 633.2 (2MH) ⁺

B. (4-isopropoxy-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-base ester

Basically press described in the embodiment 2b, with by the 4-chloro-6 for preparing described in the embodiment 26c, (4-isopropoxy-phenyl)-carboxylamine 4-nitro of 7-dimethoxy yl-quinoline-3-formonitrile HCN and above preparation-phenyl ester preparation, difference is to carry out the S of 30min under 100 ℃ _NAr reacts and add total～2-2.5 equivalent NaH in two batches in carbamate formation step, and this second step is carried out 30min under 80 ℃.Through dodging chromatography (1: 2 hexane/EtOAc), obtain title compound (4.6mg, 8.3%).

¹H NMR(300MHz，CDCl ₃)δ8.52(s，1H)，7.335(s，1H)，7.328(s，1H)，7.24(m，2H)，6.83(m，2H)，6.62(br s，1H)，5.49(m，1H)，4.48(heptet，1H)，4.46-4.31(m，2H)，4.02(s，3H)，3.97(s，3H)，4.02-3.95(m，2H)，2.39-2.31(m，2H)，1.31(d，6H).

LC/MS (ESI): Theoretical Mass 476.2, actual measurement 477.3 (MH) ⁺

Embodiment 33

(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-2-base methyl esters (No. 33 compounds)

Press preparation described in the embodiment 34, difference is that the 7-dimethoxyquinazoline replaces racemize 3-pyrrolidinol and 4-chloroquinoline respectively with racemize piperidines-2-methyl alcohol and 4-chloro-6.And replace (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester with isocyanic acid 4-sec.-propyl phenyl ester, do not add NaHMDS, replace THF, mixture is stirred 3h down at 100 ℃ with diox.Through dodging column chromatography (silica gel; 1-2%MeOH/DCM) purifying obtains pure (4-sec.-propyl-phenyl)-carboxylamine 1-[1-of 3.4mg (8%) (6,7-dimethoxy-quinazoline-4-yl)-piperidines-2-base methyl esters.

¹H NMR(300MHz，CDCl ₃)：δ8.68(s，1H)，7.62(s，1H)，7.32-7.27(m，4H)，7.16-7.11(m，2H)，4.96-4.89(m，1H)，4.74-4.64(m，1H)，4.62-4.53(m，1H)，4.28(m，1H)，4.02(s，3H)，3.74(s，3H)，3.00-2.82(m，2H)，1.98-1.86(m，1H)，1.85-1.50(m，5H)，1.22(d，6H).

LC/MS (ESI): Theoretical Mass 464.2, actual measurement 465.3 (MH) ⁺

Embodiment 34

(4-sec.-propyl-phenyl)-carboxylamine 1-quinolyl-4)-tetramethyleneimine-3-base ester (No. 34 compounds)

(48mg, 0.55mmol) (82mg adds Virahol (2.5mL) in mixture 0.5mmol), mixture is stirred down at 100 ℃ spend the night with the 4-chloroquinoline to racemize 3-pyrrolidinol.After being cooled to room temperature, vacuum concentration.Make residue at K ₂CO ₃Distribute between the aqueous solution and the DCM.Organic layer is emitted water and salt water washing.Then through anhydrous MgSO ₄Drying is filtered, and vacuum concentration obtains the thick 1-quinolyl-4-tetramethyleneimine of 105mg (100%)-3-alcohol (34a), its unprocessed next step that promptly is used for.

With thick 34a (11mg, 0.05mmol) be dissolved in anhydrous THF, at room temperature stir, add the THF solution (0.1mL of 1.0M NaHMDS simultaneously successively, 0.1mmol), by (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester for preparing described in the embodiment 2a (30mg, 0.1mmol).Mixture is at room temperature stirred 30min, stir 30min down at 80 ℃ then.With the mixture vacuum concentration, make residue then at K ₂CO ₃Distribute between the aqueous solution and the EtOAc.Organic layer is emitted water and salt water washing.Then through anhydrous MgSO ₄Drying is filtered, and vacuum concentration obtains crude product, through preparation TLC (silica gel; 5%MeOH/DCM) purifying obtains pure (4-sec.-propyl-phenyl)-carboxylamine 1-of 6.9mg (37%) quinolyl-4)-tetramethyleneimine-3-base ester.

¹H NMR(300MHz，CDCl ₃)：δ8.49(d，1H)，8.18(d，1H)，8.07(d，1H)，7.63(m，1H)，7.39(m，1H)，7.31-7.24(m，2H)，7.16(m，2H)，6.82(bs，1H)，6.48(d，1H)，5.53(m，1H)，4.16-4.08(m，1H)，4.02-3.90(m，1H)，3.86-3.70(m，2H)，2.92-2.80(m，1H)，2.40-2.2(m，2H)，1.21(d，6H).

LC/MS (ESI): Theoretical Mass 375.2, actual measurement 376.2 (MH) ⁺

Embodiment 35

N-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-2-(4-sec.-propyl-phenyl)-ethanamide (No. 35 compounds)

A.[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-t-butyl carbamate

To 4-chloro-6,7-dimethoxy-quinazoline (48.5mg, add successively in i-PrOH 0.22mmol) (2mL) solution 3-(tert-butoxycarbonyl amino) tetramethyleneimine (44.2mg, 0.24mmol), DIEA (55.8mg, 0.43mmol).Stir down, mixture is heated down at 100 ℃.After stirring 1h,, residue is distributed between EtOAc and water with the homogeneous phase solution concentrating under reduced pressure.Organic layer is merged, dry (through Na ₂SO ₄), concentrate, obtain title compound, be white solid (60mg, 78%).

¹H NMR(300MHz，CDCl ₃)δ8.40(s，1H)，7.36(s，1H)，7.22(s，1H)，5.19(d，J＝6.72Hz，1H)，4.10(m，2H)，3.98(s，3H)，3.95(s，3H)，3.84(dd，J＝11.35 and 3.70Hz，2H)，3.63(m，1H)，2.24(m，1H)，2.08(m，1H)，1.42(s，9H).

LC/MS (ESI): Theoretical Mass 374.2, actual measurement 375.3 (MH ⁺).

B.1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base amine trifluoroacetate

Will be by [1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-t-butyl carbamate (38mg, 0.10mmol) usefulness 50%TFA/DCM (5mL) processing of previous step preparation.At room temperature stir under the 3h,, obtain title compound, be semi-solid (48mg, 100%) solution evaporation.

¹H NMR(300MHz，CD ₃OD)δ8.63(s，1H)，7.68(s，1H)，7.23(s，1H)，4.31(m，1H)，4.15(m，2H)，4.05(s，3H)，4.02(s，3H)，3.72(m，1H)，3.22(m，1H)，2.58(m，1H)，2.38(m，1H).

LC/MS (ESI): the Theoretical Mass 274.1 of free alkali, actual measurement 275.2 (MH ⁺).

C.N-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-2-(4-sec.-propyl-phenyl)-ethanamide

To 1-(6 by the previous step preparation, 7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base amine trifluoroacetate (38mg, 0.10mmol) and (4-sec.-propyl-phenyl)-acetate (18mg, 0.10mmol) add HOBT (20mg successively in the mixture in anhydrous THF (2mL), 0.13mmol), HBTU (49.3mg, 0.13mmol) and DIEA (64.6mg, 0.50mmol).Suspension is at room temperature stirred 14h, concentrating under reduced pressure.Residue dodges column chromatography (5%MeOH/EtOAc makes elutriant) purifying through silica gel, obtains title compound, is white solid (40mg, 92%).

¹H NMR(300MHz，CDCl ₃)δ8.32(s，1H)，7.36(s，1H)，7.23(s，1H)，7.18(s，4H)，6.28(br，1H)，4.65(m，1H)，4.09(m，2H)，3.98(s，3H)，3.97(s，3H)，3.82(m，2H)，3.57(s，2H)，2.88(m，1H)，2.29(m，1H)，2.02(m，1H)，1.2(d，J＝6.92Hz，6H).

LC/MS (ESI): Theoretical Mass 434.2, actual measurement 435.3 (MH ⁺).

Embodiment 36

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-isopropoxy-phenyl)-1-methyl-urea (No. 36 compounds)

According to the synthetic method of embodiment 29, use by the 1-for preparing described in the embodiment 19a (6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base-methylamine trifluoroacetate.

¹H NMR(300MHz，CDCl3)δ8.52(s，1H)，7.42(s，1H)，7.27-7.24(m，3H)，6.84(d，J＝8.9Hz，2H)，6.29(s，1H)，5.22(m，1H)，4.48(m，J＝6.0Hz，1H)，4.15-3.81(m，4H)，4.01(s，3H)，3.97(s，3H)，3.01(s，3H)，2.24(m，2H)，1.30(d，J＝6.0Hz，6H).

LC/MS (ESI) Theoretical Mass 465.2, actual measurement 466.2 (MH) ⁺

Embodiment 37

(4-sec.-propyl-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-base ester (No. 37 compounds)

Basically press described in the embodiment 2b, with the 4-chloro-6 of pressing embodiment 26c preparation, 7-dimethoxy yl-quinoline-3-formonitrile HCN preparation, difference is to carry out S under 100 ℃ _NAr reacts 30min and add total～2-2.5 equivalent NaH in two batches in carbamate formation step, and this second step is carried out 30min under 80 ℃.Through dodging chromatography (1: 3 hexane/EtOAc), obtain title compound (2.2mg, 3.8%).

¹H NMR(300MHz，CDCl ₃)δ8.52(s，1H)，7.35(s，1H)，7.33(s，1H)，7.27(m，2H)，7.16(m，2H)，6.65(br s，1H)，5.50(m，1H)，4.47-4.32(m，2H)，4.03(s，3H)，3.97(s，3H)，4.03-3.97(m，2H)，2.87(heptet，1H)，2.40-2.32(m，2H)，1.22(d，6H).

LC/MS (ESI): Theoretical Mass 460.2, actual measurement 461.3 (MH) ⁺

Embodiment 38

(4-isopropoxy-phenyl)-3-(1-quinolyl-4)-tetramethyleneimine-3-base-urea (No. 38 compounds)

Press preparation described in the embodiment 27, difference is to use by (4-isopropoxy-phenyl)-carboxylamine 4-nitro for preparing described in the embodiment 32a-phenyl ester and replaces (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester.Through dodging column chromatography (silica gel; 1-2%MeOH/DCM, 90: 9: 1 DCM: MeOH: NH then ₃) purifying, obtain pure (4-isopropoxy-phenyl)-3-of 10.4mg (53%) (1-quinolyl-4)-tetramethyleneimine-3-base-urea.

¹H NMR(300MHz，CDCl ₃)：δ8.01(dd，1H)，7.96(d，1H)，7.88(dd，1H)，7.79(bs，1H)，7.58-7.52(m，1H)，7.35(br m，1H)，7.27(m，1H)，7.23(m，2H)，6.81-6.74(m，2H)，5.85(d，1H)，4.67(m，1H)，4.47-4.37(m，1H)，4.08-4.00(m，1H)，3.67-3.4(m，3H)，2.3-2.1(m，2H)，1.28(d，6H).

LC/MS (ESI): Theoretical Mass 390.2, actual measurement 391.2 (MH) ⁺

Embodiment 39

(4-isopropoxy-phenyl)-carboxylamine 1-quinolyl-4)-tetramethyleneimine-3-base ester (No. 39 compounds)

Press preparation described in the embodiment 34, difference is to use by (4-isopropoxy-phenyl)-carboxylamine 4-nitro for preparing described in the embodiment 32a-phenyl ester and replaces (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester.Through preparation TLC (silica gel; 5%MeOH/DCM) purifying obtains pure (4-isopropoxy-phenyl)-carboxylamine 1-of 5.7mg (30%) quinolyl-4)-tetramethyleneimine-3-base ester.

¹H NMR(300MHz，CDCl ₃)：δ8.71(s，1H)，8.46(d，1H)，8.21(d，1H)，7.73-7.64(m，1H)，7.48-7.39(m，1H)，7.22(m，2H)，6.83(d，2H)，6.75-6.62(m，1H)，6.5(d，1H)，5.54(m，1H)，4.52-4.42(m，1H)，4.24-4.12(m，1H)，4.08-3.94(m，1H)，3.94-3.74(m，2H)，2.50-2.18(m，2H)，1.30(d，6H).

LC/MS (ESI): Theoretical Mass 391.2, actual measurement 392.2 (MH) ⁺

Embodiment 40

(4-isopropoxy-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-piperidin-4-yl ester (No. 40 compounds)

Basically press described in the embodiment 34, with 4-chloro-6,7-dimethoxy yl-quinoline-3-formonitrile HCN (J.Med. Chem.43:3244,2000), by (4-isopropoxy-phenyl)-carboxylamine 4-nitro-phenyl ester for preparing among the embodiment 32a and 4-hydroxy piperidine (Acros, water is less than 1%, K.F.) preparation, difference is with～1.5 equivalent NaH.(1: 2 hexane/EtOAc), obtain title compound is yellow film shape thing (11.4mg, 10.5%) through dodging chromatography.

¹H NMR(300MHz，CDCl ₃)δ8.63(s，1H)，7.40(s，1H)，7.30(m，2H)，7.21(s，1H)，6.86(m，2H)，6.56(br s，1H)，5.14(m，1H)，4.49(heptet，1H)，4.05(s，3H)，4.02(s，3H)，3.87-3.74(m，2H)，3.63-3.52(m，2H)，2.30-2.18(m，2H)，2.11-1.96(m，2H)，1.33(d，6H).

LC/MS (ESI): Theoretical Mass 490.2, actual measurement 491.3 (MH) ⁺

Embodiment 41

(4-isopropoxy-phenyl)-carboxylamine 1-quinolyl-4)-piperidin-4-yl ester (No. 41 compounds)

Press preparation described in the embodiment 39, difference is to replace tetramethyleneimine-3-alcohol with the 4-hydroxy piperidine.Through preparation TLC (silica gel; 5%MeOH/DCM) purifying obtains pure (4-isopropoxy-phenyl)-carboxylamine 1-of 1mg (5%) quinolyl-4)-the piperidin-4-yl ester.

¹H NMR(300MHz，CDCl ₃)：δ8.75-8.63(m，1H)，8.13-7.86(m，3H)，7.76-7.60(m，2H)，6.92-6.84(d，2H)，6.54(m，2H)，5.25-5.12(m，1H)，4.55-4.45(m，1H)，4.2-3.6(m，4H)，2.35-2.00(m，4H)，1.32(d，6H).

LC/MS (ESI): Theoretical Mass 405.2, actual measurement 406.2 (MH) ⁺

Embodiment 42

(4-sec.-propyl-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-piperidin-4-yl ester (No. 42 compounds)

A. (4-sec.-propyl-phenyl)-carboxylamine piperidin-4-yl ester

To 1,1 '-carbonyl dimidazoles (304mg, add in DCM 1.88mmol) (10mL) solution 4-hydroxy-piperdine-1-t-butyl formate (350mg, 1.74mmol).After stirring 30min under 0 ℃, (251mg 1.86mmol), at room temperature stirs to add the 4-isopropyl aniline.After stirring is spent the night, the solvent vacuum is removed, obtain thick solid.Add TFA (20mL) and DCM (20mL) to thick solid, stir 30min,, obtain title compound, be solid (113mg, 25%) the solvent concentrating under reduced pressure.

¹H NMR(300MHz，CDCl ₃)δ7.31(m，2H)，7.14(m，2H)，4.82(br s，NH)，3.07(m，3H)，2.89-2.74(m，3H)，1.92(m，2H)，1.61(m，2H)，1.22(s，3H)，1.19(s，3H)；

LC/MS (ESI): Theoretical Mass 262.2, actual measurement 263.2[M+1] ⁺

B. (4-sec.-propyl-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-piperidin-4-yl ester

Will be by (4-sec.-propyl-phenyl)-carboxylamine piperidin-4-yl ester (44mg of previous step preparation, 0.168mmol) Virahol (1mL) solution with press the 4-chloro-6 that embodiment 26c prepares, (42mg 0.169mmol) handles 7-dimethoxy yl-quinoline-3-formonitrile HCN.Under 100 ℃, stir and spend the night, reactant is cooled to room temperature, make it at DCM (10mL) and H ₂Distribute between the O (10mL).Organic phase is through Na ₂SO ₄Drying, vacuum concentration.(purifying of 1: 1 hexane/EtOAc) obtains title compound, is light yellow solid (4.7mg, 5.9%) through preparation TLC.

¹H NMR(300MHz，CDCl ₃)δ8.63(s，1H)，7.38-7.18(m，6H)，6.69(br s，NH)，5.14(m，1H)，4.04(s，3H)，4.02(s，3H)，3.80(m，2H)，3.58(m，2H)，2.90(m，1H)，2.25(m，2H)，2.06(m，2H)，1.23(d，6H)；

LC/MS (ESI): Theoretical Mass 474.2, actual measurement 475.3[M+1] ⁺

Embodiment 43

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-morpholine-4-base-phenyl)-urea (No. 43 compounds)

A. (4-morpholine-4-base-phenyl)-carboxylamine 4-nitro-phenyl ester; Hydrochloride

At room temperature, under air, stir down, in～10s, with chloroformic acid 4-nitro phenyl ester (798mg, 3.96mmol) THF (2.0mL) solution add 4-morpholine-4-base-aniline fast by syringe (675mg, in THF 3.79mmol) (8.8mL) solution, " immediately " form the Dark grey precipitation.Immediately reactant is sealed, stirred 30min (the bottle temperature rises automatically) down, filter then in " room temperature ".(2 * 10mL) washings, under 80 ℃, drying obtains title compound under high vacuum, is grey powder (1.361g, 95%) with anhydrous THF with the grey filter cake.Make portion of product at CDCl ₃And distribute between the 0.5M trisodium citrate aqueous solution, obtain dissolving in CDCl ₃Free alkali:

¹H-NMR(300MHz，CDCl ₃)δ8.28(m，2H)，7.42-7.31(m，4H)，6.95-6.88(m，3H)，3.87(m，4H)，3.14(m，4H).

B. (4-morpholine-4-base-phenyl)-carboxylamine 4-nitro-phenyl ester

At room temperature, in 1-2min, streamed (3.033g, (10.81g is 28.48mmol) in (embodiment 43a) mixture in water (100mL) 30.0mmol) to add rapidly (4-morpholine-4-base-phenyl)-carboxylamine 4-nitro-phenyl ester hydrochloride under stirring with TEA with liquid.Soup compound is stirred 5min, filter then.At room temperature, the drabon look filter cake of olive is stirred 5min in water (50mL), filter then, remove remaining TEAHCl.Then filter cake is stirred in ether, filter, repeat (1 * 50mL, 1 * 30mL) twice.Then filter cake is partially soluble in the EtOAc that boils (100mL), by Celite pad with muddiness " solution " heat filtering.Make the clarification yellow filtrate that obtains be cooled to room temperature, at this moment, separate out the crystallization of title compound in the solution, be free alkali.Crystallization is filtered, and washing (1 * 30mL ether) is dried, and obtains title compound, is yellow spicule (5.36g, 50%).

C.1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-morpholine-4-base-phenyl)-urea

Basically press described in the embodiment 50b, with (4-morpholine-4-base-phenyl)-carboxylamine 4-nitro-phenyl ester (embodiment 43b) preparation.

¹H NMR(400MHz，CDCl ₃)δ8.37(s，1H)，7.30(s，1H)，7.18(s，1H)，7.16(m，2H)，6.85(m，2H)，6.60(br s，1H)，5.60(br s，1H)，4.61(m，1H)，4.10(dd，1H)，3.98(s，3H)，3.95(s，3H)，3.93(m，2H)，3.88-3.80(m，5H)，3.11(m，4H)，2.28(m，1H)，2.11(m，1H).

LC/MS (ESI): Theoretical Mass 478.2, actual measurement 479.1 (MH) ⁺

Embodiment 44

1-(6-cyclobutoxy group-pyridin-3-yl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea (No. 44 compounds)

Basically press described in the embodiment 50b, with (6-cyclobutoxy group-pyridin-3-yl)-carboxylamine 4-nitro-phenyl ester (embodiment 11d) preparation.

¹H NMR(400MHz，CDCl ₃)δ8.21(s，1H)，7.96(d，1H)，7.78(dd，1H)，7.60(br s，1H)，7.15(s，1H)，7.05(s，1H)，6.93(br d，1H)，6.62(d，1H)，5.04(m，1H)，4.63(m，1H)，4.00(dd，1H)，3.93(s，3H)，3.90(s，3H)，3.89-3.79(m，3H)，2.40(m，2H)，2.22(m，2H)，2.08(m，2H)，1.80(m，1H)，1.63(m，1H).

LC/MS (ESI): Theoretical Mass 464.2, actual measurement 465.1 (MH) ⁺

Embodiment 45

1-(6-cyclopentyloxy-pyridin-3-yl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea (No. 45 compounds)

A.2-cyclopentyloxy-5-nitro-pyridine

Stir down, in～30 seconds, (7.01g, (3.9g, 45.3mmol) add sodium hydride in the solution (1.3g 54.2mmol), cools off with 0 ℃ of ice bath in batches for THF 44.4mmol) (30mL) and cyclopentanol to 2-chloro-5-nitropyridine.After stirring 5min under 0 ℃, remove ice bath, reactant is at room temperature stirred 3h.Vacuum concentration is dissolved in DCM with residue then, uses 1MNaHCO ₃Thorough washing is then through anhydrous Na ₂SO ₄Drying is filtered vacuum concentration.(silica gel, 9: 1 hexanes: ethyl acetate) purifying obtains pure 2-cyclopentyloxy-5-nitro-pyridine (0.4g, 4%) to crude product through dodging column chromatography.

¹H-NMR(300MHz，CDCl ₃)：δ9.07(s，1H)，8.32(m，1H)，6.74(d，1H)，5.53(m，1H)，2.00(m，2H)，1.81(m，4H)，1.66(m，2H).

B.6-cyclopentyloxy-pyridin-3-yl amine

(0.3099g adds 10%Pd/C (90mg) in MeOH 1.49mmol) (2mL) solution to 2-cyclopentyloxy-5-nitro-pyridine.With the solution degassing, under nitrogen atmosphere, continuously stirring is spent the night.Filter by Celite pad,, obtain the product of needs, be brown oil (248mg, 94% yield) the filtrate evaporation.

¹H-NMR(300MHz，CDCl ₃)：δ7.69(d，1H)，7.04(m，1H)，6.56(d，1H)，5.25(m，1H)，1.93(m，2H)，1.78(m，4H)，1.60(m，2H).

LC/MS (ESI) C ₁₀H ₁₄N ₂O theoretical value 178.23, actual measurement [M+41+1] ⁺220.0.

C. (6-cyclopentyloxy-pyridin-3-yl)-carboxylamine 4-nitro-phenyl ester

To 6-cyclopentyloxy-pyridin-3-yl amine (0.248g, add in THF 1.39mmol) (2mL) solution in batches chloroformic acid 4-nitro phenyl ester (0.280g, 1.39mmol).After at room temperature stirring 1h, form a large amount of precipitations in the organic layer.Organic layer is filtered, obtain title compound, be baby pink solid (0.368g, 77%).

¹H-NMR(400MHz，CDCl ₃)：δ11.1(s，1H)，9.11(s，1H)，9.04(d，1H)，8.26(d，2H)，7.40(d，2H)，7.14(d，1H)，5.36(m，1H)，2.11(m，2H)，1.97(m，2H)，1.84(m，2H)，1.71(m，2H).

D.1-(6-cyclopentyloxy-pyridin-3-yl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea

Basically press described in the embodiment 50b, with (6-cyclopentyloxy-pyridin-3-yl)-carboxylamine 4-nitro-phenyl ester (embodiment 45c) preparation.

¹H NMR(400MHz，CDCl ₃)δ8.22(s，1H)，7.98(d，1H)，7.76(dd，1H)，7.56(br s，1H)，7.15(s，1H)，7.05(s，1H)，6.90(br d，1H)，6.62(d，1H)，5.24(m，1H)，4.63(m，1H)，4.01(dd，1H)，3.94(s，3H)，3.91(s，3H)，3.89-3.79(m，3H)，2.21(m，2H)，1.90(m，2H)，1.75(m，4H)，1.58(m，2H).

LC/MS (ESI): Theoretical Mass 478.2, actual measurement 479.1 (MH) ⁺

Embodiment 46

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(6-tetramethyleneimine-1-base-pyridin-3-yl)-urea (No. 46 compounds)

A. (6-tetramethyleneimine-1-base-pyridin-3-yl)-carboxylamine 4-nitro-phenyl ester; Hydrochloride;

Basically by preparation (4-morpholine-4-base-phenyl)-carboxylamine 4-nitro-phenyl ester; Described in the hydrochloride (embodiment 43a), with 6-tetramethyleneimine-1-base-pyridin-3-yl amine (WO 2002048152A2) preparation.Make portion of product at CDCl ₃And distribute between the 0.5M trisodium citrate aqueous solution, obtain being dissolved in CDCl ₃Free alkali:

¹H-NMR(300MHz，CDCl ₃)δ8.27(m，2H)，8.10(d，1H)，7.67(dd，1H)，7.39(m，2H)，6.81(br s，1H)，6.38(d，1H)，3.45(m，4H)，2.02(m，4H).

LC/MS (ESI): Theoretical Mass 328.1, actual measurement 329.0 (MH) ⁺

B.1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(6-tetramethyleneimine-1-base-pyridin-3-yl)-urea

Basically press described in the embodiment 16, with 4-chloro-6,7-dimethoxyquinazoline (Oakwood) and (6-tetramethyleneimine-1-base-pyridin-3-yl)-carboxylamine 4-nitro-phenyl ester; Hydrochloride (embodiment 46a) preparation.Basically press described in the embodiment 50b through the HPLC purifying.

¹H NMR(400MHz，CDCl ₃)δ8.37(s，1H)，7.98(d，1H)，7.43(dd，1H)，7.28(s，1H)，7.13(s，1H)，6.56(br s，1H)，6.29(d，1H)，5.56(br s，1H)，4.57(m，1H)，4.09(dd，1H)，3.98(s，3H)，3.94(s，3H)，3.96-3.87(m，2H)，3.77(dd，1H)，3.39(m，4H)，2.25(m，1H)，2.05(m，1H)，1.98(m，4H).

LC/MS (ESI): Theoretical Mass 463.2, actual measurement 464.1 (MH) ⁺

Embodiment 47

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-piperidines-1-base-phenyl)-urea (No. 47 compounds)

A. (4-piperidines-1-base-phenyl)-carboxylamine 4-nitro-phenyl ester

With chloroformic acid 4-nitro phenyl ester (1.49g, the disposable adding 4-piperidines of toluene 7.39mmol) (7.4mL) solution-1-base-aniline (1.00g, 5.68mmol) (Maybridge) and CaCO ₃(739mg is 7.39mmol) in the mixture of (10 μ m powder).With mixture jolting 5min (spontaneous intensification) at room temperature, the opaque soup compound of the little green of the consistence that obtains with other toluene (7.4mL) dilution, is at room temperature stirred 1h.The silica gel that then the crude reaction thing is installed to the hexane/EtOAc pre-equilibration with 2.5: 1 dodges on the post, with 2.5: 1 hexane/EtOAc → EtOAc → 9: the 1DCM/MeOH gradient elution, obtain title compound, be grey powder (1.42g, 73%).

LC/MS (ESI): Theoretical Mass 341.1, actual measurement 342.2 (MH) ⁺

B.1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-piperidines-1-base-phenyl)-urea

Basically press described in the embodiment 16, with 4-chloro-6,7-dimethoxyquinazoline (Oakwood) and (4-piperidines-1-base-phenyl)-carboxylamine 4-nitro-phenyl ester (embodiment 47a) preparation.Basically press described in the embodiment 50b through the HPLC purifying.

¹H NMR(400MHz，CDCl ₃)δ8.36(s，1H)，7.27(s，1H)，7.13(m，3H)，6.85(m，2H)，6.41(br s，1H)，5.82(br s，1H)，4.59(m，1H)，4.08(dd，1H)，3.96(s，3H)，3.93(s，3H)，3.89(m，2H)，3.79(dd，1H)，3.08(m，4H)，2.24(m，1H)，2.07(m，1H)，1.69(m，4H)，1.56(m，2H).

LC/MS (ESI): Theoretical Mass 476.3, actual measurement 477.1 (MH) ⁺

Embodiment 48

1-(4-chloro-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea (No. 48 compounds)

With [1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-t-butyl carbamate (55mg, 147 μ mol) (embodiment 35a), DMSO (112 μ L) and TFA (225 μ L, 3mmol) solution stirring 5min under 100 ℃.The yellow homogeneous phase solution that obtains (is distributed between 1 * 2mL) at 2.5MNaOH (2mL) and DCM.Organic layer is concentrated (undried agent pre-treatment), obtain thick amine intermediate, be yellow oil.Add DCM (300 μ L), isocyanic acid 4-chlorobenzene ester (25mg, 160 μ mol) successively, homogeneous phase solution is at room temperature stirred spend the night, obtain consistence white soup compound this moment.Make reactant at 2M K ₂CO ₃(2mL) and between the DCM (2mL) distribute, with DCM/MeOH (2 * 2mL) extractions of organic layer with 9: 1.The organic layer that merges is filtered, filtrate is concentrated, residue is through C18 reversed-phase HPLC (condition is basically with identical described in the embodiment 50b) purifying.Extract short column mutually by the supercarbonate solid then, obtain title compound { 3.2mg, 5%, by [1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-t-butyl carbamate meter }.

¹H NMR(400MHz，95∶5 CDCl ₃/CD ₃OD)δ8.35(s，1H)，7.33(s，1H)，7.28(m，2H)，7.18(m，2H)，7.10(s，1H)，4.52(m，1H)，4.12(dd，1H)，3.98(s，3H)，3.94(s，3H)，4.00-3.88(m，2H)，3.82(dd，1H)，2.28(m，1H)，2.06(m，1H).

LC/MS (ESI): Theoretical Mass 427.1, actual measurement 428.0 (MH) ⁺

Embodiment 49

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-tetramethyleneimine-1-base-phenyl)-urea (No. 49 compounds)

A. (4-tetramethyleneimine-1-base-phenyl)-carboxylamine 4-nitro-phenyl ester hydrochloride

At room temperature, stir down, in the 70mL anhydrous THF solution of 4.9g (30.4mmol) 4-tetramethyleneimine-1-base-aniline, drip the 16mL anhydrous THF solution of 6.4g (32mmol) chloroformic acid 4-nitro phenyl ester.After dripping end, mixture is stirred 1h, filter then.To precipitate use successively anhydrous THF (2 * 10mL), anhydrous DCM (3 * 10mL) washing, vacuum-drying obtains the 10g pale solid.

¹H-NMR(300MHz，CD ₃OD)：10.39(s，1H)，8.32(d，2H)，7.73(d，2H)，7.60(d，2H)，7.48(d，2H)，3.86-3.68(bs，4H)，2.35-2.24(bs，4H).LC/MS(ESI)：328(MH) ⁺.

B.1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-tetramethyleneimine-1-base-phenyl)-urea

Basically press described in the embodiment 50b, with (4-tetramethyleneimine-1-base-phenyl)-carboxylamine 4-nitro-phenyl ester hydrochloride preparation, difference is with 2.2 equivalent TEA (42mg, 420 μ mol).

¹H NMR(400MHz，CDCl ₃)δ8.44(s，1H)，7.35(s，1H)，7.18(s，1H)，7.03(m，2H)，6.48(m，2H)，6.11(br s，1H)，4.95(br d，1H)，4.56(m，1H)，4.13(dd，1H)，4.00(s，3H)，3.96(s，3H)，3.93(t，2H)，3.74(dd，1H)，3.25(m，4H)，2.29(m，1H)，2.04-1.92(m，5H).

LC/MS (ESI): Theoretical Mass 462.2, actual measurement 463.1 (MH) ⁺

Embodiment 50

1-(4-cyclohexyl-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea

(No. 50 compounds)

A. (4-cyclohexyl-phenyl)-carboxylamine 4-nitro-phenyl ester

Except that replacing described in embodiment 2a, preparing basically the 4-isopropyl aniline with 4-cyclohexyl aniline.

¹H NMR(DMSO-d ₆)δ10.37(br，1H)，8.30(d，J＝9.30Hz，2H)，7.52(d，J＝9.00Hz，2H)，7.41(d，J＝8.10Hz，2H)，7.18(d，J＝8.70Hz，2H)，1.18-1.82(11H).

B.1-(4-cyclohexyl-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea

With [1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-t-butyl carbamate (56mg, 150 μ mol) (embodiment 35a), DMSO (112 μ L) and TFA (225 μ L, 3mmol) solution stirring 5min under 100 ℃.The yellow homogeneous phase solution that obtains (is distributed between 1 * 2mL) at 2.5MNaOH (2mL) and DCM.Organic layer is concentrated (undried agent pre-treatment), obtain thick amine intermediate, be yellow oil.This material is dissolved in CH immediately ₃CN (112 μ L) and TEA (30 μ L, 225 μ mol) handle with (4-cyclohexyl-phenyl)-carboxylamine 4-nitro-phenyl ester (64mg, 190 μ mol).Mixture is stirred 20min down at 100 ℃, be cooled to room temperature, make it at 2M K ₂CO ₃(2mL) and DCM (distribute between 2 * 2mL).Organic layer is merged dry (Na ₂SO ₄), concentrate.Residue is through C18 reversed-phase HPLC (the 0.1%TFA aqueous solution-CH ₃CN/0.1%TFA linear increment gradient) purifying extracts short column, lyophilize mutually by the supercarbonate solid then, obtain title compound, be the fluffy solid of white { 16.4mg, 23%, by [1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-t-butyl carbamate meter }.

¹H NMR(400MHz，CDCl ₃)δ8.28(s，1H)，7.25-7.20(m，4H)，7.13-7.07(m，3H)，6.44(br s，1H)，4.64(br s，1H)，4.05(dd，1H)，3.94(s，3H)，3.92(s，3H)，3.87(m，3H)，2.43(m，1H)，2.21(m，2H)，1.79(m，4H)，1.42-1.17(m，6H).

LC/MS (ESI): Theoretical Mass 475.3, actual measurement 476.1 (MH) ⁺

Embodiment 51

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-phenoxy group-phenyl)-urea

(No. 51 compounds)

With 4-chloro-6, the mixture of 7-dimethoxyquinazoline (34mg, 150 μ mol), 3-(tert-butoxycarbonyl amino) tetramethyleneimine (28mg, 150 μ mol), DIEA (28 μ L, 170 μ mol) and DMSO (100 μ L) stirs 20min down at 100 ℃.After being cooled to room temperature, (230 μ L 3.1mmol) add the yellow homogeneous phase solution that obtains, and solution is stirred 5min down at 100 ℃ with TFA.After being cooled to room temperature, reactant with DCM (2mL) dilution, is used 2.5M NaOH (1 * 2mL) washing.Organic layer is collected, concentrated, be dissolved in DCM (300 μ L), at room temperature, handle with isocyanic acid 4-phenoxy group phenyl ester (34mg, 162 μ mol).After at room temperature stirring is spent the night, mixture is carried out aftertreatment, title compound is pressed purifying described in the embodiment 48.

¹H NMR(400MHz，CDCl ₃)δ8.26(s，1H)，7.40(br s，1H)，7.30(m，4H)，7.21(s，1H)，7.12(s，1H)，7.06(m，1H)，6.95(m，4H)，6.59(br s，1H)，4.66(br m，1H)，4.05(dd，1H)，3.95(s，3H)，3.93(s，3H)，3.90(m，3H)，2.24(m，2H).

LC/MS (ESI): Theoretical Mass 485.2, actual measurement 486.1 (MH) ⁺

Embodiment 52

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-dimethylamino-phenyl)-urea (No. 52 compounds)

Basically press described in the embodiment 51, with the preparation of isocyanic acid 4-(dimethylamino) phenyl ester.

¹H NMR(400MHz，95∶5 CDCl ₃/CD ₃OD)δ8.41(s，1H)，7.36(s，1H)，7.16(s，1H)，7.10(m，2H)，6.68(m，2H)，4.54(m，1H)，4.15(dd，1H)，4.00(s，3H)，3.96(s，3H)，3.99-3.91(m，2H)，3.78(dd，1H)，2.91(s，3H)，2.90(s，3H)，2.30(m，1H)，2.00(m，1H).

LC/MS (ESI): Theoretical Mass 436.2, actual measurement 437.1 (MH) ⁺

Embodiment 53

1-(4-cyclopentyloxy-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea (No. 53 compounds)

A. (4-cyclopentyloxy-phenyl)-carboxylamine 4-nitro-phenyl ester

Basically described in embodiment 45a-c, prepare, replace 2-chloro-5-nitropyridine with the 4-fluoronitrobenzene.

¹H NMR(CDCl ₃)δ8.28(m，2H)，7.39(m，2H)，7.33(m，2H)，6.87(m，3H)，4.74(m，1H)，1.96-1.72(m，6H)，1.62(m，2H).

B.1-(4-cyclopentyloxy-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea

Basically press described in the embodiment 16, with 4-chloro-6,7-dimethoxyquinazoline (Oakwood) and (4-cyclopentyloxy-phenyl)-carboxylamine 4-nitro-phenyl ester (embodiment 53a) prepare, with carboxylamine nitro phenyl ester reactant under 80 ℃ at CHCl ₃Middle heating replaces under 100 ℃ at CH ₃Heat among the CN.Basically press described in the embodiment 50b through the HPLC purifying.

¹H NMR(400MHz，CDCl ₃)δ8.36(s，1H)，7.27(s，1H)，7.17(m，2H)，7.14(s，1H)，6.80(m，2H)，6.74(br s，1H)，5.80(br d，1H)，4.70(m，1H)，4.60(m，1H)，4.09(dd，1H)，3.97(s，3H)，3.94(s，3H)，3.96-3.87(m，2H)，3.82(dd，1H)，2.33-2.20(m，1H)，2.17-2.05(m，1H)，1.95-1.52(m，8H).

LC/MS (ESI): Theoretical Mass 477.2, actual measurement 478.1 (MH) ⁺

Embodiment 54

(4-cyclopentyloxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester (No. 54 compounds)

With 4-chloro-6, the mixture of 7-dimethoxyquinazoline (35mg, 160 μ mol), 3-pyrrolidinol (14mg, 160 μ mol), DMSO (100 μ L) and DIPEA (30 μ L, 170 μ mol) stirs 5min down at 100 ℃.The homogeneous phase solution that obtains is cooled to room temperature, uses 1.07MKOtBu/THF (306 μ L, 327 μ mol) to handle then, at room temperature stirred～1 minute again.Disposable then adding (4-cyclopentyloxy-phenyl)-carboxylamine 4-nitro-phenyl ester (64mg, 190 μ mol) (embodiment 53a) is at room temperature stirred 15min with the translucent yellow " solution " that obtains.Then reactant is carried out aftertreatment, press purifying described in the embodiment 48, obtain title compound (13.9mg, 19%, press 4-chloro-6,7-dimethoxyquinazoline meter).

¹H NMR(400MHz，CDCl ₃)δ8.53(s，1H)，7.41(s，1H)，7.24(m，3H)，6.81(m，2H)，6.58(br s，1H)，5.51(m，1H)，4.70(m，1H)，4.24(dd，1H)，4.15(m，1H)，4.06(m，2H)，4.02(s，3H)，3.98(s，3H)，2.36(m，1H)，2.26(m，1H)，1.93-1.54(m，8H).

LC/MS (ESI): Theoretical Mass 478.2, actual measurement 479.1 (MH) ⁺

Embodiment 55

(4-cyclopentyloxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester (No. 55 compounds)

Basically press preparation described in the embodiment 54, replace the 3-pyrrolidinol with the 4-hydroxy piperidine.

¹H MR(400MHz，CDCl ₃)δ8.68(s，1H)，7.30-7.24(m，3H)，7.10(s，1H)，6.83(m，2H)，6.49(br s，1H)，5.08(m，1H)，4.72(m，1H)，4.03(s，3H)，4.00(s，3H)，3.93(m，2H)，3.51(m，2H)，2.18(m，2H)，2.00-1.73(m，8H)，1.61(m，2H).

LC/MS (ESI): Theoretical Mass 492.2, actual measurement 493.1 (MH) ⁺

Embodiment 56

(4-cyclopentyloxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl methyl esters (No. 56 compounds)

Basically press preparation described in the embodiment 54, replace the 3-pyrrolidinol with the 4-piperidine carbinols.

¹H NMR(400MHz，CDCl ₃)δ8.67(s，1H)，7.30-7.23(m，3H)，7.09(s，1H)，6.83(m，2H)，6.49(br s，1H)，4.72(m，1H)，4.22(m，2H)，4.12(d，2H)，4.03(s，3H)，3.99(s，3H)，3.08(m，2H)，2.05(m，1H)，1.99-1.73(m，7H)，1.67-1.52(m，5H).

LC/MS (ESI): Theoretical Mass 506.2, actual measurement 507.1 (MH) ⁺

Embodiment 57

(4-cyclopentyloxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-base methyl esters (No. 57 compounds)

Basically press preparation described in the embodiment 54, replace the 3-pyrrolidinol with the 3-piperidine carbinols.Through the HPLC purifying, title compound dodges chromatography (9: 2 EtOAc/ acetone elutriants) purifying through silica gel more then.

¹H NMR(400MHz，CDCl ₃)δ8.67(s，1H)，7.28-7.22(m，2H)，7.23(s，1H)，7.10(s，1H)，6.81(m，2H)，6.65(br s，1H)，4.71(m，1H)，4.25(dd，1H)，4.19(m，1H)，4.09-3.97(m，2H)，4.01(s，3H)，3.96(s，3H)，3.08(m，1H)，2.92(dd，1H)，2.28(m，1H)，2.03-1.71(m，9H)，1.60(m，2H)，1.48(m，1H).

LC/MS (ESI): Theoretical Mass 506.2, actual measurement 507.3 (MH) ⁺

Embodiment 58

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-3-(4-isopropoxy-phenyl)-urea (No. 58 compounds)

Basically press described in the embodiment 16, with 4-chloro-6,7-dimethoxyquinazoline (Oakwood), piperidin-4-yl-t-butyl carbamate (TCI America) and (4-isopropoxy-phenyl)-carboxylamine 4-nitro-phenyl ester (embodiment 32a) preparation.Basically press described in the embodiment 50b through the HPLC purifying.

¹H NMR(400MHz，CDCl ₃)δ8.64(s，1H)，7.23(s，1H)，7.15(m，2H)，7.05(s，1H)，6.87(m，2H)，6.00(br s，1H)，4.55-4.48(m，2H)，4.10(m，2H)，4.01(s，3H)，3.97(s，3H)，4.04(m，1H)，3.25(m，2H)，2.14(m，2H)，1.59(m，2H)，1.34(d，6H).

LC/MS (ESI): Theoretical Mass 465.2, actual measurement 466.1 (MH) ⁺

Embodiment 59

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-3-(4-morpholine-4-base-phenyl)-urea (No. 59 compounds)

Basically press described in the embodiment 16, with 4-chloro-6,7-dimethoxyquinazoline (Oakwood), piperidin-4-yl-t-butyl carbamate (TCI America) and (4-morpholine-4-base-phenyl)-carboxylamine 4-nitro-phenyl ester (embodiment 43b) preparation.Basically press described in the embodiment 50b through the HPLC purifying.

¹H NMR(400MHz，95∶5 CDCl ₃/CD ₃OD)δ8.62(s，1H)，7.22(s，1H)，7.18(m，2H)，7.06(s，1H)，6.90(m，2H)，4.10(m，2H)，4.05-3.98(m，1H)，4.02(s，3H)，3.98(s，3H)，3.86(m，4H)，3.27(m，2H)，3.14(m，4H)，2.13(m，2H)，1.59(m，2H).

LC/MS (ESI): Theoretical Mass 492.2, actual measurement 493.1 (MH) ⁺

Embodiment 60

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-3-(4-tetramethyleneimine-1-base-phenyl)-urea (No. 60 compounds)

Basically press described in the embodiment 16, with 4-chloro-6,7-dimethoxyquinazoline (Oakwood), piperidin-4-yl-t-butyl carbamate (TCI America) and (4-tetramethyleneimine-1-base-phenyl)-carboxylamine 4-nitro-phenyl ester hydrochloride (embodiment 49a) preparation.Basically press described in the embodiment 50b through the HPLC purifying.

¹H NMR(400MHz，CDCl ₃)δ8.63(s，1H)，7.22(s，1H)，7.07(m，2H)，7.04(s，1H)，6.52(m，2H)，5.86(br s，1H)，4.50(br d，1H)，4.07(m，2H)，4.03-4.00(m，1H)，4.01(s，3H)，3.97(s，3H)，3.31-3.19(m，6H)，2.11(m，2H)，2.02(m，4H)，1.60-1.50(m，2H).

LC/MS (ESI): Theoretical Mass 476.2, actual measurement 477.1 (MH) ⁺

Embodiment 61

1-(4-chloro-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-urea (No. 61 compounds)

Basically press described in the embodiment 51, with piperidin-4-yl-t-butyl carbamate (TCIAmerica) and the preparation of isocyanic acid 4-chlorobenzene ester.

¹H NMR(400MHz，95∶5 CDCl ₃/CD ₃OD)δ8.57(s，1H)，7.33(m，2H)，7.22(m，2H)，7.20(s，1H)，7.10(s，1H)，4.06(m，2H)，4.04(s，3H)，4.03-3.96(m，1H)，4.00(s，3H)，3.39(m，2H)，2.14(m，2H)，1.66(m，2H).

LC/MS (ESI): Theoretical Mass 441.2, actual measurement 442.1 (MH) ⁺

Embodiment 62

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-3-(4-dimethylamino-phenyl)-urea (No. 62 compounds)

Basically press described in the embodiment 51, with piperidin-4-yl-t-butyl carbamate (TCIAmerica) and the preparation of isocyanic acid 4-(dimethylamino) phenyl ester.

¹H NMR(400MHz，CDCl ₃)δ8.64(s，1H)，7.22(s，1H)，7.10(br m，2H)，7.05(s，1H)，6.70(brm，2H)，5.97(br s，1H)，4.55(br m，1H)，4.09(m，2H)，4.05-3.95(m，1H)，4.02(s，3H)，3.97(s，3H)，3.24(m，2H)，2.96(br s，6H)，2.12(m，2H)，1.55(m，2H).

LC/MS (ESI): Theoretical Mass 450.2, actual measurement 451.2 (MH) ⁺

Embodiment 63

1-(4-sec.-propyl-phenyl)-3-(1-quinazoline-4-base-piperidin-4-yl)-urea (No. 63 compounds)

Basically press preparation described in the embodiment 16, replace 3-(tert-butoxycarbonyl amino) tetramethyleneimine with piperidin-4-yl-t-butyl carbamate.Basically it is described through the HPLC purifying to press embodiment 50b.

¹H NMR(400MHz，CDCl ₃)δ8.71(s，1H)，7.86(dd，2H)，7.73(m，1H)，7.45(m，1H)，7.21-7.16(m，4H)，6.36(br s，1H)，4.79(brd，1H)，4.29(m，2H)，4.06(m，1H)，3.30(m，2H)，2.88(heptet，1H)，2.15(m，2H)，1.59(m，2H)，1.23(d，6H).

LC/MS (ESI): Theoretical Mass 389.2, actual measurement 390.2 (MH) ⁺

Embodiment 64

1-(4-sec.-propyl-phenyl)-3-[1-(6-methoxyl group-quinazoline-4-yl)-piperidin-4-yl]-urea (No. 64 compounds)

Basically press described in the embodiment 16, with 4-chloro-6-methoxyl group quinazoline (WO2001032632 A2, WO 9609294 A1) and piperidin-4-yl-t-butyl carbamate preparation.Basically it is described through the HPLC purifying to press embodiment 50b.

¹H NMR(400MHz，CDCl ₃)δ8.66(s，1H)，7.83(d，1H)，7.40(dd，1H)，7.18(m，4H)，7.10(d，1H)，6.45(br s，1H)，4.85(br d，1H)，4.18(m，2H)，4.05(m，1H)，3.90(s，3H)，3.27(m，2H)，2.88(heptet，1H)，2.15(m，2H)，1.60(m，2H)，1.22(d，6H).

LC/MS (ESI): Theoretical Mass 419.2, actual measurement 420.2 (MH) ⁺

Embodiment 65

1-(4-sec.-propyl-phenyl)-3-[1-(7-methoxyl group-quinazoline-4-yl)-piperidin-4-yl]-urea (No. 65 compounds)

Basically described in embodiment 74b, prepare, replace 1-(2-hydroxyl-ethyl)-pyrrolidin-2-one with methyl alcohol.

¹H NMR(400MHz，CDCl ₃)δ8.65(s，1H)，7.73(d，1H)，7.22-7.15(m，5H)，7.06(dd，1H)，6.16(br s，1H)，4.66(br d，1H)，4.23(m，2H)，4.05(m，1H)，3.93(s，3H)，3.28(m，2H)，2.89(heptet，1H)，2.15(m，2H)，1.60(m，2H)，1.23(d，6H).

LC/MS (ESI): Theoretical Mass 419.2, actual measurement 420.2 (MH) ⁺

Embodiment 66

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-3-(4-sec.-propyl-phenyl)-urea

(No. 66 compounds)

Basically press described in the embodiment 16, with 4-chloro-6,7-dimethoxyquinazoline and piperidin-4-yl-t-butyl carbamate preparation.Basically it is described through the HPLC purifying to press embodiment 50b.

¹H NMR(400MHz，CDCl ₃)δ8.64(s，1H)，7.22(s，1H)，7.19(s，4H)，7.06(s，1H)，6.48(br s，1H)，4.86(br d，1H)，4.12(m，2H)，4.07-4.01(m，1H)，4.00(s，3H)，3.97(s，3H)，3.26(m，2H)，2.88(heptet，1H)，2.15(m，2H)，1.60(m，2H)，1.23(d，6H).

LC/MS (ESI): Theoretical Mass 449.2, actual measurement 450.1 (MH) ⁺

Embodiment 67

1-(4-cyclopentyloxy-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-urea (No. 67 compounds)

Basically press described in the embodiment 16, with 4-chloro-6,7-dimethoxyquinazoline, piperidin-4-yl-t-butyl carbamate and (4-cyclopentyloxy-phenyl)-carboxylamine 4-nitro-phenyl ester preparation.Basically it is described through the HPLC purifying to press embodiment 50b.

¹H NMR(400MHz，95∶5 CDCl ₃/CD ₃OD)δ8.57(s，1H)，7.34(s，1H)，7.18(m，2H)，7.06(s，1H)，6.81(m，2H)，4.70(m，1H)，4.26(m，2H)，4.07-4.00(s，1H)，4.04(s，3H)，3.98(s，3H)，3.39(m，2H)，2.14(m，2H)，1.94-1.72(m，6H)，1.61(m，4H).

LC/MS (ESI): Theoretical Mass 491.2, actual measurement 492.1 (MH) ⁺

Embodiment 68

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-3-(6-tetramethyleneimine-1-base-pyridin-3-yl)-urea (No. 68 compounds)

Basically press described in the embodiment 16, with 4-chloro-6,7-dimethoxyquinazoline (Oakwood), piperidin-4-yl-t-butyl carbamate (TCI America) and (6-tetramethyleneimine-1-base-pyridin-3-yl)-carboxylamine 4-nitro-phenyl ester hydrochloride (embodiment 46a) preparation.Thick end reaction mixture is filtered purifying, obtain pure title compound, be pale powder (36.1mg, 50%, press 4-chloro-6,7-dimethoxyquinazoline meter).

¹H NMR(400MHz，DMSO-d ₆)δ8.51(s，1H)，7.98(d，1H)，7.92(s，1H)，7.54(dd，1H)，7.19(s，1H)，7.10(s，1H)，6.35(d，1H)，6.13(d，1H)，4.03(m，2H)，3.91(s，3H)，3.89(s，3H)，3.75(m，1H)，3.30(m，4H)，3.22(m，2H)，1.97(m，2H)，1.90(m，4H)，1.59(m，2H).

LC/MS (ESI): Theoretical Mass 477.2, actual measurement 478.2 (MH) ⁺

Embodiment 69

1-[1-(7-fluoro-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-urea (No. 69 compounds)

By during the HPLC purifying, separate (seeing embodiment 70b) the latter by each component of embodiment 70 title compounds.

¹H NMR(400MHz，CDCl ₃)δ8.42(s，1H)，8.03(dd，1H)，7.38(dd，1H)，7.21-7.13(m，4H)，7.10(ddd，1H)，6.71(br s，1H)，5.89(br d，1H)，4.63(m，1H)，4.15(dd，1H)，4.00-3.88(m，2H)，3.85(dd，1H)，2.86(heptet，1H)，2.35-2.25(m，1H)，2.16(m，1H)，1.21(d，6H).

LC/MS (ESI): Theoretical Mass 393.2, actual measurement 394.2 (MH) ⁺

Embodiment 70

1-(4-sec.-propyl-phenyl)-3-(1-{7-[2-(2-oxo-tetramethyleneimine-1-yl)-oxyethyl group]-quinazoline-4-yl }-tetramethyleneimine-3-yl)-urea (No. 70 compounds)

A.[1-(7-fluoro-quinazoline-4-yl)-tetramethyleneimine-3-yl]-t-butyl carbamate

In bottle, add successively rapidly 4-chloro-7-fluoro-quinazoline (2.00g, 11.0mmol) (WO9609294 A1), tetramethyleneimine-3-base-t-butyl carbamate (2.05g, 11.0mmol), DMSO (2.64mL) and DIPEA (2.10mL, 12.0mmol).Mixture is stirred 20min down in " room temperature ", and during this period, reactant heats up automatically, becomes little reddish-brown homogeneous phase solution.Then reactant is stirred 2.5min down at 100 ℃, guarantee to react completely.With solution and water (20mL) jolting together, DMSO is soluble in the aqueous phase, with EtOAc (1 * 20mL) extraction.(1 * 20mL) washs, dry (Na with 4M NaCl with organic layer ₂SO ₄).When with Na ₂SO ₄After adding organic phase, title compound begins precipitation and separates out.With this sedimentation and filtration (easily from wet siccative, inclining to), to collect, drying makes powdered, obtains title compound, is pale powder (1.42g, 39%).

B.1-(4-sec.-propyl-phenyl)-3-(1-{7-[2-(2-oxo-tetramethyleneimine-1-yl)-oxyethyl group]-quinazoline-4-yl-tetramethyleneimine-3-yl)-urea

With 1-(2-hydroxyl-ethyl)-pyrrolidin-2-one (50.8mg, 394 μ mol), KOtBu (41mg, 366 μ mol), DMSO (300 μ L) and [1-(7-fluoro-quinazoline-4-yl)-tetramethyleneimine-3-yl]-t-butyl carbamate (103mg, 310 μ mol) mixture stirs 20min down at 100 ℃, is cooled to room temperature then.(2 * 4mL) distribute with the DCM/MeOH of reactant water (4mL) and 9: 1.Organic layer is merged dry (Na ₂SO ₄), concentrate.With residue (the thick S of 104mg _NThe Ar product) be dissolved in TFA (182 μ L, 2.4mmol) and CHCl ₃(180 μ L) under 100 ℃, stirs 10min in air-tight bottle.Then reactant is cooled to room temperature, its DCM/MeOH 2.5M NaOH (2mL) and 9: 1 (is distributed between 2 * 4mL).With the organic layer drying (Na that merges ₂SO ₄), filter, concentrate.Residue (the thick amine of 91mg) is dissolved in CHCl ₃(600 μ L), TEA (41 μ L, 294 μ mol) and (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester (88mg, 293 μ mol) stir 10min down at 100 ℃.After being cooled to room temperature, reactant is used 2.5MNaOH (2mL) and DCM, and (1 * 4mL, 1 * 2mL) distributes, and organic layer is merged, dry (Na ₂SO ₄), filter, concentrate.Residue is dissolved in 90: 10: 1 v/v MeOH/ water/TFA, through C18 reversed-phase HPLC (water/CH ₃CN/0.1%TFA → increase to CH ₃CN/0.1%TFA) purifying.Extracting short column mutually by the supercarbonate solid removes TFA, product further dodges chromatography (95: 5 DCM/MeOH elutriants) purifying through silica gel, obtain title compound { 5.6mg, 3.6%, by [1-(7-fluoro-quinazoline-4-yl)-tetramethyleneimine-3-yl]-t-butyl carbamate }.

¹H NMR(400MHz，CDCL ₃)δ8.31(s，1H)，7.78(d，1H)，7.55(br s，1H)，7.25(m，2H)，7.11(m，2H)，7.00(d，1HD，6.85(dd，1H)，6.49(br d，1H)，4.58(m，1H)，4.12(t，2H)，4.05(dd，1H)，3.89-3.76(m，2H)，3.76-3.67(m，3H)，3.54(t，2H)，2.83(heptet，1H)，2.42(t，2H)，2.22(m，1H)，2.14-2.01(m，3H)，1.20(d，6H).

LC/MS (ESI): Theoretical Mass 502.3, actual measurement 503.2 (MH) ⁺

Embodiment 71

1-(4-sec.-propyl-phenyl)-3-{1-[7-(2-methoxyl group-oxyethyl group)-quinazoline-4-yl]-tetramethyleneimine-3-yl }-urea (No. 71 compounds)

Basically described in embodiment 70b, prepare, replace 1-(2-hydroxyl-ethyl)-pyrrolidin-2-one with 2-methyl cellosolve.

¹H NMR(400MHz，CDCl ₃)δ8.30(s，1H)，7.81(d，1H)，7.23(m，2H)，7.20(br s，1H)，7.12(m，2H)，7.06(d，1H)，6.96(dd，1H)，6.40(br s，1H)，4.62(m，1H)，4.16(m，2H)，4.05(dd，1H)，3.91-3.76(m，5H)，3.46(s，3H)，2.85(heptet，1H)，2.29-2.11(m，2H)，1.20(d，6H).

LC/MS (ESI): Theoretical Mass 449.2, actual measurement 450.1 (MH) ⁺

Embodiment 72

1-[1-(7-fluoro-quinazoline-4-yl)-piperidin-4-yl]-3-(4-sec.-propyl-phenyl)-urea (No. 72 compounds)

By during the HPLC purifying, separate (seeing embodiment 75) the latter by each component of embodiment 75 title compounds.

¹H NMR(400MHz，CDCl ₃)δ8.68(s，1H)，7.85(dd，1H)，7.49(dd，1H)，7.23-7.15(m，5H)，6.22(brs，1H)，4.69(br d，1H)，4.27(m，2H)，4.06(m，1H)，3.31(m，2H)，2.89(heptet，1H)，2.15(m，2H)，1.58(m，2H)，1.23(d，6H).

LC/MS (ESI): Theoretical Mass 407.2, actual measurement 408.2 (MH) ⁺

Embodiment 73

1-(4-sec.-propyl-phenyl)-3-{1-[7-(2-methoxyl group-oxyethyl group)-quinazoline-4-yl]-piperidin-4-yl }-urea (No. 73 compounds)

Basically described in embodiment 74b, prepare, replace 1-(2-hydroxyl-ethyl)-pyrrolidin-2-one with 2-methyl cellosolve.

¹H NMR(400MHz，CDCl ₃)δ8.64(s，1H)，7.73(d，1H)，7.22-7.15(m，5H)，7.11(dd，1H)，6.17(br s，1H)，4.67(br d，1H)，4.27-4.19(m，4H)，4.05(m，1H)，3.82(m，2H)，3.47(s，3H)，3.27(m，2H)，2.89(heptet，1H)，2.15(m，2H)，1.59(m，2H)，1.23(d，6H).

LC/MS (ESI): Theoretical Mass 463.3, actual measurement 464.2 (MH) ⁺

Embodiment 74

1-(4-sec.-propyl-phenyl)-3-(1-{7-[2-(2-oxo-tetramethyleneimine-1-yl)-oxyethyl group]-quinazoline-4-yl }-piperidin-4-yl)-urea (No. 74 compounds)

A.[1-(7-fluoro-quinazoline-4-yl)-piperidin-4-yl]-t-butyl carbamate

Basically prepare described in embodiment 70a, replace tetramethyleneimine-3-base-t-butyl carbamate with piperidin-4-yl-t-butyl carbamate, difference is after stirring 2.5min under 100 ℃ homogeneous phase solution at room temperature to be stirred 5h.And obtain title compound through the water aftertreatment, for amber oily thing but not solid precipitation (2.8g, 84%).

¹H NMR(CDCl ₃)δ8.70(s，1H)，7.86(dd，1H)，7.50(dd，1H)，7.21(dd，1H)，4.55(br d，1H)，4.25(m，2H)，3.80(brm，1H)，3.27(m，2H)，2.13(m，2H)，1.61(m，2H)，1.46(s，9H).

B.1-(4-sec.-propyl-phenyl)-3-(1-{7-[2-(2-oxo-tetramethyleneimine-1-yl)-oxyethyl group]-quinazoline-4-yl-piperidin-4-yl)-urea

With 1-(2-hydroxyl-ethyl)-pyrrolidin-2-one (51mg, 400 μ mo1), KOtBu (41mg, 370 μ mol), DMSO (150 μ L) and [1-(7-fluoro-quinazoline-4-yl)-piperidin-4-yl]-t-butyl carbamate (110mg, 310 μ mol) mixture stirs 40min down at 100 ℃, is cooled to room temperature then.(2 * 4mL) distribute with the DCM/MeOH of reactant water (4mL) and 9: 1.Organic layer is merged dry (Na ₂SO ₄), concentrate.With residue (thick S _NThe Ar product) be dissolved in TFA (180 μ L, 2.4mmol) and CHCl ₃(180 μ L) under 100 ℃, stirs 10min in air-tight bottle.Then reactant is cooled to room temperature, its DCM/MeOH 2.5M NaOH (2mL) and 9: 1 (is distributed between 2 * 4mL).With the organic layer drying (Na that merges ₂SO ₄), filter, concentrate.Residue (thick amine) is dissolved in DCM (600 μ L), TEA (41 μ L, 290 μ mol) and (4-sec.-propyl-phenyl)-carboxylamine 4-nitro-phenyl ester (88mg, 290 μ mol), stirs 2h down at 40 ℃.After being cooled to room temperature, reactant is used 2.5M NaOH (2mL) and DCM, and (1 * 4mL, 1 * 2mL) distributes, and organic layer is merged, dry (Na ₂SO ₄), filter, concentrate.Residue is dissolved in 90: 10: 1 v/v MeOH/ water/TFA, through C18 reversed-phase HPLC (water/CH ₃CN/0.1%TFA → increase to CH ₃CN/0.1%TFA) purifying.Extract short column mutually by the supercarbonate solid TFA is removed, obtain title compound { 10.8mg, 7%, by [1-(7-fluoro-quinazoline-4-yl)-piperidin-4-yl]-t-butyl carbamate }.

¹H NMR(400MHz，CDCl ₃)δ8.63(s，1H)，7.73(d，1H)，7.22-7.15(m，5H)，7.03(dd，1H)，6.23(br s，1H)，4.73(br d，1H)，4.23(m，4H)，4.05(m，1H)，3.76(t，2H)，3.58(t，2H)，3.29(m，2H)，2.89(heptet，1H)，2.41(t，2H)，2.14(m，2H)，2.05(m，2H)，1.60(m，2H)，1.23(d，6H).

LC/MS (FSI): Theoretical Mass 516.3, actual measurement 517.2 (MH) ⁺

Embodiment 75

1-(4-sec.-propyl-phenyl)-3-(1-{7-[3-(4-methyl-piperazine-1-yl)-propoxy-]-quinazoline-4-yl }-piperidin-4-yl)-urea (No. 75 compounds)

Basically described in embodiment 74b, prepare, replace 1-(2-hydroxyl-ethyl)-pyrrolidin-2-one with 3-(4-methyl-piperazine-1-yl)-third-1-alcohol.

¹H NMR(400MHz，CDCl ₃)δ8.63(s，1H)，7.72(d，1H)，7.22-7.14(m，5H)，7.04(dd，1H)，6.259(br s，1H)，4.75(br d，1H)，4.22(m，2H)，4.14(t，2H)，4.04(m，1H)，3.27(m，2H)，2.88(heptet，1H)，2.70-2.32(m，10H)，2.30(s，3H)，2.14(m，2H)，2.03(m，2H)，1.57(m，2H)，1.23(d，6H).

LC/MS (ESI): Theoretical Mass 545.3, actual measurement 546.3 (MH) ⁺

Biological activity

Measure the biological activity of compound in the scope of the invention with following representative determination experiment.According to the indefiniteness mode, provide them and illustrate the present invention.

The specificity that illustrates the FLT3 enzyme and depend on the active cell processes of FLT3 with the inhibition of FLT3 enzymic activity, MV4-11 propagation and Baf3-FLT3 phosphorylation suppresses.With FLT3 and the TrkB independent cell toxicity test of Baf3 cell inhibitory effect test as compound in the scope of the invention.All embodiment all show significantly and specificity inhibition FLT3 kinases and the cell response that relies on FLT3 herein, estimate that they show also that in enzyme assay specificity suppresses the TrkB kinases.The compounds of this invention also has cell permeability.

FLT3 fluorescence polarization kinase assays

FLT3FP measures phospho-peptide that uses fluorescein-mark and the anti-phosphotyrosine antibody that is included in Panvera phosphoric acid-tyrosine-kinase enzyme reagent kit (Green), and this test kit is provided by Invitrogen.When FLT3 will gather Glu ₄During the Tyr phosphorylation, by the poly-Glu of phosphorylation ₄Tyr replaces the phospho-peptide of fluorescein-mark from anti-phosphotyrosine antibody, so the FP value reduces.Under the following conditions, with FLT3 kinase reaction thing incubation 30 minutes at room temperature: 10nM FLT3 571-993,20 μ g/mL gather Glu ₄Tyr, 150 μ M ATP, 5mM MgCl ₂, the DMSO solution of 1% compound.Add EDTA and stop kinase reaction.Add the phospho-peptide and the anti-phosphotyrosine antibody of fluorescein-mark, at room temperature incubation is 30 minutes.

All data points are the mean value of three parts of parallel sample.Suppress and IC with GraphPad Prism ₅₀Data analysis, carry out nonlinear regression and fitting with multiparameter, S shape dose-response (variable slope) equation.The IC of kinase inhibition ₅₀Representative is compared the compound dosage that causes 50% kinase activity to suppress with the contrast of DMSO solvent.

Trk B fluorescence polarization kinase assays (TrkB IC ₅₀Data)

The compounds of this invention also is the specific inhibitor of TrkB.In the following manner, select preferred formula I compound as the TrkB inhibitor.TrkB measures phospho-peptide that uses fluorescein-mark and the anti-phosphotyrosine antibody that is included in Panvera phosphoric acid-tyrosine-kinase enzyme reagent kit (Green), and this test kit is provided by Invitrogen.When TrkB will gather Glu ₄During the Tyr phosphorylation, by the poly-Glu of phosphorylation ₄Tyr replaces the phospho-peptide of fluorescein-mark from anti-phosphotyrosine antibody, so the FP value reduces.Under the following conditions, with TrkB kinase reaction thing incubation 30 minutes at room temperature: 50nM TrkB (Upstate, catalogue # 14-507M), 20 μ g/mL gather Glu ₄Tyr, 150 μ M ATP, 5mM MgCl ₂, the DMSO solution of 1% compound.Add EDTA and stop kinase reaction.Add the phospho-peptide and the anti-phosphotyrosine antibody of fluorescein-mark, at room temperature incubation is 30 minutes.All data points are the mean value of three parts of parallel sample.Suppress and IC with GraphPad Prism ₅₀Data analysis, carry out nonlinear regression and fitting with multiparameter, S shape dose-response (variable slope) equation.The IC of kinase inhibition ₅₀Representative is compared the compound dosage that causes 50% kinase activity to suppress with the contrast of DMSO solvent.

MV4-11 and Baf3 cell growth-inhibiting

With the leukemia cell is MV4-11 (ATCC preserving number: CRL-9591) measure FLT3 specificity growth-inhibiting.The MV4-11 cell source is from the children acute myelomonocytic leukemia patient with 11q23 transposition, and this transposition causes the mll gene rearrangement and contains FLT3-ITD sudden change (AML hypotype M4) (1,2).As there not being active FLT3ITD, then the MV4-11 cell can not be grown and survive.

With IL-3 dependency mouse b-cell lymphoma cell is that Baf3 compares, by measuring the non-specific growth-inhibiting of The compounds of this invention, the selectivity of conclusive evidence The compounds of this invention.

For the propagation of measuring test compound suppresses, use CellTiterGlo reagent (Promega) based on luciferase.By 10,000 cells/well, in 100 μ l RPMI substratum, for MV4-11 and Baf3 cell, the RPMI substratum contains penicillin/streptomycin respectively, 10%FBS and 1ng/ml GM-CSF or 1ng/ml IL-3 with cell inoculation.

Diluted chemical compound liquid or 0.1%DMSO (solvent contrast) are added cell, the standard cell lines growth conditions (37 ℃, 5%CO ₂) under, allow cell grow 72 hours.According to cell number on the 0th and the 3rd day total cell number (growth in 72 hours and/or compound treatment) luminous counting (relative light unit, RLU) poor, quantitatively total cell is grown.100% growth-inhibiting is defined as the RLU that is equivalent to reading on the 0th.Suppress to be defined as the RLU signal of in DMSO solvent contrast on the 3rd, growing with 0%.All data points are the mean value of three parts of parallel sample.Growth inhibiting IC ₅₀Representative caused the compound dosage that total cell growth 50% suppresses in the contrast of DMSO solvent on 3rd.Suppress and IC with GraphPad Prism ₅₀Data analysis, carry out nonlinear regression and fitting with multiparameter, S shape dose-response (variable slope) equation.

Series connection repeats sudden change in the MV-411 cell expressing FLT3, thereby growth relies on the FLT3 activity fully.Expectation is by force the character that the present invention needs to the MV4-11 cytoactive.On the contrary, Baf3 cell proliferation is driven by cytokine IL-3, and these cells are as the non-specific toxicity contrast of test compound.All embodiment compounds of the present invention show all that under 3 μ M dosage＜50% suppresses (not comprising data), points out these compound no cytotoxicities, and FLT3 is had good selectivity.

FLT3 acceptor enzyme-linked immunosorbent assay based on cell

The cell of overexpression FLT3 acceptor derives from Dr.Michael Heinrich (OregonHealth and Sciences University).By with wild-type FLT3 stable transfection parental generation Baf3 cell (the mouse B cell lymphoma system of dependent cells factor IL-3 growth), set up Baf3FLT3 clone.Exist at no IL-3 but have in the presence of the FLT3 part, according to its energy for growth selection cell.

At 37 ℃, 5%CO ₂The Baf3 cell is maintained among the RPMI 1640 that contains 10%FCS, penicillin/streptomycin and 10ng/ml FLT part down.For measuring the direct inhibition of wild-type FLT3 receptor active and phosphorylation, developed the sandwich ELISA method (3,4) that is similar to those methods of other RTK exploitation.With preceding 1 hour of compound or DMSO solvent incubation, with 200 μ l Baf3FL T3 cells (1 * 10 ⁶/ ml) be seeded among the RPMI 1640 that contains 0.5% serum and 0.01ng/ml IL-3 in the 96 hole wares, kept 16 hours.Under 37 ℃, with cell 100ng/ml Flt part (R﹠amp; D Systems Cat# 308-FK) handles 10min.Make cell precipitation, replenish HNTG damping fluid (50mM Hepes, the 150mM NaCl of Phosphoric acid esterase (Sigma Cat# P2850) and proteinase inhibitor (Sigma Cat #P8340) with 100 μ l, 10% glycerine, 1%Triton-X-100,10mM NaF, 1mM EDTA, 1.5mM MgCl ₂, the 10mM trisodium phosphate) and wash, split born of the same parents.Under 4 ℃,, make the split product clarification by under 1000 * g centrifugal 5 minutes.With product of cell lysis be transferred to coating 50ng/ hole anti--FLT3 antibody (Santa Cruz Cat# sc-480) and white wall 96 hole microtiter plates (Costar #9018) with SeaBlock reagent (Pierce Cat#37527) sealing in.With split product 4 ℃ of following incubations 2 hours.With plate with 200 μ l/ hole PBS/0.1%triton-X-100 washing 3 *.Then at room temperature, plate and 1: 8000 dilution HRP-are puted together anti--phosphotyrosine antibody (Clone 4G10, Upstate Biotechnology Cat#16-105) incubation 1 hour together.With plate with 200 μ l/ hole PBS/0.1%triton-X-100 washing 3 *.According to manufacturers instruction, with Super Signal Pico reagent (Pierce Cat#37070), with Berthold microtest plate luminometer detection signal.All data points are the mean value of three parts of parallel sample.To be defined as 0% inhibition by total relative light unit (RLU) of the FLT3 phosphorylation of Flt ligand stimulation in the presence of the 0.1%DMSO contrast, total RLU of ground state split product is defined as 100% to be suppressed.Suppress and IC with GraphPad Prism ₅₀Data analysis, carry out nonlinear regression and fitting with multiparameter, S shape dose-response (variable slope) equation.

The biological method reference

1.Drexler HG.The Leukemia-Lymphoma Cell Line Factsbook.Academic Pres：San Diego，CA，2000。

2.Quentmeier H, Reinhardt J, Zaborski M, Drexler HG.FL T3mutations in acute myeloid leukemia cell lines (FLT3 sudden change in the acute myelocytic leukemia clone).Leukemia.2003 Jan；17：120-124。

3.Sadick, MD, Sliwkowski, MX, Nuijens, A, Bald, L, Chiang, N, Lofgren, JA, Wong WLT.Analysis of Heregulin-Induced ErbB2Phosphorylation with a High-Throughput Kinase Receptor ActivationEnzyme-Linked Immunsorbent Assay (activating the ErbB2 phosphorylation that enzyme-linked immunosorbent determination and analysis Heregulin causes), AnalyticalBiochemistry.1996 with the high-throughput kinases receptors; 235:207-214.

4.Baumann CA, Zeng L, Donatelli RR, Maroney AC.Developmentof a quantitative, high-throughput cell-based enzyme-linkedimmunosorbent assay for detection of colony-stimulating factor-1 receptortyrosine kinase inhibitors (being used to detect the exploitation based on quantitative, the high-throughput enzyme-linked immunosorbent measuring method of cell of colony-stimulating factor-1 receptor tyrosine kinase inhibitors).J.Biochem Biophys Methods.2004；60：69-79。

Biological data

The biological data of FLT3

The activity of representation compound of the present invention is listed in the table below.All activity are all by μ M, and have with lower variation of tolerance: FLT3 kinases: ± 10%; MV4-11 and Baf3-FLT3: ± 20%.

No.	The compound title	FLT3 kinases (μ M)	MV4-11 (μM)	BaF3 ELISA(μM)
No.	The compound title	FLT3 kinases (μ M)	MV4-11 (μM)	BaF3 ELISA(μM)	1	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester	0.006	0.181	0.016
2	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester	0.007	0.248	0.064	1		0.006	0.181	0.016
2		0.007	0.248	0.064	3	(4-isopropoxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester	0.008	0.467	0.118
4	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-base methyl esters	0.011	0.086	0.006	3		0.008	0.467	0.118
4		0.011	0.086	0.006	5	2-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-yl]-N-(4-sec.-propyl-phenyl)-ethanamide	0.012	0.007	0.006
6	2-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-N-(4-sec.-propyl-phenyl)-ethanamide	0.014	0.008	0.046	5		0.012	0.007	0.006
6		0.014	0.008	0.046	7	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-urea	0.016	0.909	0.14
8	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-isopropoxy-phenyl)-urea	0.023	1.88	0.36	7		0.016	0.909	0.14
8		0.023	1.88	0.36	9	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-2-base methyl esters	0.025	0.196	0.027
10	(4-sec.-propyl-phenyl)-carboxylamine 1-quinolyl-4-piperidin-4-yl ester	0.026	1.1	nd	9		0.025	0.196	0.027
10		0.026	1.1	nd	11	(6-cyclobutoxy group-pyridin-3-yl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester	0.028	0.071	nd

No.	The compound title	FLT3 kinases (μ M)	MV4-11 (μM)	BaF3 ELISA(μM)
No.	The compound title	FLT3 kinases (μ M)	MV4-11 (μM)	BaF3 ELISA(μM)	12	(6-cyclobutoxy group-pyridin-3-yl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4 base)-tetramethyleneimine-3-base ester	0.035	0.064	0.011
13	N-(4-sec.-propyl-phenyl)-1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-methane amide	0.037	0.855	0.089	12		0.035	0.064	0.011
13		0.037	0.855	0.089	14	(4-sec.-propyl-phenyl)-carboxylamine 1-[6-(the 3-hydroxyl-	0.037	0.136	0.004

	Third-1-alkynyl)-quinazoline-4-yl]-tetramethyleneimine-3-base ester
					15	(4-isopropoxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester	0.042	0.866	0.32
16	1-(4-sec.-propyl-phenyl)-3-(1-quinazoline-4-base-tetramethyleneimine-3-yl)-urea	0.045	0.278	0.242	15		0.042	0.866	0.32
16		0.045	0.278	0.242	17	(4-sec.-propyl-phenyl)-carboxylamine 1-[6-(3-diethylamino-third-1-alkynyl)-quinazoline-4-yl]-tetramethyleneimine-3-base ester	0.063	0.122	0.163
18	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-ylmethyl [3-(4-sec.-propyl-phenyl)-urea	0.066	1.3	0.049	17		0.063	0.122	0.163
18		0.066	1.3	0.049	19	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-1-methyl-urea	0.068	1.38	0.21
20	(4-sec.-propyl-phenyl)-carboxylamine 1-(6-iodo-quinazoline-4-yl)-tetramethyleneimine-3-base ester	0.096	0.262	0.043	19		0.068	1.38	0.21
20		0.096	0.262	0.043	21	N-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-2-(4-sec.-propyl-phenyl)-ethanamide	0.15	0.078	0.063
22	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl methyl esters	0.17	1.7	0.082	21		0.15	0.078	0.063
22		0.17	1.7	0.082	23	N-(4-isopropoxy-phenyl)-1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-methane amide	0.185	1.98	0.1757
24	(4-sec.-propyl-phenyl)-carboxylamine 1-quinazoline-4-base-tetramethyleneimine-3-base ester	0.29	0.22	nd	23		0.185	1.98	0.1757
24		0.29	0.22	nd	25	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-azetidine-3-ylmethyl]-3-(4-isopropoxy-phenyl)-urea	0.408	＞10	nd
26	1-[1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-urea	0.433	1.9	0.331	25		0.408	＞10	nd
26		0.433	1.9	0.331	27	1-(4-sec.-propyl-phenyl)-3-(1-quinolyl-4-tetramethyleneimine-3-yl)-urea	0.457	5.3	nd
28	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-yl]-3-(4-sec.-propyl-phenyl)-urea	0.51	1.5	1.9	27		0.457	5.3	nd
28		0.51	1.5	1.9	29	1-[1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-base [3-(4-isopropoxy-phenyl)-urea	0.531	1.7	3.1
30	N-(3-isopropoxy-phenyl)-1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-methane amide	0.563	2.31	nd	29		0.531	1.7	3.1
30		0.563	2.31	nd	31	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-base ester	0.67	1.7	1.1
32	(4-isopropoxy-phenyl)-carboxylamine 1-(3-cyano group	0.868	1.4	1.2	31		0.67	1.7	1.1

	-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-base ester
	-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-base ester				33	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-2-base methyl esters	1	0.343	0.559
34	(4-sec.-propyl-phenyl)-carboxylamine 1-quinolyl-4-tetramethyleneimine-3-base ester	1.05	6.4	nd	33		1	0.343	0.559

No.	The compound title	FLT3 kinases (μ M)	MV4-11 (μM)	BaF3 ELISA(μM)
No.	The compound title	FLT3 kinases (μ M)	MV4-11 (μM)	BaF3 ELISA(μM)	35	N-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-2-(4-sec.-propyl-phenyl)-ethanamide	1.3	1.9	＞3
36	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-isopropoxy-phenyl)-1-methyl-urea	1.68	3.19	1.3	35		1.3	1.9	＞3
36		1.68	3.19	1.3	37	(4-sec.-propyl-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-base ester	2.135	1.5	1.1
38	1-(4-isopropoxy-phenyl)-3-(1-quinolyl-4-tetramethyleneimine-3-yl)-urea	3.15	＞3	nd	37		2.135	1.5	1.1
38		3.15	＞3	nd	39	(4-isopropoxy-phenyl)-carboxylamine 1-quinoline-4-base-tetramethyleneimine-3-base ester	7.14	＞10	nd
40	(4-isopropoxy-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-piperidin-4-yl ester	＞10	nd	nd	39		7.14	＞10	nd
40		＞10	nd	nd	41	(4-isopropoxy-phenyl)-carboxylamine 1-quinoline-4-base-piperidin-4-yl ester	nd	＞10	nd
42	(4-sec.-propyl-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-piperidin-4-yl ester	nd	2.1	3	41		nd	＞10	nd
42		nd	2.1	3	43	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-morpholine-4-base-phenyl)-urea	nd	＞5	nd
44	1-(6-cyclobutoxy group-pyridin-3-yl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea	nd	1	nd	43		nd	＞5	nd
44		nd	1	nd	45	1-(6-cyclopentyloxy-pyridin-3-yl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea	nd	1.1	nd
46	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(6-tetramethyleneimine-1-base-pyridin-3-yl)-urea	nd	3.5	nd	45		nd	1.1	nd
46		nd	3.5	nd	47	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-piperidines-1-base-phenyl)-urea	nd	3.9	nd
48	1-(4-chloro-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea	nd	2.5	nd	47		nd	3.9	nd
48		nd	2.5	nd	49	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine	nd	nd	nd

	-3-yl]-3-(4-tetramethyleneimine-1-base-phenyl)-urea
	-3-yl]-3-(4-tetramethyleneimine-1-base-phenyl)-urea				50	1-(4-cyclohexyl-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea	nd	1.7	nd
51	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-phenoxy group-phenyl)-urea	nd	1.2	nd	50		nd	1.7	nd
51		nd	1.2	nd	52	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-dimethylamino-phenyl)-urea	nd	0.83	6.6
53	1-(4-cyclopentyloxy-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea	nd	1.5	nd	52		nd	0.83	6.6
53		nd	1.5	nd	54	(4-cyclopentyloxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester	nd	1.5	nd
55	(4-cyclopentyloxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester	nd	0.56	0.42	54		nd	1.5	nd
55		nd	0.56	0.42	56	(4-cyclopentyloxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl methyl esters	nd	0.74	3
57	(4-cyclopentyloxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-base methyl esters	nd	0.172	0.046	56		nd	0.74	3

No.	The compound title	FLT3 kinases (μ M)	MV4-11 (μM)	BaF3 ELISA(μM)
No.	The compound title	FLT3 kinases (μ M)	MV4-11 (μM)	BaF3 ELISA(μM)	58	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-yl]-3-(4-isopropoxy-phenyl)-urea	nd	0.007	0.180
59	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-yl]-3-(4-morpholine-4-base-phenyl)-urea	nd	0.410	0.043	58		nd	0.007	0.180
59		nd	0.410	0.043	60	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-yl]-3-(4-tetramethyleneimine-1-base-phenyl)-urea	nd	0.528	0.018
61	1-(4-chloro-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-urea	nd	9.4	nd	60		nd	0.528	0.018
61		nd	9.4	nd	62	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-yl]-3-(4-dimethylamino-phenyl)-urea	nd	0.941	0.016
63	1-(4-sec.-propyl-phenyl)-3-(1-quinazoline-4-base-piperidin-4-yl)-urea	nd	0.502	0.020	62		nd	0.941	0.016
63		nd	0.502	0.020	64	1-(4-sec.-propyl-phenyl)-3-[1-(6-methoxyl group-quinazoline-4-yl)-piperidin-4-yl]-urea	nd	0.016	0.011
65	1-(4-sec.-propyl-phenyl)-3-[1-(7-methoxyl group-quinazoline-4-yl)-piperidin-4-yl]-urea	nd	0.321	0.178	64		nd	0.016	0.011
65		nd	0.321	0.178	66	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-	nd	0.001	0.001

	Base]-3-(4-sec.-propyl-phenyl)-urea
	Base]-3-(4-sec.-propyl-phenyl)-urea				67	1-(4-cyclopentyloxy-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-urea	nd	0.47	1.4
68	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-yl]-3-(6-tetramethyleneimine-1-base-pyridin-3-yl)-urea	nd	0.134	0.016	67		nd	0.47	1.4
68		nd	0.134	0.016	69	1-[1-(7-fluoro-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-urea	nd	0.128	＜0.001
70	1-(4-sec.-propyl-phenyl)-3-(1-{7-[2-(2-oxo-tetramethyleneimine-1-yl)-oxyethyl group]-quinazoline-4-yl }-tetramethyleneimine-3-yl]-urea	nd	0.021	0.080	69		nd	0.128	＜0.001
70		nd	0.021	0.080	71	1-(4-sec.-propyl-phenyl)-3-{1-[7-(2-methoxyl group-oxyethyl group)-quinazoline-4-yl]-tetramethyleneimine-3-yl }-urea	nd	0.001	0.001
72	1-[1-(7-fluoro-quinazoline-4-yl)-piperidin-4-yl]-3-(4-sec.-propyl-phenyl)-urea	nd	0.245	0.03	71		nd	0.001	0.001
72		nd	0.245	0.03	73	1-(4-sec.-propyl-phenyl)-3-{1-[7-(2-methoxyl group-oxyethyl group)-quinazoline-4-yl]-piperidin-4-yl }-urea	nd	0.208	0.109
74	1-(4-sec.-propyl-phenyl)-3-(1-{7-[2-(2-oxo-tetramethyleneimine-1-yl)-oxyethyl group]-quinazoline-4-yl }-piperidin-4-yl)-urea	nd	0.177	0.004	73		nd	0.208	0.109
74		nd	0.177	0.004	75	1-(4-sec.-propyl-phenyl)-3-(1-{7-[3-(4-methyl-piperazine-1-yl)-propoxy-]-quinazoline-4-yl }-piperidines-4-yl)-urea	nd	0.001	0.001

The biological data of Trk B

The activity of representation compound of the present invention is listed in the table below.All activity are all by μ M, and have with lower variation of tolerance: TrkB IC ₅₀: ± 10%.

No.	The compound title	TrkB IC ₅₀(μM)
No.	The compound title	TrkB IC ₅₀(μM)	1	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester	5.72
2	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester	3.7	1		5.72
2		3.7	3	(4-isopropoxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester	5.8
4	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-base methyl esters	8.4	3		5.8
4		8.4	5	2-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-N-(4-sec.-propyl-benzene	2.4

	Base)-ethanamide
	Base)-ethanamide		6	2-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-N-(4-sec.-propyl-phenyl)-ethanamide	0.1
7	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-urea	nd	6		0.1
7		nd	8	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-isopropoxy-phenyl)-urea	3.65
9	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-2-base methyl esters	0.2	8		3.65
9		0.2	10	(4-sec.-propyl-phenyl)-carboxylamine 1-quinolyl-4-piperidin-4-yl ester	6.5
11	(6-cyclobutoxy group-pyridin-3-yl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4 base)-piperidin-4-yl ester	8.6	10		6.5
11		8.6	12	(bad butoxy of 6--pyridin-3-yl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester	21.7
13	N-(4-sec.-propyl-phenyl)-1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-methane amide	0.16	12		21.7
13		0.16	14	(4-sec.-propyl-phenyl)-carboxylamine 1-[6-(3-hydroxyl-third-1-alkynyl)-quinazoline-4-yl]-tetramethyleneimine-3-base ester	0.4
15	(4-isopropoxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester	12.52	14		0.4
15		12.52	16	1-(4-sec.-propyl-phenyl)-3-(1-quinazoline-4-base-tetramethyleneimine-3 base)-urea	2.4
17	(4-sec.-propyl-phenyl)-carboxylamine 1-[6-(3-diethylamino-third-1-alkynyl)-quinazoline-4-yl]-tetramethyleneimine-3-base ester	3.6	16		2.4
17		3.6	18	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl methyl]-3-(4-sec.-propyl-phenyl)-urea	0.5
19	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-1-methyl-urea	nd	18		0.5
19		nd	20	(4-sec.-propyl-phenyl)-carboxylamine 1-(6-iodo-quinazoline-4-yl)-tetramethyleneimine-3-base ester	13.1
21	N-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl]-2-(4-sec.-propyl-phenyl)-ethanamide	11.2	20		13.1
21		11.2	22	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl methyl esters	0.8
23	N-(4-isopropoxy-phenyl)-1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-methane amide	0.55	22		0.8

No.	The compound title	TrkB IC ₅₀(μM)
No.	The compound title	TrkB IC ₅₀(μM)	24	(4-sec.-propyl-phenyl)-carboxylamine 1-quinazoline-4-base-tetramethyleneimine-3-base ester	5.5

25	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-azetidine-3-ylmethyl]-3-(4-isopropoxy-phenyl)-urea	nd
25		nd	26	1-[1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-yl]-3-(4-sec.-propyl-phenyl)-urea	10.9
27	1-(4-sec.-propyl-phenyl)-3-(1-quinolyl-4-tetramethyleneimine-3-yl)-urea	7.7	26		10.9
27		7.7	28	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-yl]-3-(4-sec.-propyl-phenyl)-urea	0.3
29	1-[1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-yl]-3-(4-isopropoxy-phenyl)-urea	10.3	28		0.3
29		10.3	30	N-(3-isopropoxy-phenyl)-1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-4-methane amide	nd
31	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-3-base ester	0.2	30		nd
31		0.2	32	(4-isopropoxy-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy yl-quinoline-4-yl)-tetramethyleneimine-3-base ester	5.3
33	(4-sec.-propyl-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidines-2-base methyl esters	5	32		5.3
33		5	34	(4-sec.-propyl-phenyl)-carboxylamine 1-quinolyl-4-tetramethyleneimine-3-base ester	7.6
35	N-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-2-(4-sec.-propyl-phenyl)-ethanamide	6.5	34		7.6
35		6.5	36	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-isopropoxy-phenyl)-1-methyl-urea	nd
37	(4-sec.-propyl-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-tetramethyleneimine-3-base ester	8.48	36		nd
37		8.48	38	1-(4-isopropoxy-phenyl)-3-(1-quinolyl-4-tetramethyleneimine-3 base)-urea	26.8
39	(4-isopropoxy-phenyl)-carboxylamine 1-quinolyl-4-tetramethyleneimine-3-base ester	9.1	38		26.8
39		9.1	40	(4-isopropoxy-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy yl-quinoline-4-yl)-piperidin-4-yl ester	11.8
41	(4-isopropoxy-phenyl)-carboxylamine 1-quinolyl-4-piperidin-4-yl ester	14	40		11.8
41		14	42	(4-sec.-propyl-phenyl)-carboxylamine 1-(3-cyano group-6,7-dimethoxy-quinolyl-4)-piperidin-4-yl ester	＞42
43	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-morpholine-4-base-phenyl)-urea	40.6	42		＞42
43		40.6	44	1-(6-cyclobutoxy group-pyridin-3-yl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea	4.88
45	1-(6-cyclopentyloxy-pyridin-3-yl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea	11.79	44		4.88

46

1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(6-tetramethyleneimine-1-base-pyridin-3-yl)-urea

24.81

No.	The compound title	TrkBIC ₅₀(μM)
No.	The compound title	TrkBIC ₅₀(μM)	47	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-piperidines-1-base-phenyl)-urea	11.96
48	1-(4-chloro-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea	16	47		11.96
48		16	49	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-tetramethyleneimine-1-base-phenyl)-urea	3.88
50	1-(4-cyclohexyl-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea	＞46	49		3.88
50		＞46	51	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-phenoxy group-phenyl)-urea	2.74
52	1-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-3-(4-dimethylamino-phenyl)-urea	22.7	51		2.74
52		22.7	53	1-(4-cyclopentyloxy-phenyl)-3-[1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-yl]-urea	4.07
54	(4-cyclopentyloxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-tetramethyleneimine-3-base ester	44.64	53		4.07
54		44.64	55	(4-cyclopentyloxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl ester	＞46
56	(4-cyclopentyloxy-phenyl)-carboxylamine 1-(6,7-dimethoxy-quinazoline-4-yl)-piperidin-4-yl methyl esters	6.58	55		＞46

Treatment/prevention method

In another aspect of this invention, available The compounds of this invention suppresses tyrosine kinase activity among cell or the patient, comprise Flt3 activity and/or TrkB activity, or reduce the kinase activity comprise Flt3 activity and/or TrkB activity, or the treatment patient is with FLT3 and/or TrkB kinase activity or express relevant illness.

In an embodiment aspect this, the invention provides the method that reduces or suppress FLT3 in the cell and/or TrkB kinase activity, this method comprises the step that cell is contacted with formula I compound.The present invention also provides the method that reduces or suppress FLT3 among the patient and/or TrkB kinase activity, and this method comprises and gives patient's formula I the step of compound.The present invention also provides the method that suppresses cell proliferation in the cell, and this method comprises the step that cell is contacted with formula I compound.

Can measure FLT3 or TrkB kinase activity among cell or the patient by for example described FLT3 kinase assays of method well known in the art and described TrkB kinase assays method herein herein.

Term used herein " patient " is meant the animal as treatment, observation or experimental subjects, preferred mammal, and optimum is chosen.

Term used herein " contact " is meant compound is added cell, so that this compound is absorbed by cell.

In other embodiment aspect this, the invention provides treatment patient's preventative and therapeutic method, this patient has the occurrence risk of (or susceptible) cell proliferative disorders or the illness relevant with FLT3 and/or TrkB.

In an example, the present invention provides prevention method for cell proliferative disorders or the illness patient relevant with FLT3 and/or TrkB, this method comprises and gives the medicinal compositions that the patient prevents significant quantity that said composition contains formula I compound and pharmaceutically acceptable carrier.Give described preventive medicine before can appearing at the symptom characteristic of cell proliferative disorders or the illness relevant with FLT3 and/or TrkB, so that preventing disease or illness, or postpone its development.

In another example, the present invention relates to treat the method for cell proliferative disorders among the patient or the illness relevant with FL T3 and/or TrkB, described method comprises the medicinal compositions that gives the patient treatment significant quantity, and said composition contains formula I compound and pharmaceutically acceptable carrier.Give described curative drug when can appear at the symptom characteristic of illness so that described curative drug as offset cell proliferative disorders or with FL T3 and/or the relevant treatment of conditions of TrkB.

Term " prevention significant quantity " is meant that researchist, animal doctor, doctor or other clinical staff seek, and suppresses or postpone the active compound of patient's illness outbreak or the amount of medicine.

Term used herein " treatment significant quantity " is meant that researchist, animal doctor, doctor or other clinical staff seek, cause the amount of the active compound or the medicine of patient's biology or medical response, described reaction comprise alleviate the symptom of the disease for the treatment of or illness.

In the art, determine that the treatment of medicinal compositions of the present invention and the method for prevention effective dose are known.

Term used herein " composition " should comprise the product of the appointment composition that contains specified amount and any product that is directly or indirectly produced by the combination of the appointment composition of specified amount.

Term used herein " illness relevant " or " illness receptor related " or " illness relevant " with the FLT3 receptor tyrosine kinase with FLT3 with FLT3 should comprise relate to or with FLT3 activity FLT3 overacfivity diseases associated and follow the illness of these diseases for example.Term " FLT3 overacfivity " is meant: 1) FLT3 is expressed in usually and does not express in the cell of FLT3; 2) the common cell expressing FLT3 that does not express FLT3; 3) not needing to cause the FLT3 of cell proliferation to express increase; Or 4) cause the sudden change of FLT3 constitutive activation.The example of " illness relevant with FLT3 " comprises the disease that causes overstimulation FL T3 to cause because of unusual lot of F LT3 or FLT3 sudden change, perhaps the disease that causes high FL T3 live vol unusually to cause because of unusual lot of F L T3 or FL T3 sudden change.Known FL T3 overacfivity relates to the pathogenesis of multiple disease, and these diseases comprise following cell proliferative disorders, tumprigenicity illness and cancer.

Term " cell proliferative disorders " is meant in multicellular organisms cause damage one or more cell subsets unwanted cells propagation of (being the discomfort or the lost of life) of multicellular organisms.Cell proliferative disorders can take place in animal and human not of the same race.For example, " cell proliferative disorders " used herein comprises tumour and other cell proliferative disorders.

" tumprigenicity illness " used herein is meant the tumour that is produced by cell growth unusual or out of control.The example of tumprigenicity illness includes but not limited to for example bone marrow proliferative illness of hematopoietic disorders, and for example thrombocythemia, essential thrombocythemia (ET), the special property sent out myeloid metaplasia, myelofibrosis (MF), myelofibrosis merge the preceding myelodysplastic syndrome of myeloid metaplasia (MMM), chronic idiopathic myelofibrosis (IMF) and polycythemia vera (PV), cytopenia and canceration; Cancer is neurospongioma cancer, lung cancer, mammary cancer, carcinoma of the colon and rectum, prostate cancer, cancer of the stomach, the esophageal carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer for example; And leukemia, comprise myelodysplasia, multiple myeloma, leukemia and lymphoma.The example of leukemia comprises for example leukemia, lymphoma (non-Hodgkin lymphoma), the acute lymphoblastic leukemia (ALL) of Hodgkin's disease (being called Hodgkin lymphoma again) and myelomatosis-for example, acute myelocytic leukemia (AML), acute promyelocytic leukemia (APL), lymphocytic leukemia (CLL), chronic granulocytic leukemia (CML), chronic neutrophilic leukemia (CNL), acute nondifferentiated leukemia (AUL), retrogressive development large celllymphoma (ALCL), prolymphocytic leukemia (PML), teenager's myelomonocytic leukemia (JMML), adult T cell ALL, AML merges three pedigree myelodysplasias (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD) and multiple myeloma (MM).

The example of other cell proliferative disorders includes but not limited to atherosclerosis (Libby P, 2003, " Vascular biology of atherosclerosis:overview and state of theart " (atherosclerotic blood vessel biology: this field summary and state), Am J Cardiol91 (3A): 3A-6A); The vascular lesion that transplanting causes (Helisch A, Schaper W.2003, Arteriogenesis:the development and growth of collateral arteries (artery generates: the growth of side arteriae collateralis and growth) .Microcirculation, 10 (1): 83-97); Macular degeneration (Holz FG etc., 2004, " Pathogenesis of lesions in late age-related maculardisease " (pathogenesis that damage in the macula lutea disease relevant with the age late period), Am JOphthalmol.137 (3): 504-10); Neointima hyperplasia and restenosis (Schiele TM etc., 2004, " Vascular restenosis-striving for therapy. " (vascular restenosis-treatment is made great efforts) Expert Opin Pharmacother.5 (11): 2221-32); Pnemnofibrosis (Thannickal VJ etc., 2003, " Idiopathic pulmonary fibrosis:emerging concepts onpharmacotherapy (idiopathic pulmonary fibrosis: the new ideas of pharmacological agent), ExpertOpin Pharmacother.5 (8): 1671-86); Glomerulonephritis (Cybulsky AV, 2000, " Growth factor pathways in proliferative glomerulonephritis " (the somatomedin approach in the proliferative glomerulonephritis), Curr Opin Nephrol Hypertens " 9 (3): 217-23); Glomerulosclerosis (Harris RC etc., 1999, " Molecular basis of injury, and progression in focal glomerulosclerosis " (the molecules basis of damage and FGS's development) Nephron 82 (4): 289-99); Renal dysplasia and renal fibrosis (Woolf AS etc., 2004, " Evolving concepts in human renal dysplasia " (evolution of people's renal dysplasia notion), J Am Soc Nephrol.15 (4): 998-1007); Diabetic retinopathy (Grant MB etc., 2004, " The role of growth factors in thepathogenesis of diabetic retinopathy " (effect of somatomedin in the diabetic retinopathy pathogenesis), Expert Opin Investig Drugs 13 (10): 1275-93) and rheumatoid arthritis (Sweeney SE, Firestein GS, 2004, Rheumatoid arthritis:regulation of synovial inflammation (rheumatoid arthritis: the adjusting of synovial membrane inflammation), Int J Biochem Cell Biol.36 (3): 372-8).

Term used herein " illness relevant " or " illness receptor related " or " illness relevant " with the TrkB receptor tyrosine kinase with TrkB with TrkB should comprise relate to or with TrkB activity TrkB overacfivity diseases associated and follow the illness of these diseases for example.Term " TrkB overacfivity " is meant: 1) TrkB is expressed in usually and does not express in the cell of TrkB; 2) the common cell expressing TrkB that does not express TrkB; 3) not needing to cause the TrkB of cell proliferation to express increase; Or 4) cause the not TrkB expression increase of dependent cell survival of adhesion; 5) cause the sudden change of TrkB constitutive activation.The example of " illness relevant with TrkB " comprises 1) disease that causes overstimulation TrkB to cause because of unusual a large amount of TrkB or TrkB sudden change, or 2) cause the illness that unusual high TrkB live vol causes because of unusual a large amount of TrkB or TrkB sudden change.

The illness relevant with TrkB comprises multiple disease, comprises that cancer is such as but not limited to neuroblastoma, wilms' tumor, mammary gland, colon, prostate gland and lung cancer.Referring to for example BrodeurGM, (2003) " Neuroblastoma:biological insights into a clinicalenigma. " (neuroblastoma; Biology to clinical mystery is seen clearly) Nat RevCancer; 3 (3): 203-16; (2001) " Expression of the neurotrophin receptorTrkB is associated with unfavorable outcome in Wilms ' tumor " such as Eggerl A (neurotrophin acceptor TrkB expresses relevant with the adverse consequences of wilms' tumor) J Clin Oncol.19 (3): 689-96; (2001) " Nerve growth factor stimulatesproliferation and survival of human breast cancer cells through twodistinct signaling pathways. " such as Descamps S (nerve growth factor is by two kinds of unlike signal pathway stimulation human breast cancer cell propagation and survival) J Biol Chem.276 (21): 17864-70; BardelliA etc. (2003) " Mutational analysis of the tyrosine kinome in colorectalcancers. " (to the mutation analysis of Tyrosylprotein kinase in the colorectal carcinoma) Science 300 (5621): 949; (2000) " Rational basis for Trk inhibition therapyfor prostate cancer. " such as Weeraratna AT (Trk of prostate cancer suppresses the reasonable basis of therapy) Prostate45 (2): 140-8.19 (3): 689-96; Ricci etc., (2001) " Neurotrophins andneurotrophin receptors in human lung cancer " (neurotrophin in people's lung cancer and neurotrophin acceptor).Am J Respir Cell Mol Biol.25(4)：439-46。

Going back in the embodiment aspect this, the present invention includes the conjoint therapy that treatment or inhibition patient's cell proliferative disorders or the illness relevant with FLT3 and/or TrkB are shown effect.This conjoint therapy comprises formula I compound and one or more other inhibition of cell proliferation therapies that gives patient treatment or prevention significant quantity, comprises chemotherapy, radiotherapy, gene therapy and immunotherapy.

In embodiment of the present invention, can unite and give The compounds of this invention and chemotherapy.Chemotherapy used herein is meant the therapy that relates to chemotherapeutic agent.Multiple chemotherapeutics can be used for combinational therapeutic methods disclosed herein.The chemotherapeutics of Kao Lving includes but not limited to as an example: platinic compound (for example cis-platinum, carboplatin, oxaliplatin); Bearing taxanes (for example taxol, docetaxel (docetaxol)); Camptothecine (campotothecin) compound (irinotecan, Hycamtin); Vinca alkaloids (for example vincristine(VCR), vinealeucoblastine(VLB), vinorelbine); Antitumor nucleoside derivates (for example 5 FU 5 fluorouracil, folinic acid, gemcitabine, capecitabine); Alkylating agent (for example endoxan, carmustine, lomustine, plug are for group); Epipodophyllotoxin/podophyllotoxin (for example Etoposide, teniposide); Aromatase inhibitor (for example Anastrozole, letrozole, Exemestane); Estrogen antagonist compound (for example tamoxifen, fulvestrant), antifol (for example pemetrexed (premetrexed) disodium); Demethylation (hypomethylating) medicine (for example azacitidine); Biotechnological formulation (for example gemtuzumab (gemtuzamab), Cetuximab, Rituximab, handkerchief trastuzumab (pertuzumab), trastuzumab, rhuMAb-VEGF, erlotinib (erlotinib)); Microbiotic/anthracycline (for example idarubicin, dactinomycin, bleomycin, daunorubicin, Dx, ametycin, dactinomycin, Carubicin, daunomycin); Antimetabolite (for example aminopterin, Clofarex (clofarabine), cytosine arabinoside, methylpterin); Tubulin wedding agent (for example combretastatin, colchicine, R 17934); Topoisomerase enzyme inhibitor (for example camptothecine).Other active drug comprises the calcium antagonist verapamil, finds can cause chemosensitivity to generally acknowledging in the drug-fast tumour cell of chemotherapeutics after it and the antitumor drug coupling, and strengthens the effectiveness of this compounds in the drug susceptibility malignant tumour.Referring to Simpson WG, The calcium channel blocker verapamil and cancerchemotherapy (calcium channel blocker verapamil and cancer chemotherapy).Cell Calcium.1985Dec；6(6)：449-67。In addition, estimate that new chemotherapeutics and The compounds of this invention coupling are also effective.

In another embodiment of the present invention, can unite and give The compounds of this invention and radiotherapy." radiotherapy " used herein is meant and comprises that the patient who makes needs is exposed to the radiating therapy.The known this therapy of those skilled in the art.The suitable scheme of radiotherapy with in clinical treatment, used those are similar, wherein radiotherapy is used separately or is used with other chemotherapy drugs in combination.

In another embodiment of the present invention, can unite and give The compounds of this invention and gene therapy." gene therapy " used herein is meant that target relates to the therapy of tumorigenic specific gene.Feasible gene therapy strategy comprises antisense DNA transduction or the transfection corresponding to the gene of coding somatomedin and acceptor thereof of cancer-Inhibit Genes, the cell of rectification of defects; Based on the strategy of RNA for example ribozyme, RNA attractant insecticide, antisense messenger RNA and siRNA (siRNA) molecule and so-called ' suicide gene '.

In other embodiment of the present invention, can unite and give The compounds of this invention and immunotherapy." immunotherapy " used herein is meant that target relates to the therapy of tumorigenic specific protein by this albumen is had specific antibody.For example, the monoclonal antibody of anti-vascular endothelial growth factor has been used for the treatment of cancer.

When using second kind of medicine except that The compounds of this invention, two kinds of medicines can give (for example with dividing other or unit composition) simultaneously; About the same time, give or by separately relieve pain by arbitrary order is sequential.In the later case, two kinds of compounds should be during certain in, by being enough to guarantee to reach favourable or synergistic amount and mode gives.Can recognize that the corresponding dosage of each component and dosage regimen should depend on concrete chemotherapeutics and the The compounds of this invention of applied in any combination, their route of administration, the concrete tumour of being treated and the concrete host who gives in preferable methods and administration order and the combination medicine.

Such as one of ordinary skill understood, suitable chemotherapeutics dosage be similar to usually or less than in clinical treatment, used those, wherein chemotherapeutics can give separately or give with other chemotherapy drugs in combination.

Those skilled in the art can easily determine the best approach and order and the dosage and the scheme of administration with ordinary method with in view of the information that provides herein.

Only as an example, best 1-500mg/ rice according to dosage ²(mg/m ²) body surface area 50-400mg/m for example ²Give platinic compound, especially for cis-platinum, every treatment course of treatment is by about 75mg/m ²Dosed administration is for carboplatin, by about 300mg/m ²Administration.Cis-platinum can not oral absorption, therefore must be by in intravenously, subcutaneous, the tumour or the peritoneal injection release.

Only as an example, best 50-400mg/ rice according to dosage ²(mg/m ²) body surface area 75-250mg/m for example ²Give bearing taxanes, especially for taxol, every treatment course of treatment is by about 175-250mg/m ²Dosed administration is for docetaxel, by about 75-150mg/m ²Administration.

Only as an example, can be preferably 0.1-400mg/ rice according to dosage ²(mg/m ²) body surface area 1-300mg/m for example ²Give camptothecine, especially for irinotecan, every treatment course of treatment is by about 100-350mg/m ²Dosed administration is for Hycamtin, by about 1-2mg/m ²Administration.

Only as an example, best 2-30mg/ rice according to dosage ²(mg/m ²) body surface area gives vinca alkaloids, especially for vinealeucoblastine(VLB), every treatment course of treatment is by about 3-12mg/m ²Dosed administration is for vincristine(VCR), by about 1-2mg/m ²Dosed administration, for vinorelbine, according to dosage about 10-30mg/m ²Administration.

Only as an example, best 200-2500mg/ rice according to dosage ²(mg/m ²) body surface area 700-1500mg/m for example ²Give antitumor nucleoside derivates.When 5 FU 5 fluorouracil (5-FU) uses, press 200-500mg/m usually ²(preferred 3-15mg/kg/ day) dosage intravenous administration.Every treatment course of treatment is preferably by about 800-1200mg/m ²Dosage gives gemcitabine, preferably according to dosage about 1000-2500mg/m ²Give capecitabine.

Only as an example, best 100-500mg/ rice according to dosage ²(mg/m ²) body surface area 120-200mg/m for example ²Give alkylating agent, especially every treatment course of treatment is by about 100-500mg/m ²Dosage gives endoxan, and for Chlorambucil, the administration of according to dosage about 0.1-0.2mg/kg body weight is for carmustine, by about 150-200mg/m ²Dosed administration, for lomustine, according to dosage about 100-150mg/m ²Administration.

Only as an example, best 30-300mg/ rice according to dosage ²(mg/m ²) body surface area 50-250mg/m for example ²Give podophyllotoxin derivative, especially for Etoposide, every treatment course of treatment is by about 35-100mg/m ²Dosed administration is for teniposide, by about 50-250mg/m ²Administration.

Only as an example, best 10-75mg/ rice according to dosage ²(mg/m ²) body surface area 15-60mg/m for example ²Give anthracycline derivative, especially for Dx, every treatment course of treatment is by about 40-75mg/m ²Dosed administration is for daunorubicin, by about 25-45mg/m ²Dosed administration, for idarubicin, according to dosage about 10-15mg/m ²Administration.

Only as an example, preferably can give the estrogen antagonist compound, depend on concrete medicine and the illness of being treated by about 1-100mg dosage every day.Preferably press 5-50mg, preferred 10-20mg dosage, by the orally give tamoxifen, is treated the enough time to reach and to keep curative effect continuously at every day twice.Preferably by about 60mg dosage, once a day, the orally give toremifene is treated the enough time continuously to reach and to keep curative effect.Preferably press about 1mg dosage, once a day, by the orally give Anastrozole.Preferably press about 20-100mg dosage, once a day, by the bent Lip river of orally give former times sweet smell.Preferably press about 60mg dosage, once a day, by the orally give raloxifene.Preferably press about 25mg dosage, once a day, by orally give Yi Ximeitan.

Only as an example, preferably can according to dosage about 1-5mg/ rice ²(mg/m ²) body surface area, or, give biotechnological formulation by known dose in this area if any difference.For example, every treatment course of treatment best 1-5mg/m according to dosage ², 2-4mg/m especially ²Give trastuzumab.

Every treatment can give for example 1,2 or a plurality of dosage the course of treatment, for example can be by per 7,14,21 or 28 days repeat administrations.

Can be for example give the patient The compounds of this invention through intravenously, oral, subcutaneous, intramuscular, intracutaneous or parenteral whole body.But also topical administration patient The compounds of this invention.The non-limiting example of local delivery system comprises the use intraluminal medical devices, comprises and passs paving (endoluminal paving) in medicine conduit, line, pharmacology support (stents) and the chamber in the blood vessel.The compounds of this invention also can give the patient with the targeted drug combination, so that obtain the compound of high local concentrations at target site.In addition, also The compounds of this invention can be mixed with quick-release keep medicine or medicament and target tissue contact number hour to the slow release formulation of a few weeks longer purpose.

The present invention also provides the medicinal compositions of the pharmaceutically acceptable carrier that contains formula I compound and applied in any combination.This medicinal compositions can contain the 0.1mg-1000mg that has an appointment, preferably about 100-500mg compound, and can be made into any form that is fit to selected mode of administration.

Term " pharmaceutically acceptable " is meant molecular entity and the composition that does not produce bad, irritated or other unsuitable reaction when giving the animal or human when in place.Veterinary purpose is included in the present invention equally, and " pharmaceutically acceptable " preparation comprises clinical and/or veterinary formulations.

Carrier comprises and necessary and inert pharmaceutical vehicle includes but not limited to tackiness agent, suspension agent, lubricant, correctives, sweeting agent, sanitas, dyestuff and Drug coating.Suitable liquid preparations for oral administration comprises solid form for example pill, tablet, Caplet, capsule (comprise promptly separately and release, regularly discharge and sustained release preparation), granule and powder; With liquid form for example solution, syrup, elixir, emulsion and suspensoid.The form that can be used for administered parenterally comprises sterile solution agent, emulsion and suspensoid.

Medicinal compositions of the present invention also comprises the medicinal compositions that is used for slowly discharging The compounds of this invention.Said composition comprises slow-released carrier (being generally polymer support) and The compounds of this invention.

Know biodegradable slow-released carrier in the art.They are can form one or more active compounds are captured in wherein particle, and in suitable environment (for example water-based, acidity, alkalescence etc.) slow degrades/dissolves down; And therefore degrades/dissolves in body fluid, thereby discharge the material of one or more active compounds therein.Particle is preferably nano particle (being the about 1-500nm of diameter, the preferred about 50-200nm of diameter, the about 100nm of most preferred diameters).

The present invention also provides the method for preparing medicinal compositions of the present invention.According to the conventional medicine hybrid technology, will be as the formula I compound and the pharmaceutical carrier thorough mixing of activeconstituents, carrier can adopt various ways, depends on for example oral or the parenteral dosage form of intramuscular administration needs for example.When the preparation oral dosage form composition, can adopt any common drug media.Therefore, for liquid oral medicine for example suspensoid, elixir and solution, can adopt suitable carriers and additive to comprise water, glycol, oil, alcohol, correctives, sanitas, tinting material etc.; For solid orally ingestible for example powder, capsule, Caplet, soft capsule and tablet, can adopt suitable carriers and additive to comprise starch, sugar, thinner, granulation agent, lubricant, tackiness agent, disintegrating agent etc.Because they are easy to administration, tablet and capsule are represented best oral dosage unit form, in this case, obviously use solid pharmaceutical carriers.If desired, can give tablet sugar coating or enteric coating by standard technique.For parenteral administration, although can comprise other composition that for example is used for hydrotropy or anticorrosion purpose, carrier generally includes sterilized water.Also suspension for injection can be prepared, in this case, suitable liquid vehicle, suspension agent etc. can be used.When the preparation sustained release preparation, slow-released carrier is generally polymer support in elder generation and The compounds of this invention is dissolved in or is scattered in organic solvent.Then the organic solution that obtains is added the aqueous solution, obtain oil-in-water emulsion.Preferably, the aqueous solution comprises one or more tensio-active agents.With the organic solvent evaporation in the oil-in-water emulsion, obtain containing the colloidal solid suspension of slow-released carrier and The compounds of this invention then.

For example tablet, capsule, powder, injection, a dosage etc. should contain the amount that above-mentioned effective dose institute must activeconstituents that discharges to each dose unit of medicinal compositions herein.For example tablet, capsule, powder, injection, suppository, a dosage etc. should contain about 0.01mg-200mg/kg body weight/day to each dose unit of medicinal compositions herein.Preferably, this scope is the about 100mg/kg body weight/day of about 0.03-, most preferably from about the about 10mg/kg body weight/day of 0.05-.Can give compound by 1-5 time scheme every day.But, can change dosage according to patient's needs, the sanatory severity of institute and employed compound.Can use administration every day or (post-periodic) medication intermittently.

Preferred these compositions are unit dosage, for example tablet, pill, capsule, powder, granule, sterile parenteral solutions agent or suspensoid; Quantitative aerosol or liquid spray, drops, ampoule, automatic injector assembly or suppository; Be used in oral, parenteral, the nose, hypogloeeis or rectal administration, or be used for by sucking or be blown into administration.Perhaps, can provide the composition that is fit to weekly or every month single administration; For example the insoluble salt of active compound for example caprate can be fit to be provided for the depot formulation of intramuscularly.When preparation solids composition for example during tablet, with main activeconstituents and for example conventional compressing tablet composition of pharmaceutical carrier such as W-Gum, lactose, sucrose, sorbyl alcohol, talcum powder, stearic acid, Magnesium Stearate, Lin Suanergai or natural gum, with for example water mixing of other medicines thinner, form the solid preparation composition, said composition contains the uniform mixture of The compounds of this invention or its pharmacy acceptable salt.When claiming that these preparation compositions are even, the expression activeconstituents is evenly dispersed in the whole composition, so that composition can easily be subdivided into identical effective dosage form, for example tablet, pill and capsule.The unit dosage form that then this solid preparation composition is divided into the above-mentioned type that contains the about 500mg of 0.1-activeconstituents of the present invention.Can be with the tablet or the coating of pill of novel composition, or be mixed with the formulation that the long-acting advantage is provided.For example, dosage and external dose component in tablet or pill can contain, the latter is a form of sealing the former.Can two kinds of components be separated by enteric layer, enteric layer is used to stop disintegration under one's belt, and component is complete by duodenum or delay release in allowing.Multiple material can be used as this type of enteric layer or Drug coating, and this type of material comprises multiple polymers acid and material for example shellac, hexadecanol and cellulose acetate.

Wherein can mix liquid form that formula I compound is used for oral or drug administration by injection and comprise the aqueous solution, suitably syrup, water or the oil suspension of flavoring; With edible oil for example emulsion, elixir and the similar medicinal solvent of Oleum Gossypii semen, sesame oil, Oleum Cocois or peanut oil flavoring.Being used for the suitable dispersant of aqueous suspension or suspension agent comprises synthetic and natural gum for example tragacanth, gum arabic, alginate (ester), dextran, Xylo-Mucine, methylcellulose gum, polyvinylpyrrolidone or gelatin.Adopt the suspension agent of suitable flavoring or the liquid form of dispersion agent also can comprise synthetic and natural gum, for example tragacanth, gum arabic, methylcellulose gum etc.For administered parenterally, need aseptic suspensoid and solution.When the needs intravenous administration, use the grade that contains suitable preservatives to ooze preparation usually.

Formula I compound can preferably give with single per daily dose, or total per daily dose is divided into the divided dose administration of every day twice, three times or four times.In addition, can use solvent in the suitable nose to give the The compounds of this invention of form in the nose by the part, or give The compounds of this invention by the transdermal patch that those of ordinary skills know.For pressing the form administration of transdermal delivery system, in whole dosage regimen, dosed administration is successive naturally but not is interrupted.

For example, for the oral administration of tablet or Capsule form, for example ethanol, glycerine, water etc. mix with oral nontoxic pharmaceutically acceptable inert support can to make active pharmaceutical ingredient.In addition, when needs or in case of necessity, also can be with suitable binder; Lubricant, disintegrating agent and tinting material mix mixture.Suitable binder includes but not limited to starch, gelatin; Natural sugar is glucose or beta lactose, corn sweetener for example; Natural and synthetic gum is gum arabic, tragacanth for example, or sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc.Disintegrating agent includes but not limited to starch, methylcellulose gum, agar, bentonite, xanthan gum etc.

The per daily dose of product of the present invention can change in the wide region of 1-5000mg/ grownup/day.For oral administration, the composition of tablet form preferably is provided, this type of tablet contains 0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0,25.0,50.0,100,150,200,250 and 500 milligram of activeconstituents, regulates dosage according to treatment patient's symptom.The medicine of significant quantity is provided by the about 200mg/kg body weight/day of about 0.01mg/kg-dosage level usually.Especially, this scope is the about 15mmg/kg body weight/day of about 0.03-, the about 10mg/kg body weight/day of more specifically about 0.05-.Can by every day up to 4 times or more frequently scheme give The compounds of this invention, preferred 1-2 time/day.

Those skilled in the art can easily determine best dosage, and this dosage is according to concrete compound, mode of administration, formulation concentrations, mode of administration, the state of an illness changed condition of using.In addition, relevant with the patient of concrete treatment factor comprises that patient age, body weight, diet and administration time can cause necessity of adjusting dosage.

Also can give The compounds of this invention by the form of liposome delivery system for example small unilamellar vesicle, big unilamellar liposome and multilamelar liposome.Can form liposome by multiple lipid, this lipoids includes but not limited to amphoteric lipid, for example phosphatidylcholine, sphingomyelin, phosphatidylethanolamine, Yelkin TTS (phophatidylcholines), Val, phosphatidylserine, phosphatidyl glycerol, phosphatidic acid, phosphatidylinositols, diacyl trimethyl ammonium propane, diacyl Dimethyl Ammonium propane and stearylamine; Neutral lipid is triglyceride level and combination thereof for example.They can contain cholesterol or can not contain cholesterol.

But also topical administration The compounds of this invention.Can utilize any drug delivery systems, for example pass paving in medicine conduit, line, pharmacology support and the chamber in the blood vessel.The delivery system of this device can comprise the local infusion conduit that discharges compound by the speed of manager's control.

The invention provides drug delivery systems, this device contains the The compounds of this invention of preferred support of intraluminal medical devices and therapeutic dose.

Term " support " is meant any device that can pass medicine by conduit.Support is generally used for preventing inwardly vessel sealing due to the growth of the unnecessary vascular tissue that for example causes because of surgery operating wound because of the physical property deformity.It has tubulose, swelling property lattice type structure usually, and this structure is fit to place in the tube chamber to eliminate infraction.Support has chamber wall surface in contact and chamber exposed surface.Chamber wall surface in contact is the outside surface of pipe, and the chamber exposed surface is the internal surface of pipe.Support can be that polymkeric substance, metal or polymkeric substance add through metal, and it may optionally be the biological degradability support.

Usually, support is inserted in the chamber by unexpansive form, its automatic expansion then, or by the expansion of second kind of device original position.Typical expanding method is the angioplasty sacculus generation expansion that conduit is housed by use, and this sacculus expands in blood vessel that narrows down or body passage, with shearing and the destruction infraction relevant with the vessel wall composition, the chamber that obtains enlarging.Also can use United States Patent (USP) 6,776, self-expanding cribbing described in 796 (Falotico etc.).Support can provide with the medicine that prevents inflammation and propagation, medicament or compound combination and treat postangioplasty restenosis most effectively.

Can and utilize the biocompatible substance of any number by multiple mode, The compounds of this invention be mixed or attached in the support.In an exemplary embodiment, compound is directly mixed for example polypyrrole polymers of polymeric matrix, be coated in the outside surface of support then.By the diffusion in polymkeric substance, compound elutes from matrix.Support and on support the method for painting medicine detailed argumentation is arranged in the art.In another exemplary embodiment, the stratum basale with the solution that contains compound, vinyl-vinyl acetate copolymer and poly-n-butyl methacrylate is coated with support earlier.Then, again with the skin coating support that only contains poly-n-butyl methacrylate.The outer diffusion barrier that plays a part, the prevention compound is too fast to elute and enters surrounding tissue.The thickness decision compound of skin or top coat is from the speed of matrix wash-out.Support and coating process announce in WO9632907, U.S. Patent Publication number 2002/0016625 and the wherein disclosed reference that at WIPO detailed argumentation is arranged.

Can be incorporated into the solution of The compounds of this invention and biocompatible materials/polymkeric substance in the support or on it by multiple mode.For example, can with solution spraying on support, maybe support can be immersed in the solution.In preferred embodiments, solution spraying is on support, dry then.In another exemplary embodiment, can make a kind of polar electric charge of solution band, make the electric charge of supporting band opposite polarity.According to this mode, solution and support attract each other.Use this spraying coating process can reduce waste material, can realize more controls coat-thickness.Preferred compound only attached to a kind of outside surface of organizing the support that contacts.But, can apply entire bracket for some compound.The compound dosage that is coated in the polymeric coating of support and control drug release makes up very important for the validity of medicine.Preferred compound keeps at least 3 days to reaching about 6 months, more preferably 7-30 days on support.

The compounds of this invention can be united use with the non-edible biodegradable polymers of any number.It is pointed out that different supports can use different polymkeric substance very important.For example, above-mentioned vinyl-vinyl acetate copolymer and poly-n-butyl methacrylate matrix are worked well with stainless steel stent.Other polymkeric substance can more effectively be used for the support that formed by other material, and these materials comprise the material with super-elasticity character, for example the alloy of nickel and titanium.

Restenosis is the reason of the remarkable M ﹠ M of coronary artery postangioplasty.Restenosis takes place by the combination of 4 processes, and these processes comprise elasticity aftertaste, thrombosis, intimal hyperplasia and extracellular matrix reconstruction.Recently identifying several somatomedins works (referring to Schiele TM etc. in these cause the process of restenosis, 2004, " Vascular restenosis-strivingfor therapy. " (vascular restenosis-treatment is made great efforts) Expert Opin Pharmacother.5 (11): 2221-32.).As everyone knows, TrkB part BDNF and neurotrophin and TrkB express (referring to Ricci A etc. 2003, " Neurotrophins and neurotrophin receptors in human pulmonaryarteries. " (neurotrophin in people's pulmonary artery and neurotrophin acceptor) J Vasc Res.37 (5): 355-63 by vascular smooth muscle cell and endotheliocyte; In addition referring to Kim H etc., 2004 " Paracrine and autocrine functionsof brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brain-derived endothelial cells " (paracrine and the autocrine functions of brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the endotheliocyte of brain source), J BiolChem.279 (32): 33538-46).In addition, TrkB around blood vessel take place and intimal hyperplasia in work, because it has the ability that prevents anoikis and prolong cell survival (referring to Douma S etc., 2004, " Suppression of anoikis and induction of metastasis bythe neurotrophic receptor TrkB " (suppress anoikis and bring out transfer) by neurotrophic acceptor TrkB, Nature.430 (7003): 1034-9.).Therefore, during the coronary artery angioplasty and afterwards, suppressing TrkB with the support that applies provides feasible therapeutic strategy.

Therefore, the invention provides the treatment of conditions method relevant with TrkB, these illnesss comprise restenosis, vessel wall intimal hyperplasia or inflammation, and this method comprises that the realization controlled release is passed medicine by for example discharging the The compounds of this invention for the treatment of significant quantity the support from the inner chamber medical treatment device.

The method of support being introduced body cavity is well-known, preferably introduces the support of The compounds of this invention coating with conduit.As those of ordinary skills recognized, according to the position that support is implanted, method was slightly different.Implant for coronary artery bracket, the foley's tube that will have support inserts coronary artery, and will prop up the position that is placed on needs.Inflation expands support.Because support expands, support contacts with the chamber wall.In case the support location, the sacculus venting is also removed.Support keeps in position, and the chamber surface in contact has the compound that directly contacts with the chamber wall surface.Can when support is implanted, use anticoagulant therapy as required.

The top condition of the release compound that uses in support of the present invention can change according to the employed different local delivery system and the character and the concentration of employed compound.Optimizable condition comprises for example compound concentrations, the quantity that discharges volume, release rate, the degree of depth of infiltration vessel wall, proximate turgor pressure, perforation and installation big or small and that pass the medicine catheter-balloon.For example change and measure, can optimize the condition of inhibition damage location smooth muscle cell proliferation, so that do not take place because of the remarkable obstruction of artery due to the restenosis by the smooth muscle cell proliferation ability or by vascular resistance or chamber diameter.Can determine optimal conditions with conventional method of calculation according to the Research of Animal Model for Study data.

The another kind of alternative approach that gives The compounds of this invention is that compound and targeting agent are puted together, and this reagent guides to its predetermined site of action with conjugate, promptly to vascular endothelial cell or to tumour cell.Can use antibody and non-antibody targeting agent.Interact in conjunction with the specificity between the object because targeting agent is its corresponding, can near target site or its, give the The compounds of this invention of high local concentrations, thereby more effectively treat illness at target site.

Antibody target reagent comprises antibody or its Fab, but the component combination that they maybe can contact with the target of tumour cell, tumor vessel structure or tumor stroma." but component that target maybe can contact " of tumour cell, tumor vessel structure or tumor stroma is preferably the component of surface expression, surface contact or surface alignment.Antibody target reagent also comprises antibody or its Fab, and they combine with component in the cell that is discharged by downright bad tumour cell.Preferably, this antibody-like is monoclonal antibody or its Fab, and they combine with one or more insoluble intracellular antigens, and this antigen is present in and can causes in permeable cell; Or be present in basically in all tumours and Normocellular ghost, but do not exist maybe and can't contact in mammiferous normal viable cell outside.

Any immunoconjugator for example IgG, IgM, IgA, IgE, F (ab ') 2 should be made a general reference in term used herein " antibody "; The unit price fragment is Fab ', Fab, Dab for example; With engineered antibody for example recombinant antibodies, humanized antibody, bi-specific antibody etc.Although preferred mono-clonal, antibody can be polyclone or mono-clonal.Known antibodies in a variety of this areas is arranged, and they have immunologic opsonin (referring to the monoclonal antibody conclusive table of solid tumor in the U.S. Patent number 5,855,866 of Thorpe etc.) to the cell surface of any solid tumor type almost.The known preparation of those skilled in the art and the method for separating anti-tumour antibody (referring to the U.S. Patent number 6,34,2219 of the U.S. Patent number 5,855,866 of Thorpe etc. and Thorpe etc.).

Make the technology that treatment part and antibody puts together (referring to for example Amon etc. as everyone knows, " Monoclonal Antibodies For Immunotargeting Of Drugs In CancerTherapy " (the medicine immunity target monoclonal antibody that is used for cancer therapy), at Monoclonal Antibodies And Cancer Therapy, Reisfeld etc. (editor), pp.243-56 (Alan R.Liss, Inc.1985); Hellstrom etc., " Antibodies For DrugDelivery " (passing medicine antibody), Controlled Drug Delivery (the 2nd edition), Robinson etc. (editor), pp.623-53 (Marcel Dekker, Inc.1987); Thorpe, " AntibodyCarriers Of Cytotoxic Agents In Cancer Therapy:A Review " (antibody carrier of cell toxicity medicament in the cancer therapy), at Monoclonal Antibodies ' 84:Biological AndCinical Applications, Pinchera etc. (editor), pp.475-506 (1985)).Also can use similar techniques makes The compounds of this invention be connected with the non-antibody targeting agent.

Those skilled in the art should know maybe can determine to use for example method of small molecules, oligopeptides, polysaccharide or other polyanionic compound formation conjugate of non-antibody targeting agent.

Moderately stable any connection portion is connected to The compounds of this invention on the targeting agent in the blood although can be used on, preferably the key that biologically can disconnect and/or the interval body or the linker of selective dissociation." key that can disconnect biologically " and " interval body of selective dissociation or linker " still have adequate stability in circulation, but only or preferably under certain conditions, promptly in certain environment or with particular agent, contact and can discharge, dissociate or hydrolysis.This generic key comprises for example U.S. Patent number 5,474,765 and 5,762, disulfide linkage described in 918 and three sulfide linkages and to the unsettled key of acid; Enzyme susceptibility key comprises U.S. Patent number 5,474,765 and 5,762, and the peptide bond described in 918, ester, acid amides, phosphodiester and glycosides.This type of selectivity discharges DESIGNED FEATURE and helps conjugate at the lasting compound that discharges of predetermined target site.

The invention provides medicinal compositions, said composition contains the The compounds of this invention and the pharmaceutically acceptable carrier of the significant quantity of puting together with targeting agent.

The present invention also provides treatment the illness relevant with FLT3 and/or TrkB, and the method for tumour especially, this method comprise the formula I compound of puting together with targeting agent that gives the patient treatment significant quantity.

When for example antibody or somatomedin or polysaccharide were as targeting agent with albumen, preferably they gave by the form of composition for injection.Should preferably in 10-20 minute, the injection antibody-solutions be given in vein, artery or the spinal fluid at 2 minutes-Yue 45 minutes.In some cases, the tumour for being limited near the zone of skin and/or particular body cavity privileged site preferably adopts intracutaneous and intracavitary administration.In addition, for the tumour that is positioned at brain, can adopt intrathecal drug delivery.

The The compounds of this invention of puting together with targeting agent of treatment effective dose depends on individuality, disease type, morbid state, medication and other clinical variable.Use the animal model data, can easily determine effective dose.Usually optimize suitable therapeutic dose with laboratory animal, be transformed into clinical setting then with solid tumor.Known this class model is very reliable in prediction effective antitumor strategy.For example, be extensive use of the working range that the mouse with solid tumor is determined medicine in preclinical test, the medicine of this scope provides useful antitumor action and toxicity minimum.

Though aforementioned specification is the embodiment that provides of illustration purpose by way of example, has taught the principle of the invention, be appreciated that enforcement of the present invention comprise fall into claim and be equal in the claim scope all change usually, change and/or revise.

Claims

1. a formula I compound and N-oxide compound, pharmacy acceptable salt and three-dimensional chemical isomer:

Formula I

Wherein:

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or straight key;

X is N or C-CN or CH, and condition is R _BbBe not heteroaryl or halogen;

Z is NH, N (alkyl) or CH ₂

B is selected from: cycloalkyl, 9 yuan of-10 yuan of benzo-fused heteroaryls or 9 yuan of-10 yuan of benzo-fused heterocycle bases, if or have a R ₃, then B is selected from phenyl or heteroaryl, and condition is that B is not the thiadiazine base;

R ₁And R ₂Independently be selected from following group:

Wherein n is 1,2,3 or 4;

Y is straight key, O, S, NH or N (alkyl);

R _wAnd R _xIndependently be selected from following group: hydrogen, alkyl, thiazolinyl, aralkyl or heteroaralkyl, or R _wAnd R _xCan choose wantonly and be combined together to form 5 yuan of-7 yuan of rings, described ring is chosen wantonly to contain and is selected from following hetero moiety: O, NH, N (alkyl), SO, SO ₂Or S,

R ₃Be the optional one or more substituting groups that exist, and independently be selected from following group: alkyl, alkoxyl group, halogen, nitro, optional by R ₄The cycloalkyl that replaces, optional by R ₄The heteroaryl that replaces, alkylamino, optional by R ₄The heterocyclic radical that replaces, alkoxyl group ether ,-O (cycloalkyl), optional by R ₄The pyrrolidone-base that replaces, optional by R ₄The phenoxy group that replaces ,-CN ,-OCHF ₂,-OCF ₃,-CF ₃, haloalkyl, optional by R ₄The heteroaryloxy that replaces, dialkyl amido ,-NHSO ₂Alkyl or-SO ₂Alkyl; R wherein ₄Independently be selected from following group: halogen, cyano group, trifluoromethyl, amino, hydroxyl, alkoxyl group ,-C (O) alkyl ,-CO ₂Alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or alkylamino.

2. the compound of claim 1, wherein: R _wAnd R _xIndependently be selected from hydrogen, alkyl, thiazolinyl, aralkyl or heteroaralkyl, maybe can choose wantonly and be combined together to form 5 yuan of-7 yuan of rings, described ring is selected from:

3. the compound of claim 1 wherein exists phenyl or heteroaryl, and condition is that B is not the thiadiazine base; With

R ₃For independently being selected from following one or more substituting groups: alkyl, alkoxyl group, halogen, nitro, optional by R ₄The cycloalkyl that replaces, optional by R ₄The heteroaryl that replaces, alkylamino, optional by R ₄The heterocyclic radical that replaces, alkoxyl group ether ,-O (cycloalkyl), optional by R ₄The pyrrolidone-base that replaces, optional by R ₄The phenoxy group that replaces ,-CN ,-OCHF ₂,-OCF ₃,-CF ₃, haloalkyl, optional by R ₄The heteroaryloxy that replaces, dialkyl amido ,-NHSO ₂Alkyl or-SO ₂Alkyl.

4. the compound of claim 3, wherein:

B is selected from: phenyl or heteroaryl, condition are that B is not the thiadiazine base; And

R ₃For independently being selected from following one or more substituting groups: alkyl, alkoxyl group, halogen, optional by R ₄The cycloalkyl that replaces, optional by R ₄The heteroaryl that replaces, alkylamino, optional by R ₄The heterocyclic radical that replaces, alkoxyl group ether ,-O (cycloalkyl), optional by R ₄The phenoxy group or the dialkyl amido that replace.

5. the compound of claim 4, wherein:

Y is straight key, O, NH or N (alkyl);

R _aBe alkoxyl group, optional by R ₅The heteroaryl that replaces, hydroxyl, alkylamino, dialkyl amido, optional by R ₅The oxazolidine ketone group that replaces, optional by R ₅The pyrrolidone-base that replaces, optional by R ₅The piperidone base that replaces, optional by R ₅The heterocyclic radical that replaces ,-CONR _wR _x,-N (R _y) CON (R _w) (R _x) ,-N (R _w) COR _y,-SR _y,-SOR _y,-SO ₂R _yOr-NR _wSO ₂R _yAnd

R _BbBe hydrogen, halogen or alkoxyl group.

6. the compound of claim 5, wherein:

Z is NH or CH ₂

R ₁And R ₂Independently be selected from following group:

Wherein n is 1,2 or 3;

Y is O;

R ₅For independently be selected from following substituting group a :-C (O) alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or-C ( _1-4) alkyl-OH; And

R ₃For independently being selected from a following substituting group: alkyl, alkoxyl group, cycloalkyl, heterocyclic radical ,-O (cycloalkyl), phenoxy group or dialkyl amido.

7. the compound of claim 6, wherein:

Q is 1 or 2;

Q is NH, O or straight key;

X is N;

Z is NH;

B is selected from: phenyl and pyridyl;

R ₁And R ₂Independently be selected from following group:

R _BbBe hydrogen or alkoxyl group; And

R ₃For being selected from a following substituting group: alkyl, alkoxyl group, heterocyclic radical ,-O (cycloalkyl) or dialkyl amido.

8. compound, described compound is selected from:

9. compound, described compound is selected from:

10. a formula I compound and N-oxide compound, pharmacy acceptable salt and three-dimensional chemical isomer:

Formula I

Wherein:

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or straight key;

X is N or C-CN or CH, and condition is R _BbBe not heteroaryl or halogen;

Z is NH, N (alkyl) or CH ₂

Wherein n is 1,2,3 or 4;

Y is straight key, O, S, NH or N (alkyl);

R _wAnd R _xIndependently be selected from following group: hydrogen, alkyl, thiazolinyl, aralkyl or heteroaralkyl, or R _wAnd R _xCan choose wantonly and be combined together to form 5 yuan of-7 yuan of rings, described ring is selected from:

11. a medicinal compositions, described composition comprise compound and the pharmaceutically acceptable carrier of claim 1-10.

12. each compound among the claim 1-10, described compound is as medicine.

13. the purposes of each compound in the preparation medicine among the claim 1-10, this medicine is used for the treatment of cell proliferative disorders.

14. a method that reduces FLT3 kinase activity in the cell, described method comprise the step that described cell is contacted with the compound of claim 1-10.

15. a method that suppresses FLT3 kinase activity in the cell, described method comprise the step that described cell is contacted with the compound of claim 1-10.

16. a method that reduces TrkB kinase activity in the cell, described method comprise the step that described cell is contacted with the compound of claim 1-10.

17. a method that suppresses TrkB kinase activity in the cell, described method comprise the step that described cell is contacted with the compound of claim 1-10.

18. a method that reduces FLT3 kinase activity among the patient, described method comprise the step of the compound that gives described patient's claim 1-10.

19. a method that suppresses FLT3 kinase activity among the patient, described method comprise the step of the compound that gives described patient's claim 1-10.

20. a method that reduces TrkB kinase activity among the patient, described method comprise the step of the compound that gives described patient's claim 1-10.

21. a method that suppresses TrkB kinase activity among the patient, described method comprise the step of the compound that gives described patient's claim 1-10.

Give the medicinal compositions that described patient prevents significant quantity 22. a method of preventing patient's illness relevant with FLT3, described method comprise, described composition comprises compound and the pharmaceutically acceptable carrier of claim 1-10.

Give the medicinal compositions that described patient prevents significant quantity 23. a method of preventing patient's illness relevant with TrkB, described method comprise, described composition comprises compound and the pharmaceutically acceptable carrier of claim 1-10.

24. a method for the treatment of patient's illness relevant with FLT3, described method comprises the medicinal compositions that gives described patient treatment significant quantity, and described composition comprises compound and the pharmaceutically acceptable carrier of claim 1-10.

25. a method for the treatment of patient's illness relevant with TrkB, described method comprises the medicinal compositions that gives described patient treatment significant quantity, and described composition comprises compound and the pharmaceutically acceptable carrier of claim 1-10.

26. also comprising, the method for claim 22, described method give chemotherapeutics.

27. also comprising, the method for claim 22, described method give gene therapy.

28. also comprising, the method for claim 22, described method give immunotherapy.

29. also comprising, the method for claim 22, described method give radiotherapy.

30. also comprising, the method for claim 23, described method give chemotherapeutics.

31. also comprising, the method for claim 23, described method give gene therapy.

32. also comprising, the method for claim 23, described method give immunotherapy.

33. also comprising, the method for claim 23, described method give radiotherapy.

34. also comprising, the method for claim 24, described method give chemotherapeutics.

35. also comprising, the method for claim 24, described method give gene therapy.

36. also comprising, the method for claim 24, described method give immunotherapy.

37. also comprising, the method for claim 24, described method give radiotherapy.

38. also comprising, the method for claim 25, described method give chemotherapeutics.

39. also comprising, the method for claim 25, described method give gene therapy.

40. also comprising, the method for claim 25, described method give immunotherapy.

41. also comprising, the method for claim 25, described method give radiotherapy.

42. a method for the treatment of cell proliferative disorders, described method comprise the compound by the claim 1-10 that discharges sustained release treatment significant quantity from intraluminal medical devices.

43. the method for the illness that a treatment is relevant with FLT3, described method comprise the compound by the claim 1-10 that discharges sustained release treatment significant quantity from intraluminal medical devices.

44. the method for the illness that a treatment is relevant with TrkB, described method comprise the compound by the claim 1-10 that discharges sustained release treatment significant quantity from intraluminal medical devices.

45. the method for claim 42, wherein said intraluminal medical devices comprises support.

46. the method for claim 43, wherein said intraluminal medical devices comprises support.

47. the method for claim 44, wherein said intraluminal medical devices comprises support.

48. a medicinal compositions, described composition comprise compound and the pharmaceutically acceptable carrier of the claim 1-10 of the significant quantity of puting together with targeting agent.

49. a method for the treatment of cell proliferative disorders, described method comprise the compound of the claim 1-10 that gives the treatment significant quantity that described patient and targeting agent put together.

50. the method for the illness that a treatment is relevant with FLT3, described method comprise the compound of the claim 1-10 that gives the treatment significant quantity that described patient and targeting agent put together.

51. the method for the illness that a treatment is relevant with TrkB, described method comprise the compound of the claim 1-10 that gives the treatment significant quantity that described patient and targeting agent put together.

52. a combination medicine, described combination medicine are each combination of compounds among chemotherapeutics and the claim 1-10.

53. a method for preparing the compound of claim 1, wherein Q is O, and Z is NH or N (alkyl), and described method is included in and makes formula IV compound under the existence of alkali:

React with formula V compound:

54. a method for preparing the compound of claim 1, wherein Q is O, and Z is CH ₂, described method comprises with coupler makes formula IV compound:

With formula R ₃BZCO ₂The reaction of H compound:

55. a method for preparing the compound of claim 1, wherein Q is O, and Z is NH, and described method is included in and makes formula IV compound under the existence of alkali:

With formula R ₃The reaction of BCNO compound:

56. a method for preparing the compound of claim 1, wherein Q is NH or N (alkyl), and Z is CH ₂, described method comprises with coupler makes formula IX compound:

With formula R ₃BZCO ₂The reaction of H compound:

57. the method for a preparation I compound, wherein Q is NH or N (alkyl), and Z is NH or N (alkyl), and described method is included in and makes formula IX compound under the existence of alkali:

React with formula V compound:

Wherein LG is a leavings group.

58. the method for a preparation I compound, wherein Q is straight key, and Z is NH or N (alkyl), and described method is included in and makes formula XI compound under the existence of coupler:

With formula R ₃The reaction of BZH compound:

59. a method for preparing the compound of claim 1, wherein R ₁For-CC (CH ₂) _nR _a, described method is included in and makes formula XVII compound under palladium catalyst and the copper catalyst existence:

React with following formula: compound:

60. a method for preparing the compound of claim 1, wherein R ₁For-CHCH (CH ₂) _nR _a, described method is included in and makes formula XVII compound under the palladium catalyst existence:

React with formula XX compound:

61. a method for preparing the compound of claim 1, wherein R ₁Be phenyl or heteroaryl, described method is included in and makes formula XVII compound under the palladium catalyst existence:

With formula: ArB (OR) ₂The compound reaction, wherein Ar comprises aryl or heteroaryl, and R comprises H or alkyl.

62. a method for preparing the compound of claim 1, wherein R ₂For-Y (CH ₂) _nR _a, Q is NH, N (alkyl) or O, and Z is CH ₂, described method comprises with coupler makes formula XXV compound:

With formula R ₃BZCO ₂The reaction of H compound:

63. the method for a preparation I compound, wherein R ₂For-Y (CH ₂) _nR _a, Q is NH, N (alkyl) or O, and Z is NH or N (alkyl), described method is included in and makes formula XXV compound under the existence of alkali:

React with formula V compound:

Wherein LG is a leavings group.

64. a medicinal compositions, described composition comprise the product by the method preparation of claim 53-63.