CN101242844A

CN101242844A - Aminopyrimidines as kinase modulators

Info

Publication number: CN101242844A
Application number: CNA2006800295374A
Authority: CN
Inventors: M·D·高尔; 徐国章; C·A·鲍曼
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 2005-06-10
Filing date: 2006-06-07
Publication date: 2008-08-13
Also published as: ZA200800274B

Abstract

The invention is directed to aminopyrimidine compounds of Formula I: where R3, B, Z, Q, p, q and R1 are as defined herein, the use of such compounds as protein tyrosine kinase modulators, particularly inhibitors of FLT3 and/or c-kit and/or TrkB, the use of such compounds to reduce or inhibit kinase activity of FLT3 and/or c-kit 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 c-kit 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

Amino-metadiazine compound as kinase modulator

The cross reference of related application

This application requires the priority of the U.S. Provisional Application patent No. 60/689,717 submitted on June 10th, 2005 and the priority of the U.S. Provisional Application patent No. 60/751,084 that December in 2005 was submitted on the 16th, its by quote in full be bonded to this all open in.

Invention field

The present invention relates to noval chemical compound as the protein tyrosine kinase regulator.More specifically, the present invention relates to be used as the noval chemical compound of FLT3 and/or c-kit and/or TrkB inhibitor.

Background of invention

The present invention relates to Aminopyrimidines as tyrosine kinase (comprising FLT3, c-kit and/or TrkB) inhibitor.Having reported the miazines with effective therapeutic properties has: US 5104877 and WO 9214468 (being used for the treatment of the preparation of psoriasic [(tetrazole radical diphenyl) methylamino] pyrimidinecarboxylic acid and related compound); DE 10108480 and WO 2002068413 (preparation of insecticide pyrazolyl pyrimidine); WO 2002050066, WO 2002066461, WO2002068415, US 6653300, US 2003036543, US 6664247, US2003055068, US 2003078275, US 6653301, US 2003105090, US2003004164, US 6656939, US 2003022885, US 6727251, US2004116454, US 2004157893, US 2004132781 and US 2004167141; US 6107301 (as the pyrazole compound of kinases inhibitor, and therapeutic use) and US6342503 (as the preparation of the 1-N-alkyl-N-Arylpyrimidines amine of CRF inhibitor); WO2001085700, WO 2001085700 and US 2003171374 (as the substituted-amino miazines of HIV replication inhibitors and the preparation of triazines); WO 2001085699, WO2001085699 and US 2003186990 (preparation of the prodrug of the miazines that inhibition HIV duplicates); WO 2001022938 (being used as the azine aminobenzonitrile of antiviral and the preparation of related compound); WO 2000027825, US 2003114472 and US 2004039005 (being used as the preparation of the aryl aminopyrimidine of HIV replication inhibitors); WO 2004058762, WO2004058762 and US 2004152739 (as the preparation of the pyrrolopyridine ketone that suppresses mitogen activated protein kinases-activated protein kinase-2 chemical compound); WO 2003094920 (microbicidal pyrimidine or triaizine compounds that preventing property HIV propagates); WO 2004005283 and US 2004097531 (being used as the imidazolyl pyrimidines of JNK kinases inhibitor and the preparation of related compound); Also see: Wardakhan, Wagnat W., Fleita, Daisy H., Mohareb, Rafat M., Reaction of 4-aryl-3-thiosemicarbazides with phenylisothiocyanate:a facile synthesis of thiazole, pyrazole and pyrimidinederivatives (reaction of 4-aryl-3-thiosemicarbazide and phenyl isothiocyanate: the easy of thiazole, pyrazoles and pyrimidine derivatives synthesized), Journal of the Chinese Chemical Society (Taibei) (1999), 46 (1), 97-104; And Taylor, Edward C., Ehrhart, Wendell A., Tomlin, Clive O.S, Rampal, Jang B, A novel ring-switching amination:conversion of 4-amino-5-cyanopyrimidine to4, (novel ring transforms amination: the 4-amino-5-cyanopyrimidine is converted into 4 to 6-diamino-5-cyanopyrimidine, 6-diaminourea-5-cyanopyrimidine), Heterocycles (1987), 25 (1), 343-5.Also see: JP 9274290 (method of developer and processing silver halide shooting material); DE10060412, WO 2002046151 and US 2004082586 (as 3 of insecticide, 4-dihydro-2 h-pyrrole class); WO 2004039785 and US 2004152896 (method for preparing the pyrrolidinyl ethylamine compounds by the aryl amination of copper-mediated).

Protein kinase be signal transduction by way of the enzyme assembly, its terminal phosphate base catalysis with ATP is transferred on the hydroxyl of proteinic tyrosine, serine and/or threonine residues.Therefore, have the valuable means of the chemical compound of Profilin kinase function for the last result of physiology of evaluation protein kinase activation.Protein kinase excessive or unsuitable expression in mammal normal or sudden change has become the problem of broad research and proved that it plays an important role, and comprises diabetes, angiogenesis, psoriasis, restenosis, ocular disease, schizophrenia, rheumatoid arthritis, atherosclerosis, cardiovascular disease and cancer in numerous disease takes place.Equally also studied the cardiotonic of kinase inhibition.In a word, kinases inhibitor has special purposes in the humans and animals disease treatment.

Trk family receptors tyrosine kinase (TrkA, TrkB and TrkC) is the frizzled receptor of the biological agent of the peptide hormone of mediation neurotrophic factor family.This growth factor family comprises nerve growth factor (NGF), the brain source property growing nutrient factor (BDNF) and two kinds of neurotrophic factors (NT) (NT-3 and NT-4).TrkB is as the receptor of BDNF and NT-4.BDNF promotes propagation, differentiation and the survival of normal neural assembly (as retina cell and neurogliocyte).

There is report TrkB activation effectively and specifically to suppress anchorage-independent cell death (anoikis) recently and (sees Nature, on August 26th, 2004,430 (7003): 973-4; 1034-40).The survival of anchorage-independent cell makes tumor cell by body circulation migration and at the far-end organ growth.This transition process often becomes the failure of treatment of cancer and the reason of cancer mortality.Other researchs show that also the agonist BDNF of TrkB can block the cisplatin induced cell death and (see Cancer Lett, on April 10th, 2003; 193 (1): 109-14).In a word, these results show that TrkB is adjusted to the particularly attractive target spot of tumor disease of the optimum and malignant proliferation disease of treatment.

Co-expression of receptor tyrosine kinase c-kit and part stem cell factor (SCF) thereof are essential by hemopoietic, melanocyte formation and fertility.SCF acts on the multistage level of hemopoietic system and promotes cell survival, propagation, differentiation, adhesion and functional activation.This is particularly important in mastocyte and erythroid lineage, and acts on the pleiotropy stem cell and CFU-GM, megalokaryocyte and lymph CFU-GM hypotype (are seen Int J Biochem Cell Biol, in October, 1999,31 (10): 1037-51).The autocrine of the natural mutation of c-kit and SCF/c-kit approach/paracrine activate mechanism is relevant with different malignant tumor.The activation of c-kit is by promoting tumor growth and reducing programmed cell death and facilitate transfer.In addition, c-kit ligand-mediated activation of frequent sudden change and activation and c-kit in gastrointestinal stromal tumor (GISTs) is present in some pulmonary carcinoma and (sees Leuk Res, in May, 2004; 28 Suppl 1:S11-20).Described c-kit receptor is also sent out to surpass on 10% the blastocyte among the AMLs at 64% newborn acute myelogenous leukemia (AMLs) and 95% again and is expressed.Propagation and anti-apoptotic effect among the C-kit mediation AML (are seen Curr Hematol Rep, in January, 2005,4 (1): 51-8).

C-Kit is expressed among many different human malignant lesions and confirms, comprises mastocytosis, mast cell leukemia, gastrointestinal stromal tumor, sinunasal NK cell/T-cell lymphoma, spermocytoma, dysgerminoma, thyroid carcinoma, small cell lung cancer, malignant melanoma, adenoid cystic carcinoma, ovarian cancer, acute myelogenous leukemia, primary cutaneous type, angiosarcoma, carcinoma of endometrium, department of pediatrics T-cell ALL, lymphoma, breast carcinoma and carcinoma of prostate.See Heinrich, Michael C etc., survey article: the Inhibition of KITTyrosine Kinase Activity:A Novel Molecular Approach to the Treatmentof KIT-Positive Malignancies (inhibition of KIT tyrosine kinase activity: the novel molecular method of the positive malignant tumor of treatment KIT).

Fms sample tyrosine kinase 3 (FLT3) part (FLT3L) is a kind of cytokine of hematopoietic cell (the multiple hematopoietic lineages) development of the multiple disease of influence.Combine these influences of generation with the FLT3 receptor of on hematopoietic stem cell and CFU-GM, expressing (being also referred to as tire liver kinases-2 (flk-2) and STK-1, receptor tyrosine kinase (RTK)) by FLT3L.FLT3 gene code film is in conjunction with RTK, and described RTK on cell proliferation, differentiation and apoptosis in the normal plasma cell forming process have important function.The FLT3 gene is mainly expressed by early stage meyloid and lymph CFU-GM.See McKenna, Hilary J etc., the mice of damaged flt3 part has the defective hemoposieis, influences hemopoietic progenitor cell, dendritic cells and natural killer cell, Blood, in June, 2000; 95:3489-3497; Drexler, H.G. and H.Quentmeier (2004), " FLT3:receptor and ligand (FLT3: receptor and part) ", Growth Factors, 22 (2): 71-3.

The FLT3 part is worked in coordination with other cellular expressions and with other somatomedin by marrow stromal cell stimulates stem cell, CFU-GM, dendritic cells and proliferating natural killer cells.

Hematopoietic disease is for the preceding disease of the deterioration of these systems and comprise that for example myeloproliferative disease such as thrombocytosis, primary thrombocytosis (ET), agnogenic myeloid metaplasia, myelofibrosis (MF), myelofibrosis companion bone marrow alienation are given birth to the preceding myelodysplastic syndrome of (MMM), chronic idiopathic myelofibrosis (IMF) and polycythemia vera (PV), cytopenia and deterioration.See Stirewalt, D.L and J.P.Radich (2003), " The role of FLT3in haematopoietic malignancies (effect of FLT3 in the hemopoietic malignant tumor) ", NatRev Cancer, 3 (9): 650-65; Scheijen, B. and J.D.Griffin (2002), " Tyrosinekinase oncogene in normal hematopoiesis and hematological disease (tyrosine kinase oncogene in normal plasma cell generation and hematologic disease) ", Oncogene, 21 (21): 3314-33.

Hematologic malignancies is blood of human body formation and immune system, bone marrow and adenoid cancer.Yet in normal marrow, FLT3 expresses and is limited to early progenitor cell, and in hematologic malignancies, FLT3 highly expresses or the FLT3 sudden change causes the FLT3 receptor and the downstream molecules approach is uncontrolled induces, and may be the Ras activation.Hematologic malignancies comprises leukemia, lymphoma (non-Hodgkin lymphoma), the acute lymphoblastic leukemia (ALL) of Hodgkin (being also referred to as Hodgkin lymphoma) and myeloma-for example, acute myeloid leukaemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), CNL (CNL), the acute leukemia (AUL) of not breaking up, primary cutaneous type (ALCL), prolymphocyte leukemia (PML), child's grain-unicellular leukemia (JMML), adult T-cell ALL, AML is hyperplasia unusual (AML/TMDS) with bone marrow three, mixed lineage leukemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disorder (MPD), multiple myeloma (MM) and medullary sarcoma.See Kottaridis, P D., R.E.Gale etc. (2003), " Flt3 mutations and leukaemia (Flt3 sudden change and leukemia) ", Br J Haematol, 122 (4): 523-38.Medullary sarcoma is also relevant with the FLT3 sudden change.See Ansari-Lari, Ali etc., FLT3 mutations in myeloid sarcoma (the FLT3 sudden change in medullary sarcoma), British Journal of Haematology, in JIUYUE, 2004,126 (6): 785-91.

In about 30% acute myelogenous leukemia patient and minority acute lymphoblastic leukemia or myelodysplastic syndrome patient, detect the sudden change of FLT3.The patient of FLT3 sudden change goes back the relaxation time and has reduced the disease free survival prognosis mala because of having shortened.The types of two kinds of known activation FLT3 sudden changes: one type for receptor near diaphragm area in 4-40 amino acid whose duplicating (ITD sudden change) (patient of 25-30%), another kind of type is the point mutation (5-7% patient) in the kinases zone.Most sudden changes are usually directed to aminoacid polyphone small-sized in the receptor membrane-proximal region territory and repeat and produced tyrosine kinase activity.Mutant FLT3 receptor expression causes fatal myeloproliferative syndrome in the Muridae myelocyte, and research (Blood, 2002 in early stage; 100:1532-42) show that the collaborative acquisition of mutant FLT3 and other leukemia oncogenes has more aggressive Phenotype.

In a word, these results specific inhibitor of showing indivedual kinases FLT3 and c-kit and especially comprising the kinases category of FLT3 and c-kit provides the attractive target spot of treatment hematopoietic disease and hematologic malignancies.

FLT3 inhibitors of kinases known in the art comprises AG1295 and AG1296; Lestaurtinib (be also referred to as CEP 701, be called KT-5555 in the past, Kyowa Hakko licenses to Cephalon); CEP-5214 and CEP-7055 (Cephalon); CHIR-258 (Chiron company); EB-10 and IMC-EB10 (ImClone Systems Inc.); GTP14564 (MerkBiosciences UK); Midostaurin (being also referred to as PKC 412 Novartis AG); MLN608 (Millennium USA); MLN-518 (be called CT53518 in the past, CORTherapeutics Inc. licenses to Millennium Pharmaceuticals Inc.); MLN-608 (Millennium Pharmaceuticals Inc.); SU-11248 (Pfizer USA); SU-11657 (Pfizer USA); SU-5416 and SU5614; THRX-165724 (TheravanceInc.); AMI-10706 (Theravance Inc.); (VertexPharmaceuticals USA licenses to Novartis (Switzerland), Merck ﹠amp for VX-528 and VX-680; Co USA); With XL 999 (Exelixis USA).Following PCT international application and U.S. Patent Application Publication other kinase modulator, comprise FLT3 regulator: WO 2002032861, WO2002092599, WO 2003035009, WO 2003024931, WO 2003037347, WO 2003057690, WO 2003099771, WO 2004005281, WO 2004016597, WO 2004018419, WO 2004039782, WO 2004043389, WO 2004046120, WO 2004058749, WO 2004058749, WO 2003024969 and Application No. 20040049032.

Also see Levis, M., Tse KF etc., 2001, A FLT3 tyrosine kinase inhibitoris selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3internal tandem duplication mutations (the FLT3 tyrosine kinase inhibitor is to containing the paotoblastic selecting cell toxicity of acute myeloid leukaemia that the inner polyphone of FLT3 repeats to suddenly change), Blood, 98 (3): 885-7; Tse KF etc., Inhibition of FLT3-mediatedtransformation by use of a tyrosine kinase inhibitor (suppressing the conversion of FLT3-mediation) by using tyrosine kinase inhibitor, Leukemia, July calendar year 2001,15 (7): 1001-10; Smith, B.Douglas etc., Single-agent CEP-701, a hovel FLT3inhibitor, shows biologic and clinical activity in patients with relapsed orrefractory acute myeloid leukemia (single agents CEP-701, new FLT3 inhibitor is presented at biology and clinical activity in recurrent or the intractable patients with acute myeloid leukemia), Blood, in May, 2004; 103:3669-3676; Griswold, Ian J etc., Effectsof MLN518, A Dual FLT3 and KIT Inhibitor, on Normal and MalignantHematopoiesis (MLN518, dual FLT3 and KIT inhibitor, effect to normal and pernicious hemopoietic), Blood, in July, 2004, [Epub ahead of print]; Yee, KevinW.H. etc., SU5416 and SU5614 inhibit kinase activity of wild-type andmutant FLT3 receptor tyrosine kinase (SU5416 and SU5614 suppress the kinase activity of wild type and saltant FLT3 receptor tyrosine kinase), Blood, in JIUYUE, 2002,100:2941-294; O ' Farrell, Anne-Marie etc., SU11248 is a novel FLT3 tyrosinekinase inhibitor with potent activity in vitro and in vivo (SU11248 is external and the novel FLT3 tyrosine kinase inhibitor of the interior effective active of body), Blood, in May, 2003,101:3597-3605; Stone, R.M. etc., PKC 412 FLT3 inhibitor therapyin AML:results of a phase II trial (PKC 412 FLT3 inhibitor are treated in AML: II step-by-step test result), and Ann Hematol, 2004; 83 Suppl1:S89-90; And Murata, K. etc., Selective cytotoxic mechanism of GTP-14564, a hoveltyrosine kinase inhibitor in leukemia cells expressing a constitutivelyactive Fms-like tyrosine kinase 3 (FLT3) (the selecting cell toxic mechanism of GTP-14564, novel tyrosine kinase inhibitor among the leukaemia of the active Fms sample of expression structure tyrosine kinase 3 (FLT3)), J Biol Chem, on August 29th, 2003; 278 (35): 32892-8; Levis, Mark etc., Novel FLT3 tyrosine kinase inhibitors (novel FLT3 tyrosine kinase inhibitor), Expert Opin.Investmg.Drugs (2003), 12 (12), 1951-1962; Levis, Mark etc., Small Molecule FLT3 TyrosineKinase Inhibitors (micromolecule FLT3 tyrosine kinase inhibitor), CurrentPharmaceutical Design, 2004,10,1183-1193.

Summary of the invention

The invention provides new Aminopyrimidines (formula I chemical compound) as the protein tyrosine kinase regulator, particularly FLT3 and/or c-kit and/or TrkB inhibitor, be used for reducing or suppress purposes in the kinase activity of cell or experimenter FLT3 and/or c-kit and/or TrkB with these chemical compounds, and these chemical compounds are used for preventing or treat the purposes of cell breeding disease that the experimenter suffers from and/or the disease relevant with FLT3 and/or c-kit and/or TrkB.

An illustration of the present invention is the pharmaceutical composition that comprises formula I chemical compound and pharmaceutically acceptable carrier.Another illustration of the present invention is for by mixing the pharmaceutical composition that arbitrary formula I chemical compound and pharmaceutically acceptable carrier prepare.

Other features and advantages of the present invention will be by following detailed description of the present invention and apparent by claim.

Detailed Description Of The Invention

Definition

As used herein, following term has following implication (in particular cases description will provide other definition):

Term " thiazolinyl ", no matter use separately or as a substituent part, for example " C1-4 thiazolinyl (aryl) ", be meant the part unsaturated side chain with at least one carbon-to-carbon double bond or the monovalence alkyl of straight chain, wherein respectively remove a hydrogen atom and obtain two keys and remove a hydrogen atom obtaining free radical from single carbon atom by two adjacent carbon atoms of parent alkyl molecule.Each atom can be around two keys with cis (Z) or trans (E) configuration orientation.Representational thiazolinyl includes, but are not limited to vinyl, acrylic, pi-allyl (2-acrylic), cyclobutenyl etc.Example comprises C _2-8Thiazolinyl or C _2-4Thiazolinyl.

Term " C _A-b" (wherein a and b are for specifying carbon number purpose integer) be meant alkyl, thiazolinyl, alkynyl, alkoxyl or cycloalkyl, or refer to the moieties in some group, wherein alkyl contains a-b carbon atom.C for example _1-4Expression contains the group of 1,2,3 or 4 carbon atom.

No matter term " alkyl " uses separately or as a substituent part, is meant the monovalence alkyl of saturated side chain or straight chain, wherein obtains free radical by remove a hydrogen atom from single carbon atom.(for example by using the restriction term) unless stated otherwise as " terminal carbon ", otherwise the substituent group variable can replace on what carbon atom in office.Representational alkyl includes, but are not limited to methyl, ethyl, propyl group, isopropyl etc.Example comprises C _1-8Alkyl, C _1-6Alkyl and C _1-4Alkyl.

Term " alkyl amino " is meant by removing the free radical that hydrogen atom forms from the nitrogen of alkylamine (as butylamine), and term " dialkyl amido " is meant by remove the free radical that a hydrogen atom forms from the nitrogen of secondary amine (as dibutylamine).In two kinds of situations, with the junction point of molecule remainder be nitrogen-atoms.

Term " alkynyl ", no matter use separately or as a substituent part, be meant the part unsaturated side chain with at least one carbon-to-carbon triple bond or the monovalence alkyl of straight chain, wherein respectively remove two hydrogen atoms and obtain triple bond and remove a hydrogen atom obtaining free radical from single carbon atom by two adjacent carbon atoms of parent alkyl molecule.Representational alkynyl comprises acetenyl, propinyl, butynyl etc.Example comprises C _2-8Alkynyl or C _2-4Alkynyl.

Term " alkoxyl " is meant the monovalence hydrocarbon alcohol groups of undersaturated side chain of saturated or part or straight chain, obtains by removing a hydrogen atom from the hydroxyl on parent alkane, alkene or alkynes.For concrete saturation, term " alkoxyl ", " thiazolinyl oxygen base " are consistent with the definition of alkyl, thiazolinyl and alkynyl with " alkynyloxy base " use.Example comprises C _1-8Alkoxyl or C _1-4Alkoxyl.

Term " alkoxyl ether " is meant the monovalence hydrocarbon alcohol radical of saturated side chain or straight chain, and it obtains by removing a hydrogen atom from the pure oxygen substituent group hydroxyl of hydroxyl ether.Example comprises 1-hydroxyl-2-methoxyl group-ethane group and 1-(2-hydroxyl-ethyoxyl)-2-methoxyl group-ethane group.

Term " aralkyl " is meant the C that contains aryl substituent _1-6Alkyl.Example comprises benzyl, phenylethyl or 2-naphthyl methyl.With the junction point of molecule remainder be alkyl.

Term " aromatics " is meant to have cyclic hydrocarbon ring system unsaturated, the conjugated pi electron system.

Term " aryl " is meant the cyclic hydrocarbon cyclic base of aromatics group, and it obtains by removing a hydrogen from the single carbon atom of ring system.Representational aryl comprises phenyl, naphthyl, fluorenyl, indenyl, azulene base, anthryl etc.

Term " virtue is amino " is meant the amino (as ammonia) that is replaced by aryl (as phenyl).With the junction point of molecule remainder be nitrogen-atoms.

Term " aryloxy group " is meant the group that is replaced oxygen atom by aryl (as phenyl).With the junction point of molecule remainder be oxygen atom.

Term " the condensed cycloalkyl of benzene " is meant that one of them ring is the Bicyclic-fused ring system group that phenyl and another ring are cycloalkyl or cyclenes basic ring.Representational benzene fused rings alkyl comprises indanyl, 1,2,3,4-tetrahydrochysene-naphthyl, 6,7,8,9-tetrahydrochysene-5H-benzocyclohepta base, 5,6,7,8,9,10-six hydrogen-benzo cyclo-octene base etc.Benzene fused rings alkyl ring system is the subclass of aryl.

Term " the condensed heteroaryl of benzene " is meant that one of them ring is that phenyl and another ring are the Bicyclic-fused ring system group of heteroaryl ring.Representational benzene condensed heteroaryl comprises indyl, indolinyl, isoindolyl, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolines base, 2 base, quinazolyl etc.Benzene condensed heteroaryl ring is the subclass of heteroaryl.

Term " benzene condensed heterocycle base " is meant that one of them ring is that phenyl and another ring are the Bicyclic-fused ring system group of heterocyclic ring.Representational benzene-fused heterocyclic base comprises 1,3-benzodioxole base (also is known as 1, the 3-methylenedioxyphenyl), 2,3-dihydro-1,4-benzo dioxine base (also being known as 1,4-ethylenedioxy phenyl), benzo-dihydrofuran base, benzo-THP trtrahydropyranyl, benzo-dihydro-thiophene base etc.

Term " carboxyalkyl " is meant alkylating carboxyl such as tert-butoxycarbonyl, wherein with

The junction point of molecule remainder is a carbonyl.

Term " heterocyclic diones base " is meant and has two substituent heterocyclic compounds of oxo base.Example comprises thiazolidinedione base,  oxazolidinedione base and pyrrolidine-diones base.

Term " cycloalkenyl group " is meant the undersaturated cycloalkyl of part, and it obtains by remove a hydrogen atom from the hydrocarbon ring system that contains at least one carbon-to-carbon double bond.Example comprises cyclohexenyl group, cyclopentenyl and 1,2,5,6-cyclo-octadiene base.

Term " cycloalkyl " is meant saturated or undersaturated monocycle of part or bicyclic hydrocarbons cyclic group, and it obtains by remove a hydrogen atom from single ring carbon atom.Representational cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, suberyl and ring octyl group.Other examples comprise C _3-8Cycloalkyl, C _5-8Cycloalkyl, C _3-12Cycloalkyl, C _3-20Cycloalkyl, naphthalane base and 2,3,4,5,6,7-six hydrogen-1H-indenyl.

Term " condenses ring system " and is meant bicyclic molecules, wherein has two contiguous atoms to be present in simultaneously in two annulus.Can choose wantonly and have hetero atom.Example comprises benzothiazole, 1,3-benzodioxole and naphthalane.

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

Term " heteroarylalkyl " is meant and contains the substituent C of heteroaryl _1-6Alkyl.Example comprises furyl methyl and pyridine radicals propyl group.With the junction point of molecule remainder be alkyl.

Term " heteroaryl " is meant by removing the group that a hydrogen obtains from a ring carbon atom of hetero-aromatic ring system.Representational heteroaryl comprises furyl, thienyl, pyrrole radicals,  azoles base, thiazolyl, imidazole radicals, pyrazolyl, different  azoles base, isothiazolyl, the  di azoly, triazolyl, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, the indolizine base, indyl, isoindolyl, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzimidazolyl, benzothiazolyl, purine radicals, the 4H-quinolizinyl, quinolyl, isoquinolyl, the cinnolines base, phthalazinyl (phthalzinyl), quinazolyl, quinoline  quinoline base, 1, the 8-naphthyridinyl, pteridyl etc.

Term " heteroaryl-condensed cycloalkyl " is meant Bicyclic-fused ring system group, and one is that cycloalkyl and another are heteroaryl in the wherein said ring.Representational heteroaryl-condensed cycloalkyl comprises 5,6,7, and 8-tetrahydrochysene-4H-cycloheptene is (b) thienyl, 5,6 also, and 7-three hydrogen-4H-cyclohexene is (b) thienyl, 5 also, 6-dihydro-4H-cyclopenta (b) thienyl etc.

Term " heterocyclic radical " is meant saturated or the unsaturated monocyclic groups of part, and it obtains by removing a hydrogen atom from single carbon or azo-cycle atom.Representational heterocyclic group comprises 2H-pyrrole radicals, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolane base, 2-imidazolinyl (are also referred to as 4,5-dihydro-1H-imidazole radicals), imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, tetrazole radical, piperidyl, 1,4-dioxane base, morpholinyl, 1,4-dithian base, thio-morpholinyl, 1,1-titanium dioxide thio-morpholinyl, piperazinyl, azepan base, six hydrogen-1,4-diazacyclo heptenyl etc.

Term " oxo base " is meant the oxygen atom group; Described oxygen atom has two and connects same atoms, open bond valence on the carbon atom most preferably.The oxo base is the suitable substituent group of alkyl.For example containing the substituent propane of oxo base is acetone or propionic aldehyde.Heterocycle also can be replaced by the oxo base.For example the  oxazolidinyl is substituted by the  oxazolidone by the oxo base.

Term " replacement " is meant the core element that one or more hydrogen atoms are partly replaced by one or more functional groups.Replacement is not limited to core element, also can be present on the substituted radical, and wherein substituted radical becomes linking group.

Term " independent selection " is meant and is selected from one group of substituent one or more substituent group that wherein said substituent group can be identical or different.

The substituent group nomenclature of using during the present invention is open is at first indicating the atom of junction point, follow by linking group to terminal chain atom, name from left to right, substantially as:

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

Or at first indicate the end chain atom, follow by the linking group atom to the atom name that contains junction point, substantially as:

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

Two kinds of methods all refer to the following formula group:

Be drawn into the key that straight line the ring system represents to connect arbitrary suitable annular atoms from substituent group.

As any variable (R for example ₄) when in any embodiment of formula I, occurring surpassing one time, respectively be customized for independent definition.

Term in the literary composition " comprises ", " comprising " and " containing " use with its open, unrestricted implication.

Nomenclature

Except that special instruction is arranged, use the well-known naming rule of those skilled in the art to obtain the chemical compound title, by reference standard IUPAC nomenclature, as Nomenclature of OrganicChemistry, Sections A, B, C, D, E, F and H (organic chemistry nomenclature A, B, C, D, E, F and H part) (Pergamon publishes, Oxford, 1979, copyright 1979 IUPAC) or A Guide to IUPAC Nomenclature of Organic Compounds (organic compound IUPAC names guide) (recommend 1993), (Blackwell Scientific Publications, 1993, copyright 1993 IUPAC); Or commercially available software kit such as Autonom (trade mark of nomenclature software is provided in the ChemDraw Ultra by the CambridgeSoft.com listing ^Officesuite); With ACD/Index Name ^TM(trade mark of commodity nomenclature software, by AdvancedChemistry Development, Inc., Toronto, Ontario listing).

Abbreviation

Used following abbreviation will have following implication (other abbreviations need part to provide in description) in the literary composition:

The ATP adenosine triphosphate

The Boc tert-butoxycarbonyl

The DCM dichloromethane

The DMF dimethyl formamide

The DMSO dimethyl sulfoxide

The DIEA diisopropyl ethyl amine

The DTT dithiothreitol, DTT

EDC 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride

The EDTA ethylenediaminetetraacetic acid

The EtOAc ethyl acetate

The FBS hyclone

The FP fluorescence polarization

GM-CSF granulocyte and M-CSF

HBTU hexafluorophosphoric acid O-benzotriazole-1-base-N, N, N ', N '-tetramethylurea 

HOBT I-hydroxybenzotriazole hydrate

HP β CD hydroxypropyl

The HRP horseradish peroxidase

The i-PrOH isopropyl alcohol

LC/MS (ESI) liquid chromatography/mass spectrometry (electrospray ionization)

MeOH methanol

The NMM N-methylmorpholine

The NMR nuclear magnetic resonance, NMR

The PS polystyrene

The PBS phosphate buffered saline (PBS)

RPMI Rosewell Park MemorialInstitute

The RT room temperature

The RTK receptor tyrosine kinase

NaHMDS hexamethyl dimethyl silanyl Sodamide.

The SDS-PAGE SDS-PAGE

The TEA triethylamine

The TFA trifluoroacetic acid

THF hydrogen furan

The TLC thin layer chromatography

Formula I

The present invention includes formula I chemical compound and nitrogen oxide thereof, pharmaceutically acceptable salt, solvate, geometric isomer and three-dimensional chemical isomer:

Formula I

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or chemical bond;

Z is NH, N (alkyl) or CH ₂

B is a phenyl, (wherein said heteroaryl is preferably pyrrole radicals to heteroaryl, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyranose, the sulfo-pyranose, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridine radicals-nitrogen oxide or pyrrole radicals-nitrogen oxide, and most preferably be pyrrole radicals, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyridine radicals, pyrimidine radicals or pyrazinyl), or the condensed heteroaryl of 9-10 unit benzene (the condensed heteroaryl of wherein said 9-10 unit's benzene is preferably benzothiazolyl, the benzoxazol base, benzimidazolyl, benzofuranyl, indyl, quinolyl, isoquinolyl or benzo [b] thienyl);

R ₁For:

Wherein n is 1,2,3 or 4;

R _aBe hydrogen, alkoxyl, phenoxy group, phenyl, optional by R ₅The heteroaryl (wherein said heteroaryl is preferably pyrrole radicals, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyranose, sulfo-pyranose, pyridine radicals, pyrimidine radicals, triazolyl, pyrazinyl, pyridine radicals-nitrogen oxide or pyrrole radicals-nitrogen oxide, and most preferably is pyrrole radicals, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyridine radicals, pyrimidine radicals, triazolyl or pyrazinyl) that replaces, hydroxyl, amino, alkyl amino, dialkyl amido, optional by R ₅The  oxazolidone base that replaces, optional by R ₅The pyrrolidone-base that replaces, optional by R ₅The piperidone base that replaces, optional by R ₅The heterocyclic diones base that replaces, optional by R ₅The heterocyclic radical (wherein said heterocyclic radical is preferably pyrrolidinyl, tetrahydrofuran base, tetrahydro-thienyl, imidazolidinyl, thiazolidinyl,  oxazolidinyl, THP trtrahydropyranyl, tetrahydrochysene sulfo-pyranose, thio-morpholinyl, 1,1-titanium dioxide thio-morpholinyl, piperidyl, morpholinyl or piperazinyl) that replaces ,-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 ₅Be 1,2 or 3 substituent group that independently is selected from following group: halogen, cyano group, trifluoromethyl, amino, hydroxyl, alkoxyl ,-C (O) alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl ,-C _(1-4)Alkyl-OH or alkyl amino;

R _wAnd R _xBe independently selected from: (heteroaryl moieties of wherein said heteroarylalkyl is preferably pyrrole radicals, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyranose, sulfo-pyranose, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridine radicals-nitrogen oxide or pyrrole radicals-nitrogen oxide for hydrogen, alkyl, thiazolinyl, aralkyl (aryl moiety of wherein said aralkyl is preferably phenyl) or heteroarylalkyl, and most preferably be pyrrole radicals, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyridine radicals, pyrimidine radicals or pyrazinyl), or R _wAnd R _xCan choose wantonly to form together and be selected from O, NH, N (alkyl), SO optional containing ₂, SO or S the 5-7 unit ring of hetero moiety, preferentially be selected from following group:

R _yBe selected from: hydrogen, alkyl, thiazolinyl, cycloalkyl (wherein said cycloalkyl is preferably cyclopenta or cyclohexyl), phenyl, aralkyl (aryl moiety of wherein said aralkyl is preferably phenyl), (heteroaryl moieties of wherein said heteroarylalkyl is preferably pyrrole radicals to heteroarylalkyl, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyranose, the sulfo-pyranose, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridine radicals-nitrogen oxide or pyrrole radicals-nitrogen oxide, and most preferably be pyrrole radicals, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyridine radicals, pyrimidine radicals or pyrazinyl) or heteroaryl (wherein said heteroaryl is preferably pyrrole radicals, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyranose, the sulfo-pyranose, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridine radicals-nitrogen oxide or pyrrole radicals-nitrogen oxide, and most preferably be pyrrole radicals, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyridine radicals, pyrimidine radicals or pyrazinyl); With

R ₃Be one or more substituent groups that independently are selected from following group: hydrogen, alkyl, alkoxyl, halogen, alkoxyl ether, hydroxyl, sulfenyl, nitro, optional by R ₄The cycloalkyl (wherein said cycloalkyl is preferably cyclopenta or cyclohexyl) that replaces, optional by R ₄(wherein said heteroaryl is preferably pyrrole radicals, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyranose, sulfo-pyranose, pyridine radicals, pyrimidine radicals, triazolyl, pyrazinyl, pyridine radicals-nitrogen oxide or pyrrole radicals-nitrogen oxide to the heteroaryl that replaces; And most preferably be pyrrole radicals, furyl, thienyl, imidazole radicals, thiazolyl,  azoles base, pyridine radicals, pyrimidine radicals, triazolyl or pyrazinyl), alkyl amino, optional by R ₄The heterocyclic radical (wherein said heterocyclic radical is preferably tetrahydro pyridyl, tetrahydrochysene pyrazinyl, dihydrofuran base, dihydro  piperazine base, pyrrolin base, glyoxalidine base, azepine  base (azepenyl), pyrrolidinyl, tetrahydrofuran base, tetrahydro-thienyl, imidazolidinyl, thiazolidinyl,  oxazolidinyl, THP trtrahydropyranyl, tetrahydrochysene sulfo-pyranose, piperidyl, morpholinyl or piperazinyl) that replaces ,-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, alkylthio or-SO ₂Alkyl; R wherein ₄Be independently selected from halogen, cyano group, trifluoromethyl, amino, hydroxyl, alkoxyl ,-C (O) alkyl ,-CO ₂Alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or alkyl amino.

Hereinafter used term " formula I chemical compound " indication also comprises its nitrogen oxide, pharmaceutically acceptable salt, solvate, geometric isomer and three-dimensional chemical isomer.

The embodiment of formula I

In another embodiment of the present invention: nitrogen oxide is optional to be appeared on one or more N-1 or the N-3 (See Figure 1a encircles numbering).

Fig. 1 a

Fig. 1 a shows the annular atoms of the 1-6 numbering of using in this manual.

In an embodiment of the present invention, (O-N=C-) can be E or Z configuration at 5 oximidos.

The preferred embodiments of the invention are for wherein existing one or more following formula I chemical compounds that limit:

Q is 0,1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or chemical bond;

Z is NH, N (alkyl) or CH ₂

B is phenyl or heteroaryl;

R ₁For:

Wherein n is 1,2,3 or 4;

R _aBe hydrogen, alkoxyl, phenoxy group, phenyl, optional by R ₅The heteroaryl that replaces, hydroxyl, amino, alkyl amino, dialkyl amido, optional by R ₅The  oxazolidone base that replaces, optional by R ₅The pyrrolidone-base that replaces, optional by R ₅The piperidone base that replaces, optional by R ₅The heterocyclic diones base that replaces, optional by R ₅The heterocyclic radical that replaces ,-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 _wAnd R _xBe independently selected from: hydrogen, alkyl, thiazolinyl, aralkyl or heteroarylalkyl, or R _wAnd R _xCan choose wantonly to form together and be selected from O, NH, N (alkyl), SO optional containing ₂, SO or S the 5-7 unit ring of hetero moiety;

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

R ₃Be one or more substituent groups that independently are selected from following group: hydrogen, alkyl, alkoxyl, halogen, alkoxyl ether, hydroxyl, sulfenyl, nitro, optional by R ₄The cycloalkyl that replaces, optional by R ₄The heteroaryl that replaces, alkyl amino, optional by R ₄The heterocyclic radical that replaces ,-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, alkylthio or-SO ₂Alkyl; R wherein ₄Be independently selected from: halogen, cyano group, trifluoromethyl, amino, hydroxyl, alkoxyl ,-C (O) alkyl ,-CO ₂Alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or alkyl amino.

Other preferred embodiments of the present invention are for wherein existing one or more following formula I chemical compounds that limit:

Q is 1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or chemical bond;

Z is NH, N (alkyl) or CH ₂

B is phenyl or heteroaryl;

R ₁For:

Wherein n is 1,2,3 or 4;

R ₃Be one or more substituent groups that independently are selected from following group: hydrogen, alkyl, alkoxyl, halogen, alkoxyl ether, hydroxyl, optional by R ₄The cycloalkyl that replaces, optional by R ₄The heteroaryl that replaces, optional by R ₄The heterocyclic radical that replaces ,-O (cycloalkyl), optional by R ₄The phenoxy group that replaces, optional by R ₄The heteroaryloxy that replaces, dialkyl amido or-SO ₂Alkyl; R wherein ₄Be independently selected from halogen, cyano group, trifluoromethyl, amino, hydroxyl, alkoxyl ,-C (O) alkyl ,-CO ₂Alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or alkyl amino.

Another embodiment of the present invention is for wherein existing one or more following formula I chemical compounds that limit:

Q is 1 or 2;

P is 0 or 1;

Q is NH, N (alkyl), O or chemical bond;

Z is NH or CH ₂

B is phenyl or heteroaryl;

R ₁For

Wherein n is 1,2,3 or 4;

R _aBe hydrogen, alkoxyl, optional by R ₅The heteroaryl that replaces, hydroxyl, amino, alkyl amino, dialkyl amido, optional by R ₅The  oxazolidone base that replaces, optional by R ₅The pyrrolidone-base that replaces, optional quilt _R5The heterocyclic radical that replaces ,-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,-SO ₂R _y,-NR _wSO ₂R _yOr-SO ₂NR _wR _x

Particularly preferred embodiment of the present invention is for wherein existing one or more following formula I chemical compounds that limit:

Q is 1 or 2;

P is 0 or 1;

Q is NH, O or chemical bond;

Z is NH or CH ₂

B is phenyl or heteroaryl;

R ₁For

Wherein n is 1,2,3 or 4;

R _aBe hydrogen, hydroxyl, amino, alkyl amino, dialkyl amido, heteroaryl, optional by R ₅The heterocyclic radical that replaces ,-CONR _wR _x,-SO ₂R _y,-NR _wSO ₂R _yOr-N (R _y) CON (R _w) (R _x);

R ₅Be the substituent group that is selected from following group a :-C (O) alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or-C _(1-4)Alkyl-OH;

R ₃For one or two independently is selected from the substituent group of following group: alkyl, alkoxyl, halogen, cycloalkyl, heterocyclic radical ,-O (cycloalkyl), phenoxy group or dialkyl amido.

The most preferred embodiment of the present invention is for wherein existing one or more following formula I chemical compounds that limit:

Q is 1 or 2;

P is 0 or 1;

Q is NH, O or chemical bond;

Z is NH or CH ₂

B is phenyl or pyridine radicals;

R ₁For:

Wherein n is 1,2,3 or 4;

R _aBe hydrogen, hydroxyl, amino, dialkyl amido, optional by R ₅The heterocyclic radical that replaces ,-CONR _wR _x,-N (R _y) CON (R _w) (R _x) or-NR _wSO ₂R _y

R ₅Be the substituent group that is selected from following group a :-C (O) alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or C _(1-4)Alkyl-OH;

R ₃Be a substituent group that independently is selected from following group: alkyl, alkoxyl ,-O (cycloalkyl) or phenoxy group.

Pharmaceutically acceptable salt

The form of all right pharmaceutically acceptable salt of The compounds of this invention exists.

For the use in medicine, the salt of The compounds of this invention is meant nontoxic " pharmaceutically acceptable salt ".The form of the pharmaceutically acceptable salt of FDA approval (with reference to International J.Pharm., 1986,33,201-217; J.Pharm.Sci., in January, 1977,66 (1), page 1) comprise pharmaceutically acceptable acidity/anion salt or basic/cationic salts.

Pharmaceutically acceptable acidity/anion salt includes, but are not limited to acetate, benzene sulfonate, benzoate, bicarbonate, biatrate, bromide, the edetic acid calcium salt, camsilate, carbonate, chloride, citrate, dihydrochloride, edetate, ethanedisulphonate, Estolate, esilate, fumarate, glyceptate, gluconate, glutamate, Glu, to hydroxyl acetylamino phenyl arsonate, hexyl resorcin salt, hydrabamine, hydrobromate, hydrochlorate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, MB, methyl nitrate, Methylsulfate, mucate, naphthalene sulfonate, nitrate, embonate, pantothenate, phosphate/diphosphate, Polygalacturonate, Salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, toluene fulfonate and triethyl group iodate thing.Organic or inorganic acid also includes, but are not limited to hydroiodic acid, perchloric acid, sulphuric acid, phosphoric acid, propanoic acid, glycolic, methanesulfonic acid, ethylenehydrinsulfonic acid, oxalic acid, 2-LOMAR PWA EINECS 246-676-2, m-toluene sulfonic acid, cyclohexane sulfamic acid, saccharinic acid or trifluoroacetic acid.

Pharmaceutically acceptable alkali/cationic salts comprises, but be not limited to aluminium ion, 2-amino-2-methylol-the third-1,3-glycol (also being called three (methylol) aminomethane, tromethane (tromethane) or " TRIS "), ammonia, benzyl star, tert-butylamine, calcium ion, calcium gluconate, calcium hydroxide, chloroprocaine, choline, Choline Bicarbonate, choline chloride, cyclo-hexylamine, diethanolamine, ethylenediamine, lithium salts, LiOMe, L-lysine, magnesium salt, meglumine, NH ₃, NH ₄OH, N-methyl D-glucamine, piperidines, potassium salt, potassium tert-butoxide, potassium hydroxide (aqueous solution), procaine, quinoline, sodium salt, sodium carbonate, 2 ethyl hexanoic acid sodium (SEH), sodium hydroxide, triethanolamine (TEA) or zinc salt.

Prodrug

The prodrug of The compounds of this invention is included in the scope of the present invention.Usually, these prodrugs are for being easy to be converted into the functional derivatives of reactive compound in vivo.Therefore, in Therapeutic Method of the present invention, term " administration " though will comprise with concrete disclosed chemical compound or concrete open chemical compound that is included in the scope of the present invention apparently or the treatment of its prodrug, improve or the prevention literary composition described in the method for syndrome, disease or disease.The conventional method of selecting and preparing suitable prodrug derivant is as for example " Design of Prodrugs (design of prodrug) ", and H.Bundgaard edits, Elsevier, and 1985 is described.

Three-dimensional chemical isomer

Those skilled in the art will recognize that formula I chemical compound can have one or more asymmetric carbon atoms in its structure.The enantiomeric mixture of single enantiomeric forms, racemic mixture and a kind of enantiomeric excess of described chemical compound will be included in the scope of the present invention.

Used term in the literary composition " single enantiomer " has defined formula I chemical compound and nitrogen oxide, addition salts, quaternary ammonium salt or physiology go up all possible homochiral form of functional derivatives.

The pure isomeric form of spatial chemistry can obtain by the application of principle known in the art.Diastereomer can pass through physical separation method (as fractional crystallization and chromatographic technique) to be separated, and can separate with the selective freezing of photolytic activity acid or alkali or by chiral chromatogram by diastereomeric salt with enantiomer.Pure stereoisomer also can be prepared or be prepared by stereoselective reaction by the pure initiation material of suitable spatial chemistry.

Term " isomer " is meant to have same composition with molecular weight but the different chemical compound of physics and/or chemical property.These materials have identical atom number with kind but structure is different.The difference of structure can be in structure (geometric isomer) or rotatable polarized light flat (enantiomer).

Term " stereoisomer " is meant the not isomer of the steric same structure of homoatomic.Enantiomer and diastereomer are the example of stereoisomer.

Term " chirality " is meant the architectural feature of molecule, and this structure makes molecule not superpose with its mirror image.

Term " enantiomer " is meant each other mirror image and can not eclipsed a pair of molecule.

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

Substituent configuration in symbol " R " and " S " expression chiral carbon atom.

Term " racemic compound " or " racemic mixture " are meant that wherein said compositions does not have photolytic activity by two kinds of compositionss that the enantiomer type is formed of equimolar amounts.

Term " homochiral " is meant the state of enantiomeric purity.

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

Term " geometric isomer " is meant and replaces the isomer of atom with respect to carbon-to-carbon double bond, cycloalkyl ring or bridge second cycle line different orientation.The substituent group atom of each side of carbon-to-carbon double bond (not being H) can be E or Z configuration.In " E " (offside) configuration, substituent group is at the offside of carbon-to-carbon double bond; In " Z " (homonymy) configuration, substituent group is at the homonymy of carbon-to-carbon double bond.Connect isocyclic substituent group atom (dehydrogenation is outer) and can be cis or anti-configuration.In " cis " configuration, substituent group is at the homonymy of plane of a loop; In " trans " configuration, substituent group is at the offside of plane of a loop.The chemical compound that contains the mixture of " cis " and " trans " type is called " cis/trans ".The substituent group atom that is connected with bridge two member ring systems (for H) can be " interior " or " " configuration outward." in " in the configuration, the substituent group that is connected with bridge location (not being end of the bridge) is towards two major parts that remain bridges; " outside " in the configuration, the substituent group that is connected with bridge location is towards the smaller portions of two residue bridges.

The stereoisomer, geometric isomer and composition thereof that should be understood that the different substituents that is used to prepare The compounds of this invention are for commercially available, or can maybe can be prepared into isomer mixture and use the well-known technology fractionation of those of ordinary skills to obtain subsequently by the synthetic preparation of commercially available initiation material.

Isomer descriptor " R ", " S ", " E ", " Z ", " cis ", " trans " " outward " and " are interior " as described hereinly to be used to show that ((IUPAC is for stereochemical substantially suggestion for IUPACRecommendations for Fundamental Stereochemistry (Section E) with respect to the atomic configuration of core element and by document, the E part), Pure Appl.Chem., 1976,45:13-30) define use.

The compounds of this invention can synthesize or be prepared by the isomer mixture fractionation by isomer-specificity.Conventional disassemble technique comprises that the free alkali (subsequently with free alkali fractional crystallization and regeneration) that uses each right isomer of photolytic activity salt formation isomer forms the ester of each right isomer of isomer or amide (chromatographic isolation and remove chiral auxiliary) subsequently or uses preparation TLC (thin layer chromatography) or chirality HPLC post to split the isomer mixture of initiation material or end product.

Polymorph and solvate

In addition, The compounds of this invention can have one or more polymorph or metamict crystals form and suchlike form and will be included in the scope of the present invention.In addition, some chemical compounds can form solvate for example with water (being hydrate) or with organic solvent commonly used, and suchlike form will be included in the scope of the present invention.Used term " solvate " is meant the physical bond of one or more The compounds of this invention and one or more solvent molecules in the literary composition.This physical bond relates to ion and covalent bond (comprising hydrogen bond) in various degree.In some cases, solvate can be separated, for example when one or more solvent molecules are combined in the lattice of crystalline solid.Term " solvate " comprises solution phase and separable solvate.The suitable solvent thing example comprises alcoholate, methylate etc.The solvate of The compounds of this invention comprises within the scope of the invention.Therefore, in Therapeutic Method of the present invention, term " administration " though will comprise with concrete disclosed chemical compound or concrete open chemical compound that is included in the scope of the present invention apparently or the treatment of its solvate, improve or the prevention literary composition described in the method for syndrome, disease or disease.

Nitrogen oxide

Employing is converted into the prior art known method of nitrogen oxide form with trivalent nitrogen, and formula I chemical compound can be converted into corresponding nitrogen oxide form.But the initiation material of the common through type I of described N-oxidation reaction and suitable organic or inorganic peroxide reactions are carried out.Suitable inorganic peroxide comprises for example hydrogen peroxide, alkali-metal peroxide or alkaline earth metal peroxide, for example sodium peroxide, potassium peroxide; Suitable organic peroxide can comprise peroxy acid, for example peroxidating benzoic acid or halo peroxidating benzoic acid (for example 3-chloro peroxide acid), peroxide bond alkanoic acid (for example peracetic acid), alkyl peroxide (for example tert-butyl hydroperoxide).The suitable solvent is for example water; Lower alcohol is ethanol etc. for example; Hydrocarbon is toluene, ketone such as 2-butanone for example; The mixture of halogenated hydrocarbons such as dichloromethane and these solvents.

Tautomeric form

Some formula I chemical compounds can also its tautomeric form exist.Though these forms do not indicate clearly in this application, it will be included in the scope of the present invention.

The preparation of The compounds of this invention

In the process of any preparation The compounds of this invention, sensitivity or the active group of protection on any concern molecule can be necessary and/or hope.This can realize by the method for GPF (General Protection False group, as Protecting Groups (blocking group), P.Kocienski, Thieme MedicalPublishers, 2000; With T.W.Greene and P.G.M.Wuts, Protective Groupsin Organic Synthesis (blocking group in organic synthesis), the third edition, WileyInterscience is described in 1999.Blocking group can use methods known in the art to slough follow-up the convenience in the step.

General reaction process

Formula I chemical compound can be prepared by method known to those skilled in the art.Following reaction process only is intended to represent example of the present invention, and limits the present invention absolutely not.

Formula I chemical compound, wherein B, Z, Q, q, p, R ₁And R ₃Suc as formula the I definition, can be synthetic by the general synthetic route shown in the flow process 1.(DMF/POCl under the Vilsmeier reaction condition ₃), by handling pyrimidine-4,6-glycol II can obtain 4, and 6-two chloro-pyrimidine-5-formaldehyde III are subsequently by obtaining key intermediate 4-amino-6-chloro-pyrimidine-5-formaldehyde IV with ammonia treatment.Under 25 ℃-150 ℃, in the solvent (as DMSO), in the presence of the alkali (as diisopropyl ethyl amine), dichloro pyrimidine IV handles with suitable cyclic amine V, can obtain pyrimidine VI.In solvent (as MeOH), the VI R that is fit to ₁ONH ₂Handle, can obtain end product I.The trans of formula I though only drawn is contemplated in end reaction and can forms trans and cis geometric isomer.Described isomer can separate and because the methine hydrogen H of corresponding oxime by column chromatography _a ¹HNMR chemical shift (Fig. 1 b) and variant on spectrum.

" trans " isomer " cis " isomer

Fig. 1 b

H with cis-isomer _aThe chemical shift of methine hydrogen is compared, the actual measurement of main transisomer ¹The HNMR spectrum demonstrates H _aThe more downfield feature of the chemical shift of methine hydrogen.The H of trans and syn-oxime isomer _aHydrogen ¹The observable difference of H chemical shift conform to document known in the art (Biorg.Med.Chem.Lett, 2004,14,5827-5830).

Flow process 1

(wherein Q is O, NH or N (alkyl) to cyclic amine reagent V, and Z is NH or N (alkyl) and B, q, p and R ₃Suc as formula defining among the I) can be by the preparation of the reaction sequence shown in the flow process 2a.Protected amine VII (wherein PG for the amine protecting group group that is fit to as N-Boc) and suitable acylating agent VIII (wherein LG can be p-nitrophenyl oxygen base, chlorine or imidazoles) acidylate can obtain the intermediate compound I X of acidylate.Deaminate blocking group (PG) can obtain required amine V under the condition that is fit to.The cyclic amine VII of protection is commercially available or derives from known method (JOC, 1961,26,1519; EP314362; US4822895; EP401623).Acylating agent VIII is commercially available or can prepares shown in flow process 2a.In the presence of alkali (as triethylamine), the R that is fit to ₃BZH (wherein Z is NH or N (alkyl)) can obtain VIII with the acylating agent that is fit to such as carbonyl dimidazoles or p-nitrophenyl chloroformate ester processing.Many R ₃The BZH reactant is commercially available or can be by many known method preparation (for example Tet Lett 1995,36, and 2411-241 4).(wherein Q is O, NH or N (alkyl) to preparation V, and Z is CH ₂And B, p, q and R ₃Suc as formula defining among the I) alternative method such as flow process 2b listed.By using standard coupling agent such as 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) or I-hydroxybenzotriazole (HOBT), the cyclic amine VII of protection and the R that is fit to ₃BCH ₂CO ₂The H coupling can obtain the intermediate compound I X of acidylate.Under acid condition, slough

The N-Boc blocking group can obtain required amine V.

Q is O, NH or N (alkyl)

Z is NH or N (alkyl)

PG is a blocking group

LG is a leaving group

Q is O, NH or N (alkyl)

Z is CH2

PG is a blocking group

Reactant R ₁ONH ₂(R wherein ₁Suc as formula defining among the I) maybe can prepare for commercially available by the reaction sequence shown in the flow process 3a.In solvent (as DMSO), by using the electrophilic reagent R that is fit to ₁LG (wherein LG can be leaving group such as bromine or iodine) can obtain benzylidene intermediate X I with alkali (as KOH) with benzylidene X alkylation, handles down at acid condition (as 4N HCl) subsequently, obtains required reactant R ₁ONH ₂Preparation feedback thing R ₁ONH ₂Correlation technique (wherein n, R ₁And R _aSuc as formula defining among the I) shown in flow process 3b.In solvent (as DMSO), by using the electrophilic reagent PGO (CH that is fit to ₂) _nLG (wherein PG is known pure blocking group, and LG can be leaving group such as bromine or iodine) can obtain the alkylating benzylidene of O-with alkali (as KOH) with benzylidene X alkylation.Under standard conditions,, alcohol is converted into suitable leaving group well known by persons skilled in the art such as methanesulfonic acid group, carries out SN with the nucleophilic heterocyclic, heteroaryl, amine, alcohol, sulfonamide or the mercaptan that are fit to subsequently pure blocking group deprotection known to the skilled ₂Displacement reaction is taken off the benzylidene reaction and can be obtained reactant R by acid mediated subsequently ₁ONH ₂If R _aNucleopilic reagent is a mercaptan, and the further oxidation of mercaptan can be obtained corresponding sulfoxide and sulfone.If R _aNucleopilic reagent is amino, and nitrogen can obtain corresponding amide, carbamate, urea and sulfonamide with the acylating agent or the sulfonylation agent acidylate that are fit to.If required R _aBe COOR _yOr CONR _wR _x, they can be obtained by corresponding hydroxyl.Hydroxyl oxidize is acid, forms ester or amide subsequently under condition known in the art, can obtain wherein R _aBe COOR _yOr CONR _wR _xExample.

Flow process 3a

Flow process 3b

Wherein

PG is a blocking group

LG is a leaving group

Nuc is a nucleophilic group

Perhaps, (Q is O, NH or N (alkyl) and B, Z, q, p, R to formula I chemical compound ₁And R ₃) can synthesize by general as shown in Scheme 4 synthesis path.In solvent (as acetonitrile), in the presence of the alkali (as diisopropyl ethyl amine), 4-chloropyrimide IV handles with the cyclammonium XII that is fit to, and can obtain pyrimidine XIII.In solvent (as MeOH), the 5-formaldehyde pyrimidine XIII R that is fit to ₁ONH ₂Handle, can obtain intermediate X IV, under standard deprotection condition known in the art, slough blocking group on the substituent group Q (PG) subsequently and can obtain pyrimidine XV.In the presence of alkali (as diisopropyl ethyl amine), by with the reactant VIII that is fit to (wherein Z is that NH or N (alkyl) and LG can be chlorine, imidazoles or p-nitrophenyl oxygen base) the XV acidylate can being obtained end product I, or to work as Z be CH ₂, the coupling agent that uses standard is (as 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) or I-hydroxybenzotriazole (HOBT) and suitable R ₃BCH ₂CO ₂The H coupling can obtain end product I.The trans of formula I though only drawn should be understood in reactions steps and can form trans and cis geometric isomer.Described isomer can be by column chromatography separation and variant on spectrum.

Flow process 4

Perhaps, (wherein Z is NH to formula I chemical compound, and Q is O, NH or N (alkyl) and B, q, p, R ₁And R ₃Suc as formula defining among the I) can synthesize by general as shown in Scheme 5 synthesis path.In solvent (as acetonitrile), in the presence of the alkali (as diisopropyl ethyl amine), 4-chloropyrimide IV handles with the cyclic amine XII that is fit to can obtain pyrimidine XIII.In solvent (as MeOH), the 5-formaldehyde pyrimidine XIII R that is fit to ₁ONH ₂Processing can obtain intermediate X IV, and the blocking group of sloughing on the substituent group Q under standard deprotection condition known in the art (PG) can obtain pyrimidine XV subsequently.The XV R that is fit to ₃BNCO handles can obtain end product I.The trans of formula I though only drawn should be understood in reactions steps and can form trans and cis geometric isomer.Described isomer can be by column chromatography separation and variant on spectrum.

Flow process 5

(wherein Q is a chemical bond to formula I chemical compound, and Z is NH or N (alkyl) and B, q, p, R ₁And R ₃Suc as formula defining among the I) can synthesize by general as shown in Scheme 6 synthesis path.In solvent (as acetonitrile), in the presence of the alkali (as diisopropyl ethyl amine), 4-chloropyrimide IV handles with the cyclic amino ester XVI that is fit to (wherein PG be known in the art ester protecting group) can obtain pyrimidine XVII.At solvent (in MeOH) the 5-formaldehyde pyrimidine XVII R that is fit to ₁ONH ₂Processing can obtain intermediate X VIII, sloughs blocking group (PG) subsequently under standard deprotection condition known in the art and obtains pyrimidine XIX.By using standard coupling agent known in the art such as 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) with the reactant R that is fit to ₃BZH and XIX coupling can obtain end product I.The trans of formula I though only drawn is contemplated in end product and can forms trans and cis geometric isomer.Described isomer can be by column chromatography separation and variant on spectrum.

Flow process 6

Typical compound

Below listed by the representational chemical compound of the synthetic the present invention of said method.To introduce the synthetic embodiment of particular compound after this.Preferred chemical compound is the chemical compound of numbering 2,5,6,7,8,11,12,15,19,21,23; Particularly preferred chemical compound is the chemical compound of numbering 2,5,6,8 and 11.

Embodiment 1

(4-isopropoxy-phenyl) carbamic acid 1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester

A. (4-isopropoxy-phenyl) carbamic acid piperidin-4-yl ester

Under 0 ℃, past at CH ₂Cl ₂(5mL) 1, (CDI, 1.64g are added in CH in 10mmol) to 1 '-carbonyl dimidazoles ₂Cl ₂4-isopropoxy-phenyl amine (10mL) (1.52g, 10mmol).After at room temperature stirring 1 hour, be added in CH ₂Cl ₂(2.05g 10mmol) and at room temperature keeps this mixture to stir and spends the night 4-hydroxy-piperdine (5mL)-1-t-butyl formate.CH is used in the quencher of reactant water subsequently ₂Cl ₂Extraction.Organic extract salt water washing is through Na ₂SO ₄Drying, evaporation subsequently.(0.35g 0.93mmol) is dissolved in CH to the product part that BOC-is protected again ₂Cl ₂(5mL).Add the 1mL trifluoroacetic acid in this solution and the mixture that obtains was stirred under room temperature 1 hour.Vacuum is removed organic solvent, subsequently crude product 2MNH ₃/ MeOH neutralization.After solvent boiled off, rough residue was through quick purification by silica gel column chromatography (5%MeOH/CH ₂Cl ₂), obtain the product (250mg, 97%) of light brown solid, shaped.

¹H NMR(CDCl ₃)δ7.26(m，2H)，6.84(d，J＝8.70Hz，2H)，6.49(br，1H)，4.88(m，1H)，4.48(sep，J＝6.0Hz，1H)，3.12(m，2H)，2.83(m，2H)，2.04(m，2H)，1.71(m，2H)，1.31(d，J＝6.0Hz，6H)；

C ₁₅H ₂₃N ₂O ₃(MH) ⁺LC/MS (ESI) value of calculation 279.2; Measured value 279.3.

B.4,6-two chloro-pyrimidine-5-formaldehydes

Under 0 ℃, with DMF (3.2mL) and POCl ₃Mixture (10mL) stirred 1 hour, and with 4, (2.5g 22.3mmol) handles the 6-dihydroxy-pyrimidine, stirs 0.5 hour under ambient temperature subsequently.In the heating down 3 hours that refluxes, volatile matter is removed in decompression subsequently with the heterogeneous body mixture.In this residue impouring frozen water, use extracted with diethyl ether subsequently six times.Organic facies NaHCO ₃Solution washing is through Na ₂SO ₄Drying concentrates subsequently, obtains yellow solid (3.7g, 95%). ¹H NMR(CDCl ₃)δ10.46(s，1H)，8.90(s，1H).

C.4-amino-6-chloro-pyrimidine-5-formaldehyde

Toward 4, (1g, 5.68mmol) bubbling fed ammonia 10 minutes to 6-two chloro-pyrimidine-5-formaldehydes in the solution in toluene (100mL), this solution is stirred under room temperature spend the night subsequently.Yellow mercury oxide is leached, and with the EOAc washing, vacuum drying obtains pure product (880mg, 99%) subsequently.

¹H MR(DMSO-d ₆)δ10.23(s，1H)，8.72(br，1H)，8.54(br，1H)，8.38(s，1H).

D. (4-isopropoxy-phenyl) carbamic acid 1-(6-amino-5-formoxyl-pyrimidine-4-yl)-piperidin-4-yl ester

Toward 4-amino-6-chloro-pyrimidine-5-formaldehyde (60.6mg, 0.39mmol) and (4-isopropoxy-phenyl) carbamic acid piperidin-4-yl ester (102.3mg, 0.37mmol) add in the solution in DMSO (1mL) DIEA (118.9mg, 0.92mmol).This mixture was stirred 4 hours down in 100 ℃, it is cooled to room temperature and dilute with water.With EtOAc extraction, organic extract salt water washing subsequently, dry (Na ₂SO ₄), evaporation subsequently.The yellow solid that obtains washs with EtOAc, obtains the product (93.7mg, 63.5%) of white solid.

¹H NMR(CDCl ₃)δ9.77(s，1H)，9.16(br，1H)，9.07(br，1H) 8.08(s，1H)，7.26(m，2H)，6.86(d，J＝8.82 Hz，2H)，6.51(br，1H)，5.13(m，1H)，4.50(sep，J＝6.01Hz，1H)，4.10(m，2H)，3.96(m，2H)，2.08-2.15(m，2H)，1.93-1.99(m，2H)，1.32(d，J＝6.06Hz，6H)；

C ₂₀H ₂₆N ₅O ₄(MH) ⁺LC/MS (ESI) value of calculation 400.2; Measured value 400.3.

E. (4-isopropoxy-phenyl) carbamic acid 1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester

Toward (4-isopropoxy-phenyl) carbamic acid 1-(6-amino-5-formoxyl-pyrimidine-4-yl)-(14mg 0.035mmol) adds MeONH in the solution in MeOH (1mL) to the piperidin-4-yl ester ₂HCl (8.8mg, 0.11mmol).This mixture was stirred 1 hour down in 100 ℃, subsequently removal of solvent under reduced pressure.Crude product is through flash chromatography purification (eluent: EtOAc), obtain the title compound (13mg, 86.7%) of white solid.

¹H NMR(CDCl ₃)δ8.16(s，1H)，8.05(s，1H)，7.25(m，2H)，7.24(br，2H)，6.84(d，J＝8.97Hz，2H)，6.48(br，1H)，5.01(m，1H)，4.49(sep，J＝6.05Hz，1H)，3.96(s，3H)，3.69(m，2H)，3.37(m，2H)，2.01-2.11(m，2H)，1.77-1.89(m，2H)，1.31(d，J＝6.06Hz，6H)；

C ₂₁H ₂₉N ₆O ₄(MH) ⁺LC/MS (ESI) value of calculation 429.2; Measured value 429.3.

Embodiment 2

(4-isopropoxy-phenyl) carbamic acid 1-[6-amino-5-(ethyoxyl imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester

Basically as preparation as described in the embodiment le, use ethoxy amine hydrochloride (9.2mg, 95%).

¹H NMR(CDCl ₃)δ8.18(br，1H)，8.07(s，1H)，721-7.29(m，4H)，6.85(d，J＝8.97 Hz，2H)，6.49(br，1H)，5.01(m，1H)，4.49(sep，.J＝6.04Hz，1H)，4.20(q，J＝7.06Hz，2H)，3.70(m，2H)，3.39(m，2H)，2.01-2.11(m，2H)，1.77-1.89(m，2H)，1.32(t，J＝6.98Hz，3H)，1.31(d，J＝5.82Hz，6H)；

C ₂₂H ₃₁N ₆O ₄(MH) ⁺LC/MS (ESI) value of calculation 443.2; Measured value 443.3.

Embodiment 3

(4-isopropoxy-phenyl) carbamic acid 1-{6-amino-5-[(2-morpholine-4-base-ethyoxyl imido grpup)-methyl]-pyrimidine-4-yl }-the piperidin-4-yl ester

A.O-(2-morpholine-4-base-ethyl)-diphenyl-ketoxime

At room temperature, toward the KOH powder (1.24g, 22mmol) and the benzophenone oxime (1.97g, 10mmol) in the suspension of DMSO (23mL), add in batches N-(2-chloroethyl) morpholine hydrochloride (2.10g, 11mmol).This reactant mixture is kept stirring 3 days under room temperature, and dilute with water is also used extracted with diethyl ether.Organic facies salt water washing, dry (Na ₂SO ₄) and evaporation, obtain almost pure product.

¹H NMR(CDCl ₃)δ7.32-7.50(m，10H)，4.35(t，J＝5.59 Hz，2H)，3.69(t，J＝4.52Hz，4H)，2.74(m，2H)，2.49(m，4H)；

C ₁₉H ₂₃N ₂O ₂(MH) ⁺LC/MS (ESI) value of calculation 311.2; Measured value 311.2.

B.O-(2-morpholine-4-base-ethyl)-hydroxylamine dihydrochloride

Under agitation, with O-(2-morpholine-4-base-ethyl)-diphenyl-ketoxime (2.5g, 8.06mmol) suspension reflux in 6N HCl (13.5mL).After 2 hours, this mixture is cooled to room temperature and uses the EtOAc extracted several times.Water vacuum evaporation to doing, is obtained title compound (740mg, 63%).

¹H NMR(DMSO-d ₆)δ4.45(t，J＝4.49Hz，2H)，3.89(t，J＝4.48Hz，4H)，3.47(t，J＝4.64Hz，2H)，3.29(m，4H)；

C ₆H ₁₅N ₂O ₂(MH) ⁺LC/MS (ESI) value of calculation 147.1; Measured value 147.1.

C. (4-isopropoxy-phenyl) carbamic acid 1-{6-amino-5-[(2-morpholine-4-base-ethyoxyl imido grpup)-methyl]-pyrimidine-4-yl }-the piperidin-4-yl ester

Basically as preparation as described in the embodiment le, use O-(2-morpholine-4-base-ethyl)-hydroxy amine hydrochloric acid salt (10.9mg, 62.6%).

¹H NMR(CD ₃OD)δ8.19(s，1H)，8.06(s，1H)，7.29(d，J＝8.36Hz，2H)，6.83(d，J＝9.02Hz，2H)，4.91(m，1H)，4.51(sep，J＝6.04Hz，1H)，4.40(t，J＝5.09Hz，2H)，3.77(t，J＝4.64Hz，4H)，3.70(t，J＝4.52Hz，2H)，3.63(m，2H)，3.35(m，2H)，2.99(m，2H)，2.81(m，4H)，2.05(m，2H)，1.81(m，2H)，1.27(d，J＝6.04Hz，6H)；

C ₂₆H ₃₈N ₇O ₅(MH) ⁺LC/MS (ESI) value of calculation 528.3; Measured value 528.4.

Embodiment 4

(4-isopropoxy-phenyl) carbamic acid 1-{6-amino-5-[(3-dimethylamino-propoxyl group imido grpup)-methyl]-pyrimidine-4-yl }-the piperidin-4-yl ester

A.O-(3-dimethylamino-propyl group)-diphenyl-ketoxime

Basically as preparation as described in the embodiment 3a, difference is to use (3-chloro-propyl group)-dimethyl-amine to replace N-(2-chloroethyl) morpholine hydrochloride.

¹HNMR(CDCl ₃)δ7.31-7.50(m，10H)，4.22(t，.J＝6.46Hz，2H)，2.33(t，J＝7.23Hz，2H)，2.21(s，6H)，1.88(m，2H)；

C ₁₈H ₂₃N ₂O (MH) ⁺LC/MS (ESI) value of calculation 283.2; Measured value 283.2.

B.O-(3-dimethylamino-propyl group)-azanol dihydrochloride

Basically as preparation as described in the embodiment 3b, difference is to use O-(3-dimethylamino-propyl group)-diphenyl-ketoxime to replace O-(2-morpholine-4-base-ethyl)-diphenyl-ketoxime.

¹H NMR(CD ₃OD)δ4.21(t，J＝5.90Hz，2H)，3.30(t，J＝7.11Hz，2H)，2.92(s，6H)，2.18(m，2H)；

C ₅H ₁₅N ₂O (MH) ⁺LC/MS (ESI) value of calculation 119.1; Measured value 119.2.

C. (4-isopropoxy-phenyl) carbamic acid 1-{6-amino-5-[(3-dimethylamino-propoxyl group imido grpup)-methyl]-pyrimidine-4-yl }-the piperidin-4-yl ester

Basically as preparation as described in the embodiment le, use O-(3-dimethylamino-propyl group)-hydroxylamine hydrochloride (2.0mg, 14.4%).

¹H NMR(CD ₃OD)δ8.19(s，1H)，8.07(s，1H)，7.29(d，J＝8.79Hz，2H)，6.82(d，J＝9.05Hz，2H)，4.94(m，1H)，4.51(sep，J＝6.02Hz，1H)，4.28(t，J＝5.84Hz，2H)，3.66(m，2H)，3.36(m，2H)，3.28(m，2H)，2.91(s，6H)，2.11-2.22(m，2H)，2.01-2.10(m，2H)，1.76-1.86(m，2H)，1.28(d，J＝6.04Hz，6H)；

C ₂₅H ₃₈N ₇O ₄(MH) ⁺LC/MS (ESI) value of calculation 500.3; Measured value 500.4.

Embodiment 5

(4-isopropyl-phenyl) carbamic acid 1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester

A. (4-isopropyl-phenyl) carbamic acid piperidin-4-yl ester

Toward 1, (304mg is 1.88mmol) at CH for 1 '-carbonyl dimidazoles ₂Cl ₂Adding 4-hydroxy-piperdine-1-formic acid tertiary butyl ester in the solution (10mL) (350mg, 1.74mmol).Stirring is after 30 minutes down at 0 ℃, and (251mg 1.86mmol), at room temperature stirs this mixture subsequently and spends the night to add the 4-isopropyl aniline.Solvent removed in vacuo obtains rough solid, and it uses TFA (20mL) and CH ₂Cl ₂(20mL) handle, stirred subsequently 30 minutes.Removal of solvent under reduced pressure obtains the title compound (113mg, 25%) of solid, shaped.

¹H NMR(CDCl ₃)δ7.31(m，2H)，7.14(m，3H)，4.82(m，1H)，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)；

C ₁₅H ₂₂N ₂O ₂LC/MS (ESI) value of calculation 262.35; Measured value [M+1] ⁺263.2.

B. (4-isopropyl-phenyl) carbamic acid 1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester

Toward (4-isopropyl-phenyl) carbamic acid piperidin-4-yl ester (67mg, 0.26mmol) and 4-amino-6-chloro-pyrimidine-5-formaldehyde (40.1mg, 0.26mmol) add in the mixture in DMSO (1mL) DIEA (165mg, 1.28mmol).Stir this solution down at 100 ℃.After 2 hours, adding methoxyl group amine. (65.1mg 0.78mmol) and under 100 ℃ keeps this mixture to stir 1 hour hydrochlorate.It is cooled to room temperature and at CH ₂Cl ₂And distribute between water.Organic facies salt water washing, dry (Na ₂SO ₄), evaporation subsequently.Crude product is through quick purification by silica gel column chromatography (eluent: EtOAc), obtain the required product (23mg, 21.9%) of white solid.

¹H NMR(CDCl ₃)δ 8.83(br，1H)，8.40(br，1H)，8.05(s，1H)，7.92(s，1H)，7.24-7.31(m，2H)，7.18(d，J＝8.62Hz，2H)，6.56(br，1H)，5.08(m，1H)，3.97(s，3H)，3.88-3.96(m，2H)，3.64-3.74(m，2H)，2.88(m，1H)，2.03-2.13(m，2H)，1.81-1.92(m，2H)，1.23(d，J＝6.92Hz，6H)；

C ₂₁H ₂₉N ₆O ₃(MH) ⁺LC/MS (ESI) value of calculation 413.2; Measured value 413.3.

Embodiment 6

2-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-N-(4-isopropyl-phenyl)-acetamide

A.3-[(4-isopropyl-phenylamino formoxyl)-methyl]-pyrrolidine-1-t-butyl formate

Toward 3-carboxymethyl-pyrrolidine-1-formic acid tertiary butyl ester (665.7mg, 2.9mmol) and 4-isopropyl-phenyl amine (435mg, 3.19mmol) add HOBT (577.6mg in the mixture in anhydrous THF (30mL), 3.78mmol), add HBTU (1.43g subsequently, 3.78mmol) and DIEA (1.13g, 8.71mmol).This mixture stirred under room temperature spend the night, subsequently removal of solvent under reduced pressure.Residue is distributed organic extract salt water washing, dry (Na between EtOAc and water ₂SO ₄), evaporation subsequently.Crude product obtains required product (558mg, 56%) through quick purification by silica gel column chromatography (EtOAc/ hexane, 1: 1 volume ratio).

¹H NMR(CDCl ₃)δ7.56(br，1H)，7.42(m，2H)，7.16(m，2H)，3.60(dd，J＝10.72and 7.25 Hz，1H)，3.44(m，1H)，3.29(m，1H)，2.99(m，1H)，2.86(m，1H)，2.69(m，1H)，2.30-2.49(m，2H)，2.09(m，1H)，1.59(m，1H)，1.44(s，9H)，1.21(d，J＝6.92Hz，6H)；

C ₂₀H ₃₁N ₂O ₃(MH) ⁺LC/MS (ESI) value of calculation 347.2; Measured value 347.4.

B.N-(4-isopropyl-phenyl)-2-pyrrolidine-3-base-acetamide trifluoroacetate

With 3-[(4-isopropyl-phenylamino formoxyl)-methyl]-(558mg 1.61mmol) is dissolved in 50%TFA/CH to pyrrolidine-1-formic acid tertiary butyl ester ₂Cl ₂(10mL), subsequently this solution was stirred under room temperature 4 hours.Removal of solvent under reduced pressure obtains the title compound of solid, shaped, and it need not to be further purified and is used for next step.

¹H NMR(CDCl ₃)δ9.34(br，1H)，8.68(br，1H)，8.20(br，1H)，7.42(d，J＝8.77Hz，2H)，7.19(d，J＝8.50Hz，2H)，3.53(m，1H)，3.36(m，2H)，3.00(m，1H)，2.88(m，1H)，2.65(d，J＝6.75Hz，2H)，2.33(m，1H)，1.90(m，1H)，1.22(d，J＝6.91Hz，6H)；

C ₁₅H ₂₃N ₂O (MH) ⁺LC/MS (ESI) value of calculation 247.2; Measured value 247.3.

C.2-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-N-(4-isopropyl-phenyl)-acetamide

Toward N-(4-isopropyl-phenyl)-2-pyrrolidine-3-base-acetamide trifluoroacetate (as preparation as described in the previous step) and 4-amino-6-chloro-pyrimidine-5-formaldehyde (252mg, 1.61mmol) add in the mixture in DMSO (8mL) DIEA (457mg, 3.54mmol).This solution is stirred down in 100 ℃.After 2 hours, (538mg 6.44mmol) and with this mixture stirred 1 hour down in 100 ℃ to add methoxy amine hydrochlorate.It is cooled to room temperature, subsequently at CH ₂Cl ₂And distribute between water.Organic facies salt water washing, dry (Na ₂SO ₄), evaporation subsequently.Crude product is through quick purification by silica gel column chromatography (eluent: EtOAc), obtain the required product (200mg, 31%) of white solid.

¹H NMR(CD ₃OD)δ8.41(s，1H)，7.88(s，1H)，7.43(d，J＝8.60Hz，2H)，7.17(d，J＝8.40Hz，2H)，3.91(s，3H)，3.78(dd，J＝10.49and 8.69Hz，1H)，3.69(m，2H)，3.42(dd，J＝10.61 and 9.30 Hz，1H)，2.86(sep，J＝6.87 Hz，1H)，2.65(m，1H)，2.48(d，J＝7.83Hz，2H)，2.15(m，1H)，1.70(m，1H)，1.22(d，J＝6.93Hz，6H)；

C ₂₁H ₂₉N ₆O ₂(MH) ⁺LC/MS (ESI) value of calculation 397.2; Measured value 397.4; C ₂₁H ₂₈N ₆O ₂Value of calculation: C, 63.61; H, 7.1 2; N, 21.20; Measured value C, 63.32; H, 6.95; N, 21.04.

Embodiment 7

2-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-N-(4-isopropyl-phenyl)-acetamide

A. N-(4-isopropyl-phenyl)-2-piperidin-4-yl-acetamide

Toward 4-carboxymethyl-piperidines-(73mg is 0.3mmol) at anhydrous CH for 1-formic acid tertiary butyl ester ₂Cl ₂In solution in add PS-carbodiimides (0.4mmol) and with the jolting 15 minutes under room temperature of this mixture.Subsequently, add in this mixture the 4-isopropyl aniline (27mg, 0.2mmol) and at room temperature its jolting is spent the night.Subsequent filtration, this resin CH ₂Cl ₂Washed twice with merging filtrate and eluent vacuum concentration, obtains rough 4-[(4-isopropyl-phenylamino formoxyl)-methyl]-piperidines-1-t-butyl formate, it was handled 1 hour with 3M HCl/MeOH solution (2mL).With the mixture vacuum concentration that obtains, obtain rough N-(4-isopropyl-phenyl)-2-piperidin-4-yl-acetamide hydrochloride.C ₁₆H ₂₅N ₂O (MH) ⁺LC/MS (ESI) value of calculation 261.2; Measured value 261.3.This raw material need not to be further purified and is directly used in next step reaction.

B.2-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-N-(4-isopropyl-phenyl)-acetamide

As preparation as described in the embodiment 6c, difference is to use N-(4-isopropyl-phenyl)-2-piperidin-4-yl-acetamide to replace N-(4-isopropyl-phenyl)-2-pyrrolidine-3-base-acetamide trifluoroacetate.

¹H NMR(CDCl ₃)δ8.13(s，1H)，8.03(s，1H)，7.42(d，J＝8.51 Hz，2H)，7.18(d，J＝8.58 Hz，2H)，3.94(s，3H)，3.90(m，2H)，3.05(m，2H)，2.88(sep，J＝6.77Hz，1H)，2.30(d，J＝6.85Hz，2H)，2.19(m，1H)，1.90(m，2H)，1.39(m，2H)，1.22(d，J＝6.92Hz，6H)；

C ₂₂H ₃₁N ₆O ₃(MH) ⁺LC/MS (ESI) value of calculation 411.2; Measured value 411.4.

Embodiment 8

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-isopropoxy-phenyl)-urea

A.[1-(6-amino-5-formoxyl-pyrimidine-4-yl)-pyrrolidine-3-yl] the carbamic acid tertiary butyl ester

Toward 4-amino-(239mg is 1.52mmol) at CH for 6-chloro-pyrimidine-5-formaldehyde ₃Add in the suspension among the CN (2mL) 3-(tert-butoxycarbonyl amino) pyrrolidine (312mg, 1.67mmol), add subsequently DIEA (392.9mg, 3.04mmol).This mixture was stirred 1 hour in 90 times.It is cooled to room temperature, leaches precipitation subsequently, use CH ₃CN washing, vacuum drying obtains the product (290.6mg, 62.2%) of white solid.

¹H NMR(DMSO-d ₆)δ9.92(s，1H)，8.58(br，1H)，7.95(s，1H)，7.68(br，1H)，7.22(d，J＝6.16Hz，1H)，4.02(m，1H)，3.80(m，2H)，3.66(m，1H)，3.45(m，1H)，2.03(m，1H)，1.82(m，1H)，1.38(s，9H)；

C ₁₄H ₂₂N ₅O ₃(MH) ⁺LC/MS (ESI) value of calculation 308.2; Measured value 308.3.

B.4-amino-6-(3-amino-pyrrolidine-1-yl)-pyrimidine-5-O-methyl-formaldoxime trifluoroacetate

(290.6mg 0.945mmol) adds MeONH in the solution in MeOH (1.5mL) to the carbamic acid tertiary butyl ester toward [1-(6-amino-5-formoxyl-pyrimidine-4-yl)-pyrrolidine-3-yl] ₂(197.2mg 2.36mmol) and with this mixture stirred 0.5 hour down in 95 ℃ HCl.With its concentrating under reduced pressure, residue is at CH subsequently ₂Cl ₂And distribute between water.With extract drying (Na ₂SO ₄), evaporation obtains white foam shape thing, and it uses 50%TFA/CH ₂Cl ₂(10mL) handled 4 hours.Solvent removed in vacuo obtains title compound, and it need not purification and is directly used in next step reaction.

C ₁₀H ₁₆N ₆O (MH) ⁺LC/MS (ESI) value of calculation 237.1; Measured value 237.1.

C. (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester

Under of short duration ice bath, stirring, (9.06g is 60.0mmol) at CH toward the 4-isopropoxy aniline in about 1 minute ₂Cl ₂(120mL) and add in the solution in the pyridine (30mL) in batches chloro-carbonic acid 4-nitro phenyl ester (10.9g, 54.0mmol).After at room temperature stirring 1 hour, this homogeneous solution CH ₂Cl ₂(300mL) dilution, use subsequently 0.6M HCl (1 * 750mL) and 0.025MHCl (1 * 1L) washs.With organic layer drying (Na ₂SO ₄), concentrate, obtain the title compound (16.64g, 98%) of the solid, shaped of grey violet-white.

¹H NMR(CDCl ₃)δ8.31-8.25(m，2H)，7.42-7.32(m，4H)，7.25-7.20(m，2H)，6.93(br s，1H)，2.90(sep，J＝6.9Hz，1H)，1.24(d，J＝6.9Hz，6H).

C ₁₆H ₁₇N ₂O ₅(MH) ⁺LC/MS (ESI) value of calculation 317.1; Measured value 633.2 (2MH) ⁺

D.1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-isopropoxy-phenyl)-urea

Toward 4-amino-6-(3-amino-pyrrolidine-1-yl)-(69.2mg is 0.20mmol) at CH for pyrimidine-5-O-methyl-formaldoxime trifluoroacetic acid ₃Add in the suspension among the CN (1.5mL) (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester (62.4mg, 0.20mmol), add subsequently DIEA (102.4mg, 0.79mmol).This mixture was stirred 1 hour down in 95 ℃, be cooled to room temperature subsequently.Precipitation is leached, use CH ₃CN washing, vacuum drying subsequently obtains the product (54mg, 66%) of white solid.

¹HNMR(DMSO-d ₆)δ8.37(s，1H)，8.11(s，1H)，7.93(s，1H)，7.35(br，2H)，7.23(d，J＝8.99 Hz，2H)，6.77(d，J＝9.06 Hz，2H)，6.36(d，J＝6.32 Hz，1H)，4.47(m，1H)， 4.15(m，1H)，3.86(s，3H)，3.75(m，1H)，3.51-3.69(m，2H)，3.33(m，1H)，2.06(m，1H)，1.81(m，1H)，1.21(d，J＝6.01Hz，6H)；

C ₂₀(H ₂₈N ₇O ₃(MH) ⁺LC/MS (ESI) value of calculation 414.2; Measured value 414.3.

Embodiment 9

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-piperidines-1-base-phenyl)-urea

A. (4-piperidines-1-base-phenyl) carbamic acid 4-nitro-phenylester

Basically as preparation as described in the embodiment 8c, use 4-piperidines-1-base aniline and toluene solvant.Through quick silica gel column chromatography purification (hexane/EtOAc of 5: 2 → EtOAc → 9: 1 DCM/MeOH), obtain the pulverous target compound of Lycoperdon polymorphum Vitt (1.416g, 73%).

¹HNMR(CDCl ₃)δ8.31-8.25(m，2H)，7.42-7.36(m，2H)，7.34-7.28(m，2H)，6.97-6.90(m，2H)，6.82(br s，1H)，3.17-3.09(m，4H)，1.77-1.66(m，4H)，1.63-1.54(m，2H).

C ₁₈H ₁₉N ₃O ₄(MH ⁺) LC/MS (ESI) value of calculation 342.1; Measured value 342.2.

B.1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-piperidines-1-base-phenyl)-urea

As preparation as described in the embodiment 8d, difference is to use (4-piperidines-1-base-phenyl) carbamic acid 4-nitro-phenylester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.Title compound is a gray solid.

¹H NMR(DMSO-d ₆)δ8.37(s，1H)，8.03(s，1H)，7.93(s，1H)，7.36(s，2H)，7.18(d，J＝8.98Hz，2H)，6.80(d，J＝9.08Hz，2H)，6.32(d，J＝6.93Hz，1H)，4.14(m，1H)，3.86(s，3H)，3.76(m，1H)，3.62(m，2H)，3.38(m，1H)，2.98(t，J＝4.49H2，4H)，2.07(m，1H)，1.81(m，1H)，1.60(m，4H)，1.48(m，2H)；

C ₂₂H ₃₁N ₈O ₂(MH) ⁺LC/MS (ESI) value of calculation 439.3; Measured value 439.3.

Embodiment 10

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-morpholine-4-base-phenyl)-urea

A. (4-morpholine-4-base-phenyl) carbamic acid 4-nitro-phenylester

In air, on the ice bath, and 4-morpholino aniline (1.01g, 5.68mmol) and CaCO ₃(743mg, 7.42mmol) (1.49g is 7.39mmol) at CH with chloro-carbonic acid 4-nitro phenyl ester for the mixture of (10 microns powder) ₂Cl ₂Solution-treated (7.5mL).The reaction slurry of thickness, easily stirring was stirred on ice bath 1-2 minute, at room temperature stirred subsequently 1 hour.Subsequently with the CH of slurry with 9: 1 ₂Cl ₂/ MeOH (7.5mL) dilution loads on directly that (eluent is 95: 5 CH on the quick silicagel column ₂Cl ₂/ MeOH), obtain the 0.7g product.Be further purified by grinding, obtain title compound (444mg, 23%), be shallow pausiaceous powder with hot toluene (25mL).

¹H NMR(CDCl ₃)δ8.31-8.25(m，2H)，7.42-7.31(m，4H)，6.95-6.85(m，3H)，3.89-3.84(m，4H)，3.16-3.11(m，4H).

B.1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-morpholine-4-base-phenyl)-urea

As preparation as described in the embodiment 8d, difference is to use (4-morpholine-4-base-phenyl) carbamic acid 4-nitro-phenylester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.Title compound is light brown solid.

¹H NMR(DMSO-d ₆)δ8.37(s，1H)，8.07(s，1H)，7.93(s，1H)，7.35(s，2H)，7.21(d，J＝9.06Hz，2H)，6.82(d，J＝9.10Hz，2H)，6.33(d，J＝6.58Hz，1H)，4.15(m，1H)，3.86(s，3H)，3.75(m，1H)，3.71(t，J＝4.52Hz，4H)，3.52-3.69(m，2H)，3.33(m，1H)，2.98(t，J＝4.79Hz，4H)，2.06(m，1H)，1.81(m，1H)；

C ₂₁H ₂₉N ₈O ₃(MH) ⁺LC/MS (ESI) value of calculation 441.2; Measured value 441.2.

Embodiment 11

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(6-cyclobutoxy group-pyridin-3-yl)-urea

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

Under 0 ℃, with 2-chloro-5-nitropyridine (7.12g, 45.0mmol) and cyclobutanol (3.40g, 47.2mmol) the mixture vigorous stirring in THF (30mL), (1.18g 46.7mmol) (notes: a large amount of gases generations) simultaneously to add NaH in three batches second through about 10-20 under air atmosphere.The THF that reaction residue adds with other (5mL) washes, subsequently under the argon normal pressure, stir more than 1-2 minute in the ice bath.Remove ice bath subsequently and with the solution stirring of brown homogenizing 1 hour.Under 80 ℃,, toward wherein adding 0.75M EDTA (tetrasodium salt) (150mL), and use CH with the reactant mixture concentrating under reduced pressure ₂Cl ₂(1 * 100mL, 1 * 50mL) extraction.With the organic layer drying (Na that merges ₂SO ₄), concentrate, toward wherein add MeOH (2 * 100mL), subsequently at 60 ℃ of following concentrating under reduced pressure, obtain title product (7.01g, 80%), for heavy-gravity dark amber grease, leave standstill crystallization.

¹H NMR (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).

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

Slowly add MeOH (50mL) when with argon cleaning the flask of 10% weight Pd/C (485mg) being housed carefully along the flask edge, add 2-cyclobutoxy group-5-nitro-pyridine (4.85g, 25mmol) (as previous step preparation) solution in MeOH (30mL) (note: a large amount of adding volatile organic matters can catch fire in the Pd/C in the presence of air) with each about 5mL subsequently in batches.Subsequently once, subsequently at room temperature, H with this flask evacuation ₂Gasbag pressure stirred 2 hours down.Should react filtration subsequently, clarifying amber filtrate is concentrated, (2 * 50mL) remove remaining MeOH, and concentrating under reduced pressure obtains having the buttery rough title compound of translucent dark brown (4.41g) that faint toluene is distinguished the flavor of subsequently toward wherein adding toluene.

¹H NMR (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).

C ₉H ₁₃N ₂O (MH) ⁺LC/MS (ESI) value of calculation 165.1; Measured value 165.2.

C. (6-cyclobutoxy group-pyridin-3-yl) carbamic acid 4-nitro-phenylester

At room temperature, 6-cyclobutoxy group-pyridin-3-yl amine (4.41g, 25mmol) (as above step preparation) and CaCO ₃(3.25g, 32.5mmol) the disposable usefulness of the mixture of (10 microns powder) chloro-carbonic acid 4-nitro phenyl ester (5.54g, 27.5mmol) handle, and subsequently it stirred 2 hours by the homogeneous solution in toluene (28mL).This reactant mixture is directly loaded on the quick silicagel column (DCM/MeOH that eluent is 95: 5 DCM/MeOH → 9: 1) and obtain the 5.65g product, it is by (1 * 200mL) grinding is further purified with hot toluene, obtain title compound (4.45g, 54%).

¹HNMR(CDCl ₃)δ8.32-8.25(m，2H)，8.12(d，1H)，7.81(m，1H)，7.42-7.36(m，2H)，6.85(brs，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).

C ₁₆H ₁₅N ₃O ₅(MH ⁺) LC-MS (ESI) value of calculation 330.1; Measured value 330.1.

D.1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(6-cyclobutoxy group-pyridin-3-yl)-urea

As preparation as described in the embodiment 8d, difference is to use (6-cyclobutoxy group-pyridin-3-yl) carbamic acid 4-nitro-phenylester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.Title compound is a white solid.

¹H NMR (DMSO-d ₆) δ 8.37 (s, 1H), 8.22 (s, 1H), 8.05 (d, J=2.75Hz, 1H), 7.93 (s, 1H), 7.72 (dd, J=8.92 and 2.74Hz, 1H), 7.35 (br, 2H), 6.67 (d, J=8.80Hz, 1H), 6.51 (d, J=6.79 Hz, 1H), 5.02 (m, 1H), 4.16 (m, 1H), 3.86 (s, 3H), 3.75 (m, 1H), 3.51-3.69 (m, 2H), 3.33 (m, 1H), 2.35 (m, 2H), 1.92-2.12 (m, 3H), 1.71-1.86 (m, 2H), 1.60 (m, 1H);

C ₂₀H ₂₇N ₈O ₃(MH) ⁺LC/MS (ESI) value of calculation 427.2; Measured value 427.2.

Embodiment 12

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-isopropoxy-phenyl)-urea

A.[1-(6-amino-5-formoxyl-pyrimidine-4-yl)-piperidin-4-yl] the carbamic acid tertiary butyl ester

Toward 4-amino-6-chloro-pyrimidine-5-formaldehyde (226mg, 1.44mmol) and 4-(N-BOC amino)-piperidines (318mg is 1.59mmol) at CH ₃Add in the mixture among the CN (2mL) DIEA (372mg, 2.88mmol).This mixture is heated under 90 ℃ and stirred 1 hour, it is cooled to room temperature.Precipitation is leached, use CH ₃(3 * 5mL) washings, vacuum drying obtains white solid (400mg, 86%) to CN subsequently.

¹H NMR(DMSO-d ₆)δ9.66(s，1H)，8.22(br，1H)，8.03(s，1H)，7.77(br，1H)，6.91(d，J＝7.90Hz，1H)，3.99(m，2H)，3.54(m，1H)，3.18-3.29(m，2H)，1.79(m，2H)，1.40(m，2H)，1.38(s，9H)；

C ₁₅H ₂₄N ₅O ₃(MH) ⁺LC/MS (ESI) value of calculation 322.2; Measured value 322.2.

B.{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl } the carbamic acid tertiary butyl ester

Toward [1-(6-amino-5-formoxyl-pyrimidine-4-yl)-piperidin-4-yl] carbamic acid tertiary butyl ester (231.2mg, 0.72mmol) add in the mixture in MeOH (1.5mL) methoxy amine hydrochlorate (150.2mg, 1.80mmol).This solution was stirred 0.5 hour down in 95 ℃.With its concentrating under reduced pressure, residue is through quick purification by silica gel column chromatography (eluent: EtOAc), obtain the required product (180mg, 72%) of white solid.

¹H NMR (CDCl ₃) δ 8.10 (br, 2H), 8.09 (s, 1H), 8.06 (s, 1H), 6.95 (br, 1H), 4.07 (m, 2H), 3.96 (s, 3H), 3.74 (m, 1H), 3.23 (td, J=12.72 and 2.61Hz, 2H), 2.08 (m, 2H), 1.49 (m, 2H);

C ₁₆H ₂₇N ₆O ₃(MH) ⁺LC/MS (ESI) value of calculation 351.2; Measured value 351.3.

C.4-amino-6-(4-amino-piperadine-1-yl)-pyrimidine-5-O-methyl-formaldoxime trifluoroacetate

With 1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl } (180mg 0.51mmol) is dissolved in 15mL 50%TFA/CH to the carbamic acid tertiary butyl ester ₂Cl ₂In.At room temperature, it is kept stirring 4 hours, subsequently the pressure reducing and steaming organic solvent.Product need not to be further purified and is directly used in next step reaction.

¹H NMR(CD ₃OD)δ8.22(s，1H)，8.06(s，1H)，4.32(m，2H)，3.99(s，3H)，3.47(m，1H)，3.36(m，2H)，2.12(m，2H)，1.69(m，2H)；

C ₁₁H ₁₉N ₆O (MH) ⁺LC/MS (ESI) value of calculation 251.2; Measured value 251.2.

D.1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-isopropoxy-phenyl)-urea

Toward 4-amino-6-(4-amino-piperadine-1-yl)-(51.7mg is 0.14mmol) at CH for pyrimidine-5-O-methyl-formaldoxime trifluoroacetate ₃Add in the suspension among the CN (2mL) (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester (44.9mg, 0.14mmol), add subsequently DIEA (73.4mg, 0.57mmol).Under 95 ℃, this mixture was stirred 1 hour, be cooled to room temperature subsequently.Precipitation is leached, use CH ₃(3 * 1.5mL) washings, vacuum drying subsequently obtain the product (36mg, 59%) of white solid to CN.

¹H NMR(DMSO-d ₆)δ8.12(s，1H)，8.07(s，1H)，8.06(s，1H)，7.42(br，2H)，7.24(d，J＝9.05Hz，2H)，6.78(d，J＝8.98Hz，2H)，6.09(d，J＝7.54Hz，1H)，4.47(sep，J＝5.96Hz，1H)，3.89(s，3H)，3.69(m，1H)，3.60(m，2H)，3.06(t，J＝11.98Hz，2H)，1.86 (m，2H)，1.43(m，2H)，1.21(d，J＝6.02Hz，6H)；

C ₂₁H ₃₀N ₇O ₃(MH) ⁺LC/MS (ESI) value of calculation 428.2; Measured value 428.3.

Embodiment 13

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-piperidines-1-base-phenyl)-urea

Toward 4-amino-6-(4-amino-piperadine-1-yl)-(41.4mg is 0.12mmol) at CH for pyrimidine-5-O-methyl-formaldoxime trifluoroacetate ₃Add in the suspension among the CN (2mL) (4-piperidines-1-base-phenyl) carbamic acid 4-nitro-phenylester (40.4mg, 0.12mmol), add subsequently DIEA (61mg, 0.47mmol).Under 95 ℃, this mixture was stirred 1 hour and be cooled to room temperature.Precipitation is leached, use CH ₃(3 * 1.5mL) washings, vacuum drying subsequently obtain the product (26.8mg, 52%) of light gray solid shape to CN.

¹H NMR(DMSO-d ₆)δ8.07(s，1H)，8.06(s，1H)，8.04(s，1H)，7.41(br，2H)，7.19(d，J＝9.04Hz，2H)，6.81(d，J＝9.11Hz，2H)，6.06(d，J＝7.14Hz，1H)，3.90(s，3H)，3.68(m，1H)，3.61(m，2H)，3.06 (t，J＝11.03Hz.2H)，2.98(t，J＝5.05Hz，4H)，1.87(m，2H)，1.60(m，4H)，1.48(m，2H)；

C ₂₃H ₃₃N ₈O ₂(MH) ⁺LC/MS (ESI) value of calculation 453.3; Measured value 453.3.

Embodiment 14

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-morpholine-4-base-phenyl)-urea

Toward 4-amino-6-(4-amino-piperadine-1-yl)-(44.5mg is 0.13mmol) at CH for pyrimidine-5-O-methyl-formaldoxime trifluoroacetate ₃Add in the suspension among the CN (2mL) (4-morpholine-4-base-phenyl) carbamic acid 4-nitro-phenylester (43.6mg, 0.13mmol), add subsequently DIEA (65.7mg, 0.51mmol).Under 95 ℃, this mixture was stirred 1 hour, subsequently removal of solvent under reduced pressure.Rough residue obtains the required product (7.5mg, 13.4%) of white solid through preparation TLC plate purification (5%MeOH/EtOAc).

¹H NMR(DMSO-d ₆)δ8.08(s，1H)，8.07(s，1H)，8.06(s，1H)，7.42(br，2H)，7.23(d，J＝9.00Hz，2H)，6.83(d，J＝9.12Hz，2H)，6.07(d，J＝7.59Hz，1H)，3.89(s，3H)，3.71(t，J＝4.22Hz，4H)，3.67(m，1H)，3.61(m，2H)，3.06(t，J＝1.31Hz，2H)，2.98(t，J＝4.70Hz，4H)，1.86(m，2H)，1.44(m，2H)；

C ₂₂H ₃₁N ₈O ₃(MH) ⁺LC/MS (ESI) value of calculation 455.2; Measured value 455.3.

Embodiment 15

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(6-cyclobutoxy group-pyridin-3-yl)-urea

Toward 4-amino-6-(4-amino-piperadine-1-yl)-(50mg is 0.14mmol) at CH for pyrimidine-5-O-methyl-formaldoxime trifluoroacetate ₃Add in the suspension among the CN (2mL) (6-cyclobutoxy group-pyridin-3-yl) carbamic acid 4-nitro-phenylester (45.2mg, 0.14mmol), add subsequently DIEA (70.8mg, 0.55mmol).Under 95 ℃, this mixture was stirred 1 hour and be cooled to room temperature.Precipitation is leached, and (3 * 3mL) washings, vacuum drying subsequently obtain the product (31.5mg, 52.3%) of white solid with EtOAc.

¹H NMR (DMSO-d ₆) δ 8.24 (s, 1H), 8.07 (s, 1H), 8.06 (d, J=2.44Hz, 1H), 8.05 (s, 1H), 7.73 (dd, J=8.90 and 2.78Hz, 1H), 7.42 (br, 2H), 6.67 (d, J=8.76Hz, 1H), 6.25 (d, J=7.88Hz, 1H), 5.03 (m, 1H), 3.89 (s, 3H), 3.70 (m, 1H), 3.61 (m, 2H), 3.05 (m, 2H), 2.35 (m, 2H), 1.99 (m, 2H), 1.86 (m, 2H), 1.75 (m, 1H), 1.60 (m, 1H), 1.46 (m, 2H);

C ₂₁H ₂₉N ₈O ₃(MH) ⁺LC/MS (ESI) value of calculation 441.2; Measured value 441.3.

Embodiment 16

N-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-2-(4-isopropyl-phenyl)-acetamide

Toward 4-amino-6-(4-amino-piperadine-1-yl)-pyrimidine-5-O-methyl-formaldoxime trifluoroacetate (57.8mg, 0.16mmol) add (4-isopropyl-phenyl)-acetic acid (0.21mmol), HOBT (31.6mg in the suspension in anhydrous THF (2mL), 0.21mmol), add HBTU (78.5mg subsequently, 0.21mmol) and DIEA (102.8mg, 0.80mmol).This mixture stirred under room temperature spend the night, organic solvent is removed in decompression subsequently.This mixture stirred under room temperature spend the night, organic solvent is removed in decompression subsequently.Rough residue is through preparation TLC plate purification (eluent: EtOAc), obtain the required product (21.3mg, 32.6%) of white solid.

¹H NMR (CDCl ₃) δ 8.14 (s, 1H), 8.01 (s, 1H), 7.22 (d, J=8.29Hz, 2H), 7.15 (d, J=8.14Hz, 2H), 4.00 (m, 1H), 3.94 (s, 3H), 3.71 (m, 2H), 3.54 (s, 2H), 3.06 (td, J=12.36 and 2.32Hz, 2H), 2.91 (sep, J=7.07Hz, 1H), 1.94 (m, 2H), 1.38 (m, 2H), 1.25 (d, J=6.92Hz, 6H);

C ₂₂H ₃₁N ₆O ₂(MH) ⁺LC/MS (ESI) value of calculation 411.2; Measured value 411.3.

Embodiment 17

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-cyclohexyl-phenyl)-urea

A. (4-cyclohexyl-phenyl) carbamic acid 4-nitro-phenylester

Basically as preparation as described in the embodiment 8c, difference is to use 4-cyclohexyl aniline to replace the 4-isopropoxy 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-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-cyclohexyl-phenyl)-urea

Basically as preparation as described in the embodiment 8d, difference is to use (4-cyclohexyl-phenyl) carbamic acid 4-nitro-phenylester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.

¹H NMR(DMSO-d ₆)δ8.35(s，1H)，8.18(s，1H)，7.91(s，1H)，7.33(br，2H)，7.22(d，J＝8.58Hz，2H)，7.03(d，J＝8.56Hz，2H)，6.38(d，J＝6.58Hz，1H)，4.14(m，1H)，3.84(s，3H)，3.75(m，1H)，3.65(m，1H)，3.55(m，1H)，3.41(m，1H)，2.36(m，1H)，2.05(m，1H)，1.62-1.82(6H)，1.31(4H)，1.18(m，1H)；

C ₂₃H ₃₂N ₇O ₂(MH) ⁺LC/MS (ESI) value of calculation 438.3; Measured value 438.3.

Embodiment 18

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-chloro-phenyl)-urea

Basically as preparation as described in the embodiment 8d, difference is to use Carbimide. 4-chlorphenyl ester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.

¹H NMR(DMSO-d ₆)δ8.45(s，1H)，8.35(s，1H)，7.91(s，1H)，7.37(d，J＝8.93Hz，2H)，7.33(br，2H)，7.23(d，J＝8.92Hz，2H)，6.49(d，J＝6.52Hz，1H)，4.15(m，1H)，3.84(s，3H)，3.75(m，1H)，3.65(m，1H)，3.55(m，1H)，3.41(m，1H)，2.04(m，1H)，1.80(m，1H)；

C ₁₇H ₂₁ClN ₇O ₂(MH) ⁺LC/MS (ESI) value of calculation 390.1; Measured value 390.2.

Embodiment 19

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-phenoxy group-phenyl)-urea

Basically as preparation as described in the embodiment 8d, difference is to use Carbimide. 4-phenoxy group phenyl ester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.

¹H NMR(DMSO-d ₆)δ8.36(s，1H)，8.32(s，1H)，7.91(s，1H)，7.29-7.38(6H)，7.04(m，1H)，6.90(m，4H)，6.43(d，J＝6.57 H2，1H)，4.15(m，1H)，3.84(s，3H)，3.75(m，1H)，3.65(m，1H)，3.55(m，1H)，3.41(m，1H)，2.06(m，1H)，1.82(m，1H)；

C ₂₃H ₂₆N ₇O ₃(MH) ⁺LC/MS (ESI) value of calculation 448.2; Measured value 448.3.

Embodiment 20

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl] pyrrolidine-3-yl }-3-(4-pyrrolidine-1-base-phenyl)-urea

A. (4-pyrrolidine-1-base-phenyl) carbamic acid 4-nitro-phenyl ester salt hydrochlorate

At room temperature, in 4.9g (30.4mmol) 4-pyrrolidine-solution of 1-base-phenyl amine in the anhydrous THF of 70mL that stirs, drip the solution of 6.4g (32mmol) chloro-carbonic acid 4-nitro phenyl ester in the anhydrous THF of 16mL.After adding is finished, this mixture was stirred 1 hour subsequent filtration.This precipitation is at first used anhydrous THF, and (2 * 10mL) washings, (3 * 10mL) washings, vacuum drying obtains 10g off-white color solid to use anhydrous DCM subsequently.

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-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-pyrrolidine-1-base-phenyl)-urea

Basically as preparation as described in the embodiment 8d, difference is to use (4-pyrrolidine-1-base-phenyl) carbamic acid 4-nitro-phenylester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.

¹H NMR(DMSO-d ₆)δ 8.35(s，1H)，7.91(s，1H)，7.85(s，1H)，7.33(br，2H)，7.11(d，J＝8.96Hz，2H)，6.41(d，J＝9.02Hz，2H)，6.22(d，J＝6.62Hz，1H)，4.12(m，1H)，3.84(s，3H)，3.72(m，1H)，3.64(m，1H)，3.55(m，1H)，3.32(m，1H)，3.12(t，J＝6.54Hz，4H)，2.03(m，1H)，1.89(m，4H)，1.77(m，1H)；

C ₂₁H ₂₉N ₈O ₂(MH) ⁺LC/MS (ESI) value of calculation 425.2; Measured value 425.3.

Embodiment 21

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(6-cyclopentyloxy-pyridin-3-yl)-urea

A.2-cyclopentyloxy-5-nitro-pyridine

At 0 ℃ ice bath, stir under, in about 30 seconds toward 2-chloro-5-nitropyridine (7.01g, 44.4mmol) THF (30mL) and cyclopentanol (3.9g, 45.3mmol) add in the solution in batches sodium hydride (1.3g, 54.2mmol).After stirring 5 minutes under 0 ℃, remove ice bath, subsequently this is reacted under the room temperature and stirred 3 hours.With its vacuum concentration, residue is dissolved among the DCM also with a large amount of 1M NaHCO subsequently ₃Washing is with after anhydrous Na ₂SO ₄Drying is filtered and vacuum concentration.(silica gel, eluent are 9: 1 hexane to crude product: ethyl acetate), obtain pure 2-cyclopentyloxy-5-nitro-pyridine (0.4g, 4%) through the rapid column chromatography purification.

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

Toward the 2-cyclopentyloxy-(0.3099g 1.49mmol) adds 10%Pd/C (90mg) in the solution in MeOH (2mL) to 5-nitro-pyridine.With the degassing of this solution and under hydrogen atmosphere, keep stirring spending the night.It filters through Celite pad, with the filtrate evaporation, obtains the buttery required product of brown (248mg, 94% productive rate) subsequently.

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).

C ₁₀H ₁₄N ₂O LC/MS (ESI) value of calculation 178.23; Measured value [M+41+1] ⁺220.0.

C. (6-cyclopentyloxy-pyridin-3-yl) carbamic acid 4-nitro-phenylester

Toward 6-cyclopentyloxy-pyridin-3-yl amine (0.248g, 1.39mmol) add in the solution in THF (2mL) in batches chloro-carbonic acid 4-nitro phenyl ester (0.280g, 1.39mmol).After 1 hour, in organic layer, form a large amount of precipitations in stirring at room.Filter organic layer, obtain the title compound (0.368g, 77%) of baby pink solid, shaped.

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-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(6-cyclopentyloxy-pyridin-3-yl)-urea

Basically as preparation as described in the embodiment 8d, difference is to use (6-cyclopentyloxy-pyridin-3-yl) carbamic acid 4-nitro-phenylester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.

¹H NMR (CD ₃OD) δ 8.40 (s, 1H), 8.05 (d, J=2.76Hz, 1H), 7.91 (s, 1H), 7.68 (dd, J=8.88 and 2.80 Hz, 1H), 6.68 (d, J=8.89Hz, 1H), 5.22 (m, 1H), 4.31 (m, 1H), 3.92 (s, 3H), 3.88 (m, 1H), 3.78 (m, 1H), 3.68 (m, 1H), 3.50 (dd, J=11.12 and 4.45Hz, 1H), 2.19 (m, 1H), 1.88-1.99 (3H), 1.76 (m, 4H), 1.63 (m, 2H);

Embodiment 22

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-cyclohexyl-phenyl)-urea

Basically as preparation as described in the embodiment 12d, difference is to use (4-cyclohexyl-phenyl) carbamic acid 4-nitro-phenylester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.

¹H NMR(CDCl ₃)δ8.16(s，1H)，8.05(s，1H)，7.16(m，4H)，3.94(s，3H)，3.74(m，1H)，3.09(m，2H)，3.05(m，2H)，2.05(m，2H)，1.84(m，4H)，1.74(m，1H)，1.22-1.52(8H)；

C ₂₄H ₃₄N ₇O ₂(MH) ⁺LC/MS (ESI) value of calculation 452.3; Measured value 452.3.

Embodiment 23

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(6-cyclopentyloxy-pyridin-3-yl)-urea

Basically as preparation as described in the embodiment 12d, difference is to use (6-cyclopentyloxy-pyridin-3-yl) carbamic acid 4-nitro-phenylester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.

¹H NMR(DMSO-d ₆)δ8.21(br，1H)，8.07(m，1H)，8.05(s，1H)，8.04(s，1H)，7.69(m，1H)，7.40(br，1H)，6.63(d，J＝8.84Hz，1H)，6.22(d，J＝7.58Hz，1H)，6.23(m，1H)，3.87(s，3H)，2.98-3.70(6H)，1.81-1.89(4H)，1.38-1.68(8H)；

C ₂₂H ₃₁N ₈O ₃(MH) ⁺LC/MS (ESI) value of calculation 455.2; Measured value 455.4.

Embodiment 24

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-pyrrolidine-1-base-phenyl)-urea

Basically as preparation as described in the embodiment 12d, difference is to use (4-pyrrolidine-1-base-phenyl) carbamic acid 4-nitro-phenylester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.

¹H NMR(DMSO-d ₆)δ8.05(s，1H)，8.04(s，1H)，7.87(br，1H)，7.40(br，2H)，7.12(d，J＝9.10 Hz，2H)，6.42(d，J＝9.19 Hz，2H)，5.96 (m，1H)，3.87(s，3H)，2.80-3.68(9H)，1.90(m，4H)，1.84(m，2H)，1.41(m，2H)；

Embodiment 25

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-chloro-phenyl)-urea

Basically as preparation as described in the embodiment 12d, difference is to use Carbimide. 4-chlorphenyl ester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.

¹H NMR(DMSO-d ₆)δ 8.48(br，2H)，8.05(s，1H)，8.04(s，1H)，7.38(d，J＝9.00Hz，2H)，7.23(d，J＝9.00Hz，2H)，6.25(m，1H)，6.23(m，1H)，3.87(s，3H)，3.22-3.60(3H)，3.05(m，2H)，1.85(m，2H)，1.44(m，2H)；

C ₁₈H ₂₃ClN ₇O ₂(MH) ⁺LC/MS (ESI) value of calculation 404.2; Measured value 404.3.

Embodiment 26

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-phenoxy group-phenyl)-urea

Basically as preparation as described in the embodiment 12d, difference is to use Carbimide. 4-phenoxy group phenyl ester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.

¹H NMR(DMSO-d ₆)δ8.35(br，2H)，8.05(s，1H)，8.04(s，1H)，7.45(m，1H)，7.38(d，J＝8.94Hz，2H)，7.32(m，2H)，7.05(m，2H)，6.90(m，2H)，6.17(m，2H)，3.88(s，3H)，3.25-3.62(3H)，3.05(m，2H)，1.86(m，2H)，1.44(m，2H)；

C ₂₄H ₂₈N ₇O ₃(MH) ⁺LC/MS (ESI) value of calculation 462.2; Measured value 462.3.

Embodiment 27

1-(1-{6-amino-5-[(2-amino-ethyoxyl imido grpup)-methyl]-pyrimidine-4-yl }-pyrrolidine-3-yl)-3-(4-isopropyl-phenyl)-urea

(a) .1-[1-(6-amino-5-formoxyl-pyrimidine-4-yl)-pyrrolidine-3-yl]-3-(4-isopropyl-phenyl)-urea

(200mg 0.65mmol) is dissolved in 3mL 50%TFA/CH with [1-(6-amino-5-formoxyl-pyrimidine-4-yl)-pyrrolidine-3-yl] carbamic acid tertiary butyl ester ₂Cl ₂In, subsequently reactant mixture was stirred 1 hour.Remove and desolvate, residue is dissolved in CH again ₃Among the CN.Add in the above solution Carbimide. 4-isopropyl phenyl ester (125.7mg, 0.78mmol) and DIEA (336mg, 2.6mmol).After 1 hour, precipitation is leached, with EtOAc washing, vacuum drying subsequently obtains the required product of white solid.

¹H NMR(DMSO-d ₆)δ9.94(s，1H)，8.57(br，1H)，8.21(s，1H)，7.97(s，1H)，7.70(br，1H)，7.24(d，J＝8.56Hz，2H)，7.06(d，J＝8.54 Hz，2H)，6.42(d，J＝6.39Hz，1H)，4.19(m，1H)，3.88(m，1H)，3.66-3.80(m，2H)，3.48(m，1H)，2.77(m，1H)，2.10(m，1H)，1.86(m，1H)，1.13(d，J＝6.91Hz，6H)；

C ₁₉H ₂₅N ₆O ₂(MH) ⁺LC/MS (ESI) value of calculation 369.2; Measured value 369.3.

(b) .1-(1-{6-amino-5-[(2-amino-ethyoxyl imido grpup)-methyl]-pyrimidine-4-yl }-pyrrolidine-3-yl)-3-(4-isopropyl-phenyl)-urea

Basically as preparation as described in the embodiment le, use dichloride 1-[1-(6-amino-5-formoxyl-pyrimidine-4-yl)-pyrrolidine-3-yl]-3-(4-isopropyl-phenyl)-urea and 2-(ammonium oxygen base)-1-second ammonium (2-(ammoniooxy)-1-ethanaminium).

¹H NMR(CD ₃OD)δ8.48(s，1H)，7.91(s，1H)，7.23(d，J＝8.55 Hz，2H)，7.11(d，J＝8.68Hz，2H)，4.31(m，1H)，4.17(m，2H)，3.90(m，1H)，3.80(m，1H)，3.70(m，1H)，3.51(m，1H)，3.30(m，2H)，2.83(m，1H)，2.20(m，1H)，1.95(m，1H)，1.20(d，J＝6.93 Hz，6H)；

C ₂₁H ₃₁N ₈O ₂(MH) ⁺LC/MS (ESI) value of calculation 427.3; Measured value 427.3.

Embodiment 28

1-[1-(6-amino-5-{[2-(3-ethyl-urea groups)-ethyoxyl imido grpup]-methyl }-pyrimidine-4-yl)-pyrrolidine-3-yl]-3-(4-isopropyl-phenyl)-urea

Toward 1-(1-{6-amino-5-[(2-amino-ethyoxyl imido grpup)-methyl]-pyrimidine-4-yl }-pyrrolidine-3-yl)-(14.5mg is 0.034mmol) at CH for 3-(4-isopropyl-phenyl)-urea ₂Cl ₂Add in the solution (1.5mL) ethyl isocyanate (4.8mg, 0.068mmol).Precipitation is leached water, CH ₂Cl ₂Washing, vacuum drying obtains required product subsequently.

¹HNMR(DMSO-d ₆)δ8.38(s，1H)，8.20(s，1H)，7.92(s，1H)，7.33(br，1H)，7.24(d，J＝8.58 Hz，2H)，7.06(d，J＝8.52Hz，2H)，6.40(d，J＝6.66 Hz，1H)，5.90(t，J＝5.58Hz，1H)，5.85(t，J＝5.45Hz，1H)，4.16(m，1H)，4.02(m，2H)，3.75(m，1H)，3.66(m，1H)，3.57 (m，1H)，3.24-3.37(3H)，3.12(m，1H)，2.96(m， 2H)，2.76(m，1H)，2.04(m，1H)，1.80(m，1H)，1.13(d，J＝6.91 Hz，6H)，0.94(t，J＝7.15 Hz，3H)；

C ₂₄H ₃₆N ₉O ₃(MH) ⁺LC/MS (ESI) value of calculation 498.3; Measured value 498.4.

Embodiment 29

1-(1-{6-amino-5-[(2-morpholine-4-base-2-oxo-ethyoxyl imido grpup)-methyl]-pyrimidine-4-yl }-pyrrolidine-3-yl)-3-(4-isopropyl-phenyl)-urea

Basically as preparation as described in the embodiment 27b, difference is to use chlorination 4-[2-(ammonium oxygen base) acetyl group] morpholino is for dichloride 2-(ammonium oxygen base)-1-second ammonium.

¹H NMR(CD ₃OD)δ8.51(s，1H)，7.92(br，1H)，7.23(d，J＝8.65 Hz，2H)，7.11(d，J＝8.45 Hz，2H)，4.87(s，2H)，4.31(m，1H)，3.89(m，1H)，3.78(m，1H)，3.48-3.75(10H)，2.83(m，1H)，2.19(m，1H)，1.95(m，1H)，1.20(d，J＝6.92 Hz，6H)；

C ₂₅H ₃₅N ₈O ₄(MH) ⁺LC/MS (ESI) value of calculation 511.3; Measured value 511.3.

Embodiment 30

1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-isopropyl-phenyl)-urea

Basically as preparation as described in the embodiment 8d, difference is to use Carbimide. 4-isopropyl phenyl ester to replace (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenylester.

¹H NMR(DMSO-d ₆)δ 835(s，1H)，8.19(br，1H)，7.91(s，1H)，7.33(br，2H)，7.23(d，J＝8.59 Hz，2H)，7.06(d，J＝8.49Hz，2H)，6.38(d，J＝6.54 Hz，1H)，4.14(m，1H)，3.84(s，3H)，3.74(m，1H)，3.64(m，1H)，3.28-3.58(2H)，2.77(m，1H)，2.04(m，1H)，1.80(m，1H)，1.13(d，J＝6.91 Hz，6H)；

C ₂₀H ₂₈N ₇O ₂(MH) ⁺LC/MS (ESI) value of calculation 398.2; Measured value 398.3.

Biological activity

External test

For the biological activity of measuring chemical compound in the scope of the invention carries out following representational external test.They set forth the present invention with infinite form.

The inhibition illustration of FLT3 enzymatic activity, MV4-11 propagation and Baf3-FLT3 phosphorylation the specificity of FLT3 enzyme suppress and depend on the active cell processes of FLT3.FLT3, c-Kit and TrkB that the inhibition of Baf3 cell proliferation is used as chemical compound in the scope of the invention do not rely on Cytotoxic test.All embodiment show FLT3 kinases and the obvious and specific inhibition of FLT3-dependent cells response in the literary composition.Embodiment also shows the kinase whose specificity inhibition of TrkB and c-kit in the literary composition in enzyme assay.The compounds of this invention also is that cell is permeable.

FLT3 fluorescence polarization kinases is analyzed

For measuring the activity of The compounds of this invention in vitro kinase is measured, use following fluorescence polarization (FP) testing program to measure the inhibition in the separation kinases zone of people FLT3 receptor (a.a.571-993).FLT3 FP measures fluorescein-labeled phosphoeptide and the anti--phosphotyrosine antibody that comprises in the Panvera phosphoric acid-tyrosine-kinase enzyme reagent kit (Green) that is provided by Invitrogen has been provided.As FLT3 phosphorylation polyGlu ₄During Tyr, fluorescein-labeled phosphoeptide from anti--phosphotyrosine antibody by the polyGlu of phosphorylation ₄Tyr replaces, thereby has reduced the FP value.Under room temperature, following condition, the FLT3 kinase reaction was cultivated 30 minutes: 10nM FLT3571-993,20ug/mL polyGlu ₄Tyr, 150uM ATP, 5mM MgCl ₂, 1% chemical compound in DMSO.Adding EDTA stops kinase reaction.Add fluorescein-labeled phosphoeptide and anti--phosphotyrosine antibody, under room temperature, cultivated 30 minutes subsequently.

All data points are the meansigma methods of three duplicate samples.Suppress and IC ₅₀Data analysis GraphPad Prism uses multiparameter, S shape dosage-response (variable slope) equation to carry out nonlinear regression and fitting.Kinase inhibition IC ₅₀Expression relatively produces the chemical compound dosage that 50% kinase activity suppresses with DMSO solvent blank product.

C-Kit fluorescence polarization kinase assays

The compounds of this invention also is the c-Kit specific inhibitor.Select preferred formula I chemical compound as the c-Kit inhibitor, adopt following method to use the vitro kinase algoscopy to be determined at the inhibition in the separation kinases zone of people c-kit receptor in following fluorescence polarization (FP) testing program.Described c-kit measures fluorescein-labeled phosphoeptide and the anti--phosphotyrosine antibody that comprises in the Panvera phosphoric acid-tyrosine-kinase enzyme reagent kit (Green) that is provided by Invitrogen has been provided.As c-Kit phosphorylation polyGlu ₄During Tyr, fluorescein-labeled phosphoeptide from anti--phosphotyrosine antibody by the polyGlu of phosphorylation ₄Tyr replaces, and has therefore reduced the FP value.Under room temperature, following condition, the c-kit kinase reaction was cultivated 45 minutes: 1nM c-kit (ProQinase, lot number SP005), 100ug/mL polyGlu ₄Tyr, 50uM ATP, 5mM MgCl ₂, 1mM DTT, 0.01%Tween-20,1%DMSO or the chemical compound in 100nM Hepes, pH7.5.Adding EDTA stops kinase reaction.Add fluorescein-labeled phosphoeptide and anti--phosphotyrosine antibody, under room temperature, cultivated 30 minutes subsequently and read fluorescence polarization numerical value.All data points are the meansigma methods of three duplicate samples.Suppress and IC ₅₀Data analysis uses multiparameter, S shape dosage-response (variable slope) equation to carry out nonlinear regression and fitting with GraphPad Prism.Kinase inhibition IC ₅₀Expression relatively produces the chemical compound dosage that 50% kinase activity suppresses with DMSO solvent blank product.

TrkB fluorescence polarization kinase assays (TrkB IC ₅₀Data)

The compounds of this invention also is the TrkB specific inhibitor.Select preferred formula I chemical compound to implement following method as the TrkB inhibitor.Described TrkB measures fluorescein-labeled phosphoeptide and the anti--phosphotyrosine antibody that comprises in the Panvera phosphoric acid-tyrosine-kinase enzyme reagent kit (Green) that is provided by Invitrogen has been provided.As TrkB phosphorylation polyGlu ₄During Tyr, fluorescein-labeled phosphoeptide from anti--phosphotyrosine antibody by the polyGlu of phosphorylation ₄Tyr replaces, and has therefore reduced the FP value.Under room temperature, following condition, the TrkB kinase reaction was cultivated 30 minutes: 50nM TrkB (fresh, numbering 14-507M), 20ug/mL polyGlu ₄Tyr, 150uM ATP, 5mM MgCl ₂, 1% chemical compound in DMSO.Adding EDTA stops kinase reaction.Add fluorescein-labeled phosphoeptide and anti--phosphotyrosine antibody, under room temperature, cultivated 30 minutes subsequently.All data points are the meansigma methods of three duplicate samples.Suppress and IC ₅₀Data analysis GraphPad Prism uses multiparameter, S shape dosage-response (variable slope) equation to carry out nonlinear regression and fitting.Kinase inhibition IC ₅₀Expression relatively produces the chemical compound dosage that 50% kinase activity suppresses with DMSO solvent blank product.

The inhibition of MV4-11 and Baf3 cell proliferation

In order to estimate the cell usefulness of The compounds of this invention, the growth inhibiting leukaemia of being determined at of FLT3 specificity is a MV4-11 (ATCC numbering: carry out CRL-9591).The mll gene that the MV4-11 cell causes available from the 11q23 transposition is reset and with the children acute monocytic leukemia patient of FLT3-ITD sudden change (AML hypotype M4) (1,2).The MV4-11 cell does not have active FLT3ITD then can not to grow and survive.

By measuring the non-specific growth inhibited of The compounds of this invention, compare the selectivity that confirms The compounds of this invention with Baf3 (IL-3 dependence, muroid b-cell lymphoma cell system).

For the propagation inhibition of determination test chemical compound, use CellTiterGlo reagent (Promega) based on luciferase, it is based on the quantitatively total cell number of total cell ATP concentration.With MV4-11 and Baf3 cell separately with 10,000 cell inoculations in every hole in containing the 100ul RPMI medium of penicillin/streptomycin, 10%FBS and 1ng/ml GM-CSF or 1ng/ml IL-3.

Add diluted chemical compound liquid or 0.1%DMSO (solvent blank) in the cell and allow described cell under the standard cell lines growth conditions (37 ℃, 5%CO ₂) grew 72 hours.The determination of activity of in 50% blood plasma, growing for the MV4-11 cell, with cell with 10,000 cell inoculations in every hole (final volume 100 μ L) in 1: 1 mixture of somatomedin and human plasma.For measuring total cell growth, in each hole, add isopyknic CellTiterGlo reagent (according to supplier's description), and quantitative luminosity.(relative light unit RLU) is counted the quantitatively total cell growth of difference relatively with the fluorescence of the 3rd day (growth and/or compound treatment 72 hours) total cell number to the fluorescence counting of 0 day cell number.Hundred-percent growth inhibited is defined as 0 day RLU reading.Percent null suppression is defined as the RLU signal of 3 days DMSO solvents of growth regulation blank.All data points are the meansigma methods of the mensuration of three duplicate samples.Growth inhibiting IC ₅₀The dosage of the chemical compound that total cell growth 50% of the 3rd day DMSO solvent blank of expression generation suppresses.Suppress and IC ₅₀Data analysis GraphPad Prism uses multiparameter, S shape dosage-response (variable slope) equation to carry out nonlinear regression and fitting.

The inner polyphone of MV4-11 cellular expression FLT3 repeats sudden change, the FLT3 activity thereby its growth places one's entire reliance upon.Strong anti-MV4-11 cytoactive is a character required for the present invention.Otherwise, thereby the non-specific toxicity that the Baf3 cell proliferation is driven as test compound by cytokine IL-3 contrasts.All examples of compounds of the present invention show＜50% inhibition (not comprising data) at 3uM dosage, and this shows that described chemical compound does not have cytotoxicity and FLT3 is had good selectivity.

FLT3 receptor enzyme-linked immunosorbent assay based on cell

The specific cell that adopts following method to measure the inductive wild type FLT3 of FLT part phosphorylation suppresses: the Baf3FLT3 cell of overexpression FLT3 receptor is available from Dr.MichaelHeinrich (Oregon Health and Sciences University).Baf3 FLT3 cell line produces with wild type FLT3 stable transfection by parental generation Baf3 cell (the muroid B cell lymphoma system of dependent cells factor IL-3 growth).There is not IL-3 and existing under the FLT3 part with regard to energy for growth selection cell.

At 37 ℃, 5%CO ₂Middle Baf3 cell remains among the RPMI 1640 that contains 10%FBS, penicillin/streptomycin and 10ng/ml FLT part.Directly suppress and phosphorylation for measuring wild type FLT3 receptor active, developed similar method sandwich ELISA method (sandwich ELISA method) with other RTKs of research (3,4).With 200 μ L Baf3 FLT3 cells (1 * 10 ⁶/ mL) be seeded in the 96 hole dish of the RPMI 1640 that contains 0.5% serum and 0.01ng/mL IL-3 and cultivated 16 hours, cultivated 1 hour with chemical compound or DMSO solvent subsequently.Cell is used 100ng/mL Flt part (R﹠amp down in 37 ℃; D Systems, numbering 308-FK) handled 10 minutes.Cell is smashed, is washed and is dissolved in interpolation phosphatase (Sigma, numbering P2850) and 100ul lysis buffer (50mMHepes, 150mM NaCl, 10% glycerol, 1%Triton-X-100,10mM NaF, 1mMEDTA, the 1.5mM MgCl of protease inhibitor (Sigma, number P8340) ₂, the 10mM tetrasodium pyrophosphate) in.Lysate by clarifying at 4 ℃ of following 1000xg in centrifugal 5 minutes.Cell lysates is transferred to anti-FLT3 antibody (Santa Cruz, numbering sc-480) that scribbles the 50ng/ hole and the white wall 96 hole ELISA Plate of blocking with SeaBlock reagent (Pierce, numbering 37527) (Costar, numbering 9018).Lysate was cultivated 2 hours down in 4 ℃.Plate washs 3 times with the PBS/0.1%Triton-X-100 of every hole 200ul.Subsequently plate and HRP-bonded anti--1: 8000 diluent of phosphotyrosine antibody (Clone 4G10, UpstateBiotechnology, numbering 16-105) cultivated under room temperature 1 hour.PBS/0.1%Triton-X-100 with every hole 200ul washs 3 times with plate.Use Berthold microwell plate photometer to carry out signal detection with Super Signal Pico reagent (Pierce, numbering 37070) according to the description of manufacturer.All data points are the meansigma methods of three duplicate samples.In the presence of 0.1%DMSO contrast, total relative light unit (RLU) of Flt ligand stimulation FLT3 phosphorylation is defined as 0% to be suppressed and 100% inhibition is defined as total RLU of ground state lysate.Suppress and IC ₅₀Data analysis GraphPad Prism uses multiparameter, S shape dosage-response (variable slope) equation to carry out nonlinear regression and fitting.

The list of references of biological method

1.Drexler HG, The Leukemia-Lymphoma Cell Line Factsbook (Factsbook of leukemia-lymphoma cell line), Academic Pres:San Diego, CA, 2000.

2.Quentmeier H, Reinhardt J, Zaborski M, Drexler HG, FLT3mutations in acute myeloid leukemia cell lines (sudden change of FLT3 in acute myeloid leukemia cell line), Leukemia, in January, 2003,17:120-124.

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 ActivationELISA mmunsorbent Assay (transferring protein induced ErbB2 phosphorylation) by the analysis of high flux kinases receptors kinase linked immunosorbent assay, Analytical Biochemistry, 1996; 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-1receptor tyrosine kinase inhibitors (quantitatively, high flux is used to detect the development of colony-stimulating factor-1 receptor tyrosine kinase inhibitors based on the enzyme-linked immunosorbent assay analysis of cell), J Biochem Biophys Methods, 2004; 60:69-79.

Biological data

The FLT3 biological data

Representative compounds of the present invention active as shown in the table.All active units are μ M and have following excursion: FLT3 kinases: ± 10%; MV4-11 and Baf3-FLT3: ± 20%.

Numbering

Title

FLT3 kinases (μ M)

MV4-1 1(μM)

BaF3 ELISA (μM)

1	(4-isopropoxy-phenyl) carbamic acid 1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester	0.15	0.74	0.204
1		0.15	0.74	0.204	2	(4-isopropoxy-phenyl) carbamic acid 1-[6-amino-5-(ethyoxyl imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester	0.055	0.135	0.074
3	(4-isopropoxy-phenyl) carbamic acid 1-{6-amino-5-[(2-morpholine-4-base-ethyoxyl imido grpup)-methyl]-pyrimidine-4-yl }-the piperidin-4-yl ester	0.82	2.8	nd	2		0.055	0.135	0.074
3		0.82	2.8	nd	4	(4-isopropoxy-phenyl) carbamic acid 1-{6-amino-5-[(3-dimethylamino-propoxyl group imido grpup)-methyl]-pyrimidine-4-yl }-the piperidin-4-yl ester	0.3	1.4	0.345
5	(4-isopropyl-phenyl) carbamic acid 1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester	0.029	0.011	0.004	4		0.3	1.4	0.345
5		0.029	0.011	0.004	6	2-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-N-(4-isopropyl-phenyl)-acetamide	0.016	0.031	0.015
7	2-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-N-(4-isopropyl-phenyl)-acetamide	0.081	0.208	0.169	6		0.016	0.031	0.015
7		0.081	0.208	0.169	8	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-isopropoxy-phenyl)-urea	0.29	0.455	0.176
9	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-piperidines-1-base-phenyl)-urea	0.45	0.764	0.127	8		0.29	0.455	0.176

10	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-morpholine-4-base-phenyl)-urea	1.1	0.569	1.3
10		1.1	0.569	1.3	11	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(6-cyclobutoxy group-pyridin-3-yl)-urea	0.16	0.398	0.229
12	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-isopropoxy-phenyl)-urea	0.46	0.672	0.217	11		0.16	0.398	0.229
12		0.46	0.672	0.217	13	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-piperidines-1-base-phenyl)-urea	0.310	0.587	0.468
14	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-morpholine-4-base-phenyl)-urea	0.88	1.2	0.292	13		0.310	0.587	0.468
14		0.88	1.2	0.292	15	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(6-cyclobutoxy group-pyridin-3-yl)-urea	0.41	0.578	0.195
16	N-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-2-(4-isopropyl-phenyl)-acetamide	1.8	1.4	nd	15		0.41	0.578	0.195
16		1.8	1.4	nd	17	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-cyclohexyl-phenyl)-urea	＞10	0.386	0.299
18	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-chloro-phenyl)-urea	2.97	0.735	0.309	17		＞10	0.386	0.299

19	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-phenoxy group-phenyl)-urea	2.5	0.371	0.134
19		2.5	0.371	0.134	20	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-pyrrolidine-1-base-phenyl)-urea	4.5	0.491	0.299
21	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(6-cyclopentyloxy-pyridin-3-yl)-urea	4.5	0.249	0.099	20		4.5	0.491	0.299
21		4.5	0.249	0.099	22	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-cyclohexyl-phenyl)-urea	0.078	0.672	0.040
23	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(6-cyclopentyloxy-pyridin-3-yl)-urea	0.065	0.651	0.035	22		0.078	0.672	0.040
23		0.065	0.651	0.035	24	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-pyrrolidine-1-base-phenyl)-urea	0.198	1.1	nd
25	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-chloro-phenyl)-urea	0.034	0.890	0.078	24		0.198	1.1	nd
25		0.034	0.890	0.078	26	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-phenoxy group-phenyl)-urea	0.020	0.856	0.175
27	1-(1-{6-amino-5-[(2-amino-ethyoxyl imido grpup)-methyl]-pyrimidine-4-yl }-pyrrolidine-3-yl)-3-(4-isopropyl-phenyl)-urea	＞10	1.7	nd	26		0.020	0.856	0.175

28	1-[1-(6-amino-5-{[2-(3-ethyl-urea groups)-ethyoxyl imido grpup]-methyl }-pyrimidine-4-yl)-pyrrolidine-3-yl]-3-(4-isopropyl-phenyl)-urea	2.7	0.498	2.3
28		2.7	0.498	2.3	29	1-(1-{6-amino-5-[(2-morpholine-4-base-2-oxo-ethyoxyl imido grpup)-methyl]-pyrimidine-4-yl }-pyrrolidine-3-yl)-3-(4-isopropyl-phenyl)-urea	1.2	0.856	2.4
30	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-isopropyl-phenyl)-urea	4.7	0.209	nd	29		1.2	0.856	2.4

The TrkB biological data

Representative compounds of the present invention active as shown in the table.All active units are μ M and have following excursion: TrkB IC ₅₀: ± 10%.

Numbering	Title	TrkB IC ₅₀ M
Numbering	Title	TrkB IC ₅₀ M	1	(4-isopropoxy-phenyl) carbamic acid 1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester	29.4
2	(4-isopropoxy-phenyl) carbamic acid 1-[6-amino-5-(ethyoxyl imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester	＞42	1		29.4
2		＞42	3	(4-isopropoxy-phenyl) carbamic acid 1-{6-amino-5-[(2-morpholine-4-base-ethyoxyl imido grpup)-methyl]-pyrimidine-4-yl }-the piperidin-4-yl ester	＞42
4	(4-isopropoxy-phenyl) carbamic acid 1-{6-amino-5-[(3-dimethylamino-propoxyl group imido grpup)-methyl]-pyrimidine-4-yl }-the piperidin-4-yl ester	＞42	3		＞42

5	(4-isopropyl-phenyl) carbamic acid 1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester	23.9
5		23.9	6	2-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-N-(4-isopropyl-phenyl)-acetamide	0.3
7	2-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-N-(4-isopropyl-phenyl)-acetamide	2.16	6		0.3
7		2.16	8	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-isopropoxy-phenyl)-urea	14.2
9	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-piperidines-1-base-phenyl)-urea	11.9	8		14.2
9		11.9	10	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(4-morpholine-4-base-phenyl)-urea	32.1
11	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-3-(6-cyclobutoxy group-pyridin-3-yl)-urea	4.2	10		32.1
11		4.2	12	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-isopropoxy-phenyl)-urea	8.5
13	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-piperidines-1-base-phenyl)-urea	2.9	12		8.5
13		2.9	14	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(4-morpholine-4-base-phenyl)-urea	15.6
15	1-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-3-(6-cyclobutoxy group-pyridin-3-yl)-urea	＞42	14		15.6
15		＞42	16	N-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-piperidin-4-yl }-2-(4-isopropyl-phenyl)-acetamide	7.4

The c-kit biological data

Representative compounds of the present invention active as shown in the table.All active units are nM and have following excursion: C-Kit IC50: ± 10%.

Numbering	Title	c-kit IC ₅₀nM
Numbering	Title	c-kit IC ₅₀nM	2	(4-isopropoxy-phenyl) carbamic acid 1-[6-amino-5-(ethyoxyl imido grpup-methyl)-pyrimidine-4-yl]-the piperidin-4-yl ester	380
6	2-{1-[6-amino-5-(methoxyl group imido grpup-methyl)-pyrimidine-4-yl]-pyrrolidine-3-yl }-N-(4-isopropyl-phenyl)-acetamide	16	2		380

Treatment/prevention method

Another aspect of the present invention, chemical compound of the present invention can be used for suppressing tyrosine kinase activity among cell or the experimenter (comprising Flt3 activity and/or c-kit activity and/or TrkB activity), or reduce kinase activity (comprising Flt3 activity and/or c-kit activity and/or TrkB activity), or be used for the treatment of among the experimenter with FLT3 and/or c-kit and/or TrkB kinase activity or express relevant disease.

In the embodiment aspect this, the invention provides a kind of method that reduces or suppress FLT3 in the cell and/or c-kit and/or TrkB kinase activity, described method comprises the step that described cell is contacted with formula I chemical compound.The present invention also provides a kind of method that reduces or suppress FLT3 among the experimenter and/or c-kit and/or TrkB kinase activity, and described method comprises the step that gives described experimenter's formula I chemical compound.The present invention further provides a kind of method that suppresses cell proliferation in the cell, described method comprises the step that described cell is contacted with formula I chemical compound.

Can measure the kinase activity of FLT3, c-kit among cell or the experimenter or TrkB, TrkB kinase assays described in c-kit kinase assays and the literary composition described in FLT3 kinase assays as described herein, the literary composition by method well-known in the art.

Used term " experimenter " is meant to animal, preferred mammal, the optimum of treatment, observation or subjects and chooses in the literary composition.

Used term " contact " is meant that adding chemical compound in the cell makes chemical compound be absorbed by cell in the literary composition.

In another embodiment aspect this, the invention provides to be used for the treatment of and exist (or being easy to) to develop into experimenter's the prevention and the Therapeutic Method of the risk of cell proliferative disorders or the disease relevant with FLT3 and/or c-kit and/or TrkB.

In one example, the invention provides prevention cell proliferative disorders that the experimenter suffers from or have the method for related disorders, described method to comprise to give the pharmaceutical composition of the prevention effective dose that the experimenter comprises formula I chemical compound and pharmaceutically acceptable carrier with FLT3 and/or c-kit and/or TrkB.Described preventive drug gives before can occurring at the symptom characteristic of cell proliferative disorders or the disease relevant with FLT3 and/or c-kit and/or TrkB, prevents disease or disease like this or has delayed the process of disease or disease.

In another example, the present invention relates to treat cell proliferative disorders that the experimenter suffers from or have the method for related disorders, described method to comprise to give the pharmaceutical composition of the treatment effective dose that the experimenter comprises formula I chemical compound and pharmaceutically acceptable carrier with FLT3 and/or c-kit and/or TrkB.Described curative gives in the time of can occurring at the symptom characteristic of these diseases, and described like this curative is treated as cell proliferative disorders or with the compensation of FLT3 and/or c-kit and/or TrkB associated conditions.

Term " prevention effective dose " is meant research worker, inhibition that veterinary, doctor or other clinicists sought or delays the reactive compound of experimenter's morbidity or the amount of medicine.

Used term in the literary composition " treatment effective dose " is meant the reactive compound of research worker, initiation experimenter biology that veterinary, doctor or other clinicists sought or medical response (it comprise alleviate the disease of curing the disease or disease symptoms) or the amount of medicine.

Determine that the treatment of pharmaceutical composition of the present invention and the method for prevention effective dose are known in the art.

Used term " compositions " is meant the product of the special component that comprises specified quantitative in the literary composition, and makes up any product that directly or indirectly produces by the special component of specified quantitative.

Used term in the literary composition " disease relevant with FLT3 " or " disease receptor related with FLT3 " or " disease relevant with the FLT3 receptor tyrosine kinase " are active relevant or relate to the disease of FLT3 activity (for example overactivity of FLT3) and the symptom of following these diseases with FLT3 with comprising.Term " overactivity of FLT3 " is meant 1) express at the FLT3 that does not express usually in the FLT3 cell; 2) by not expressing the FLT3 expression that the FLT3 cell produces usually; 3) not needing to cause the FLT3 that increases of cell proliferation to express; Or 4) cause the structural activatory sudden change of FLT3.The example of " disease relevant with FLT3 " comprises owing to unusual lot of F LT3 or FLT3 sudden change cause the disease that overstimulation FLT3 causes, or because the disease that unusual lot of F LT3 or FLT3 sudden change causing lot of F LT3 activity cause.The overactivity of known FLT3 involves the numerous disease pathogeny of (comprising cell proliferative disorders, neoplastic disease and following cancer).

Term " cell proliferative disorders " is meant the unwanted cells propagation of the hypotype of one or more cells in multicellular organisms, and it causes the infringement (promptly uncomfortable or minimizing life expectancy) of multicellular organism.Cell proliferative disorders can take place in dissimilar animal and humans.Example " cell proliferative disorders " as used herein comprises tumor and other cell proliferative disorders.

Used in the literary composition " neoplastic disease " is meant the tumor that unusual or uncontrolled cell growth causes.The neoplastic disease example comprises, but be not limited to the hemopoietic disease, for example myeloproliferative disorder such as thrombocytosis, primary thrombocytosis (ET), agnogenic myeloid metaplasia, myelofibrosis (MF), myelofibrosis companion bone marrow alienation are given birth to the preceding myelodysplastic syndrome of (MMM), chronic idiopathic myelofibrosis (IMF) and polycythemia vera (PV), cytopenia and deterioration; Cancer such as glioma, pulmonary carcinoma, breast carcinoma, colorectal carcinoma, carcinoma of prostate, gastric cancer, the esophageal carcinoma, colon cancer, cancer of pancreas, ovarian cancer; Comprise myelodysplasia, multiple myeloma, leukemia and lymphoma with hematologic malignancies.The hematologic malignancies example comprises, for example leukemia, lymphoma (Hodgkin lymphoma), the acute lymphoblastic leukemia (ALL) of Hodgkin (being also referred to as Hodgkin lymphoma) and myeloma-for example, acute myeloid leukaemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), CNL (CNL), the acute leukemia (AUL) of not breaking up, between become large celllymphoma (ALCL), prolymphocyte leukemia (PML), child's grain-unicellular leukemia (JMML), adult T-cell ALL, AML is hyperplasia unusual (AML/TMDS) with bone marrow three, mixed lineage leukemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disorder (MPD) and multiple myeloma (MM).

Other cell proliferative disorders examples comprise, but be not limited to atherosclerosis (Libby P, 2003, " Vascular biology of atherosclerosis:overview and state of theart (atherosclerotic blood vessel biology: the review of technology and present situation) ", Am J Cardiol91 (3A): 3A-6A); Transplant inductive vascular lesion (Helisch A, Schaper W, 2003, Arteriogenesis:the development and growth of collateral arteries (tremulous pulse generates: the generation of collateral artery and growth), Microcirculation, 10 (1): 83-97); Degeneration of macula (Holz FG etc., 2004, " Pathogenesis of lesiohs in lateage-related macular disease (pathogeny of damaging in the aged relevant macule disease) ", Am J Ophthalmol, 137 (3): 504-10); Neointimal hyperplasia and restenosis (Schiele TM etc., 2004, " Vascular restenosis-striving for therapy (vascular restenosis-striving for therapy) ", Expert Opin Pharmacother, 5 (11): 2221-32); Pulmonary fibrosis (Thannickal VJ etc., 2003, " Idiopathic pulmonary fibrosis:emerging concepts on pharmacotherapy (idiopathic pulmonary fibrosis: the emerging notion of pharmacotherapy) ", Expert Opin Pharmacother, 5 (8): 1671-86); Glomerulonephritis (Cybulsky AV, 2000, " Growth factor pathways in proliferativeglomerulonephritis (the somatomedin approach in the hypertrophy glomerulonephritis) ", CurrOpin Nephrol Hypertens, 9 (3): 217-23); Glomerulosclerosis (Harris RC etc., 1999, " Molecular basis of injury and progression in focalglomerulosclerosis (molecular basis of damage and process in the FGS) ", Nephron, 82 (4): 289-99); Renal hypoplasia and renal fibrosis (WoolfAS etc., 2004, " Evolving concepts in human renal dysplasia (unfolded notion in people's renal hypoplasia ", J Am Soc Nephrol, 15 (4): 998-1007); Diabetic retinopathy (Grant MB etc., 2004, " The role of growth factors in the patho genesis ofdiabetic retinopathy (effect of somatomedin in the diabetic retinopathy pathogeny) ", Expert Opin Investig Drugs, 13 (10): 1275-93) and rheumatoid arthritis (Sweeney SE, Firestein GS, 2004, Rheumatoid arthritis:regulationof synovial inflammation (rheumatoid arthritis: the adjusting of synovial fluid inflammation), Int JBiochem Cell Biol, 36 (3): 372-8).

Used term in the literary composition " disease relevant with TrkB " or " disease receptor related with TrkB " or " disease relevant with the TrkB receptor tyrosine kinase " are active relevant or relate to the disease of TrkB activity (for example overactivity of TrkB) and the symptom of following these diseases with TrkB with comprising.Term " overactivity of TrkB " is meant 1) express at the TrkB that does not express usually in the TrkB cell; 2) by not expressing the TrkB expression that the TrkB cell produces usually; 3) not needing to cause the TrkB that increases of cell proliferation to express; Or 4) causing adhering to the TrkB that increases that does not rely on cell survival expresses; 5) cause the structural activatory sudden change of TrkB.The example of " disease relevant with TrkB " comprises 1) owing to unusual a large amount of TrkB or TrkB sudden change causes the disease that overstimulation TrkB causes, or 2) because the disease that a large amount of TrkB activity that unusual a large amount of TrkB or TrkB sudden change cause cause.

The disease relevant with TrkB comprises many diseases, comprise cancer as, but be not limited to neuroblastoma, wilms' tumor, breast carcinoma, colon cancer, carcinoma of prostate and pulmonary carcinoma.See Brodeur GM for example, (2003), " Neuroblastoma:biological insights into aclinical enigma (neuroblastoma: see clearly clinical fan's biology) ", NatRevCancer, 3 (3): 203-16; Eggerl A etc., (2001), " Expression of theneurotrophin receptor TrkB is associated with unfavorable outcome inWilms ' tumor (expression of neurotrophic factor acceptor TrkB is relevant with wilms' tumor deterioration result) ", J Clin Oncol, 19 (3): 689-96; Descamps S etc., (2001), " Nervegrowth factor stimulates proliferation and survival of human breast cancercells through two distinct signaling pathways (nerve growth factor stimulates human breast cancer cell propagation and survival by two kinds of different signal pathways) ", J Biol Chem, 276 (21): 17864-70; BardelliA etc., (2003), " Mutational analysis ofthetyrosine kinome in colorectal cancers (mutation analysis of tyrosine kinase group in the colorectal carcinoma) ", Science 300 (5621): 949; Weeraratna AT etc., (2000), " Rationalbasis for Trk inhibition therapy for prostate cancer (the Trk suppression therapy is used for the reasonability basis of prostate cancer therapy) ", Prostate 45 (2): 140-8,19 (3): 689-96; Ricci etc., (2001), " Neurotrophins and neurotrophin receptors in humanlung cancer (neurotrophic factor and neurotrophic factor acceptor in people's pulmonary carcinoma) ", Am JRespir Cell Mol Biol, 25 (4): 439-46.

Used term in the literary composition " disease relevant with c-kit " or " disease receptor related with c-kit " or " disease relevant with the c-kit receptor tyrosine kinase " are active relevant or relate to the disease of c-kit activity (for example overactivity of c-kit) and the symptom of following these diseases with c-kit with comprising.Term " overactivity of c-kit " is meant 1) express at the c-kit that does not express usually in the c-kit cell; 2) by not expressing the c-kit expression that the c-kit cell produces usually; 3) not needing to cause the c-kit that increases of cell proliferation to express; Or 4) cause the structural activatory sudden change of c-kit.Comprise owing to unusual a large amount of c-kit or c-kit sudden change causes the disease that overstimulation c-kit causes with the example of " disease that c-kit is relevant ", or because unusual a large amount of c-kit or c-kit sudden change cause the disease that a large amount of c-kit activity cause.

The disease relevant with c-Kit comprises a large amount of diseases, as mastocytosis, mast cell leukemia, gastrointestinal stromal tumor, nasal sinuses natural killer cell/T-cell lymphoma, spermocytoma, dysgerminoma, thyroid carcinoma; Small cell lung cancer, malignant melanoma, adenoid cystic carcinoma, ovarian cancer, acute myelogenous leukemia, primary cutaneous type, angiosarcoma, carcinoma of endometrium, department of pediatrics T-cell ALL, lymphoma, breast carcinoma and carcinoma of prostate.See Heinrich, Michael C etc., summary document: Inhibition of KIT Tyrosine KinaseActivity:A Novel Molecular Approach to the Treatment ofKIT-Positive Malignancies (inhibition of KIT tyrosine kinase activity: the recruit of the positive malignant tumor of treatment KIT learns method).

In other embodiments aspect this, the present invention includes the therapeutic alliance of treatment or prevention cell proliferative disorders that the experimenter suffers from or the disease generation relevant with FLT3 and/or c-kit and/or TrkB.Therapeutic alliance comprises formula I chemical compound and one or more cell proliferations treatment (comprising chemotherapy, radiotherapy, gene therapy and immunization therapy) that gives experimenter's treatment or prevention effective dose.

In an embodiment of the present invention, The compounds of this invention can give with chemotherapy combined.Used chemotherapy is meant the treatment that comprises chemotherapeutic in the literary composition.Can use different chemotherapeutic in the disclosed in the text combinational therapeutic methods.Exemplary chemotherapeutic includes, but are not limited to: platinum compounds (for example cisplatin, carboplatin, oxaliplatin); Taxane compounds (for example paclitaxel, docetaxel); Comptothecin compounds (according to for upright health, hycamtin); Vincaleucoblastine (for example vincristine, vinblastine, vinorelbine); Antitumor nucleoside derivates (for example 5-fluorouracil, folinic acid, gemcitabine, capecitabine); Alkylating agent (for example cyclophosphamide, carmustine, lomustine, plug are for group); Epipodophyllotoxin/podophyllotoxin (for example etoposide, teniposide); Aromatase inhibitor (for example Anastrozole, letrozole, exemestane); Estrogen antagonist chemical compound (for example tamoxifen, fulvestrant), antifol (for example premetrexed disodium); Hypomethylation agent (hypomethylating agents) (for example azacitidine); Biological product (for example gemtuzumab, Cetuximab, Rituximab, pertuzumab, trastuzumab, bevacizumab, erlotinib); Antibiotic/anthracycline antibiotics (for example idarubicin, actinomycin D, bleomycin, daunorubicin, amycin, ametycin, actinomycin D, Carubicin, daunomycin); Antimetabolite (for example aminopterin, clofazimine, cytosine arabinoside, methotrexate); Microtubule bonding agent (for example combretastatin, colchicine, nocodazole); Topoisomerase suppresses body (for example camptothecine).Other useful medicines comprise verapamil, calcium ion antagonist, and these medicines are found with the antineoplastic agent binding energy and set up chemosensitivity effectively and bring into play the lateral reactivity of these medicines in the medicaments insensitive tumor in the tumor cell of anti-chemotherapeutic.See SimpsonWG, The calcium channel blocker verapamil and cancerchemotherapy (chemotherapy of calcium ion channel blocker verapamil and cancer), CellCalcium, in December, 1985; 6 (6): 449-67.In addition, will occur effectively and The compounds of this invention is united the chemotherapeutic of use.

In another embodiment of the present invention, The compounds of this invention can be united with radiotherapy and given.Used in the literary composition " radiotherapy " is meant and comprises the treatment that the experimenter of these treatments of needs is exposed to lonizing radiation.These treatments are well known to those skilled in the art.Radiocurable suitable flow process will be similar with the flow process used in the clinical treatment, wherein said radiotherapy can use separately or with other chemotherapy couplings.

In another embodiment of the present invention, The compounds of this invention can be united with gene therapy and given.Used in the literary composition " gene therapy " is meant that targeting participates in the treatment of the specific gene of tumor development.Possible strategies in gene therapy comprise the cell transduction of antisense DNA of gene of repair-deficiency tumor suppressor gene, corresponding coding somatomedin and receptor thereof or transfection, based on the strategy of RNA such as ribozyme, RNA bait, antisense messenger RNAs and siRNA (siRNA) molecule and so-called ' suicide gene '.

In another embodiment of the present invention, The compounds of this invention can be united with immunization therapy and given.Used in the literary composition " immunization therapy " is meant the treatment that participates in the specified protein of tumor development by these proteinic specific antibody targeting.For example in treatment of cancer, used the anti-vascular endothelial growth factor monoclonal antibody.

If except that The compounds of this invention, use second kind of medicine, then two kinds of medicines can any order continuously, almost give (for example to cut apart or the administration of entire combination thing) at one time simultaneously, or give by the separate administration scheme.In one situation of back, two kinds of chemical compounds gave in a period of time, and the amount of being given and mode are enough to guarantee to obtain effectively or synergism.Should be understood that the dosage separately of preferred medication and order and each composition of administering drug combinations and scheme will depend on and the concrete chemotherapeutic of The compounds of this invention coupling, its route of administration, the concrete tumor of being controlled, the concrete host who is controlled.

As one of ordinary skill in the understanding, be similar to usually or be less than the dosage that in clinical treatment, has used at the dosage of suitable chemotherapeutic, wherein chemotherapeutic give separately or with other chemotherapeutic couplings.

The technology of the present invention personnel can easily use conventional method and consider that given information in the literary composition determines the best approach and order, dosage and the scheme of administration.

Only be example, platinum compounds is preferably with every square metre of body surface area 1-500mg (mg/m ²) dosage give 50-400mg/m for example ², cisplatin per course of treatment is with per course of treatment of about 75mg/m particularly ²With carboplatin with per course of treatment of about 300mg/m ²Dosage give.Cisplatin is oral not to be absorbed, therefore must be in vein, subcutaneous, tumor or peritoneal injection give.

Only be example, taxane compounds is preferably with every square metre of body surface area 50-400mg (mg/m ²) dosage give 75-250mg/m for example ², paclitaxel is with per course of treatment of about 175-250mg/m particularly ²With Docetaxel with per course of treatment of about 75-150mg/m ²Dosage give.

Only be example, Comptothecin compounds is preferably with every square metre of body surface area 0.1-400mg (mg/m ²) dosage give 1-300mg/m for example ², irinotecan is with per course of treatment of about 100-350mg/m particularly ²With hycamtin with per course of treatment of about 1-2mg/m ²Dosage give.

Only be example, vincaleucoblastine is preferably with every square metre of body surface area 2-30mg (mg/m ²) dosage give, vinblastine per course of treatment is with per course of treatment of about 3-12mg/m particularly ², vincristine is with per course of treatment of about 1-2mg/m ²And vinorelbine is with per course of treatment of about 10-30mg/m ²Dosage give.

Only be example, the antitumor nucleoside derivates is preferably with every square metre of body surface area 200-2500mg (mg/m ²) dosage give 700-1500mg/m for example ²5-fluorouracil (5-FU) is usually with 200-500mg/m ²The dosage range vein of (preferred 3-15mg/kg/ days) gives.Gemcitabine is preferably with per course of treatment of about 800-1200mg/m ²Dosage give with capecitabine preferably with per course of treatment of about 1000-2500mg/m ²Dosage give.

Only be example, alkylating agent is preferably with every square metre of body surface area 100-500mg (mg/m ²) dosage give 120-200mg/m for example ², cyclophosphamide is with per course of treatment of about 100-500mg/m particularly ²Dosage, chlorambucil is with the dosage of per course of treatment of about 0.1-0.2mg/kg body weight, carmustine is with per course of treatment of about 150-200mg/m ²Dosage and lomustine with per course of treatment of about 100-150mg/m ²Dosage give.

Only be example, podophyllotoxin derivative is preferably with every square metre of body surface area 30-300mg (mg/m ²) dosage give 50-250mg/m for example ², etoposide is with per course of treatment of about 35-100mg/m particularly ²Dosage and teniposide with per course of treatment of about 50-250mg/m ²Dosage give.

Only be example, anthracycline derivatives is preferably with every square metre of body surface area 10-75mg (mg/m ²) dosage give 15-60mg/m for example ², amycin is with per course of treatment of about 40-75mg/m particularly ²Dosage, daunorubicin is with per course of treatment of about 25-45mg/m ²Dosage, idarubicin is with per course of treatment of about 10-15mg/m ²Dosage give.

Only be example, the estrogen antagonist chemical compound preferably with every day about 1-100mg dosage give, this depends on concrete medicine and the disease of curing the disease.Tamoxifen is preferably with dosage twice oral administration every day of 5-50mg, preferred 10-20mg, continues enough to treat for a long time to obtain and keep therapeutic effect.Toremifene is preferably with the dosage of about 60mg oral administration once a day, continues enough to treat for a long time to obtain and keep therapeutic effect.Anastrozole is preferably with the dosage of about 1mg oral administration once a day.Droloxifene is preferably with the dosage of about 20-100mg oral administration once a day.Raloxifene is preferably with the dosage of about 60mg oral administration once a day.Exemestane is preferably with the dosage of about 25mg oral administration once a day.

Only be example, biological product are preferably with every square metre of about 1-5mg (mg/m of body surface area ²) dosage give, or give by dosage known in the art if any difference.For example trastuzumab is preferably with per course of treatment of 1-5mg/m ²2-4mg/m particularly ²Dosed administration.

Dosage can for example per course of treatment once, twice or repeatedly give, it can repeat for example per 7,14,21 or 28 days.

But the The compounds of this invention whole body is vein, oral, subcutaneous, intramuscular, Intradermal or parenteral administration experimenter for example.But The compounds of this invention is the topical administration experimenter also.The non-limiting example of local medicine-applying system comprises the intraluminal medical device use of (comprising that intravascular administration conduit, wires, pharmacology's support and intracavity apply film).The compounds of this invention also can be united targeted drug and be given the experimenter to obtain the high local concentrations of chemical compound at target position.In addition, for keeping described medicine or reagent and target tissue contact number hour to a few weeks longer, The compounds of this invention can be prepared into rapid release or slow releasing preparation.

The present invention also provides a kind of pharmaceutical composition, and described compositions comprises formula I chemical compound and pharmaceutically acceptable carrier.Described pharmaceutical composition can contain about 0.1mg-1000mg, preferably about 100-500mg chemical compound and can be made into any form that is fit to selected administering mode.

Term " pharmaceutically acceptable " is meant and ought suitably gives molecular entity and the compositions that animal, man-hour do not produce harmful, irritated or other untoward reaction.Use on the veterinary is included in the scope of the present invention equally and " pharmaceutically acceptable " preparation comprises dosage form clinical and/or that the veterinary uses.

Carrier comprises essential and inert pharmacy adjuvant, includes but not limited to binding agent, suspending agent, lubricant, correctives, sweeting agent, antiseptic, dyestuff and coating material.The compositions of suitable for oral administration administration comprises solid form such as pill, tablet, lozenge, capsule (comprise separately immediately and discharge, regularly discharge and sustained release forms), granule and powder and liquid form such as solution, syrup, elixir, Emulsion and suspensoid.The form that is used for the gastrointestinal tract external administration comprises sterile solution, Emulsion and suspensoid.

Pharmaceutical composition of the present invention also comprises the pharmaceutical composition of slow release The compounds of this invention.Described compositions comprises the carrier (being generally polymer support) and the chemical compound of the present invention of slow release.

The biodegradable carrier of slow release is that this area is well-known.These materials can form the granule that comprises one or more reactive compounds and under adapt circumstance (for example aqueous, acidity, alkalescence etc.) thus slow degrades/dissolves degrades/dissolves and discharge one or more reactive compounds herein in body fluid.These granules are preferably nanoparticle (be that diameter range is about 1-500nm, preferred diameter is about 50-200nm, and most preferred diameters is about 100nm).

The present invention also provides the method for preparing pharmaceutical composition of the present invention.Fully mix with pharmaceutical carriers as the formula I chemical compound of the active component medicine preparation technique according to routine, described carrier is adoptable multi-form, and this depends on the required dosage form of administration (for example oral or gastrointestinal tract is outer as intramuscular administration).In the compositions of preparation peroral dosage form, can use any common drug medium.Therefore, for liquid oral medicine (as suspensoid, elixir and solution), suitable carrier and additive comprise water, ethylene glycol, oils and fats, alcohols, correctives, antiseptic, coloring agent etc.; For solid orally ingestible (as powder, capsule, lozenge, soft capsule and tablet), suitable carrier and additive comprise starch, sucrose, diluent, granulating agent, lubricant, binding agent, disintegrating agent etc.Because it is easy to administration, tablet and capsule have been represented best oral dosage unit form, use the solid pharmaceutical carriers in this kind situation significantly.If desired, tablet can use standard technique sugar coating or enteric coating.For the gastrointestinal tract external administration, carrier generally includes sterilized water, though for for example hydrotropy or anticorrosionly also can comprise other compositions.Also injectable suspensions can be prepared, suitable liquid-carrier, suspending agent etc. can be used in this kind situation kind.For slow releasing preparation, usually at first with slow-released carrier (being generally high molecular carrier) and compound dissolution of the present invention or be dispersed in the organic solvent.Subsequently the organic solution that obtains is added to and obtain oil-in-water emulsion in the aqueous solution.Preferred described aqueous solution comprises one or more surfactants.Then organic solvent is evaporated the particulate colloidal suspensions that obtains containing slow-released carrier and The compounds of this invention from oil-in-water emulsion.

The literary composition every dosage unit of Chinese medicine compositions (for example tablet, capsule, powder, injection, teaspoonful etc.) contains the amount that discharges the necessary active component of above-mentioned effective dose.The literary composition every dosage unit of Chinese medicine compositions (for example tablet, capsule, powder, injection, suppository, teaspoonful etc.) contains about 0.01mg-200mg/kg body weight every day.Preferable range is the about 100mg/kg body weight of about 0.03-every day, and most preferred range is the about 10mg/kg body weight of about 0.05-every day.Described chemical compound can be according to 1-5 time relieve pain every day.But dosage can change according to the order of severity and the employed chemical compound of patient's demand, the disease of curing the disease.Can use and give every day or back-circulation (post-periodic) administration.

Preferred these compositionss are dosage unit form such as tablet, pill, capsule, powder, granule, aseptic injection with solution or suspending agent, metered aerosol or liquid spray, drop, ampoule, automatic injector assembly or suppository; , intranasal outer, Sublingual or rectally for oral, gastrointestinal tract, or for sucking or be blown into administration.Perhaps, described compositions can suit weekly or January single administration; For example can adopt the not dissolved salt of reactive compound such as the durative action preparation that caprate obtains intramuscular injection.For preparation solid composite (as tablet), main active is mixed the solid dosage forms that forms the uniform homogeneous blend that contains The compounds of this invention or its pharmaceutically acceptable salt with pharmaceutical carriers, described pharmaceutical carriers is for example conventional tablet composition such as corn starch, lactose, sucrose, sorbitol, Pulvis Talci, stearic acid, magnesium stearate, dicalcium phosphate or natural gum and other pharmacy diluent such as water.When the compositions of referring to prescription design is homogenizing, this means that active component is evenly dispersed in that described like this compositions can easily be divided into equal effectively dosage form (as tablet, pill and capsule) in the whole compositions.Subsequently the compositions of this solid prescription design is divided into the dosage forms unit of the above-mentioned type that contains the about 500mg of 0.1-active component of the present invention.But the tablet of new compositions or pill coating or mixing obtain the dosage form of long-acting advantage.For example described tablet or pill can comprise internal dose composition and outside dose components, and the latter is overlying on the former with the form of shell.Enteric layer that can be by being used to resist the gastric disintegrate with two compositions separately and allow internal component intactly enter duodenum or to postpone to discharge.Different materials can be used for these enteric layers or enteric coating, and these materials comprise a large amount of polymer acids and material such as Lac, the pure and mild cellulose acetate of acetyl group.

But the liquid form that is used for the fusion formula I chemical compound of oral or drug administration by injection comprises aqueous solution, the syrup of suitable flavoring, aqueous or oily suspensions and the flavoring Emulsion that contains edible oil (as Oleum Gossypii semen, Oleum sesami, Oleum Cocois or Oleum Arachidis hypogaeae semen) and elixir and similar pharmaceutical carriers.The suitable dispersant or the suspending agent that are used for waterborne suspension comprise synthetic and natural gum such as tragacanth, arabic gum, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin.Liquid form also can comprise synthetic and natural gum such as tragacanth, arabic gum, methylcellulose etc. in suitable flavoring suspending agent or dispersant.For the gastrointestinal tract external administration, what need is aseptic suspensoid and solution.When wishing intravenously administrable, then use the grade that contains suitable antiseptic usually to ooze preparation.

Best, formula I chemical compound can the single daily dose gives maybe total daily dose to be divided into and gives for 2,3 or 4 times every day.In addition, The compounds of this invention can the intranasal form administration, uses suitable intranasal administration device through the part, or through the administration of the well-known percutaneous patch of those of ordinary skills.For the form administration with the releasing medicine through skin penetration system, dosage gives to lasting rather than interruption in whole dosage regimen certainly.

For example, for the oral administration with tablet or capsule form, active pharmaceutical ingredient can mix with oral, nontoxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water etc.And as needs or essential, suitable binding agent, lubricant, disintegrating agent and coloring agent also can be blended in the described mixture.Suitable binding agent includes, but are not limited to starch, gelatin, natural saccharide (as glucose or β lactose), corn sweetener, natural and synthetic natural gum (as arabic gum, tragacanth) or enuatrol, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc.Disintegrating agent includes, but are not limited to starch, methylcellulose, agar, Bentonite, xanthan gum etc.

The daily dose of product of the present invention can change in 1-5000mg/ adult's every day wide region.For oral administration, preferred composition is to contain 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 the tablet form of the active component of 500mg, and dosage is regulated according to treatment patient's symptom.Effective amount of drug is generally the dosage level of the about 200mg/kg body weight of about 0.01mg/kg-every day.Especially, scope is the about 15mg/kg body weight of about 0.03-every day, and more particularly, the about 10mg/kg body weight of about 0.05-every day.Chemical compound of the present invention can be by up to every day 4 times or relieve pain more frequently, gives for 1-2 time preferred every day.

Those skilled in the art can easily determine the optimal dose that gives, and this dosage will change according to the particular compound of using, administering mode, formulation concentrations, administering mode and disease symptoms progress.In addition, treat the needs that the relevant factor of patient (comprise patient age, weight, recipe and give the time) will cause adjusting dosage with concrete.

The compounds of this invention can also the liposome transmission system form give, as small unilamellar vesicle, large unilamellar vesicle and multilamelar liposome.Liposome can be formed by different lipids; include but not limited to amphoteric lipid such as phosphoric acid lecithin, sphingomyelins, PHOSPHATIDYL ETHANOLAMINE, phosphatidylcholine, cuorin, Phosphatidylserine, phosphatidyl glycerol, phosphatidic acid, phosphatidylinositols, diacyl trimethyl ammonium propane, diacyl Dimethyl Ammonium propane and stearmide; neutral lipid such as triglyceride, and composition thereof.They can comprise cholesterol or can not contain cholesterol.

But The compounds of this invention is topical administration also.Can use any doser, apply film as intravascular administration conduit, wires, pharmacology's support and intracavity.The drug-supplying system that is used for this kind device can comprise the local infusion conduit, and its speed with administration person's control is transmitted medicine.

The invention provides a kind of medicament release device that comprises the The compounds of this invention of intraluminal medical device (preferred support) and therapeutic dose.

Term " support " is meant can be by any device of conduit conveying.The support routine is used to prevent because the vessel sealing that body abnormality (vascular tissue that causes as wound does not need inside growth) causes.It has usually and is fit to stay tubular, the extensible network that tube cavity alleviates obstruction.Support has the surface of contact internal chamber wall and exposes the surface of inner chamber.The surface of contact internal chamber wall is that the outer surface of pipe and the surface that exposes inner chamber are the inner surface of pipe.Described support can be polymer, metal or polymer and metal, and it may optionally be biodegradable.

Usually, support inserts inner chamber with non-unfolded form, automatic subsequently or original position expansion under the help of another device.Expansible conventional method is embedded with the revascularization air bag of conduit by use, expands in narrow blood vessel or body internal channel (body passageway) for making the gorge fracture relevant with the blood vessel wall component and this air bag of inner chamber broken and that obtain enlarging.Also can use as U.S.6 automatic stent described in 776,796 (Falotico etc.).Support with prevent that the complex of medicine, reagent or the chemical compound of inflammation and propagation from can provide the most effective treatment of vascularization postoperative restenosis.

The compounds of this invention can numerous method and is adopted any amount of biocompatible materials to blend to support or attached on the support.In an exemplary, described chemical compound directly blends in the polymer matrix, as the polymer Polypyrrole, subsequently it is coated in rack outer surface.Described chemical compound diffuses through polymer and disengages from substrate.This area describes support and the method for coated medicament on support in detail.In another exemplary, support at first applies the basal layer of the solution that contains described chemical compound, ethylene-be total to-vinylacetate and polybutyl methacrylate.Subsequently, the further coating of support only contains the skin of polybutyl methacrylate.Skin prevents that chemical compound release is too fast and enters peripheral organization as diffusion barrier.The thickness of skin or external coating has determined the speed that described medicine discharges from substrate.In WIPO publication No. WO9632907, U.S. publication No. 2002/0016625 and wherein disclosed list of references, describe support and painting method in detail.

The solution of The compounds of this invention and biocompatible materials/polymer can numerous modes be blended in the support or be combined on the support.For example described solution is sprayed on the support and maybe support can be immersed in the described solution.In a preferred embodiment, described solution is sprayed on subsequent drying on the support.In another exemplary, described solution electric charge extremely can be gone up and the support electric charge is extremely gone up opposite one one.In the method, described solution and support attract each other.In using this kind spraying method, can cut the waste also can obtain more manageable coating thickness.Chemical compound is preferably only attached to the outer surface that contacts a support of organizing.But,, can apply entire bracket for some chemical compounds.The dosage of support compound used therefor and control drug release polymer coating are important to drug effectiveness all.Described chemical compound preferably keeps at least 3 days extremely up to about 6 months or more on support, preferred 7-30 days.

Any amount of non-erosibility biocompatible polymer can with the The compounds of this invention coupling.Importantly different supports can use different polymer.For example above-mentioned ethylene-co-vinyl acetate and polybutyl methacrylate substrate and stainless steel stent no-float.Other polymer can more effectively use with the support of the formation of other materials (material such as the Nitinol that comprise performance super-elasticity matter).

It is responsible that restenosis forms the significant M ﹠ M of postoperative for coronary artery.The restenosis course of emergency comprises four processes that elastical retraction, thrombosis, neointimal hyperplasia and extracellular matrix are reinvented.Nearest several somatomedin is determined to be in and causes playing a role in the processes of restenosis.(see Schiele TM etc., 2004, " Vascular restenosis-striving fortherapy (vascular restenosis-striving for therapy) ", Expert Opin Pharmacother, 5 (11): 2221-32).And TrkB part BDNF and neurotrophic factor and TrkB are expressed by vascular smooth muscle cell and epithelial cell and (see Ricci A etc., 2003, " Neurotrophins and neurotrophin receptors in human pulmonaryarteries (neurotrophic factor in people's pulmonary artery and neurotrophic factor acceptor) ", J VascRes, 37 (5): 355-63; Also see Kim H etc., 2004, " Paracrine and autocrinefunctions ofbrain-derived neurotrophic factor (BDNF) and nerve growthfactor (NGF) in brain-derived endothelial cells (Brain Derived Neurotrophic Factor (BDNF) in the property epithelial cell of brain source and the paracrine and the autocrine function of nerve growth factor) ", J Biol Chem, 279 (32): 33538-46).In addition, TrkB can work in periphery angiogenesis and neointimal hyperplasia and (see Douma S etc. because of it can suppress anoikis with inhibition prolongation cell survival, 2004, " Suppression of anoikis and inductionof metastasis by the neurotrophic receptor TrkB (neurotrophic factor acceptor TrkB is to anoikis and shift inductive inhibition) ", Nature, 430 (7003): 1034-9).Therefore, using coating bracket to suppress TrkB with the back in coronary artery formation art is an effective therapeutic strategy.

Therefore, the invention provides a kind of treatment experimenter trouble and the related disorders method of (comprising restenosis in the blood vessel wall, neointimal hyperplasia or inflammation) is arranged with TrkB, described method comprises and gives the The compounds of this invention that the experimenter treats effective dose that described chemical compound is by intraluminal medical device such as support sustained release.

The method that intracoelomic cavity is introduced support is that the well-known and of the present invention support that scribbles described chemical compound preferably uses conduit to introduce.As one of ordinary skill in the understanding, method will change based on the position that support is implanted is little.Implant for crown support, the balloon catheter that will have support inserts coronary artery and support is placed on desired location.Airbag inflation launches support.When the support expansion, support contact internal chamber wall.In case lose heart air bag and remove in support location.Support keeps being loaded with the direct and direct position contacting in internal chamber wall surface of inner chamber contact surface of described chemical compound.Support implant as need can with the Anticoagulation Therapy coupling.

The optimum condition of the drug release that uses in support of the present invention can change because of used different local delivery of drug system and the character and the concentration of compound used therefor.Optimizable condition comprises for example compound concentration, release volume, rate of releasing drug, blood vessel wall thickness, contiguous turgor pressure, perforation quantity and size and drug release catheter air bag fitness.Can optimize the condition that suppresses smooth muscle cell proliferation at damage location, not take place like this because restenosis and the obstruction of artery of significance,,, or pass through the change of vascular resistance or intracavity diameter for example by the smooth muscle cell proliferation ability as measuring.Optimum condition can use conventional computational methods to determine based on the Research of Animal Model for Study data.

But other systems of selection that give The compounds of this invention can be by combining described chemical compound with targeted drug, described targeted drug targeting conjugate to the action site of expection is blood vessel epithelial cell or tumor cell.Can use antibody or non-antibody targeted drug.Because targeted drug interacts with the specificity that combines accordingly object, The compounds of this invention can or give and so on target position, more effectively treat described disease near target position place high local concentrations.

Antibody target medicine comprises that antibody or its antigen binding fragment are disconnected, but it is in conjunction with tumor cell, tumor vascular system or or the targeting or the enterable composition of mesenchyma stroma of tumors.Tumor cell, tumor vascular system or or " but targeting or enterable composition " of mesenchyma stroma of tumors be preferably surface expression, the surface is enterable or the composition of surface alignment.Antibody target medicine comprises that also antibody or its antigen binding fragment break, and it is in conjunction with the cellular content that is discharged by downright bad tumor cell.Preferred these antibody are that monoclonal antibody or its antigen binding fragment are disconnected; in can inducing permeable cell or exist, but there is not the insoluble intracellular antigen that maybe can not enter in it in the normal living cells of mammal outside in conjunction with one or more in all basically tumors and Normocellular cell ghosts.

Used term " antibody " refers to any immunoconjugator such as IgG, IgM, IgA, IgE, F (ab ') 2, monovalent fragments such as Fab ', Fab, Dab and genetic engineering antibody such as recombinant antibodies, humanized antibodies, bi-specific antibody etc. widely in the literary composition.Described antibody can be polyclone or monoclonal, though preferred monoclonal.Cell surface to any solid tumor type known in the art has that the wide range of antibody of immunologic opsonin is general (sees the US patent No. 5 that licenses to Thorpe etc., Summary Table on monoclonal antibodies for solidtumors in 855,866 (the summary table of the monoclonal antibody of solid tumor)).Preparation is known for those skilled in the art with the method for separating anti-tumour antibody.(see the US patent No. 5,855,866 that licenses to Thorpe etc. and license to the US patent No. 6,34,2219 of Thorpe etc.).

The technology for the treatment of partly conjugated binding antibody (is for example seen Amon etc. for well-known, " Monoclonal Antibodies For Immunotargeting Of Drugs In CancerTherapy (monoclonal antibody of oncotherapy Chinese medicine immunity targeting) ", MonoclonalAntibodies And Cancer Therapy, editors such as Reisfeld, the 243-56 page or leaf (AlanR.Liss, Inc.1985); Hellstrom etc., " Antibodies For Drug Delivery (antibody that is used for drug delivery) ", Controlled Drug Delivery (second edition), editors such as Robinson, the 623-53 page or leaf (Marcel Dekker, Inc.1987); Thorpe, " AntibodyCarriers Of Cytotoxic Agents In Cancer Therapy:A Review (summary of the antibody carrier of cytotoxic agent in treatment of cancer) ", Monoclonal Antibodies ' 84:Biological And Clinical Applications, editors such as Pinchera, 475-506 page or leaf (1985)).Also can use similar techniques that The compounds of this invention is connected with the non-antibody targeted drug.One skilled in the art will know that the method that maybe can determine to form conjugate with non-antibody targeted drug such as micromolecule, oligopeptide, polysaccharide or other polyanionic compounds.

Though anyly in blood, can all can be used for The compounds of this invention is connected with targeted drug by the stable bound fraction of appropriateness, preferably the interval base or the connecting key of biologically releasable key and/or selectivity cleavable." but release key biology " and " the interval base or the connecting key of selectivity cleavable " still has adequate stability in circulation, but only or preferentially under certain conditions promptly in certain environment or with the contacting of specific reagent in be releasable, cleavable or hydrolyzable.These keys comprise for example U.S. patent No. 5,474,765 and 5,762, disulfide bond described in 918 and three sulfide linkages and acid-sensitive sense key and comprise the U.S. patent No. 5,474,765 and 5,762, the peptide bond described in 918, ester bond, amido link, phosphodiester bond and glycosidic bond.These selectivitys discharge the feature of design and impel described chemical compound to continue to discharge from conjugate at the expection target position.

The invention provides a kind of pharmaceutical composition, described compositions comprise effective dose with bonded The compounds of this invention of targeted drug and pharmaceutically acceptable carrier.

The present invention also comprises the method for the disease (particularly tumor) that a kind of treatment and FLT3 and/or c-kit and/or TrkB are relevant, described method comprise give that the experimenter treats effective dose with the bonded formula I chemical compound of targeted drug.

When protein such as antibody or somatomedin or polysaccharide during as targeted drug, they preferably give with the Injectable composition form.The injectable antibody-solutions was injected into into vein, tremulous pulse or spinal fluid through 2 minutes to about 45 minutes in preferred 10-20 minute.In some cases, Intradermal and intracavity are preferably used in the tumor that is limited near the specific regional and/or specific body cavity of skin.In addition, can be used for being positioned at the tumor of brain in the sheath.

Depend on individuality, disease type, disease condition with the treatment effective dose of the bonded The compounds of this invention of targeted drug, give method and other clinical variables.Use can easily be determined effective dose available from the data of animal model.Before transferring clinical experiment to, lotus has the experimental animal of solid tumor through being usually used in optimizing suitable therapeutic dose.Known these models are quite reliable in prediction effective antitumor strategy.For example lotus has the mice of solid tumor to be widely used in the working range that preclinical test determines to have antitumor action and minimum toxicity curative.

Though pointed out principle of the present invention for setting forth the above description of the present invention by example is provided, be understood that enforcement of the present invention is included in interior all common variations, adjustment and/or the correction of scope of following claim and equivalent thereof.

Claims

1. the chemical compound of a following formula I and nitrogen oxide thereof, pharmaceutically acceptable salt, solvate, geometric isomer 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 chemical bond;

Z is NH, N (alkyl) or CH ₂

B is phenyl, heteroaryl or the condensed heteroaryl of 9-10 unit's benzene;

R ¹For:

Wherein n is 1,2,3 or 4;

2. the chemical compound of claim 1, wherein: R _wAnd R _xBe independently selected from hydrogen, alkyl, thiazolinyl, aralkyl or heteroarylalkyl, or R _wAnd R _xCan choose wantonly and form the 5-7 unit ring that is selected from following group together:

3. the chemical compound of claim 1, wherein: B is phenyl or heteroaryl.

4. the chemical compound of claim 3, wherein:

Q is 1 or 2; With

R ₃Be one or more substituent groups that independently are selected from following group: hydrogen, alkyl, alkoxyl, halogen, alkoxyl ether, hydroxyl, optional by R ₄The cycloalkyl that replaces, optional by R ₄The heteroaryl that replaces, optional by R ₄The heterocyclic radical that replaces ,-O (cycloalkyl), optional by R ₄The phenoxy group that replaces, optional by R ₄The heteroaryloxy that replaces, dialkyl amido or-SO ₂Alkyl.

5. the chemical compound of claim 4, wherein:

Z is NH or CH ₂With

R _aBe hydrogen, alkoxyl, optional by R ₅The heteroaryl that replaces, hydroxyl, amino, alkyl amino, dialkyl amido, optional by R ₅The  oxazolidone base that replaces, optional by R ₅The pyrrolidone-base that replaces, optional by R ₅The heterocyclic radical that replaces ,-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,-SO ₂R _y,-NR _wSO ₂R _yOr-SO ₂NR _wR _x

6. the chemical compound of claim 5, wherein:

Q is NH, O or chemical bond;

R ₅Be the substituent group that is selected from following group a :-C (O) alkyl ,-SO ₂Alkyl ,-C (O) N (alkyl) ₂, alkyl or-C _(1-4)Alkyl-OH; With

7. the chemical compound of claim 6, wherein:

B is phenyl or pyridine radicals;

R _aBe hydrogen, hydroxyl, amino, dialkyl amido, optional by R ₅The heterocyclic radical that replaces ,-CONR _wR _x,-N (R _y) CON (R _w) (R _x) or-NR _wSO ₂R _yWith

8. the chemical compound of claim 7, wherein:

R _wAnd R _xCan choose wantonly and form the 5-7 unit ring that is selected from following group together:

9. one kind is selected from following chemical compound:

10. one kind is selected from following chemical compound:

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

12. as each chemical compound among the claim 1-10 of medicine.

13. the purposes of each chemical compound in preparation treatment cell proliferative disorders medicine among the claim 1-10.

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

18. a method that reduces c-Kit kinase activity in the cell, described method comprise the step that described cell is contacted with the chemical compound of claim 1-10.

19. a method that suppresses c-Kit kinase activity in the cell, described method comprise the step that described cell is contacted with the chemical compound of claim 1-10.

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

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

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

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

24. a method that reduces c-Kit kinase activity among the experimenter, described method comprise the step of the chemical compound that gives described experimenter's claim 1-10.

25. a method that suppresses c-Kit kinase activity among the experimenter, described method comprise the step of the chemical compound that gives described experimenter's claim 1-10.

26. comprising, a method of preventing experimenter's trouble disease relevant with FLT3, described method give the chemical compound that comprises claim 1-10 that the experimenter prevents effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.

27. comprising, a method of preventing experimenter's trouble disease relevant with TrkB, described method give the chemical compound that comprises claim 1-10 that the experimenter prevents effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.

28. comprising, a method of preventing experimenter's trouble disease relevant with c-Kit, described method give the chemical compound that comprises claim 1-10 that the experimenter prevents effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.

29. comprising, a method for the treatment of experimenter's trouble disease relevant with FLT3, described method give the chemical compound that comprises claim 1-10 that the experimenter treats effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.

30. comprising, a method for the treatment of experimenter's trouble disease relevant with TrkB, described method give the chemical compound that comprises claim 1-10 that the experimenter treats effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.

31. comprising, a method for the treatment of experimenter's trouble disease relevant with c-Kit, described method give the chemical compound that comprises claim 1-10 that the experimenter treats effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.

32. also comprising, the method for claim 26, described method give chemotherapeutic.

33. also comprising, the method for claim 26, described method give gene therapy.

34. also comprising, the method for claim 26, described method give immunization therapy.

35. also comprising, the method for claim 26, described method give radiotherapy.

36. also comprising, the method for claim 27, described method give chemotherapeutic.

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

38. also comprising, the method for claim 27, described method give immunization therapy.

39. also comprising, the method for claim 27, described method give radiotherapy.

40. also comprising, the method for claim 28, described method give chemotherapeutic.

41. also comprising, the method for claim 28, described method give gene therapy.

42. also comprising, the method for claim 28, described method give immunization therapy.

43. also comprising, the method for claim 28, described method give radiotherapy.

44. also comprising, the method for claim 29, described method give chemotherapeutic.

45. also comprising, the method for claim 29, described method give gene therapy.

46. also comprising, the method for claim 29, described method give immunization therapy.

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

48. also comprising, the method for claim 30, described method give chemotherapeutic.

49. also comprising, the method for claim 30, described method give gene therapy.

50. also comprising, the method for claim 30, described method give immunization therapy.

51. also comprising, the method for claim 30, described method give radiotherapy.

52. also comprising, the method for claim 31, described method give chemotherapeutic.

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

54. also comprising, the method for claim 31, described method give immunization therapy.

55. also comprising, the method for claim 31, described method give radiotherapy.

56. a method for the treatment of cell proliferative disorders that the experimenter suffers from, described method comprise by the administration of intraluminal medical device sustained release, give the chemical compound that the experimenter treats the claim 1-10 of effective dose.

57. a method for the treatment of experimenter's trouble disease relevant with FLT3, described method comprise by the administration of intraluminal medical device sustained release, give the chemical compound that the experimenter treats the claim 1-10 of effective dose.

58. a method for the treatment of experimenter's trouble disease relevant with TrkB, described method comprise by the administration of intraluminal medical device sustained release, give the chemical compound that the experimenter treats the claim 1-10 of effective dose.

59. a method for the treatment of experimenter's trouble disease relevant with c-Kit, described method comprise by the administration of intraluminal medical device sustained release, give the chemical compound that the experimenter treats the claim 1-10 of effective dose.

60. the method for claim 56, wherein said intraluminal medical device comprises support.

61. the method for claim 57, wherein said intraluminal medical device comprises support.

62. the method for claim 58, wherein said intraluminal medical device comprises support.

63. the method for claim 59, wherein said intraluminal medical device comprises support.

64. a pharmaceutical composition, described compositions comprise effective dose and the chemical compound bonded claim 1-10 of targeted drug and pharmaceutically acceptable carrier.

65. a method for the treatment of cell proliferative disorders, described method comprise that giving the experimenter treats effective dose and the chemical compound bonded claim 1-10 of targeted drug.

66. the method for the disease that a treatment is relevant with FLT3, described method comprise that giving the experimenter treats effective dose and the chemical compound bonded claim 1-10 of targeted drug.

67. the method for the disease that a treatment is relevant with TrkB, described method comprise that giving the experimenter treats effective dose and the chemical compound bonded claim 1-10 of targeted drug.

68. the method for the disease that a treatment is relevant with c-Kit, described method comprise that giving the experimenter treats effective dose and the chemical compound bonded claim 1-10 of targeted drug.

69. a combination medicine, described combination medicine comprise among chemotherapeutic and the claim 1-10 each chemical compound.

70. being included in alkali, a method for preparing the chemical compound of claim 1, described method exist down, with formula IV chemical compound:

React with formula V chemical compound:

71. a method for preparing the chemical compound of claim 1, wherein Q is O, NH or N (alkyl), and described method is included in alkali and exists down, with formula IV chemical compound:

React with formula XII chemical compound

Wherein PG comprises blocking group.

72. the method for claim 71, described method further comprise the chemical compound with formula XIII

With contain R ₁ONH ₂Chemical compound reaction, wherein PG comprises blocking group.

73. a method for preparing the chemical compound of claim 1, described method comprise the chemical compound with formula VI:

With contain R ₁ONH ₂Chemical compound reaction.

74. a pharmaceutical composition, described compositions comprise the product with the method preparation of claim 70-73.