CN101103017A

CN101103017A - Novel aminopyridine derivatives having Aurora-A selective inhibitory action

Info

Publication number: CN101103017A
Application number: CNA2005800455646A
Authority: CN
Inventors: 大久保满; 加藤哲也; 川西宣彦; 三田隆; 下村俊泰
Original assignee: Banyu Phamaceutical Co Ltd
Current assignee: MSD KK
Priority date: 2004-10-29
Filing date: 2005-10-25
Publication date: 2008-01-09
Also published as: RU2007119776A

Abstract

The present invention relates to a compound represented by the general formula (I): wherein Ra and Rb are each independently hydrogen atom or lower alkyl, or alternatively Ra and Rb are combined together to form -CH2 -; Rc is halogen atom; Rd is halogen atom or methyl substituted with one to three halogen atoms; X is CH, N, etc. ; and W is selected from: wherein W1 is hydrogen atom, halogen atom, etc., or a pharmaceutically acceptable salt or ester thereof; a pharmaceutical composition or antitumor agent containing the same; and combinations of the antitumor agent with other antitumor agent(s).

Description

Novel aminopyridine derivative with Aurora-A selective inhibitory

Technical field

The present invention relates in field of medicaments useful, more particularly, relate to by the Aurora-A selective inhibitory and suppress the propagation of tumour cell, the novel aminopyridine derivative of performance antitumous effect, and the Aurora-A selective depressant and the anticarcinogen that contain this aminopyrazole derivatives.

Background technology

The Aurora kinases is to participate in fissional serine/threonine kinase.Present known Aurora kinases has A, B, three kinds of hypotypes of C, has high similarity (homology) mutually.The maturation of Aurora-A and centrosome is relevant with the formation of distribution and spindle body.On the other hand, Aurora-B may with the outpost of the tax office and the cytokinesis relevant [Nat.Rev.Mol.Cell Biol, No. 4,842-854 page or leaf] of chromosomal gathering, pairing, spindle body.Aurora C and Aurora-B interact, and bring into play same function [J.Biol.Chem, Epub ahead (2004)].At present, because the high level expression of Aurora-A obtains confirming in a lot of cancer cells, if and in normal cell high level expression Aurora-A, then to transform the normal cell strain of rodents, therefore a kind of as the cancer gene of Aurora-A is considered to the preferred target [EMBO J, No. 17,3052-3065 page or leaf (1998)] of anticarcinogen.

Have report to point out: the cancer cells of Aurora-A high level expression has taxol resistance [Cancer Cell, the 3rd volume, 51-62 page or leaf (2003)].And about the Aurora kinase inhibitor, from aspects such as high similarity between the hypotype or protein structure analyses, be difficult to the medicine of exploitation subtype-selective, the present known ZM447439 of having etc. suppresses report [J.Cell Biol, No. 161, the 267-280 page or leaf (2003) of the medicine of Aurora-A, Aurora-B simultaneously; J.Cell Biol, No. 161,281-294 page or leaf (2003); Nat.Med, No. 10,262-267 page or leaf (2004)], but the relevant report of not seeing the Aurora-A alternative medicine as yet.That is the anticancer effect when, just disclosing the medicine that will suppress Aurora-A, Aurora-B simultaneously in these reports with the form administration of unitary agent.And reported simultaneously: suppress at the same time in the medicine of Aurora-A and Aurora-B, the Aurora kinase inhibitory activity weakens result's [J.CellBiol, No. 161,281-294 page or leaf (2003)] of the effect of taxol simultaneously.

Wherein also mentioned the past about the patent application of compound (international No. 02/057259 specification sheets, No. 6664247 specification sheets of United States Patent (USP) etc. of disclosing), also relevant for the patent application (No. 6586424 specification sheets of United States Patent (USP) etc.) of aminopyrazole derivatives with Aurora kinase inhibitory activity.But, then do not appear in the newspapers so far about aminopyrazole derivatives with excellent Aurora-A selective inhibitory.

Summary of the invention

The problem that the present invention will solve is that exploitation a kind ofly shows excellent Aurora-A selective inhibitory, also shows cell inhibitory effect effect based on this effect, can bring into play synergistic novel aminopyridine derivative with other anticarcinogen drug combination simultaneously.

The inventor is for solving above-mentioned problem, synthesized novel aminopyrazole derivatives widely, the Aurora-A that finds the compound exhibits excellence shown in the following general formula [I] selects restraining effect and based on the cell inhibitory effect effect of this effect, simultaneously by with other anticarcinogen drug combination, can bring into play synergy, thereby finish the present invention.At present, in existing anticarcinogens such as taxol, from considerations such as its side effect or resistance, for the cancer of not using enough amounts promptly can't cure, by giving compound of the present invention, perhaps, be expected to obtain the effect that alleviates of excellent anticancer effect (comprising the effect that strengthens other anticarcinogen) and side effect with compound of the present invention and other anticarcinogen drug combination.

That is, the present invention relates to compound (m shown in the general formula [I] ₁Be 1, m ₂Be 1, Z ₁And Z ₂Be except the compound of N) or its pharmacologically acceptable salt or ester,

[in the formula,

m ₁Be 1,2 or 3;

m ₂Be 1,2 or 3;

n ₁Be 0 or 1;

n ₂Be 0 or 1;

I is 1～m ₁Arbitrary integer;

J is 1～m ₂Arbitrary integer;

R is can substituted aryl, heteroaryl or cycloalkyl;

R _AiAnd R _Ai' identical or different, be hydrogen atom or low alkyl group, R _BjAnd R _Bj' identical or different, be hydrogen atom or low alkyl group, wherein, m ₁Be 2 or 3 and i be i ₀(i ₀Be 1～m ₁Arbitrary integer) and m ₂Be 2 or 3 and j be j ₀(j ₀Be 1～m ₂Arbitrary integer) time, R _Ai0And R _Ai0' in any one party and R _Bj0And R _Bj0' one can form together-(CH ₂) _n-(in the formula, n is 1 or 2);

R _c, R _dAnd R _eIdentical or different, be hydrogen atom or low alkyl group;

X ₁Be CH, CX _1aOr N (wherein, X _1aFor can substituted low alkyl group);

X ₂Be CH, CX _2aOr N (wherein,

X _2aBe low alkyl group, perhaps

X _2aFor being selected from＜substituting group group A ₁Substituting group or can be selected from by one or more＜substituting group group A ₁The low alkyl group that replaces of identical or different substituting group (wherein,＜substituting group group A ₁Be halogen atom, cyano group, hydroxyl, low-grade alkyl amino, two elementary alkyl amido, lower alkoxy, lower alkylthio and the low alkyl group alkylsulfonyl that can be replaced by one or more hydroxyls), perhaps

X _2aBe COOR ₁, CONR ₂R ₃, NHCOR ₁, NHCONR ₂R ₃, NHSO ₂NR ₂R ₃, NR ₄R ₅, or CH ₂NR ₄R ₅(wherein, R ₁Be hydrogen atom or can substituted low alkyl group, R ₂And R ₃Identical or different, for hydrogen atom, can substituted low alkyl group or cycloalkyl, perhaps R ₂And R ₃5 yuan or 6 yuan of aliphatic heterocyclic radicals that forming with their institute's bonded nitrogen-atoms can be substituted, contain at least one atom that is selected from N, O and S, R ₄And R ₅Identical or different, for hydrogen atom, can substituted low alkyl group or cycloalkyl), perhaps

X _2aSubstituent for having, contain 5 yuan of at least one atom of being selected from N, O and S or 6 yuan of aliphatic heterocyclic radicals (wherein, can be replaced by the oxo base with two hydrogen atoms of same carbon atom bonded of this aliphatic series heterocyclic radical, the adjacent carbons that constitutes the ring of this aliphatic series heterocyclic radical can be two keys), or can be by the low alkyl group of this aliphatic series heterocyclic radical replacement, perhaps

X _2aSubstituent for having, as to contain at least one atom that is selected from N, O and S 5 yuan or 6 yuan of aromatic heterocyclic radicals, the perhaps low alkyl group that can be replaced by this aromatic heterocyclic radical);

X ₃Be CH, CX _3aOr N (wherein, X _3aFor can substituted low alkyl group);

X ₄Be CH or N;

X ₁, X ₂, X ₃And X ₄In, 1～2 is N;

Y ₁, Y ₂And Y ₃Identical or different, be CH or N, but, Y ₁Be CH, R _eDuring for hydrogen atom, these 2 hydrogen atoms can be replaced by the oxo base;

Z ₁And Z ₂Identical or different, be CH or N;

W is following group:

Wherein, W ₁Be CH, N, NH, O or S,

W ₂Be CH, CW _2a, N, NW _2b, O or S (wherein, W _2aAnd W _2bIdentical or different, for hydrogen atom, halogen atom, cyano group, carbonatoms are that 1～2 low alkyl group, carbonatoms are that 3～5 the cycloalkyl or the carbonatoms that can be replaced by one or more halogen atoms are 1～2 low alkyl group),

W ₃Be C or N,

W ₁, W ₂, W ₃In at least one be carbon atom, but W ₁, W ₂, W ₃In two be not O and S simultaneously].

In another embodiment, the present invention relates to the compound (m shown in the general formula [I] ₁Be 1, m ₂Be 1, Z ₁And Z ₂Be except the compound of N, in addition, W ₁Be CH, W ₂Be CH or CW _2a, W ₃During for N, X ₁Be CH or X _1a, X ₂Be N and X _3aBe CH or CX _3a),

[in the formula,

m ₁Be 1,2 or 3;

m ₂Be 1,2 or 3;

n ₁Be 0 or 1;

n ₂Be 0 or 1;

I is 1～m ₁Arbitrary integer;

J is 1～m ₂Arbitrary integer;

R is can substituted aryl, heteroaryl or cycloalkyl;

R _c, R _dAnd R _eIdentical or different, be hydrogen atom or low alkyl group;

X ₁Be CH, CX _1aOr N (wherein, X _1aFor can substituted low alkyl group);

X ₂Be CH or N;

X ₃Be CH, CX _3aOr N (wherein, X _3aFor can substituted low alkyl group);

X ₄Be CH or N;

X ₁, X ₂, X ₃And X ₄In, preferred 1～2 is N;

Z ₁And Z ₂Identical or different, be CH or N;

W is following group:

Wherein, W ₁Be CH, N, NH, O or S,

W ₃Be C or N,

The present invention be in cancer therapy, be used for simultaneously, the combination preparation of administration respectively or successively, be the combination preparation that contains following two kinds of different preparations:

* the preparation that contains compound or pharmaceutically acceptable salt thereof shown in the above-mentioned general formula [1] or ester with pharmaceutically acceptable carrier or thinner; And

* with pharmaceutically acceptable carrier or thinner contain be selected from cancer resistance alkylating agent, cancer resistance metabolic antagonist, cancer resistance microbiotic, the anticarcinogen of anticarcinogen, cancer resistance iridium-platinum complex, cancer resistance camptothecin derivative, cancer resistance tyrosine kinase inhibitor, monoclonal antibody, Interferon, rabbit, biological response modifier and other anticarcinogen or its pharmacologically acceptable salt or ester from plant preparation (wherein

The cancer resistance alkylating agent be N-nitromin, endoxan, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, plug for group, ranomustine, nimustine, Temozolomide or carmustine,

The cancer resistance metabolic antagonist is methylamine pterin, Ismipur glycosides, mercaptopurine, 5 FU 5 fluorouracil, Tegafur, Doxyfluridine, carmofur, cytosine arabinoside, Cytarbine Ocfostate, Yi Nuota shore, S-1, gemcitabine, fludarabine or pemetrexed disodium

The cancer resistance microbiotic is dactinomycin, Dx, daunorubicin, neocarzinostatin, bleomycin, peplomycin, ametycin, aclacinomycin, pirarubicin, epirubicin, Zinostatin stimalamer, idarubicin, sirolimus or valrubicin

Anticarcinogen from plant is vincristine(VCR), vinealeucoblastine(VLB), vindesine, Etoposide, sobuzoxane, docetaxel, taxol or vinorelbine,

The cancer resistance iridium-platinum complex is cis-platinum, carboplatin, S 254 or oxaliplatin,

The cancer resistance camptothecin derivative is irinotecan, Hycamtin or camptothecine,

The cancer resistance tyrosine kinase inhibitor is Gefitinib (gefitinib), imatinib or erlotinib,

Monoclonal antibody is Cetuximab, rhuMAb-VEGF, Rituximab, rhuMAb-VEGF, alemtuzumab or trastuzumab,

Interferon, rabbit is interferon alpha, Intederon Alpha-2a, Interferon Alpha-2b, interferon beta, interferon-gamma-1a or interferon-gamma-n1,

Biological response modifier is krestin, lentinan, sizofiran, Picibanil or ubenimex,

Other anticarcinogen is a mitoxantrone, the altheine enzyme, Procarbazine, Dacarbazine, hydroxyurea, pentostatin, tretinoin, alefacept, A Fadabeiting (darbepoetin alfa), Anastrozole, Yi Ximeitan, bicalutamide, Leuprolide, flutamide, fulvestrant, pegaptanib octasodium, denileukin diftitox, rIL-2, thyrotropin alfa, white arsenic, Velcade (Bortezomib), card is accompanied his shore, goserelin).

The invention still further relates to a kind of pharmaceutical composition, it is characterized in that: contain compound or pharmaceutically acceptable salt thereof or ester shown in the above-mentioned general formula [I] with pharmaceutically acceptable carrier or thinner, and the anticarcinogen or its pharmacologically acceptable salt or the ester that are selected from cancer resistance alkylating agent, cancer resistance metabolic antagonist, cancer resistance microbiotic, anticarcinogen, cancer resistance iridium-platinum complex, cancer resistance camptothecin derivative, cancer resistance tyrosine kinase inhibitor, monoclonal antibody, biological response modifier and other anticarcinogen (definition of each anticarcinogen is same as described above) here, from plant.

The invention still further relates to cancer treatment method, it is characterized in that: will treat compound or pharmaceutically acceptable salt thereof or ester shown in the above-mentioned general formula [I] of significant quantity and be selected from the cancer resistance alkylating agent, the cancer resistance metabolic antagonist, the cancer resistance microbiotic, anticarcinogen from plant, the cancer resistance iridium-platinum complex, the cancer resistance camptothecin derivative, the cancer resistance tyrosine kinase inhibitor, monoclonal antibody, Interferon, rabbit, biological response modifier and other anticarcinogen are (here, the definition of each anticarcinogen is same as described above) treatment on the anticarcinogen of significant quantity or its pharmacologically acceptable salt or ester combination, simultaneously, difference or administration successively.

The present invention relates to the application of Aurora-A selective depressant in the preparation cancer treatment drugs and the application of Aurora-A selective depressant in the preparation cancer treatment drugs of making up with anticarcinogen again, the invention still further relates to the method for cancer of treatment mammals (particularly people), it is characterized in that: the Aurora-A selective depressant of this mammals being treated significant quantity; The present invention relates to the method for cancer of treatment mammals (particularly people) again, it is characterized in that: the Aurora-A selective depressant that will treat significant quantity and the treatment upward anticarcinogen of significant quantity are made up and are given this mammals.

The present invention relates to contain the Aurora-A selective depressant and contain the novel remedies for cancer of Aurora-A selective depressant as effective constituent as the novel remedies for cancer of effective constituent and with anticarcinogen.

Symbol described in this specification sheets and term are carried out following explanation.

" low alkyl group " in the following formula (I) is meant the straight or branched alkyl of carbonatoms 1～6, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl etc. for example arranged, wherein preferable methyl.

" aryl " in the following formula (I) is meant the aromatic hydrocarbyl etc. of monocyclic, dicyclic or the three-ring type of carbonatoms 6～14, and phenyl, naphthyl, indenyl, anthryl etc. are arranged specifically, wherein for example preferred phenyl.

" heteroaryl " in the following formula (I) is meant and also contains the aromatic heterocyclic radical that at least one is selected from the atom of nitrogen-atoms, Sauerstoffatom and sulphur atom except that carbon atom, for example be 5～7 yuan of monocyclic type heteroaromatic bases, condensed 3～8 yuan of condensed ring formula heterocyclic radicals etc., thienyl, pyrryl, furyl, thiazolyl, imidazolyl, pyrazolyl,  azoles base, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, different  azoles base, isoquinolyl, pseudoindoyl, indazolyl, indyl, quinoxalinyl, quinolyl, benzimidazolyl-, benzofuryl etc. are specifically arranged.

" cycloalkyl " in the following formula (I) is 3 yuan～8 yuan aliphatic cyclic group, and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc. are for example arranged.

" 5 yuan or 6 yuan of aliphatic heterocyclic radicals " in the following formula (I) are meant 5 yuan or 6 yuan of aliphatic cyclic groups that also contain at least one atom that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except that carbon atom, and pyrrolidyl, piperidyl, piperazinyl, morpholino base, tetrahydrofuran base, imidazolidyl, thiomorpholine Dai Ji etc. are for example arranged.In the aliphatic series heterocyclic radical, can be replaced by the oxo base with two hydrogen atoms of same carbon atom bonded, the adjacent carbons that constitutes the ring of this aliphatic series heterocyclic radical can be two keys.

" 5 yuan or 6 yuan of aromatic heterocyclic radicals " in the following formula (I) are meant 5 yuan or 6 yuan of aromatics cyclic groups that also contain at least one atom that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except that carbon atom, and thienyl, pyrryl, furyl, thiazolyl, imidazolyl,  azoles base etc. are for example arranged.

" halogen atom " in the following formula (I) for example has fluorine atom, chlorine atom, bromine atoms, iodine atom etc., wherein for example preferred fluorine atom, chlorine atom or bromine atoms.

" lower alkoxy " in the following formula (I) is meant the group of " low alkyl group " and Sauerstoffatom be combined into, and methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, neopentyl oxygen, hexyloxy, different hexyloxy etc. are for example arranged.

" lower alkylthio " in the following formula (I) is meant the group of above-mentioned " low alkyl group " and sulphur atom be combined into, and methylthio group, ethylmercapto group, butylthio etc. are for example arranged.

" low alkyl group alkylsulfonyl " in the following formula (I) is meant the substituting group that above-mentioned " low alkyl group " and alkylsulfonyl bonded form, and methyl sulphonyl, ethylsulfonyl, butyl alkylsulfonyl etc. are for example arranged.

" low-grade alkyl amino " in the following formula (I) is meant the substituting group that above-mentioned " low alkyl group " and amino N-replacement form, and N-methylamino, N-ethylamino, N-propyl group amino, N-sec.-propyl amino, N-butyl amino, N-isobutylamino, N-tertiary butyl amino, N-amyl group amino, N-hexyl amino etc. are for example arranged.

" two elementary alkyl amido " in the following formula (I) is meant above-mentioned " low alkyl group " and amino N, N-two replaces the substituting group that forms, and N is for example arranged, N-dimethylamino, N, N-diethylamino, N, N-dipropyl amino, N, N-diisopropylaminoethyl, N, N-dibutylamino, N, N-diisobutyl amino, N, N-di-t-butyl amino, N, N-diamyl amino, N, N-dihexyl amino, N-ethyl-N-methylamino, N-methyl-N-propyl group amino etc.

" low-grade alkane acidyl " in the following formula (I) is meant the group of above-mentioned " low alkyl group " and carbonyl be combined into, and ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, valeryl, pentanoyl etc. are for example arranged.

" low-grade alkane acidyl amino " in the following formula (I) is meant the group of above-mentioned " low-grade alkane acidyl " and amino be combined into, and acetylamino, propionyl amino, butyryl radicals amino, isobutyryl amino, pentanoyl amino, isovaleryl amino, valeryl amino, pentanoyl amino etc. are for example arranged.

" elementary alkyl amido methanoyl " in the following formula (I) is meant that above-mentioned " low alkyl group " and formamyl N-replace the substituting group that forms, and for example have N-methylamino formyl radical, N-ethylamino formyl radical, N-propyl group formamyl, N-sec.-propyl formamyl, N-butyl formamyl, N-isobutylamino formyl radical, N-tertiary butyl formamyl, N-amyl group formamyl, N-hexyl formamyl etc.

" the Aurora-A selective depressant " that use in this specification sheets is to compare with Aurora-B, optionally suppresses compound and the medicine of Aurora-A." Aurora-A selective depressant " is preferably compound and the medicine that suppresses Aurora-A than the strong at least 10 times of ground of Aurora-B, further preferably suppresses compound and the medicine of Aurora-A than the strong at least 100 times of ground of Aurora-B.

" its pharmacologically acceptable salt or the ester " that uses in this specification sheets and the explanation of " its pharmaceutically acceptable carrier or thinner " are as described later.

The term that uses in this specification sheets " cancer therapy " is meant and gives cancer therapy drug to the cancer patients, the propagation of anticancer.Preferred described treatment is that the propagation of cancer is retreated, can be so that the size reduction of the cancer that can measure.Further preferred described treatment makes the cancer completely dissolve.

The term " cancer " that uses in this explanation is meant solid carcinoma and hemopoietic system cancer.Wherein, solid carcinoma for example has cerebral tumor, incidence cancer, esophagus cancer, thyroid carcinoma, small cell lung cancer, nonsmall-cell lung cancer, mammary cancer, cancer of the stomach, gall-bladder cholangiocarcinoma, liver cancer, carcinoma of the pancreas, colorectal carcinoma, the rectum cancer, ovarian cancer, chorioepithelium cancer, uterus carcinoma, cervical cancer, renal pelvis ureters cancer, bladder cancer, prostate cancer, penile cancer, carcinoma of testis, embryonal carcinoma, dimension Mu Shi tumour, skin carcinoma, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma etc.And the hemopoietic system cancer for example has acute leukemia, chronic lymphatic leukemia, chronic lymphocytic leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, non_hodgkin lymphoma etc.

The terms " formulation " of using in this specification sheets comprises oral preparations and non-oral formulation.Oral preparations for example has tablet, capsule, powder, granule etc., and non-oral formulation for example has the liquid preparation through sterilization such as solution or suspension, be specially injection, infusion solution etc., preferred intravenous injection agent or intravenous fluids agent, further preferred intravenous fluids agent.

The term that uses in this specification sheets " combination preparation " is meant and contains in when treatment preparation of the two or more preparations of administration simultaneously, respectively or successively that they can form the preparation or the pharmaceutical composition of so-called reagent boxlike.On the basis of the combination preparation of two kinds of independent preparations that in comprising cancer therapy, use as mentioned above, further combination more than a kind the preparation of preparation gained be also included within above-mentioned " combination preparation ".

For above-mentioned two kinds of preparations independently, can also further make up more than one preparations, said preparation comprises pharmaceutically acceptable carrier or thinner and at least a or multiple cancer therapy drug or its pharmacologically acceptable salt or the ester that are selected from cancer resistance alkylating agent, cancer resistance metabolic antagonist, cancer resistance microbiotic, the anticarcinogen from plant, cancer resistance iridium-platinum complex, cancer resistance camptothecin derivative, cancer resistance tyrosine kinase inhibitor, monoclonal antibody, Interferon, rabbit, biological response modifier and other anticarcinogen (definition of each anticarcinogen is same as described above) here.In this case, the preparation of more than one that further increase can with above-mentioned two kinds independently preparation is simultaneously, respectively or administrations successively.The combination preparation that for example contains three kinds of preparations has the preparation that contains the compound shown in the above-mentioned general formula (I), the preparation that contains the preparation of 5 FU 5 fluorouracil and contain folinic acid.

In the aforesaid combination preparation, two kinds independently one or both in the preparation can be non-oral formulation, preferably injection or infusion solution, further preferred intravenous fluids agent.

In " preparation " of the present invention, can contain The compounds of this invention and the pharmaceutically acceptable carrier or the thinner for the treatment of significant quantity usually simultaneously.The said preparation technology is a technology general knowledge for those skilled in the art, is known.Preferably, make intravenous fluids according to a lot of methods known in the field and use or injection preparation with pharmaceutically acceptable carrier or thinner.

The term that uses in this specification sheets " administration " is meant non-oral administration and/or oral administration when using combination preparation of the present invention, preferred non-oral administration.That is, when giving combination preparation, can be both all non-oral administrations, also can be a kind of another kind of for oral administration for non-oral administration, can also be two kinds of equal oral administrations.Two kinds of all non-oral administrations of preferably combination preparation.Here, " non-oral administration " for example is intravenous administration, subcutaneous administration, intramuscular administration etc., preferred intravenous administration.In addition, during preparation combination medicine-feeding more than three kinds, at least a preparation is non-oral administration, preferred intravenous administration, further preferred intravenous fluids or intravenous injection.

In embodiment of the present invention, the compound shown in the above-mentioned general formula (I) can with the administration simultaneously of other cancer therapy drug.Can also give other cancer therapy drug continuously after giving the compound shown in the above-mentioned general formula (I), also can be to give the compound shown in the above-mentioned general formula (I) after giving other cancer therapy drug continuously.Can also be to give the compound shown in the above-mentioned general formula (I), give other cancer therapy drug respectively every for some time then; Also can be to give other cancer therapy drug, give the compound shown in the above-mentioned general formula (I) respectively every for some time then.For described order of administration and dosing interval, those skilled in the art can suitably select according to the employed kind that contains the preparation of the compound shown in the above-mentioned general formula (I) and contain the cancer cells of the preparation of uniting the cancer therapy drug of use with it, needs treatment, patient's state etc.For example, when giving compound shown in the above-mentioned general formula (I) and taxol, preferably at first give taxol, give the compound shown in the above-mentioned general formula (I) continuously or every for some time afterwards.

" simultaneously " that use in this specification sheets is meant in the roughly the same time and is used for the treatment of, and " difference " be meant in the different time and be respectively applied for treatment, for example refers to first day with a kind of medicine, situation about another kind of medicine being used for the treatment of in second day." successively " be meant in order and use, for example at first use a kind of medicine, then situation about other medicines being used for the treatment of after at the appointed time.

" the cancer resistance alkylating agent " that use in this specification sheets is meant the alkylating agent with antitumour activity, and here, " alkylating agent " is meant in the common alkylated reaction that the hydrogen atom of organic compound is replaced with alkyl, can gives the material of alkyl." cancer resistance alkylating agent " for example is: N-nitromin, endoxan, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, plug are for group, ranomustine, nimustine, Temozolomide or carmustine etc.

" the cancer resistance metabolic antagonist " that use in this explanation is meant the metabolic antagonist with antitumour activity, here, " metabolic antagonist " in a broad sense with metabolite (VITAMIN, coenzyme, amino acid, carbohydrate etc.) very important for organism structurally or similar on the function, thereby therefore comprising making it can not carry out the metabolic material of koinomatter or suppressing electron transfer system makes it can't produce the material of high-energy intermediate product." cancer resistance metabolic antagonist " for example is methylamine pterin, Ismipur glycosides, mercaptopurine, 5 FU 5 fluorouracil, Tegafur, Doxyfluridine, carmofur, cytosine arabinoside, Cytarbine Ocfostate, Yi Nuota shore, S-1, gemcitabine, fludarabine or pemetrexed disodium etc., preferred 5 FU 5 fluorouracil, S-1, gemcitabine etc.

" the cancer resistance microbiotic " that use in this specification sheets is meant the microbiotic with antitumour activity, here, " microbiotic " comprise by microorganism preparation, suppress microorganism and the growth of other biomass cells and the material of function thereof." cancer resistance microbiotic " for example is dactinomycin, Dx, daunorubicin, neocarzinostatin, bleomycin, peplomycin, ametycin, aclacinomycin, pirarubicin, epirubicin, Zinostatin stimalamer, idarubicin, sirolimus or valrubicin etc.

" from the cancer therapy drug of plant " that uses in this specification sheets comprise with the plant be the origin and found compound with antitumour activity perhaps carries out this compound the resulting compound of chemical modification." from the cancer therapy drug of plant " for example is vincristine(VCR), vinealeucoblastine(VLB), vindesine, Etoposide, sobuzoxane, docetaxel, taxol or vinorelbine etc., preferred docetaxel and taxol.

" the cancer resistance camptothecin derivative " that uses in this specification sheets is meant and comprises cancer cell multiplication inhibition compound relevant with camptothecine on camptothecine itself, its structure." cancer resistance camptothecin derivative " is not particularly limited, and camptothecine, 10-hydroxycamptothecine, Hycamtin, irinotecan, 9-aminocamptothecin etc. are arranged, preferred camptothecine, Hycamtin and irinotecan.Irinotecan is metabolism in vivo, with the form demonstration antitumous effect of SN-38.Can think the mechanism of action of camptothecin derivative and active and camptothecine roughly the same people, cancer and chemotherapy, 14,850-857 (1987) etc. such as () new fields.

" the cancer resistance iridium-platinum complex " that use in this specification sheets is meant the iridium-platinum complex with antitumour activity.Here, " iridium-platinum complex " is meant the iridium-platinum complex that platinum is provided with the ionic form.Preferred iridium-platinum complex is: cis-platinum, cis-diamines two hydration platinum (II)-ion (cis-diamminediaquoplatinum (II)-ion), chlorine (diethylenetriamine) chloro-platinum chloride (II) (chloro (diethylenetriamine)-platinum (II) chloride), (quadrol) dichloro closes platinum (II) (dichloro (ethylenediamine)-platinum (II)), (1,1-tetramethylene dioctyl phthalate) (diammine (1 for two ammino platinum (II), 1-cyclobutanedicarboxylato) platinum (II)) (carboplatin), spiral shell platinum, iproplatin, (2-ethyl malonic acid) two ammino platinum (II) (diammine (2-ethylmalonato) platinum (II)), NSC 146068 (II) (ethylenediaminemalonatoplatinum (II)), (1,2-diamino bicyclohexane) (aqua (1 for hydration platinic sulfate (II), 2-diaminodicyclohexane) sulfatoplatinum (II)), (1,2-diamino bicyclohexane) (aqua (1 for hydration propanedioic acid platinum (II), 2-diaminodicyclohexane) malonatoplatinum (II)), (1,2-diamino bicyclohexane) propanedioic acid platinum (II) ((1,2-diaminocyclohexane) malonatoplatinum (II)), (1,2-diamino bicyclohexane) (4-carboxyl phthalic acid) platinum (II) ((4-carboxyphthalato) (1,2-diaminocyclohexane) platinum (II)), (1,2-diamino bicyclohexane) (isocitric acid) platinum (II) ((1,2-diaminocyclohexane)-(isocitrato) platinum (II)), (1,2-diamino bicyclohexane) RP-54780 (II) ((1,2-diaminocyclohexane) oxalatoplatinum (II)), ormaplatin, four platinum, carboplatin, S 254 or oxaliplatin.Other cancer resistance iridium-platinum complex of enumerating in this specification sheets is known, can obtain from the commercial channel, and/or be prepared by the technician by common technology.

" the cancer resistance tyrosine kinase inhibitor " that use in this specification sheets is meant the tyrosine kinase inhibitor with antitumour activity, wherein, " tyrosine kinase inhibitor " is meant that inhibition transfers to γ-phosphate of ATP the chemical substance of " Tyrosylprotein kinase " on the hydroxyl of proteinic specific tyrosine." cancer resistance tyrosine kinase inhibitor " has Gefitinib (gefitinib), imatinib or erlotinib etc.

" monoclonal antibody " used in this specification sheets is also referred to as monoclonicity antibody, is meant the antibody that antibody-producting cell produced of monospecific polyclonal, and Cetuximab, rhuMAb-VEGF, Rituximab, alemtuzumab or trastuzumab etc. are for example arranged.

" Interferon, rabbit " that use in this specification sheets is meant the Interferon, rabbit with antitumour activity, be usually when infective virus nearly all zooblast all can generate the glycoprotein of the molecular weight about 20,000 of justacrine, not only suppress virus multiplication, also have various immune effector molecule effects such as inhibition cell (particularly tumour cell) propagation, enhancing natural killer cell activity, be defined as a kind of of cytokine." Interferon, rabbit " for example has interferon alpha, Intederon Alpha-2a, Interferon Alpha-2b, interferon beta, interferon-gamma-1a, interferon-gamma-n1 etc.

" biological response modifier " that uses in this specification sheets is so-called biological response modifier (biological response modifier; BRM), typically refer to, come tumour or infection or other disease to the material that the favourable direction of individuality is changed or the general name of medicine by regulating defense mechanism or the biologicallies such as histiocytic existence, propagation or differentiation that organism had." biological answer-reply regulator " for example has krestin, lentinan, sizofiran, Picibanil or ubenimex etc.

" other cancer therapy drug " that uses in this specification sheets is meant to have antitumour activity but do not belong to above-mentioned any one anticarcinogen." other cancer therapy drug " has mitoxantrone, altheine enzyme, Procarbazine, Dacarbazine, hydroxyurea, pentostatin, tretinoin, alefacept, A Fadabeiting, Anastrozole, Yi Ximeitan, bicalutamide, Leuprolide, flutamide, fulvestrant, pegaptanib octasodium, denileukin diftitox, rIL-2, thyrotropin alfa, white arsenic, Velcade, card to accompany his shore, goserelin

Above-mentioned " cancer resistance alkylating agent ", " cancer resistance metabolic antagonist ", " cancer resistance microbiotic ", " from the cancer therapy drug of plant ", " cancer resistance iridium-platinum complex ", " cancer resistance camptothecin derivative ", " cancer resistance tyrosine kinase inhibitor ", " monoclonal antibody ", " Interferon, rabbit ", " biological response modifier " and " other anticarcinogen " are known, can obtain from the commercial channel, perhaps those skilled in the art can according to itself known method and method preparation known, commonly used.In addition, preparation method of gefitinib for example is recorded in No. 5770599 specification sheets of United States Patent (USP); The preparation method of Cetuximab for example is recorded in international open WO96/40210 specification sheets; The preparation method of rhuMAb-VEGF for example is recorded in international open WO94/10202 specification sheets; The preparation method of oxaliplatin for example is recorded in No. 5420319 specification sheets of United States Patent (USP), No. 5959133 specification sheetss; The preparation method of gemcitabine for example is recorded in No. 5434254 specification sheets of United States Patent (USP), No. 5223608 specification sheetss; The preparation method of camptothecine is recorded in No. 5162532 specification sheets of United States Patent (USP), No. 5247089 specification sheets, No. 5191082 specification sheets, No. 5200524 specification sheets, No. 5243050 specification sheets, No. 5321140 specification sheets; The preparation method of irinotecan for example is recorded in No. 4604463 specification sheets of United States Patent (USP); The preparation method of Hycamtin for example is recorded in No. 5734056 specification sheets of United States Patent (USP); The preparation method of Temozolomide for example is recorded in Japan special permission communique 4-5029 specification sheets; The preparation method of Rituximab is recorded in Japan public table special permission communique 2-503143 specification sheets.

Above-mentioned cancer resistance alkylating agent can followingly respectively be obtained by market channel: for example the N-nitromin is available from the Na イトロミ Application (trade(brand)name) of the ウエ of Mitsubishi Le Off ア one マ; Endoxan is available from the エ Application De キサ Application (trade(brand)name) of Shionogi; Ifosfamide is available from the イ Off オミ De (trade(brand)name) of Shionogi; Melphalan is available from the ア Le ケラ Application (trade(brand)name) of グラ Network ソスミス Network ライ Application; Busulfan is available from the マ Block リ Application (trade(brand)name) of military field medicine; Mitobronitol is available from ミエ Block ロ one Le (trade(brand)name) of apricot woods pharmacy; Carboquone is available from three common エスキノ Application (trade(brand)name); Plug replaces assigned purchase from the テ of Sumitomo pharmacy スパミ Application (trade(brand)name); Ranomustine is available from the シメリ Application (trade(brand)name) of the ウエ of Mitsubishi Le Off ア one マ; Nimustine is available from three common ニダラ Application (trade(brand)name); Temozolomide is available from テモダ one Le (trade(brand)name) of シエリ Application グ; Carmustine is available from グリアデ Le ウオ Off ア one (trade(brand)name) of グリ Off オ one De.

Above-mentioned cancer resistance metabolic antagonist can followingly respectively be obtained by market channel: the methylamine pterin is available from メトトレキセ one ト (trade(brand)name) of military field medicine; The Ismipur glycosides is available from the チオイノシ (trade(brand)name) of アベ Application テイス; Mercaptopurine is available from the ロイケリ Application (trade(brand)name) of military field medicine; 5 FU 5 fluorouracil is available from the 5-FU (trade(brand)name) of consonance fermentation; Tegafur is available from Off トラ Off one Le (trade(brand)name) of roc medicine; Doxyfluridine is available from the Off Le Star ロ Application (trade(brand)name) of Japanese ロシユ; Carmofur is available from ヤマ Off one Le (trade(brand)name) of Yamanouchi pharmacy; Cytosine arabinoside is available from the シロサイ De (trade(brand)name) of Japanese new drug; Cytarbine Ocfostate is available from the ストラシ De (trade(brand)name) of Japanese chemical drug; The Yi Nuota shore is available from the サ Application ラ PVC Application (trade(brand)name) of Asahi Chemical Industry; S-1 is available from the TS-1 (trade(brand)name) of roc medicine; Gemcitabine is available from ゲザ one Le (trade(brand)name) of リリ one; Fludarabine is available from the Off Le ダラ (trade(brand)name) of Japanese シエ one リ Application グ; Pemetrexed disodium is available from the アリ system (trade(brand)name) of イ one ライリリ one.

Above-mentioned cancer resistance microbiotic can followingly respectively be obtained by market channel: dactinomycin is available from the コスメゲ Application (trade(brand)name) of universal pharmacy; Dx is available from the ア De リアシ Application (trade(brand)name) of consonance fermentation; Daunorubicin is available from the ダウノマイシ Application (trade(brand)name) of Mingzhi's pharmacy; Neocarzinostatin is available from the ネオカ Le チノスチ Application (trade(brand)name) of Yamanouchi pharmacy; Bleomycin is available from the プレオ (trade(brand)name) of Japanese chemical drug; Peplomycin is available from the ペプロ (trade(brand)name) of Japanese chemical drug; Ametycin is available from the マイトマイシ Application (trade(brand)name) of consonance fermentation; Aclacinomycin is available from the ア Network ラシノ Application (trade(brand)name) of Yamanouchi pharmacy; Pirarubicin is available from the ピノ Le PVC Application (trade(brand)name) of Japanese chemical drug; Epirubicin is available from the Off ア Le モ Le PVC シ Application (trade(brand)name) of Off ア Le マシア; Zinostatin stimalamer is available from the スマ Application Network ス (trade(brand)name) of Yamanouchi pharmacy; Idarubicin is available from the イダマイシ Application (trade(brand)name) of Off ア Le マシア; Sirolimus is available from the ラパ system Application (trade(brand)name) of ワイス; Valrubicin is available from パ Le ス one (trade(brand)name) of ア Application スラ Off ア one マシユ one テイカ Le.

Above-mentioned cancer therapy drug from plant can followingly respectively be obtained by market channel: for example vincristine(VCR) is available from the オ Application コ PVC Application (trade(brand)name) of Shionogi; Vinealeucoblastine(VLB) is available from the PVC Application Block ラスチ Application (trade(brand)name) of apricot woods pharmacy; Vindesine is available from the Off イ Le デシ Application (trade(brand)name) of Shionogi; Etoposide is available from the ラステ Star ト (trade(brand)name) of Japanese chemical drug; Sobuzoxane is available from the ペラゾリ Application (trade(brand)name) of full pharmaceutical worker's industry; Docetaxel is available from キソテ one Le (trade(brand)name) of アベ Application テイス; Taxol is available from キソ one Le (trade(brand)name) of Block リスト Le; Vinorelbine is available from the Na ベ Le PVC Application (trade(brand)name) of consonance fermentation.

Above-mentioned cancer resistance iridium-platinum complex can followingly respectively be obtained by market channel: for example cis-platinum is available from the ラ Application ダ (trade(brand)name) of Japanese chemical drug; Carboplatin is available from the パラプラチ Application (trade(brand)name) of Block リスト Le; S 254 is available from the ア Network プラ (trade(brand)name) of Shionogi; Oxaliplatin is available from the エロキサチ Application (trade(brand)name) of サノ Off イ.

Above-mentioned cancer resistance camptothecin derivative can followingly respectively be obtained by market channel: for example irinotecan is available from the カ Application プト (trade(brand)name) of ヤ Network Le ト; Hycamtin is available from the Ha イカ system チ Application (trade(brand)name) of グラ Network ソスミス Network ライ Application; Camptothecine is available from U.S. ア Le De リ Star チケミカ Le.

Above-mentioned cancer resistance tyrosine kinase inhibitor can followingly respectively be obtained by market channel: for example Gefitinib is available from the イレ Star サ (trade(brand)name) of アストラゼネカ; Imatinib is available from the グリベ Star Network (trade(brand)name) of ノバ Le テイス; Erlotinib is available from the Le セバ (trade(brand)name) of オ one エスアイ Off ア one マシユ one テイカ Le.

Said monoclonal antibody can followingly respectively be obtained by market channel: for example Cetuximab is available from the エ Le PVC Star Network ス (trade(brand)name) of Block リスト Le マイヤ one ズス Network イ Block; RhuMAb-VEGF is available from the アバスチ Application (trade(brand)name) of ジエネ Application テ Star Network; Rituximab is available from the リ Star キサ Application (trade(brand)name) of バイオジエ Application; Alemtuzumab is available from the カ Application パス (trade(brand)name) of ベ Le レ Star Network ス; Trastuzumab is available from the Ha one セプチ Application (trade(brand)name) of Chugai.

Above-mentioned Interferon, rabbit can followingly respectively be obtained by market channel: for example interferon alpha is available from the スミ Off エロ Application (trade(brand)name) of Sumitomo pharmacy; Intederon Alpha-2a is available from the カ Application アエロ Application-A (trade(brand)name) of military field medicine; Interferon Alpha-2b is available from the イ Application トロ Application A (trade(brand)name) of シエリ Application グプラウ; Interferon beta is available from the IFN β (trade(brand)name) that holds the field pharmacy; Interferon-gamma-1a is available from the イ system ノマ Star Network ス-γ (trade(brand)name) of Shionogi; Interferon-gamma-n1 is available from the オガ Application マ (trade(brand)name) of Da mound pharmacy.

Above-mentioned biological response modifier can followingly respectively be obtained by market channel: for example krestin is available from three common Network レスチ Application (trade(brand)name); Lentinan is available from the レ Application チ Na Application (trade(brand)name) of アベ Application テイス; Sizofiran is available from the ソニ Off イラ Application (trade(brand)name) of scientific research pharmacy; Picibanil is available from ピシバニ one Le (trade(brand)name) of Chugai; Ubenimex is available from the ベスチ Application (trade(brand)name) of Japanese chemical drug.

Above-mentioned other anticarcinogen can followingly respectively be obtained by market channel: for example mitoxantrone is available from the ノバ Application トロ Application (trade(brand)name) of Japanese ワイスレダリ one; The altheine enzyme is available from ロイ Na one ゼ (trade(brand)name) of consonance fermentation; Procarbazine is available from the Na Star ラ Application (trade(brand)name) of Japanese ロシユ; Dacarbazine is available from the ダカ Le ジ Application (trade(brand)name) of consonance fermentation; Hydroxyurea is available from the Ha イ De レア (trade(brand)name) of Block リスト Le; Pentostatin is available from the コ Off オリ Application (trade(brand)name) of chemistry and serotherapy institute; Tretinoin is available from the ベサノイ De (trade(brand)name) of Japanese ロシユ; Alefacept is available from the アメ PVC Block (trade(brand)name) of バイオジエ Application; A Fadabeiting is available from the アラネスプ (trade(brand)name) of ア system ジエ Application; Anastrozole is available from the アリミデ Star Network ス (trade(brand)name) of アストラゼネカ; Yi Ximeitan is available from the アロマシ Application (trade(brand)name) of Off アイザ one; Bicalutamide is available from the カソデ Star Network ス (trade(brand)name) of アストラゼネカ; Leuprolide is available from the リユ one プリ Application (trade(brand)name) of military field medicine; Flutamide is available from the ユ one レキシ Application (trade(brand)name) of シエリ Application グプラウ; Fulvestrant is available from the Off アスロデ Star Network ス (trade(brand)name) of アストラゼネカ; Pegaptanib octasodium is available from the マ Network ゲ Application (trade(brand)name) of ギリ one De サイエ Application ス; Denileukin diftitox is available from the オ Application Star Network (trade(brand)name) of リガ Application De; RIL-2 is available from the プロリユ one キ Application (trade(brand)name) of キロ Application; Thyrotropin alfa is available from the チロゲ Application (trade(brand)name) of ゲ Application ザイ system; White arsenic is available from the トリセノ Star Network ス (trade(brand)name) of セ Le セラピユ one テイ Network ス; Velcade is available from the ベ Le ケイ De (trade(brand)name) of ミレニウ system; Card is accompanied his shore ゼロダ (trade(brand)name) available from ロシユ; Goserelin is available from the ゾラデ Star Network ス (trade(brand)name) of アストラゼネカ.

" anticarcinogen " that uses in this specification sheets is meant the anticarcinogen that is selected from above-mentioned " cancer resistance alkylating agent ", " cancer resistance metabolic antagonist ", " cancer resistance microbiotic ", " from the cancer therapy drug of plant ", " cancer resistance iridium-platinum complex ", " cancer resistance iridium-platinum complex ", " cancer resistance camptothecin derivative ", " cancer resistance tyrosine kinase inhibitor ", " monoclonal antibody ", " Interferon, rabbit ", " biological response modifier ", " other anticarcinogen ".

" aminopyrazole derivatives " that uses in this specification sheets is meant the compound of the pyridine that contains tool amino, for example is the compound shown in the following formula (I) etc., the compound of (a)-(cc) preferred shown below.

Embodiment to compound shown in the following formula (I) further describes below.

m ₁Be 1,2 or 3; Preferred m ₁Be 2 or 3; Further preferred m ₁Be 2.

m ₂Be 1,2 or 3; Preferred m ₂Be 2.

n ₁Be 0 or 1, preferred n ₁Be 0.

n ₂Be 0 or 1, preferred n ₂Be 0.

I is 1～m ₁Arbitrary integer, j is 1～m ₂Arbitrary integer.

R is can substituted aryl, heteroaryl or cycloalkyl.

R be preferably phenyl or contain 5 yuan of at least one atom that is selected from N, O and S or 6 yuan of aromatic heterocyclic radicals (wherein, this phenyl or aromatic heterocyclic radical can be replaced by one or more identical or different following substituting groups that are selected from:

1) low alkyl group

2) be selected from＜substituting group group A ₂Substituting group and

3) be selected from＜substituting group group A ₂The substituting group of the low alkyl group that replaces of substituting group replace);

＜substituting group group A ₂Be halogen atom, cyano group, hydroxyl, amino, low-grade alkyl amino, two elementary alkyl amido, low-grade alkane acidyl, low-grade alkane acidyl amino, formamyl, elementary alkyl amido methanoyl and low alkyl group alkylsulfonyl.Wherein, when R is 5 yuan of aromatic heterocyclic radicals, for example be preferably the pyrryl that can suitably be replaced, furyl, thienyl, thiazolyl, pyrazolyl, pyridyl, pyrazinyl etc.

More preferably 2,3 of R are by the phenyl that identical or different halogen atom replaces, perhaps be 2,3 respectively by halogen atom, methyl substituted phenyl, wherein said methyl is replaced by 1～3 halogen atom.

R _AiAnd R _Ai' (i is 1～m ₁Integer) identical or different, be hydrogen atom or low alkyl group, R _BjAnd R _Bj' (j is 1～m ₂Integer) identical or different, be hydrogen atom or low alkyl group.Here, m ₁Be 2 or 3, i ₀(i ₀Be 1～m ₁Arbitrary integer) and m ₂Be 2 or 3, j is j ₀(j ₀Be 1～m ₂Arbitrary integer) time, R _Ai0And R _Ai0' any one party can with R _Bj0And R _Bj0' a side form together-(CH ₂) _n-(wherein, n is 1 or 2).For example, for R _AiAnd R _Ai' (i is 1～m ₁Integer) and R _BjAnd R _Bj' (j is 1～m ₂Integer), work as m ₁Be 2, m ₂Be 2 o'clock, preferred R _A2And R _A2' any one party and R _B1And R _B1' any one party form together-CH ₂-.

About R _AiAnd R _Ai' (i is 1～m ₁Integer) and R _BjAnd R _Bj' (j is 1～m ₂Integer), work as m ₁Be 2 or 3 and m ₂Be 2 o'clock, R _Ai, R _Ai', R _Bj, R _Bj' preferably be hydrogen atom, perhaps one of them is a methyl, all the other are hydrogen atom, all is hydrogen atom preferably further.For example, work as m ₁Be 2 and m ₂Be 2 o'clock, preferred R _A1, R _A1', R _A2, R _A2', R _B1, R _B1', R _B2, R _B2' all be hydrogen atom.

R _c, R _dAnd R _eIdentical or different, be hydrogen atom or low alkyl group.

R _eBe preferably hydrogen atom.

X ₁Be CH, CX _1aOr N, wherein, X _1aFor can substituted low alkyl group.X ₁Be preferably CH.

X ₂Be CH, CX _2aOr N (wherein,

X _2aBe low alkyl group, perhaps

X _2aFor being selected from＜substituting group group A ₁Substituting group or can be by one or more being selected from＜substituting group group A ₁The low alkyl group that replaces of substituting group (wherein,＜substituting group group A ₁Be halogen atom, cyano group, hydroxyl, low-grade alkyl amino, two elementary alkyl amido, lower alkoxy, lower alkylthio, the low alkyl group alkylsulfonyl that can be replaced by one or more hydroxyls), perhaps

X _2aBe COOR ₁, CONR ₂R ₃, NHCOR ₁, NHCONR ₂R ₃, NHSO ₂NR ₂R ₃, NR ₄R ₅Or CH ₂NR ₄R ₅(wherein, R ₁Be hydrogen atom or can substituted low alkyl group, R ₂And R ₃Identical or different, for hydrogen atom, can substituted low alkyl group or cycloalkyl, perhaps R ₂And R ₃5 yuan or 6 yuan of aliphatic heterocyclic radicals that forming with their institute's bonded nitrogen-atoms can be substituted, contain at least one atom that is selected from N, O and S, R ₄And R ₅Identical or different, for hydrogen atom, can substituted low alkyl group or cycloalkyl), perhaps

X ₂Be preferably CH, CX ₂A or N are (wherein,

X _2aFor being selected from＜substituting group group A ₁Substituting group or can be by one or more being selected from＜substituting group group A ₁The low alkyl group that replaces of substituting group, perhaps

X _2aFor can be replaced by low alkyl group, be selected from＜substituting group group A ₃5 yuan of aromatic heterocyclic radicals or the low alkyl group that can be replaced by this aromatic heterocyclic radical, perhaps

X _2aFor can be replaced by low alkyl group, be selected from＜substituting group group A ₄5 yuan or the 6 yuan of aliphatic heterocyclic radicals or the low alkyl group that can be replaced by this aliphatic series heterocyclic radical.

Wherein,＜substituting group group A ₃As follows:

＜substituting group group A ₄As follows:

＜substituting group group A ₄Be preferably as follows:

X ₂Further preferred CH or N.

X ₃Be CH, CX _3aOr N, wherein X _3aFor can substituted low alkyl group.

X ₃Preferred CH.

X ₄For CH or N, be preferably N.

X ₁, X ₂, X ₃And X ₄In, 1～2 is N; Preferred X ₄Be N and X ₁～X ₃In maximum one be N; Further preferred X ₁And X ₃Be CH, X ₂Be CH or N, X ₄Be N; Preferred especially X ₁, X ₂And X ₃All be CH, X ₄Be N.

W ₁Be CH, W ₂Be CH or CW _2a, W ₃During for N, X ₁Be preferably CH or X _1a, X ₂Be preferably N, and X _3aBe preferably CH or CX _3a

Y ₁, Y ₂And Y ₃Identical or different, be CH or N, but Y ₁Be CH, R _eDuring for hydrogen atom, these two hydrogen atoms can be replaced by the oxo base.

Y ₁Be preferably CH.

Z ₁And Z ₂Identical or different, be CH or N.

Z ₁And Z ₂Preferred one of them side is N.

Further preferred Z ₁Be N, Z ₂Be CH or N.

Preferred especially Z ₁And Z ₂Both are N.

W is following group:

Wherein,

W ₁Be CH, N, NH, O or S;

W ₂Be CH, CW _2a, N, NW _2b, O or S (wherein, W _2aAnd W _2bIdentical or different, for hydrogen atom, halogen atom, cyano group, carbonatoms are that 1～2 low alkyl group, carbonatoms are that 3～5 the cycloalkyl or the carbonatoms that can be replaced by one or more halogen atoms are 1～2 low alkyl group);

W ₃Be C or N;

W ₁, W ₂, W ₃In at least one be carbon atom, W ₁, W ₂, W ₃In two be not O and S simultaneously.

W is preferably selected from following radicals.

Further preferred W is selected from following radicals:

Wherein,

W _2aBe hydrogen atom, halogen atom, cyano group or the methyl that can be replaced by 1～3 fluorine atom.

Preferred especially W is selected from following group:

The preferred configuration of compound can followingly show shown in the following formula (I).That is,

(1) compound or pharmaceutically acceptable salt thereof or ester shown in the following formula (I), wherein, W is selected from following group.

Perhaps

(2) compound or pharmaceutically acceptable salt thereof of above-mentioned (I) or ester, wherein,

m ₁Be 2 or 3;

m ₂Be 2;

n ₁Be 0;

n ₂Be 0;

Z ₁Be N;

Z ₂Be CH or N; And

R be phenyl or contain 5 yuan of at least one atom that is selected from N, O and S or 6 yuan of aromatic heterocyclic radicals (wherein, this phenyl or aromatic heterocyclic radical can be replaced by one or more identical or different following substituting groups that are selected from,

1) low alkyl group,

2) be selected from＜substituting group group A ₂Substituting group and

3) can be selected from＜substituting group group A ₂The low alkyl group that replaces of substituting group;

＜substituting group group A ₂Be halogen atom, cyano group, hydroxyl, amino, low-grade alkyl amino, two elementary alkyl amido, low-grade alkane acidyl, low-grade alkane acidyl amino, formamyl, elementary alkyl amido methanoyl, low alkyl group alkylsulfonyl).Perhaps

(3) compound or pharmaceutically acceptable salt thereof of above-mentioned (2) or ester, wherein, Y ₁Be CH; R _eBe hydrogen atom.Perhaps

(4) compound or pharmaceutically acceptable salt thereof of above-mentioned (3) or ester, wherein, m ₁Be 2; R _A1, R _A1', R _A2, R _A2', R _B1, R _B1', R _B2, R _B2' be hydrogen atom.

(5) compound or pharmaceutically acceptable salt thereof of above-mentioned (4) or ester, wherein, X ₄Be N, and X ₁～X ₃In maximum 1 be N, R is 2,3 phenyl that replaced by identical or different halogen atom, perhaps be 2,3 respectively by halogen atom, methyl substituted phenyl, wherein said methyl is replaced by 1～3 halogen atom.Perhaps

(6) compound or pharmaceutically acceptable salt thereof of above-mentioned (5) or ester, wherein, X ₂Be CH, CX _2aOr N (wherein,

X _2aFor being selected from substituting group group A ₁Substituting group or can be by one or more being selected from＜substituting group group A ₁The low alkyl group that replaces of substituting group, perhaps

Wherein,＜substituting group group A ₃As follows:

＜substituting group group A ₄As follows:

Perhaps

(7) compound or pharmaceutically acceptable salt thereof of above-mentioned (6) or ester, wherein, W is selected from following group:

W _2aBe hydrogen atom, halogen atom, cyano group or the methyl that can be replaced by 1～3 fluorine atom.Perhaps

(8) compound or pharmaceutically acceptable salt thereof of above-mentioned (7) or ester, wherein, X ₁, X ₂And X ₃All be CH, Z ₁And Z ₂Both are N.

More preferably following compound or pharmaceutically acceptable salt thereof of the compound of following formula (I) or ester:

(a) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine,

(b) 6-((4-(2,3-dichloro-benzoyl base) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine,

(c) 6-(((1S, 4S)-5-(3-chloro-2-fluoro benzoyl)-2,5-diazabicyclo [2.2.1] oenanthyl-2-yl) methyl)-N-thiazol-2-yl pyridine-2-amine,

(d) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(1H-pyrazole-3-yl) pyridine-2-amine,

(e) 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine,

(f) 6-((4-(3-(difluoromethyl)-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine,

(g) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyridine-2-amine,

(h) 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyridine-2-amine,

(i) 6-((4-(2-chloro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyridine-2-amine,

(j) 6-((4-(2,3-dichloro-benzoyl base) piperazine-1-yl) methyl)-N-1,2,4-thiadiazoles-5-yl pyridines-2-amine,

(k) 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1,2,4-thiadiazoles-5-yl pyridines-2-amine,

(l) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine,

(m) 6-(((1S, 4S)-5-(3-chloro-2-fluoro benzoyl)-2,5-diazabicyclo [2.2.1] oenanthyl-2-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine,

(n) 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine,

(o) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyrazine-2-amine,

(p) 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1,2,4-thiadiazoles-5-base pyrazine-2-amine,

(q) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyrazine-2-amine,

(r) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine,

(s) 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N, the amino Isonicotinamide of N-dimethyl-6-(thiazol-2-yl),

(t) (2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) pyridin-4-yl) methyl alcohol,

(u) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(methoxymethyl)-N-thiazol-2-yl pyridine-2-amine,

(v) 1-(2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) pyridin-4-yl)-3-Methylimidazole alkane-2-ketone,

(w) 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino)-4-cyanopyridine (isonicotinonitrile),

(x) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(1-methyl isophthalic acid H-tetrazolium-5-yl)-N-thiazol-2-yl pyridine-2-amine,

(y) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(2-methyl-2H-tetrazolium-5-yl)-N-thiazol-2-yl pyridine-2-amine,

(z) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl-4-(1H-1,2,4-triazole-5-yl) pyridine-2-amine,

(aa) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-fluorine thiazol-2-yl) pyridine-2-amine,

(bb) 6-((4-(2-fluoro-3-trifluoromethyl benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyrazine-2-amine or

(cc) 2-{[4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl] methyl }-N, N-dimethyl-6-(1H-pyrazole-3-yl amino) Isonicotinamide.

In another embodiment, the present invention relates to following compound or its pharmaceutically acceptable salt or ester:

(d) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(1H-pyrazole-3-yl) pyrazine-2-amine,

(s) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-fluorine thiazol-2-yl) pyridine-2-amine or

(t) 6-((4-(2-fluoro-3-trifluoromethyl benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyrazine-2-amine.

The present invention contains in the combination preparation of two kinds of independent preparations, and preferred two kinds independently one or both are non-oral formulation in the preparation, and further preferred two kinds independently one or both are injection or infusion solution in the preparation.

The present invention contains in the combination preparation of two kinds of independent preparations, and preferred a kind of preparation is the preparation that comprises pharmaceutically acceptable carrier or thinner and following compound or pharmaceutically acceptable salt thereof or ester:

(w) 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino)-4-cyanopyridine,

(cc) 2-{[4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl] methyl }-N, N-dimethyl-6-(1H-pyrazole-3-yl amino) Isonicotinamide;

Another kind of preparation is the preparation that comprises pharmaceutically acceptable carrier or thinner and taxol or docetaxel or its pharmacologically acceptable salt or ester.

In yet another embodiment, the present invention comprise two kinds of independent preparations combination preparation further preferred a kind of preparation be the preparation that comprises pharmaceutically acceptable carrier or thinner and following compound or pharmaceutically acceptable salt thereof or ester:

(s) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-fluorine thiazol-2-yl) pyridine-2-amine,

(t) 6-((4-(2-fluoro-3-trifluoromethyl benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyrazine-2-amine;

And another kind of preparation is the preparation that comprises pharmaceutically acceptable carrier or thinner and taxol or docetaxel or its pharmacologically acceptable salt or ester.

Can also be to the present invention contain two kinds independently the combination preparation of preparation further make up more than one preparations, said preparation is to comprise pharmaceutically acceptable carrier or thinner and be selected from cancer resistance alkylating agent, cancer resistance metabolic antagonist, cancer resistance microbiotic, the anticarcinogen from plant, cancer resistance iridium-platinum complex, cancer resistance camptothecin derivative, cancer resistance tyrosine kinase inhibitor, monoclonal antibody, Interferon, rabbit, biological response modifier and the anticarcinogen of other anticarcinogen (definition of each anticarcinogen is same as described above) or the preparation of its pharmacologically acceptable salt or ester here.

Pharmaceutical composition of the present invention preferably contains pharmaceutically acceptable carrier or thinner and following compound or pharmaceutically acceptable salt thereof or ester and taxol or docetaxel or its pharmacologically acceptable salt or ester:

(m) 6-(((1 S, 4S)-5-(3-chloro-2-fluoro benzoyl)-2,5-diazabicyclo [2.2.1] oenanthyl-2-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine,

(t) (2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) pyridine-2-yl) methyl alcohol,

(cc) 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl] methyl)-N, N-dimethyl-6-(1H-pyrazole-3-yl amino) Isonicotinamide.

The preparation method of the compound of general formula (I)

General formula of the present invention (I)

(in the formula, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, X ₁, X ₂, X ₃, X ₄, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with above-mentioned implication) shown in the compound, Y ₁Be CH, Z ₁Formula (I-1) for N

Compound for example can prepare by the following method shown in (symbol in the formula is identical with the symbol implication of following formula (I)).Below, " symbol of following formula (I) " in " identical with the symbol implication of following formula (I) " is meant " each symbol described in the general formula (I) of initial record in this specification sheets ".

(this step of step 1) is to compound (II) (wherein, LG ¹Leavings groups such as expression halogen, X ₁, X ₂, X ₃, X ₄And R _eThe symbol implication of following formula (I) is identical) in import blocking group PG such as t-butyldimethylsilyl ¹, preparation compound (III) (wherein, LG ¹And PG ¹Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄And R _eIdentical with the symbol implication of following formula (I)) method.

The above-claimed cpd that uses in this step (II) for example has (6-bromopyridine-2-yl) methyl alcohol, 1-(6-bromopyridine-2-yl) ethanol, (3-iodophenyl) methyl alcohol etc.Above-claimed cpd (II) can obtain by the commercial channel, perhaps prepares according to known method.

Blocking group PG ¹According to its kind and difference, can be according to the method for document record [with reference to Protective Groups in Organic Synthesis, T.W.Greene work, John Wiley ﹠amp; Sons publishes (1981)] or method proximate with it importing.For example, at N, in the dinethylformamide equal solvent, in the presence of alkali such as imidazoles, use synthetic above-claimed cpds (II) such as tertiary butyl dimethyl chloride silicomethane.When using tertiary butyl dimethyl chloride silicomethane in protective reaction, with respect to 1mol compound (II), the consumption of tertiary butyl dimethyl chloride silicomethane is 1-10mol, preferably uses 1-3mol, uses 1-20mol, preferred 1-5mol alkali.In this case, temperature of reaction can suitably be selected by those skilled in the art according to employed starting compound or reaction solvent, is generally the boiling point of 0 ℃-solvent.Reaction finished in 1 hour-24 hours usually, and the reaction times can suitably increase and decrease.

Separation purifying such as the above-claimed cpd that obtains like this (HI) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram perhaps need not separation and purification, promptly can be used for subsequent step.

(step 2) this step is compound (III) (wherein, the LG that makes above-mentioned steps 1 gained ¹And PG ¹Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄And R _eIdentical with the symbol implication of following formula (I)) and compound (IV) (wherein, PG ²Can not exist; if exist; it then is 4-methoxy-benzyl, 2; 4-dimethoxy-benzyl, benzyl, methoxymethyl, (2-(trimethyl silyl) oxyethyl group) methyl, the tertiary butyl etc.; be preferably 2-(trimethyl silyl) oxyethyl group) blocking group such as methyl, methoxymethyl, the tertiary butyl, in addition, W is identical with the symbol implication of following formula (I)) carry out ammoxidation; preparation compound (V) (in the formula, PG ¹And PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄, R _eIdentical with W with the symbol implication of following formula (I)) method.

The above-claimed cpd that uses in this step (IV) for example has thiazolamine-5-formonitrile HCN, thiazolamine, 2-amino-5-methylthiazol, 5-amino-1,2,4-thiadiazoles, 5-methyl isophthalic acid-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazoles-3-amine, 1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazoles-3-amine, the 1-tertiary butyl-3-methyl isophthalic acid H-pyrazoles-5-amine etc.Above-claimed cpd (IV) can obtain from market channel, perhaps according to known method (Phosphorus for example, Sulfurand Silicon and the Related Elements,, the 177th volume No. 11,2651-2659 page or leaf in 2002; Journal of Chemical Research, Synopses, 1979, the 6th volume, 198 pages) preparation.

The ammoxidation that adopts in this step can adopt those skilled in the art known method.Ammoxidation in this step for example is 1 specifically, 4-two  alkane, 1, in 2-glycol dimethyl ether, tetrahydrofuran (THF), methylene dichloride, chloroform, the toluene equal solvent, use three (dibenzalacetones) to close palladium catalysts such as two palladiums (0), acid chloride, 2,2 '-two (diphenylphosphine)-1,1 '-dinaphthalene, 4, two (diphenylphosphine)-9 of 5-, dentates such as 9-dimethyl xanthene, and alkali such as cesium carbonate, sodium tert-butoxide, make the reaction of above-claimed cpd (III) and above-claimed cpd (IV) synthetic.In this reaction, with respect to 1mol compound (III), use 0.5-3mol, preferably use 1mol compound (IV), use 0.001-1mol, preferably use the 0.05-0.5mol palladium catalyst, use 0.002-2mol, preferably use the 0.1-1.0mol dentate, use 1-10mol, preferably use 1-3mol alkali.Temperature of reaction can suitably be selected according to the starting compound or the reaction solvent that use, is generally the boiling point of employed solvent in the 50 ℃-reaction.Reaction finished in 1-24 hour usually, and the reaction times can suitably increase and decrease.

Separation purifying such as above-mentioned gained compound (V) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram perhaps need not separation and purification, promptly can be used for subsequent step.

(this step of step 3) is with the compound of above-mentioned steps 2 gained (V) (wherein, PG ¹And PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄, R _eIdentical with W with the symbol implication of following formula (I)) blocking group PG ¹Carry out deprotection, preparation compound (VI) (wherein, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄, R _eIdentical with W with the symbol implication of following formula (I)) method.

The blocking group PG that uses in this step ¹Remove according to the stability of its kind and compound and different, can be according to the method for document record [with reference to Protective Groups in OrganicSynthesis, T.W.Greene work, John Wiley ﹠amp; Sons publishes (1981)] or method proximate with it carry out.For example, in the tetrahydrofuran (THF) equal solvent, use tetrabutylammonium etc. are to PG1 ^ForThe above-claimed cpd of t-butyldimethylsilyl (V) carries out deprotection.When deprotection reaction used tetrabutylammonium, with respect to 1mol compound (V), the consumption of tetrabutylammonium was 1-10mol, preferred 1-3mol.Temperature of reaction can suitably be selected according to the starting compound or the reaction solvent that use by those skilled in the art, is generally the boiling point of 0 ℃-solvent.Reaction finished in 1 hour-24 hours usually, and the reaction times can suitably increase and decrease.

Separation purifying such as above-mentioned gained compound (VI) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram perhaps need not separation and purification, promptly can be used for subsequent step.

(this step of step 4) is with the compound of above-mentioned steps 3 gained (VI) (wherein, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄, R _eIdentical with W with the symbol implication of following formula (I)) hydroxyl be transformed to leavings groups such as mesyloxy, chloro, preparation compound (VII) (wherein, LG ²Leavings groups such as expression mesyloxy or halogen atom, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄, R _eIdentical with W with the symbol implication of following formula (I)) method.

The reaction of adopting in this step can use those skilled in the art known method.Reaction in this step is specifically for example at chloroform, methylene dichloride, tetrahydrofuran (THF), N, in dinethylformamide, ether, the ethyl acetate equal solvent, in the presence of alkali such as triethylamine, diisopropylethylamine,, can obtain LG by making above-claimed cpd (VI) and methylsulfonyl chloride reaction ²Above-claimed cpd (VII) for mesyloxy.In this case,, use 1-10mol, preferred 1-3mol methylsulfonyl chloride, use 1-20mol, preferred 1-6mol alkali with respect to 1mol compound (VI).Temperature of reaction can suitably be selected according to employed starting compound by those skilled in the art, is generally 0 ℃-room temperature.Reaction finished in 10 minutes-2 hours usually, suitably the on-off reaction time.

Separation purifying such as above-mentioned gained compound (VII) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram perhaps need not separation and purification, promptly can be used for subsequent step.

(this step of step 5) is by above-mentioned steps 4 resulting compound (VII) (wherein, LG ²And PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄, R _eIdentical with W with the symbol implication of following formula (I)) and compound (VIII) (wherein, m ₁, m ₂, n ₁, n ₂, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, Y ₂, Y ₃And Z ₂Identical with the symbol implication of following formula (I)) ammoxidation, preparation compound (IX) (wherein, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄, R _eWith W and m ₁, m ₂, n ₁, n ₂, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, Y ₂, Y ₃And Z ₂Identical with the symbol implication of following formula (I)) method.

The above-claimed cpd that uses in this step (VIII) for example has 1-(3-chloro-2-fluoro benzoyl) piperazine, 1-(3-(trifluoromethyl)-2-fluoro benzoyl) piperazine, 1-((6-fluorine pyridine-2-yl) carbonyl) piperazine, phenyl (piperidin-4-yl) ketone, 2-benzoyl-2; 5-diazabicyclo [2.2.1] heptane, 1-benzoyl-1,4-Diazesuberane etc.Above-claimed cpd (VIII) can obtain by market channel, or according to known method (Journal of Medicinal Chemistry,, the 29th volume No. 5,630-634 page or leaf in 1986) preparation.

The ammoxidation that adopts in this step can use those skilled in the art known method.Ammoxidation in this step is specifically for example at tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), N, dinethylformamide, 1, in 4-two  alkane, methylene dichloride, the chloroform equal solvent, use sodium bicarbonate, triethylamine, diisopropylethylamine, sodium hydroxide etc. as alkali, above-claimed cpd (VII) and above-claimed cpd (VIII) are synthesized.In this case,, use 1-10mol, preferred 1-3mol compound (VIII), use 1-20mol, preferred 1-5mol alkali with respect to 1mol compound (VII).Temperature of reaction can suitably be selected according to employed starting compound or reaction solvent by those skilled in the art, is generally the boiling point of room temperature-solvent.Reaction finished in 1 hour-24 hours usually, and the reaction times can suitably increase and decrease.

Separation purifying such as above-mentioned gained compound (IX) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram perhaps need not separation and purification, promptly can be used for subsequent step.

In the above-claimed cpd (IX), if need not deprotection, then need not to carry out subsequent step 6, above-claimed cpd (IX) is compound of the present invention.

(this step of step 6) is by to above-mentioned steps 5 gained compound (IX) (wherein, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄, R _eWith W and m ₁, m ₂, n ₁, n ₂, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, Y ₂, Y ₃And Z ₂Identical with the symbol implication of following formula (I)) carry out deprotection reaction, prepare compound (I-1) (wherein, X ₁, X ₂, X ₃, X ₄, R _eWith W and m ₁, m ₂, n ₁, n ₂, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, Y ₂, Y ₃And Z ₂Identical with the symbol implication of following formula (I)) method.

PG ²Deprotection reaction according to the stability of its kind and compound and different, can be according to the method for document record [with reference to Protective Groups in Organic Synthesis, T.W.Greene work, John Wiley ﹠amp; Sons publishes (1981)] or method proximate with it, for example undertaken by the solvolysis of using acid.

Specifically, for example above-claimed cpd (IX) (wherein, W is the 1H-pyrazole-3-yl, PG ²Be (2-(trimethyl silyl) oxyethyl group) methyl, PG ²1 of the pyrazoles of replacement W, X ₁, X ₂, X ₃, X ₄And R _e, and m ₁, m ₂, n ₁, n ₂, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, Y ₂, Y ₃And Z ₂Identical with the symbol implication of following formula (I)) solvolysis of mixed solvent that can be by using trifluoroacetic acid and water carries out deprotection reaction, and (wherein, W is identical with aforementioned implication, X for synthetic corresponding compound (I-1) ₁, X ₂, X ₃, X ₄And R _e, and m ₁, m ₂, n ₁, n ₂, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, Y ₂, Y ₃And Z ₂Identical with the symbol implication of following formula (I)).In this case, temperature of reaction can suitably be selected according to employed starting compound or reaction solvent by those skilled in the art, is generally the boiling point of 0 ℃-solvent.Reaction finished in 1 hour-24 hours usually, and the reaction times can suitably increase and decrease.

Separation purifying such as the compound of the present invention (I-1) of above-mentioned gained can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram.

Compound of the present invention (VIII) (wherein, m ₁, m ₂, n ₁, n ₂, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, Y ₂, Y ₃And Z ₂Identical with the symbol implication of following formula (I)) in, compound (VIII-1) (wherein, Z ₂Be N, n ₁Be 0, m ₁, m ₂, n ₂, R, R _Ai, R _Ai', R _Bj, R _Bj', R _dAnd Y ₃Identical with the symbol implication of following formula (I)) for example can be by following method preparation.

(this step of step 7) is by compound (X) (wherein, PG ³Be blocking groups such as tertiary butyl oxygen base carbonyl, m ₁, m ₂, R _Ai, R _Ai', R _BjAnd R _Bj' identical with the symbol implication of following formula (I)) and compound (XI) (wherein, n ₂, R, R _dAnd Y ₃Identical with the symbol implication of following formula (I)) amidate action, preparation compound (XII) (wherein, PG ³Identical with above-mentioned implication, m ₁, m ₂, R _Ai, R _Ai', R _BjAnd R _Bj' and n ₂, R, R _dAnd Y ₃Identical with the symbol implication of following formula (I)) method.

The above-claimed cpd that uses in this step (X) for example has piperazine-1-t-butyl formate, 2-methylpiperazine-1-t-butyl formate, 2,5-diazabicyclo [2.2.1] heptane-2-t-butyl formate, 1,4-Diazesuberane-1-t-butyl formate etc.Above-claimed cpd (X) can obtain from market channel, or by known method (for example Journal of Medicinal Chemistry,, the 29th volume No. 5,630-634 page or leaf in 1986) preparation.

The above-claimed cpd that uses in this step (XI) for example has 6-fluorine pyridine-2-formic acid, thiophene-2-carboxylic acid, 2 3,dichloro benzoic acid 99,3-chloro-2-fluorobenzoic acid, 3-(trifluoromethyl)-2-fluorobenzoic acid, furans-3-formic acid, 2-fluorine Nicotinicum Acidum etc.Above-claimed cpd (XI) can obtain from market channel, perhaps can prepare according to known method.

The amidate action that adopts in this step can use the carboxylic acid shown in the above-claimed cpd (XI) or its reactive derivatives, above-claimed cpd (X) to carry out." reactive derivatives " of above-claimed cpd (XI) for example has mixed acid anhydride, active ester, active amide etc., and they for example can obtain by the method that the open WO98/05641 communique in the world is put down in writing.Specifically, for example at tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), N, dinethylformamide, 1, in 4-two  alkane, methylene dichloride, the chloroform equal solvent, use 1-(3-dimethylaminopropyl)-condensing agent and I-hydroxybenzotriazoles such as 3-ethyl carbodiimide, it is synthetic to make above-claimed cpd (X) and above-claimed cpd (XI) carry out condensation.In this case,, use 1-3mol, preferred 1mol compound (XI), use 1-10mol, preferred 1-3mol condensing agent with respect to 1mol compound (X).Temperature of reaction can suitably be selected according to employed starting compound or reaction solvent, normally the boiling point of room temperature-employed solvent of reaction.Reaction finished in 1-24 hour usually, and the reaction times can suitably increase and decrease.

Separation purifying such as the compound of the present invention (XII) of above-mentioned gained can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram perhaps need not separation and purification, promptly can be used for subsequent step.

(this step of step 8) is with the compound of above-mentioned steps 7 gained (XII) (wherein, PG ³Identical with above-mentioned implication, m ₁, m ₂, R _Ai, R _Ai', R _BjAnd R _Bj' and n ₂, R, R _dAnd Y ₃Identical with the symbol implication of following formula (I)) blocking group PG ³Carry out deprotection, preparation (VIII-1) (wherein, m ₁, m ₂, R _Ai, R _Ai', R _BjAnd R _Bj' and n ₂, R, R _dAnd Y ₃Identical with the symbol implication of following formula (I)) shown in the method for compound.

Deprotection reaction in this step can adopt those skilled in the art known method.In this step, removing according to the stability of its kind and compound of the blocking group of above-claimed cpd (XII) and different can be according to the method for document record [with reference to Protective Groups in OrganicSynthesis, T.W.Greene work, John Wiley ﹠amp; Sons publishes (1981)] or method proximate with it carry out.For example, (XII) shown in compound (wherein, PG ³Be tert-butoxycarbonyl) deprotection reaction can by use acid solvolysis carry out.

Separation purifying such as the compound of above-mentioned gained (VIII-1) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram perhaps need not separation and purification, promptly can be used for subsequent step.

Compound of the present invention (VI) (wherein, PG ²Identical with aforementioned implication, R _e, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) in, compound (VI-1) (R wherein _eBe hydrogen atom, PG ²Identical with aforementioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) for example can prepare by the following method.

(this step of step 9) is by compound (XIII) (wherein, LG ³And LG ⁴Leavings groups such as expression halogen atom, X ₁, X ₂, X ₃And X ₄Identical with the symbol implication of following formula (I)) and compound (IV) (wherein, PG ²Identical with above-mentioned implication, W is identical with the implication of the symbol of following formula (I)) ammoxidation, preparation compound (XIV) (wherein, PG ²And LG ⁴Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄With W with identical with the symbol implication of following formula (I)) method.

The above-claimed cpd that uses in this step (IV) for example has thiazolamine, 5-amino-1,2,4-thiadiazoles, 5-methyl isophthalic acid-((2-trimethyl silyl) oxyethyl group) methyl)-1H-pyrazoles-3-amine, 1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazoles-3-amine, the 1-tertiary butyl-3-methyl isophthalic acid H-pyrazoles-5-amine etc.Above-claimed cpd (IV) can obtain from market channel, perhaps also can be according to known method (Phosphorus for example, Sulfur and Silicon and the RelatedElements,, the 177th volume No. 11,2651-2659 page or leaf in 2002; And Journal of ChemicalResearch, Synopses, 1979, the 6th volume, 198 pages) preparation.

The above-claimed cpd that uses in this step (XIII) for example has 2,6-dichloropyridine, 2,4-dichloro pyrimidine, 2,6-dichloropyrazine etc.Compound (XIII) can obtain from market channel, perhaps prepares by known method.

This step can be by carrying out with the combination of the same method of above-mentioned steps 2, method proximate with it or they and ordinary method.

The above-mentioned above-claimed cpd that obtains (XIV) (wherein, PG ²And LG ⁴Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄With W with identical with the symbol implication of following formula (I)) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram etc. separate purifying, perhaps need not separation and purification, promptly can be used for subsequent step.

(this step of step 10) is by the compound that obtains in the above-mentioned steps 9 (XIV) (wherein, PG ²And LG ⁴Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) carbonylation reaction, preparation compound (XV) (wherein, R _fBe low alkyl group, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) method.

The carbonylation reaction that adopts in this step can use those skilled in the art known method.The carbonylation reaction concrete example that uses in this step as: at N, N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, N, add alcohols such as methyl alcohol, ethanol in the dinethylformamide equal solvent, in the gained mixed solvent, 1, alkali such as dentate such as 1 '-two (diphenylphosphine) ferrocene and acid chloride palladium catalysts such as (II) and sodium bicarbonate, triethylamine exist down, by making above-claimed cpd (XIV) and reaction of carbon monoxide, can synthesize above-claimed cpd (XV).In this case,, use 0.01-1mol, preferred 0.05-0.5mol palladium catalyst, use 0.02-1mol, preferred 0.1-1mol dentate, use 1-10mol, preferred 1-3mol alkali with respect to 1mol compound (XIV).Temperature of reaction can suitably be selected according to employed starting compound or reaction solvent by those skilled in the art, is generally the boiling point of the employed solvent of 50 ℃-reaction.Reaction was finished in 1-24 hour usually, and the reaction times can suitably increase and decrease.

Separation purifying such as above-claimed cpd (XV) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram perhaps need not separation and purification, promptly can be used for subsequent step.

(step 11-1) this step is compound (XV) (wherein, the R by above-mentioned steps 10 gained _fAnd PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) hydrolysis reaction, preparation compound (XVI) (wherein, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) method.

The hydrolysis reaction that uses in this step can use those skilled in the art known method.The hydrolysis reaction concrete example that adopts in this step as: in methyl alcohol, ethanol, tetrahydrofuran (THF) equal solvent, use aqueous sodium hydroxide solution etc., compound (XV) synthesized above-claimed cpd (XVI) as alkali.In this case, with respect to 1mol compound (XV), use 1-1000mol, preferred 1-100mol alkali.Temperature of reaction can suitably be selected according to employed starting compound or reaction solvent by those skilled in the art, is generally the boiling point of room temperature-solvent.Reaction was finished in 1 hour-24 hours usually, and the reaction times can suitably increase and decrease.

Separation purifying such as the above-mentioned above-claimed cpd that obtains (XVI) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram perhaps need not separation and purification, promptly can be used for subsequent step.

(step 11-2) this step is compound (XVI) (wherein, the PG by above-mentioned steps 11-1 gained ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) reduction reaction, preparation compound (VI-1) (wherein, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) method.

The reduction reaction that adopts in this step can use those skilled in the art known method.The reduction reaction concrete example that uses in this step as: can be at N, in dinethylformamide, the tetrahydrofuran (THF) equal solvent, at room temperature, make above-claimed cpd (XVI) and N, N '-carbonyl dimidazoles reacted 12-24 hour, then with the reaction of reductive agent such as sodium borohydride, synthetic above-claimed cpd (VI-1).In this case, with respect to 1mol compound (XVI), use 1-10mol, preferred 1-3mol N, N '-carbonyl dimidazoles uses 1-20mol, preferred 1-5mol reductive agent.Temperature of reaction can suitably be selected according to employed starting compound or reaction solvent by those skilled in the art, is generally 0 ℃-room temperature.Reaction was finished in 10 minutes-24 hours usually, and the reaction times can suitably increase and decrease.

Separation purifying such as the above-mentioned above-claimed cpd that obtains (VI-1) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram perhaps need not separation and purification, promptly can be used for subsequent step.

(this step of step 12) is by above-mentioned steps 10 gained compound (XV) (wherein, R _fAnd PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) reduction reaction prepare compound (VI-1) (wherein, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) method.

The reduction reaction that adopts in this step can use those skilled in the art known method.The reduction reaction concrete example that adopts in this reaction as: at tetrahydrofuran (THF), 1, in the 4-two  alkane equal solvents, make above-claimed cpd (XV) and reductive agents reactions such as lithium borohydride, lithium aluminum hydride, synthetic above-claimed cpd (VI-1).In this case, with respect to 1mol compound (XV), use 1-20mol, preferred 1-5mol reductive agent.Temperature of reaction can suitably be selected according to employed starting compound or reaction solvent by those skilled in the art, is generally the boiling point of the employed solvent of 0 degree-reaction.Reaction was finished in 10 minutes-24 hours usually, and the reaction times can suitably increase and decrease.

Compound of the present invention (XV) (wherein, R _fBe low alkyl group, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) for example can prepare by the following method.

(this step of step 13) is by compound (XVII) (wherein, R _fBe low alkyl group, LG ⁵Leavings groups such as expression halogen atom, X ₁, X ₂, X ₃And X ₄Identical with the symbol implication of following formula (I)) and compound (IV) (wherein, PG ²Identical with above-mentioned implication, W is identical with the symbol implication of following formula (I)) ammoxidation, preparation compound (XV) (wherein, R _fBe low alkyl group, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) method.

The above-claimed cpd that uses in this step (IV) for example has thiazolamine, 5-amino-1,2,4-thiadiazoles, 5-methyl isophthalic acid-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazoles-3-amine, 1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazoles-3-amine, the 1-tertiary butyl-3-methyl isophthalic acid H-pyrazoles-5-amine etc.Above-claimed cpd (IV) can obtain by market channel, perhaps according to known method (Phosphorus for example, Sulfur and Silicon and the Related Elements,, the 177th volume No. 11,2651-2659 page or leaf in 2002; Journal of Chemical Research, Synopses, 1979, the 6th volume, 198 pages) preparation.

The above-claimed cpd that uses in this step (XVII) for example has 6-chloro-2-pyridine carboxylic acid methyl esters, 6-chloro-4-methoxyl group-2-pyridine carboxylic acid methyl esters etc.Compound (XVII) can obtain from market channel, perhaps prepares according to known method.

Above-mentioned gained above-claimed cpd (XV) (wherein, R _fBe low alkyl group, PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram etc. separate purifying, perhaps need not separation and purification, promptly can be used for subsequent step.

When above-claimed cpd imports blocking group, can carry out in any stage of above-mentioned synthetic intermediate as required.The blocking group that is imported can carry out and the above-mentioned corresponding same reaction of step; and these compounds can by with the combination of the same method of above-mentioned steps 6 or method proximate or they and ordinary method with it, the blocking group that imports is carried out deprotection.

Below, the example that imports blocking group in subtend above-claimed cpd (IV) and the above-claimed cpd (XV) describes.Those skilled in the art can be by suitable employing known method and/or following method of enumerating or method proximate with it, but imports blocking group by the known compound that market obtains to above-mentioned synthetic intermediate.

(this step of step 14) be by to compound (IV) (wherein ,-W-PG ²Be 5-methyl isophthalic acid H-pyrazole-3-yl, 5-cyclopropyl-1H-pyrazole-3-yl, 1H-pyrazole-3-yl etc.) import blocking group, prepare compound (XVIII-1) or compound (XVIII-2) (wherein, PG ⁴Be blocking groups such as methoxymethyl, (2-(trimethyl silyl) oxyethyl group) methyl, R _gBe substituting groups such as hydrogen atom, methyl, cyclopropyl) method.

The protective reaction of adopting in this step is for example at tetrahydrofuran (THF), N; dinethylformamide, 1; in 4-two  alkane, toluene, methylene dichloride, the chloroform equal solvent; use alkali such as sodium hydride; chloromethyl methyl ether, chloromethyl-2-(trimethyl silyl) ethyl ether etc. are with synthetic pairing above-claimed cpd (XVIII-1) of above-claimed cpd (IV) or above-claimed cpd (XVIII-2).In this case,, use 1-20mol, preferred 1-5mol alkali, use 1-10mol, preferred 1-3mol protection reagent with respect to 1mol compound (IV).Temperature of reaction can suitably be selected according to employed starting compound or reaction solvent by those skilled in the art, is generally 0 ℃-room temperature.Reaction finished in 10 minutes-24 hours usually, but the reaction times can suitably increase and decrease.

Separation purifying such as above-claimed cpd that obtains like this (XVIII-1) or above-claimed cpd (XVIII-2) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram, perhaps need not separation and purification, promptly can be used for subsequent step.

(this step of step 15) is by to compound (XV) (wherein, R _fAnd PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) import blocking group PG such as methoxymethyl, (2-(trimethyl silyl) oxyethyl group) methyl ⁵, preparation compound (XIX-1) or compound (XIX-2) (wherein, R _fAnd PG ²Identical with above-mentioned implication, X ₁, X ₂, X ₃And X ₄Identical with the symbol implication of following formula (I)) method.

The protective reaction of adopting in this step for example can be at tetrahydrofuran (THF), N; dinethylformamide, 1; in 4-two  alkane, toluene, methylene dichloride, the chloroform equal solvent; use alkali such as sodium hydride, diisopropylethylamine, usefulness compounds (XV) such as chloromethyl methyl ether, chloromethyl-2-(trimethyl silyl) ethyl ether carry out.In this case,, use 1-20mol, preferred 1-5mol alkali, use 1-10mol, preferred 1-3mol protection reagent with respect to 1mol compound (XV).Temperature of reaction can suitably be selected according to employed starting compound or reaction solvent by those skilled in the art, is generally 0 ℃-room temperature.Reaction was finished in 10 minutes-24 hours usually, and the reaction times can suitably increase and decrease.

Separation purifying such as above-claimed cpd that obtains like this (XIX-1) or above-claimed cpd (XIX-2) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram, perhaps need not separation and purification, promptly can be used for subsequent step.

X _1a, X _2aOr X _3aImporting or conversion, can carry out in any stage of above-mentioned synthetic intermediate with due care group.Below to compound (wherein, X shown in the formula (I) ₁Be CH, X ₂Be CX _2a, X ₃Be CH, X ₄Be N, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)), above-claimed cpd (XV) (wherein, R _f, PG ², X ₁, X ₂, X ₃And X ₄Identical with W with above-mentioned implication), above-claimed cpd (V) (wherein, PG ¹, PG ², X ₁, X ₂, X ₃And X ₄, R _eIdentical with W with above-mentioned implication) in X _2aSubstituent importing or conversion example describe.The compound of the formula V described in the explanation can have suitable blocking group in compound, step (18-1) and the step (18-2) of the formula (XV) described in wherein, the compound of the formula (I) described in the explanation of following steps (16-1)～(16-7), step (17) illustrate on the position of substitution that can import blocking group.Those skilled in the art can carry out X by the known compound that market channel obtains by suitable known method and/or following method of enumerating or method proximate with it _1a, X _2aOr X _3aSubstituent importing or conversion.

Step 16 is the methods by compound (I) synthetic compound (XX), below in (step 16-1)～(step 16-7) for example.

(step 16-1) this step is by carbonylation reaction, by compound (I) (wherein, X ₁Be CH, X ₂Be CX _2a, X _2aBe bromine atoms, X ₃Be CH, X ₄Be N, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) preparation compound (XX) (wherein, X ₁Be CH, X ₂Be CX _2a, X _2aBe alkoxy carbonyl, X ₃Be CH, X ₄Be N, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) method.

This step can be according to carrying out with the combination of the same method of above-mentioned steps 10, method proximate with it or they and ordinary method.

Separation purifying such as the compound of the present invention (XX) that obtains like this can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram.

(step 16-2) this step is by hydrolysis reaction, by compound (I) (wherein, X ₁Be CH, X ₂Be CX _2a, X _2aBe alkoxy carbonyl, X ₃Be CH, X ₄Be N, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) preparation compound (XX) (wherein, X ₁Be CH, X ₂Be CX _2a, X _2aBe carboxyl, X ₃Be CH, X ₄Be N, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) method.

This step can be according to carrying out with the combination of the same method of above-mentioned steps 11, method proximate with it or they and ordinary method.

(step 16-3) this step is by amidate action, by compound (I) (wherein, X ₁Be CH, X ₂Be CX _2a, X _2aBe carboxyl, X ₃Be CH, X ₄Be N, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) preparation compound (XX) (wherein, X _2aBe formamyl, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) method.

This step can be according to carrying out with the combination of the same method of above-mentioned steps 7, method proximate with it or they and ordinary method.The amine that uses in this step has dimethylamine, methylamine, tetramethyleneimine and 2 hydroxy ethylamine etc.

(step 16-4) this step is by reduction reaction, by compound (I) (wherein, X ₁Be CH, X ₂Be CX _2a, X _2aBe carboxyl, X ₃Be CH, X ₄Be N, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) preparation compound (XX) (wherein, X _2aBe hydroxymethyl, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) method.

This step can be according to carrying out with the combination of the same method of above-mentioned steps 11-2, method proximate with it or they and ordinary method.

(step 16-5) this step is by reaction, by compound (I) (wherein, X ₁Be CH, X ₂Be CX _2a, X _2aBe hydroxymethyl, X ₃Be CH, X ₄Be N, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) preparation compound (XX) (wherein, X _2aBe the mesyloxy methyl, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) method.

This step can be according to carrying out with the combination of the same method of above-mentioned steps 4, method proximate with it or they and ordinary method.

(step 16-6) this step is by substitution reaction, by compound (I) (wherein, X ₁Be CH, X ₂Be CX _2a, X _2aBe mesyloxy methyl, X ₃Be CH, X ₄Be N, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) preparation compound (XX) (wherein, X _2aBe R _iR _hNCH ₂-Ji (wherein, R _iAnd R _hIdentical or different, for hydrogen atom, can substituted low alkyl group etc., perhaps R _iAnd R _hForm together and can have substituent aliphatic heterocyclic radical), m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) method.

The substitution reaction of adopting in this step for example can be at chloroform, methylene dichloride, tetrahydrofuran (THF), N, in dinethylformamide, the dimethyl sulfoxide (DMSO) equal solvent, at salt of wormwood, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] 11 carbon-alkali such as 7-alkene exist down, with compound (I) (wherein, X ₁Be CH, X ₂Be CX _2a, X _2aBe mesyloxy methyl, X ₃Be CH, X ₄Be N, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) with dimethylamine, 1,2,3-triazoles, 1,2, R such as 4-triazole _iR _hThe nucleophilic reagent reaction that NH represents is synthesized.In this case,, use 1-20mol, preferred 1-5mol alkali, use 1-10mol, preferred 1-3mol nucleophilic reagent with respect to 1mol compound (I).Temperature of reaction can suitably be selected according to the starting compound or the reaction solvent that use by those skilled in the art, but is generally the boiling point of the solvent of room temperature-reaction use.Reaction finished in 1-24 hour usually, and the reaction times can suitably increase and decrease.

The above-claimed cpd of the present invention (XX) that obtains like this can pass through known method, for example concentrates, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram etc. separate purifying.

(step 16-7) this step is by linked reaction, by compound (I) (wherein, X ₁Be CH, X ₂Be CX _2a, X _2aBe bromine atoms, X ₃Be CH, X ₄Be N, m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) preparation compound (XX) (wherein, X _2aBe R _jR _kN-base (wherein, R _jAnd R _kIdentical or different, for hydrogen atom, can substituted low alkyl group, lower acyl, rudimentary formamyl or elementary alkoxy carbonyl etc., perhaps R _jAnd R _kForm together and can have substituent heterocyclic radical), m ₁, m ₂, n ₁, n ₂, i, j, R, R _Ai, R _Ai', R _Bj, R _Bj', R _c, R _d, R _e, Y ₁, Y ₂, Y ₃, Z ₁, Z ₂Identical with W with the symbol implication of following formula (I)) method.

This step can be according to carrying out with the combination of the same method of above-mentioned steps 2, method proximate with it or they and ordinary method.The nucleophilic reagent that uses in this step has R such as 1-methyl-2-imidazolidone, 2-Pyrrolidone, 2- oxazolidone, piperazine or morpholine _jR _kThe amine that NH represents, acid amides, urea or carbamate etc.

(step 17) this step is with compound (XV) (wherein, R _fBe low alkyl group, PG ²Identical with above-mentioned implication, X ₁Be CH, X ₂Be CX _2a, X _2aBe benzyloxy, X ₃Be CH, X ₄Be N, W is identical with the symbol implication of following formula (I)) the blocking group benzyl of hydroxyl remove preparation compound (XXI) (wherein, R _f, PG ²Identical with W with above-mentioned implication) method.

Removing of the blocking group of this step can be according to method [, 2nd edition, the John Wiley ﹠amp outstanding with reference to ProtectiveGroups in Organic Synthesis, T.W.Greene of document record; Sons publishes (1991)], the combination of method proximate with it or they and ordinary method carries out, for example adopt and use the hydroxide palladium carbon catalyst to carry out catalytic hydrogenation etc.

When using the hydroxide palladium carbon catalyst in the removing of benzyl, the amount of catalyzer is generally the 0.01-1000 equivalent, preferred 0.1-10 equivalent.

The reaction solvent that uses in this reaction only otherwise cause obstruction to get final product to reaction is not particularly limited, and methyl alcohol, ethanol etc. are for example arranged.

The above-claimed cpd of the present invention (XXI) that obtains like this can pass through known method, for example concentrates, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram etc. separate purifying.

Step 18 is the methods by compound (V) synthetic compound (XXII), below enumerates in (step 18-1) and (step 18-2).

(step 18-1) this step be by compound (V) (in the formula, R _e, W, PG ¹And PG ²Identical with above-mentioned implication, X ₁Be CH, X ₂Be CX _2a, X _2aBe hydroxyl, X ₃Be CH, X ₄Be N) and preparation compound (XXII) (in the formula, R _e, W, PG ¹And PG ²Identical with above-mentioned implication, X _2aBe trifluoro-methanesulfonyl oxy) method.

The reaction of adopting in this step can use those skilled in the art known method.The reaction concrete example that adopts in this step as: at chloroform, methylene dichloride, tetrahydrofuran (THF), N, in dinethylformamide, ether, the ethyl acetate equal solvent, in the presence of alkali such as 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, by making above-claimed cpd (V) and trifluoromethanesulfonic acid anhydride reactant, can obtain compound (XXII) (in the formula, R _e, W, PG ¹And PG ²Identical with above-mentioned implication, X _2aBe trifluoro-methanesulfonyl oxy).In this case, with respect to 1mol compound (V), use 1-10mol, preferred 1-3mol trifluoromethanesulfanhydride anhydride, use 1-20mol, preferred 1-6mol alkali, temperature of reaction can suitably be selected according to employed starting compound by those skilled in the art, is generally 0 ℃-room temperature.Reaction finished at 10 minutes-2 hours usually, and the reaction times can suitably increase and decrease.

Separation purifying such as the above-claimed cpd that obtains like this (XXII) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram, or, be used for subsequent step without separation and purification.

(step 18-2) this step is by carbonylation reaction, by compound (V) (in the formula, R _e, W, PG ¹And PG ²Identical with above-mentioned implication, X ₁Be CH, X ₂Be CX _2a, X _2aBe trifluoro-methanesulfonyl oxy, X ₃Be CH, X ₄Be N) and preparation compound (XXII) (in the formula, R _e, W, PG ¹And PG ²Identical with above-mentioned implication, X _2aBe alkoxy carbonyl) method.

The compound of the present invention (XXII) that obtains like this can pass through known method, for example concentrates, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram etc. separate purifying.

Importing or conversion substituting group can carry out in any stage of above-mentioned synthetic intermediate or its blocking group in W.(wherein, W is a thiazol-2-yl to compound shown in the following subtend formula V, PG ¹And PG ²Identical with above-mentioned implication, R _e, X ₁, X ₂, X ₃, X ₄Identical with W with the symbol implication of following formula (I)) W in import substituent example and describe.Those skilled in the art can be according to suitable known method and/or following method of enumerating or method proximate with it; in any stage of above-mentioned synthetic intermediate or its blocking group, undertaken to substituent importing of W or conversion by the known compound that can obtain from market.

(step 19) this step is by halogenating reaction, by compound (V) (wherein ,-W-PG ²Be thiazol-2-yl, PG ¹Identical with above-mentioned implication, R _e, X ₁, X ₂, X ₃And X ₄Identical with the symbol implication of following formula (I)) (wherein, G is halogen atoms such as chlorine, bromine, iodine to preparation compound (XXHI), PG ¹Identical with above-mentioned implication, R _e, X ₁, X ₂, X ₃And X ₄Identical with the symbol implication of following formula (I)) method.

The halogenating reaction of using in this step for example is at tetrahydrofuran (THF), water, acetate, methyl alcohol, ethanol, 1, in 4-two  alkane, methylene dichloride, chloroform, the toluene equal solvent, make compound (V) (wherein ,-W-PG ²Be thiazol-2-yl, PG ¹Identical with above-mentioned implication, R _e, X ₁, X ₂, X ₃And X ₄Identical with the symbol implication of following formula (I)) carry out with halide reagent reactions such as N-chloro-succinimide, N-bromine succinimide, N-iodine succinimides.In this reaction,, use 1-3mol, preferred 1mol halide reagent with respect to 1mol compound (V).In this case, temperature of reaction can suitably be selected according to employed starting compound or reaction solvent, is generally 0 ℃-boiling point.Reaction finished in 1-24 hour usually, and the reaction times can suitably increase and decrease.

The compound of the present invention (XXIII) that obtains like this can pass through known method, for example concentrates, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram etc. separate purifying, perhaps need not separation and purification, promptly can be used for subsequent step.

(step 20) this step is by fluoridation, by compound (XXIV) (wherein, PG ⁵Be blocking groups such as methoxymethyl, (2-(trimethyl silyl) oxyethyl group) methyl, PG ¹Identical with above-mentioned implication, R _e, X ₁, X ₂, X ₃And X ₄Identical with the symbol implication of following formula (I)) preparation compound (XXV) (wherein, PG ⁵Be blocking groups such as methoxymethyl, (2-(trimethyl silyl) oxyethyl group) methyl, PG ¹Identical with above-mentioned implication, R _e, X ₁, X ₂, X ₃And X ₄Identical with the symbol implication of following formula (I)) method.

The fluoridation that adopts in this step for example can be passed through to compound (XXIV) (wherein, PG ⁵Be blocking groups such as methoxymethyl, (2-(trimethyl silyl) oxyethyl group) methyl, PG ¹Identical with above-mentioned implication, R _e, X ₁, X ₂, X ₃And X ₄Identical with the symbol implication of following formula (I)) tetrahydrofuran (THF) or solution such as toluene in drip the hexane solution of n-Butyl Lithium, the tetrahydrofuran solution that drips N-fluorobenzene sulfimide then carries out.In this reaction,, use 1-3mol, preferred 1mol fluorination reagent with respect to 1mol compound (XXIV).In this case, temperature of reaction can suitably be selected according to employed starting compound or reaction solvent, is generally-78 ℃ to-20 ℃.Reaction finished in 15 minutes-2 hours usually, and the reaction times can suitably increase and decrease.

Separation purifying such as the above-claimed cpd that obtains like this (XXV) can for example concentrate by known separation purification method, concentrating under reduced pressure, crystallization, solvent extraction, redeposition, chromatogram perhaps need not separation and purification, promptly can be used for subsequent step.

Aurora-A and B restraining effect to the compound of general formula of the present invention (I) describes below.

The Aurora-A restraining effect

(1) purifying of Aurora-A

To import in the expression vector high level expression in e. coli bl21-Codon Plus (DE3)-RIL bacterial strain at the cDNA that N-terminal merges the Aurora-A that histidine mark is arranged.Reclaim intestinal bacteria, make its dissolving, the Aurora-A protein adsorption that will have histidine mark then by wash-out in the pillar, is carried out desalination with desalting column to active fraction with imidazoles on the nickel chelate column, make purifying enzyme.

(2) determination of activity of Aurora-A

In the determination of activity of Aurora-A, substrate uses the synthetic peptide ケ Application プチ De (Kemptide:Lys-Arg-Arg-Ala-Ser-Lys-Gly) bought by SIGMA (SEQ.ID.NO.:1) [Certificate of analysis (upstate)].

Reaction is with the method for upstate company [Kinase Profiler ^TMAssay Protocols] partly change and carry out.Load responsive fluid is 21.1 μ l, the composition of reaction buffer (R2 damping fluid) is 50mMTris-hydrochloride buffer (pH 7.4)/15mM magnesium acetate/0.2mM quadrol-N, N, N ', N '-tetraacethyl (EDTA), to the peptide substrate of Aurora-A that wherein adds purifying and 100 μ M and unlabelled Triphosadens of 20 μ M (ATP) and 0.5 μ Ci [γ- ³³P] mark ATP (more than the 2500Ci/mmole), reacted 20 minutes down at 30 ℃.The 350mM phosphoric acid buffer that in reaction system, adds 10 μ l then, termination reaction.Peptide substrate is adsorbed on P81 filter paper 96 orifice plates, then repeatedly with the washing of 130mM phosphoric acid buffer, with its radioactivity of liquid flashing counting determining.[γ- ³³P] mark ATP buys by アマシヤ system バイオサイエ Application スス.

When in reaction system, adding test-compound, at first prepare dimethyl sulfoxide (DMSO) (DMSO) dilution series of compound, add 1.1 μ l then.With the sample that in reaction system, adds 1.1 μ l DMSO gained in contrast.

The Aurora-B restraining effect

(1) purifying of Aurora-B

To import in the expression vector high level expression in e. coli bl21-Codon Plus (DE3)-RIL bacterial strain at the cDNA that N-terminal merges the Aurora-B that histidine mark is arranged.Reclaim intestinal bacteria, make its dissolving, the Aurora-B protein adsorption that will have histidine mark then by wash-out in the pillar, is carried out desalination with desalting column to active fraction with imidazoles on the nickel chelate column, make purifying enzyme.

(2) determination of activity of Aurora-B

In the determination of activity of Aurora-B, substrate uses the synthetic peptide ケ Application プチ De (Kemptide:Lys-Arg-Arg-Ala-Ser-Lys-Gly) bought by SIGMA (SEQ.ID.NO.:1) [Certificate of analysis (upstate)].

Reaction is that the activity determination method with Aurora-A partly changes and carries out.Load responsive fluid is 21.1 μ l, the composition of reaction buffer (R2 damping fluid) is 50mM Tris-hydrochloride buffer (pH 7.4)/15mM magnesium acetate/0.2mM quadrol-N, N, N ', N '-tetraacethyl (EDTA), to the peptide substrate of Aurora-B that wherein adds purifying and 100 μ M and unlabelled Triphosadens of 100 μ M (ATP) and 1 μ Ci [γ- ³³P] mark ATP (more than the 2500Ci/mmole), reacted 20 minutes down at 30 ℃.The 350mM phosphoric acid buffer that in reaction system, adds 10 μ l then, termination reaction.Peptide substrate is adsorbed on P81 filter paper 96 orifice plates, then repeatedly with the washing of 130mM phosphoric acid buffer, with its radioactivity of liquid flashing counting determining.[γ- ³³P] mark ATP buys by アマシヤ system バイオサイエ Application ス.

As shown in table 1, the Aurora-A selective inhibitory activity effect of compound exhibits excellence of the present invention.

[table 1]

Embodiment	Aurora-A restraining effect (IC ₅₀，nM)	Aurora-B restraining effect (IC ₅₀，nM)	Embodiment	Aurora-A restraining effect (IC ₅₀，nM)	Aurora-B restraining effect (IC ₅₀，nM)
Embodiment	Aurora-A restraining effect (IC ₅₀，nM)	Aurora-B restraining effect (IC ₅₀，nM)	Embodiment	Aurora-A restraining effect (IC ₅₀，nM)	Aurora-B restraining effect (IC ₅₀，nM)	Embodiment 5	0.67	440	Embodiment 61	17	530
Embodiment 6	0.5	200	Embodiment 62	12	380	Embodiment 5	0.67	440	Embodiment 61	17	530
Embodiment 6	0.5	200	Embodiment 62	12	380	Embodiment 8	1.9	1400	Embodiment 63	1.3	570
Embodiment 9	1.3	760	Embodiment 64	110	2500	Embodiment 8	1.9	1400	Embodiment 63	1.3	570
Embodiment 9	1.3	760	Embodiment 64	110	2500	Embodiment 10	0.49	92	Embodiment 65	2.4	160
Embodiment 11	1.3	570	Embodiment 66	3.4	250	Embodiment 10	0.49	92	Embodiment 65	2.4	160
Embodiment 11	1.3	570	Embodiment 66	3.4	250	Embodiment 12	0.52	400	Embodiment 67	17	320
Embodiment 13	0.89	380	Embodiment 68	11	670	Embodiment 12	0.52	400	Embodiment 67	17	320
Embodiment 13	0.89	380	Embodiment 68	11	670	Embodiment 15	1.4	1000	Embodiment 69	32	920
Embodiment 16	1.8	1300	Embodiment 70	2.4	96	Embodiment 15	1.4	1000	Embodiment 69	32	920
Embodiment 16	1.8	1300	Embodiment 70	2.4	96	Embodiment 17	1.2	3200	Embodiment 71	3	370
Embodiment 18	1.8	830	Embodiment 72	27	170	Embodiment 17	1.2	3200	Embodiment 71	3	370
Embodiment 18	1.8	830	Embodiment 72	27	170	Embodiment 19	0.9	530	Embodiment 73	17	410
Embodiment 20	1.1	1800	Embodiment 74	47	850	Embodiment 19	0.9	530	Embodiment 73	17	410
Embodiment 20	1.1	1800	Embodiment 74	47	850	Embodiment 21	16	6800	Embodiment 75	0.44	89
Embodiment 22	2.9	1500	Embodiment 76	0.44	47	Embodiment 21	16	6800	Embodiment 75	0.44	89
Embodiment 22	2.9	1500	Embodiment 76	0.44	47	Embodiment 23	3.6	1200	Embodiment 77	4.1	1300
Embodiment 24	23	26000	Embodiment 78	2	240	Embodiment 23	3.6	1200	Embodiment 77	4.1	1300
Embodiment 24	23	26000	Embodiment 78	2	240	Embodiment 25	1.1	770	Embodiment 79	26	2200
Embodiment 26	1.1	450	Embodiment 81	0.33	300	Embodiment 25	1.1	770	Embodiment 79	26	2200
Embodiment 26	1.1	450	Embodiment 81	0.33	300	Embodiment 27	3.3	1700	Embodiment 82	0.51	210
Embodiment 28	0.52	310	Embodiment 83	0.64	800	Embodiment 27	3.3	1700	Embodiment 82	0.51	210
Embodiment 28	0.52	310	Embodiment 83	0.64	800	Embodiment 29	0.97	590	Embodiment 84	0.72	400
Embodiment 30	1.1	320	Embodiment 85	1	610	Embodiment 29	0.97	590	Embodiment 84	0.72	400
Embodiment 30	1.1	320	Embodiment 85	1	610	Embodiment 31	37	760	Embodiment 86	0.66	560
Embodiment 32	3.7	4800	Embodiment 87	1.2	1400	Embodiment 31	37	760	Embodiment 86	0.66	560
Embodiment 32	3.7	4800	Embodiment 87	1.2	1400	Embodiment 33	50	3000	Embodiment 88	0.72	1000
Embodiment 35	31	3400	Embodiment 89	0.38	200	Embodiment 33	50	3000	Embodiment 88	0.72	1000
Embodiment 35	31	3400	Embodiment 89	0.38	200	Embodiment 36	2.6	3200	Embodiment 90	1.5	860
Embodiment 37	4.9	8800	Embodiment 91	1.4	1200	Embodiment 36	2.6	3200	Embodiment 90	1.5	860
Embodiment 37	4.9	8800	Embodiment 91	1.4	1200	Embodiment 38	9.1	9500	Embodiment 92	0.93	830
Embodiment 39	67	9100	Embodiment 93	0.36	250	Embodiment 38	9.1	9500	Embodiment 92	0.93	830
Embodiment 39	67	9100	Embodiment 93	0.36	250	Embodiment 40	0.99	1900	Embodiment 94	1.1	1100
Embodiment 41	2.9	5000	Embodiment 95	0.59	250	Embodiment 40	0.99	1900	Embodiment 94	1.1	1100
Embodiment 41	2.9	5000	Embodiment 95	0.59	250	Embodiment 42	1	530	Embodiment 96	0.57	690
Embodiment 43	1.1	460	Embodiment 97	0.62	830	Embodiment 42	1	530	Embodiment 96	0.57	690
Embodiment 43	1.1	460	Embodiment 97	0.62	830	Embodiment 44	0.89	1100	Embodiment 98	0.36	230
Embodiment 45	2.5	4800	Embodiment 99	0.77	460	Embodiment 44	0.89	1100	Embodiment 98	0.36	230
Embodiment 45	2.5	4800	Embodiment 99	0.77	460	Embodiment 46	6.1	1400	Embodiment 100	2.6	1300
Embodiment 47	5.5	2200	Embodiment 103	0.76	250	Embodiment 46	6.1	1400	Embodiment 100	2.6	1300
Embodiment 47	5.5	2200	Embodiment 103	0.76	250	Embodiment 48	2.8	2900	Embodiment 104	1.1	1400
Embodiment 49	1.4	4400	Embodiment 105	1.4	1000	Embodiment 48	2.8	2900	Embodiment 104	1.1	1400
Embodiment 49	1.4	4400	Embodiment 105	1.4	1000	Embodiment 50	2.2	5400	Embodiment 106	0.88	400
Embodiment 51	0.98	930	Embodiment 107	0.32	190	Embodiment 50	2.2	5400	Embodiment 106	0.88	400
Embodiment 51	0.98	930	Embodiment 107	0.32	190	Embodiment 55	20	7400	Embodiment 108	0.59	800
Embodiment 56	2.1	2900	Embodiment 109	0.42	520	Embodiment 55	20	7400	Embodiment 108	0.59	800
Embodiment 56	2.1	2900	Embodiment 109	0.42	520	Embodiment 57	15	28000	Embodiment 110	0.59	750
Embodiment 58	4.8	9900	Embodiment 112	0.81	230	Embodiment 57	15	28000	Embodiment 110	0.59	750
Embodiment 58	4.8	9900	Embodiment 112	0.81	230	Embodiment 60	2.6	4800	Embodiment 113	8.0	8400

Cell inhibitory effect effect to the compound of general formula of the present invention (I) describes below.

The effect of drugs decision method that uses cell to carry out

A) reagent

Foetal calf serum (FCS) is available from モ Le グ one ト company, and the DMEM substratum is available from イ Application PVC トロジエ Application company.WST-8 is available from キシダ KCC.

B) cell

Human cervical carcinoma cell (HeLa S3) is by American type culture collection (AmericanType Culture Collection; ATCC) obtain.

C) effect decision method

In the DMEM substratum that has added 10% FCS, dispensing makes the cell suspending liquid that 750 cells/100 μ l are arranged in every hole in 96 hole plastic plates with cell suspension.Under 37 ℃, at 5%CO ₂Cultivate a night in-95% air.Divide gradient dilution with medicine with dimethyl sulfoxide (DMSO), with the DMEM substratum dilution of having added 10%FCS, dispensing 100 μ l are to the plate of having inoculated cell in advance then again.Again at 37 ℃, 5%CO ₂Cultivated three days in-95% air.(people, Anal.Commun. such as H.Tominaga, 36,47-50 (1999)) measures the propagation of cultivating the back cell by the WST-8 method.Here, the WST-8 method is to point to add 20 μ l WST-8 reagent solutions in each hole, continues to cultivate 45 minutes agitating plate then, the first that generates with colorimetric method for determining down at 37 ℃ Amount, obtain the method for medicine inhibiting rate.Obtain 50% propagation inhibition concentration (EC of compound ₅₀, μ M).

As shown in table 2, compound of the present invention shows excellent cell inhibitory effect effect for the cancer cells (HeLa S3) from the people.

[table 2]

Embodiment	Cell inhibitory effect effect (IC ₅₀.μM)	Embodiment	Cell inhibitory effect effect (IC ₅₀.μM)
Embodiment	Cell inhibitory effect effect (IC ₅₀.μM)	Embodiment	Cell inhibitory effect effect (IC ₅₀.μM)	Embodiment 5	11.00	Embodiment 56	1.40
Embodiment 6	0.40	Embodiment 58	3.00	Embodiment 5	11.00	Embodiment 56	1.40
Embodiment 6	0.40	Embodiment 58	3.00	Embodiment 8	0.25	Embodiment 62	0.86
Embodiment 17	1.10	Embodiment 66	2.90	Embodiment 8	0.25	Embodiment 62	0.86
Embodiment 17	1.10	Embodiment 66	2.90	Embodiment 19	0.92	Embodiment 68	5.10
Embodiment 22	3.50	Embodiment 71	3.00	Embodiment 19	0.92	Embodiment 68	5.10
Embodiment 22	3.50	Embodiment 71	3.00	Embodiment 25	0.80	Embodiment 76	11.00
Embodiment 28	1.10	Embodiment 77	1.60	Embodiment 25	0.80	Embodiment 76	11.00
Embodiment 28	1.10	Embodiment 77	1.60	Embodiment 29	3.30	Embodiment 86	0.51
Embodiment 30	2.50	Embodiment 89	0.36	Embodiment 29	3.30	Embodiment 86	0.51
Embodiment 30	2.50	Embodiment 89	0.36	Embodiment 36	6.80	Embodiment 95	0.22
Embodiment 39	11.00	Embodiment 104	0.99	Embodiment 36	6.80	Embodiment 95	0.22
Embodiment 39	11.00	Embodiment 104	0.99	Embodiment 40	6.50	Embodiment 106	0.40
Embodiment 44	2.40	Embodiment 107	0.21	Embodiment 40	6.50	Embodiment 106	0.40
Embodiment 44	2.40	Embodiment 107	0.21	Embodiment 46	4.10	Embodiment 108	1.20
Embodiment 50	3.60			Embodiment 46	4.10	Embodiment 108	1.20

Use cell to carry out the method that the drug combination effect is judged

(a) reagent

Foetal calf serum (FCS) is available from モ Le グ one ト company, and the DMEM substratum is available from イ Application PVC トロジエ Application company, and taxol is available from シグマ (trade(brand)name キソ one Le).WST-8 is available from キシダ KCC.

B) cell

Human cervical carcinoma cell (HeLa S3) is obtained by American type culture collection (ATCC).

C) effect decision method

Cell suspension in the DMEM substratum that has added 10%FCS, in dispensing to the 2 96 hole plastic plate, is made the cell suspending liquid that 750 cells/100 μ l are arranged in every hole.Under 37 ℃, at 5%CO ₂Cultivate a night in-95% air.Divide gradient dilution with medicine with dimethyl sulfoxide (DMSO), again with DMEM or contain the 2nM taxol and added the DMEM substratum dilution of 10%FCS, then dispensing to the plate of having inoculated cell in advance, every each 100 μ l, the taxol final concentration of this moment is 1nM.Concentration when giving compound of the present invention separately is 0.03,0.1,0.3,1 and 3 μ M.Again at 37 ℃, 5%CO ₂Cultivated three days in-95% air.(people, Anal.Commun. such as H.Tominaga, 36,47-50 (1999)) measures the propagation of cultivating the back cell by the WST-8 method.Here, the WST-8 method is to point to add 20 μ l WST-8 reagent solutions in each hole, continues to cultivate 45 minutes agitating plate then, the first that generates with colorimetric method for determining down at 37 ℃

Amount, obtain the method for medicine inhibiting rate.Value during with the DMSO individual curing is 0%, obtains the proliferation inhibiting effect of this moment taxol and compound of the present invention.

As shown in table 3, compound of the present invention shows excellent cell inhibitory effect effect for the cancer cells (HeLa S3) from the people, shows the synergy with taxol simultaneously.

[table 3]

Embodiment	Cell inhibitory effect effect (%) when giving taxol (1nM) separately	Embodiment compound concentrations (μ M)	Cell inhibitory effect effect (%) when giving the embodiment compound separately	Unite the cell inhibitory effect effect (%) when giving taxol and embodiment compound
Embodiment		Embodiment compound concentrations (μ M)			Embodiment 5	44.1	0.1	0.0	72.8
Embodiment 6	44.1	0.3	19.6	89.0	Embodiment 5	44.1	0.1	0.0	72.8
Embodiment 6	44.1	0.3	19.6	89.0	Embodiment 8	37.8	0.1	4.6	87.1
Embodiment 17	45.4	0.3	0.0	73.8	Embodiment 8	37.8	0.1	4.6	87.1
Embodiment 17	45.4	0.3	0.0	73.8	Embodiment 19	44.1	0.1	0.0	77.6
Embodiment 22	43.3	1.0	18.5	80.9	Embodiment 19	44.1	0.1	0.0	77.6
Embodiment 22	43.3	1.0	18.5	80.9	Embodiment 25	45.4	0.1	0.0	65.1
Embodiment 28	45.4	0.3	0.0	84.5	Embodiment 25	45.4	0.1	0.0	65.1
Embodiment 28	45.4	0.3	0.0	84.5	Embodiment 29	45.4	0.3	0.0	77.3
Embodiment 30	36.8	1.0	29.1	90.1	Embodiment 29	45.4	0.3	0.0	77.3
Embodiment 30	36.8	1.0	29.1	90.1	Embodiment 36	45.4	3.0	17.2	83.4
Embodiment 39	43.3	3.0	5.4	72.2	Embodiment 36	45.4	3.0	17.2	83.4
Embodiment 39	43.3	3.0	5.4	72.2	Embodiment 40	43.3	1.0	6.5	76.9
Embodiment 44	44.1	0.3	7.1	86.5	Embodiment 40	43.3	1.0	6.5	76.9
Embodiment 44	44.1	0.3	7.1	86.5	Embodiment 46	36.8	1.0	8.5	75.0
Embodiment 50	45.4	1.0	6.0	82.0	Embodiment 46	36.8	1.0	8.5	75.0
Embodiment 50	45.4	1.0	6.0	82.0	Embodiment 56	37.8	0.3	6.5	81.8
Embodiment 58	45.4	1.0	0.0	81.4	Embodiment 56	37.8	0.3	6.5	81.8
Embodiment 58	45.4	1.0	0.0	81.4	Embodiment 62	36.8	0.1	2.9	68.0
Embodiment 66	36.8	1.0	7.2	60.9	Embodiment 62	36.8	0.1	2.9	68.0
Embodiment 66	36.8	1.0	7.2	60.9	Embodiment 68	36.8	3.0	27.3	71.8
Embodiment 71	36.8	1.0	13.2	60.7	Embodiment 68	36.8	3.0	27.3	71.8
Embodiment 71	36.8	1.0	13.2	60.7	Embodiment 75	45.4	0.3	27.1	91.5
Embodiment 77	36.8	0.3	2.2	51.8	Embodiment 75	45.4	0.3	27.1	91.5
Embodiment 77	36.8	0.3	2.2	51.8	Embodiment 86	43.3	0.03	6.2	71.6
Embodiment 89	43.3	0.1	19.1	85.8	Embodiment 86	43.3	0.03	6.2	71.6
Embodiment 89	43.3	0.1	19.1	85.8	Embodiment 95	44.1	0.03	0.0	73.5
Embodiment 104	43.3	0.3	6.3	81.6	Embodiment 95	44.1	0.03	0.0	73.5
Embodiment 104	43.3	0.3	6.3	81.6	Embodiment 106	43.3	0.1	6.1	76.7
Embodiment 107	43.3	0.03	11.5	74.1	Embodiment 106	43.3	0.1	6.1	76.7
Embodiment 107	43.3	0.03	11.5	74.1	Embodiment 108	44.1	1.0	17.2	86.4

As known from the above, compound of the present invention not only has the excellent cell inhibitory effect effect based on the Aurora-A selective inhibitory activity, by uniting use with other cancer therapy drug, can show synergy, so useful as anti-cancer agents.That is, the anticarcinogen that contains the pharmaceutical composition and the Aurora-A selective depressant of novel aminopyridine derivative of the present invention or its pharmacologically acceptable salt or ester or contain compound or pharmaceutically acceptable salt thereof of the present invention or ester in cancer patients's treatment effectively.

This pharmaceutical composition and this inhibitor and this anticarcinogen can contain pharmaceutically acceptable carrier or thinner.Wherein, " pharmaceutically acceptable carrier or thinner " has vehicle [for example fat, beeswax, semisolid and liquid polyol, natural or curing wet goods]; Water (for example distilled water, particularly distilled water for injection etc.), physiological saline, alcohol (for example ethanol), glycerine, polyvalent alcohol, D/W, mannitol, plant wet goods; Additive [extender, disintegrating agent, binding agent, lubricant, wetting agent, stablizer, emulsifying agent, dispersion agent, sanitas, sweeting agent, tinting material, seasonings or perfume compound, densifier, thinner, buffer substance, solvent or solubilizing agent are for example arranged, can realize storage effect medicament, change salt, Drug coating or the antioxidant of osmotic pressure] etc.

The preferred tumour that is expected to obtain compounds for treating effect of the present invention for example has solid carcinoma of people etc.People's solid carcinoma for example has the cancer of the brain, the incidence cancer, esophagus cancer, thyroid carcinoma, small cell lung cancer, nonsmall-cell lung cancer, mammary cancer, cancer of the stomach, the gall-bladder cholangiocarcinoma, liver cancer, carcinoma of the pancreas, colorectal carcinoma, the rectum cancer, ovarian cancer, the chorioepithelium cancer, uterus carcinoma, cervical cancer, the renal pelvis ureters cancer, bladder cancer, prostate cancer, penile cancer, carcinoma of testis, embryonal carcinoma, dimension Mu Shi cancer, skin carcinoma, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma etc.

Below, above-mentioned " its pharmacologically acceptable salt or ester " described.

Compound of the present invention can use with the form of its pharmacologically acceptable salt during as anticarcinogen etc.The exemplary of pharmacologically acceptable salt for example has alkali-metal salt such as sodium, potassium, inorganic acid salts such as hydrochloride, vitriol, nitrate, phosphoric acid salt, carbonate, supercarbonate, perchlorate; Organic acid salts such as second hydrochloric acid, propionic salt, lactic acid salt, maleate, fumarate, tartrate, malate, Citrate trianion, ascorbate salt for example; Sulfonate such as mesylate, isethionate, benzene sulfonate, tosylate for example; Acidic amino acid such as aspartate, glutaminate salt etc. for example.The salt of the compound of above-mentioned formula (I) is preferably inorganic acid salts such as hydrochloride, vitriol, nitrate, phosphoric acid salt, carbonate, supercarbonate, perchlorate, further the preferably salt hydrochlorate.

The preparation method of the pharmacologically acceptable salt of The compounds of this invention can carry out normally used method appropriate combination in the synthetic field of organic chemistry.Have specifically: the free state solution of compound of the present invention is carried out neutralization titration etc. with alkaline solution or acid solution.

The ester of The compounds of this invention for example has methyl esters, ethyl ester etc.These esters can carry out esterification with free carboxy according to ordinary method and prepare.

Each preparation in the combination preparation of the present invention can be selected various forms, and oral preparations such as tablet, capsule, powder, granule or liquid preparation are for example arranged, perhaps for example solution or suspension etc. through the liquid non-oral formulation, suppository, ointment etc. of sterilization.

Solid preparation can also can use appropriate carriers (additive) preparation directly with tablet, capsule, granule or form of powder preparation.Described carrier (additive) for example has carbohydrates such as lactose or glucose; Starch based such as corn, wheat or rice are for example arranged; Lipid acid such as stearic acid are for example arranged; Inorganic salt such as metasilicic acid magnesium aluminate or anhydrous ca phosphate are for example arranged; Synthetic macromolecules such as polyvinylpyrrolidone or polyalkylene glycol are for example arranged; Soaps such as calcium stearate or Magnesium Stearate are for example arranged; Alcohols such as stearyl alcohol or benzylalcohol are for example arranged; Synthetic cellulose derivatives such as methylcellulose gum, carboxymethyl cellulose, ethyl cellulose or Vltra tears are for example arranged; Other also has normally used additives such as gelatin, talcum powder, vegetables oil, gum arabic.

Solid preparations such as these tablets, capsule, granule and powder are benchmark with the total formulation weight amount normally, for example contain 0.1-100 weight %, preferably contain the effective constituent of compound shown in the 5-98 weight % following formula (I).

Liquid preparation can make water, alcohols or for example soybean oil, peanut oil, sesame wet goods are made suspension, syrup, injection, infusion solution forms such as (intravenous fluids) from wet goods normally used suitable additive in liquid preparation of plant.

During particularly with non-oral intramuscularly, intravenous injection or hypodermic form administration, appropriate solvent or thinner for example have distilled water for injection, the Xylotox aqueous solution (intramuscular injection), physiological saline, D/W, ethanol, polyoxyethylene glycol, propylene glycol, intravenous injection liquid (for example aqueous solution of citric acid and Trisodium Citrate etc.) or electrolyte solution (transfusion vein injection and intravenous injection are used) etc., perhaps their mixing solutions.

These injections can also be to dissolve in use to contain the powder or the suitable form of the material of carrier (additive) except that dissolved substances in advance.With the total formulation weight amount is benchmark, and described injection liquid for example can contain the effective ingredient of 0.1-10 weight %.

With the total formulation weight amount is benchmark, and liquid preparations such as suspensoid for oral use, syrup for example can contain the effective constituent of 0.1-10 weight %.

Each preparation in the combination preparation of the present invention can also easily be prepared by those skilled in the art according to ordinary method or common technology.For example,, when it is oral preparations, for example an amount of this anticarcinogen can be mixed with an amount of lactose, prepare in the hard gelatine capsule that is fit to oral administration of packing into for containing the preparation of uniting other cancer therapy drug of use with compound shown in the above-mentioned general formula (I).When the preparation that contains this anticarcinogen is injection, for example an amount of this anticarcinogen can be mixed in right amount with 0.9% physiological saline, this mixture is packed into to be prepared in the injection ampoule.

When containing the mixture of the compound shown in the above-mentioned general formula of the present invention (I) and other anticarcinogen, also can easily prepare by those skilled in the art according to ordinary method or common technology.

In the method for the present invention, preferably the unit of treatment can be according to the formulation of compound shown in the kind of compound shown in the form of medication of compound shown in the above-mentioned general formula (I), the employed above-mentioned general formula (I), the employed above-mentioned general formula (I); The kind of other anticarcinogen of associating use, form of medication, formulation etc.; And the cancer cells that will treat, patient's variations such as state.Optimal treatment under defined terms is to determine unit based on treatment commonly used, and/or considers this specification sheets, is determined by those skilled in the art.

In the method for the present invention, the treatment unit of compound shown in the above-mentioned general formula (I) specifically can be according to the weight of kind, frequency of utilization and the privileged site that will treat of the composition of the kind of employed compound, cooperation, illness, patient's age, doctor's diagnosis, the changes such as kind of cancer, roughly for example as follows: as, for example can be in the 1-1000mg scope during for oral administration for adult's dosage for each person every day.Non-oral administration, preferred intravenous administration, when further preferred transfusion vein was injected, for example every day can be at 1-100mg/m ²In the scope of (body surface area).Wherein, during venoclysis, for example administration in 1-48 hour continuously.And different, for example administration every day is 1-5 time according to medication and symptom for administration number of times.Can also adopt administration every other day, every administration in two days administering mode such as administration uniformly-spaced.During non-oral administration, for example 1-6 week between the withdrawal time of treatment.

The treatment unit that unites other anticarcinogen of use with compound shown in the above-mentioned general formula (I) is not particularly limited, can be according to known document etc., determine as required by those skilled in the art.For example as follows.

The treatment unit of 5-fluor-uracil (5-SU) is as follows: during for oral administration, for example every day 200-300mg, divide successive administration 1-3 time; During for injection, for example initial 5 days intravenous injection once a day or venoclysis 5-15mg/kg continuously, later on 5-7.5mg/kg, the next day intravenous injection once a day or venoclysis (dosage can suitably increase and decrease).

The treatment unit of S-1 (Tegafur, Gimestat and Ostat potassium) is as follows: combination surface-area for example, with first dosage (for the first time amount) as later datum quantity, early after the meal with dinner after twice of every day, continuous 28 days oral administration, drug withdrawal is 14 days then.With it as a course of treatment, repetitively administered.The first datum quantity of determining according to body surface area (amount that is equivalent to Tegafur) is: be lower than 1.25m ², then be 40mg/ time; 1.25m ²More than-be lower than 1.5m ², then be 50mg/ time; 1.5m ²More than, then be 60mg/ time, can suitably increase and decrease according to patient's state.

The treatment unit of gemcitabine is as follows: for example each 1g/m ², 30 minutes venoclysis gemcitabines, be administered once continuous 3 weeks, the 4th all drug withdrawals weekly.With it as a course of treatment, repetitively administered.Can suitably increase and decrease according to the performance of age, symptom or side effect.

The treatment unit of Dx (for example doxorubicin hydrochloride) is as follows: during for intravenous injection, for example with 1 10mg every day (0.2mg/kg) (tiring) intravenous injection administration in 4-6 days continuously, drug withdrawal 7-10 days then, with it as a course of treatment, 2-3 course of treatment repeatedly.Wherein, the preferred 500mg of administration total amount (tiring)/m ²(body surface area) or below, can be in this scope suitably increase and decrease.

The treatment unit of Etoposide is as follows: during intravenous injection, for example with 60-100mg/m every day ²(body surface area) successive administration 5 days, 3 weeks of drug withdrawal (dosage can suitably increase and decrease).With its as a course of treatment repeatedly.During oral administration, for example with 175-200mg successive administration 5 days every day, 3 weeks of drug withdrawal (dosage can suitably increase and decrease).With its as a course of treatment repeatedly.

The treatment unit of docetaxel (docetaxel hydrate) is as follows: for example every day 1 time, with venoclysis 60mg/m more than 1 hour ²(body surface area) docetaxel is with the interval venoclysis (dosage can suitably increase and decrease) in 3-4 week.

The treatment unit of taxol is as follows: for example every day 1 time, with 3 hours venoclysis 210mg/m ²(body surface area), 3 weeks of drug withdrawal at least.With its as a course of treatment repeatedly, dosage can suitably increase and decrease.

The treatment unit of cis-platinum is as follows: during intravenous injection, for example with 50-70mg/m ²1 administration of (body surface area), every day, 3 week of drug withdrawal above (dosage can suitably increase and decrease).With its as a course of treatment repeatedly.

The treatment unit of carboplatin is as follows: for example use the time venoclysis 300-400mg/m more than 30 minutes ², every day 1 time, 4 weeks of drug withdrawal (dosage can suitably increase and decrease) at least.With its as a course of treatment repeatedly.

The treatment unit of oxaliplatin is as follows: every day 1 intravenous injection 85mg/m ², 2 weeks of drug withdrawal, with its as a course of treatment repeatedly.

The treatment unit of irinotecan (for example U 101440E) is as follows: for example every day 1 venoclysis 100mg/m ², 3-4 time weekly, 2 weeks of drug withdrawal at least.

The treatment unit of Hycamtin is as follows: venoclysis 1.5mg/m for example ², every day 1 time, totally 5 days, 3 weeks of drug withdrawal at least.

The treatment unit of endoxan is as follows: during intravenous injection, continuous intravenous injection 100mg for example, every day 1 time, if the patient can tolerate also can increment to 200mg every day, with total amount 3000-8000mg administration, can suitably increase and decrease.Also can take in intramuscularly, the thoracic cavity as required or interior injection of tumour or injection.During oral administration, for example with 100-200mg administration every day.

The treatment unit of Gefitinib is as follows: for example every day 1 oral administration 250mg.

The treatment unit of Cetuximab is as follows: the 1st day venoclysis 400mg/m for example ², venoclysis 250mg/m weekly afterwards ²

The treatment unit of rhuMAb-VEGF is as follows: venoclysis 3mg/kg weekly for example.

The treatment unit of trastuzumab is as follows: for example common per day for adults 1 time is 4mg/kg (body weight) trastuzumab during administration for the first time, for the second time later on every interval one all venoclysis 2mg/kg of the time more than 90 minutes.

The treatment unit of Exemestane is as follows: for example common per day for adults 1 time, oral meal administration 25mg.

The treatment unit of Leuprolide (for example acetate Leuprolide) is as follows: 1 time, subcutaneous administration 11.25mg of per 12 weeks usually for example are grown up.

The treatment unit of imatinib is as follows: for example usually for the chronic lymphocytic leukemia adult of chronic phase, and oral meal administration 400mg, every day 1 time.

Treatment unit during the combination of 5-FU and folinic acid is as follows: the 1st day to the 5th day venoclysis 425mg/m for example ²5-FU, 200mg/m ²Folinic acid, with the interval in 4 weeks repeatedly.

Embodiment

In the thin-layer chromatography of embodiment and reference example, plate uses Silica gel60F ₂₅₄(Merck), detection method is used the UV detector.Post uses Wakogel with silica gel ^TMC-300 or C-200 (with the pure medicine of light) or NH (FUJI SILYSIA CHEMICAL).The pillar of anti-phase preparative liquid chromatography uses CombiPrep Pro C18 (YMC), and moving phase is used 0.1% trifluoroacetic acid aqueous solution, 0.1% trifluoroacetic acid acetonitrile solution.The MS spectrum uses JMS-SX102A (NEC (JEOL)) or QUATTROII (マイケロマス) to measure.The NMR spectrum is used Gemini-200 (200MHz; Varian), Gemini-300 (300MHz; Varian),, VXR-300 (300MHz; Varian), Mercury 400 (400MHz; Varian) or Inova 400 (400MHz; Varian) the type spectrum instrument is measured, and whole δ values are represented with ppm.

The implication of abbreviation was as follows during NMR measured.

S: unimodal

D: bimodal

Dd: double doublet

T: triplet

Dt: two triplets

Q: quartet

Qui: quintet (Network イ Application テ Star ト)

M: multiplet

Br: broad peak

J: coupling constant

Hz: hertz

DMSO-d6: deuterated dimethyl sulfoxide

TBS: t-butyldimethylsilyl

Ms: methylsulfonyl

SEM:2-(trimethyl silyl) ethoxyl methyl

MOM: methoxymethyl

THP: tetrahydropyrans-2-base

Boc: tert-butoxycarbonyl

Embodiment 1

Synthesizing of (5-bromo-thiazol-2-yl)-(6-(4-benzoyl-piperazine-1-ylmethyl)-pyridine-2-yl)-amine

(1) (6-chloro-pyridine-2-yl)-thiazol-2-yl-amine is synthetic

With 1.37g (9.26mmol) thiazolamine, 0.74g (7.39mmol) 2,6-dichloropyridine, 387mg (0.621mmol) are (S)-(-)-2,2 '-(two diphenylphosphine)-1, the mixture heating up that 1 '-dinaphthalene, 322mg (0.311mmol) three (dibenzalacetone) close two palladiums (0)-chloroform complex compound, 2.77g (8.50mmol) cesium carbonate, 10ml toluene refluxed 1 hour 30 minutes, return back to room temperature, dilute with ethyl acetate then.With the insoluble substance diatomite filtration, then with gained ethyl acetate solution water, saturated common salt water washing.Use the anhydrous magnesium sulfate drying organic layer, filter concentrated filtrate then.Resistates by silica gel chromatography, is obtained 990mg (4.68mmol) and is the title compound of white solid.

(2) 6-(thiazol-2-yl amino)-pyridine-2-methyl-formiate is synthetic

Add at carbon monoxide depress (3 normal atmosphere), under 100 ℃, with 1.94g (9.17mmol) (6-chloro-pyridine-2-yl) thiazol-2-yl-amine, 206mg (0.918mmol) acid chloride, 508mg (0.916mmol) 1,1 '-two (diphenylphosphine) ferrocene, 2.40ml (13.8mmol) N, N-diisopropylethylamine, 10ml methyl alcohol, 15ml N, the mixture of dinethylformamide stirred 3 hours 15 minutes, cooled off in ice bath then.The solid that leaching generates, with the ether washing, obtaining 1.53g (6.50mmol) is filbert solid title compound.

(3) 6-(3-methoxymethyl-3H-thiazole-2-ylides amino)-pyridine-2-methyl-formiate is synthetic

To 4.85g (20.6mmol) 6-(thiazol-2-yl amino)-pyridine-2-methyl-formiate, 7.20ml (41.2mmol) N, add 2.35ml (30.9mmol) chloromethyl methyl ether in the mixture of N-diisopropylethylamine, 100ml chloroform, at room temperature stirred 1 hour.Reaction mixture with 100ml water washing 3 times, is used the anhydrous magnesium sulfate drying organic layer, filter then.It is about 20ml that filtrate is concentrated into total amount, the solid that leaching generates.The gained solid is washed with ether, and drying under reduced pressure obtains 6.38g (20.6mmol) and is the title compound of white solid then.

(4) 6-(5-bromo-3-methoxymethyl-3H-thiazole-2-ylides amino)-pyridine-2-methyl-formiate is synthetic

6.38g (20.6mmol) 6-(3-methoxymethyl-3H-thiazole-2-ylides amino)-pyridine-2-methyl-formiate is dissolved in 60ml 1, in the 4-two  alkane, at room temperature adds 3.67g (20.6mmol) N-bromine succinimide.With reaction mixture reflux 30 minutes, return back to room temperature then, with the dilution of 200ml ethyl acetate, then with 150ml water washing 3 times.Use the water washing of 150ml saturated common salt then, use anhydrous magnesium sulfate drying, filter then, concentrating under reduced pressure filtrate obtains 7.10g (19.8mmol) and is the title compound of white solid.

(5) (6-(5-bromo-3-methoxymethyl-3H-thiazole-2-ylides amino)-pyridine-2-yl)-methyl alcohol is synthetic

6.50g (18.0mmol) 6-(5-bromo-3-methoxymethyl-3H-thiazole-2-ylides amino)-pyridine-2-methyl-formiate is dissolved in the 80ml tetrahydrofuran (THF), adds 790mg (36.0mmol) lithium borohydride, reflux.After 1 hour, add 790mg (36.0mmol) lithium borohydride, reheat refluxed 1 hour, then reaction mixture was returned back to room temperature, added entry until not foaming, and used ethyl acetate extraction then.The gained ethyl acetate solution with 100ml water washing twice, is used the water washing of 100ml saturated common salt then.Use the anhydrous magnesium sulfate drying organic layer, filter concentrating under reduced pressure filtrate then.The gained resistates by silica gel chromatography, is obtained 2.67g (8.09mmol) and is the title compound of white solid.

(6) 1-(6-(5-bromo-3-methoxymethyl-3H-thiazole-2-ylides amino)-pyridine-2-ylmethyl)-piperazine is synthetic

At room temperature, to 330mg (1.00mmol) 6-(5-bromo-3-methoxymethyl-3H-thiazole-2-ylides amino)-pyridine-2-yl)-methyl alcohol, 0.348ml (2.00mmol) N, add 0.116ml (1.50mmol) methylsulfonyl chloride in the mixture of N-diisopropylethylamine, 15ml chloroform, stirred 1 hour.With reaction mixture saturated common salt water washing, use the anhydrous magnesium sulfate drying organic layer, filter back concentrating under reduced pressure filtrate.The gained resistates is dissolved in the 4ml dimethyl sulfoxide (DMSO), is added drop-wise in the 2ml dimethyl sulphoxide solution of 861mg (10.0mmol) piperazine, at room temperature stirred then 4 hours 30 minutes.Filtering reacting solution by anti-phase preparative liquid chromatography purifying, obtains 281mg (0.706mmol) and is the title compound of white solid.

(7) 1-(6-(5-bromo-3-methoxymethyl-3H-thiazole-2-ylides amino)-pyridine-2-ylmethyl)-4-benzoyl-piperazine is synthetic

With 77mg (0.217mmol) 1-(6-(5-bromo-3-methoxymethyl-3H-thiazole-2-ylides amino)-pyridine-2-ylmethyl)-piperazine dissolved in the 10ml aminoform, add 0.363ml (2.60mmol) triethylamine, slowly drip 0.126ml (1.09mmol) Benzoyl chloride, at room temperature stirred 30 minutes.With the ethyl acetate dilution, use the saturated common salt water washing, use anhydrous magnesium sulfate drying, filter concentrating under reduced pressure filtrate.The gained resistates by silica gel chromatography, is obtained 81mg (0.161mmol) and is the title compound of white solid.

(8) synthesizing of (5-bromo-thiazol-2-yl)-(6-(4-benzoyl-piperazine-1-ylmethyl)-pyridine-2-yl)-amine

With 81mg (0.161mmol) 1-(6-(5-bromo-3-methoxymethyl-3H-thiazole-2-ylides amino)-pyridine-2-ylmethyl)-4-benzoyl-piperazine dissolved in the 10ml chloroform; add hydrochloric acid-1; (4M 4ml), at room temperature stirred 18 hours 4-two  alkane solution.The concentrating under reduced pressure reaction mixture by methyl alcohol-ether recrystallization, filters resistates, and the gained white solid is dissolved in the 10ml water, and with the sodium bicarbonate neutralization, leaching gained throw out obtains 32mg (0.070mmol) and is the title compound of white solid.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：11.50(brs，1H)，7.78-7.62(m、1H)，7.50-7.30(m，6H)，7.02(d，J＝6.9Hz，1H)，6.90(d，J＝8.6Hz，1H)，3.80-3.20(m，10H).

Mass spectrum: 458,460 (M+1) ⁺.

Embodiment 2

Synthesizing of (5-methyl isophthalic acid H-pyrazole-3-yl)-(6-(4-benzoyl-piperazine-1-base-methyl)-pyridine-2-yl)-amine

(1) 2-amino-6-(tertiary butyl dimethyl-silicon alcoxyl ylmethyl) pyridine is synthetic

1.26g (10.2mmol) 2-amino-6-hydroxy-methyl pyridine (Journal ofHeterocyclic Chemistry, 2001,38,173) is dissolved in the 5.1ml dimethyl formamide, adds 1.7g (25mmol) imidazoles.Ice-cooled 1.8g (12mmol) tert-butyldimethylsilyl chloride that adds down at room temperature stirred 1 hour then.Reaction solution is diluted with ethyl acetate, then water and saturated common salt water washing organic layer.It is used dried over mgso, filter concentrated filtrate then.The gained resistates by silica gel chromatography, is obtained the title compound that 1.9g is an orange.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.45(dd，J＝8.0，7.6Hz，1H)，6.86(dd，J＝7.6，0.8Hz，1H)，6.37(dd，J＝8.0，0.8Hz，1H)，4.65(s，2H)，4.34(brs，2H)，0.95(s，9H)，0.11(s，6H).

Mass spectrum: 239 (M+1) ⁺,

(2) N-(6-(tertiary butyl dimethyl-silicon alcoxyl ylmethyl) pyridine-2-yl)-3-oxo butyl amide is synthetic

The 6.6ml tert-butyl acetoacetate is dissolved in the 10ml toluene, stirred 1 hour down at 100 ℃.Adding is dissolved in the solution of gained in the 5ml toluene with 1.9g (8.1mmol) 2-amino-6-(t-butyldimethylsilyloxy ylmethyl) pyridine in reaction solution, stirs 15 hours under this temperature.Concentration of reaction solution by silica gel chromatography, obtains the title compound that 2.2g is a yellow oil with the gained resistates.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：9.03(brs，1H)，7.99(brd，J＝7.6Hz，1H)，7.69(dd，J＝8.0，7.6Hz，1H)，7.25(brd，J＝8.0Hz，1H)，4.72(s，2H)，3.58(s，2H)，2.33(s，3H)，0.96(s，9H)，0.12(s，6H).

Mass spectrum: 323 (M+1) ⁺.

(3) 3-(6-hydroxy-methyl pyridine-2-yl) amino-5-1H-methylpyrazole is synthetic

2.2g (6.8mmol) N-(6-(tertiary butyl dimethyl-silicon alcoxyl ylmethyl) pyridine-2-yl)-3-oxo butyl amide is separated in 68ml 1, in the 2-glycol dimethyl ether, under 0 ℃, add 8.9ml (140mmol) methylsulfonic acid and 3.3ml (68mmol) hydrazine monohydrate successively.At room temperature stirred 15 hours, and stirred 6 hours down at 80 ℃ then.Under the ice bath, in reaction solution, add 30ml 25% ammoniacal liquor and 30ml water, use chloroform extraction then.Concentrate organic layer, the gained resistates by silica gel chromatography, is obtained the title compound that 630mg is an orange.

The spectrum data of title compound is as follows.

¹H-NMR(CD ₃OD)δ：7.53(t，J＝7.6Hz，1H)，6.83(brd，J＝7.6Hz，2H)，4.57(s，2H)，2.23(s，3H).

Mass spectrum: 205 (M+1) ⁺.

(4) 3-(6-chloromethylpyridine-2-yl) amino-5-methyl isophthalic acid H-pyrazoles is synthetic

68mg (340 μ mol) 3-(6-hydroxy-methyl pyridine-2-yl) amino-5-methyl isophthalic acid H-pyrazoles is dissolved in the mixed solvent of 4ml according to 6: 1 blended chloroform-dimethyl formamides, under ice bath, adds 250 μ l (3.4mmol) thionyl chloride.At room temperature stirred 18 hours, concentration of reaction solution by the silica gel thin-layer chromatography purifying, obtains the 87mg brown oil with the gained resistates then.This oily matter is directly used in subsequent reactions.

(5) 3-(6-(4-benzoyl-1H-piperazine-1-ylmethyl) pyridine-2-yl) amino-5-methylpyrazole is synthetic

The above-mentioned oily matter of 87mg is dissolved in the 2ml dimethyl sulfoxide (DMSO), adds 340 μ l (1.95mmol) N successively, N-diisopropylethylamine and 134mg (706 μ mol) N-benzoyl-piperazine.Reacted 30 minutes down at 90 ℃, then reaction solution is passed through anti-phase preparative column chromatogram purification, obtain the title compound that 52mg is a faint yellow solid.

The spectrum data of title compound is as follows.

¹H-NMR(CD ₃OD)δ：7.93(d，J＝8.8，7.6Hz，1H)，7.52-7.44(m，5H)，7.10(d，J＝7.6Hz，1H)，7.09(d，J＝8.8Hz，1H)，5.99(s，1H)，4.22(s，2H)，4.06-3，60(m，4H)，3.15-2-85(m，4H)，2.39(s，3H).

Mass spectrum: 377 (M+1) ⁺.

Embodiment 3

Synthesizing of (5-bromo-thiazol-2-yl)-(6-(4-(2, the 3-difluoro benzoyl)-piperazine-1-base-methyl)-pyridine-2-yl)-amine

(1) synthesizing of (5-bromo-thiazol-2-yl)-(6-(piperazine-1-ylmethyl)-pyridine-2-yl)-amine

Add hydrochloric acid-1 in 509mg (1.28mmol) embodiment 1-(6) gained compound, 5ml chloroform, 14ml methanol mixture, (4M 5ml), at room temperature stirred 10 hours 4-two  alkane solution.Add hydrochloric acid-1 in reaction solution, 4-two  alkane solution 1ml at room temperature stirred 18 hours again.The concentrating under reduced pressure reaction mixture dilutes resistates with ethyl acetate, uses 1M aqueous sodium hydroxide solution, saturated common salt water washing then.It is used dried over mgso, filter, concentrating under reduced pressure obtains 367mg (1.04mmol) and is the title compound of white solid then.

(2) synthesizing of (5-bromo-thiazol-2-yl)-(6-(4-(2, the 3-difluoro benzoyl)-piperazine-1-ylmethyl)-pyridine-2-yl)-amine

At room temperature, with 20mg (0.056mmol) above-mentioned (1) gained compound, 32.5mg (0.169mmol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, 22.9mg (0.169mmol) I-hydroxybenzotriazole, 26.8mg (0.169mmol) 2, the mixture of 3-difluoro-benzoic acid, 1ml chloroform stirred 4 hours.Add entry, use ethyl acetate extraction, use the saturated common salt water washing then.It is used dried over mgso, filter the back concentrating under reduced pressure, by preparation thin-layer chromatography purifying, obtaining 17.0mg (0.034mmol) is colourless amorphous title compound with the gained resistates.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.63(dd，J＝7.8，7.6Hz，1H)，7.34(s，1H)，7.32-7.09(m，3H)，7.06(d，J＝7.2Hz，1H)，6.76(d，J＝8.0Hz，1H)，3.90-3.82(m，2H)，3.76(s，2H)，3.47-3.37(m，2H)，2.76-2.63(m，2H)，2.63-2.50(m，2H)

Mass spectrum: 494,496 (M+1) ⁺

Embodiment 4

Synthesizing of (thiazol-2-yl)-(6-(4-(2, the 3-difluoro benzoyl)-piperazine-1-ylmethyl)-pyridine-2-yl)-amine

8.5mg (0.017mmol) embodiment 3-(2) gained compound dissolution in 1ml methyl alcohol, is added 10mg 10% palladium-carbon, under atmosphere of hydrogen, normal pressure, room temperature, stirred 1 hour.Filtering reacting liquid, the concentrating under reduced pressure solvent passes through the gained resistates preparation thin-layer chromatography purifying then, and obtaining 4.1mg (0.010mmol) is colourless amorphous title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CD ₃OD)δ：7.65(t，J＝7.4Hz，1H)，7.32(d，J＝3.7Hz，1H)7.40-7.30(m，1H)，7.28-7.22(m，1H)，7.19-7.14(m，1H)，7.04(d，J＝7.2Hz，1H)，6.92-6.85(m，2H)，3.82(dd，J＝5.3，5.1Hz，2H)，3.74(s，2H)3.39(t，J＝4.7Hz，2H)，2.69(t，J＝5.1Hz，2H)，2.58(dd，J＝5.7，4.1Hz，2H)

Mass spectrum: 416 (M+1) ⁺

Embodiment 5

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

(1) 2-bromo-6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl) pyridine is synthetic

5.00g (6-bromo-pyridine-2-yl)-dissolve with methanol in the 50ml dimethyl formamide, is added the 2.72g imidazoles.At the ice-cooled 5.21g tert-butyldimethylsilyl chloride that adds down, at room temperature stirred then 1 hour.Reaction solution is diluted with ethyl acetate, then water and saturated common salt water washing.With gained organic layer dried over mgso, filter concentrated filtrate then.(eluting solvent: hexane/ethyl acetate=10/1～1/1) purifying obtains title compound by silica gel column chromatography with the gained resistates.

(2) 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-thiazol-2-yl pyridine-2-amine is synthetic

Under 100 ℃, with 7.85g 2-bromo-6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl) pyridine, 3.12g thiazolamine, 1.50g 9,9-dimethyl-4, two (diphenylphosphine) xanthenes of 5-, 1.35g three (dibenzalacetone) close two palladiums (0)-chloroform complex compound, 13.8g potassiumphosphate, 80ml 1, the mixture of 4-two  alkane stirred 4.5 hours, return back to room temperature, dilute with ethyl acetate then.With diatomite filtering insoluble substance, with gained ethyl acetate solution water, saturated common salt water washing.Use the anhydrous magnesium sulfate drying organic layer, filter concentrated filtrate then.(eluting solvent: hexane/ethyl acetate=10/1～1/1) purifying obtains title compound by silica gel column chromatography with resistates.

(3) (6-(thiazol-2-yl amino) pyridine-2-yl) methyl alcohol is synthetic

With 6.48g 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-thiazol-2-yl pyridine-2-amine solvent in the 100ml tetrahydrofuran (THF), at the ice-cooled tetrabutyl fluoride amine-tetrahydrofuran solution (1.0M, 20.2ml) that adds down, at room temperature stirred then 1 hour.Reaction solution is diluted with ethyl acetate, use phosphoric acid buffer (pH 6.8) washing then.Use the anhydrous magnesium sulfate drying organic layer, filter then, concentrated filtrate obtains title compound.

(4) 6-(chloromethyl)-N-thiazol-2-yl pyridine-2-amine is synthetic

(6-(thiazol-2-yl amino) pyridine-2-yl) methyl alcohol that aforesaid operations is obtained all is suspended in the 150ml chloroform, adds the 7.37ml thionyl chloride.At room temperature stirred 2 hours, then concentration of reaction solution.The gained resistates is diluted with ethyl acetate, use 2M aqueous sodium hydroxide solution, saturated common salt water washing then.Use the anhydrous magnesium sulfate drying organic layer, filter concentrated filtrate then.(eluting solvent: chloroform～chloroform/methanol=20/1) purifying obtains title compound by silica gel column chromatography with resistates.

(5) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine is synthetic

Under 90 ℃, with 1-(3-chloro-2-fluoro benzoyl) piperazine, the 6.25ml N that 2.70g 6-(chloromethyl)-N-thiazol-2-yl pyridine-2-amine, 4.00g reference example 1 obtain, the mixture of N-diisopropylethylamine, 30ml dimethyl formamide stirred 2 hours.Reaction solution is diluted with ethyl acetate, then water and saturated common salt water washing.With gained organic layer dried over mgso, filter concentrated filtrate then.With the gained resistates by silica gel column chromatography (eluting solvent: chloroform～chloroform/methanol=10/1) purifying, then the gained compound is suspended in the ethyl acetate, filter then, obtain being colourless amorphous title compound.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：11.20(s，1H)，7.65(t，J＝7.8Hz，2H)，7.41-7.33(m，2H)，7.29(t，J＝7.8Hz，1H)，7.00-6.87(m，3H)，3.72-3.61(m，4H)，3.27-3.20(m，2H)，2.60-2.36(m，4H).

Mass spectrum: 432 (M+1) ⁺

Below, according to carrying out the synthetic of embodiment 6-15,32-43 and 63 with the same method of the foregoing description 5.

Embodiment 6

Synthesizing of 6-((4-(2,3-dichloro-benzoyl base) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.21(s，1H)，7.72-7.61(m，2H)，7.42(t，J＝7.8Hz，1H)，7.39-7.29(m，2H)，7.02-6.90(m，3H)，3.73-3.61(m，4H)，3.19-3.12(m，2H)，2.60-2.38(m，4H).

Mass spectrum: 448 (M+1) ⁺

Embodiment 7

Synthesizing of 6-((4-(3-chlorobenzene formacyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(DMSO-d ₆)6：11.20(s，1H)，7.65(t，J＝7.8Hz，1H)，7.54-7.39(m，3H)，7.38-7.28(m，2H)，7.00-6.88(m，3H)，3.64(s，4H)，3.48-3.19(m，2H)，2.62-2.34(m，4H).

Mass spectrum: 414 (M+1) ⁺

Embodiment 8

Synthesizing of 6-((4-(2-fluoro-3-methyl benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.21(s，1H)，7.65(t，J＝7.8Hz，1H)，7.39-7.31(m，2H)，7.20-7.10(m，2H)，7.00-6.89(m，3H)，3.73-3.62(m，4H)，3.22(t，J＝4.7Hz，2H)，2.56-2.34(m，4H)，2.24(d，J＝1.6Hz，3H).

Mass spectrum: 412 (M+1) ⁺

Embodiment 9

Synthesizing of 6-((4-(2-chloro-3-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.21(brs，1H)，7.65(t，J＝7.8Hz，1H)，7.51-7.42(m，2H)，7.36(d，J＝3.9Hz，1H)，7.25-7.18(m，1H)，7.02-6.81(m，3H)，3.75-3.60(m，4H)，3.16(t，J＝4.3Hz，2H)，2.61-2.40(m，4H).

Mass spectrum: 432 (M+1) ⁺

Embodiment 10

6-(the trifluoroacetate of ((1S, 4S)-5-(3-chloro-2-fluoro benzoyl)-2,5-diazabicyclo [2.2.1] oenanthyl-2-yl) methyl)-N-thiazol-2-yl pyridine-2-amine synthetic

¹H-NMR(DMSO-d ₆)δ：7.84-7.71(m，2H)，7.48-7.40(m，2H)，7.38-7.30(m，1H)，7.19-7.07(m，3H)，5.00-3.36(m，8H)，2.54-2.14(m，2H).

Mass spectrum: 444 (M+1) ⁺

Embodiment 11

6-(((1R, 4R)-5-(3-chloro-2-fluoro benzoyl)-2,5-diazabicyclo [2.2.1] oenanthyl-2-yl) methyl)-N-thiazol-2-yl pyridine-2-amine synthetic

¹H-NMR(CDCl ₃)δ：7.63-7.57(m，1H)，7.50-7.44(m，2H)，7.37-7.31(m，1H)，7.19-7.13(m，1H)，7.04-6.99(m，1H)，6.87-6.77(m，2H)，4.98-2.82(m，8H)，2.05 and 1.99(each d，J＝10.0Hz，total 1H)，1.83(d，J＝10.0Hz，1H)

Mass spectrum: 444,446 (M+1) ⁺

Embodiment 12

Synthesizing of the trifluoroacetate of 6-((4-(3-bromo-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.94(dd，J＝8.4，7.2Hz，1H)，7.80-7.74(m，1H)，7.53(d，J＝3.6Hz，1H)，7.46-7.40(m，1H)，7.32(d，J＝7.2Hz，1H)，7.26(d，J＝8.4Hz，1H)，7.23(t，J＝8.0Hz，1H)，7.19(d，J＝3.6Hz，1H)，4.53(s，2H)，4.15-4.00(m，2H)，3.72-3.64(m，2H)，3.59-3.52(m，2H)，3.48-3.41(m，2H)

Mass spectrum: 478 (M+1) ⁺

Embodiment 13

Synthesizing of the trifluoroacetate of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.95(dd，J＝8.4，7.2Hz，1H)，7.86(brt，J＝7.6Hz，1H)，7.75(brt，J＝6.4Hz，1H)，7.55(d，J＝4.4Hz，1H)，7.49(t，J＝8.0Hz，1H)，7.34(d，J＝7.2Hz，1H)，7.27(d，J＝8.4Hz，1H)，7.20(d，J＝4.4Hz，1H)4.54(s，2H)，4.16-4.00(m，2H)，3.74-3.66(m，2H)，3.61-3.53(m，2H)，3.50-3.42(m，2H)

Mass spectrum: 466 (M+1) ⁺

Embodiment 14

Synthesizing of 6-(((3R)-4-(3-chloro-2-fluoro benzoyl)-3-methylpiperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(CDCl ₃)δ：7，60(t，J＝7.6Hz，1H)，7.49(d，J＝3.7Hz，1H)，7.43(t，J＝7.6Hz，1H)，7.26-7.11(m，2H)，7.06-7.01(m，1H)，6.85(d，J＝3.1Hz，1H)，6.80(d，J＝8.0Hz，1H)，5.00-2.20(m，9H)，1.50-1.25(m，3H)

Mass spectrum: 446,448 (M+1) ⁺

Embodiment 15

Synthesizing of 6-((4-(3-(difluoromethyl)-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(CDCl ₃)δ：7.65(brt，J＝7.6Hz，1H)，7.60(dd，J＝8.0，7.2Hz，1H)，7.51(brt，J.＝7.8Hz，1H)，7.48(d，J＝3.6Hz，1H)，7.31(t，J＝7.6Hz，1H)，7.00(d，J＝7.2Hz，1H)，6.89(t，J＝54.8Hz，1H)，6.85(d，J＝3.6Hz，1H)，6.82(d，J＝8.0Hz，1H)，3.90-3.83(m，2H)，3.76(s，2H)，3.41-3.33(m，2H)，2.71(brt，J＝4.8Hz，2H)，2.61-2.52(m，2H)

Mass spectrum: 448 (M+1) ⁺

Embodiment 16

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine

(1) (6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridine-2-yl) methyl alcohol is synthetic

Use 2-bromo-6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl) pyridine of embodiment 5-(1) gained and 1-((2-(trimethyl silyl) oxyethyl group) the methyl)-1-H-pyrazoles-3-amine of reference example 2 gained, according to embodiment 5-(2)～(3) same method, obtain title compound.

(2) 6-(mesyloxy methyl)-N-(1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) pyridine-2-amine is synthetic

At room temperature, to 10mg (6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridine-2-yl) methyl alcohol, 27 μ l N, add 7.3 μ l methylsulfonyl chlorides in the mixture of N-diisopropylethylamine, 1ml chloroform, stirred 1 hour.With reaction mixture saturated common salt water washing, use the anhydrous magnesium sulfate drying organic layer, filter back concentrating under reduced pressure filtrate, obtain title compound.

(3) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) pyridine-2-amine is synthetic

Under 60 ℃; with hydrochloride, the 27 μ l N of 1-(the 3-chloro-2-fluoro benzoyl) piperazine of 10mg 6-(mesyloxy methyl)-N-(1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) pyridine-2-amine, 40mg reference example 1 gained, the mixture of N-diisopropylethylamine, 1ml chloroform stirred 5 hours.Reaction solution is diluted with chloroform, then water and saturated common salt water washing.With gained organic layer dried over mgso, filter concentrated filtrate then.(eluting solvent: chloroform～chloroform/methanol=20/1) purifying obtains title compound by silica gel column chromatography with the gained resistates.

(4) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine is synthetic

(6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) pyridine-2-amine solvent at room temperature stirred 5 hours in 900 μ l trifluoroacetic acids and 100 μ l water with 18mg.The concentrating under reduced pressure reaction solution is then with the ethyl acetate dilution, with saturated sodium bicarbonate water, water and saturated common salt water washing.With gained organic layer dried over mgso, filter concentrated filtrate.(eluting solvent: chloroform～chloroform/methanol=10/1) purifying obtains title compound by silica gel column chromatography with the gained resistates.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.51(dd，J＝8.2，7.4Hz，1H)，7.48-7，39(m，2H)，7.36-7.20(m，2H)7.17-7.10(m，1H)，6.90(d，J＝8.2Hz，1H)，6.82(d，J＝7.2Hz，1H)，5.98(s，1H)，3.87(brs，2H)，3.62(s，2H)，3.37(brs，2H)，2.63(t，J＝5.2Hz，2H)，2.51(brs，2H)

Mass spectrum: 415 (M+1) ⁺

Below according to the method synthetic embodiment 17-31 same with the foregoing description 16.

Embodiment 17

Synthesizing of 6-((4-(2,3-dichloro-benzoyl base) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine

¹H-NMR(CDCl ₃)δ：7.57-7.47(m，3H)，7.31-7.10(m，4H)，6.90(d，J＝8.0Hz，1H)，6.82(d，J＝7.4Hz，1H)，5.98(d，J＝2.0Hz，1H)，3.97-3.80(m，2H)，3.62(s，2H)，3.38-3.23(m，2H)，2.68-2.59(m，2H)，2.59-2.40(m，2H)

Mass spectrum: 431 (M+1) ⁺

Embodiment 18

Synthesizing of the trifluoroacetate of 6-((4-(2-chloro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine

¹H-NMR(CD ₃OD)δ：8.01(dd，J＝8.8，7.2Hz，1H)，7.89(dd，J＝7.2，2.4Hz，1H)，7.79(d，J＝2.4Hz，1H)，7.67-7.58(m，2H)，7.14(d，J＝8.8Hz，1H)，7.04(brd，J＝7.2Hz，1H)，6.16(d，J＝2.4Hz，1H)，4.13-4.03(m，1H)，4.00-3.89(m，1H)，3.97(s，2H)，3.44(brt，J＝5.2Hz，2H)，2.88-2.80(m，2H)，2.73-2.66(m，2H)

Mass spectrum: 465 (M+1) ⁺

Embodiment 19

Synthesizing of the trifluoroacetate of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine

¹H-NMR(CD ₃OD)δ：8.01(dd，J＝8.8，7.2Hz，1H)，7.84(brt，J＝7.2Hz，1H)，7.79(d，J＝2.4Hz，1H)，7.71(brt，J＝7.2Hz，1H)，7.49(brt，J＝7.6Hz，1H)，7.14(d，J＝8.8Hz，1H)，7.04(dd，J＝7.2，1.2Hz，1H)，6.16(d，J＝2.4Hz，1H)，4.05-3.97(m，2H)，3.97(s，2H)，3.58-3.51(m，2H)，2.82(brt，J＝4.8Hz，2H)，2.70(brt，J＝4.8Hz，2H)

Mass spectrum: 449 (M+1) ⁺

Embodiment 20

Synthesizing of the trifluoroacetate of 6-((4-(3-bromo-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine

¹H-NMR(CD ₃OD)δ：8.01(dd，J＝8.8，7.2Hz，1H)，7.81-7.73(m，2H)，7.43-7.37(m，1H)，7.23(t，J＝7.6Hz，1H)，7.14(d，J＝8.8Hz，1H)，7.04(d，J＝7.2Hz，1H)，6.16(d，J＝2.4Hz，1H)，4.05-3.93(m，4H)，3.57-3.50(m，2H)，2.82(brt，J＝4.8Hz，2H)，2.70(brt，J＝4.8Hz，2H)

Mass spectrum: 459 (M+1) ⁺

Embodiment 21

Synthesizing of the trifluoroacetate of 6-((4-((3, the 4-dichlorophenyl) ethanoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.97(dd，J＝8.8，7.6Hz，1H)，7.80(d，J＝2.4Hz，1H)，7.47(d，J＝8.4Hz，1H)7.44(d，J＝2.0Hz，1H)，7.19(dd，J＝8.4，2.0Hz，1H)，7.13(brd，J＝8.8Hz，1H)，7.04(brd，J＝7.6Hz，1H)，6.17(d，J＝2.4Hz，1H)，4.02(s，2H)，3.97(s，1H)，3.86-3.76(m，6H)，2.83-2.74(m，4H)

Mass spectrum: 445 (M+1) ⁺

Embodiment 22

Synthesizing of 6-((4-(3-(difluoromethyl)-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine

¹H-NMR(CDCl ₃)δ：7.64(brt，J＝7.2Hz，1H)，7.55-7.44(m，3H)，7.31(t，J＝8.0Hz，1H)，6.91(d，J＝8.0Hz，1H)，6.89(t，J＝54.8Hz，1H)，6.82(d，J＝7.6Hz，1H)，5.99(s，1H)，3.92-3.84(m，2H)，3.62(s，2H)，3.42-3.34(m，2H)，2.66-2.60(m，2H)，2.55-2.47(m，2H)

Mass spectrum: 431 (M+1) ⁺

Embodiment 23

6-(((1S, 4S)-5-(3-chloro-2-fluoro benzoyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine synthetic

¹H-NMR(CDCl ₃)δ：7.58-7.42(m，3H)，7.36-7.28(m，1H)，7.28-7.10(m，2H)，6.97-6.81(m，2H)，6.06-5.96(m，1H)，4.95-2.72(m，8H)，2.10-2.00(m，1H)，1.86-1.78(m，1H)

Mass spectrum: 427 (M+1) ⁺

Embodiment 24

Synthesizing of 6-(1-(4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) ethyl)-N-1H-pyrazole-3-yl pyridine-2-amine

¹H-NMR(CDCl ₃)δ：7.52(dd，J＝8.2，7.6Hz，1H)，7.50-7.40(m，2H)，7.27-7.21(m，1H)7.17-7.11(m，1H)，6.87(d，J＝8.4Hz，1H)，6.80(d，J＝7.2Hz，1H)，6.01(d，J＝1.8Hz，1H)，3.83(brs，2H)，3.58-3.52(m，1H)，3.34(brs，2H)，2.72-2.40(m，4H)，1.42(d，J＝6.8Hz，3H)

Mass spectrum: 429 (M+1) ⁺

Embodiment 25

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.99(dd，J＝8.8，7.2Hz，1H)，7.64-7.57(m，1H)，7.38-7.26(m，2H)，7.11(d，J＝8.8Hz，1H)，7.01(d，J＝7.2Hz，1H)，5.91(s，1H)，4.03-3.95(m，2H)，3.94(s，2H)，3.56-3.50(m，2H)，2.82-2.75(m，2H)，2.69-2.64(m，2H)，2.35(s，3H)

Mass spectrum: 429 (M+1) ⁺

Embodiment 26

Synthesizing of the trifluoroacetate of 6-((4-(2,3-dichloro-benzoyl base) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.96(dd，J＝8.8，7.2Hz，1H)，7.64(dd，J＝8.0，1.6Hz，1H)，7.42(t，J＝8.0Hz，1H)，7.32(dd，J＝8.0，1.6Hz，1H)，7.09(dd，J＝8.0，0.8Hz，1H)，7.05(dd，J＝7.2，0.8Hz，1H)，5.95(d，J＝0.8Hz，1H)，4.13-4.03(m，1H)，4.07(s，2H)，3.98-3.88(m，1H)，3.47(brt，J＝5.2Hz，2H)，3.03-2.89(m，2H)，2.82(brt，J＝5.2Hz，2H)，2.37(s，3H)

Mass spectrum: 445 (M+1) ⁺

Embodiment 27

6-(((1S, 4S)-5-(3-chloro-2-fluoro benzoyl)-2,5-diazabicyclo [2.2.1] oenanthyl-2-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyridine-2-amine synthetic

¹H-NMR(CD ₃OD)δ：7.85-7.81(m，1H)，7.67-7.60(m，1H)，7.45-7.38(m，1H)，7.33-7.25(m，1H)，7.15-7.08(m，1H)，7.04(d，J＝8.8Hz，1H)，6.02(s，1H)，4.63-4.51(m，1H)，4.49-4.36(m，3H)，4.00-3.93(m，1H)，3.81-3.75(m，1H)，3.68-3.58(m，1H)，3.56-3.50(m，1H)，3.38-3.31(m，1H)，2.40(s，3H)，2.30-2.20(m，1H)

Mass spectrum: 441 (M+1) ⁺

Embodiment 28

Synthesizing of 6-((4-(3-bromo-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.90(d，J＝0.8Hz，1H)，7.75-7.69(m，1H)，7.53(dd，J＝8.0，7.2Hz，1H)，7.40-7.33(m，1H)，7.20(t，J＝8.0Hz，1H)，6.82(d，J＝7.2Hz，1H)，3.90-3.78(m，2H)，3.67-3.55(m，2H)，3.44-3.34(m，2H)，2.64(brt，J＝4.8Hz，2H)，2.53(brt，J＝4.8Hz，2H)，2.23(s，3H)

Mass spectrum: 473 (M+1) ⁺

Embodiment 29

Synthesizing of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.90(s，1H)，7.81(brt，J＝7.2Hz，1H)，7.68(brt，J＝6.8Hz，1H)，7.53(t，J＝8.0Hz，1H)，7.46(t，J＝7.6Hz，1H)，6.82(d，J＝7.2Hz，1H)，3.89-3.82(m，2H)，3.65-3.57(m，2H)，3.43-3.37(m，2H)，2.65(brt，J＝4.8Hz，2H)，2.54(brt，J＝4.8Hz，2H)，2.23(s，3H)

Mass spectrum: 463 (M+1) ⁺

Embodiment 30

Synthesizing of 6-((4-(2-chloro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.91-7.84(m，2H)，7.64-7.50(m，3H)，6.82(brd，J＝7.2Hz，1H)，3.90-3.80(m，2H)，3.65-3.56(m，2H)，2.66(brt，J＝4.8Hz，2H)，2.63-2.49(m，2H)，2.23(s，3H)

Mass spectrum: 479 (M+1) ⁺

Embodiment 31

Synthesizing of 6-((4-benzoyl-piperazine-1-yl) methyl)-N-(5-cyclopropyl-1H-pyrazole-3-yl) pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.96(dd，J＝8.8，7.6Hz，1H)，7.53-7.43(m，5H)，7.09(brd，J＝8.8Hz，1H)，7.02(brd，J＝7.6Hz，1H)，5.76(s，1H)，4.04-3.60(m，4H)，3.99(s，2H)，2.95-2.65(m，4H)，2.02-1.93(m，1H)，1.10-1.05(m，2H)，0.82-0.77(m，2H)

Mass spectrum: 403 (M+1) ⁺

Embodiment 32

6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1,2,4-thiadiazoles-5-yl pyridines-2-amine synthetic

Mass spectrum: 433 (M+1) ⁺

Embodiment 33

6-(((3R)-4-benzoyl-3-methylpiperazine-1-yl) methyl)-N-1,2, the trifluoroacetate of 4-thiadiazoles-5-yl pyridines-2-amine synthetic

¹H-NMR(DMSO-d ₆)δ：12.31(brs，1H)，8.34(s，1H)，7.99-7.82(m，1H)，7.50-7.10(m，7H)，4.60-2.80(m，9H)，1.31(d，J＝7.0Hz，3H).

Mass spectrum: 395 (M+1) ⁺

Embodiment 34

Synthesizing of the trifluoroacetate of phenyl (1-((6-(1,2,4-thiadiazoles-5-base is amino) pyridine-2-yl) methyl) piperidin-4-yl) ketone

¹H-NMR(DMSO-d ₆)δ：12.39(s，1H)，9.94(brs，1H)，8.36(s，1H)，8.02-7.90(m，3H)，7.70-7.61(m，1H)，7.60-7.50(m，2H)，7.38-7.20(m，2H)，4.60-4.20(m，2H)，4.00-3.20(m，5H)，2.10-1.75(m，4H).

Mass spectrum: 380 (M+1) ⁺

Embodiment 35

6-((4-benzoyl-1,4-Diazesuberane-1-yl) methyl)-N-1,2,4-thiadiazoles-5-yl pyridines-2-amine synthetic

Mass spectrum: 395 (M+1) ⁺

Embodiment 36

6-((4-(2,3-dichloro-benzoyl base) piperazine-1-yl) methyl)-N-1,2, the trifluoroacetate of 4-thiadiazoles-5-yl pyridines-2-amine synthetic

¹H-NMR(DMSO-d ₆)δ：12.35(brs，1H)，8.35(s，1H)，7.99-7.90(m，1H)，7.75-7.70(m，1H)，7.55-7.40(m，2H)，7.38-7.20(m，2H)，4.60-3.10(m，10H).

Mass spectrum: 449 (M+1) ⁺

Embodiment 37

6-((4-(3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1,2,4-thiadiazoles-5-yl pyridines-2-amine synthetic

Mass spectrum: 449 (M+1) ⁺

Embodiment 38

6-((4-(3-benzoyl bromide) piperazine-1-yl) methyl)-N-1,2,4-thiadiazoles-5-yl pyridines-2-amine synthetic

Mass spectrum: 459,461 (M+1) ⁺

Embodiment 39

6-((4-(2-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1,2,4-thiadiazoles-5-yl pyridines-2-amine synthetic

Mass spectrum: 449 (M+1) ⁺

Embodiment 40

6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1,2,4-thiadiazoles-5-yl pyridines-2-amine synthetic

¹H-NMR(DMSO-d ₆)δ：12.18(brs，1H)，8.30(s，1H)，7.83-7.75(m，3H)，7.55-7.45(m，1H)，7.13(d，J＝7.3Hz，1H)，7.05(d，J＝8.3Hz，1H)，3.78-3.65(m，4H)，3.32-3.22(m，2H)，2.62-2.52(m，2H)，2.51-2.43(m，2H).

Mass spectrum: 467 (M+1) ⁺

Embodiment 41

6-((4-(2-fluoro-3-(difluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1,2, the trifluoroacetate of 4-thiadiazoles-5-yl pyridines-2-amine synthetic

¹H-NMR(CD ₃OD)δ：8.27(s，1H)，7.94(dd，J＝8.0，7.2Hz，1H)，7.76(brt，J＝7.2Hz，1H)，7.64(brt，J＝6.8Hz，1H)，7.44(t，J＝7.6Hz，1H)，7.32(d，J＝7.2Hz，1H)，7.24(d，J＝8.0Hz，1H)，7.02(t，J＝54.8Hz，1H)，4.58(s，2H)，3.73-3.46(m，6H)

Mass spectrum: 449 (M+1) ⁺

Embodiment 42

Synthesizing of the trifluoroacetate of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-methyl-thiazol-2-yl) pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.98(dd，J＝8.4，7.2Hz，1H)，7.62(dt，J＝8.0，1.2Hz，1H)，7.44-7.37(m，2H)，7.32-7.25(m，3H)，4.58(s，2H)，4.20-3.92(m，2H)，3.69(brs，2H)，3.57(brs，2H)，3.45(brs，2H)，2.45(d，J＝1.2Hz，3H)

Mass spectrum: 446 (M+1) ⁺

Embodiment 43

6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-cyano group-thiazol-2-yl) pyridine-2-yl) amine is synthetic

¹H-NMR(CDCl ₃)δ：11.06(brs，1H)，8.00(s，1H)，7.72(dd，J＝8.0，7.2Hz，1H)，7.47-7.42(m，1H)，7.33-7.25(m，1H)，7.20-7.12(m，2H)，6.82(d，J＝8.0Hz，1H)，3.92-3.83(m，2H)，3.79(s，2H)，3.45-3.29(m，2H)，2.71-2.45(m，4H)

Mass spectrum: 457 (M+1) ⁺

Embodiment 44

Synthesizing of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine

(1) 6-chloro-N-(1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) pyrazine-2-amine is synthetic

Under 100 ℃, with 1.78g 2, the 1-of 6-dichloropyrazine, 2.84g reference example 2 gained ((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazoles-3-amine, 690mg 9,9-dimethyl-4, two (diphenylphosphine) xanthenes of 5-, 620mg three (dibenzalacetone) close two palladiums (0)-chloroform complex compound, 5.07g potassiumphosphate, 25ml 1, the mixture of 4-two  alkane stirred 2 hours, returned back to room temperature, diluted with ethyl acetate then.With the insoluble substance diatomite filtration, with gained ethyl acetate solution water, saturated common salt water washing.With the organic layer anhydrous magnesium sulfate drying, filter concentrated filtrate then.(eluting solvent: hexane/ethyl acetate=10/1～1/1) purifying obtains title compound by silica gel column chromatography with resistates.

(2) 6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyrazine-2-methyl-formiate is synthetic

Add at carbon monoxide depress (3 normal atmosphere), under 100 ℃, with 2.41g 6-chloro-N-(1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) pyrazine-2-amine, 320mg acid chloride, 790mg 1,1 '-two (diphenylphosphine) ferrocene, 890mg sodium bicarbonate, 10ml methyl alcohol, 10ml N, the mixture of dinethylformamide stirred 15 hours, return back to room temperature, dilute with ethyl acetate then.With diatomite filtering insoluble substance, with gained ethyl acetate solution water, saturated common salt water washing.Use the anhydrous magnesium sulfate drying organic layer, filter concentrated filtrate then.(eluting solvent: hexane/ethyl acetate=10/1～1/1) purifying obtains title compound by silica gel column chromatography with resistates.

(3) 6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyrazine-2-formic acid is synthetic

In 52mg 6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyrazine-2-methyl-formiate, 0.5ml tetrahydrofuran (THF), 1ml methanol mixture, add aqueous sodium hydroxide solution (1.0M, 0.5ml), at room temperature stirred 15 hours.The gained reaction solution is diluted with ethyl acetate, use aqueous ammonium chloride solution, saturated common salt water washing then.Use the anhydrous magnesium sulfate drying organic layer, filter then, concentrated filtrate obtains title compound.

(4) (6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyrazine-2-yl) methyl alcohol is synthetic

To 28mg 6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyrazine-2-formic acid, 1ml N, add 84mg N in the mixture of dinethylformamide, N '-carbonyl dimidazoles, at room temperature stirred 15 hours, the 200 μ l aqueous solution that add the 20mg sodium borohydride then stir.In reaction mixture, add entry, use ethyl acetate extraction then,, filter concentrated filtrate then gained ethyl acetate solution anhydrous magnesium sulfate drying.(eluting solvent: chloroform～chloroform/methanol=10/1) purifying obtains title compound by silica gel column chromatography with resistates.

(5) 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-(1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) pyrazine-2-amine is synthetic

At room temperature, to 2.14g (6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyrazine-2-yl) methyl alcohol, 2.32ml N, add 619 μ l methylsulfonyl chlorides in the mixture of N-diisopropylethylamine, 40ml chloroform, stirred 1 hour.Add 2.32ml N in reaction mixture, the N-diisopropylethylamine adds the hydrochloride of 1-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine of gained in the 3.13g reference example 7 then, stirs 2 hours down at 50 ℃.With gained reaction mixture sodium bicarbonate water, saturated common salt water washing, with gained organic layer anhydrous magnesium sulfate drying, filter back concentrating under reduced pressure filtrate, (eluting solvent: chloroform～chloroform/methanol=20/1) purifying obtains title compound by silica gel column chromatography with the gained resistates.

(6) 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine is synthetic

2.49g 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-(1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) pyrazine-2-amine solvent was at room temperature stirred 2 hours in 25ml trifluoroacetic acid and 2.5ml water.The concentrating under reduced pressure reaction solution is then with the ethyl acetate dilution, with saturated sodium bicarbonate water, water and saturated common salt water washing.With gained organic layer dried over mgso, filter concentrated filtrate then.(eluting solvent: chloroform～chloroform/methanol=5/1) purifying obtains the title compound of solid form by silica gel column chromatography with the gained resistates.In the gained solid, add ethanol, be heated to 80 ℃, make its dissolving.In this solution, add heptane, stop heating then, slowly cool to room temperature.Add heptane again, cross filter solid, drying obtains title crystal.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：8.51(s，1H)，8.09(s，1H)，7.70-7.56(m，2H)，7.52(s，1H)，7.37-7.20(m，2H)，6.26(s，1H)，3.89(brs，2H)，3.64(s，2H)，3.37(brs，2H)，2.66(dd，J＝5.1，4.9Hz，2H)，2.54(brs，2H)

Mass spectrum: 450 (M+1) ⁺

Melting point: 160-163 ℃

Below, according to method synthetic embodiment 45-54,56-60 and the 113-115 same with the foregoing description 44.

Embodiment 45

Synthesizing of 6-((4-(2,3-dichloro-benzoyl base) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine

¹H-NMR(CDCl ₃)δ：8.45(s，1H)，8.06(s，1H)，7.77(s，1H)，7.51-7.47(m，2H)，7.28-7.17(m，2H)，6.26(s，1H)，3.96-3.78(m，4H)，3.63(s，2H)，2.72-2.43(m，4H)

Mass spectrum: 432 (M+1) ⁺

Embodiment 46

6-(((1S, 4S)-5-(3-chloro-2-fluoro benzoyl)-2,5-diazabicyclo [2.2.1] oenanthyl-2-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine synthetic

¹H-NMR(CDCl ₃)δ：8.44(s，1H)，8.11-8.03(m，1H)，7.87-7，65(m，1H)，7.57-7.42(m，2H)，7.40-7.30(m，1H)，7.22-7.13(m，1H)，6.34-6.22(m，1H)，4.97-2.70(m，8H)，2.10-1.80(m，2H)

Mass spectrum: 428 (M+1) ⁺

Embodiment 47

6-(((1S, 4S)-5-(2-fluoro-3-(trifluoromethyl) benzoyl)-2,5-diazabicyclo [2.2.1] oenanthyl-2-yl) methyl)-N-1 H-pyrazole-3-yl pyrazine-2-amine synthetic

¹H-NMR(CDCl ₃)δ：8.46(s，1H)，8.08 and 8.05(each s，total 1H)，8.02-7.80(m，1H)，7.72-7.61(m，2H)，7.51and 7.48(each d，J＝2.3Hz，total 1H)，7.33(t，J＝7.8Hz，1H)，6.30 and 6.26(each s，total 1H)，4.95-2.72(m，8H)，2.07 and 2.02(each d，J＝10.0Hz，total 1H)，1.85(d，J＝10.0Hz，1H)

Mass spectrum: 462 (M+1) ⁺

Embodiment 48

6-(((1R, 4R)-5-(2-fluoro-3-(trifluoromethyl) benzoyl)-2,5-diazabicyclo [2.2.1] oenanthyl-2-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine synthetic

Mass spectrum: 462 (M+1) ⁺

Embodiment 49

Synthesizing of the trifluoroacetate of 6-((4-(3-bromo-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine

¹H-NMR(DMSO-d ₆)δ：10.05(s，1H)，8.45(s，1H)，8.01(s，1H)，7.85-7.80(m，1H)，7.64(s，1H)，7.47(dd，J＝6.3，6.0Hz，1H)，7.27(dd，J＝8.0，7.6Hz，1H)，6.52(s，1H)，4.40(s，2H)，3.58-3.24(m，4H)，2.55-2.48(m，4H)

Mass spectrum: 460,462 (M+1) ⁺

Embodiment 50

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine

¹H-NMR(CDC1 ₃)δ：8.51(s，1H)，8.09(s，1H)，7.52(s，1H)，7.45(dd，J＝7.0，6.3Hz，1H)，7.37-7.24(m，2H)，7.15(t，J＝7.8Hz，1H)，6.26(s，1H)，3.86(brs，2H)，3.64(s，2H)，3.38(brs，2H)，2.65(dd，J＝5.3，4.7Hz，2H)，2.53(brs，2H)

Embodiment 51

Synthesizing of the trifluoroacetate of 6-((4-(2-chloro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine

¹H-NMR(DMSO-d ₆)δ：10.05(s，1H)，8.45(s，1H)，8.01(s，1H)，7.98-7.93(m，1H)，7.80-7.74(m，1H)，7.70-7.62(m，2H)，6.52(s，1H)，4.41(s，2H)，3.60-3.20(m，4H)，2.55-2.40(m，4H)

Mass spectrum: 466 (M+1) ⁺

Embodiment 52

Synthesizing of 6-(((3R)-4-(2-fluoro-3-(trifluoromethyl) benzoyl)-3-methylpiperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine

¹H-NMR(CDCl ₃)δ：8.42(s，1H)，8.12(s，1H)，7.79(s，1H)，7.66(t，J＝7.0Hz，1H)，7.63-7.51(m，1H)，7.50(d，J＝2.4Hz，1H)，7.31(t，J＝7.8Hz，1H)，6.31(s，1H)，5.00-2.20(m，9H)，1.50-1.25(m，3H)

Mass spectrum: 464 (M+1) ⁺

Embodiment 53

Synthesizing of 6-((4-(3-cyclopropyl-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine

¹H-NMR(CDCl ₃)δ：8.50(s，1H)，8.10(s，1H)，7.51(d，J＝2.0Hz)，7.30-7.05(m，4H)，6.94-6.90(m，1H)，6.24(s，1H)，4.00-3.80(m，2H)，3.64(s，2H)，3.50-3.30(m，2H)，2.65(t，J＝5.1Hz，2H)，2.60-2.40(m，2H)，2.11-2.07(m，1H)，1.00(dd，J＝8.5，1.7Hz，2H)，0.72(d，J＝5.9Hz，2H)

Mass spectrum: 422 (M+1) ⁺

Embodiment 54

Synthesizing of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl)-1,4-Diazesuberane-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine

¹H-NMR(CDCl ₃)δ：8.47-8.42(m，1H)，8.12-8.02(m，1H)，7.92-7.79(m，1H)，7.68-7.50(m，3H)，7.35-7.25(m，1H)，6.27(s，1H)，3.93-3.71(m，4H)，3.48-3.36(m，2H)，2.93(t，J＝4.8Hz，1H)，2.83(dd，J＝5.6，5.2Hz，1H)，2.78-2.68(m，2H)，2.07-1.98(m，1H)，1.91-1.80(m，1H)

Mass spectrum: 464 (M+1) ⁺

Embodiment 55

Synthesizing of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl)-6-hydroxyl-1,4-Diazesuberane-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine

(1) 6-((6-(tetrahydrochysene-2H-pyrans-2-base oxygen base)-1,4-Diazesuberane-1-yl) methyl)-N-(1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) pyrazine-2-amine is synthetic

At room temperature, to 44.9mg 6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyrazine-2-yl) methyl alcohol, 73 μ l N, add 16 μ l methylsulfonyl chlorides in the mixture of N-diisopropylethylamine, 4ml chloroform, stirred 1 hour.This reaction mixture is added drop-wise to the 6-(tetrahydrochysene-2H-pyrans-2-base oxygen base)-1 that obtains in the reference example 5, in the 2ml chloroformic solution of 4-Diazesuberane, reaction mixture was at room temperature stirred 15 hours.With gained reaction mixture water, saturated common salt water washing, with gained organic layer anhydrous magnesium sulfate drying, filter, then concentrating under reduced pressure filtrate, (eluting solvent: chloroform/methanol=30/1) purifying obtains title compound by alkaline thin-layer chromatography with the gained resistates.

(2) 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl)-6-hydroxyl-1,4-Diazesuberane-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine is synthetic

Use 6-((6-(tetrahydrochysene-2H-pyrans-2-base oxygen base)-1; 4-Diazesuberane-1-yl) methyl)-N-(1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) pyrazine-2-amine and 2-fluoro-3-(trifluoromethyl) phenylformic acid; according to carrying out amidate action with the same method of embodiment 3-(2); according to carrying out deprotection reaction, obtain title compound then with the same method of the embodiment 16-(4) that uses trifluoroacetic acid.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：8.48-8.39(m，1H)，7.93(s，1H)，7.70-7.43(m，3H)，7.22-7.10(m，1H)，6.37-6.27(m，1H)，4.17-2.67(m，11H)

Mass spectrum: 480 (M+1) ⁺

Embodiment 56

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyrazine-2-amine

¹H-NMR(CDCl ₃)δ：8.48(s，1H)，8.06(s，1H)，7.48-7.33(m，2H)，7.33-7.25(m，1H)，7.15(dd，J＝8.0，7.6Hz，1H)，6.02(s，1H)，3.87(brs，2H)，3.62(s，2H)，3.37(brs，2H)，2.64(t，J＝5.1Hz，2H)，2.52(brs，2H)，2.31(s，3H)

Mass spectrum: 430 (M+1) ⁺

Embodiment 57

6-((4-(2-fluoro-(3-trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1,2,4-thiadiazoles-5-base pyrazine-2-amine synthetic

¹H-NMR(CDCl ₃)δ：12.16(brs，1H)，8.49(s，1H)，8.44-8.39(m，2H)，7.72-7.59(m，2H)，7.33(dd，J＝8.0，7.6Hz，1H)，3.96-3.80(m，4H)，3.40(brs，2H)，2.78-2.51(m，4H)

Mass spectrum: 468 (M+1) ⁺

Embodiment 58

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyrazine-2-amine

¹H-NMR(CDCl ₃)δ：8.33(s，1H)，8.24(s，1H)，7.56(d，J＝3.5Hz，1H)，7.49-7.42(m，1H)，7.30-7.23(m，2H)，7.14(t，J＝8.1Hz，1H)，6.95(d，J＝3.7Hz，1H)，3.87(brs，2H)，3.79(s，2H)，3.34(brs，2H)，2.72(t，J＝5.2Hz，2H)，2.59(brs，2H)

Mass spectrum: 433 (M+1) ⁺

Embodiment 59

Synthesizing of 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrimidine-4-amine

¹H-NMR(CDCl ₃)δ：8.35(d，J＝5.9Hz，1H)，7.53(d，J＝2.4Hz，2H)，7.46-7.42(m，1H)，7.28-7.26(m，1H)，7.15(t，J＝7.8Hz，1H)，7.10-7.00(m，1H)，6.23(s，1H)，4.00-3.80(m，2H)，3.73(s，2H)，3.60-3.30(m，2H)，2.71(t，.J＝5.1Hz，2H)，2.71-2.51(m，2H)

Mass spectrum: 416 (M+1) ⁺

Embodiment 60

Synthesizing of 2-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrimidine-4-amine

¹H-NMR(CDCl ₃)δ：8.35(d，J＝5.9Hz，1H)，7.66(t，J＝7.1Hz，1H)，7.64-7.50(m，3H)，7.53(d，J＝2.0Hz，1H)，7.32(t，J＝7.8Hz，1H)，7.05(s，1H)，6.24(s，1H)，4.00-3.80(m，2H)，3.73(s，2H)，3.50-3.35(m，2H)，2.72(t，J＝5.1Hz，2H)，2.70-2.55(m，2H)

Mass spectrum: 450 (M+1)

Embodiment 61

Synthesizing of 6-((4-(3-furancarbonyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

(1) 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine is synthetic

2g embodiment 5-(2) gained 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-thiazol-2-yl pyridine-2-amine solvent in 20ml 1, in the 4-two  alkane, is at room temperature added the 832mg N-chloro-succinimide.With reaction mixture reflux 2 hours, return back to room temperature then, with ethyl acetate dilution, water, saturated common salt water washing then, with gained organic layer anhydrous magnesium sulfate drying, filtration then, concentrating under reduced pressure filtrate obtains title compound.

(2) 6-(chloromethyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine is synthetic

Use 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine, according to embodiment 5-(3) and (4) same method, obtain title compound.

(3) 6-((4-(3-furancarbonyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine is synthetic

Use 6-(chloromethyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine, with reference example 1 similarly according to method synthetic 1-(3-furancarbonyl) piperazine of step (7)-(8), according to the same method of embodiment 5-(5), obtain title compound.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：11.47(s，1H)，8.01(s，1H)，7.72-7.68(m，2H)，7.37(s，1H)，7.02(d，J＝7.4Hz，1H)，6.89(d，J＝8.2Hz，1H)，6.64-6.63(m，1H)，3.66(s，2H)，3.60-3.58(m，4H)，2.50-2.48(m，4H).

Mass spectrum: 404 (M+1) ⁺

Below, according to method synthetic embodiment 62, the 64-77 same with the foregoing description 61.

Embodiment 62

6-(synthesizing of (4-(2-furancarbonyl) piperazine-1-yl) methyl-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.48(s，1H)，7.82-7.80(m，1H)，7.71(t，J＝7.8Hz，1H)，7.37(s，1H)，7.03(d，J＝7.0Hz，1H)，6.97(dd，J＝3.5，0.8Hz，1H)，6.90(d，J＝8.2Hz，1H)，6.61-6.59(m，1H)，3.73-3.64(m，6H)，2.53-2.47(m，4H).

Mass spectrum: 404 (M+1) ⁺

Embodiment 63

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl)-1,4-Diazesuberane-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(CDCl ₃)δ：7.64-7.55(m，1H)，7.55-7.37(m，2H)，7.33-7.22(m，1H)，7.18-6，98(m，2H)，6.86-6.81(m，1H)，6.78(dd，J＝9.2，8.6Hz，1H)，3.92-3.78(m，4H)，3.49-3.36(m，2H)，2.96(dd，J＝5.7，4.1Hz，1H)，2.85(t，J＝5.5Hz，1H)，2.81-2.70(m，2H)，2.07-1.78(m，2H)

Mass spectrum: 446 (M+1) ⁺

Embodiment 64

Synthesizing of 6-((4-(pyrazine-2-base carbonyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.48(s，1H)，8.83(d，J＝1.2Hz，1H)，8.73(d，J＝2.3Hz，1H)，8.65(dd，J＝2.7，1.6Hz，1H)，7.69(t，J＝7.4Hz，1H)，7.38(s，1H)，7.02(d，J＝7.4Hz，1H)，6.90(d，J＝7.4Hz，1H)，3.74-3.64(m，4H)，3.48-3.40(m，2H)，2.62-2.53(m，2H)，2.51-2.44(m，2H).

Mass spectrum: 416 (M+1) ⁺

Embodiment 65

Synthesizing of 6-((4-(3-thienyl carbonyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.48(s，1H)，7.76(d，J＝1.6Hz，1H)，7.70(t，J＝7.6Hz，1H)，7.59(dd，J＝4.7，2.7Hz，1H)，7.37(s，1H)，7.18(dd，J＝5.1，1.2Hz，1H)，7.02(d，J＝7.4Hz，1H)，6.90(d，J＝8.2Hz，1H)，3.74(s，2H)，3.65-3.45(m，2H)，3.39-3.37(m，2H)，2.54-2.41(m，4H).

Mass spectrum: 420 (M+1) ⁺

Embodiment 66

Synthesizing of 6-((4-(2-thienyl carbonyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.48(s，1H)，7.76-7.67(m，2H)，7.15-7.05(m，2H)，7.10(dd，J＝5.1，3.9Hz，1H)，7.03(d，J＝6.6Hz，1H)，6.90(d，J＝8.6Hz，1H)，3.76-3.60(m，4H)，3.39-3.24(m，2H)，2.58-2.42(m，4H).

Mass spectrum: 420 (M+1) ⁺

Embodiment 67

Synthesizing of 6-((4-(thiazol-2-yl carbonyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.48(s，1H)，8.03-7.97(m，2H)，7.71(t，J＝7.8Hz，1H)，7.37(s，1H)，7.04(d，J＝7.0Hz，1H)，6.90(d，J＝8.2Hz，1H)，4.31(brs，2H)，3.68(brs，4H)，2.64-2.51(m，4H).

Mass spectrum: 421 (M+1) ⁺

Embodiment 68

Synthesizing of 6-((4-((2-methyl-thiazole-4-yl) carbonyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.48(s，1H)，7.90(brs，1H)，7.75-7.66(m，1H)，7.38(s，1H)，7.02(d，J＝6.2Hz，1H)，6.89(d，J＝8.6Hz，1H)，3.66(brs，4H)，3.36-3.25(m，2H)，2.66(s，3H)，2.51-2.45(m，4H).

Mass spectrum: 435 (M+1) ⁺

Embodiment 69

Synthesizing of 6-((4-((1-methyl isophthalic acid H-pyrazole-3-yl) carbonyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.50(brs，1H)，7.75-7.69(m，2H)，7.38(s，1H)，7.04(brs，1H)，6.91(brs，1H)，6.52(s，1H)，4.07-3.80(m，2H)，3.86(s，3H)，3.79-3.56(m，2H)，3.38-3.21(m，2H)，2.51-2.38(m，4H).

Mass spectrum: 418 (M+1) ⁺

Embodiment 70

Synthesizing of 6-((4-(2-cyano group benzoyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.47(s，1H)，7.93(dd，J＝7.8，0.8Hz，1H)，7.77(dt，J＝1.2，7.6Hz，1H)，7.70(dd，J＝8.2，7.4Hz，1H)，7.62(dt，J＝1.2，7.6Hz，1H)，7.56(dd，J＝7.8，0.8Hz，1H)，7.37(s，1H)，7.02.(d，J＝7.0Hz，1H)，6.89(d，J＝8.2Hz，1H)，3.74-3-64(m，4H)，3.26-3.20(m，2H)，2.60-2.53(m，2H)，2.51-2.43(m，2H).

Mass spectrum: 439 (M+1) ⁺

Embodiment 71

Synthesizing of 6-((4-(3-cyano group benzoyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.47(s，1H)，7.93-7.86(m，2H)，7.74-7.61(m，3H)，7.37(s，1H)，7.01(d，J＝7.4Hz，1H)，6.89(d，J＝8.2Hz，1H)，3.66(s，4H)，3.41-3.25(m，2H)，2.60-2.38(m，4H).

Mass spectrum: 439 (M+1) ⁺

Embodiment 72

Synthesizing of 6-((4-(3-(acetylamino) benzoyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.47(s，1H)，10.05(s，1H)，7.70(dd，J＝8.2，7.4Hz，1H)，7.65(t，J＝1.6Hz，1H)，7.59-7.54(m，1H)，7.37(s，1H)，7.33(t，J＝8.0Hz，1H)，7.01(d，J＝7.4Hz，2H)，6.88(d，J＝8.2Hz，1H)，3.77-3.56(m，4H)，3.48-3.22(m，2H)，2.59-2.37(m，4H)，2.03(s，3H).

Mass spectrum: 471 (M+1) ⁺

Embodiment 73

Synthesizing of 6-((4-(3-(dimethylamino) benzoyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.47(s，1H)，7.69(t，J＝7.8Hz，1H)，7.37(s，1H)，7.20(t，J＝8.0Hz，1H)，7.01(d，J＝7.4Hz，1H)，6.88(t，J＝8.4Hz，1H)，6.75(dd，J＝8.6，2.7Hz，1H)，6.63-6.56(m，2H)，3.73-3.53(m，4H)，3.48-3.20(m，2H)，2.87(s，6H)，2.53-2.46(m，4H).

Embodiment 74

Synthesizing of 6-((4-(3-(methylsulfonyl) benzoyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.47(s，1H)，7.99(dt，J＝7.4，1.8Hz，1H)，7.91(t，J＝1.4Hz，1H)，7.76-7.68(m，3H)，7.37(s，1H)，7.02(d，J＝7.4Hz，1H)，6.89(d，J＝8.2Hz，1H)，3.67(s，4H)，3.48-3.29(m，2H)，3.26(s，3H)，2.62-2.40(m，4H).

Mass spectrum: 492 (M+1) ⁺

Embodiment 75

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.46(s，1H)，7.73-7.62(m，2H)，7.41-7.33(m，2H)，7.29(t，J＝8.0Hz，1H)，7.01(d，J＝7.4Hz，1H)，6.89(d，J＝8.2Hz，1H)，3.73-3.62(m，4H)，3.36-3.20(m，2H)，2.59-2.39(m，4H).

Mass spectrum: 466 (M+1) ⁺

Embodiment 76

Synthesizing of 6-((4-(2,3-dichloro-benzoyl base) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(DMSO-d ₆)δ：11.46(s，1H)，7.72-7.64(m，2H)，7.43(t，J＝7.8Hz，1H)，7.37-7.34(m，2H)，7.01(d，J＝7.4Hz，1H)，6.89(d，J＝8.2Hz，1H)，3.76-3.59(m，4H)，3.21-3.11(m，2H)，2.61-2.37(m，4H).

Mass spectrum: 482 (M+1) ⁺

Embodiment 77

Synthesizing of the trifluoroacetate of 6-((4-((4-chloro-phenyl-) ethanoyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.81(dd，J＝8.4，7.6Hz，1H)，7.29(d，J＝8.4Hz，2H)，7.28(s，1H)，7.21(d，J＝8.4Hz，2H)，7.17(d，J＝7.6Hz，1H)，7.10(d，J＝8.4Hz，1H)，4.46(s，2H)，4.10-3.70(m，4H)，3.80(s，2H)，3.52-3.34(m，4H)

Mass spectrum: 462 (M+1) ⁺

Embodiment 78

Synthesizing of 6-((4-((2-fluorine pyridin-3-yl) carbonyl) piperazine-1-yl) methyl)-N-(5-bromo thiazole-2-yl) pyridine-2-amine

(1) 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(5-bromo thiazole-2-yl) pyridine-2-amine is synthetic

Use 6-(((tertiary butyl (dimethyl) silyl) oxygen base) the methyl)-N-thiazol-2-yl pyridine-2-amine and the N-bromine succinimide of embodiment 5-(2) gained, according to the same method of embodiment 61-(1), obtain title compound.

(2) 6-(chloromethyl)-N-(5-bromo thiazole-2-yl) pyridine-2-amine is synthetic

Use 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(5-bromo thiazole-2-yl) pyridine-2-amine, according to synthesizing with the same method in embodiment 5-(3) and (4).

(3) 6-((4-((2-fluorine pyridin-3-yl) carbonyl) piperazine-1-yl) methyl)-N-(5-bromo thiazole-2-yl) pyridine-2-amine is synthetic

Use 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(5-bromo thiazole-2-yl) pyridine-2-amine and with reference example 1 similarly according to method synthetic 1-((the 2-fluorine pyridin-3-yl) carbonyl) piperazine of step (7)-(8), according to the same method of embodiment 5-(5), obtain title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：8.29(d，J＝3.5Hz，1H)，7.89(t，J＝7.6Hz，1H)，7.63(t，J＝7.6Hz，1H)，7.35(s，1H)，7.33-7.20(m，1H)，7.05(d，J＝7.4Hz，1H)，6.72(d，J＝8.2Hz，1H)，3.87(s，2H)，3.77(s，2H)，3.39(s，2H)，2.69(s，2H)，2.58(s，2H)

Mass spectrum: 477,479 (M+1) ⁺

Below, according to the method synthetic embodiment 79 and 80 same with the foregoing description 78.

Embodiment 79

Synthesizing of 6-((4-(the different nicotinoyl of 2-fluorine) piperazine-1-yl) methyl)-N-(5-bromo thiazole-2-yl) pyridine-2-amine

¹H-NMR(CDCl ₃)δ：8.30(d，J＝4.9Hz，1H)，7.64(dd，J＝7.6，7.2Hz，1H)，7.37(s，1H)，7.19(d，J＝4.9Hz，1H)，7.03(d，J＝7.2Hz，1H)，6.95(s，1H)，6.74(d，J＝8.0Hz，1H)，3.85(s，2H)，3.77(s，2H)，3.41(s，2H)，2.70(s，2H)，2.55(s，2H)

Mass spectrum: 477,479 (M+1) ⁺

Embodiment 80

Synthesizing of 6-((4-((6-fluorine pyridine-2-yl) carbonyl) piperazine-1-yl) methyl)-N-(5-bromo thiazole-2-yl) pyridine-2-amine

¹H-NMR(CDCl ₃)δ：7.95-7.88(m，1H)，7.63(dd，J＝8.2，7.6Hz，1H)，7.57(d，J＝7.4Hz，1H)，7.35(s，1H)，7.06(d，J＝8.0Hz，1H)，7.00(d，J＝7.2Hz，1H)，6.72(d，J＝7.6Hz，1H)，3.89-3.81(m，2H)，3.77(s，2H)，3.70-3.63(m，2H)，2.74-2.67(m，2H)，2.67-2.55(m，2H)

Mass spectrum: 477,479 (M+1) ⁺

Embodiment 81

Synthesizing of 4-bromo-6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

(1) 4-bromopyridine-2,6-dioctyl phthalate dimethyl ester synthetic

At room temperature, with 7.38g according to Tetrahedron lett., 42 (29), 4849 (2001) method synthetic 4-bromopyridine-2,6-dioctyl phthalate, hydrochloric acid-methanol reagent 10ml, 100ml methanol mixture stirred 15 hours, then concentrating under reduced pressure.In resistates, add ethyl acetate, use the mixed solution of saturated aqueous common salt-saturated sodium bicarbonate water (1: 1) to wash three times, use the anhydrous magnesium sulfate drying organic layer.Filter the back concentrating under reduced pressure, obtain title compound.

(2) 4-bromopyridine-2,6-dioctyl phthalate one methyl esters synthetic

At room temperature, with 6.09g 4-bromopyridine-2, the mixture of 6-dioctyl phthalate dimethyl ester, 1.08g potassium hydroxide, 200ml methyl alcohol, 20ml methylene dichloride stirred 3 hours, added the 200ml ether.The white solid that leaching generates washs with ether.The gained white solid is dissolved in the water, adds 12ml hydrochloric acid (2M) then, use chloroform extraction, use the anhydrous magnesium sulfate drying organic layer.Filter the back concentrating under reduced pressure, obtain title compound.

(3) 4-bromo-6-tert-butoxycarbonyl aminopyridine-2-methyl-formiate is synthetic

At room temperature, to 4.62g 4-bromopyridine-2,6-dioctyl phthalate one methyl esters, 2.97ml triethylamine, the 25ml trimethyl carbinol, 70ml 1 add the 4.59ml diphenyl phosphate azide in the mixture of 4-two  alkane.With reaction mixture reflux 3 hours, return back to room temperature then, add entry, use ethyl acetate extraction.With gained ethyl acetate solution water, saturated common salt water washing, use anhydrous sodium sulfate drying then, filter the back concentrating under reduced pressure, obtain title compound.

(4) 6-amino-4-bromopyridine-2-methyl-formiate is synthetic

7.23g 4-bromo-6-tert-butoxycarbonyl aminopyridine-2-methyl-formiate is dissolved in the 30ml chloroform, adds the 15ml trifluoroacetic acid then, at room temperature stirred 1 hour.After concentrating resistates is dissolved in the ethyl acetate, with saturated sodium bicarbonate water, saturated common salt water washing.Use the anhydrous magnesium sulfate drying organic layer, filter the back concentrating under reduced pressure.(eluting solvent: chloroform～chloroform/methanol=20/1) purifying obtains title compound by silica gel column chromatography with resistates.

(5) 6-(3-benzoylthioureas base)-4-bromopyridine-2-methyl-formiate is synthetic

2.74g 6-amino-4-bromopyridine-2-methyl-formiate is dissolved in the 15ml tetrahydrofuran (THF), adds 1.63ml isothiocyanic acid benzoyl ester, at room temperature stirred 13 hours.Add the 40ml hexane in reaction mixture, the solid that leaching generates is used hexane wash.With gained solid drying under reduced pressure, obtain title compound.

(6) 4-bromo-6-(thiazol-2-yl amino) pyridine-2-methyl-formiate is synthetic

In 2.37g 6-(3-benzoylthioureas base)-4-bromopyridine-2-methyl-formiate, 20ml tetrahydrofuran (THF), 40ml methanol mixture, add 673mg potassium hydroxide.At room temperature reaction mixture was stirred 1.5 hours, add methanol hydrochloride solution furnishing acidity then, decompression is heated up in a steamer and is desolvated.The gained resistates is dissolved in 60ml 1, and 4-two  alkane add the 3.53ml 40% monochloroacetaldehyde aqueous solution.With reaction mixture reflux 1 hour, at room temperature add 40ml methanol hydrochloride solution, 60ml methyl alcohol then, stirring is spent the night.The concentrating under reduced pressure reaction mixture by methyl alcohol-ether recrystallization, obtains title compound with resistates.

(7) (4-bromo-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) pyridine-2-yl) methyl alcohol is synthetic

Use 4-bromo-6-(thiazol-2-yl amino) pyridine-2-methyl-formiate, according to embodiment 1-(3) and (5) same method, obtain title compound.

(8) 4-bromo-6-(mesyloxy methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) pyridine-2-amine is synthetic

Use (4-bromo-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) pyridine-2-yl) methyl alcohol, according to the same method of embodiment 16-(2), obtain title compound.

(9) 4-bromo-6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) pyridine-2-amine is synthetic

Use 4-bromo-6-(mesyloxy methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) pyridine-2-amine, according to the same method of embodiment 16-(3), obtain title compound.

(10) 4-bromo-6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine is synthetic

Use 4-bromo-6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) pyridine-2-amine, according to the same method of embodiment 1-(8), obtain title compound.

The spectrum data of title compound is as follows.

Mass spectrum: 510,512 (M+1) ⁺

Embodiment 82

Synthesizing of 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) iso methyl nicotinate

(1) 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) iso methyl nicotinate is synthetic

Use 4-bromo-6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino of embodiment 81-(9) gained) pyridine-2-amine; according to the same method of embodiment 1-(2), obtain title compound.

(2) 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) iso methyl nicotinate is synthetic

Use 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) iso methyl nicotinate, according to the same method of embodiment 1-(8), obtain title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.57-7.52(m，2H)，7.47-7.42(m，2H)，7.30-7.25(m，1H)，7.15(t，J＝8.0Hz，1H)，6.91(d，J＝3.6Hz，1H)，3.98(s，3H)，3.91-3.85(m，2H)，3.81(s，2H)，3.43-3.32(m，2H)，2.71(brt，J＝4.8Hz，2H)，2.63-2.52(m，2H)

Mass spectrum: 490 (M+1) ⁺

Embodiment 83

Synthesizing of 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) Yi Yansuan

(1) 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) Yi Yansuan is synthetic

Use embodiment 82-(1) gained 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) iso methyl nicotinate; according to the same method of embodiment 44-(3), obtain title compound.

(2) 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) Yi Yansuan trifluoroacetate is synthetic

Use 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) Yi Yansuan, according to the same method of embodiment 16-(4), obtain title compound.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：7.74-7.68(m，1H)，7.63(s，1H)，7.61(s，1H)，7.47-7.41(m，2H)，7.33(t，J＝8.0Hz，1H)，7.13(d，J＝4.0Hz，1H)，4.49(brs，2H)

Mass spectrum: 476 (M+1) ⁺

Embodiment 84

Synthesizing of the trifluoroacetate of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(tetramethyleneimine-1-base carbonyl)-N-thiazol-2-yl pyridine-2-amine

Use embodiment 83-(1) gained 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) Yi Yansuan and tetramethyleneimine; according to carrying out amidate action with the same method of embodiment 3-(2); carry out deprotection reaction then, obtain title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CD ₃OD)δ：7.67-7.61(m，1H)，7.52-7.49(m，1H)，7.43-7.37(m，1H)，7.33-7.26(m，3H)，7.18-7.14(m，1H)，4.57(s，2H)，4.17-4.00(m，2H)，3.70(brs，2H)，3.64-3.57(m，4H)，3.52-3.43(m，4H)，2.06-1.90(m，4H)

Mass spectrum: 490 (M+1) ⁺

Below, according to the method synthetic embodiment 85-88 same with the foregoing description 84.

Embodiment 85

Synthesizing of the trifluoroacetate of 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-methyl-6-(thiazol-2-yl amino) Isonicotinamide

¹H-NMR(CD ₃OD)δ：7.67-7.60(m，1H)，7.54(S，1H)，7.52(s，1H)，7.51(d，J＝4.0Hz，1H)，7.43-7.37(m，1H)，7.30(t，J＝8.0Hz，1H)，7.16(d，J＝4.0Hz，1H)，4.57(s，2H)，4.15-4.01(m，2H)，3.70(brs，2H)，3.60(brs，2H)，3.48(brs，2H)，2.95(s，3H)

Mass spectrum: 489 (M+1) ⁺

Embodiment 86

2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N, the trifluoroacetate of N-dimethyl-6-(thiazol-2-yl amino) Isonicotinamide synthetic

¹H-NMR(CD ₃OD)δ：7.66-7.60(m，1H)，7.54(d，J＝4.0Hz，1H)，7.43-7.37(m，1H)，7.30(t，J＝8.0Hz，1H)，7.29(d，J＝1.2Hz，1H)，7.24(d，J＝1.2Hz，1H)，7.20(d，J＝4.0Hz，1H)，4.58(s，2H)，4.09(brs，2H)，3.70(brs，2H)，3.61(brs，2H)，3.49(brs，2H)，3.12(s，3H)，3.01(s，3H)

Mass spectrum: 503 (M+1) ⁺

Embodiment 87

Synthesizing of the trifluoroacetate of 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) Isonicotinamide

¹H-NMR(CD ₃OD)δ：7.67-7.59(m，3H)，7.55(d，J＝4.0Hz，1H)，7.43-7.37(m，1H)，7.30(t，J＝8.0Hz，1H)，7.20(d，J＝4.0Hz，1H)，4.60(s，2H)，4.09(brs，2H)，3.70(brs，2H)，3.60(brs，2H)，3.49(brs，2H)

Mass spectrum: 475 (M+1) ⁺

Embodiment 88

Synthesizing of the trifluoroacetate of 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(2-hydroxyethyl)-6-(thiazol-2-yl amino) Isonicotinamide

¹H-NMR(CD ₃OD)δ：7.66-7.60(m，1H)，7.49(s，2H)，7.45(d，J＝3.6Hz，1H)，7.42-7.37(m，1H)，7.29(t，J＝8.0Hz，1H)，7.09(d，J＝3.6Hz，1H)，4.52(s，2H)，4.07(brs，2H)，3.72(t，J＝5.6Hz，2H)，3.68(brs，2H)，3.56(brs，2H)，3.52(t，J＝5.6Hz，2H)，3.44(brs，2H)

Mass spectrum: 519 (M+1) ⁺

Embodiment 89

Synthesizing of (2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) pyridin-4-yl) methyl alcohol

(1) (2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) pyridin-4-yl) methyl alcohol is synthetic

Use 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) iso methyl nicotinate of embodiment 82-(1) gained; according to the same method of embodiment 1-(5), obtain title compound.

(2) (2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) pyridin-4-yl) methyl alcohol is synthetic

Use (2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) pyridin-4-yl) methyl alcohol, according to the same method of embodiment 16-(4), obtain title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.47-7.42(m，1H)，7.40(d，J＝3.6Hz，1H)，7.30-7.23(m，1H)，7.15(brt，J＝8.0Hz，1H)，6.97(brs，1H)，6.84-6.81(m，2H)，4.74(s，2H)，3.89-3，83(m，2H)，3.73(s，2H)，3.41-3.32(m，2H)，2.72-2.66(m，2H)，2.60-2.52(m，2H)

Mass spectrum: 462 (M+1) ⁺

Embodiment 90

Synthesizing of the trifluoroacetate of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl-4-(1H-1,2,3-thiazole-1-ylmethyl) pyridine-2-amine

(1) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit)-4-(mesyloxy methyl) pyridine-2-amine is synthetic

Use embodiment 89-(1) gained (2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) pyridin-4-yl) methyl alcohol; according to the same method of embodiment 16-(2), obtain title compound.

(2) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit)-4-(1H-1; 2; 3-triazol-1-yl methyl) pyridine-2-amine and 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit)-4-(2H-1; 2,3-triazole-2-ylmethyl) pyridine-2-amine is synthetic

At room temperature; with 26mg 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit)-4-(mesyloxy methyl) pyridine-2-amine, 5.2 μ l1H-1; 2; 3-triazole, 14 μ l1, the mixture of 8-diazabicyclo [5.4.0] 11 carbon-7-alkene, 0.47ml chloroform stirred 19 hours.(eluting solvent: chloroform～chloroform/methanol=10/1) purifying obtains title compound by silica gel column chromatography with reaction solution.

(3) trifluoroacetate of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl-4-(1H-1,2,3-triazol-1-yl methyl) pyridine-2-amine is synthetic

Use 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit)-4-(1H-1; 2; 3-triazol-1-yl methyl) pyridine-2-amine, according to the same method of embodiment 16-(4), obtain title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CD ₃OD)δ：8.13(s，1H)，7.84(d，J＝1.2Hz，1H)，7.66-7.60(m，1H)，7.55(d，J＝3.6Hz，1H)，7.42-7.36(m，1H)，7.29(brt，J＝7.6Hz，1H)，7.22(d，J＝3.6Hz，1H)，7.21(s，1H)，7.04(s，1H)，5.79(s，2H)，4.54(s，2H)，4.07(brs，2H)，3.68(brs，2H)，3.57(brs，2H)，3.46(brs，2H)

Mass spectrum: 513 (M+1) ⁺

Embodiment 91

Synthesizing of the trifluoroacetate of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl-4-(2H-1,2,3-triazole-2-ylmethyl) pyridine-2-amine

Use embodiment 90-(2) gained 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit)-4-(2H-1; 2; 3-triazole-2-ylmethyl) pyridine-2-amine; according to the same method of embodiment 16-(4), obtain title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CD ₃OD)δ：7.80(s，2H)，7.67-7.61(m，1H)，7.46(d，J＝3.6Hz，1H)，7.43-7.37(m，1H)，7.30(brt，J＝8.0Hz，1H)，7.11(d，J＝3.6Hz，1H)，7.09(s，1H)，6.94(s，1H)，5.75(s，2H)，4.48(s，2H)，4.06(brs，2H)，3.67(brs，2H)，3.56(brs，2H)，3.44(brs，2H)

Mass spectrum: 513 (M+1) ⁺

Below, according to the method synthetic embodiment 92-95 same with the foregoing description 90.

Embodiment 92

Synthesizing of the trifluoroacetate of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl-4-(1H-1,2,4-triazol-1-yl methyl) pyridine-2-amine

¹H-NMR(CD ₃OD)δ：8.71(s，1H)，8.12(s，1H)，7.66-7.60(m，1H)，7.56(d，J＝3.6Hz，1H)，7.44-7.36(m，1H)，7.29(t，J＝8.0Hz，1H)，7.23(s，1H)，7.22(d，J＝3.6Hz，1H)，7.07(s，1H)，5.60(s，2H)，4.54(s，2H)，4.07(brs，2H)，3.69(brs，2H)，3.57(brs，2H)，3.46(brs，2H)

Mass spectrum: 513 (M+1) ⁺

Embodiment 93

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-((methylsulfonyl) methyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(CDCl ₃)δ：11.37(brs，1H)，7.69-7.63(m，1H)，7.40-7.34(m，2H)，7.30(t，J＝8.0Hz，1H)，7.04(s，1H)，7.00(d，J＝3.6Hz，1H)，6.96(s，1H)，4.53(s，2H)，3.72-3.64(m，4H)，2.97(s，3H)

Mass spectrum: 524 (M+1) ⁺

Embodiment 94

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-((dimethylamino) methyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(CDCl ₃)δ：7.48(d，J＝4.0Hz，1H)，7.47-7.41(m，1H)，7.29-7.24(m，1H)，7.14(brt，J＝8.0Hz，1H)，6.97(s，1H)，6.84(d，J＝4.0Hz，1H)，6.81(s，1H)，3.86(brt，J＝4.8Hz，2H)，3.74(s，2H)，3.42(s，2H)，3.37(brs，2H)，2.70(brt，J＝4.8Hz，2H)，2.57(brs，2H)，2.27(s，6H)

Mass spectrum: 489 (M+1) ⁺

Embodiment 95

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(methoxymethyl)-N-thiazol-2-yl pyridine-2-amine

¹H-NMR(CDCl ₃)δ：7.49(brd，J＝3.6Hz，1H)，7.47-7.41(m，1H)，7.30-7.24(m，1H)，7.14(t，J＝8.0Hz，1H)，6.93(s，1H)，6.85(d，J＝3.6Hz，1H)，6.83(s，1H)，4.47(s，2H)，3.87(brt，J＝4.8Hz，2H)，3.74(s，2H)，3.46(s，3H)，3.37(brs，2H)，2.71(brt，J＝4.8Hz，2H)，2.57(brs，2H)

Mass spectrum: 476 (M+1) ⁺

Embodiment 96

Synthesizing of 1-(2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) pyridin-4-yl) pyrrolidin-2-one

1ml 1 to 25.5mg embodiment 81 gained 4-bromo-6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine; add 0.011ml pyrrolidin-2-one, 32mg potassiumphosphate, 8.7mg 9 successively in the 4-two  alkane solution; 9-dimethyl-4; two (diphenylphosphine) xanthenes of 5-, 7.8mg three (dibenzalacetone) close two palladiums (0)-chloroform complex compound; under 100 ℃, reaction solution was stirred 3 hours.The cooling reaction solution with the ethyl acetate dilution, washes with water then, uses anhydrous magnesium sulfate drying.Decompression is heated up in a steamer and is desolvated, with the gained resistates by anti-phase medium pressure liquid chromatography [ODS-AS-360-CC (YMC manufacturing), moving phase: water-acetonitrile-0.1% trifluoroacetic acid] purifying.The gained fraction is diluted with ethyl acetate,, use anhydrous magnesium sulfate drying then with the saturated sodium bicarbonate water washing.Decompression is heated up in a steamer and is desolvated, and obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.62(s，1H)，7，50(s，1H)，7.44(t，J＝6.8Hz，1H)，7.30-7.23(m，1H)，7.19-7.11(m，2H)，6.85(s，1H)，3.94-3.82(m，4H)，3.73(s，2H)，3.42-3.30(m，2H)，2.77-2.45(m，6H)，2.26-2.16(m，2H)

Mass spectrum: 515,517 (M+1) ⁺

Below, according to the method synthetic embodiment 97-103 same with the foregoing description 96.

Embodiment 97

3-(2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) pyridin-4-yl)-1,3- azoles alkane-2-ketone synthetic

¹H-NMR(DMSO-d ₆)δ：7.67(t，J＝8.0Hz，1H)，7.40-7.25(m，4H)，7.13(s，1H)，6.99(d，J＝3.3Hz，1H)，4.46(t，J＝7.8Hz，2H)，4.04(t，J＝7.8Hz，2H)，3.72-3.65(m，2H)，3.64(s，2H)，3.30-3.20(m，2H)，2.60-2.41(m，4H)

Mass spectrum: 517,519 (M+1) ⁺

Embodiment 98

Synthesizing of 3-(2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) pyridin-4-yl)-3-Methylimidazole alkane-2-ketone

¹H-NMR(DMSO-d ₆)δ：11.06(s，1H)，7.70-7.60(m，1H)，7.40-7.20(m，5H)，7.03(s，1H)，6.95-6.92(m，1H)，3.80-3.40(m，8H)，3.30-3.15(m，2H)，2.77(s，3H)，2.65-2.40(m，4H)

Mass spectrum: 530 (M+1) ⁺

Embodiment 99

Synthesizing of 3-(2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) pyridin-4-yl) piperidines-2-ketone

¹H-NMR(CDCl ₃)δ：7.47-7.40(m，2H)，7.29-7.22(m，1H)，7.14(t，J＝7.8Hz，1H)，6.99(s，1H)，6.90(s，1H)，6.82(s，1H)，3.91-3.80(m，2H)，3.75-3.64(m，4H)，3.42-3.29(m，2H)，2.74-2.46(m，6H)，2.03-1.92(m，4H)

Mass spectrum: 529,531 (M+1) ⁺

Embodiment 100

6-((4-(2, the 3-difluoro benzoyl) piperazine-1-yl) methyl)-N ⁴-(2,2-two fluoro ethyls)-N2-thiazol-2-yl pyridine-2,4-diamines synthetic

Mass spectrum: 495 (M+1) ⁺

Embodiment 101

Synthesizing of 6-((4-(2, the 3-difluoro benzoyl) piperazine-1-yl) methyl)-4-piperazine-1-base-N-thiazol-2-yl pyridine-2-amine

Mass spectrum: 500 (M+1) ⁺

Embodiment 102

1-(2-((4-(2, the 3-difluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino) pyridin-4-yl)-1,5-dihydro-2 h-pyrrole-2-ketone synthetic

Mass spectrum: 497 (M+1) ⁺

Embodiment 103

Synthesizing of 6-((4-(2, the 3-difluoro benzoyl) piperazine-1-yl) methyl)-4-morpholine-4-base-N-thiazol-2-yl pyridine-2-amine

Mass spectrum: 501 (M+1) ⁺

Embodiment 104

Synthesizing of 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino)-4-cyanopyridine

(1) 4-bromo-6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit) pyridine-2-amine is synthetic

Use embodiment 81-(7) gained (4-bromo-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) pyridine-2-yl) methyl alcohol, according to the same method of embodiment 5-(1), obtain title compound.

(2) 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-6-((3-(methoxymethyl) thiazole-2 (3H)-subunit) amino)-4-cyanopyridine is synthetic

Under 140 ℃, with 2.04g 4-bromo-6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(3-(methoxymethyl)-thiazole-2 (3H)-subunit) pyridine-2-amine, 379mg zinc cyanide, 266mg 4, two (diphenylphosphine)-9 of 5-, the mixture that 9-dimethyl xanthene, 133mg two (dibenzalacetone) close palladium (0), 92mg zinc, 9.2ml N,N-dimethylacetamide stirred 3 hours.The gained reaction mixture is diluted with ethyl acetate, remove insoluble substance with diatomite filtration then.Water and saturated aqueous common salt wash filtrate are used the anhydrous magnesium sulfate drying organic layer, filter concentrated filtrate.(eluting solvent: hexane～hexane/ethyl acetate=3/1) purifying obtains title compound by silica gel column chromatography with resistates.

(3) 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino)-4-cyanopyridine is synthetic

Use 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-6-((3-(methoxymethyl) thiazole-2 (3H)-subunit) amino)-4-cyanopyridine, carry out same step with embodiment 5-(3), then carry out and embodiment 16-(2)-(4) same step, obtain title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.53(d，J＝3.7Hz，1H)，7.50-7.43(m，1H)，7.32-7.25(m，2H)，7.16(t，J＝7.8Hz，1H)，7.05(s，1H)，6.97(d，J＝3.5Hz，1H)，3.89(brs，2H)，3.79(s，2H)，3.39(brs，2H)，2.69(t，J＝4.9Hz，2H)，2.57(brs，2H)

Mass spectrum: 457 (M+1) ⁺

Embodiment 105

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(2H-tetrazolium-5-yl)-N-thiazol-2-yl pyridine-2-amine

Under 110 ℃; with 25.2mg embodiment 104 gained 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino)-4-cyanopyridine, 17.9mg sodiumazide, 38.0mg triethylamine hydrochloride, 2ml N; the mixture of dinethylformamide stirred 13 hours, then concentration of reaction solution.(eluting solvent: chloroform/methanol=5/1) purifying obtains title compound by the preparation thin-layer chromatography with the gained resistates.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.84(s，1H)，7.43(dd，J＝7.0，6.3Hz，1H)，7.38-7.23(m，3H)，7.13(dd，J＝8.0，7.6Hz，1H)，6.85-6.81(m，1H)，3.92-3.89(m，4H)，3.44-3.30(m，2H)，2.81-2.49(m，4H)

Mass spectrum: 500 (M+1) ⁺

Embodiment 106

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(1-methyl isophthalic acid H-tetrazolium-5-yl)-N-thiazol-2-yl pyridine-2-amine

(1) 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit)-4-(2H-tetrazolium-5-yl) pyridine-2-amine is synthetic

Use embodiment 104-(2) gained 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-6-((3-(methoxymethyl) thiazole-2 (3H)-subunit) amino)-4-cyanopyridine, method according to same with embodiment 105 obtains title compound.

(2) 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit)-4-(1-methyl isophthalic acid H-tetrazolium-5-yl) pyridine-2-amine and 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit)-4-(2-methyl-2H-tetrazolium-5-yl) pyridine-2-amine is synthetic

With 194mg 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit)-4-(1H-tetrazolium-5-yl) pyridine-2-amine solvent in 3ml N, in the dinethylformamide, add the 190mg cesium carbonate.Stirred 1.5 hours down at 60 ℃, return back to room temperature, add 29.3 μ l methyl-iodides then, at room temperature stirred 1.5 hours.Use the ethyl acetate dilute reaction solution, then water and saturated common salt water washing.With gained organic layer dried over mgso, filter concentrated filtrate then.(eluting solvent: hexane～hexane/ethyl acetate=2/1) purifying obtains title compound respectively by silica gel column chromatography with the gained resistates.

(3) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(1-methyl isophthalic acid H-tetrazolium-5-yl)-N-thiazol-2-yl pyridine-2-amine is synthetic

Use 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit)-4-(1-methyl isophthalic acid H-tetrazolium-5-yl) pyridine-2-amine, the method according to similarly to Example 16 obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：11.56(brs，1H)，7.68-7.62(m，1H)，7.44-7.40(m，3H)，7.37(dd，J＝8.0，7.2Hz，1H)，7.30(d，J＝7.8，7.6Hz，1H)，7.07(d，J＝3.3Hz，1H)，4.21(s，3H)，3.77(s，2H)，3.69(brs，2H)，3.30-3.23(m，2H)，2.64-2.45(m，4H)

Mass spectrum: 514 (M+1) ⁺

Embodiment 107

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(2-methyl-2H-tetrazolium-5-yl)-N-thiazol-2-yl pyridine-2-amine

Use embodiment 106-(2) gained 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit)-4-(2-methyl-2H-tetrazolium-5-yl) pyridine-2-amine, method according to same with embodiment 106 obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.73(s，1H)，7.59(s，1H)，7.57-7.41(m，2H)，7.30-7.10(m，2H)，6.89(s，1H)，4.46(s，3H)，3.89(brs，2H)，3.83(s，2H)，3.44-3.36(m，2H)，2.80-2.2.51(m，4H)

Mass spectrum: 514 (M+1) ⁺

Embodiment 108

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl-4-(1H-1,2,4-triazole-5-yl) pyridine-2-amine

In 25.2mg embodiment 104 gained 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-(thiazol-2-yl amino)-4-cyanopyridine, 1ml methanol mixture, add 0.3ml 28% methanol solution of sodium methylate, at room temperature stirred 5 hours.Add the methyl alcohol 1ml solution of 3.3mg formyl hydrazine in reaction solution, at room temperature stirred 17 hours, reflux is 24 hours then.Add the methyl alcohol 1.5ml solution of 16.6mg formyl hydrazine in reaction solution, reheat refluxed 22 hours.Return back to concentration of reaction solution after the room temperature, (eluting solvent: chloroform/methanol=7/1) purifying obtains title compound by the preparation thin-layer chromatography with the gained resistates.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：8.59(s，1H)，7.69-7.58(m，3H)，7.41-7.28(m，3H)，7.03-6.98(m，1H)，3.72(s，2H)，3.60-3.05(m，6H)，2.63-2.45(m，2H)

Mass spectrum: 499 (M+1) ⁺

Embodiment 109

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(5-methyl isophthalic acid, 2,4- diazole-3-yl)-N-thiazol-2-yl pyridine-2-amine

(1) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit)-4-(5-methyl isophthalic acid, 2,4- diazole-3-yl) pyridine-2-amine is synthetic

Refluxed 18 hours to 31.1mg embodiment 104-(3) gained 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino)-4-cyanopyridine, 13.0mg hydrochloric acid hydroxylammonium, 17.2mg salt of wormwood, 3ml alcoholic acid mixture heating up.Return back to room temperature, concentration of reaction solution adds 3.0ml diacetyl oxide, reflux 4 hours then in resistates.Return back to room temperature, concentration of reaction solution with the chloroform dilution, is used the saturated potassium carbonate solution washing then then.With gained organic layer dried over mgso, filter concentrated filtrate then.(eluting solvent: chloroform/methanol=10/1) purifying obtains title compound by the preparation thin-layer chromatography with the gained resistates.

(2) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(5-methyl isophthalic acid, 2,4- diazole-3-yl)-N-thiazol-2-yl pyridine-2-amine is synthetic

Use 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit)-4-(5-methyl isophthalic acid; 2; 4- diazole-3-yl) pyridine-2-amine is according to obtaining title compound with the same method of embodiment 16-(4).

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.64(s，1H)，7.62-7.58(m，1H)，7.54(s，1H)，7.44(dd，J＝8.0，7.0Hz，1H)，7.28-7.23(m，1H)，7.14(t，J＝7.8Hz，1H)，6.91(d，J＝3.5Hz，1H)，3.91-3.84(m，2H)，3.82(s，2H)，3.38(brs，2H)，2.71(s，3H)，2.77-2.50(m，4H)

Mass spectrum: 514 (M+1) ⁺

Embodiment 110

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(3-methyl isophthalic acid, 2,4- diazole-5-yl)-N-thiazol-2-yl pyridine-2-amine

(1) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit)-4-(3-methyl isophthalic acid, 2,4- diazole-5-yl) pyridine-2-amine is synthetic

In the mixture of 9.4mg N-hydroxyl acetamidine, molecular sieve 4A, 1ml tetrahydrofuran (THF), add sodium hydride; stirred 1 hour down at 65 ℃; the 1ml tetrahydrofuran solution that in reaction solution, adds 22.6mg 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl) 6-((3-(methoxymethyl)-thiazole-2 (3H)-subunit) amino) iso methyl nicotinate, reflux 6 hours.Reaction solution is returned back to room temperature, then with the ethyl acetate dilution, with saturated sodium bicarbonate water and saturated common salt water washing.With gained organic layer dried over mgso, filter concentrated filtrate then.(eluting solvent: chloroform/methanol=10/1) purifying obtains title compound by the preparation thin-layer chromatography with the gained resistates.

(2) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-4-(3-methyl isophthalic acid, 2,4- diazole-5-yl)-N-thiazol-2-yl pyridine-2-amine is synthetic

Use 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit)-4-(3-methyl isophthalic acid; 2; 4- diazole-5-yl) pyridine-2-amine, according to the same method of embodiment 16-(4), obtain title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.68(s，1H)，7.57-7.42(m，3H)，7.31-7.10(m，2H)，6.95-6.90(m，1H)，3.98-3.88(m，2H)，3.83(s，2H)，3.44-3.36(m，2H)，2.80-2.66(m，2H)，2.63-2.55(m，2H)，2.53(s，3H)

Mass spectrum: 514 (M+1) ⁺

Embodiment 111

Synthesizing of (2-((4-benzoyl-piperazine-1-yl) methyl)-6-(1,2,4-thiadiazoles-5-base is amino) pyridin-3-yl) methyl alcohol

(1) (2,6-dibromo pyridine-3-yl) methyl alcohol is synthetic

Under 0 ℃,, add the 0.57ml Vinyl chloroformate in the mixture of 6-two bromo-nicotinic acids (Helvetica Chimica Acta, 1976,59,229), 0.72ml triethylamine, 30ml tetrahydrofuran (THF) to 1.51g 2.At room temperature stirred 30 minutes, and filtered insoluble substance then.In filtrate, add the 30ml tetrahydrofuran (THF), add the 717mg sodium borohydride then.At 5 ℃, in this mixture, add 13ml methyl alcohol, stirred 15 minutes.Reaction mixture is diluted with ethyl acetate, with saturated aqueous ammonium chloride and saturated common salt water washing.Use the anhydrous magnesium sulfate drying organic layer, filter then, concentrated filtrate obtains title compound.

Synthesizing of (2) 2,6-two bromo-3-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl) pyridine

Use (2,6-dibromo pyridine-3-yl) methyl alcohol, according to the same method of embodiment 5-(1), obtain title compound.

(3) 6-bromo-5-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(1,2,4-thiadiazoles-5-yl) pyridine-2-amine is synthetic

Use 2,6-two bromo-3-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl) pyridine and 1,2,4-thiadiazoles-5-amine, according to the same method of embodiment 5-(2), obtain title compound.

(4) 6-(mesyloxy methyl)-5-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(1,2,4-thiadiazoles-5-yl) pyridine-2-amine is synthetic

Use 6-bromo-5-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(1,2,4-thiadiazoles-5-yl) pyridine-2-amine, according to obtaining title compound with the same method of embodiment 1-(2), (5) and embodiment 16-(2).

(5) (2-((4-benzoyl-piperazine-1-yl) methyl)-6-(1,2,4-thiadiazoles-5-base is amino) pyridin-3-yl) methyl alcohol is synthetic

Use 6-(mesyloxy methyl)-5-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(1; 2; 4-thiadiazoles-5-yl) pyridine-2-amine and according to the hydrochloride of the 1-benzoyl-piperazine that obtains with the same method of reference example 1; according to carrying out ammoxidation with the same method of embodiment 16-(3); carry out same deprotection reaction then, obtain title compound with embodiment 5-(3).

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：12.11(brs，1H)，8.28(s，1H)，7.85(d，J＝8.4Hz，1H)，7.45-7.35(m，5H)，7.07(d，J＝8.4Hz，1H)，4.63(s，2H)，3.75(s，2H)，3.66-3.43(m，2H)，3.40-3.20(mn，2H)，2.57-2.33(m，4H)

Mass spectrum: 411 (M+1) ⁺

Embodiment 112

Synthesizing of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-fluorine thiazol-2-yl) pyridine-2-amine

(1) 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit) pyridine-2-amine is synthetic

Use embodiment 5-(2) gained 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-thiazol-2-yl pyridine-2-amine, according to the same method of embodiment 1-(3), obtain title compound.

(2) 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(5-fluoro-3-(methoxymethyl) thiazole-2 (3H)-subunit) pyridine-2-amine is synthetic

The 5ml tetrahydrofuran (THF) is cooled to-78 ℃, drips 1.05ml butyllithium (1.6M, hexane solution) then.In the gained reaction soln, drip the 5ml tetrahydrofuran solution of 280mg 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(3-(methoxymethyl) thiazole-2 (3H)-subunit) pyridine-2-amine, stirred 30 minutes down at-78 ℃, drip the 5ml tetrahydrofuran solution of N-fluorobenzene sulfimide then.Make the gained reaction soln be-30 ℃, drip 230 μ l acetate then.The gained reaction soln is diluted with ethyl acetate, then water and saturated common salt water washing.With gained organic layer anhydrous sodium sulfate drying, filter, then concentrating under reduced pressure.(eluting solvent: hexane～hexane/ethyl acetate=3/1) purifying obtains title compound by silica gel column chromatography with the gained resistates.

(3) 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-fluorine thiazol-2-yl) pyridine-2-amine is synthetic

Use 6-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N-(5-fluoro-3-(methoxymethyl) thiazole-2 (3H)-subunit) pyridine-2-amine, carry out same step with embodiment 5-(3), then carry out and embodiment 16-(2)～(4) same step, obtain title compound.

The spectrum data of title compound is as follows.

Mass spectrum: 450 (M+1) ⁺

Embodiment 113

Synthesizing of 4-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyrimidine-2-amine

¹H-NMR(CDCl ₃)δ：8.58(d，J＝4.8Hz，1H)，7.55(d，J＝3.2Hz，1H)，7.48-7.42(m，1H)，7.31-7.25(m，1H)，7.19-7.13(m，1H)，7.06(d，J＝4.8Hz，1H)，6.90(d，J＝3.2Hz，1H)，3.88(brs，2H)，3.70(s，2H)，3.39(brs，2H)，2.68(t，J＝4.8Hz，2H)，2.55(brs，2H)

Mass spectrum: 433 (M+1) ⁺

Embodiment 114

Synthesizing of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-(3-methyl isophthalic acid H-pyrazoles-5-yl) pyrazine-2-amine

Mass spectrum: 450 (M+1) ⁺

Embodiment 115

6-(((1S, 4S)-5-(3-chloro-2-fluoro benzoyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl) methyl)-N-(3-methyl isophthalic acid H-pyrazoles-5-yl) pyridine-2-amine synthetic

¹H NMR(CD ₃OD)δ：8.45(s，1H)，8.08(s，1H)，7.47(t，J＝6.8Hz，1H)，7.33(t，J＝5.9Hz，1H)，7.19-7.14(m，2H)，6.07(s，1H)，4.94-2.71(m，8H)，2.32(s，3H)，2.07-1.99(m，1H)，1.88-1.79(m，1H)

Mass spectrum: 442 (M+1) ⁺

Embodiment 116

2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl] methyl)-N, the trifluoroacetate of N-dimethyl-6-(1H-pyrazole-3-yl amino) Isonicotinamide synthetic

(1) 4-pyridone-2, the hydrochloride of 6-dioctyl phthalate dimethyl ester synthetic

As starting raw material, according to J.Am.Chem.Soc., 70,3908 (1948) method obtains title compound with chelidamic acid.

(2) 4-benzyloxy pyridine-2,6-dioctyl phthalate dimethyl ester synthetic

At room temperature, to 100g 4-pyridone-2, the hydrochloride and the 500mlN of 6-dioctyl phthalate dimethyl ester add 122g salt of wormwood in the mixture of dinethylformamide, at room temperature stirred 1 hour.In the gained reaction mixture, add the 52.5ml bromotoluene, stir down at 50 ℃ and spend the night.The gained reaction mixture is poured in the water, and leaching gained white solid washes with water, and drying under reduced pressure obtains title compound.

(3) 4-benzyloxy pyridine-2,6-dioctyl phthalate one methyl esters synthetic

Under 50 ℃, to 97g 4-benzyloxy pyridine-2, add 18.0g potassium hydroxide in the 1.5L methanol solution of 6-dioctyl phthalate dimethyl ester, stirred 2 hours down at 60 ℃.The gained reaction mixture is poured in the mixed solution of ether, hexane and water.Separating obtained water layer with the ether washing, neutralizes with concentrated hydrochloric acid.Leaching gained white solid washes with water, and drying under reduced pressure obtains title compound then.

(4) 6-amino-4-(benzyloxy) pyridine-2-methyl-formiate is synthetic

Use 4-benzyloxy pyridine-2,6-dioctyl phthalate one methyl esters, according to embodiment 81-(3) and (4) same method, obtain title compound.

(5) 4-(benzyloxy)-6-chloropyridine-2-methyl-formiate is synthetic

In the 5ml chloroformic solution of 258mg 6-amino-4-(benzyloxy) pyridine-2-methyl-formiate, add 170mg nitrite tert-butyl and 210mg cupric chloride (II), under lucifuge, stirred 6 hours then.In the gained reaction mixture, add saturated sodium bicarbonate water, use ethyl acetate extraction then, the concentrating under reduced pressure organic layer, (eluting solvent: hexane/ethyl acetate) purifying obtains title compound by silica gel column chromatography with the gained resistates then.

(6) 4-(benzyloxy)-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridine-2-methyl-formiate is synthetic

Use 1-((2-(trimethyl silyl) oxyethyl group) the methyl)-1-H-pyrazoles-3-amine of 4-(benzyloxy)-6-chloropyridine-2-methyl-formiate and reference example 2 gained, according to the same method of embodiment 5-(2), obtain title compound.

(7) 4-hydroxyl-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridine-2-methyl-formiate is synthetic

In 18g 4-(benzyloxy)-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) the 200ml methyl alcohol of pyridine-2-methyl-formiate and the mixing solutions of 200ml tetrahydrofuran (THF), add 1.8g 20% hydroxide palladium carbon catalyst, under atmosphere of hydrogen, normal pressure, normal temperature, stirred 2 hours.Filtering reacting liquid, concentrated solvent obtains title compound.

(8) 2-(hydroxymethyl)-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridine-4-alcohol is synthetic

Tetrahydrofuran solution (the 2.0M that in the 200ml tetrahydrofuran solution of 16g 4-hydroxyl-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridine-2-methyl-formiate, adds lithium borohydride, 30ml), stirred 1 hour at 60 ℃.Making the gained reaction mixture is 0 ℃, adds 10% hydrochloric acid then, and transferring to pH is 4, at room temperature stirs 30 minutes.Concentrate the gained reaction solution, obtain title compound.

(9) 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridine-4-alcohol is synthetic

Use 2-(hydroxymethyl)-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridine-4-alcohol, according to the same method of embodiment 5-(1), obtain title compound.

(10) 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridin-4-yl triflate is synthetic

Under 0 ℃, in the mixture of 2.9g 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridine-4-alcohol, 14.2g 4-(dimethylamino) pyridine and 290ml chloroform, add the 9.7ml trifluoromethanesulfanhydride anhydride.At room temperature the gained reaction mixture was stirred 2 hours, dilute with ethyl acetate then.At the hydrochloric acid that in the gained reaction solution, adds 100ml 0.1M under 0 ℃, with gained organic layer saturated sodium bicarbonate water, water and saturated common salt water washing, use dried over mgso gained organic layer then, filter the back concentrating under reduced pressure, (eluting solvent: hexane/ethyl acetate=10/1～1/1) purifying obtains title compound by silica gel column chromatography with the gained resistates.

(11) 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) iso methyl nicotinate is synthetic

Use 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridin-4-yl triflate, according to the same method of embodiment 1-(2), obtain title compound.

(12) 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N, N-dimethyl-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) Isonicotinamide synthetic

Use 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) iso methyl nicotinate, method according to same with embodiment 84 obtains title compound.

(13) 2-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N, N-dimethyl-6-(1H-pyrazole-3-yl amino) Isonicotinamide synthetic

Use 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-N, N-dimethyl-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) Isonicotinamide, method according to similarly to Example 16 obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.91(brs，1H)，7.47-7.41(m，2H)，7.29-7.24(m，1H)，7.15(t，J＝8.0Hz，1H)，6.99(brs，1H)，6.78(s，1H).6.01(brs，1H)，3.85(brs，2H)，3.60(s，2H)，3.35(brs，2H)，3.10(s，3H)，2.95(s，3H)，2.61(brt，J＝5.2Hz，2H)，2.48(brs，2H)

Mass spectrum: 486 (M+1) ⁺

Below, according to the method synthetic embodiment 117-121 same with the foregoing description 116.

Embodiment 117

2-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N, N-dimethyl-6-(1H-pyrazole-3-yl amino) Isonicotinamide synthetic

¹H-NMR(CDCl ₃)δ：7.71-7.65(m，1H)，7.63-7.58(m，1H)，7.48(brs，1H)，7.38(t，J＝8.0Hz，1H)，6.84(s，1H)，6.13(brs，1H)，3.90(brs，2H)，3.70(s，2H)，3.40(brs，2H)，3.11(s，3H)，2.98(s，3H)，2.74-2.67(m，2H)，2.59(brs，2H)

Mass spectrum: 520 (M+1) ⁺

Embodiment 118

Synthesizing of the trifluoroacetate of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-4-((4-methylpiperazine-1-yl) carbonyl)-N-1H-pyrazole-3-yl pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.85(brt，J＝6.8Hz，1H)，7.77(d，J＝2.4Hz，1H)，7.74(brt，J＝7.2Hz，1H)，7.49(t，J＝8.0Hz，1H)，7.19(s，1H)，7.01(s，1H)，6.21(d，J＝2.4Hz，1H)，4.23(s，2H)，4.06(brs，2H)，3.63(brs，2H)，3.18(brs，2H)，3.06(brs，2H)，2.95(s，3H)

Mass spectrum: 575 (M+1) ⁺

Embodiment 119

Synthesizing of the trifluoroacetate of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-4-(piperazine-1-base carbonyl)-N-1H-pyrazole-3-yl pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.85(brt，J＝7.2Hz，1H)，7.79(d，J＝2.4Hz，1H)，7.74(brt，J＝6.4Hz，1H)，7.49(t，J＝8.0Hz，1H)，7.18(s，1H)，7.03(s，1H)，6.22(d，J＝2.4Hz，1H)，4.24(s，2H)，4.06(brs，2H)，3.98(brs，2H)，3.71(brs，2H)，3.63(brs，2H)，3.19(brs，2H)，3.07(brs，2H)

Mass spectrum: 561 (M+1) ⁺

Embodiment 120

Synthesizing of the trifluoroacetate of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl-4-((4-pyridine-2-base piperazine-1-yl) carbonyl) pyridine-2-amine

¹H-NMR(CD ₃OD)δ：8.08(ddd，J＝9.2，7.2，1.6Hz，1H)，8.01(dd，J＝6.4，1.6Hz，1H)，7.85(brt，J＝7.2Hz，1H)，7.79(d，J＝2.4Hz，1H)，7.74(brt，J＝6.8Hz，1H)，7.49(t，J＝8.0Hz，1H)，7.39(d，J＝9.2Hz，1H)，7.19(s，1H)，7.08-7.02(m，2H)，6.22(d，J＝2.4Hz，1H)，4.24(s，2H)，4.06(s，2H)，3.96(s，2H)，3.89(s，2H)，3.76(brs，2H)，3.73(brs，2H)，3.63(brs，2H)，3.18(brs，2H)，3.07(brs，2H)

Mass spectrum: 638 (M+1) ⁺

Embodiment 121

Synthesizing of the trifluoroacetate of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-4-(morpholine-4-base carbonyl)-N-1H-pyrazole-3-yl pyridine-2-amine

¹H-NMR(CD ₃OD)δ：7.85(brt，J＝7.2Hz，1H)，7.79(d，J＝2.4Hz，1H)，7.73(brt，J＝6.8Hz，1H)，7.49(t，J＝7.6Hz，1H)，7.09(s，1H)，7.00(s，1H)，6.20(d，J＝2.4Hz，1H)，4.19(s，2H)，4.05(brs，2H)，3.75(brs，4H)，3.66-3.58(m，4H)，3.47-3.41(m，2H)，3.16-3.10(m，2H)，3.03-2.97(m，2H)

Mass spectrum: 562 (M+1) ⁺

Embodiment 122

Synthesizing of 2-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-6-(1H-pyrazole-3-yl amino)-4-cyanopyridine

Use embodiment 116-(10) gained 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl)-6-((1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazole-3-yl) amino) pyridin-4-yl triflate, according to embodiment 104-(2)～(3) same method, obtain title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.71(brs，1H)，7.68(brt，J＝7.6Hz，1H)，7.61(brt，J＝6.4Hz，1H)，7.51(brd，J＝2.0Hz，1H)，7.46(brs，1H)，7.33(t，J＝7.6Hz，1H)，7.05(brs，1H)，6.15(brs，1H)，3.89(brs，2H)，3.62(s，2H)，3.38(brs，2H)，2.64(brt，J＝5.2Hz，2H)，2.52(brs，2H)

Mass spectrum: 474 (M+1) ⁺

Embodiment 123

Synthesizing of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-4-(2-methyl-2H-tetrazolium-5-yl)-N-1H-pyrazole-3-yl pyridine-2-amine

Use embodiment 122 gained 2-(((tertiary butyl (dimethyl) silyl) oxygen base) methyl-6-((1-((2-trimethyl silyl) oxyethyl group) methyl)-6-1H-pyrazole-3-yl) amino)-4-cyanopyridine, method according to same with embodiment 106 obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：7.71(brs，1H)，7.68(brt，J＝7.6Hz，1H)，7.61(brt，J＝6.4Hz，1H)，7.51(brd，J＝2.0Hz，1H)，7.46(brs，1H)，7.33(t，J＝7.6Hz，1H)，7.05(brs，1H)，6.15(brs，1H)，3.89(brs，2H)，3.62(s，2H)，3.38(brs，2H)，2.64(brt，J＝5.2Hz，2H)，2.5.2(brs，2H)

Mass spectrum: 474 (M+1) ⁺

Embodiment 124

Synthesizing of (thiazol-2-yl)-(6-(4-(2, the 3-difluoro benzoyl)-piperazine-1-ylmethyl)-pyridine-2-yl)-amine hydrochlorate

Add hydrochloric acid-1 in 293mg (thiazol-2-yl)-(6-(4-(2, the 3-difluoro benzoyl)-piperazine-1-ylmethyl)-pyridine-2-yl)-amine (embodiment 4), 1ml methanol mixture, (4M 3ml), at room temperature stirred 1 hour 4-two  alkane solution.The concentrating under reduced pressure reaction mixture is suspended in resistates in the ether, and leaching then obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：7.88-7.81(m，1H)，7.60-7.49(m，1H)，7.49-7.43(m，1H)，7.36-7.25(m，3H)，7.21-7.10(m，2H)，4.43(s，2H)，3.74-3.23(m，8H)

Mass spectrum: 416 (M+1) ⁺

Embodiment 125

Synthesizing of the hydrochloride of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine

5.09g 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine (embodiment 5) is suspended in the 100ml ethanol, at room temperature adds 11.8ml 1M-hydrochloric acid.Stirred 30 minutes down at 80 ℃, be cooled to room temperature then, concentration of reaction solution.In the gained resistates, add 250ml ethanol, carry out reflux and make its dissolving.Stir and also to stop heating, slowly cool to room temperature, filter the solid that generates, drying obtains the hydrochloride crystal of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：11.49(brs，1H)，7.79(t，J＝7.8Hz，1H)，7.73-7.67(m，1H)，7.47-7.41(m，2H)，7.32(t，J＝7.8Hz，1H)，7.27(d，J＝7.0Hz，1H)，7.11(d，J＝8.4Hz，1H)，7.07(d，J＝3.5Hz，1H)，4.39(s，2H)，3.69-3.20(m，8H)

Mass spectrum: 432 (M+1) ⁺

Melting point: 141-167 ℃ (ethanol)

Embodiment 126

Synthesizing of the hydrochloride of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyridine-2-amine

Use the compound of embodiment 16, the method according to embodiment 124 obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：10.98(brs，1H)，7.91(d，J＝2.3Hz，1H)，7.82(dd，J＝8.5，7.3Hz，1H)，7.77-7.65(m，1H)，7.47-7.41(m，1H)，7.39-7.30(m，1H)，.15(d，J＝8.6Hz，1H)，7.09(d，J＝7.0Hz，1H)，6.27(d，J＝2.5Hz，1H)，4.34(s，2H)，4.30-3.50(m，4H)，3.23(brs，2H)，3.11(brs，2H)

Mass spectrum: 415 (M+1) ⁺

Embodiment 127

Synthesizing of the hydrochloride of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyridine-2-amine

Use the compound of embodiment 25, the method according to embodiment 124 obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CD ₃OD)δ：7.88(dd，J＝8.0，7.8Hz，1H)，7.66-7.60(m，1H)，7.43-7.37(m，1H)，7.30(bt，J＝8.8Hz，1H)，7.16(d，J＝7.8Hz，1H)，7.05(d，J＝8.0Hz，1H)，6.02(s，1H)，4.40(bs，2H)，3.73(bs，2H)，3.37-3.14(m，6H)，2.41(s，3H)

Mass spectrum: 429 (M+1) ⁺

Embodiment 128

Synthesizing of the hydrochloride of 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine

19.8g 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine (embodiment 44) is suspended in the 200ml ethanol, adds 44.1ml 1M-hydrochloric acid.At room temperature stirred concentration of reaction solution 1 hour.In the gained resistates, add the 200ml heptane, make its curing, the concentrating under reduced pressure solvent.The dry solid that generates obtains 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine hydrochlorate.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：10.10(s，1H)，8.45(s，1H)，8.12(s，1H)，7.91(t，J＝7.3Hz，1H)，7.82(t，J＝7.0Hz，1H)，7.64-7.61(m，1H)，7.52(t，J＝7.7Hz，1H)，6.54(s，1H)，.4.37(s，2H)，3.66-3.18(m，8H)

Mass spectrum: 450 (M+1) ⁺

Embodiment 129

Synthesizing of the hydrochloride of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyrazine-2-amine

Use the compound of embodiment 56, the method according to embodiment 124 obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CD ₃OD)δ：8.41(s，1H)，8.31(s，1H)，7.67-7.61(m，1H)，7.42(t，J＝6.8Hz，1H)，7.31(t，J＝7.8Hz，1H)，6.17(s，1H)，4.57(s，2H)，3.83-3.77(m，2H)，3.76-3.25(m，6H)，2.44(s，3H)

Mass spectrum: 430 (M+1) ⁺

Embodiment 130

Synthesizing of the hydrochloride of 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-chlorine thiazol-2-yl) pyridine-2-amine

Use the compound of embodiment 75, the method according to embodiment 124 obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：11.68(brs，1H)，7.83(dd，J＝8.0，7.6Hz，1H)，7.70(dd，J＝7.4，7.0Hz，1H)，7.50-7.30(m，4H)，7.09(d，J＝8.4Hz，1H)，4.44(s，2H)，3.90-3.18(m，8H)

Mass spectrum: 466 (M+1) ⁺

Embodiment 131

2-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N, the hydrochloride of N-dimethyl-6-(1H-pyrazole-3-yl amino) Isonicotinamide synthetic

Use the compound of embodiment 117, the method according to embodiment 128 obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(CD ₃OD)δ：7.85(brt，J＝7.2Hz，1H)，7.82(d，J＝2.4Hz，1H)，7.77-7.71(m，1H)，7.49(brt，J＝8.0Hz，1H)，7.07(s，1H)，7.02(s，1H)，6.21(d，J＝2.4Hz，1H)，4.21(s，2H)，4.07(brs，2H)，3.67-3.60(m，2H)，3.17-3.08(m，5H)，3.04-2.97(m，5H)

Mass spectrum: 520 (M+1) ⁺

[reference example]

Reference example 1

Synthesizing of the hydrochloride of 1-(3-chloro-2-fluoro benzoyl) piperazine

(1) 4-(3-chloro-2-fluoro benzoyl) piperazine-1-t-butyl formate is synthetic

At room temperature, the mixture with the hydrochloride of 19.4g 1-Boc-piperazine, 24.0g 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 19.1g I-hydroxybenzotriazole, 20.0g 3-chloro-2-fluorobenzoic acid, 200ml chloroform stirred 4 hours.With the chloroform dilution, with diatomite filtering insoluble substance, with filtrate water, saturated common salt water washing.With gained organic layer dried over mgso, filter the back concentrating under reduced pressure, (eluting solvent: hexane/ethyl acetate=9/1～1/1) purifying obtains title compound by silica gel column chromatography with the gained resistates.

(2) hydrochloride of 1-(3-chloro-2-fluoro benzoyl) piperazine is synthetic

Add hydrochloric acid-1 in 35.1g 4-(3-chloro-2-fluoro benzoyl) piperazine-1-t-butyl formate, 50ml methanol mixture, (4M 100ml), at room temperature stirred 2.5 hours 4-two  alkane solution.The concentrating under reduced pressure reaction mixture is suspended in resistates in the ether, filters then, obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：9.68(br，1H)，7.7.4-7.65(m，1H)，7.50-7.41(m，1H)，7.37-7.28(m，1H)，3.88(br，2H)，3.57-3.30(m，2H)，3.16(br，2H)，3.03(br，2H)

Mass spectrum: 243 (M+1) ⁺

Reference example 2

Synthesizing of 1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazoles-3-amine

Ice-cooled down, to the N of 10g 1H-pyrazoles-3-amine, add 9.6g sodium hydride (60%, oiliness) among the dinethylformamide solution 100ml.Reaction mixture was stirred 30 minutes, add 21.3ml 2-(trimethyl silyl) ethoxyl methyl chlorine then.At room temperature the gained mixture was stirred 1 hour, add chlorination ammoniacal liquor then, use chloroform extraction.With gained organic layer water, saturated common salt water washing, use dried over mgso then.Filter organic layer, concentrating under reduced pressure, (eluting solvent: hexane/ethyl acetate=4/1～1/2) purifying obtains title compound by silica gel column chromatography with the gained resistates.

Reference example 3

Synthesizing of 5-methyl isophthalic acid-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazoles-3-amine

According to the method for reference example 2, obtain title compound by 5-methyl isophthalic acid H-pyrazoles-3-amine.

Reference example 4

Synthesizing of 5-cyclopropyl-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1-H-pyrazoles-3-amine or 3-cyclopropyl-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrazoles-5-amine

According to the method for reference example 2, obtain title compound by 5-cyclopropyl-1H-pyrazoles-3-amine.

The spectrum data of title compound is as follows.

¹H-NMR(CDCl ₃)δ：5.31(s，2H)，5.26(s，1H)，3.62-3.56(m，2H)，1.84-1.76(m，1H)，0.97-0.88(m，4H)，0.67-0.62(m，2H)，-0.02(s，9H)

Mass spectrum: 254 (M+1) ⁺

Reference example 5

6-(tetrahydrochysene-2H-pyrans-2-base oxygen base)-1,4-Diazesuberane synthetic

(1) 2-(2-bromo-1-(brooethyl) oxyethyl group) tetrahydrochysene-2H-pyrans is synthetic

To 10mg 1,3-dibromopropane-2-alcohol, 5.0ml 3, the tosic acid monohydrate of adding catalytic amount at room temperature stirred 3 hours in the mixture of 4-dihydro-2H-pyrans, 50ml chloroform.Concentration of reaction solution is then with the ether dilution, with saturated sodium bicarbonate water and saturated common salt water washing.With gained organic layer dried over mgso, filter then, concentrated filtrate obtains title compound.

(2) 1,4-dibenzyl-6-(tetrahydrochysene-2H-pyrans-2-base oxygen base)-1,4-Diazesuberane synthetic

Under 120 ℃, with 2-(2-bromo-1-(brooethyl) oxyethyl group) tetrahydrochysene-2H-pyrans, the 10.8ml N of above-mentioned gained, N '-dibenzyl ethane-1,2-diamines, 19.0g salt of wormwood, 50ml N, the mixture of N '-dimethyl formamide stirred 3 hours.Reaction solution is diluted water and saturated common salt water washing with ether.With gained organic layer dried over mgso, filter concentrated filtrate then.(eluting solvent: hexane～hexane/ethyl acetate=4/1) purifying obtains title compound by silica gel column chromatography with the gained resistates.

(3) 6-(tetrahydrochysene-2H-pyrans-2-base oxygen base)-1,4-Diazesuberane synthetic

With 3.06g 1,4-dibenzyl-6-(tetrahydrochysene-2H-pyrans-2-base oxygen base)-1, the 4-Diazesuberane is dissolved in the 50ml methyl alcohol, adds 1g 20% hydroxide palladium carbon catalyst, and at atmosphere of hydrogen, normal pressure, normal temperature stirred 5 hours down.Filtering reacting liquid, concentrated solvent obtains title compound.

Reference example 6

Synthesizing of the hydrochloride of 1-(2-fluoro-3-(difluoromethyl) benzoyl) piperazine

(1) 4-(3-bromo-2-fluoro benzoyl) piperazine-1-t-butyl formate is synthetic

Under ice bath, in the mixture of 220mg 3-bromo-2-fluorobenzoic acid, 199mg piperazine-1-t-butyl formate and 5.0ml chloroform, add 171mg hydroxybenzotriazole monohydrate, 215mg1-(3-dimethylaminopropyl)-3-ethyl carbon two imide salt hydrochlorates successively.At room temperature stirred 4 hours, and in reaction mixture, added saturated sodium bicarbonate water then, use chloroform extraction.Use the anhydrous magnesium sulfate drying organic layer, filter concentrated filtrate then.(eluting solvent: hexane/ethyl acetate=9/1～1/1) purifying obtains title compound by silica gel column chromatography with resistates.

(2) 4-(2-fluoro-3-formyl benzoyl) piperazine-1-t-butyl formate is synthetic

194mg 4-(3-bromo-2-fluoro benzoyl) piperazine-1-t-butyl formate is dissolved in the 5.0ml tetrahydrofuran (THF), at-78 ℃ of tetrahydrofuran solution (2.0M) 1.25ml that add isobutyl-chlorination magnesium down.Under this temperature, stirred 2 hours, add 0.39ml (5.0mmol) N then, dinethylformamide.Under this temperature, stirred 30 minutes, stirred 30 minutes down at 0 ℃ again.In reaction mixture, add saturated aqueous ammonium chloride, use chloroform extraction.With saturated common salt water washing organic layer, concentrate then.(eluting solvent: hexane/ethyl acetate=9/1～1/1) purifying obtains title compound by silica gel column chromatography with resistates.

(3) 4-(3-difluoromethyl-2-fluoro benzoyl) piperazine-1-t-butyl formate is synthetic

130mg 4-(2-fluoro-3-formyl benzoyl) piperazine-1-t-butyl formate is dissolved in the 4.8ml methylene dichloride, at room temperature adds 0.13ml diethylamino sulfur trifluoride.Under this temperature, stirred 2 hours, add 0.13ml diethylamino sulfur trifluoride then, under this temperature, stirred 2 hours again.(eluting solvent: hexane/ethyl acetate=9/1～1/1) purifying obtains title compound with silica gel column chromatography with reaction mixture.

(4) hydrochloride of 1-(3-(difluoromethyl)-2-fluoro benzoyl) piperazine is synthetic

According to the method for reference example 1-(2), obtain title compound by 4-(3-(difluoromethyl)-2-fluoro benzoyl) piperazine-1-t-butyl formate.

Reference example 7

The hydrochloride of 1-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine

(1) 4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-t-butyl formate is synthetic

At room temperature, the mixture with the hydrochloride of 3.66g 1-Boc-piperazine, 4.53g 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 3.61g I-hydroxybenzotriazole, 4.50g 2-fluoro-3-(trifluoromethyl) phenylformic acid, 40ml chloroform at room temperature stirred 4 hours.With chloroform dilution, water, saturated common salt water washing then.With gained organic layer dried over mgso, filter, concentrating under reduced pressure then, (eluting solvent: hexane/ethyl acetate=4/1～2/1) purifying obtains title compound by silica gel column chromatography with the gained resistates.

(2) hydrochloride of 1-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine is synthetic

Add hydrochloric acid-1 in 7.74g 4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-t-butyl formate, 10ml methanol mixture, (4M 20ml), at room temperature stirred 4 hours 4-two  alkane solution.The concentrating under reduced pressure reaction mixture obtains title compound.

The spectrum data of title compound is as follows.

¹H-NMR(DMSO-d ₆)δ：7.95-7.81(m，2H)，7.56-7.49(m，1H)，3.92-3.79(m，2H)，3.45(br，2H)，3.19(br，2H)，3.04(br，2H)

Mass spectrum: 277 (M+1) ⁺

Reference example 8

Synthesizing of 4-(3-cyclopropyl-2-fluoro benzoyl) piperazine-1-t-butyl formate

In the 2.0ml toluene-0.1ml aqueous solution of 107mg 4-(3-bromo-2-fluoro benzoyl) piperazine-1-t-butyl formate; add 72mg cyclopropylboronic acid, 3.2mg acid chloride, 0.052ml tricyclohexyl phosphine (15% toluene solution) and 207mg potassiumphosphate successively, with reaction solution usefulness microgrid reaction unit, 150 ℃ of following stirrings 10 minutes.In reaction mixture, add entry, use ethyl acetate extraction.With saturated common salt water washing organic layer, concentrate then.(eluting solvent: hexane～hexane/ethyl acetate=1/1) purifying obtains title compound by silica gel column chromatography with resistates.

Industrial applicability

Compound of the present invention have based on the cell inhibitory effect effect of the Aurora-A selective inhibitory of excellence and with the synergy of other anticarcinogen, therefore be expected in field of medicaments, be used as useful antitumor agent.

Sequence table

<110>Banyu Pharmaceutical Co.，Ltd.

Ohkubo，Mitsuru

Kato，Tetsuya

Kawanishi，Nobuhiko

Mita，Takashi

Shimomura，Toshiyasu

＜120〉has the novel aminopyridine derivative of Aurora-A selective inhibitory

<130>BY0045Y

<150>JP2004-315152

<151>2004-10-29

<150>JP2005-161156

<151>2005-06-01

<160>1

<170>FastSEQ for Windows Version 4.0

<210>1

<211>7

<212>PRT

＜213〉artificial sequence

<220>

＜223〉complete synthetic aminoacid sequence

<400>1

Lys Arg Arg Ala Ser Lys Gly

1 5

Claims

1. compound (m shown in the general formula [I] ₁Be 1, m ₂Be 1, Z ₁And Z ₂Be except the compound of N W ₁Be CH, W ₂Be CH or CW _2a, W ₃During for N, X ₁Be CH or X _1a, X ₂Be N and X _3aBe CH or CX _3a):

[in the formula,

m ₁Be 1,2 or 3;

m ₂Be 1,2 or 3;

n ₁Be 0 or 1;

n ₂Be 0 or 1;

I is 1～m ₁Arbitrary integer;

J is 1～m ₂Arbitrary integer;

R is can substituted aryl, heteroaryl or cycloalkyl;

R _AiAnd R _Ai' identical or different, be hydrogen atom or low alkyl group, R _BjAnd R _Bj' identical or different, be hydrogen atom or low alkyl group, wherein, m ₁Be 2 or 3 and i be i ₀(i ₀Be 1～m ₁Arbitrary integer) and m ₂Be 2 or 3 and j be j ₀(j ₀Be 1～m ₂Arbitrary integer) time, R _Ai0And R _Ai0' in any one party can with R _Bj0And R _Bj0' a side form together-(CH ₂) _n-(in the formula, n is 1 or 2);

R _c, R _dAnd R _eIdentical or different, be hydrogen atom or low alkyl group;

X ₁Be CH, CX _1aOr N (wherein, X _1aFor can substituted low alkyl group);

X ₂Be CH or N;

X ₃Be CH, CX _3aOr N (wherein, X _3aFor can substituted low alkyl group);

X ₄Be CH or N;

X ₁, X ₂, X ₃And X ₄In, 1～2 is N;

Z ₁And Z ₂Identical or different, be CH or N;

W is following group:

Wherein, W ₁Be CH, N, NH, O or S,

W ₃Be C or N,

2. the compound or pharmaceutically acceptable salt thereof of claim 1 or ester, wherein, W is selected from following any group:

3. the compound or pharmaceutically acceptable salt thereof of claim 2 or ester, wherein,

m ₁Be 2 or 3;

m ₂Be 2;

n ₁Be 0;

n ₂Be 0;

Z ₁Be N;

Z ₂Be CH or N; And

R is phenyl or contains 5 yuan of at least one atom that is selected from N, O and S or 6 yuan of aromatic heterocyclic radicals (wherein, this phenyl or aromatic heterocyclic radical can identical or different be selected from following 1 by one or more)～3) substituting group replace:

1) low alkyl group,

2) be selected from＜substituting group group A ₂Substituting group and

＜substituting group group A ₂Be halogen atom, cyano group, hydroxyl, amino, low-grade alkyl amino, two elementary alkyl amido, low-grade alkane acidyl, low-grade alkane acidyl amino, formamyl, elementary alkyl amido methanoyl, low alkyl group alkylsulfonyl).

4. the compound or pharmaceutically acceptable salt thereof of claim 3 or ester, wherein, Y ₁Be CH; R _eBe hydrogen atom.

5. the compound or pharmaceutically acceptable salt thereof of claim 4 or ester, wherein, m ₁Be 2; R _A1, R _A1', R _A2, R _A2', R _B1, R _B1', R _B2, R _B2' be hydrogen atom.

6. the compound or pharmaceutically acceptable salt thereof of claim 5 or ester, wherein, X ₄Be N, and X ₁～X ₃In maximum 1 be N; R is 2,3 phenyl that replaced by identical or different halogen atom, perhaps be 2,3 respectively by halogen atom, methyl substituted phenyl, wherein said methyl is replaced by 1～3 halogen atom.

7. the compound or pharmaceutically acceptable salt thereof of claim 6 or ester, wherein, W is selected from following radicals:

8. the compound or pharmaceutically acceptable salt thereof of claim 7 or ester, wherein, Z ₁And Z ₂Both are N.

9. following compound or pharmaceutically acceptable salt thereof or ester:

(m) 6-(((1S, 4S)-5-(3-chloro-2-fluoro benzoyl)-2,5-diazabicyclo [2.2.1] heptan-2-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine,

10. the compound or pharmaceutically acceptable salt thereof of claim 9 or ester, this compound is 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-thiazol-2-yl pyridine-2-amine.

11. the compound or pharmaceutically acceptable salt thereof of claim 9 or ester, this compound are 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine.

12. the compound or pharmaceutically acceptable salt thereof of claim 9 or ester, this compound are 6-((4-(2-fluoro-3-(trifluoromethyl) benzoyl) piperazine-1-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine.

13. the compound or pharmaceutically acceptable salt thereof of claim 9 or ester, this compound are 6-((4-(3-chloro-2-fluoro benzoyl) piperazine-1-yl) methyl)-N-(5-fluorine thiazol-2-yl) pyridine-2-amine.

14. the compound or pharmaceutically acceptable salt thereof of claim 9 or ester, this compound are 6-((4-(2,3-dichloro-benzoyl base) piperazine-1-yl) methyl)-N-1,2, and 4-thiadiazoles-5-yl pyridines-2-amine.

15. the compound or pharmaceutically acceptable salt thereof of claim 9 or ester, this compound are 6-(((1S, 4S)-5-(3-chloro-2-fluoro benzoyl)-2,5-diazabicyclo [2.2.1] oenanthyl-2-yl) methyl)-N-1H-pyrazole-3-yl pyrazine-2-amine.

16. pharmaceutical composition is characterized in that: the compound that contains more than one claims 1 is as effective constituent, and contains pharmaceutically acceptable carrier or thinner.

17.Aurora-A selective depressant is characterized in that: the compound that contains more than one claims 1 is as effective constituent, and contains pharmaceutically acceptable carrier or thinner.

18. cancer therapy drug is characterized in that: the compound that contains more than one claims 1 is as effective constituent, and contains pharmaceutically acceptable carrier or thinner.

19. combination preparation, this combination preparation are to be used in cancer therapy simultaneously, respectively or the combination preparation that gives successively, comprise following two kinds of preparations independently:

^*The preparation that contains compound or pharmaceutically acceptable salt thereof shown in pharmaceutically acceptable carrier or thinner and the above-mentioned general formula [1] or ester; And

^*Contain pharmaceutically acceptable carrier or thinner and be selected from the anticarcinogen of cancer resistance alkylating agent, cancer resistance metabolic antagonist, cancer resistance microbiotic, anticarcinogen, cancer resistance iridium-platinum complex, cancer resistance camptothecin derivative, cancer resistance tyrosine kinase inhibitor, monoclonal antibody, Interferon, rabbit, biological response modifier and other anticarcinogen from plant or the preparation of its pharmacologically acceptable salt or ester (wherein

The cancer resistance tyrosine kinase inhibitor is Gefitinib, imatinib or erlotinib,

Other anticarcinogen is that mitoxantrone, altheine enzyme, Procarbazine, Dacarbazine, hydroxyurea, pentostatin, tretinoin, alefacept, A Fadabeiting, Anastrozole, Yi Ximeitan, bicalutamide, Leuprolide, flutamide, fulvestrant, pegaptanib octasodium, denileukin diftitox, rIL-2, thyrotropin alfa, white arsenic, Velcade, card are accompanied his shore, goserelin).

20. the preparation of claim 19, wherein, any one or two kinds of in two kinds of independent preparations are non-oral formulation.

21. the preparation of claim 20, wherein, any one or two kinds of in two kinds of independent preparations are injection or infusion solution.

22. the preparation of claim 19, said preparation further makes up more than one following preparations: comprise pharmaceutically acceptable carrier or thinner and be selected from cancer resistance alkylating agent, cancer resistance metabolic antagonist, cancer resistance microbiotic, the anticarcinogen from plant, cancer resistance iridium-platinum complex, cancer resistance camptothecin derivative, cancer resistance tyrosine kinase inhibitor, monoclonal antibody, Interferon, rabbit, biological response modifier and the cancer therapy drug of other anticarcinogen (definition of each anticarcinogen is identical with claim 19) or the preparation of its pharmacologically acceptable salt or ester here.

23. the preparation of claim 19, wherein, in the combination preparation, a kind of preparation comprise pharmaceutically acceptable carrier or thinner and

(t) 6-((4-(2-fluoro-3-trifluoromethyl benzoyl) piperazine-1-yl) methyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) pyrazine-2-amine

Or its pharmacologically acceptable salt;

Another kind of preparation comprises pharmaceutically acceptable carrier or thinner and taxol.

24. pharmaceutical composition, it is characterized in that, comprise compound or pharmaceutically acceptable salt thereof shown in the general formula [1] of pharmaceutically acceptable carrier or thinner and claim 1 and cancer therapy drug or its pharmacologically acceptable salt or the ester that is selected from cancer resistance alkylating agent, cancer resistance metabolic antagonist, cancer resistance microbiotic, anticarcinogen, cancer resistance iridium-platinum complex, cancer resistance camptothecin derivative, cancer resistance tyrosine kinase inhibitor, monoclonal antibody, biological response modifier and other anticarcinogen (definition of each anticarcinogen is identical with claim 19) here, from plant.

25. the pharmaceutical composition of claim 24, this pharmaceutical composition contain compound or pharmaceutically acceptable salt thereof and taxol or the docetaxel shown in the general formula [I] of claim 1.