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CN103965161A - Substituted 2-aminopyridine inhibitor for protein kinase - Google Patents

Substituted 2-aminopyridine inhibitor for protein kinase Download PDF

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Publication number
CN103965161A
CN103965161A CN201310051825.1A CN201310051825A CN103965161A CN 103965161 A CN103965161 A CN 103965161A CN 201310051825 A CN201310051825 A CN 201310051825A CN 103965161 A CN103965161 A CN 103965161A
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alkyl
chloro
group
phenyl
fluorophenyl
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CN201310051825.1A
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Inventor
校登明
许新合
刘希杰
胡远东
于洪灏
刘志华
彭勇
孙颖慧
罗鸿
孔繁胜
韩永信
孙键
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Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
Original Assignee
Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
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Application filed by Centaurus Biopharma Co Ltd, Chia Tai Tianqing Pharmaceutical Group Co Ltd, Lianyungang Runzhong Pharmaceutical Co Ltd filed Critical Centaurus Biopharma Co Ltd
Priority to CN201310051825.1A priority Critical patent/CN103965161A/en
Priority to AU2014211856A priority patent/AU2014211856C1/en
Priority to EP14746385.5A priority patent/EP2952510B1/en
Priority to ES14746385T priority patent/ES2716617T3/en
Priority to CN201480007081.6A priority patent/CN104968654B/en
Priority to KR1020157023826A priority patent/KR101791762B1/en
Priority to JP2015555577A priority patent/JP6200520B2/en
Priority to RU2015136909A priority patent/RU2671212C2/en
Priority to US14/765,313 priority patent/US9708295B2/en
Priority to PCT/CN2014/071595 priority patent/WO2014117718A1/en
Priority to CA2899968A priority patent/CA2899968C/en
Priority to PT14746385T priority patent/PT2952510T/en
Publication of CN103965161A publication Critical patent/CN103965161A/en
Priority to HK15111439.9A priority patent/HK1210774A1/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a substituted 2-aminopyridine inhibitor for protein kinase, and concretely relates to 2-aminopyridine derivatives with protein kinase inhibition activity, a preparation method thereof, and pharmaceutical compositions thereof, and the invention also discloses application of the compounds and the pharmaceutical compositions thereof to treat diseases related to protein kinase.

Description

The PA proteinoid kinase inhibitor replacing
Technical field
Generality of the present invention relates to new PA derivative, its preparation method, the pharmaceutical composition with protein kinase inhibiting activity, also relates to the purposes of this compounds and medicine composite for curing thereof the disease relevant with protein kinase.
Background technology
Cancer and cardiovascular disorder are two large class disease, especially cancers of serious threat human health and life, and sickness rate in recent years and mortality ratio are fast rise trend, and having surmounted cardiovascular disorder becomes the No.1 killer of human health.
In a series of signal conduction path inside and outside the propagation of tumour, apoptosis, transfer etc. and cell, certain link is extremely closely related.In these signal transduction paths, the important molecule of a class is exactly protein kinase.Protein kinase activity extremely not only directly related with tumour, is also to cause a series of other human diseasess relevant with inflammation or proliferative response, the such as major cause of rheumatoid arthritis, cardiovascular and refreshing footpath systemic disease, asthma, psoriatic etc.At present known have more than 400 kind of human diseases directly or indirectly relevant to protein kinase, and this makes protein kinase become another the large class important drugs target after g protein coupled receptor.
Nucleophosmin-anaplastic lymphoma kinase (ALK) is a kind of receptor tyrosine kinase, be found in a hypotype of primary cutaneous type (ALCL) early than 1994, belong to a member in insulin receptor superfamily, it plays an important role in growth of tumour cell and evolution.ALK is a kind of transmembrane protein, and its central part has cross-film region, and N end has territory, extracellular region, and C end has Tyrosylprotein kinase region in born of the same parents.ALK is neural separated region Normal appearances in growth, and ALKmRNA expresses in small intestine, and in brain, colon, prostate gland and testis, content is low, and lung does not detect, and alk protein matter detected in human retina.
ALK gene can merge with multiple protein gene, expresses and produces alk protein, also can produce the variations such as sudden change, amplification.In 1997, carinogenicity ALK gene recombination on karyomit(e) 2 galianconism on allobiosis large celllymphoma has been described first, also be found in other malignant tumours afterwards, comprise diffuse large B cell lymphoma and malignant tissue's ball increase disease, also have multiple parenchymal tumor to be also found, comprise inflammatory myofibroblastic tumor, esophagus squamous cell cancer, neuroblastoma and the nonsmall-cell lung cancer (NSCLC) proposing recently.
Reported first ALK gene in 2007 can be encoded and produces ALK by being formed fusion gene with EML4 gene, thereby promotes lung cancer cell growth.EML4-ALK merges by No. 2 the short arm of a chromosome insertions and causes, has found so far multiple variation type.Analyze the topology discovery of these fusion genes, ALK part includes the gene fragment of tyrosine kinase domain in the Codocyte that starts from the 20th exon, and EML4 part comprises the gene fragment of proteins encoded N end part different in size.After testing, all these fusion genes all have biological function, and its expression product is a kind of chimeric Tyrosylprotein kinase, start to be seen in gradually NSCLC correlative study report in 2007.
The uniqueness effect that the discovery of EML4-ALK fusion gene and ALK inhibitor show in its subgroup crowd, will change existing NSCLC molecule parting and therapeutic strategy.NSCLC is no longer an independence disease, but according to the difference of Molecular pathogenesis, different hypotypes can be divided into as EGFR saltant type, KRAS saltant type, EML4-ALK gene fusion type etc., according to the molecular biology characteristics of different subtype, active drug targetedly can be selected with a definite target in view.The confidence of the more lung cancer molecule partings of researchist's searching that this is firm, and determining one by one of molecule parting is the prerequisite of the real individualized treatment of lung cancer.
In general Patients with Non-small-cell Lung, EML4-ALK fusion gene positive rate is lower, is about 3%～7% left and right.EML4-ALK fusion gene is mainly seen in non-smoking adenocarcinoma of lung, and mutually repels with EGFR sudden change and KRAS sudden change.One of 2010 annual reports studies show that, in Chinese patients with lung adenocarcinoma, EML4-ALK fusion gene positive rate, apparently higher than American-European patient, is 16.13%; In non-smoking adenocarcinoma of lung, its positive rate is 19.23%; Lack in the adenocarcinoma of lung of EGFR and KRAS sudden change, its mutation rate is up to 42.8%.
Although people after deliberation a large amount of protein kinase is had to the compound that suppresses active, and some kinases inhibitors have gone on the market for antineoplastic treatment, can produce resistance.Thereby, be necessary the kinases inhibitor that continual exploitation is new, for example ALK kinase inhibitor, for prevention, delay for example, cancer by protein kinase (ALK) mediation of its progress and/or treatment, as the nonsmall-cell lung cancer of the ALK positive (NSCLC) etc.
Summary of the invention
The invention provides the compound of a kind of formula I and pharmacy acceptable salt thereof, solvate, polymorphic, metabolite,
Wherein:
A 1be selected from hydrogen ,-O-(CHR 1)-A 4,-CH 2oR 2, by one or more R 3the aryl replacing;
R 1the methyl that is selected from methyl, is replaced by 1-3 halogen;
A 4being selected from can be by one or more R 4the aryl replacing;
R 2being selected from can be by one or more R 3the aryl replacing;
R 3be selected from halogen ,-SO 2(C 1-6alkyl) ,-SO 2nR 6r 7,-NR 6r 7,-NHSO 2(C 1-6alkyl) ,-P (O) R 6r 7;
R 4be selected from halogen, C 1-6alkyl ,-NR 6r 7,-P (O) R 6r 7;
R 6, R 7independently be selected from respectively hydrogen, C 1-6alkyl, or form 3-12 unit heterolipid cyclic group be connected atom;
A 2be selected from phenyl, pyridyl, pyrimidyl, pyrazolyl, can be selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group;
A 5for 3-12 unit heterolipid cyclic group, can be selected from following group and replace by one or more :=zero, unsubstituted C 1-6alkyl, is independently selected from by one or more C that hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group replace 1-6alkyl, 3-12 unit heterolipid cyclic group;
A 3be selected from the heteroaryl that hydrogen ,-NH aryl, aryl replaces, the heteroaryl that heteroaryl replaces, the heteroaryl that arylalkyl replaces, the heteroaryl that heteroarylalkyl replaces, the heteroaryl ethynyl that arylalkyl replaces, the heteroaryl ethynyl that heteroarylalkyl replaces, described aryl, heteroaryl can be replaced by one or more following groups: halogen, optionally can be by the C of halogen, hydroxyl or the heterolipid cyclic group replacement of 3-12 unit 1-6alkyl ,-OH ,-OC 1-6alkyl ,-CN ,-COOH ,-C 1-6alkyl NH 2,-C 1-6alkyl NH (C 1-6alkyl) ,-C 1-6alkyl N (C 1-6alkyl) 2,-COOC 1-6alkyl ,-SO 2(C 1-6alkyl) ,-SO 2n (C 1-6alkyl) 2,-SO 2nH (C 1-6alkyl) ,-NR 6r 7,-NHSO 2(C 1-6alkyl) ,-P (O) R 6r 7;
Condition is: A 1and A 3when different, be hydrogen, and A 1and A 3one of them must be hydrogen.
In some embodiments, A 3the heteroaryl that be selected from-NH phenyl, phenyl replace, the heteroaryl that heteroaryl replaces, the heteroaryl that phenyl methyl replaces, the heteroaryl that hetervaromatic methyl replaces, the heteroaryl ethynyl that phenyl methyl replaces, the heteroaryl ethynyl that hetervaromatic methyl replaces, described phenyl, heteroaryl can be replaced by one or more following groups: halogen, the C that can be replaced by halogen, hydroxyl or 3-12 unit heterolipid cyclic group 1-6alkyl ,-OH ,-OC 1-6alkyl ,-CN ,-COOH ,-C 1-6alkyl NH 2,-C 1-6alkyl NH (C 1-6alkyl) ,-C 1-6alkyl N (C 1-6alkyl) 2,-COOC 1-6alkyl ,-SO 2(C 1-6alkyl) ,-SO 2n (C 1-6alkyl) 2,-SO 2nH (C 1-6alkyl) ,-NR 6r 7,-NHSO 2(C 1-6alkyl) ,-P (O) R 6r 7; In some preferred embodiments, A 3the heteroaryl that be selected from-NH phenyl, phenyl replace, the heteroaryl that heteroaryl replaces, the heteroaryl that phenyl methyl replaces, the heteroaryl that hetervaromatic methyl replaces, the heteroaryl ethynyl that phenyl methyl replaces, the heteroaryl ethynyl that hetervaromatic methyl replaces, wherein phenyl, heteroaryl can be replaced by one or more following groups: halogen, and can be by halogen, hydroxyl or 5 or 6 yuan of C that heterolipid cyclic group replaces 1-4alkyl ,-OH ,-OC 1-4alkyl ,-CN ,-COOH ,-C 1-4alkyl NH 2,-C 1-4alkyl NH (C 1-4alkyl) ,-C 1-4alkyl N (C 1-4alkyl) 2,-COOC 1-4alkyl ,-SO 2(C 1-4alkyl) ,-SO 2n (C 1-4alkyl) 2,-SO 2nH (C 1-4alkyl) ,-NH 2,-NH (C 1-4alkyl) ,-N (C 1-4alkyl) 2,-NHSO 2(C 1-4alkyl) ,-P (O) (C 1-4alkyl) 2; In some preferred embodiments, A 3the pyrazolyl ethynyl of the pyrazolyl that be selected from-NH phenyl, phenyl replace, the pyrazolyl that phenyl methyl replaces, phenyl methyl replacement, wherein phenyl can be replaced by one or more following groups: halogen, by the C of halogen or hydroxyl replacement 1-4alkyl ,-OH ,-OC 1-4alkyl ,-CN ,-COOH ,-C 1-4alkyl NH 2,-C 1-4alkyl NH (C 1-4alkyl) ,-C 1-4alkyl N (C 1-4alkyl) 2,-COOC 1-4alkyl ,-SO 2(C 1-4alkyl) ,-NH 2,-NH (C 1-4alkyl) ,-N (C 1-4alkyl) 2,-NHSO 2(C 1-4alkyl) ,-SO 2n (C 1-4alkyl) 2,-SO 2nH (C 1-4alkyl) ,-P (O) (C 1-4alkyl) 2; In some the most preferred embodiment, A 3the pyrazolyl ethynyl of the pyrazolyl that be selected from-NH phenyl, phenyl replace, the pyrazolyl that phenyl methyl replaces, phenyl methyl replacement, wherein phenyl can be replaced by one or more following groups: F, Cl, trifluoromethyl ,-COOH ,-CH 2oH ,-OCH 3,-OC 2h 5,-CN ,-SO 2nHCH (CH 3) 2,-COOCH 3,-SO 2cH 3,-NH 2,-P (O) (CH 3) 2.
In some embodiments of the present invention, A 3for hydrogen.
In some embodiments of the present invention, work as A 3for hydrogen, and A 1for by one or more R 3the aryl replacing, and R 3for-NR 6r 7time, R 6, R 7independently be selected from respectively C 1-6alkyl, or form 3-12 unit heterolipid cyclic group be connected atom.
In some embodiments, R 2being selected from can be by one or more R 3the phenyl replacing; In some preferred embodiments, R 2being selected from can be by one or more R 3the phenyl replacing, R 3be selected from halogen ,-SO 2(C 1-6alkyl) ,-SO 2n (C 1-6alkyl) 2,-SO 2nH (C 1-6alkyl) ,-NH (C 1-6alkyl) ,-N (C 1-6alkyl) 2,-NHSO 2(C 1-6alkyl) ,-P (O) (C 1-6alkyl) 2; At some more preferably in embodiment, R 2be selected from by one or more R 3the phenyl replacing, R 3be selected from F, Cl ,-SO 2cH 3,-SO 2n (CH 3) C 2h 5,-SO 2nHCH (CH 3) 2,-NHCH 3,-N (CH 3) C 2h 5,-NHSO 2cH 3,-P (O) (CH 3) 2.
In some embodiments, R 1be selected from methyl, trifluoromethyl.
In some embodiments, A 4be selected from by one or more R 4the phenyl replacing; In some preferred embodiments, A 4be selected from by one or more R 4the phenyl replacing, wherein R 4be selected from the C of halogen, halogen replacement 1-6alkyl ,-NR 6r 7,-P (O) R 6r 7, wherein R 6, R 7independently be selected from respectively C 1-6alkyl; At some more preferably in embodiment, A 4be selected from by one or more R 4the phenyl replacing, wherein R 4be selected from the methyl of F, Cl, halogen replacement, ethyl, the-N (CH that halogen replaces 3) 2,-P (O) (CH 3) 2; In some preferred embodiments, A 4be selected from by one or more R 4the phenyl replacing, wherein R 4be selected from F, Cl ,-CHF 2,-CF 3,-CF 2cH 3,-N (CH 3) 2,-P (O) (CH 3) 2, A 4at least replaced by a F atom.
In some embodiments, A 2be selected from phenyl, pyridyl, pyrimidyl, pyrazolyl; In some preferred embodiments, A 2be selected from
In some embodiments, A 2can be selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, morpholinyl, tetrahydrofuran base, piperidyl, piperazinyl, tetrahydro pyridyl, dihydropyridine base, tetrahydro-thienyl, pyrrolidyl, oxazolidinyl, thiazolidyl, imidazolidyl, isoxazole alkyl, isothiazole alkyl, pyrazolidyl, thio-morpholinyl, piperazine-2-ketone group, pyrrolinyl, dihydrofuran base, dihydro-thiophene base; In some preferred embodiments, A2 can be selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, morpholinyl; At some more preferably in embodiment, A 2can be selected from F, Cl, methoxyl group, oxyethyl group ,-OCH by one or more 2cH 2oH, group replace.
In some embodiments, A 5be 5 or 6 yuan of heterolipid cyclic groups; At some more preferably in embodiment, A 5for morpholinyl, tetrahydrofuran base, piperidyl, piperazinyl, tetrahydro pyridyl, dihydropyridine base, tetrahydro-thienyl, pyrrolidyl, oxazolidinyl, thiazolidyl, imidazolidyl, isoxazole alkyl, isothiazole alkyl, pyrazolidyl, thio-morpholinyl, piperazine-2-ketone group, pyrrolinyl, dihydrofuran base, dihydro-thiophene base; In some preferred embodiments, A 5for morpholinyl, 1,2,3,4-tetrahydro pyridyl, 1,2,3,6-tetrahydro pyridyl, 2,3,4,5-tetrahydro pyridyl, piperazinyl, piperazine-2-ketone group, piperidyl; In some preferred embodiments, A 5for piperazine-1-base, piperazine-2-base, piperazine-3-base, piperidin-4-yl, piperidin-1-yl, piperidin-2-yl, piperidines-3-base, morpholine-4-base, morpholine-2-Ji, morpholine-3-base, 1,2,3,4-tetrahydropyridine-4-base, 1,2,3,6-tetrahydropyridine-4-base, 2,3,4,5-tetrahydropyridine-4-base, piperazine-2-ketone group; In some the most preferred embodiment, A 5for
In some embodiments, A 5can be selected from following group and replace by one or more :=zero, unsubstituted C 1-6alkyl, is independently selected from by one or more C that hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group replace 1-6alkyl, 3-12 unit heterolipid cyclic group; Wherein 3-12 unit heterolipid cyclic group can be replaced by following group further: C 1-6alkyl ,=zero ,-OH ,-COOH ,-CN, halogen ,-NH (C 1-6alkyl) ,-N (C 1-6alkyl) 2.In some preferred embodiments, A 5can be selected from following group and replace by one or more :=zero, methyl, ethyl, n-propyl, sec.-propyl, the methyl, ethyl, n-propyl or the sec.-propyls that be independently selected from by one or more-OH ,-COOH, 5 or 6 yuan of heterolipid cyclic groups replace, 5 or 6 yuan of heterolipid cyclic groups, wherein 5 or 6 yuan of heterolipid cyclic groups can be selected from further following group and be replaced: methyl, ethyl, n-propyl, sec.-propyl ,=zero,-OH ,-COOH ,-CN, halogen ,-NH (C 1-3alkyl) ,-N (C 1-3alkyl) 2; In some preferred embodiments, A 5can be selected from following group and replace by one or more: methyl, ethyl, n-propyl, sec.-propyl ,=zero, piperidyl, piperazinyl, wherein piperidyl, piperazinyl can be by methyl substituted.
In some embodiments ,-A 2-A 5structure as follows:
In some preferred embodiments ,-A 2-A 5structure as follows:
In some preferred embodiments, work as A 3for hydrogen, A 1for-O-(CHR 1)-A 4, R 1during for methyl, A 2be selected from phenyl, pyridyl, pyrimidyl, pyrazoles, and A 2at least by one-OC 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group.
The present invention provides the compound of formula II and pharmacy acceptable salt thereof, solvate, polymorphic, metabolite on the other hand,
Wherein:
A 1be selected from-O-(CHR 1)-A 4,-CH 2oR 2, by one or more R 3the aryl replacing;
R 1the methyl that is selected from methyl, is replaced by 1-3 halogen;
A 4being selected from can be by one or more R 4the aryl replacing;
R 2being selected from can be by one or more R 3the aryl replacing;
R 3be selected from halogen ,-SO 2(C 1-6alkyl) ,-SO 2nR 6r 7,-NR 6r 7,-NHSO 2(C 1-6alkyl) ,-P (O) R 6r 7;
R 4be selected from halogen, C 1-6alkyl ,-NR 6r 7,-P (O) R 6r 7;
R 6, R 7independently be selected from respectively hydrogen, C 1-6alkyl, or form 3-12 unit heterolipid cyclic group be connected atom;
A 2be selected from phenyl, pyridyl, pyrimidyl, pyrazolyl, can be selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group;
A 5for 3-12 unit heterolipid cyclic group, can be selected from following group and replace by one or more :=zero, unsubstituted C 1-6alkyl, is independently selected from by one or more C that hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group replace 1-6alkyl, 3-12 unit heterolipid cyclic group.
In the compound of formula II, in some embodiments, work as A 1for by one or more R 3the aryl replacing, and R 3for-NR 6r 7time, R 6, R 7independently be selected from respectively C 1-6alkyl, or form 3-12 unit heterolipid cyclic group be connected atom.
In some embodiments, R 2being selected from can be by one or more R 3the phenyl replacing; In some preferred embodiments, R 2being selected from can be by one or more R 3the phenyl replacing, R 3be selected from halogen ,-SO 2(C 1-6alkyl) ,-SO 2n (C 1-6alkyl) 2,-SO 2nH (C 1-6alkyl) ,-NH (C 1-6alkyl) ,-N (C 1-6alkyl) 2,-NHSO 2(C 1-6alkyl) ,-P (O) (C 1-6alkyl) 2; At some more preferably in embodiment, R 2be selected from by one or more R 3the phenyl replacing, R 3be selected from F, Cl ,-SO 2cH 3,-SO 2n (CH 3) C 2h 5,-SO 2nHCH (CH 3) 2,-NHCH 3,-N (CH 3) C 2h 5,-NHSO 2cH 3,-P (O) (CH 3) 2.
In some embodiments, R 1be selected from methyl, trifluoromethyl.
In some embodiments, A 4be selected from by one or more R 4the phenyl replacing; In some preferred embodiments, A 4be selected from by one or more R 4the phenyl replacing, wherein R 4be selected from the C of halogen, halogen replacement 1-6alkyl ,-NR 6r 7,-P (O) R 6r 7, wherein R 6, R 7independently be selected from respectively C 1-6alkyl; At some more preferably in embodiment, A 4be selected from by one or more R 4the phenyl replacing, wherein R 4be selected from the methyl of F, Cl, halogen replacement, ethyl, the-N (CH that halogen replaces 3) 2,-P (O) (CH 3) 2; In some preferred embodiments, A 4be selected from by one or more R 4the phenyl replacing, wherein R 4be selected from F, Cl ,-CHF 2,-CF 3,-CF 2cH 3,-N (CH 3) 2,-P (O) (CH 3) 2, A 4at least replaced by a F atom.
In some embodiments, A 2be selected from phenyl, pyridyl, pyrimidyl, pyrazolyl; In some preferred embodiments, A 2be selected from
In some embodiments, A 2can be selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, morpholinyl, tetrahydrofuran base, piperidyl, piperazinyl, tetrahydro pyridyl, dihydropyridine base, tetrahydro-thienyl, pyrrolidyl, oxazolidinyl, thiazolidyl, imidazolidyl, isoxazole alkyl, isothiazole alkyl, pyrazolidyl, thio-morpholinyl, piperazine-2-ketone group, pyrrolinyl, dihydrofuran base, dihydro-thiophene base; In some preferred embodiments, A 2can be selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, morpholinyl; At some more preferably in embodiment, A 2can be selected from F, Cl, methoxyl group, oxyethyl group ,-OCH by one or more 2cH 2oH, group replace.
In some embodiments, A 5be 5 or 6 yuan of heterolipid cyclic groups; At some more preferably in embodiment, A 5for morpholinyl, tetrahydrofuran base, piperidyl, piperazinyl, tetrahydro pyridyl, dihydropyridine base, tetrahydro-thienyl, pyrrolidyl, oxazolidinyl, thiazolidyl, imidazolidyl, isoxazole alkyl, isothiazole alkyl, pyrazolidyl, thio-morpholinyl, piperazine-2-ketone group, pyrrolinyl, dihydrofuran base, dihydro-thiophene base; In some preferred embodiments, A 5for morpholinyl, 1,2,3,4-tetrahydro pyridyl, 1,2,3,6-tetrahydro pyridyl, 2,3,4,5-tetrahydro pyridyl, piperazinyl, piperazine-2-ketone group, piperidyl; In some preferred embodiments, A 5for piperazine-1-base, piperazine-2-base, piperazine-3-base, piperidin-4-yl, piperidin-1-yl, piperidin-2-yl, piperidines-3-base, morpholine-4-base, morpholine-2-Ji, morpholine-3-base, 1,2,3,4-tetrahydropyridine-4-base, 1,2,3,6-tetrahydropyridine-4-base, 2,3,4,5-tetrahydropyridine-4-base, piperazine-2-ketone group; In some the most preferred embodiment, A 5for
In some embodiments, A 5can be selected from following group and replace by one or more :=zero, unsubstituted C 1-6alkyl, is independently selected from by one or more C that hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group replace 1-6alkyl, 3-12 unit heterolipid cyclic group, wherein 3-12 unit heterolipid cyclic group can be replaced by following group further: C 1-6alkyl ,=zero ,-OH ,-COOH ,-CN, halogen ,-NH (C 1-6alkyl) ,-N (C 1-6alkyl) 2; In some preferred embodiments, A 5can be selected from following group and replace by one or more :=zero, methyl, ethyl, n-propyl, sec.-propyl, the methyl, ethyl, n-propyl or the sec.-propyls that be independently selected from by one or more-OH ,-COOH, 5 or 6 yuan of heterolipid cyclic groups replace, 5 or 6 yuan of heterolipid cyclic groups, wherein 5 or 6 yuan of heterolipid cyclic groups can be selected from further following group and be replaced: methyl, ethyl, n-propyl, sec.-propyl ,=zero,-OH ,-COOH ,-CN, halogen ,-NH (C 1-3alkyl) ,-N (C 1-3alkyl) 2; In some preferred embodiments, A 5can be selected from following group and replace by one or more: methyl, ethyl, n-propyl, sec.-propyl ,=zero, piperidyl, piperazinyl, wherein piperidyl, piperazinyl can be by methyl substituted.
In some embodiments ,-A 2-A 5structure as follows:
In some preferred embodiments ,-A 2-A 5structure as follows:
In some preferred embodiments, work as A 1for-O-(CHR 1)-A 4, R 1during for methyl, A 2be selected from phenyl, pyridyl, pyrimidyl, pyrazoles, and A 2at least by one-OC 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group.
The present invention provides the compound of formula III, formula IV on the other hand, or its pharmacy acceptable salt, solvate, polymorphic, metabolite,
Wherein:
R 4 'independently be selected from hydrogen, halogen, C 1-6alkyl ,-NR 6r 7,-P (O) R 6r 7;
R 6, R 7independently be selected from respectively hydrogen, C 1-6alkyl, or form 3-12 unit heterolipid cyclic group be connected atom;
A 2be selected from phenyl, pyridyl, pyrimidyl, can be independently selected from halogen ,-OC by 1,2,3 or 4 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group;
A 5for 3-12 unit heterolipid cyclic group, can be selected from following group and replace by one or more :=zero, unsubstituted C 1-6alkyl, is independently selected from by one or more C that hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group replace 1-6alkyl, 3-12 unit heterolipid cyclic group.
In the compound of formula III or formula IV, in some embodiments, R 4 'can be identical or different, and be not all hydrogen; In some preferred embodiments, the R of 3 4 'substituting group is halogen; In some preferred embodiments, the R of 3 4 'substituting group is F, remaining R 4 'substituting group is independently selected from the C of hydrogen, halogen, halogen replacement 1-6alkyl ,-NR 6r 7,-P (O) R 6r 7, wherein R 6, R 7independently be selected from C 1-6alkyl; In some preferred embodiments, the R of 3 4 'substituting group is F, remaining R 4 'substituting group is independently selected from the methyl of hydrogen, halogen, halogen replacement, ethyl, the-N (CH that halogen replaces 3) 2,-P (O) (CH 3) 2; In some preferred embodiments, the R of 3 4 'substituting group is F, remaining R 4 'substituting group is independently selected from hydrogen, F, Cl ,-CHF 2,-CF 2cH 3,-N (CH 3) 2,-P (O) (CH 3) 2; In some preferred embodiments, the R of 3 4 'substituting group is F, 2 and 6 s' R 4 'substituting group is Cl, the R of 4 4 'for hydrogen.
In some embodiments, A 2be selected from
In some embodiments, A 2can be independently selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, morpholinyl, tetrahydrofuran base, piperidyl, piperazinyl, tetrahydro pyridyl, dihydropyridine base, tetrahydro-thienyl, pyrrolidyl, oxazolidinyl, thiazolidyl, imidazolidyl, isoxazole alkyl, isothiazole alkyl, pyrazolidyl, thio-morpholinyl, piperazine-2-ketone group, pyrrolinyl, dihydrofuran base, dihydro-thiophene base; In some preferred embodiments, A 2can be selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, morpholinyl; At some more preferably in embodiment, A 2can be selected from F, Cl, methoxyl group, oxyethyl group ,-OCH by one or more 2cH 2oH, group replace.
In some embodiments, A 5be 5 or 6 yuan of heterolipid cyclic groups; At some more preferably in embodiment, A 5for morpholinyl, tetrahydrofuran base, piperidyl, piperazinyl, tetrahydro pyridyl, dihydropyridine base, tetrahydro-thienyl, pyrrolidyl, oxazolidinyl, thiazolidyl, imidazolidyl, isoxazole alkyl, isothiazole alkyl, pyrazolidyl, thio-morpholinyl, piperazine-2-ketone group, pyrrolinyl, dihydrofuran base, dihydro-thiophene base; In some preferred embodiments, A 5for morpholinyl, 1,2,3,4-tetrahydro pyridyl, 1,2,3,6-tetrahydro pyridyl, 2,3,4,5-tetrahydro pyridyl, piperazinyl, piperazine-2-ketone group, piperidyl; In some preferred embodiments, A 5for piperazine-1-base, piperazine-2-base, piperazine-3-base, piperidin-4-yl, piperidin-1-yl, piperidin-2-yl, piperidines-3-base, morpholine-4-base, morpholine-2-Ji, morpholine-3-base, 1,2,3,4-tetrahydropyridine-4-base, 1,2,3,6-tetrahydropyridine-4-base, 2,3,4,5-tetrahydropyridine-4-base, piperazine-2-ketone group; In some the most preferred embodiment, A 5for
In some embodiments, A 5can be selected from following group and replace by one or more :=zero, unsubstituted C 1-6alkyl, is independently selected from by one or more C that hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group replace 1-6alkyl, 3-12 unit heterolipid cyclic group, wherein 3-12 unit heterolipid ring can be replaced by following group further: C 1-6alkyl ,=zero ,-OH ,-COOH ,-CN, halogen ,-NH (C 1-6alkyl) ,-N (C 1-6alkyl) 2; In some preferred embodiments, A 5can be selected from following group and replace by one or more :=zero, methyl, ethyl, n-propyl, sec.-propyl, methyl, ethyl, n-propyl or the sec.-propyl, the 5 or 6 yuan of heterolipid cyclic groups that be independently selected from by one or more-OH ,-COOH, 5 or 6 yuan of heterolipid cyclic groups replace, wherein 5 or 6 yuan of heterolipid cyclic groups can be selected from further following group and be replaced: methyl, ethyl, n-propyl, sec.-propyl ,=zero ,-OH,-COOH,-CN, halogen ,-NH (C 1-3alkyl) ,-N (C 1-3alkyl) 2; In some preferred embodiments, A 5can be selected from following group and replace by one or more: methyl, ethyl, n-propyl, sec.-propyl ,=zero, piperidyl, piperazinyl, wherein piperidyl, piperazinyl can be by methyl substituted.
In some embodiments ,-A 2-A 5structure as follows:
In some preferred embodiments ,-A 2-A 5structure as follows:
In some embodiments, A 2can be selected from halogen ,-OC by 1 or 2 1-6the group of alkyl replaces.In some preferred embodiments, A 2at least by one-OC 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group.
Compound concrete example provided by the invention is as follows, but is not limited to following compounds:
The present invention also provides a kind of method of preparing the compounds of this invention, comprises following synthetic schemes:
Synthetic schemes 1
The compound of formula 1-3 can use synthetic schemes 1 synthetic.Bromine adds alcohol to obtain bromo intermediate 1-1 after adding the dichloromethane solution of triphenylphosphine again.Intermediate 1-1 and 2-amino-3-hydroxyl-5-bromopyridine (for example N in solvent, dinethylformamide or other aprotic solvents) reaction obtains intermediate 1-2, intermediate 1-2, connection pinacol borate and for example Pd of palladium class catalyzer (dppf) Cl 2, use (for example dioxane, the methyl-sulphoxide) reaction in solvent of alkali for example salt of wormwood, Potassium ethanoate to obtain the compound of formula 1-3.
Synthetic schemes 2
The compound of formula 2-3 can use synthetic schemes 2 synthetic.Chiral alcohol and 3-hydroxyl-2-nitropyridine and DIAD, triphenylphosphine react the intermediate 2-1 that obtains chirality upset in tetrahydrofuran (THF).Adopt popular response condition, the nitro of intermediate 2-1 obtains intermediate 2-2 through reduction, and intermediate 2-2 for example, reacts with bromo-succinimide and obtains bromo compound 2-3 in organic solvent (acetonitrile, chloroform, tetracol phenixin).
Synthetic schemes 3
The compound of formula 3-3 can use synthetic schemes 3 synthetic.L is leavings group (for example Cl, Br), NR ' R " be the heterolipid cyclic group of the 3-12 unit that can be protected by Boc, X is independently selected from N or CH; R 5be selected from hydrogen, substituted or non-substituted C 1-6alkyl, can be at sodium hydride and N, under the existence of dinethylformamide, prepare intermediate 3-1, under the existence of for example acetonitrile, chloroform, tetracol phenixin and bromo-succinimide of organic solvent, carry out bromo and obtain compound 3-2, intermediate 3-2 can further react and make intermediate 3-3 with connection pinacol borate.
Synthetic schemes 3 '
The compound of formula 3 '-3 can use synthetic schemes 3 ' synthetic.L is leavings group (for example Cl, Br), NR ' R " be the heterolipid cyclic group of the 3-12 unit that can be protected by Boc, R 5be selected from hydrogen, substituted or non-substituted C 1-6alkyl.Can be at sodium hydride and N, under the existence of dinethylformamide, prepare intermediate 3 '-1, for example, under the existence of organic solvent (acetonitrile, chloroform, tetracol phenixin) and bromo-succinimide, carry out bromo and obtain compound 3 '-2, intermediate 3 '-2 can further be reacted and make intermediate 3 '-3 with connection pinacol borate.
Synthetic schemes 4
Formula 4-5 compound can be synthetic by synthetic schemes 4.Wherein, Ar is selected from aryl, heteroaryl, arylalkyl, heteroarylalkyl, and L is leavings group (for example Cl, Br), NR ' R " be the heterolipid cyclic group of the 3-12 unit that can be protected by Boc, X is independently selected from N or CH, R 5be selected from hydrogen, substituted or non-substituted C 1-6alkyl.1-(2-halogen pyridin-4-yl)-3-(dimethylamino) third-2-alkene-1-ketone and hydrazine closed loop in the organic solvent of for example ethanol obtain intermediate 4-1.The coupling under palladium catalysis of intermediate 4-1 and benzophenone imine obtains intermediate 4-2, then uses acid (for example dilute hydrochloric acid) to remove benzophenone protecting group to obtain intermediate 4-3.Intermediate 4-3 carries out bromo with bromo-succinimide and obtains intermediate 4-4, then obtains final compound 4-5 with boric acid ester coupling under palladium catalysis.If for example,, with protecting group (Boc), further deprotection base obtains target compound in 4-5.
Synthetic schemes 5
The compound of formula 5-4 can be synthetic by synthetic schemes 5.Wherein, Ar is selected from aryl, heteroaryl, arylalkyl, heteroarylalkyl, and L is leavings group (for example Cl, Br).2-halogen-4-pyridylaldehyde first for example reacts in toluene at organic solvent with amine, then obtains intermediate 5-1 with toluenesulfomethyl isocyanide closed loop under alkaline condition.The coupling under palladium catalysis of intermediate 5-1 and benzophenone imine obtains intermediate 5-2, then removes benzophenone protecting group with for example dilute hydrochloric acid of acid and obtain intermediate 5-3.Intermediate 5-3 carries out bromo with bromo-succinimide and obtains intermediate 5-4.
Synthetic schemes 6
The compound of formula 6-3 can be synthetic by synthetic schemes 6.Wherein, Ar is selected from aryl, heteroaryl, and L is leavings group (for example Cl, Br), NR ' R " be the heterolipid cyclic group of the 3-12 unit that can be protected by Boc, X is independently selected from N or CH, R 5be selected from hydrogen, substituted or non-substituted C 1-6alkyl.The coupling under palladium catalysis of 4-halo-PA and amine obtains intermediate 6-1, and intermediate 6-1 carries out bromo with bromo-succinimide and obtains intermediate 6-2, then obtains final compound 6-3 with boric acid ester coupling under palladium catalysis.If with protecting group, can obtain target compound at deprotection base under acidic conditions in 6-3.
Synthetic schemes 7
The compound of formula 7-5 can be synthetic by synthetic schemes 7.NR ' R " be the heterolipid cyclic group of the 3-12 unit that can be protected by Boc, X is independently selected from N or CH, R 5be selected from hydrogen, substituted or non-substituted C 1-6alkyl.Under existing, prepare boric acid ester 7-1 at connection pinacol borate, palladium.Intermediate 7-1 coupling under palladium catalysis obtains intermediate 7-2, then reduces and obtain intermediate 7-3 with iron powder and dilute hydrochloric acid.Intermediate 7-3 carries out bromo with bromo-succinimide and obtains intermediate 7-4, then obtains final compound 7-5 with boric acid ester coupling under palladium catalysis.If with protecting group, can obtain target compound at deprotection base under acidic conditions in 7-5.
Synthetic schemes 8
The compound of formula 8-2 can be synthetic by synthetic schemes 8.NR ' R " be the heterolipid cyclic group of the 3-12 unit that can be protected by Boc, X is independently selected from N or CH, R 5be selected from hydrogen, substituted or non-substituted C 1-6alkyl.The coupling under palladium catalysis of the bromo-PA of 3-methylol-5-and boric acid ester obtains intermediate 8-1, then reacts by Mitsunobu the compound that obtains formula 8-2, if in 8-2 with protecting group, can obtain target compound at deprotection base under acidic conditions.
Synthetic schemes 9
The compound of formula 9-1 can be synthetic by synthetic schemes 9.Wherein, NR ' R " be the heterolipid cyclic group of the 3-12 unit that can be protected by Boc, X is independently selected from N or CH; R 5be selected from hydrogen, substituted or non-substituted C 1-6alkyl.The coupling under palladium catalysis of pyridine boric acid ester obtains target compound 9-1.If with protecting group, can obtain target compound at deprotection base under acidic conditions in 9-1.If participate in reaction by the compound of formula 1-3, obtain corresponding target compound.
Synthetic schemes 10
The compound of formula 10-2 can be synthetic by synthetic schemes 10.Wherein, A 5for the 3-12 unit heterolipid cyclic group that can be protected by Boc, the heteroatoms in heterolipid cyclic group can directly not be connected with the boron atom in boric acid ester; R 5be selected from C 1-6alkyl.Boric acid ester coupling under palladium catalysis obtains intermediate 10-1, then obtains final compound 10-2 with the coupling under palladium catalysis of another kind of boric acid ester.If with protecting group, can obtain target compound at deprotection base under acidic conditions in 10-2.
Except as otherwise noted, the implication of group, term described in above-mentioned synthetic schemes is identical with the implication in formula I, II, III and IV compound.
Above-mentioned synthetic schemes has just been enumerated the preparation method of part of compounds in the present invention, and according to the known technology of this area, technician, on the basis of above-mentioned synthetic schemes, adopts similar method also can synthesize compound of the present invention.
In the present invention, in the time relating to the compound of formula III, formula IV, wherein the numbering on phenyl is as follows:
" compound " of the present invention comprises all steric isomers, geometrical isomer, tautomer and isotropic substance.
The compounds of this invention can be asymmetric, for example, has one or more steric isomers.Except as otherwise noted, all steric isomers all comprise, as enantiomer and diastereomer.The compound that contains unsymmetrical carbon of the present invention can be separated with the pure form of optical activity or racemic form.The pure form of optical activity can be from racemic mixture, or by using chiral raw material or chiral reagent synthetic.
The compounds of this invention also comprises tautomeric forms.Tautomeric forms derive from a singly-bound and adjacent two keys exchanges and together with follow the migration of a proton.
The present invention also comprises all isotopic atoms, no matter is at intermediate or last compound.Isotopic atom comprises having identical atomicity, but different mass number.For example, the isotropic substance of hydrogen comprises tritium and deuterium.
In the above-mentioned definition of general formula I-IV compound, term used herein has following implication:
Term " halogen " refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Refer to-OH of term " hydroxyl ".
Refer to-COOH of term " carboxyl ".
Refer to-NH of term " amino " 2,-NH (alkyl) and-N (alkyl) 2.Amino include but not limited to-NH of object lesson 2,-NHCH 3,-NHCH (CH 3) 2,-N (CH 3) 2,-NHC 2h 5,-N (CH 3) C 2h 5deng.
Term " alkyl " refers to the stable hydrocarbon group of the straight or branched being made up of carbon atom and hydrogen atom, as C 1-20alkyl, is preferably C 1-6alkyl, such as methyl, ethyl, propyl group (such as n-propyl and sec.-propyl), butyl (such as normal-butyl, isobutyl-, sec-butyl or the tertiary butyl), amyl group (such as n-pentyl, isopentyl, neo-pentyl), n-hexyl, 2-methyl hexyl etc.Described alkyl can be that non-substituted or substituted, described substituting group includes but not limited to alkyl, alkyl oxy, cyano group, carboxyl, aryl, heteroaryl, amino, halogen, alkylsulfonyl, sulfinyl, phosphoryl and hydroxyl.
Term " aryl " refers to full carbon monocycle or the fused rings of the π-electron system with total conjugated, and it has 6-14 carbon atom, preferably has 6-12 carbon atom, most preferably has 6 carbon atoms.Aryl can be non-substituted or be replaced by one or more substituting group, and described substituent example includes but not limited to alkyl, alkyl oxy, aryl, aralkyl, amino, halogen, hydroxyl, alkylsulfonyl, sulfinyl, phosphoryl and heterolipid cyclic group.The limiting examples of non-substituted aryl includes but not limited to phenyl, naphthyl and anthryl.
Term " arylalkyl " refers to the alkyl being replaced by aryl as hereinbefore defined, the C preferably being replaced by aryl 1-6alkyl.Include but not limited to-CH of the limiting examples of arylalkyl 2-phenyl ,-(CH 2) 2-phenyl ,-(CH 2) 3-phenyl ,-CH (CH 3)-phenyl ,-CH 2-CH (CH 3)-phenyl ,-(CH 2) 4-phenyl ,-CH 2-CH (CH 3)-CH 2-phenyl ,-CH 2-CH 2-CH (CH 3)-phenyl etc.
Term " heteroaryl " refers to monocycle or the fused rings of 5-12 annular atoms, there are 5,6,7,8,9,10,11 or 12 annular atomses, wherein contain 1,2,3 or 4 annular atoms that is selected from N, O, S, all the other annular atomses are C, and have the π-electron system of total conjugated.Heteroaryl can be non-substituted or replacement, and described substituting group includes but not limited to alkyl, alkyl oxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano group, nitro, carbonyl and heterolipid cyclic group.The limiting examples of non-substituted heteroaryl includes but not limited to pyrryl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, tetrazyl, triazinyl.
Term " heteroarylalkyl " refers to the alkyl being replaced by heteroaryl as hereinbefore defined, the C that preferably heteroaryl replaces 1-6alkyl.Include but not limited to-CH of the limiting examples of heteroarylalkyl 2-pyrazolyl ,-(CH 2) 2-pyridyl ,-(CH 2) 3-thienyl ,-CH (CH 3)-pyrazinyl ,-CH 2-CH (CH 3)-furyl etc.
Term " heterolipid cyclic group " refers to monocycle or the fused rings with 3-12 annular atoms, has 3,4,5,6,7,8,9,10,11 or 12 annular atomses, and wherein 1 or 2 annular atoms is to be selected from N, O, S (O) nthe heteroatoms of (wherein n is 0,1 or 2), all the other annular atomses are C.Such ring can be saturated or unsaturated (for example having one or more pairs of keys), but does not have the π-electron system of total conjugated.The example of 3 yuan of saturated heterolipid cyclic groups includes but not limited to Oxyranyle, thiirane base, azirane base, the example of 4 yuan of saturated heterolipid rings includes but not limited to azetidine base, Evil fourth cyclic group, thiophene fourth cyclic group, the example of 5 yuan of saturated heterolipid cyclic groups includes but not limited to tetrahydrofuran base, tetrahydro-thienyl, pyrrolidyl, isoxazole alkyl, oxazolidinyl, isothiazole alkyl, thiazolidyl, imidazolidyl, tetrahydro-pyrazole base, the example of 6 yuan of saturated heterolipid cyclic groups includes but not limited to piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, morpholinyl, piperazinyl, Isosorbide-5-Nitrae-thioxane bases, Isosorbide-5-Nitrae-dioxane base, thio-morpholinyl, Isosorbide-5-Nitrae-dithiane base, the example of 7 yuan of saturated heterolipid rings includes but not limited to azepan base, oxepane alkyl, thia suberane base, the example of 5 yuan of unsaturated heterolipid rings includes but not limited to pyrrolinyl, dihydrofuran base, dihydro-thiophene base, the example of 6 yuan of unsaturated heterolipid rings includes but not limited to dihydropyridine base, tetrahydro pyridyl, dihydro pyranyl, THP trtrahydropyranyl, dihydro thiapyran base.Heterolipid cyclic group can be that hydrogen atom non-substituted or wherein can be substituted base and replaces, described substituting group include but not limited to alkyl, alkoxyl group ,=zero, aryl, aralkyl ,-COOH ,-CN, amino, halogen and hydroxyl.
" treatment significant quantity " refers in the time needing the Mammals of such treatment, is enough to the effectively amount of the general formula compound for the treatment of.Treatment significant quantity will depend on given activity, patient's the existence of age, physiological situation, other diseases state of healing potion used and nutritional status and changes.Determining of the treatment significant quantity of the healing potion that the other medicines treatment that in addition, patient may just accept will give impact.
" treatment " means any treatment to disease in mammalian body, comprising:
(i) prevent disease, cause the clinical symptom of disease not develop;
(ii) suppress disease, stop the development of clinical symptom; And/or
(iii) palliate a disease, cause disappearing of clinical symptom.
It is individually dosed that compound or its salt of the present invention can be used as active substance, preferably with the form administration of its pharmaceutical composition.
The present invention provides a kind of pharmaceutical composition on the other hand, and its compound that contains general formula I, II, III or IV, solvate, polymorphic, metabolite or its pharmacy acceptable salt are as active ingredient, and one or more pharmaceutically acceptable carriers.
" pharmaceutical composition " refer to one or more compound or its salts of the present invention with conventionally accept in the art for example, for bioactive compounds being delivered to the preparation of carrier of organism (people).The object of pharmaceutical composition is to be conducive to organism to give compound of the present invention.
Term " pharmaceutically acceptable carrier " refers to organism without obvious stimulation effect, and can not damage those carriers of biological activity and the performance of this active compound." pharmaceutically acceptable carrier " refers to and together inert substance administration, that be conducive to active ingredient administration of active ingredient, includes but not limited to acceptable for example, any glidant for human or animal (domestic animal), sweetener, thinner, sanitas, dyestuff/tinting material, flavoring toughener, tensio-active agent, wetting agent, dispersion agent, disintegrating agent, suspending agent, stablizer, isotonic agent, solvent or the emulsifying agent of State Food and Drug Administration's license.The limiting examples of described carrier comprises calcium carbonate, calcium phosphate, various sugar and each kind of starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol.
That pharmaceutical composition of the present invention can be mixed with is solid-state, semi-solid state, liquid state or gaseous state preparation, as tablet, pill, capsule, pulvis, granule, paste, emulsion, suspension agent, solution, suppository, injection, inhalation, gelifying agent, microballoon and aerosol etc.
That the typical approach that gives the compounds of this invention or its pharmacy acceptable salt or its pharmaceutical composition includes but not limited to is oral, rectum, thoroughly mucous membrane, through enteral administration, or local, in skin, suction, parenteral, hypogloeeis, intravaginal, nose, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.Preferred route of administration is oral administration.
Pharmaceutical composition of the present invention can adopt the known method manufacture in this area, as conventional hybrid system, dissolution method, granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc.
In preferred embodiments, pharmaceutical composition is oral form.For oral administration, can, by active compound is mixed with pharmaceutically acceptable carrier well known in the art, prepare this pharmaceutical composition.These carriers can make compound of the present invention be formulated into tablet, pill, lozenge, sugar-coat agent, capsule, liquid, gelifying agent, slurry agent, suspension agent etc., for the oral administration to patient.
Can prepare Peroral solid dosage form pharmaceutical composition by conventional mixing, filling or tabletting method.For example, can obtain by following method: described active compound is mixed with solid excipient, the mixture of the gained of optionally milling, if need to, add other suitable assistant agent, then this mixture is processed into particle, has obtained the core of tablet or sugar-coat agent.Applicable auxiliary material includes but not limited to: tackiness agent, thinner, disintegrating agent, lubricant, glidant, sweeting agent or correctives etc.As Microcrystalline Cellulose, glucose solution, mucialga of arabic gummy, gelatin solution, sucrose and starch paste; Talcum, starch, Magnesium Stearate, calcium stearate or stearic acid; Lactose, sucrose, starch, mannitol, Sorbitol Powder or Si Liaodengji dicalcium phosphate feed grade; Silicon-dioxide; Croscarmellose sodium, pre-paying starch, primojel, alginic acid, W-Gum, yam starch, methylcellulose gum, agar, carboxymethyl cellulose, cross-linked polyvinylpyrrolidone etc.Can optionally carry out dressing to the core of sugar-coat agent according to known method in common medicinal practice, especially use enteric coating.
Pharmaceutical composition is also applicable to administered parenterally, as sterile solution agent, suspensoid or the freeze-drying prods of suitable unit dosage.Can use suitable vehicle, for example weighting agent, buffer reagent or tensio-active agent.
On the other hand, the invention provides a kind of method that regulates protein kinase activity, comprising described protein kinase is contacted with above-claimed cpd or its pharmacy acceptable salt.
Preferably, described protein kinase is selected from ALK.In addition, described protein kinase comprises the kinases of sudden change, and wherein mutant kinase is selected from the ALK kinases of sudden change.
Moreover, the present invention provides the application in the medicine for the preparation for the treatment of disease of above-claimed cpd or its pharmacy acceptable salt or their pharmaceutical composition simultaneously, wherein said disease is and the active relevant disease of protein kinase (for example ALK), for example abnormal cell proliferation, wherein abnormal cell proliferation comprises cancer.The present invention also provides the application in the medicine of the disease being mediated by ALK for the preparation for the treatment of of above-claimed cpd or its pharmacy acceptable salt or their pharmaceutical composition.
The disease of described ALK mediation comprises nonsmall-cell lung cancer, primary cutaneous type, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, mammary cancer, colorectal cancer, Diffuse Large B-Cell Lymphoma, body tissue's cellular proliferative disorder and the neuroblastoma etc. of the ALK positive, preferably includes the nonsmall-cell lung cancer of the ALK positive.
In addition, the present invention also provides one to treat the method for Mammals (for example people) disease, wherein said disease is for example, to protein kinase (ALK) active relevant, comprises the above-claimed cpd from effective dose to people or its pharmacy acceptable salt or their pharmaceutical composition that give.
Embodiment
Specific embodiment below, its objective is and make those skilled in the art can more clearly understand and implement the present invention.They should not be considered to limitation of the scope of the invention, and are exemplary illustration of the present invention and Typical Representative.Those skilled in the art should understand that: form in addition other route of synthesis of the compounds of this invention, provide nonrestrictive embodiment below.
The all operations of all raw materials that relates to oxidizable or facile hydrolysis all carries out under nitrogen protection.Except as otherwise noted, the raw material that the present invention uses is all on market, directly to have bought without being further purified direct use.
The silica gel (200-300 order) that column chromatography chromatogram adopts Qingdao Chemical Co., Ltd. to produce.Precoated plate (the silica gel 60PF that thin-layer chromatography adopts E.Merck company to produce 254, 0.25 millimeter).Chipal compounds separation and enantiomeric excess value (ee) mensuration use Agilent LC1200series (pillar: CHIRALPAK AD-H, millimeter, 5 microns, 30 DEG C).Nucleus magnetic resonance chromatogram (NMR) is used Varian VNMRS-400 nmr determination; Liquid matter is used in conjunction (LC/MS) and uses FINNIGAN Thermo LCQ Advantage MAX, Agilent LC1200series (pillar: Waters Symmetry C18, millimeter, 5 microns, 35 DEG C), adopt ESI (+) ion mode.
Experimental section
intermediate 1:4-(3-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester
Step 1:4-(3-p-methoxy-phenyl) piperazine-1-carboxylic acid tert-butyl ester
By Meta Bromo Anisole (1.0g, 5mmol), N-tert-butoxycarbonyl-piperazine (1.2g, 6mmol), Pd 2(dba) 3(229mg, 0.25mmol), BINAP (328mg, 0.5mmol) and sodium tert-butoxide (0.72g, 7.5mmol) are added in dry toluene (20mL), nitrogen replacement, and 80 DEG C of stirrings are spent the night.Cooling rear silica gel column chromatography separates, and obtains 4-(3-p-methoxy-phenyl) piperazine-1-carboxylic acid tert-butyl ester (1.4g), yield: 96%.MS m/z[ESI]：293.2[M+1]。
Step 2:4-(3-methoxyl group-4-bromophenyl) piperazine-1-carboxylic acid tert-butyl ester
Under 0 DEG C, agitation condition, to 4-(3-p-methoxy-phenyl) piperazine-1-carboxylic acid tert-butyl ester (1.6g, in methylene dichloride (100mL) solution 5mmol), be added dropwise to bromine (0.87g, methylene dichloride (10mL) solution 5mmoL), finish, at 0 DEG C, react 1 hour.Add saturated sodium bicarbonate solution washing, dry concentrated rear silica gel column chromatography separates, and obtains 4-(3-methoxyl group-4-bromophenyl) piperazine-1-carboxylic acid tert-butyl ester (756mg), yield: 40%.MS m/z[ESI]：371.1[M+1]。
Step 3:4-(3-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester
By 4-(3-methoxyl group-4-bromophenyl) piperazine-1-carboxylic acid tert-butyl ester (740mg, 2mmol), connection pinacol borate (1008mg, 4mmol), Pd (dppf) Cl 2(73mg, 0.1mmol) and Glacial acetic acid potassium (588mg, 6mmol) are added in dry diox (20mL), nitrogen replacement, and 120 DEG C are reacted 2 hours.Cooling rear silica gel column chromatography separates, and obtains 4-(3-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester (640mg), yield: 76%.MS m/z[ESI]：419.3[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.212(d，J＝6.8Hz，1H)，6.58-6.40(m，2H)，3.861(s，3H)，3.593-3.555(m，4H)，3.125-3.110(m，4H)，1.483(s，9H)，1.240(s，12H)。
intermediate 2:1-(3-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) phenyl)-4-methylpiperazine
Step 1:1-(3-methoxyl group-4-nitrophenyl)-4-methylpiperazine
Fluoro-5-2-Nitroanisole (14.0g, 83mmol), N methyl piperazine (9.1g, 91mmol) and salt of wormwood (34.5g, 250mmol) are added in methyl-sulphoxide (200mL), and 90 DEG C of stirrings are spent the night.In cooling rear impouring 3L water, filter the solid of separating out, dry, obtain 1-(3-methoxyl group-4-nitrophenyl)-4-methylpiperazine (20.9g).MS m/z[ESI]：252.1[M+1]。
Step 2:1-(3-methoxyl group-4-aminophenyl)-4-methylpiperazine
By 1-(3-methoxyl group-4-nitrophenyl)-4-methylpiperazine (20.8g, 83mmol), Raney's nickel (4.0g) adds in 200mL methyl alcohol, with hydrogen exchange air, under atmosphere of hydrogen, stirring reaction spends the night, filter, after solvent is concentrated, obtain 1-(3-methoxyl group-4-aminophenyl)-4-methylpiperazine (17.0g), yield: 93%.MS m/z[ESI]：222.2[M+1]。
Step 3:1-(3-methoxyl group-4-bromophenyl)-4-methylpiperazine
By 1-(3-methoxyl group-4-aminophenyl)-4-methylpiperazine (16.6g, 75mmol), cuprous bromide (21.5g, 0.15mol) add in tetrahydrofuran (THF) (200mL), under stirring, be added dropwise to Isopentyl nitrite (17.6g, 0.15mol).Room temperature reaction 1 hour, reflux 3 hours.After cool to room temperature, filter, concentrated filtrate, obtains 1-(3-methoxyl group-4-bromophenyl)-4-methylpiperazine (5.98g), yield: 28% with column chromatography separating purification (taking sherwood oil: ethyl acetate=1: 1 as eluent).MSm/z[ESI]：285.1[M+1]
Step 4:1-(3-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) phenyl)-4-methylpiperazine
By 1-(3-methoxyl group-4-bromophenyl)-4-methylpiperazine (2.85g, 10mmol), connection pinacol borate (3.78g, 15mmol), Pd (dppf) Cl 2(366mg, 0.5mmol) and Glacial acetic acid potassium (1.96g, 20mmol) are added in dry diox (100mL), nitrogen replacement, and 120 DEG C are reacted 3 hours.Cooling rear silica gel column chromatography separates, and obtains 1-(3-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) phenyl)-4-methylpiperazine (1.86g), yield: 56%.MS m/z[ESI]：333.2[M+1]。 intermediate 3:4-(4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) piperidines-1-carboxylic acid tert-butyl ester
Step 1:4-sulfonyloxy methyl oxygen phenylpiperidines-1-carboxylic acid tert-butyl ester
0 DEG C, under agitation condition, to 4-hydroxy piperidine-1-carboxylic acid tert-butyl ester (20.1g, 0.1mol) and triethylamine (14.1g, in dichloromethane solution (200mL) 0.14mol), slowly drip the dichloromethane solution (50mL) of methylsulfonyl chloride (12.6g, 0.11mol).Dropwise rear 0 DEG C of reaction 1 hour.Reaction solution is poured into water (500mL), with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filters, filtrate is concentrated, obtains 4-sulfonyloxy methyl oxygen phenylpiperidines-1-carboxylic acid tert-butyl ester (25.2g), yield: 90%.Step 2:4-(the iodo-1H-pyrazol-1-yl of 4-) piperidines-1-carboxylic acid tert-butyl ester
At O DEG C, under agitation condition, sodium hydride (4.0g, 60%, 0.1mol) repeatedly join on a small quantity the anhydrous N of 4-iodine pyrazoles (17.5g, 0.09mol), in dinethylformamide solution (200mL), finish 0 DEG C of rear maintenance and continue reaction 20 minutes.The anhydrous DMF solution (50mL) of 4-sulfonyloxy methyl oxygen phenylpiperidines-1-carboxylic acid tert-butyl ester (25.2g, 0.09mol) is added dropwise in reaction solution, rises to stirring at room temperature 2 hours, then in 80 DEG C of reactions 2 hours.Cooling rear reaction solution is poured in frozen water, be extracted with ethyl acetate, organic phase anhydrous sodium sulfate drying, filter, filtrate is concentrated, column chromatography separating purification (taking sherwood oil: ethyl acetate (v/v)=10: 1 is as eluent), obtains 4-(the iodo-1H-pyrazol-1-yl of 4-) piperidines-1-carboxylic acid tert-butyl ester (21.7g) yield: 64%.MS m/z[ESI]：378.1[M+1]。
Step 3:4-(4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) piperidines-1-carboxylic acid tert-butyl ester
By 4-(the iodo-1H-pyrazol-1-yl of 4-) piperidines-1-carboxylic acid tert-butyl ester (7.54g, 20mol), connection pinacol borate (7.56g, 30mmol), Pd (dppf) Cl 2(732mg, 1mmol) and Glacial acetic acid potassium (4.90g, 50mmol) are added in dry diox (200mL), nitrogen replacement, and 100 DEG C are reacted 3 hours.Cooling rear silica gel column chromatography separates, and obtains 4-(4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) piperidines-1-carboxylic acid tert-butyl ester (4.83g), yield: 64%.MSm/z[ESI]：378.3[M+1]。
intermediate 4:1-(2-chloropyridine-4-yl)-3-(dimethylamino) third-2-alkene-1-ketone
The chloro-N-methoxyl group-N-of step 1:2-methyl Isonicotinamide
Room temperature under stirring, adds N, N '-carbonyl dimidazoles (17.0g, 0.105mol) in the dichloromethane solution (250mL) of 2-chloroisonicotinic acid (18.0g, 0.115mol) in batches.Add rear stirring 0.5 hour, then add rapidly N, O-dimethyl hydroxylamine (10.2g, 0.167mol), reaction solution stirred overnight at room temperature.In reaction solution, add 200mL ether, washing, dry, concentrated, obtains 2-chloro-N-methoxyl group-N-methyl Isonicotinamide (18.0g), yield: 78%.MS m/z[ESI]：201.0[M+1]。
Step 2:1-(2-chloropyridine-4-yl) ethyl ketone
At 0 DEG C, under agitation condition, 3M methyl-magnesium-bromide (50mL, 150mmol) is added dropwise to the chloro-N-methoxyl group-N-of 2-methyl Isonicotinamide (10.0g, in anhydrous tetrahydrofuran solution 50mmol) (50mL), finish rear stirred overnight at room temperature.Reaction solution saturated ammonium chloride solution cancellation, ethyl acetate extraction, dry, concentrated, column chromatography separating purification, obtains 1-(2-chloropyridine-4-yl) ethyl ketone (7.5g), yield 96%.MS m/z[ESI]：156.0[M+1]。
Step 3:1-(2-chloropyridine-4-yl)-3-(dimethylamino) third-2-alkene-1-ketone
1-(2-chloropyridine-4-yl) ethyl ketone (7.5g, 48mmol) joins in 40mL DMFDMA, 100 DEG C of stirring reactions 2 hours.In the cooling rear impouring 500mL sherwood oil of reaction solution, filter, ether obtains 1-(2-chloropyridine-4-yl)-3-(dimethylamino) third-2-alkene-1-ketone (7.4g), yield: 74% after washing, being dried.MS m/z[ESI]：211.1[M+1]。
intermediate 5:3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-PA
Step 1:1, the chloro-2-of 3-bis-(1-bromotrifluoromethane)-4-fluorobenzene
0 DEG C, under agitation condition, to triphenylphosphine (27.8g, in dichloromethane solution (200mL) 0.106mol), slowly drip bromine (16.8g, 0.105mol), dropwise rear stirring 10 minutes, continue wherein to drip 1-(2, the chloro-3-fluorophenyl of 6-bis-) ethanol (20.9g, 0.10mol).Dropwise rear stirring 30 minutes.Add ethanol cancellation reaction, reaction solution is poured in saturated sodium bicarbonate solution, with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filters, and filtrate is concentrated, column chromatography separating purification, obtain the chloro-2-of 1,3-bis-(1-bromotrifluoromethane)-4-fluorobenzene (25.8g), yield: 95%. 1H-NMR(400MHz，CDCl 3)：δ＝7.28(m，1H)，7.05(t，1H)，5.97(q，1H)，2.16(d，3H)。
The bromo-3-of step 2:5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-PA
Under room temperature, 1, the chloro-2-of 3-bis-(1-bromotrifluoromethane)-4-fluorobenzene (25.8g, 95mmol), 2-amino-3 hydroxyl-5-bromopyridine (28.7g, 152mmol) and salt of wormwood (26.2g, 190mmol) join (400mL) in DMF, after finishing, under nitrogen atmosphere, react 6 hours.Reaction solution is concentrated, add methylene dichloride, washing, dry, concentrated, column chromatography separating purification, obtains the bromo-3-of 5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-PA (15.2g), yield: 42%.MSm/z[ESI]：380.9[M+1]。
Step 3:3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-PA
By bromo-5-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-PA (7.6g, 20mol), connection pinacol borate (7.56g, 30mmol), Pd (dppf) Cl 2(732mg, 1mmol) and Glacial acetic acid potassium (4.90g, 50mmol) are added in dry diox (200mL), nitrogen replacement, and 100 DEG C are reacted 4 hours.Cooling rear silica gel column chromatography separates, and obtains 3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-PA (5.12g), yield: 60%.MS m/z[ESI]：427.1[M+1]。
intermediate 6:(R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-PA
Step 1:(R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-2-nitropyridine
(S)-1-(2, the chloro-3-fluorophenyl of 6-bis-) ethanol (20.9g, 0.10mol) be dissolved in 200mL anhydrous tetrahydro furan, under nitrogen atmosphere, add successively 3-hydroxyl-2-nitropyridine (16.0g, 0.11mol) and triphenylphosphine (40.0g, 0.15mol), reaction solution at room temperature stirs 1 hour.Be chilled to 0 DEG C, drip DIAD (40mL, 0.15mol), finish rear stirring 12 hours.Boil off solvent, oily matter silica gel column chromatography separates to obtain (R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-2-nitropyridine (20.2g), yield: 61%.
Step 2:(R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-PA
0 DEG C, under agitation condition, to (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-2-nitropyridine (20.0g, in ethanolic soln (300mL) 60mmol), add 2M hydrochloric acid 15mL, reduced iron powder (27g, 480mmol).Finish reacting by heating 12 hours.Be cooled to room temperature, filter, filtrate is concentrated, obtains (R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-PA (17.0g) and is directly used in next step, yield: 94%.MS m/z[ESI]：301.0[M+1]。
Step 3:(R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) the bromo-PA of-5-
0 DEG C, under agitation condition, to (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-PA (15.0g, in acetonitrile solution (200mL) 50mmol), add bromo-succinimide (10g, 56mmol) in batches.Finish 0 DEG C of reaction 1 hour.Boil off solvent, add methylene dichloride, saturated sodium bicarbonate solution is washed, dry, after concentrated, silica gel column chromatography separates to obtain (R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) bromo-PA of-5-(9.88g), yield: 52%.MS m/z[ESI]：380.9[M+1]。
Step 4:(R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-PA
By (R)-3-(1-(2,-bis-chloro-3-fluorophenyls) oxyethyl group) the bromo-PA (7.6g of-5-, 20mmol), connection pinacol borate (7.56g, 30mmol), Pd (dppf) Cl 2(732mg, 1mmol) and Glacial acetic acid potassium (4.90g, 50mmol) are added in dry diox (200mL), nitrogen replacement, and 100 DEG C are reacted 4 hours.Cooling rear silica gel column chromatography separates, obtain (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-PA (5.46g), yield: 64%.MS m/z[ESI]：427.1[M+1]。
the bromo-2-of intermediate 7:5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine
Step 1:2-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine
Sodium hydride (600mg, 60%, 15mmol) add N-sec.-propyl piperazine (1.27g, anhydrous N 10mmol), in dinethylformamide solution (60mL), stir and add 2-chloro-4-methoxy pyrimidine (1.44g, 10mmol) after 10 minutes, after finishing, continue reaction 3 hours at 80 DEG C.Boil off solvent, oily matter silica gel column chromatography separates to obtain 2-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine (1.75g), yield: 74%.MS m/z[ESI]：237.2[M+1]。
The bromo-2-of step 2:5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine
0 DEG C, under agitation condition, in the acetonitrile solution (50mL) of 2-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine (1.65g, 7mmol), add bromo-succinimide (1.37g, 7.7mmol) in batches.Finish room temperature reaction 2 hours.Boil off solvent, add methylene dichloride, saturated sodium bicarbonate solution is washed, dry, and concentrated rear silica gel column chromatography separates to obtain the bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine (1.58g), yield: 72%.MS m/z[ESI]：315.1[M+1]。
intermediate 8:1-(the bromo-3-Methoxy Pyridine-2-of 5-yl)-4-methylpiperazine
The chloro-3-Methoxy Pyridine of step 1:2-
2-chloro-3-hydroxyl pyridine (2.59g, 20mmol), methyl iodide (2.98g, 21mmol) and salt of wormwood (5.52g, 40mmol) add in DMF (50mL), reaction solution stirs 4 hours at 60 DEG C.In cooling falling back, be extracted with ethyl acetate, dry, boil off solvent, silica gel column chromatography separates and obtains the chloro-3-Methoxy Pyridine of 2-(2.58g), yield: 90%.MS m/z[ESI]：144.0[M+1]。
Step 2:1-(3-methoxyl group-pyridine-2-yl)-4-methylpiperazine
By chloro-2-3-Methoxy Pyridine (2.58g, 18mmol), N methyl piperazine (2.7g, 27mmol), Pd 2(dba) 3(824mg, 0.9mmol), BINAP (1.12g, 1.8mmol) and cesium carbonate (14.4g, 45mmol) add in dry toluene (200mL), under nitrogen atmosphere, reflux 16 hours, reacting liquid filtering, after concentrated, silica gel column chromatography separates to obtain 1-(3-methoxyl group-pyridine-2-yl)-4-methylpiperazine (1.71g), yield: 46%.MS m/z[ESI]：208.1[M+1]。
Step 3:1-(the bromo-3-methoxyl group-pyridine-2-of 5-yl)-4-methylpiperazine
0 DEG C, under agitation condition, in the acetonitrile solution (50mL) of 1-(3-methoxyl group-pyridine-2-yl)-4-methylpiperazine (1.66g, 8mmol), add bromo-succinimide (1.57g, 8.8mmol) in batches.Finish room temperature reaction 2 hours.Boil off solvent, add methylene dichloride, saturated sodium bicarbonate solution is washed, dry, and concentrated rear silica gel column chromatography separates to obtain 1-(the bromo-3-methoxyl group-pyridine-2-of 5-yl)-4-methylpiperazine (1.58g), yield: 69%.MS m/z[ESI]：286.1[M+1]。
intermediate 9:1-(the bromo-4-methoxyl group-pyridine-2-of 5-yl)-4-methylpiperazine
Step 1:1-(4-methoxyl group-pyridine-2-yl)-4-methylpiperazine
With reference to the method for step 2 in intermediate 8, with the chloro-3-Methoxy Pyridine of 2-chloro-4-methoxy pyridine replacement 2-, make target compound, yield: 51%.MS m/z[ESI]：208.1[M+1]。
Step 2:1-(the bromo-4-methoxyl group-pyridine-2-of 5-yl)-4-methylpiperazine
With reference to the method for step 3 in intermediate 8, with 1-(4-methoxyl group-pyridine-2-yl)-4-methylpiperazine replacement 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, make target compound, yield: 83%.MS m/z[ESI]：286.1[M+1]。
intermediate 10:(S)-1-(the bromo-4-methoxypyridine-2-of 5-yl)-2,4-lupetazin
Step 1:(S)-1-(4-methoxypyridine-2-yl)-2,4-lupetazin
With reference to the method for step 2 in intermediate 8, with the chloro-3-Methoxy Pyridine of 2-chloro-4-methoxy pyridine replacement 2-, with (S)-1,3-lupetazin replaces N methyl piperazine, makes target compound, yield: 43%.MS m/z[ESI]：222.2[M+1]。
Step 2:(S)-1-(the bromo-4-methoxypyridine-2-of 5-yl)-2,4-lupetazin
With reference to the method for step 3 in intermediate 8, with (S)-1-(4-methoxypyridine-2-yl)-2,4-lupetazin replaces 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, makes target compound, yield: 80%.MS m/z[ESI]：300.1[M+1]。
intermediate 11:(R)-1-(the bromo-4-methoxypyridine-2-of 5-yl)-2,4-lupetazin
Step 1:(R)-1-(4-methoxypyridine-2-yl)-2,4-lupetazin
With reference to the method for step 2 in intermediate 8, with the chloro-3-Methoxy Pyridine of 2-chloro-4-methoxy pyridine replacement 2-, with (R)-1,3-lupetazin replaces N methyl piperazine, makes target compound, yield: 42%.MS m/z[ESI]：222.2[M+1]。
Step 2:(R)-1-(the bromo-4-methoxypyridine-2-of 5-yl)-2,4-lupetazin
With reference to the method for step 3 in intermediate 8, with (R)-1-(4-methoxypyridine-2-yl)-2,4-lupetazin replaces 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, makes target compound, yield: 82%.MS m/z[ESI]：300.1[M+1]。
intermediate 12:(S)-1-(the bromo-3-Methoxy Pyridine-2-of 5-yl)-2,4-lupetazin
Step 1:(S)-1-(3-Methoxy Pyridine-2-yl)-2,4-lupetazin
With reference to the method for step 2 in intermediate 8, with (S)-1,3-lupetazin replaces N methyl piperazine, makes target compound, yield: 43%.MS m/z[ESI]：222.2[M+1]。
Step 2:(S)-1-(the bromo-3-Methoxy Pyridine-2-of 5-yl)-2,4-lupetazin
With reference to the method for step 3 in intermediate 8, with (S)-1-(3-Methoxy Pyridine-2-yl)-2,4-lupetazin replaces 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, makes target compound, yield: 80%.MS m/z[ESI]：300.1[M+1]。
intermediate 13:(S)-1-(the bromo-4-methoxypyridine-2-of 5-yl)-2-methyl-4-(1-methyl piperidine-4-yl) piperazine
Step 1:(S)-4-benzyl-3-methyl isophthalic acid-tert-butoxycarbonyl-piperazine
(S)-3-methyl isophthalic acid-tert-butoxycarbonyl-piperazine (10.0g, 50mmol), bromobenzyl (8.89g, 52mmol) and salt of wormwood (13.8g, 100mmol) join in acetonitrile (200mL), reflux 2 hours.Boil off solvent, add ethyl acetate, washing, dry, concentrated rear silica gel column chromatography separates to obtain (S)-4-benzyl-3-methyl isophthalic acid-tert-butoxycarbonyl-piperazine (12.2g), yield: 84%.MS m/z[ESI]：291.2[M+1]。
Step 2:(S)-1-benzyl-2-methylpiperazine
(S)-4-benzyl-3-methyl isophthalic acid-tert-butoxycarbonyl-piperazine (11.6g, 40mmol) is dissolved in methylene dichloride (100mL), splashes into trifluoroacetic acid (20mL), stir 30 minutes.Under ice bath, be greater than 13 with strong caustic adjust pH, be extracted with ethyl acetate, dry, after concentrating, obtain (S)-1-benzyl-2-methylpiperazine (6.84g) and be directly used in next step, yield: 90%.MSm/z[ESI]：191.2[M+1]。
Step 3:(S)-1-benzyl-2-methyl-4-(1-methyl piperidine-4-yl) piperazine
By (S)-1-benzyl-2-methylpiperazine (6.84g, 36mmol), N-methyl-4-piperidone (4.87g, 43mmol) and Glacial acetic acid (4.32g, 72mmol) add successively in dehydrated alcohol (100mL), stir and be chilled to 0 DEG C after 1 hour, add sodium triacetoxy borohydride (31.6g in batches, 150mmol), room temperature reaction 6 hours, boil off solvent, add acetic acid ethyl dissolution, washing, dry, after concentrated, silica gel column chromatography separates to obtain (S)-1-benzyl-2-methyl-4-(1-methyl piperidine-4-yl) piperazine (7.86g), yield: 76%.MS m/z[ESI]：288.2[M+1]。
Step 4:(S)-3-methyl isophthalic acid-(1-methyl piperidine-4-yl) piperazine
(S)-1-benzyl-2-methyl-4-(1-methyl piperidine-4-yl) piperazine (7.19g, 25mmol) is dissolved in methyl alcohol (100mL),
Add palladium carbon (1g, 10%), under hydrogen atmosphere, stir and spend the night, filter, after filtrate is concentrated, obtain (S)-3-methyl isophthalic acid-(1-methyl piperidine-4-yl) piperazine (4.64g), yield: 94%.MS m/z[ESI]：198.2[M+1]。
Step 5:(S)-1-(4-methoxypyridine-2-yl)-2-methyl-4-(1-methyl piperidine-4-yl) piperazine
With reference to the method for step 2 in intermediate 8, with the chloro-3-Methoxy Pyridine of 2-chloro-4-methoxy pyridine replacement 2-, with (S)-2-methyl-4-(1-methyl piperidine-4-yl) piperazine replacement N methyl piperazine, make target compound, yield: 37%.MSm/z[ESI]：305.2[M+1]。
Step 6:(S)-1-(the bromo-4-methoxypyridine-2-of 5-yl)-2-methyl-4-(1-methyl piperidine-4-yl) piperazine
With reference to the method for step 3 in intermediate 8, with (S)-1-(4-methoxypyridine-2-yl)-2-methyl-4-(1-methyl piperidine-4-yl) piperazine replacement 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, make target compound, yield: 62%.MSm/z[ESI]：383.1[M+1]。
intermediate 14:(S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
Step 1:(S)-4-(4-methoxypyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 2 in intermediate 8, replace 2-chloro-3-Methoxy Pyridine with 2-chloro-4-methoxy pyridine, replace N methyl piperazine with (S)-3-methyl isophthalic acid-tert-butoxycarbonyl-piperazine, replace cesium carbonate with potassium tert.-butoxide, make target compound, yield: 50%.MS m/z[ESI]：308.2[M+1]。
Step 2:(S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 3 in intermediate 8, with (S)-4-(4-methoxypyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, make target compound, yield: 75%.MS m/z[ESI]：386.1[M+1]。1H-NMR(400MHz，CDCl3)：δ＝8.104(s，1H)，6.030(s，1H)，4.60-3.85(br，7H)，3.20-2.90(br，3H)，1.135(d，J＝6.8Hz，3H)。
intermediate 15:4-(the bromo-4-methoxypyridine-2-of 5-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
Step 1:4-(trifluoro-methanesulfonyl oxy)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
1-tertbutyloxycarbonyl-4-piperidone (22.8g; 115mmol) be dissolved in 150mL anhydrous tetrahydro furan; be chilled to-78 DEG C; drip the tetrahydrofuran solution (100mL of N-Lithiodiisopropylamide; 126mmol), finish and stir 30 minutes, then drip two (trifyl) aniline (45.0g; tetrahydrofuran solution (100mL) 126mmol), rises to stirred overnight at room temperature.Boil off solvent, add ether dissolution, wash with 2M sodium hydroxide solution, dry, concentrated rear pillar chromatographic separation obtains 4-(trifluoro-methanesulfonyl oxy)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (23.4g), yield: 61%.
Step 2:4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
By 4-(trifluoro-methanesulfonyl oxy)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (23.2g, 70mmol), connection pinacol borate (25.4g, 100mmol), Pd (dppf) Cl 2(2.93g, 4mmol) and Glacial acetic acid potassium (13.7g, 140mmol) are added in dry diox (500mL), nitrogen replacement, and 100 DEG C are reacted 4 hours.Cooling rear silica gel column chromatography separates, and obtains 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (13.0g), yield: 60%.
The bromo-4-methoxyl group-PA of step 3:5-
0 DEG C, under agitation condition, in the acetonitrile solution (500mL) of 4-methoxyl group-PA (12.4g, 100mmol), add bromo-succinimide (17.8g, 100mmol) in batches.Finish room temperature reaction 1 hour.Boil off solvent, add methylene dichloride, saturated sodium bicarbonate solution is washed, dry, obtains the bromo-4-methoxyl group-PA of 5-(20.3g) and is directly used in next step, yield: 100% after concentrating.MS m/z[ESI]：203.0[M+1]。
Step 4:2, the bromo-4-methoxypyridine of 5-bis-
-10 DEG C, under agitation condition, bromo-5-4-methoxyl group-PA (20.3g, 100mmol) is dissolved in 40% Hydrogen bromide (60mL) and 40mL water, be added dropwise to Sodium Nitrite (17.3g, 250mmol) and be dissolved in the solution being made in 25mL water.Under low temperature, stir 30 minutes, splash into bromine (48.0g, 300mmol) stirring reaction 2 hours.Reaction solution, is extracted with ethyl acetate to being greater than 12 with strong caustic adjust pH, dry, after filtrate is concentrated silica gel column chromatography separate 2, the bromo-4-methoxypyridine of 5-bis-(13.8g), yield: 52%.MS m/z[ESI]：267.9[M+1]。
Step 5:4-(the bromo-4-methoxypyridine-2-of 5-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
By 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (3.09g, 10mol), 2, the bromo-4-methoxypyridine of 5-bis-(2.67g, 10mmol), tetrakis triphenylphosphine palladium (578mg, 0.5mmol) and salt of wormwood (3.34g, 24mmol) be added in diox (50mL) and water (10mL), nitrogen replacement, 100 DEG C of reactions are spent the night.Cooling rear silica gel column chromatography separates, and obtains 4-(the bromo-4-methoxypyridine-2-of 5-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (1.55g), yield: 42%.MS m/z[ESI]：369.1[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.49(s，1H)，7.26(s，1H)，6.58(s，1H)，4.13(t，2H)，3.97(s，3H)，2.62(d，2H)，1.49(s，9H)。
the chloro-3-Methoxy Pyridine of the bromo-2-of intermediate 16:5-
The bromo-2-chlorine-3-aminopyridine of step 1:5-
By the chloro-3-nitropyridine of bromo-5-2-(2.38g, 10mmol) be dissolved in methyl alcohol (50mL), add Raney's nickel (0.5g), under hydrogen atmosphere, stir and spend the night, filtering Raney's nickel, filtrate is concentrated that the bromo-2-chlorine-3-aminopyridine of 5-(2.08g) is directly used in next step, yield: 100%.MS m/z[ESI]：208.9[M+1]。
The bromo-2-chloro-3-hydroxyl of step 2:5-pyridine
0 DEG C, under agitation condition, by bromo-5-2-chlorine-3-aminopyridine (2.08g, 10mmol) be dissolved in 4M sulfuric acid (50mL), be added dropwise to Sodium Nitrite (760mg, 11mmol) be dissolved in 5mL water join solution, stir and after 30 minutes, be warming up to 80 DEG C and stir again two hours.Coolingly be adjusted to pH7-8 by strong caustic afterwards, filter the solid of separating out, washing and drying obtains the bromo-2-chloro-3-hydroxyl of 5-pyridine (1.88g), yield: 90%.MS m/z[ESI]：209.9[M+1]。
The chloro-3-Methoxy Pyridine of the bromo-2-of step 3:5-
Bromo-5-2-chloro-3-hydroxyl pyridine (1.88g, 9mmol), methyl iodide (1.42g, 10mmol) and salt of wormwood (2.76g, 20mmol) are added in acetonitrile, 80 DEG C are reacted 4 hours, steam solvent, add methylene dichloride to dissolve, washing, dry
Concentrated, silica gel column chromatography separates to obtain the chloro-3-Methoxy Pyridine of the bromo-2-of 5-(1.62g), yield: 81%.MS m/z[ESI]：223.9[M+1]。
intermediate 17:1-(1-(4-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridine-2-yl) piperidin-4-yl)-4-methylpiperazine
Step 1:4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid tert-butyl ester
By 1-tertbutyloxycarbonyl-4-piperidone (4.0g, 20mmol), N methyl piperazine (2.4g, 24mmol) and Glacial acetic acid (2.4g, 40mmol) add successively in dehydrated alcohol (100mL), stir and be chilled to 0 DEG C after 1 hour, add sodium triacetoxy borohydride (17.0g in batches, 80mmol), room temperature reaction 6 hours, boils off solvent, adds acetic acid ethyl dissolution, washing, dry, concentrated rear silica gel column chromatography separates to obtain 4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid tert-butyl ester (4.25g), yield: 75%.MS m/z[ESI]：284.2[M+1]。
Step 2:1-methyl-4-(piperidin-4-yl) piperazine hydrochloride
4-(4-methylpiperazine-1-yl) piperidines-1-carboxylic acid tert-butyl ester (4.25g, 15mmol) is dissolved in methyl alcohol (100mL), passes into hydrogen chloride gas to saturated, return stirring 1 hour.After being spin-dried for solvent, must be directly used in next step, yield by 1-methyl-4-(piperidin-4-yl) piperazine hydrochloride (4.39g): 100%.MS m/z[ESI]：184.2[M+1]。
Step 3:1-(1-(4-methoxypyridine-2-yl) piperidin-4-yl)-4-methylpiperazine
With reference to the method for step 2 in intermediate 8, with the chloro-3-Methoxy Pyridine of 2-chloro-4-methoxy pyridine replacement 2-, with 1-methyl-4-(piperidin-4-yl) piperazine hydrochloride replacement N methyl piperazine, add 3 equivalent cesium carbonates, make target compound, yield: 58%.MSm/z[ESI]：291.2[M+1]。
Step 4:1-(1-(the bromo-4-methoxypyridine-2-of 5-yl) piperidin-4-yl)-4-methylpiperazine
With reference to the method for step 3 in intermediate 8, with 1-(1-(4-methoxypyridine-2-yl) piperidin-4-yl)-4-methylpiperazine replacement 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, make target compound, yield: 62%.MS m/z[ESI]：369.1[M+1]。
Step 5:1-(1-(4-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridine-2-yl) piperidin-4-yl)-4-methylpiperazine
With reference to the method for step 3 in intermediate 1, with 1-(1-(the bromo-4-methoxypyridine-2-of 5-yl) piperidin-4-yl)-4-methylpiperazine replacement 4-(3-methoxyl group-4-bromophenyl) piperazine-1-carboxylic acid tert-butyl ester, make target compound, yield: 81%.MSm/z[ESI]：417.3[M+1]。
intermediate 18:4-(the bromo-3-Methoxy Pyridine-2-of 6-yl) piperazine-1-carboxylic acid tert-butyl ester
intermediate 19:4-(the bromo-5-methoxypyridine-2-of 6-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 2 in intermediate 8, with 2, the bromo-3-Methoxy Pyridine of 6-bis-replaces the chloro-3-Methoxy Pyridine of 2-, with N-tert-butoxycarbonyl-piperazine replacement N methyl piperazine, final silica gel column chromatography separates to obtain intermediate 18:4-(the bromo-3-Methoxy Pyridine-2-of 6-yl) piperazine-1-carboxylic acid tert-butyl ester, yield: 21%; And intermediate 19:4-(the bromo-5-methoxypyridine-2-of 6-yl) piperazine-1-carboxylic acid tert-butyl ester, yield: 43%, MS m/z[ESI]: 372.1[M+1].
intermediate 20:4-(5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester
Step 1:4-(5-bromopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in intermediate 1, with 3,5-dibromo pyridine replacement Meta Bromo Anisole, make target compound, yield: 62%.MS m/z[ESI]：342.1[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.208(d，J＝2.4Hz，1H)，8.150(d，J＝1.6Hz，1H)，7.300(t，1H)，3.589(m，4H)，3.187(m，4H)，1.486(s，9H).
Step 2:4-(5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 4 in intermediate 2, with 4-(5-bromopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester replacement 1-(3-methoxyl group-4-bromophenyl)-4-methylpiperazine, make target compound, yield: 26%, MS m/z[ESI]: 390.3[M+1].
intermediate 21:4-(the bromo-4-methoxypyridine-2-of 5-yl) piperazine-2-ketone
Step 1:N-tertbutyloxycarbonyl-N '-(4-methoxypyridine-2-yl) quadrol
With reference to the method for step 2 in intermediate 8, with the chloro-3-Methoxy Pyridine of 2-chloro-4-methoxy pyridine replacement 2-, with N-tertbutyloxycarbonyl quadrol replacement N methyl piperazine, make target compound,
Yield: 53%.MS m/z[ESI]：268.2[M+1]。
Step 2:N-(2-aminoethyl)-4-methoxypyridine-2-amine
N-tertbutyloxycarbonyl-N '-(4-methoxypyridine-2-yl) quadrol (2.66g, 10mmol) is dissolved in methylene dichloride (50mL), splashes into trifluoroacetic acid (10mL), stir 1 hour.Under ice bath, be greater than 13 with strong caustic adjust pH, be extracted with ethyl acetate, dry, concentrated rear silica gel column chromatography separates to obtain N-(2-aminoethyl)-4-methoxypyridine-2-amine (1.27g), yield: 76%.MS m/z[ESI]：168.1[M+1]。
Step 3:4-(4-methoxypyridine-2-yl) piperazine-2-ketone
N-(2-aminoethyl)-4-methoxypyridine-2-amine (1.17g, 7mmol) and Anhydrous potassium carbonate (2.90g, 21mmol) are added in dry acetonitrile, be chilled to 0 DEG C, drip chloroacetyl chloride (790mg, 7mmol).Finish and stir 30 minutes, then reflux 6 hours.Filter, after filtrate is concentrated, silica gel column chromatography separates to obtain 4-(4-methoxypyridine-2-yl) piperazine-2-ketone (855mg), yield: 59%.MS m/z[ESI]：208.1[M+1]。
Step 4:4-(the bromo-4-methoxypyridine-2-of 5-yl) piperazine-2-ketone
With reference to the method for step 3 in intermediate 8, with 4-(4-methoxypyridine-2-yl) piperazine-2-ketone replacement 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, make target compound, yield: 87%.MS m/z[ESI]：286.0[M+1]。
intermediate 22:4-(6-chloro-4-methoxy pyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester
Step 1:2-chloro-4-methoxy pyridine nitric oxide
Chloro-2-4-nitropyridine oxynitride (5.12g, 30mmol) is dissolved in anhydrous methanol (50mL), adds sodium methylate (1.78g, 33mmol), reaction solution refluxes 2 hours.Be spin-dried for solvent, silica gel column chromatography separates to obtain 2-chloro-4-methoxy pyridine nitric oxide (3.35g), yield: 70%.MS m/z[ESI]：160.0[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.312(d，J＝7.6Hz，1H)，7.473(d，J＝3.2Hz，1H)，7.066(m，1H)，3.849(s，3H).
Step 2:2, the chloro-4-methoxypyridine of 6-bis-
2-chloro-4-methoxy pyridine nitric oxide (3.35g, 21mmol) is added in toluene (50mL), splash into phosphorus oxychloride (20mL), reflux 8 hours.In cooling rear impouring trash ice, under ice bath, with sodium hydroxide solution adjust pH 8-9, be extracted with ethyl acetate, dry, concentrated after silica gel column chromatography separate 2, the chloro-4-methoxypyridine of 6-bis-(1.12g), yield: 30%.MSm/z[ESI]：178.0[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.264(s，1H)，6.796(s，1H)，3.875(s，3H).
Step 3:4-(6-chloro-4-methoxy pyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 2 in intermediate 8, with the chloro-3-Methoxy Pyridine of the chloro-4-methoxypyridine replacement 2-of 2,6-bis-, with N-tertbutyloxycarbonyl replacement N methyl piperazine, make target compound, yield: 48%.MS m/z[ESI]：328.1[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝6.266(d，J＝1.6Hz，1H)，5.944(d，J＝1.6Hz，1H)，3.804(s，3H)，3.54-3.47(m，8H)，1.481(s，9H).
intermediate 23:4-(the bromo-4-methoxypyridine-2-of 5-yl) piperazine-1-carboxylic acid tert-butyl ester
Step 1:4-(4-methoxypyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 2 in intermediate 8, with N-tert-butoxycarbonyl-piperazine replacement N methyl piperazine, with the chloro-3-Methoxy Pyridine of 2-chloro-4-methoxy pyridine replacement 2-, make target compound, yield: 79%.MS m/z[ESI]：294.2[M+1]。
Step 2:4-(the bromo-4-methoxypyridine-2-of 5-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 3 in intermediate 8, with 4-(4-methoxypyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester replacement 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, make target compound, yield: 87%.MS m/z[ESI]：372.1[M+1]。
intermediate 24:4-(the bromo-5-methoxypyridine-2-of 4-yl) piperazine-1-carboxylic acid tert-butyl ester
intermediate 25:4-(the bromo-5-methoxypyridine-4-of 2-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 2 in intermediate 8, with 2, the bromo-5-methoxypyridine of 4-bis-replaces the chloro-3-Methoxy Pyridine of 2-, with N-tert-butoxycarbonyl-piperazine replacement N methyl piperazine, final silica gel column chromatography separates to obtain intermediate 24:4-(the bromo-5-methoxypyridine-2-of 4-yl) piperazine-1-carboxylic acid tert-butyl ester, yield: 37%; And intermediate 25:4-(the bromo-5-methoxypyridine-4-of 2-yl) piperazine-1-carboxylic acid tert-butyl ester, yield: 21%, MS m/z[ESI]: 372.1[M+1].
intermediate 26:3-(1-(2-difluoromethyl-5-fluorophenyl) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-PA
Step 1:2-difluoromethyl-5-bromofluorobenzene
The fluoro-phenyl aldehyde of the bromo-4-of 2-(8.04g, 40mmol) joins in methylene dichloride (80mL), is chilled to 0 DEG C, splash into diethylin sulfur trifluoride (DAST) (7.96mL, 60mmol), stir 30 minutes under low temperature, backflow is spent the night.Add methyl alcohol cancellation reaction, washing, dry, concentrated rear silica gel column chromatography separates to obtain 2-difluoromethyl-5-bromofluorobenzene (8.36g), yield: 93%. 1H-NMR(400MHz，CDCl 3)：δ＝7.579(m，1H)，7.385(m，1H)，7.091(m，1H)，6.993-6.720(t，J＝54.6Hz，1H).
Step 2:2-difluoromethyl-5-fluoro acetophenone
2-difluoromethyl-5-bromofluorobenzene (8.36g, 37.5mmol) is dissolved in anhydrous diethyl ether (100mL), is chilled to-78 DEG C, under nitrogen atmosphere, splash into 2.4M n-butyllithium solution (18.7mL, 45mmol), stir 1 hour.Keep-78 DEG C, splash into N-methyl-N-methoxyl acetamide (7.73g, 75mmol), stir 2 hours.After rising to room temperature, wash by saturated salt, be extracted with ethyl acetate, dry, concentrated rear silica gel column chromatography separates to obtain 2-difluoromethyl-5-fluoro acetophenone (4.2g), yield: 60%. 1H-NMR(400MHz，CDCl 3)：δ＝7.45-7.40(m，1H)，7.31-7.27(m，1H)，7.20-7.12(m，1H)，6.78-6.50(t，J＝56Hz，1H)，2.42(s，3H).
Step 3:1-(2-difluoromethyl-5-fluorophenyl) ethanol
By 2-difluoromethyl-5-fluoro acetophenone (3.0g, 16mmol) add in dehydrated alcohol (100mL), be chilled to 0 DEG C, add sodium borohydride (1.22g in batches, 32mmol), room temperature reaction 4 hours, boils off solvent, adds acetic acid ethyl dissolution, washing, dry, concentrated rear silica gel column chromatography separates to obtain 1-(2-difluoromethyl-5-fluorophenyl) ethanol (1.82g), yield: 60%. 1H-NMR(400MHz，CDCl 3)：δ＝7.598-7.562(m，1H)，7.292-7.262(m，1H)，7.20-7.15(m，1H)， 7.124-6.848(t，J＝45.2Hz，1H)，5.197(t，J＝6.4Hz，1H)，1.97(s，1H)，1.515(d，J＝6.4Hz，3H).
Step 4:2-(1-bromotrifluoromethane)-1-(difluoromethyl)-4-fluorobenzene
Triphenylphosphine (1.57g, 6mmol) is dissolved in dichloro methyl alcohol (30mL), is chilled to 0 DEG C, splash into bromine (1.08g, 6mmol), stir 10 minutes.Splash into 1-(2-difluoromethyl-5-fluorophenyl) ethanol (950mg, methylene dichloride (5mL) solution 5mmol), stir 30 minutes, washing, dry, after concentrated, silica gel column chromatography separates to obtain 2-(1-bromotrifluoromethane)-1-(difluoromethyl)-4-fluorobenzene (1.25g), yield: 100%.
The bromo-3-of step 5:5-(1-(2-(difluoromethyl)-5-fluorophenyl) oxyethyl group)-PA
With reference to the method for step 2 in intermediate 5, with 2-(1-bromotrifluoromethane)-1-(difluoromethyl)-4-fluorobenzene replacement chloro-2-of 1,3-bis-(1-bromotrifluoromethane)-4-fluorobenzene, make target compound, yield: 62%.MS m/z[ESI]：361.0[M+1]。
Step 6:3-(1-(2-difluoromethyl-5-fluorophenyl) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-PA
With reference to the method for step 3 in intermediate 5, with the bromo-3-of 5-, (1-(2-(difluoromethyl)-5-fluorophenyl) oxyethyl group-PA replaces the bromo-3-of 5-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-PA, make target compound, yield: 54%.MSm/z[ESI]：409.2[M+1]。
intermediate 27:4-(the bromo-3-Methoxy Pyridine-2-of 6-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With reference to the method for step 5 in intermediate 15, with 2, the bromo-3-Methoxy Pyridine of 6-bis-replaces 2, the bromo-4-methoxypyridine of 5-bis-, final silica gel column chromatography separates to obtain intermediate 27:4-(the bromo-3-Methoxy Pyridine-2-of 6-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester, yield: 39%, MS m/z[ESI]: 369.1[M+1].
intermediate 28:(S)-4-(the bromo-5-methoxypyridine-2-of 6-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 2 in intermediate 8, with 2, the bromo-3-Methoxy Pyridine of 6-bis-replaces the chloro-3-Methoxy Pyridine of 2-, with (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement N methyl piperazine, final silica gel column chromatography separates to obtain (S)-4-(the bromo-5-methoxypyridine-2-of 6-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, yield: 38%, MS m/z[ESI]: 386.1[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝7.124(d，J＝2.0Hz，1H)，6.470(d，J＝8.4Hz，1H)，4.20-3.85(br，3H)，3.825(s，3H)，3.80-3.70(br，1H)，3.162(d，J＝10.8Hz，1H)，3.085(t，J＝6.8Hz，1H)，3.03-2.87(br，1H)，1.482(s， 9H)，1.088(d，J＝6.8Hz，3H)。
intermediate 29:4-(the bromo-4-methoxypyridine-3-of 5-yl) piperazine-1-carboxylic acid tert-butyl ester
Step 1:3,4,5-pyridinium tribromide
Bromo-3,5-bis-4-pyridone (13.7g, 54mmol) and phosphorus pentabromide (11.62g, 27mmol) are placed in to tube sealing, in 180 DEG C of reactions 3 hours.In cooling rear impouring trash ice, under ice bath, with sodium hydroxide solution adjust pH to 8, be extracted with ethyl acetate, dry, concentrated after silica gel column chromatography separate 3,4,5-pyridinium tribromide (12.1g), yield: 71%.MSm/z[ESI]：315.8[M+1]。
Step 2:3, the bromo-4-methoxypyridine of 5-bis-
3,4,5-pyridinium tribromide (12.1g, 38.3mmol) is added in tetrahydrofuran (THF) (50mL), add sodium methylate (3.11g,
57.5mmol), room temperature reaction 18 hours.Add water (100mL), be extracted with ethyl acetate, dry, concentrated after silica gel column chromatography separate 3, the bromo-4-methoxypyridine of 5-bis-(6.44g), yield: 63%.MS m/z[ESI]：267.9[M+1]。
Step 3:4-(the bromo-4-methoxypyridine-3-of 5-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 2 in intermediate 8, with the chloro-3-Methoxy Pyridine of the bromo-4-methoxypyridine replacement 2-of 3,5-bis-, with N-tertbutyloxycarbonyl quadrol replacement N methyl piperazine, make target compound, yield: 53%.MS m/z[ESI]：372.1[M+1]。
intermediate 30:4-(the bromo-4-methoxypyridine-2-of 5-yl) morpholine
Step 1:4-(4-methoxypyridine-2-yl) morpholine
With reference to the method for step 2 in intermediate 8, for N methyl piperazine, with the chloro-3-Methoxy Pyridine of 2-chloro-4-methoxy pyridine replacement 2-, make target compound, yield: 76% with morpholino.MS m/z[ESI]：195.1[M+1]。
Step 2:4-(the bromo-4-methoxypyridine-2-of 5-yl) morpholine
With reference to the method for step 3 in intermediate 8, for 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, make target compound, yield: 91% with 4-(4-methoxypyridine-2-yl) morpholino.MS m/z[ESI]：273.0[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.119(s，1H)，6.080(s，1H)，3.905(s，3H)，3.816(t，J＝4.8Hz，4H)，3.478(t，J＝5.0 Hz，4H)。
intermediate 31:(S)-4-(the bromo-3-Methoxy Pyridine-2-of 6-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
In intermediate 28, final silica gel column chromatography separates isomer (S)-4-(the bromo-3-Methoxy Pyridine-2-of 6-the yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester that simultaneously obtains intermediate 28, yield: 16.5%, MS m/z[ESI]: 386.1[M+1].
the bromo-2-chloro-3-ethoxy of intermediate 32:5-pyridine
With reference to step 3 in intermediate 16, replace methyl iodide with iodoethane, make the bromo-2-chloro-3-ethoxy of 5-pyridine, yield: 100%.MS m/z[ESI]：237.9[M+1]。
intermediate 33:5-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
Step 1:1-tertbutyloxycarbonyl-3-methyl-4-piperidone
1-tertbutyloxycarbonyl-4-piperidone (5.0g, 25mmol) be dissolved in 50mL anhydrous tetrahydro furan, be chilled to 0 DEG C, add 70% sodium hydride (857mg, 25mmol), finish and stir 30 minutes, then drip methyl iodide (3.55g, 25mmol), rise to stirred overnight at room temperature.Add water, be extracted with ethyl acetate, dry, concentrated rear pillar chromatographic separation obtains 1-tertbutyloxycarbonyl-3-methyl-4-piperidone (1.12g), yield: 21%.
Step 2:5-methyl-4-(trifluoro-methanesulfonyl oxy)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With reference to step 1 in intermediate 15, with 1-tertbutyloxycarbonyl-3-methyl-4-piperidone replacement 1-tertbutyloxycarbonyl-4-piperidone, make 5-methyl-4-(trifluoro-methanesulfonyl oxy)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester, yield: 46%.
Step 3:5-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With reference to step 2 in intermediate 15, with 5-methyl-4-(trifluoro-methanesulfonyl oxy)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester replaces 4-(trifluoro-methanesulfonyl oxy)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester, obtain 5-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester, yield: 29%.
the chloro-3-hydroxyethyl of the bromo-2-of intermediate 34:5-pyridine
With reference to step 3 in intermediate 16, replace methyl iodide with ethylene bromohyrin, make the chloro-3-hydroxyethyl of the bromo-2-of 5-pyridine, yield: 50%.MS m/z[ESI]：253.9[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.094(d，J＝2.0Hz，1H)，7.378(d，J＝2.0Hz，1H)，4.176-4.154(t，J＝4.4Hz，2H)，4.056-4.018(m，2H)，2.055-2.023(t，J＝4.4Hz，1H)。
intermediate 35:(S)-4-(the bromo-4-ethoxy pyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
The chloro-4-ethoxy pyridine of step 1:2-oxynitride
2-chloro-4-nitropyridine oxynitride (5.12g, 30mmol) adds in dehydrated alcohol (50mL), then splashes into the ethanolic soln (50mL) of sodium ethylate (2.04g, 30mmol).At room temperature stir 6 hours.Be spin-dried for, with acetic acid ethyl dissolution, silica gel column chromatography separates and obtains the chloro-4-ethoxy pyridine of 2-oxynitride (4.70g), yield: 90%.MSm/z[ESI]：174.0[M+1]。
The chloro-4-ethoxy pyridine of step 2:2-
By chloro-2-4-ethoxy pyridine oxynitride (2.0g, 11.5mmol), triphenylphosphine (6.0g, 23mmol) add N, in dinethylformamide (80mL), under nitrogen atmosphere, at 135 DEG C, react 6 hours, boil off solvent after silica gel column chromatography separate to obtain the chloro-4-ethoxy pyridine of 2-(0.90g), yield: 50%.MS m/z[ESI]：158.0[M+1]。
Step 3:(S)-4-(4-ethoxy pyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 2 in intermediate 8, with (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement N methyl piperazine, with the chloro-3-Methoxy Pyridine of the chloro-4-ethoxy pyridine replacement 2-of 2-, make target compound, yield: 76%.MSm/z[ESI]：322.2[M+1]。
Step 4:(S)-4-(the bromo-4-ethoxy pyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 3 in intermediate 8, with (S)-4-(4-ethoxy pyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, make target compound, yield: 91%.MS m/z[ESI]：400.1[M+1]。
intermediate 36:4-(2-(the bromo-2-morpholinyl of 5-pyridin-3-yl oxygen) ethyl) morpholine
Step 1:2-(the bromo-2-chloropyridine-3-of 5-base oxygen) ethyl methane sulfonate ester
The bromo-2-of intermediate 34:5-chloro-3-hydroxyethyl pyridine (609mg, 2.41mmol) and triethylamine (487mg, 4.82mmol) add in methylene dichloride (10mL), be chilled to 0 DEG C, splash into methylsulfonyl chloride (387mg, 3.38mmol), stir 2 hours.Washing, dry, concentratedly obtain 2-(the bromo-2-chloropyridine-3-of 5-base oxygen) ethyl methane sulfonate ester (796mg) and be directly used in next step, yield: 100%.MS m/z[ESI]：331.9[M+1]。
Step 2:4-(2-(the bromo-2-morpholinyl of 5-pyridin-3-yl oxygen) ethyl) morpholine
2-(the bromo-2-chloropyridine-3-of 5-base oxygen) ethyl methane sulfonate ester (796mg, 2.41mmol) and sodium carbonate (511mg, 4.82mmol) are added in morpholine (10mL), spend the night at 100 DEG C of stirring reactions.After concentrated, silica gel column chromatography separates (methylene chloride/methanol, 80:1) and obtains 4-(2-(the bromo-2-morpholinyl of 5-pyridin-3-yl oxygen) ethyl) morpholine (820mg), yield: 92%.MSm/z[ESI]：372.1[M+1]。
intermediate 37:(S)-4-(the bromo-4-of 5-(2-morpholine oxyethyl group) pyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
The chloro-4-of step 1:2-(2-morpholine oxyethyl group) pyridine
Hydroxyethyl morpholine (3.15g, 24mmol) adds in dry DMF, and sodium hydride (891mg, 26mmol) is added in batches, stirs 30 minutes.Add again the chloro-4-nitropyridine of 2-(3.17g, 20mmol), at room temperature stir 3 hours.Be spin-dried for, with acetic acid ethyl dissolution, silica gel column chromatography separates and obtains the chloro-4-of 2-(2-morpholine oxyethyl group) pyridine (1.60g), yield: 33%.MS m/z[ESI]：243.1[M+1]。
Step 2:(S)-3-methyl-4-(4-(2-morpholine oxyethyl group) pyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 2 in intermediate 8, with (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement N methyl piperazine, with the chloro-3-Methoxy Pyridine of the chloro-4-of 2-(2-morpholine oxyethyl group) pyridine replacement 2-, make target compound, yield: 36%.MS m/z[ESI]：407.3[M+1]。
Step 3:(S)-4-(the bromo-4-of 5-(2-morpholine oxyethyl group) pyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 3 in intermediate 8, with (S)-3-methyl-4-(4-(2-morpholine oxyethyl group) pyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester replacement 1-(3-Methoxy Pyridine-2-yl)-4-methylpiperazine, make target compound, yield: 71%.MSm/z[ESI]：487.2[M+1]。
the chloro-4-of intermediate 38:2-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) ethynyl) pyridine
The chloro-3-fluorobenzyl bromide of step 1:4-
0 DEG C, under agitation condition, to triphenylphosphine (27.0g, in dichloromethane solution (200mL) 0.103mol), slowly drip bromine (16.5g, 0.103mol), dropwise rear stirring 10 minutes, continue wherein to drip the chloro-3-fluoro benzyl alcohol of 4-(15.8g, 0.098mol).Dropwise rear stirring 30 minutes.Add ethanol cancellation reaction, reaction solution is poured in saturated sodium bicarbonate solution, with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filters, and filtrate is concentrated, column chromatography separating purification, obtains the chloro-3-fluorobenzyl bromide of 4-(18.6g), yield: 85%. 1H-NMR(400MHz，CDCl 3)：δ＝7.27(t，J＝7.9Hz，1H)，7.10(dd，J＝7.9Hz，2.1Hz，1H)，7.04-6.99(m，1H)，4.32(s，2H)。
Step 2:1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles
The chloro-3-fluorobenzyl bromide of 4-(16.0g, 72mmol), pyrazoles (5.35g, 79mmol) and salt of wormwood (20.0g, 145mmol) add in dry DMF, at room temperature stir and spend the night.Be spin-dried for, with acetic acid ethyl dissolution, silica gel column chromatography separates and obtains 1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles (13.7g), yield: 91%.MS m/z[ESI]：211.0[M+1]。
Step 3:1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-2-oxide compound
1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles (9.7g, 46mmol) and urea hydrogen peroxide (9.1g, 97mmol) add in methylene dichloride (200mL), be chilled to 0 DEG C, drip trifluoroacetic anhydride (19.4g, 92mmol), stirring at room temperature 5 hours.Sodium sulfite solution is washed, and extraction, is spin-dried for, and silica gel column chromatography separates and obtains 1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-2-oxide compound (7.30g), yield: 70%.MS m/z[ESI]：227.0[M+1]。
The bromo-1-of step 4:5-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-2-oxide compound
1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-2-oxide compound (5.44g, 24mmol) and salt of wormwood (5.96g, 43mmol) add in methylene dichloride (100mL), be chilled to-80 DEG C, in 2 minutes, drip the bromine (4.0g that is chilled in advance-80 DEG C, dichloromethane solution (10mL) 25mmol) stirs 15 minutes at this temperature, rises to 0 DEG C and stirs 30 minutes again.Sodium sulfite solution is washed, and extraction, is spin-dried for, and silica gel column chromatography separates and obtains the bromo-1-of 5-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-2-oxide compound (6.67g), yield: 91%.MS m/z[ESI]：306.9[M+1]。
The bromo-1-of step 5:5-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles
The bromo-1-of 5-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-2-oxide compound (3.84g, 12.6mmol) add in methylene dichloride (50mL), be chilled to 0 DEG C, drip phosphorus trichloride (3.97g, dichloromethane solution (10mL) 28.9mmol), at this temperature, stir 1 hour, rise to 50 DEG C and stir again 3 hours.The methanol solution (170mL) that adds the sodium-acetate of 1.21M, is spin-dried for, and silica gel column chromatography separates and obtains the bromo-1-of 5-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles (3.10g), yield: 85%.MSm/z[ESI]：290.9[M+1]。
Trimethyl silicon based ethynyl-the 1-of step 6:5-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles
The bromo-1-of 5-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles (2.0g, 6.9mmol), trimethyl silicane ethyl-acetylene (1.0g, 10.4mmol), palladium (155mg, 0.69mmol), X-phos (657mg, 1.38mmol), cesium carbonate (3.4g, 10mmol) and Isosorbide-5-Nitrae-dioxane (20mL) add in microwave reaction pipe, under nitrogen atmosphere in 150 DEG C reaction 3 hours.Be spin-dried for, silica gel column chromatography separates and obtains the trimethyl silicon based ethynyl-1-of 5-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles (510mg), yield: 24%.MSm/z[ESI]：307.1[M+1]。
Step 7:5-ethynyl-1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles
By trimethyl silicon based 5-ethynyl-1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles (510mg, 1.66mmol) and salt of wormwood (460mg, 3.33mmol) add in methyl alcohol (30mL), stirring at room temperature 2 hours, filtering solid, filtrate is spin-dried for, and silica gel column chromatography separates and obtains 5-ethynyl-1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles (350mg), yield: 90%.MSm/z[ESI]：235.0[M+1]。
The chloro-4-of step 8:2-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) ethynyl) pyridine
5-ethynyl-1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles (348mg, 1.48mmol), the chloro-4-trimethyl fluoride sulfonyl of 2-oxygen yl pyridines (1.78mmol), two (triphenylphosphine) palladium chloride (0.148mmol), cuprous iodide (562mg, 2.96mmol) and triethylamine (300mg, 2.96mmol) add N, in dinethylformamide (20mL), under nitrogen atmosphere, spend the night in 70 DEG C of reactions.Be spin-dried for, silica gel column chromatography separates and obtains the chloro-4-of 2-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) ethynyl) pyridine (360 mg), yield: 70%.MS m/z[ESI]：346.0[M+1]。
the bromo-3-of intermediate 39:5-(1-(2-(solutions of dimethyl phosphoryl base)-5-fluorophenyl) oxyethyl group)-PA
Step 1:1-(the bromo-5-fluorophenyl of 2-) ethanol
Under 0 DEG C, nitrogen atmosphere, agitation condition, to the bromo-5-fluorobenzaldehyde of 2-(17.0g, in anhydrous tetrahydrofuran solution (100mL) 0.084mol), slowly drip 3M methyl-magnesium-bromide tetrahydrofuran solution (31mL, 0.093mol), dropwise rear stirring 45 minutes, add wherein saturated ammonium chloride solution cancellation reaction, with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filter, filtrate is concentrated, column chromatography separating purification, obtain 1-(the bromo-5-fluorophenyl of 2-) ethanol (9.0g), yield: 49%.
Step 2:3-(1-(the bromo-5-fluorophenyl of 2-) oxyethyl group)-2-nitropyridine
With reference to the method for intermediate 6 steps 1, with 1-(the bromo-5-fluorophenyl of 2-) ethanol replacement (S)-1-(the chloro-3-fluorophenyl of 2,6-bis-) ethanol, make target compound, yield: 71%.MS m/z[ESI]：341.0[M+1]。
Step 3:3-(1-(2-(solutions of dimethyl phosphoryl base)-5-fluorophenyl) oxyethyl group)-2-nitropyridine
By 3-(1-(the bromo-5-fluorophenyl of 2-) oxyethyl group)-2-nitropyridine (371mg, 1.1mmol), dimethyl oxidation phosphine (94mg, 1.2mmol), palladium (22mg, 0.1mmol), X-phos (95mg, 0.2mmol) and potassiumphosphate (244mg, 1.1mmol) be added in DMF (10mL), nitrogen replacement, 130 DEG C are reacted 1 hour.After cooling, be spin-dried for, silica gel column chromatography separates and makes target compound, yield: 35%.MS m/z[ESI]：339.1[M+1]。
Step 4:3-(1-(2-(solutions of dimethyl phosphoryl base)-5-fluorophenyl) oxyethyl group)-PA
With reference to the method for intermediate 6 steps 2; with 3-(1-(2-(solutions of dimethyl phosphoryl base)-5-fluorophenyl) oxyethyl group)-2-nitropyridine replacement (R)-3-(1-(2; the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-2-nitropyridine; make target compound, yield: 73%.MSm/z[ESI]：309.1[M+1]。
The bromo-3-of step 5:5-(1-(2-(solutions of dimethyl phosphoryl base)-5-fluorophenyl) oxyethyl group)-PA
With reference to the method for intermediate 6 steps 3; with 3-(1-(2-(solutions of dimethyl phosphoryl base)-5-fluorophenyl) oxyethyl group)-PA replacement (R)-3-(1-(2; the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-PA; make target compound, yield: 75%.MSm/z[ESI]：387.0[M+1]。
the bromo-3-of intermediate 40:5-(1-(the chloro-5-fluorophenyl of 2-(dimethylamino)-4-) oxyethyl group)-PA
The chloro-4-fluoroaniline of the bromo-5-of step 1:2-
0 DEG C, under agitation condition, in the dichloromethane solution (150mL) of the chloro-4-fluoroaniline of 3-(5.82g, 0.04mol), add N-bromo-succinimide (7.12g, 0.04mol) in batches, finish and stir 30 minutes, filter, filtrate is concentrated, column chromatography separating purification, obtain the chloro-4-fluoroaniline of the bromo-5-of 2-(6.16g), yield: 69%. 1H-NMR(400MHz，CDCl 3)：δ＝7.234(d，J＝8.4Hz，1H)，6.788(d，J＝6.4Hz，1H)，3.982(br，2H)。MS m/z[ESI]：225.9[M+1]。
The fluoro-DMA of the chloro-4-of the bromo-5-of step 2:2-
The chloro-4-fluoroaniline of the bromo-5-of 2-(2.25g, 0.01mol), 40% formaldehyde solution (10mL, 0.133mol) and formic acid (4.6g, 0.1mol) were in 100 DEG C of reactions 3 hours.Add sodium hydroxide solution to strong basicity, with dichloromethane extraction, dry, be spin-dried for, column chromatography separating purification, obtains the fluoro-DMA of the chloro-4-of the bromo-5-of 2-(2.46g), yield: 97%. 1H-NMR(400MHz，CDCl 3)：δ＝7.368(d，J＝8.4Hz，1H)，7.079(d，J＝6.8Hz，1H)，2.748(s，6H)。MS m/z[ESI]：253.9[M+1]。
The chloro-5-fluoro acetophenone of step 3:2-(dimethylamino)-4-
The dry tetrahydrofuran solution (50mL) of the bromo-2-5-fluoro-DMA of chloro-4-(2.46g, 9.7mmol) is chilled to-78 DEG C.Under nitrogen atmosphere, drip 2.5M n-butyllithium solution (4.1mL, 10.2mmol), under low temperature, stir 2 hours, splash into N-methyl-N-methoxyl acetamide (1.00g, 9.7mmol) low temperature and stir 2 hours, rise to room temperature and continue to stir 2 hours.Be spin-dried for, column chromatography separating purification, obtains 2-(two bases) the chloro-5-fluoro acetophenone of-4-(0.66g), yield: 32%. 1H-NMR(400MHz，CDCl 3)：δ＝7.234(d，J＝9.2Hz，1H)，7.032(d，J＝6.0Hz，1H)，2.760(s，6H)，2.597(s，3H)。MS m/z[ESI]：216.0[M+1]。
Step 4:1-(the chloro-5-fluorophenyl of 2-(dimethylamino)-4-) ethanol
2-(dimethylamino)-chloro-5-fluoro acetophenone of 4-(646mg, 3mmol) is dissolved in ethanol (10mL), under ice bath, adds sodium borohydride (342mg, 9mmol) in batches, stirring reaction 2 hours.Be spin-dried for, column chromatography separating purification, obtains 1-(the chloro-5-fluorophenyl of 2-(dimethylamino)-4-) ethanol (458mg), yield: 70%. 1H-NMR(400MHz，CDCl 3)：δ＝7.25(d，J＝6.6 Hz，1H)，7.03(d，J＝10.0Hz，1H)，5.77(brs，1H)，5.06(q，J＝6.5Hz，1H)，2.68(s，6H)，1.51(d，J＝6.5Hz，3H)。。MS m/z[ESI]：218.1[M+1]。
The fluoro-DMA of step 5:2-(1-bromotrifluoromethane) the chloro-4-of-5-
With reference to the method for intermediate 5 steps 1, with 1-(the chloro-5-fluorophenyl of 2-(dimethylamino)-4-) ethanol replacement 1-(the chloro-3-fluorophenyl of 2,6-bis-) ethanol, make target compound, yield: 31%.MS m/z[ESI]：282.0[M+1]。
The bromo-3-of step 6:5-(1-(the chloro-5-fluorophenyl of 2-(dimethylamino)-4-) oxyethyl group)-PA
With reference to the method for intermediate 5 steps 2, with the fluoro-DMA replacement chloro-2-of 1,3-bis-of 2-(1-bromotrifluoromethane) the chloro-4-of-5-(1-bromotrifluoromethane)-4-fluorobenzene, make target compound, yield: 22%.MS m/z[ESI]：390.0[M+1]。
intermediate 41:4-(2-(the bromo-2-chloropyridine-3-of 5-base oxygen base) ethyl) morpholine
With reference to step 3 in intermediate 16, with 4-(2-chloroethyl) morpholine hydrochloride replacement methyl iodide, make 4-(2-(the bromo-2-chloropyridine-3-of 5-base oxygen base) ethyl) morpholine, yield: 67%.MS m/z[ESI]：323.0[M+1]。
Embodiment 1: 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA
Universal synthesis method:
The chloro-4-of step 1:2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine
By 1-(2-chloropyridine-4-yl)-3-(dimethylamino) third-2-alkene-1-ketone (2.11g, 10mmol), the chloro-4-fluorine phenylhydrazine of 3-(1.61g, 10mmol), several Glacial acetic acid and water (1mL) add in ethanol (50mL), reflux 1.5 hours, be spin-dried for solvent, add ethyl acetate and water, extraction, organic phase is dry, silica gel chromatography, obtain the chloro-4-of 2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine (2.50g), yield: 81%.MSm/z[ESI]：308.0[M+1]。
Step 2:4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA
By chloro-2-4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine ((2.0g, 6.5mmol), benzophenone imine (1.4g, 7.7mmol), three (dibenzalacetone) two palladium (297mg, 0.325mmol), BINAP (0.42g, 0.65mmol), sodium tert-butoxide (0.94g, 9.75mmol) and toluene (30mL) add in tube sealing, with after nitrogen replacement air, at 120 DEG C, react 3 hours.Be spin-dried for solvent, add ethyl acetate and water, extraction, organic phase is dry, silica gel chromatography, obtains 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA (1.4g), yield: 48%. 1H-NMR(400MHz，CDCl 3)：δ＝8.235(t，1.8Hz，1H)，7.803(d，J＝7.2Hz，2H)，7.679(d，J＝1.6Hz，1H)，7.502(d，J＝7.6Hz，1H)，7.44-7.26(m，6H)，7.155(d，J＝6.8Hz，2H)，7.052(t，J＝8.3Hz，1H)，6.92-6.88(m，1H)，6.551-6.536(q，2H)，6.389(d，J＝1.6Hz，1H)。MS m/z[ESI]：453.1[M+1]。
Step 3:4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA
Under agitation condition, by 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA (1.4g, 3.1mmol) add in 2N hydrochloric acid (50mL), at room temperature stir and spend the night.First be extracted with ethyl acetate and remove benzophenone, water is greater than 12 with sodium hydroxide solution adjust pH, be extracted with ethyl acetate again, dry, be spin-dried for and obtain 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA (0.77g) and be directly used in next step, yield: 87%.MS m/z[ESI]：289.1[M+1]。
The bromo-4-of step 4:5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA
Under ice bath agitation condition, to 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA (0.72g, in dichloromethane solution 2.5mmol) (25mL), drip bromine (400mg, 2.5mmol), stir 1 hour, wash with sodium carbonate solution, with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filter, filtrate is concentrated, column chromatography separating purification (taking dichloromethane methanol=50: 1 is eluent), obtain the bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA (588mg), yield: 64%. 1H-NMR(400MHz，CDCl 3)：δ＝8.49(s，1H)，7.746(d，J＝2.0Hz，1H)，7.523(dd，J＝7.2Hz，2.0Hz，1H)，7.066-7.048(m，2H)，6.517(d，J＝2.0Hz，1H)，6.424(s，1H)，4.622(s，2H)。MSm/z[ESI]：369.0[M+1].
Step 5:4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA
By 5-bromine 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA (237mg, 0.644mmol), 4-(3-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester (297mg, 0.709mmol), tetrakis triphenylphosphine palladium (75mg, 0.064mmol) and cesium carbonate (419mg, 1.29mmol) be added in diox (10mL) and water (1.5mL), nitrogen replacement, 100 DEG C of reactions are spent the night.Cooling rear silica gel column chromatography separates, obtain 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA (112mg), yield: 30%.MS m/z[ESI]：579.2[M+1]。
Step 6:4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA
Under stirring to 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA (110mg, in dichloromethane solution 0.19mmol), (10mL) adds trifluoroacetic acid (1mL), stir 1 hour, be greater than 13 with sodium hydroxide solution adjust pH, with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filter, filtrate is concentrated, column chromatography separating purification (taking methylene dichloride: methyl alcohol (v/v)=8:1 is as eluent), obtain 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA (64mg), yield: 70%. 1H-NMR(400MHz，CDCl 3)：δ＝7.650-7.631(m，2H)，7.079-7.035(m，2H)，6.872-6.850(m，1H)，6.812(m，1H)，6.589(d，J＝1.6Hz，1H)，6.355(d，J＝9.2Hz，1H)，6.295(d，J＝7.2Hz，2H)，3.416-3.364(m，4H)，3.341(s，3H)，3.297-3.273(m，4H)。MS m/z[ESI]：479.2[M+1].
Embodiment 2:4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA hydrochloride
The chloro-4-of step 1:2-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl) pyridine
With reference to the method for step 1 in embodiment 1, with the chloro-4-fluorine phenylhydrazine of 4-fluorine phenylhydrazine replacement 3-, make target compound, yield: 86%.MS m/z[ESI]：274.0[M+1]。
Step 2:4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA
With reference to the method for step 2 in embodiment 1, with the chloro-4-of 2-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl) the pyridine replacement chloro-4-of 2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine, make target compound, yield: 56%.MSm/z[ESI]：419.2[M+1]。
Step 3:4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 3 in embodiment 1, with 4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA, make target compound, yield: 77%.MSm/z[ESI]：255.1[M+1]。
The bromo-4-of step 4:5-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 4 in embodiment 1, with 4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 52%.MSm/z[ESI]：333.0[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.176(s，1H)，7.742(d，J＝2.0Hz，1H)，7.291-7.256(m，2H)，7.022(t，J＝8.6Hz，2H)，6.521(d，J＝2.0Hz，1H)，6.394(s，1H)，4.502(s，2H)。
Step 5:4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA
With reference to the method for step 5 in embodiment 1, with the bromo-4-of 5-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-PA replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 35%.MSm/z[ESI]：545.3[M+1]。
Step 6:4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA hydrochloride
By 4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA (54mg, 0.1mmol) be dissolved in methyl alcohol (20mL), pass into hydrogen chloride gas to saturated, stir 1 hour, be spin-dried for, wash with ether, after dry, make 4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA hydrochloride (46mg), MS m/z[ESI]: 445.2[M+1].
Embodiment 3:4-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA hydrochloride
The chloro-4-of step 1:2-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl) pyridine
With reference to the method for step 1 in embodiment 1, with the chloro-4-fluorine phenylhydrazine of 3-fluorine phenylhydrazine replacement 3-, make target compound, yield: 79%.MS m/z[ESI]：274.0[M+1]。
Step 2:4-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA
With reference to the method for step 2 in embodiment 1, with the chloro-4-of 2-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl) the pyridine replacement chloro-4-of 2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine, make target compound, yield: 69%.MSm/z[ESI]：419.2[M+1]。
Step 3:4-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 3 in embodiment 1, with 4-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA, make target compound, yield: 80%.MSm/z[ESI]：255.1[M+1]。
The bromo-4-of step 4:5-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 4 in embodiment 1, with 4-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 58%.MS m/z[ESI]：333.0[M+1]。
Step 5:4-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA
With reference to the method for step 5 in embodiment 1, with the bromo-4-of 5-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl)-PA replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 30%.MSm/z[ESI]：545.3[M+1]。
Step 6:4-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA hydrochloride
With reference to the method for step 6 in embodiment 2, with 4-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA replacement 4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA, make 4-(1-(3-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA hydrochloride (38mg), yield: 77%.MS m/z[ESI]：445.2[M+1]。 1H-NMR(400MHz，DMSO-d 6)：δ＝9.362(br，2H)，8.233(br，2H)，7.833(s，1H)，7.769(d，J＝2.0Hz，1H)，7.384-7.327(m，1H)，7.189-7.142(m，1H)，6.986(s，1H)，6.849-6.779(m，2H)，6.508-6.467(m，2H)，6.343(d，J＝6.8Hz，2H)，3.451-3.356(m，4H)，3.327(s，3H)，3.185(m，4H)。
Embodiment 4: 4-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA
The chloro-4-of step 1:2-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl) pyridine
With reference to the method for step 1 in embodiment 1, with the chloro-4-fluorine phenylhydrazine of the chloro-3-fluorine phenylhydrazine replacement 3-of 4-, make target compound, yield: 79%.MS m/z[ESI]：308.0[M+1]。
Step 2:4-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA
With reference to the method for step 2 in embodiment 1, with the chloro-4-of 2-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl) the pyridine replacement chloro-4-of 2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine, make target compound, yield: 69%.MSm/z[ESI]：453.1[M+1]。
Step 3:4-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 3 in embodiment 1, with 4-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA, make target compound, yield: 80%.MS m/z[ESI]：289.1[M+1]。
The bromo-4-of step 4:5-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 4 in embodiment 1, with 4-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 58%.MS m/z[ESI]：369.0[M+1]。
Step 5:4-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA
With reference to the method for step 5 in embodiment 1, with the bromo-4-of 5-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl)-PA replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 30%.MSm/z[ESI]：579.2[M+1]。
Step 6:4-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA
With reference to the method for step 6 in embodiment 1, with 4-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA, make 4-(1-(the chloro-3-fluorophenyl of 4-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA (56mg), yield: 77%.MS m/z[ESI]：479.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.049(s，1H)，7.598(d，J＝1.6Hz，1H)，7.157(t，J＝8.0Hz，1H)，6.873-6.842(dd，J＝10.0Hz，2.4Hz，1H)，6.756(d，J＝8.8Hz，1H)，6.502(m，2H)，6.315-6.281(m，2H)，6.168(d，J＝2.0Hz，1H)，4.491(s，2H)，3.359(s，3H)，3.138-3.114(m，4H)，3.052-3.028(m，4H)。Embodiment 5: 4-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA
The chloro-4-of step 1:2-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl) pyridine
With reference to the method for step 1 in embodiment 1, with the chloro-4-fluorine phenylhydrazine of 3-trifluoromethyl phenyl hydrazine replacement 3-, make target compound, yield: 40%.MSm/z[ESI]：324.0[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.331(d，J＝8.8Hz，1H)，7.806(s，1H)，7.713(s，1H)，7.665(d，J＝7.6Hz，1H)，7.526(t，J＝7.6Hz，1H)，7.393(d，J＝8.0Hz，1H)，7.272-7.249(m，1H)，6.971-6.956(m，1H)，6.964(s，1H)。
Step 2:4-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA
With reference to the method for step 2 in embodiment 1, with the chloro-4-of 2-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl) the pyridine replacement chloro-4-of 2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine, make target compound, yield: 66%.MSm/z[ESI]：469.2[M+1]。
Step 3:4-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 3 in embodiment 1, with 4-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA, make target compound, yield: 79%.MSm/z[ESI]：305.1[M+1]。
The bromo-4-of step 4:5-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 4 in embodiment 1, with 4-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 57%.MS m/z[ESI]：383.0[M+1]。
Step 5:4-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA
With reference to the method for step 5 in embodiment 1, with the bromo-4-of 5-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl)-PA replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 42%.MS m/z[ESI]：595.3[M+1]。
Step 6:4-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA
With reference to the method for step 6 in embodiment 1, with 4-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA, make 4-(1-(3-trifluoromethyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl)-PA (65mg), yield: 83%.MS m/z[ESI]：495.2[M+1]。 1H-NMR(400 MHz，CDCl 3)：δ＝7.82(s，1H)，7.76(d，J＝2.0 Hz，1H)，7.67(d，J＝7.6 Hz，1H)，7.57(t，J＝7.6 Hz，1H)，7.33-7.30(m，2H)，6.48(s，1H)，6.43-6.40(m，2H)，6.28-6.27(m，2H)，6.12(s，2H)，3.31(s，3H)，3.16-3.14(m，4H)，2.98-2.96(m，4H)。
Embodiment 6: 4-(1-(4-luorobenzyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-PA
The chloro-4-of step 1:2-(1-(4-luorobenzyl)-1H-pyrazoles-5-yl) pyridine
With reference to the method for step 1 in embodiment 1, with the chloro-4-fluorine phenylhydrazine of 4-fluorine benzyl hydrazine replacement 3-, make target compound, yield: 56%.MS m/z[ESI]：288.1[M+1]。
Step 2:4-(1-(4-luorobenzyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA
With reference to the method for step 2 in embodiment 1, with the chloro-4-of 2-(1-(4-luorobenzyl)-1H-pyrazoles-5-yl) the pyridine replacement chloro-4-of 2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine, make target compound, yield: 65%.MSm/z[ESI]：433.2[M+1]。
Step 3:4-(1-(4-luorobenzyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 3 in embodiment 1, with 4-(1-(4-luorobenzyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA, make target compound, yield: 90%.MS m/z[ESI]：269.1[M+1]。
The bromo-4-of step 4:5-(1-(4-luorobenzyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 4 in embodiment 1, with 4-(1-(4-luorobenzyl)-1H-pyrazoles-5-yl)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 97%.MS m/z[ESI]：347.0[M+1]。
Step 5:4-(1-(4-luorobenzyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-methyl base piperazine-1-yl) phenyl)-PA
With reference to the method for step 5 in embodiment 1, with the bromo-4-of 5-(1-(4-luorobenzyl)-1H-pyrazoles-5-yl)-PA replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, with 1-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl)-4-methylpiperazine replacement 4-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester, make target compound, yield: 42%.MS m/z[ESI]：473.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.065(s，1H)，7.798(m，1H)，7.696-7.552(m，3H)，7.428(d，J＝1.6Hz，1H)，6.82(d，J＝8.0Hz，1H)，6.396(dd，J＝8.0Hz，2.0Hz，1H)，6.310(d，J＝3.6Hz，2H)，6.065(d，J＝1.6Hz，1H)，4.936(s，2H)，4.762(brs，2H)，3.969(s，3H)，3.50(m，4H)，3.14(m，4H)，2.757(s，3H)。
Embodiment 7: 4-(1-(3-fluorophenyl)-1H-imidazoles-5-yl)-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-PA
Universal synthesis method:
The bromo-4-of step 1:2-(1-(3-fluorophenyl)-1H-imidazoles-5-yl) pyridine
By bromo-2-4-pyridine-formaldehyde (1.96g, 10mmol), 3-fluoroaniline (1.11g, 10mmol), tosic acid (50mg) adds in toluene (50mL), with reflux band water 12 hours of water trap, is spin-dried for solvent.Add Methyl benzenesulfonyl methyl isonitrile (1.95g, 10mmol), sodium carbonate (9.66g, 91mmol) and ethanol (50mL), reflux 6 hours.Be spin-dried for solvent, add ethyl acetate and water, extraction, organic phase is dry, and silica gel chromatography, obtains the bromo-4-of 2-(1-(3-fluorophenyl)-1H-imidazoles-5-yl) pyridine (1.39g), yield: 44%.MS m/z[ESI]：318.0[M+1]。
Step 2:4-(1-(3-fluorophenyl)-1H-imidazoles-5-yl)-N-(diphenylmethylene)-PA
With reference to the method for step 2 in embodiment 1, with the bromo-4-of 2-(1-(3-fluorophenyl)-1H-imidazoles-5-yl) the pyridine replacement chloro-4-of 2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine, yield: 70%. 1H-NMR(400MHz，CDCl 3)：δ＝8.235(t，1.8Hz，1H)，7.803(d，J＝7.2Hz，2H)，7.679(d，J＝1.6Hz，1H)，7.502(d，J＝7.6Hz，1H)，7.44-7.26(m，6H)，7.155(d，J＝6.8Hz，2H)，7.052(t，J＝8.3Hz，1H)，6.92-6.88(m，2H)，6.551-6.536(q，2H)，6.389(d，J＝1.6Hz，1H)。MS m/z[ESI]：419.2[M+1]。
Step 3:4-(1-(3-fluorophenyl)-1H-imidazoles-5-yl)-PA
With reference to the method for step 3 in embodiment 1, with 4-(1-(3-fluorophenyl)-1H-imidazoles-5-yl)-N-(diphenylmethylene)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA, make target compound, yield: 87%.MS m/z[ESI]：255.1[M+1]。
The bromo-4-of step 4:5-(1-(3-fluorophenyl)-1H-imidazoles-5-yl)-PA
With reference to the method for step 4 in embodiment 1, with 4-(1-(3-fluorophenyl)-1H-imidazoles-5-yl)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 64%.MS m/z[ESI]：333.0[M+1]
Step 5:4-(1-(3-fluorophenyl)-1H-imidazoles-5-yl)-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-PA
With reference to the method for step 5 in embodiment 1, with the bromo-4-of 5-(1-(3-fluorophenyl)-1H-imidazoles-5-yl)-PA replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, with 1-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl)-4-methylpiperazine replacement 4-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester, make target compound, yield: 33%.MS m/z[ESI]：459.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.969(s，1H)，7.501(d，J＝1.2Hz，1H)，7.159-7.118(m，1H)，7.09(s，1H)，6.954-6.927(m，1H)，6.593(d，J＝8.0Hz，1H)，6.504-6.429(m，3H)，6.284-6.258(dd，J＝8.2Hz，2.2Hz，1H)，4.483(s，2H)，3.373(s，3H)，3.254(m，4H)，2.68(m，4H)，2.436(s，3H)。Embodiment 8: 4-(1-(4-methylsulfonyl phenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-PA
The chloro-4-of step 1:2-(1-(4-methylsulfonyl phenyl)-1H-pyrazoles-5-yl) pyridine
With reference to the method for step 1 in embodiment 1, with the chloro-4-fluorine phenylhydrazine of 4-methylsulfonyl phenylhydrazine replacement 3-, make target compound, yield: 40%.MS m/z[ESI]：334.0[M+1]。
Step 2:4-(1-(4-methylsulfonyl phenyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA
With reference to the method for step 2 in embodiment 1; with the chloro-4-of 2-(1-(4-methylsulfonyl phenyl)-1H-pyrazoles-5-yl) the pyridine replacement chloro-4-of 2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine, yield: 70%.MS m/z[ESI]：479.1[M+1]。
Step 3:4-(1-(4-methylsulfonyl phenyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 3 in embodiment 1; with 4-(1-(4-methylsulfonyl phenyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA; make target compound, yield: 87%.MS m/z[ESI]：315.1[M+1]。
The bromo-4-of step 4:5-(1-(4-methylsulfonyl phenyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 4 in embodiment 1; with 4-(1-(4-methylsulfonyl phenyl)-1H-pyrazoles-5-yl)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA; make target compound, yield: 64%.MS m/z[ESI]：395.0[M+1]
Step 5:4-(1-(4-methylsulfonyl phenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-PA
With reference to the method for step 5 in embodiment 1, with the bromo-4-of 5-(1-(4-methylsulfonyl phenyl)-1H-pyrazoles-5-yl)-PA replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, with 1-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl)-4-methylpiperazine replacement 4-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester, make target compound, yield: 33%.MS m/z[ESI]：519.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.99(d，J＝8.8Hz，2H)，7.88(s，1H)，7.80(d，J＝5.6Hz，1H)，7.58(d，J＝8.8Hz，2H)，7.00(d，J＝8.4Hz，1H)，7.59(d，J＝2.0Hz，1H)，6.53(dd，J＝8.4Hz，2.0Hz，1H)，6.33(s，1H)，6.29(d，J＝5.6Hz，1H)，3.61(s，3H)，3.30-3.33(m，4H)，3.17(s，3H)，2.79-2.87(m，4H)，2.52(s，3H)。
Embodiment 9: 3-(5-(2-amino-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl) pyridin-4-yl)-1H-pyrazol-1-yl) phenylformic acid
Universal synthesis method:
Step 1:3-hydrazino-benzoic acid ethyl ester
By 3-subcutin (5.0g, 30mmol) be dissolved in concentrated hydrochloric acid (25mL), be chilled to 0 DEG C, drip the solution that is made into of Sodium Nitrite (2.09g, 30mmol) water-soluble (10mL), stir 30 minutes at 0 DEG C, add tin protochloride (12.86g, 57mmol), rise to room temperature, stir 1 hour.With strong caustic adjust pH, to strong basicity, by extracted with diethyl ether, dry, silica gel column chromatogram separating purification, makes 3-hydrazino-benzoic acid ethyl ester (3.9g), yield: 72%.MSm/z[ESI]：181.1[M+1]。
Step 2:3-(5-(2-chloropyridine-4-yl)-1H-pyrazol-1-yl) ethyl benzoate
With reference to the method for step 1 in embodiment 1, with the chloro-4-fluorine phenylhydrazine of 3-hydrazino-benzoic acid ethyl ester replacement 3-, make target compound, yield: 49%.MS m/z[ESI]：328.1[M+1]。
Step 3:3-(5-(2-(diphenylmethylene amino) pyridin-4-yl)-1H-pyrazol-1-yl) ethyl benzoate
With reference to the method for step 2 in embodiment 1, with 3-(5-(2-chloropyridine-4-yl)-1H-pyrazol-1-yl) the ethyl benzoate replacement chloro-4-of 2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine, yield: 50%.MS m/z[ESI]：473.2[M+1]。
Step 4:3-(5-(PA-4-yl)-1H-pyrazol-1-yl) ethyl benzoate
With reference to the method for step 3 in embodiment 1, with 3-(5-(2-(diphenylmethylene amino) pyridin-4-yl)-1H-pyrazol-1-yl) ethyl benzoate replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA, make target compound, yield: 70%.MS m/z[ESI]：309.1[M+1]。
Step 5:3-(5-(the bromo-PA-4-of 5-yl)-1H-pyrazol-1-yl) ethyl benzoate
With reference to the method for step 4 in embodiment 1, with 3-(5-(PA-4-yl)-1H-pyrazol-1-yl) ethyl benzoate replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 90%. 1H-NMR(400MHz，CDCl 3)：δ＝8.60-8.24(brs，2H)，8.17(s，1H)，8.03(t，J＝1.7Hz，1H)，7.97(dt，J＝7.6，1.4Hz，1H)，7.78(d，J＝1.8Hz，1H)，7.47(ddd，J＝8.0，2.2，1.3Hz，1H)，7.40(t，J＝7.8Hz，1H)，6.54(s，1H)，6.47-6.42(m，1H)，4.34(q，J＝7.1Hz，2H)，1.36(t，J＝7.1Hz，3H)。MSm/z[ESI]：387.0[M+1].
Step 6:3-(5-(2-amino-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl) pyridin-4-yl)-1H-pyrazol-1-yl) ethyl benzoate
With reference to the method for step 5 in embodiment 1, with 3-(5-(the bromo-PA-4-of 5-yl)-1H-pyrazol-1-yl) the ethyl benzoate replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, with 1-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl)-4-methylpiperazine replacement 4-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester, make target compound, yield: 30%.MSm/z[ESI]：513.3[M+1].
Step 7:3-(5-(2-amino-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl) pyridin-4-yl)-1H-pyrazol-1-yl) phenylformic acid
By 3-(5-(2-amino-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl) pyridin-4-yl)-1H-pyrazol-1-yl) ethyl benzoate (103mg, 0.2mmol) be dissolved in methyl alcohol (10mL), add saturated sodium hydroxide solution (5mL), stirring at room temperature 3 hours, be neutralized to neutrality with hydrochloric acid, be spin-dried for, with silica gel column chromatogram separating purification, make 3-(5-(2-amino-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl) pyridin-4-yl)-1H-pyrazol-1-yl) phenylformic acid (63mg), yield: 65%.MS m/z[ESI]： 485.2[M+1]。 1H-NMR(400MHz，DMSO-d 6)：δ＝8.54(s，1H)，7.89(s，1H)，7.78-7.83(m，2H)，7.57(s，1H)，7.27(t，J＝6.8Hz，1H)，6.14(d，J＝6.8Hz，1H)，6.77(d，J＝8.0Hz，1H)，6.38-6.42(m，2H)，6.14(s，1H)，6.03(s，1H)，5.91(s，2H)，3.41(s，3H)，3.12-3.24(m，4H)，2.44-2.51(m，4H)，2.26(s，3H)。
Embodiment 10: 3-(5-(2-amino-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl) pyridin-4-yl)-1H-pyrazol-1-yl) phenylcarbinol
The product 3-of step 6 in embodiment 9 (5-(2-amino-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl) pyridin-4-yl)-1H-pyrazol-1-yl) ethyl benzoate (51mg, 0.1mmol) be dissolved in anhydrous tetrahydro furan (10mL), add lithium aluminum hydride (23mg, 0.6mmol), stirring at room temperature 4 hours.Add several methyl alcohol cancellation reactions, be spin-dried for, with silica gel column chromatogram separating purification, make 3-(5-(2-amino-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl) pyridin-4-yl)-1H-pyrazol-1-yl) phenylcarbinol (23mg), yield: 49%.MS m/z[ESI]：471.2[M+1]。 1H-NMR(400MHz，DMSO-d 6)：δ＝7.793(s，1H)，7.636(s，1H)，7.251(s，2H)，7.122(s，1H)，6.923(s，1H)，6.578(d，J＝8.8Hz，1H)，6.354(d，J＝8.0Hz，3H)，6.228(s，1H)，6.013(s，2H)，5.29(s，1H)，4.496(s，2H)，3.36(br，4H)，3.23(s，3H)，2.886(br，4H)，2.56(s，3H)。
Embodiment 11: 2-(2-amino-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl) pyridin-4-yl amino)-benzene sulfonyl isopropylamine hydrochloride
Universal synthesis method:
Step 1:2-(PA-4-base amino)-benzene sulfonyl Isopropylamine
The chloro-PA of 4-(1.28g, 10mmol), 2-amino-benzene sulphonyl Isopropylamine (2.35g, 11mmol), Pd 2(dba) 3(915mg, 1mmol), BINAP (1.31g, 2mmol), cesium carbonate (6.50g, 20mmol) and dry toluene (80mL) add in tube sealing, after nitrogen replacement, spend the night in 130 DEG C of stirrings.Cooling rear silica gel column chromatography separates (methylene chloride/methanol, 30:1-10:1), obtains 2-(PA-4-base amino)-benzene sulfonyl Isopropylamine (740mg), yield: 24%.MS m/z[ESI]：307.1[M+1]。
Step 2:2-(2-amino-5-bromopyridine-4-base amino)-benzene sulfonyl Isopropylamine
With reference to the method for step 4 in embodiment 1, with 2-(PA-4-base amino)-benzene sulfonyl Isopropylamine replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 36%.MS m/z[ESI]：387.0[M+1]。
Step 3:2-(2-amino-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl) pyridin-4-yl amino)-benzene sulfonyl Isopropylamine
With reference to the method for step 5 in embodiment 1, with 2-(2-amino-5-bromopyridine-4-base amino)-benzene sulfonyl Isopropylamine replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 21%.MS m/z[ESI]：597.3[M+1]
Step 4:2-(2-amino-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl) pyridin-4-yl amino)-benzene sulfonyl isopropylamine hydrochloride
With reference to the method for step 6 in embodiment 2, with 2-(2-amino-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl) pyridin-4-yl amino)-benzene sulfonyl Isopropylamine replacement 4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA, make target compound, yield: 75%.MSm/z[ESI]：497.2[M+1]。 1H-NMR(400MHz，DMSO-d 6)：δ＝13.02(s，1H)，9.49(s，2H)，7.81(d，J＝7.2Hz，1H)，7.80(s，1H)，7.63-7.67(m，2H)，7.61(d，J＝7.2Hz，1H)，7.53(s，1H)，7.50(d，J＝8.0Hz，1H)，7.34(td，J＝8.0Hz，1.6Hz，1H)，7.17(d，J＝8.4Hz，1H)，6.69(s，1H)，6.65(dd，J＝8.0Hz，1.6Hz，1H)，6.48(s，1H)，3.72(s，3H)，3.46-3.49(m，4H)，3.14-3.19(m，5H)，0.89(d，J＝6.0Hz，6H)。
Embodiment 12: 4-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) ethynyl)-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-PA
Step 1:4-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) ethynyl)-N-(phenylbenzene methylene radical)-PA
With reference to the method for step 2 in embodiment 1, with the chloro-4-of 2-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) ethynyl) the pyridine replacement chloro-4-of 2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine, make target compound, yield: 35%.MSm/z[ESI]：491.1[M+1]。
Step 2:4-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) ethynyl)-PA
With reference to the method for step 3 in embodiment 1, with 4-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) ethynyl)-N-(phenylbenzene methylene radical)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA, make target compound, yield: 67%.MS m/z[ESI]：327.1[M+1]。
The bromo-4-of step 3:5-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) ethynyl)-PA
With reference to the method for step 4 in embodiment 1, with 4-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) ethynyl)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 76%.MS m/z[ESI]：407.0[M+1]。
Step 4:4-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) ethynyl)-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-PA
With reference to the method for step 5 in embodiment 1, with the bromo-4-of 5-((1-(the chloro-3-luorobenzyl of 4-)-1H-pyrazoles-5-yl) the ethynyl)-PA replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, with 1-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl)-4-methylpiperazine replacement 4-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester, make target compound, yield: 49%.MSm/z[ESI]：531.2[M+1]。
Embodiment 13: 4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-yl)-PA hydrochloride
Step 1:4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(1-(1-tertbutyloxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl)-PA
With reference to the method for step 5 in embodiment 1, with the bromo-4-of 5-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-PA replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, with 4-(4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) piperidines-1-carboxylic acid tert-butyl ester replacement 4-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester, make target compound, yield: 76%.MS m/z[ES]：504.2[M+1]。
Step 2:4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-yl)-PA hydrochloride
With reference to the method for step 6 in embodiment 2, with 4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(1-(1-tertbutyloxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl)-PA replacement 4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA, make target compound, yield: 49%.MS m/z[ESI]：404.2[M+1]。 1H-NMR(400MHz，DMSO-d 6)：δ＝9.06-9.17(1H，brs)，8.81-8.98(1H，brs)，8.13-8.24(2H，brs)，7.92(1H，s)，7.87(1H，d，J＝1.6Hz)，7.17(1H，s)，7.05-7.10(2H，m)，7.00(1H，s)，6.90-6.94(2H，m)，6.83(1H，d，J＝1.6Hz)，6.64(1H，s)，4.23-4.34(1H，m)，3.33(2H，d，J＝12.8Hz)，2.95-3.05(2H，m)，1.92-2.08(4H，m)。
Embodiment 14: 4-(1-(3-(solutions of dimethyl phosphoryl base) phenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-PA
The chloro-4-of step 1:2-(1-(3-bromophenyl)-1H-pyrazoles-5-yl) pyridine
With reference to the method for step 1 in embodiment 1, with the chloro-4-fluorine phenylhydrazine of 3-bromophenyl-hydrazine replacement 3-, make target compound, yield: 77%.MS m/z[ESI]：336.0[M+1]。
The chloro-4-of step 2:2-(1-(3-(solutions of dimethyl phosphoryl base) phenyl)-1H-pyrazoles-5-yl) pyridine
By chloro-2-4-(1-(3-bromophenyl)-1H-pyrazoles-5-yl) pyridine (335mg, 1mmol), dimethyl oxidation phosphine (94mg, 1.2 mmol), palladium (22mg, 0.1mmol), X-phos (95mg, 0.2mmol) and potassiumphosphate (244mg, 1.1mmol) be added in DMF (10mL), nitrogen replacement, 150 DEG C are reacted 2 hours.After cooling, be spin-dried for, silica gel column chromatography separates and makes target compound, yield: 36%.MS m/z[ESI]：332.1[M+1]。
Step 3:4-(1-(3-(solutions of dimethyl phosphoryl base) phenyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA
With reference to the method for step 2 in embodiment 1; with the chloro-4-of 2-(1-(3-(solutions of dimethyl phosphoryl base) phenyl)-1H-pyrazoles-5-yl) the pyridine replacement chloro-4-of 2-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl) pyridine; make target compound, yield: 65%.MSm/z[ESI]：477.2[M+1]。
Step 4:4-(1-(3-(solutions of dimethyl phosphoryl base) phenyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 3 in embodiment 1; with 4-(1-(3-(solutions of dimethyl phosphoryl base) phenyl)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-N-(diphenylmethylene)-PA; make target compound, yield: 90%.MS m/z[ESI]：313.1[M+1]。
The bromo-4-of step 5:5-(1-(3-(solutions of dimethyl phosphoryl base) phenyl)-1H-pyrazoles-5-yl)-PA
With reference to the method for step 4 in embodiment 1; with 4-(1-(3-(solutions of dimethyl phosphoryl base) phenyl)-1H-pyrazoles-5-yl)-PA replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA; make target compound, yield: 89%.MS m/z[ESI]：391.0[M+1]。
Step 6:4-(1-(3-(solutions of dimethyl phosphoryl base) phenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-PA
With reference to the method for step 5 in embodiment 1, with the bromo-4-of 5-(1-(3-(solutions of dimethyl phosphoryl base) phenyl)-1H-pyrazoles-5-yl)-PA replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, with 1-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl)-4-methylpiperazine replacement 4-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester, make target compound, yield: 42%.MSm/z[ESI]：517.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.24(1H，s)，8.18(1H，d，J＝12.4Hz)，7.95(1H，d，J＝8.0Hz)，7.66-7.76(3H，m)，7.61(1H，s)，7.17(1H，d，J＝8.0Hz)，6.70(1H，d，J＝8.0Hz)，6.63(1H，s)，6.98(1H，d，J＝1.6Hz)，3.93-3.96(2H，m)，3.59-3.62(2H，m)，3.50(3H，s)，3.10-3.26(4H，m)，2.97(3H，s)，1.84(6H，d，J＝13.2Hz)。
Embodiment 15: 2-(2-amino-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl) pyridin-3-yl) benzene sulfonyl Isopropylamine
Universal synthesis method:
Step 1:2-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) benzene sulfonyl Isopropylamine
By 2-bromobenzene sulphonyl Isopropylamine (2.4g, 8.6mmol), connection pinacol borate (3.3g, 12.9mmol), Pd (dppf) Cl 2(630mg, 0.86mmol) and Glacial acetic acid potassium (1.7g, 17.2mmol) are added in dry diox (100mL), nitrogen replacement, and 110 DEG C are reacted 2 days.Reacting liquid filtering, is spin-dried for, and silica gel column chromatogram separating purification obtains target product, productive rate 37%.
Step 2:2-(2-nitropyridine-3-yl) benzene sulfonyl Isopropylamine
By 2-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) benzene sulfonyl Isopropylamine (390mg, 1.2mmol), 2-nitro-3-(trimethyl fluoride sulfonyl oxygen base) pyridine (272mg, 1mmol), tetrakis triphenylphosphine palladium (58mg, 0.05mmol) and cesium carbonate (650mg, 2mmol) be added in diox (20mL) nitrogen replacement, 120 DEG C of microwave reactions 2 hours.Reacting liquid filtering, is spin-dried for, and silica gel column chromatogram separating purification obtains target product, yield: 47%.MS m/z[ESI]：322.1[M+1]。
Step 3:2-(PA-3-yl) benzene sulfonyl Isopropylamine
By 2-(2-nitropyridine-3-yl) benzene sulfonyl Isopropylamine (150mg, 0.47mmol) be dissolved in ethanol (15mL), add 2M hydrochloric acid (0.5mL), reduced iron powder (185mg, 3.29mmol), reflux 2 hours.Filter, be spin-dried for, silica gel column chromatogram separating purification makes target compound, yield: 80%.MS m/z[ESI]：292.1[M+1]。
Step 4:2-(2-amino-5-bromopyridine-3-yl) benzene sulfonyl Isopropylamine
With reference to the method for step 4 in embodiment 1, with 2-(PA-3-yl) benzene sulfonyl Isopropylamine replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 58%.MSm/z[ESI]：372.0[M+1]。
Step 5:2-(2-amino-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl) pyridin-3-yl) benzene sulfonyl Isopropylamine
With reference to the method for step 5 in embodiment 1, with 2-(2-amino-5-bromopyridine-3-yl) the benzene sulfonyl Isopropylamine replacement bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, make target compound, yield: 30%.MSm/z[ESI]：582.3[M+1]。
Step 6:2-(2-amino-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl) pyridin-3-yl) benzene sulfonyl Isopropylamine
With reference to the method for step 6 in embodiment 1, with 2-(2-amino-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl) pyridin-3-yl) benzene sulfonyl Isopropylamine replacement 4-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA, make target compound, yield: 77%.MSm/z[ESI]：482.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.15(d，J＝8.0Hz，1H)，8.07(d，J＝1.6Hz，1H)，7.95(d，J＝2.0Hz，1H)，7.70-7.80(m，2H)，7.49(d，J＝7.2Hz，1H)，7.33(d，J＝8.4Hz，1H)，6.73(d，J＝1.6Hz，1H)，6.69(dd，J＝8.8Hz，2.4Hz，1H，)，3.87(s，3H)，3.30-3.60(m，9H)，1.09(d，J＝6.4Hz，6H)。
Embodiment 16: 3-((3-fluorophenoxy) methyl)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-yl)-PA hydrochloride
Universal synthesis method:
Step 1:3-methylol-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-yl)-PA
With reference to the method for step 5 in embodiment 1, with the bromo-PA replacement of the 3-methylol-5-bromo-4-of 5-(1-(the chloro-4-fluorophenyl of 3-)-1H-pyrazoles-5-yl)-PA, with 4-(4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-1H-pyrazol-1-yl) piperidines-1-carboxylic acid tert-butyl ester replacement 4-(3-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester, make target compound, productive rate 37%.MS m/z[ESI]：374.2[M+1]。
Step 2:3-((3-fluorophenoxy) methyl)-5-(1-(1-tertbutyloxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl)-PA
By 3-methylol-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-yl)-PA (187mg, 0.5mmol), 3-fluorophenol (61.6mg, 0.55mmol) and triphenylphosphine (200mg, 0.75mmol) be added in dry tetrahydrofuran (THF) (20mL), nitrogen replacement, stirs 1 hour, be chilled to 0 DEG C, splash into diisopropyl azo-2-carboxylic acid (152mg, 0.75mmol), stirred overnight at room temperature.Reaction solution is spin-dried for, and silica gel column chromatogram separating purification obtains target product (50mg), yield: 21%.MSm/z[ESI]：468.2[M+1]。
Step 3:3-((3-fluorophenoxy) methyl)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-yl)-PA hydrochloride
With reference to the method for step 6 in embodiment 2, with 3-((3-fluorophenoxy) methyl)-5-(1-(1-tertbutyloxycarbonyl piperidin-4-yl)-1H-pyrazoles-4-yl)-PA replacement 4-(1-(4-fluorophenyl)-1H-pyrazoles-5-yl)-5-(2-methoxyl group-4-(4-tert-butoxycarbonyl-piperazine-1-yl) phenyl)-PA, make target compound, yield: 68%.MS m/z[ESI]：368.2[M+1]。 1H-NMR(400MHz，DMSO-d 6)：δ＝8.93(1H，brs)，8.75(1H，brs)，8.421(1H，s)，8.343(1H，s)，8.301(1H，s)，8.016(1H，s，7.95(2H，brs)，7.417-7.358(1H，m)，7.012(1H，dd，J＝11.2Hz，2.4Hz)，6.947(1H，dd，J＝8.4H，2.4Hz)，6.852(1H，m)，5.085(2H，s)，4.508(1H，m)，3.384(4H，m)，2.17(4H，m)。
Embodiment 17: 3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(2-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine-5-yl)-PA
Universal synthesis method:
With reference to the method for step 5 in embodiment 1, with the bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine (158mg, 0.5mmol), 3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-PA (235mg, 0.55mmol), tetrakis triphenylphosphine palladium (58mg, 0.05mmol) and cesium carbonate (325mg, 1mmol) be added in diox (10mL) and water (1.5mL), nitrogen replacement, 100 DEG C of reactions are spent the night.Cooling rear silica gel column chromatography separates, and makes target compound, productive rate 58%.MS m/z[ESI]：535.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.00(s，1H)，7.69(d，J＝1.6Hz，1H)，7.31-7.27(m，1H)，7.05(t，J＝8.2Hz，1H)，6.94(s，1H)，6.04(q，J＝6.5Hz，1H)，4.79(s，2H)，3.85(s，3H)，3.84-3.79(m，4H)，2.73(dt，J＝12.9，6.4Hz，1H)，2.58(dd，J＝9.9，4.9Hz，4H)，1.83(d，J＝6.7Hz，3H)，1.08(d，J＝6.5Hz，6H)。
Embodiment 18: 5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-methoxyl group-6 '-(4-methylpiperazine-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for embodiment 17, with the bromo-2-of 5-(4-the methylpiperazine-1-yl)-3-Methoxy Pyridine replacement bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine, make target compound, productive rate 55%.MS m/z[ESI]：506.1[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.71(s，1H)，7.63(s，1H)，7.37(dd，J＝8.8Hz，4.8Hz，1H)，7.15(t，J＝9.2Hz，1H)，7.06(s，1H)，6.84(s，1H)，6.11(q，J＝6.4Hz，1H)，3.81(s，3H)，3.37-3.52(m，4H)，2.87-2.97(m，4H)，2.56(s，3H)，1.79(d，J＝6.8Hz，3H)。
Embodiment 19: 5-(1-(the chloro-3-fluorophenyl of 2,66-bis-) oxyethyl group)-4 '-methoxyl group-6 '-(4-methylpiperazine-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for embodiment 17, with the bromo-2-of 5-(4-the methylpiperazine-1-yl)-4-methoxypyridine replacement bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine, make target compound, productive rate 64%.MS m/z[ESI]：506.1[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.91(1H，s)，7.69(1H，s)，7.28-7.31(1H，m)，7.06(1H，t，J＝8.0Hz)，6.95(1H，s)，6.12(1H，s)，6.04(1H，q，J＝6.8Hz)，4.96(2H，s)，3.75(3H，s)，3.67-3.72(4H，m)，2.66-2.75(4H，m)，2.47(3H，s)，1.83(3H，d，J＝6.8Hz)。
Embodiment 20: 3-(1-(2-(solutions of dimethyl phosphoryl base)-5-fluorophenyl) oxyethyl group)-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-PA
With reference to the method for embodiment 17, with the bromo-3-of 5-(1-(2-(solutions of dimethyl phosphoryl base)-5-fluorophenyl) the oxyethyl group)-PA replacement bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine, with 1-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl)-4-methylpiperazine replacement 3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA, make target compound, productive rate 64%.MS m/z[ESI]：513.2[M+1]。 1H-NMR(400MHz，DMSO-d 6)：δ＝7.78-7.69(m，2H)，7.65(d，J＝10.5Hz，1H)，7.58(s，1H)，7.29(dd，J＝15.6，6.8Hz，1H)，7.20(d，J＝8.4Hz，1H)，7.09(q，J＝5.3Hz，1H)，6.64(s，1H)，6.61(q，J＝6.5Hz，1H)，3.67(s，3H)，3.37-2.93(m，8H)，2.86(s，3H)，1.74(dd，J＝13.3，5.6Hz，6H)，1.67(d，J＝6.3Hz，3H)。
Embodiment 21: 3-(1-(the chloro-2-of 4-(dimethylamino)-5-fluorophenyl) oxyethyl group)-5-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-PA
With reference to the method for embodiment 17, with the bromo-3-of 5-(1-(the chloro-5-fluorophenyl of 2-(dimethylamino)-4-) the oxyethyl group)-PA replacement bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine, with 1-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl)-4-methylpiperazine replacement 3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA, make target compound, productive rate 64%.MS m/z[ESI]：514.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝8.035(1H，s)，7.534(1H，s)，7.105(1H，s)，6.987(1H，d，J＝8.4Hz)，6.546(1H，s)，6.460-6.422(2H，m)，6.385(1H，s)，5.564(1H，q)，3.612(3H，s)，3.453(4H，m)，2.983(4H，m)，2.815(6H，s)，2.620(3H，s)，1.64(3H，d，J＝6.4Hz)。
Embodiment 22: 5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2,4-lupetazin-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for embodiment 17, with (S)-1-(the bromo-4-methoxypyridine-2-of 5-yl)-2,4-lupetazin replaces the bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine, makes target compound, productive rate 64%.MS m/z[ESI]：520.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.90(1H，s)，7.63(1H，s)，7.27-7.30(1H，m)，7.05(1H，t，J＝8.0Hz)，6.95(1H，s)，6.05(1H，s)，6.02(1H，q，J＝6.8Hz)，5.29(2H，s)，4.40-4.50(1H，m)，3.87-4.15(1H，m)，3.74(3H，s)，3.12(1H，t，J＝12.4Hz)，2.93(1H，d，J＝11.2Hz)，2.77(1H，d，J＝11.2Hz)，2.32(3H，s)，2.30(1H，m)，2.07-2.14(1H，m)1.82(3H，d，J＝6.8Hz)，1.28(3H，d，J＝6.8Hz)。
Embodiment 23: 5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((R)-2,4-lupetazin-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for embodiment 17, with (R)-1-(the bromo-4-methoxypyridine-2-of 5-yl)-2,4-lupetazin replaces the bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine, makes target compound, productive rate 64%.MS m/z[ESI]：520.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.91(s，1H)，7.69(s，1H)，7.31-7.28(m，1H)，7.05(t，J＝8.4Hz，1H)，6.96(s，1H)，6.06(s，1H)，6.03(q，J＝6.5Hz，1H)，4.98(s，2H)，4.54(m，1H)，3.99(d，J＝12.4Hz，1H)，3.74(s，3H)，3.28(t，J＝13.8Hz，1H)，2.99(d，J＝10.8Hz，1H)，2.83(d，J＝11.2Hz，1H)，2.37(s，3H)，2.32(m，1H)，2.23-2.11(m，1H)，1.83(d，J＝6.6Hz，3H)，1.31(d，J＝6.4Hz，3H)。
Embodiment 24: 5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2,4-lupetazin-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for embodiment 17, with (S)-1-(the bromo-4-methoxypyridine-2-of 5-yl)-2, 4-lupetazin replaces the bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine, with (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA replacement 3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA makes target compound, productive rate 64%.MSm/z[ESI]：520.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.91(1H，s)，7.65(1H，s)，7.27-7.30(1H，m)，7.05(1H，t，J＝8.4Hz)，6.96(1H，s)，6.02-6.10(2H，m)，5.25(2H，s)，4.43-4.50(1H，m)，3.97(1H，d，J＝12.8Hz)，3.74(3H，s)，3.23(1H，td，J＝12.8Hz，3.2Hz)，2.94(1H，d，J＝11.2Hz)，2.78(1H，d，J＝11.2Hz)，2.29-2.32(4H，m)，2.07-2.14(1H，m)，1.82(3H，d，J＝6.8Hz)，1.28(3H，d，J＝6.4Hz)。
Embodiment 25: 5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((R)-2,4-lupetazin-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for embodiment 17, with (R)-1-(the bromo-4-methoxypyridine-2-of 5-yl)-2, 4-lupetazin replaces the bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine, with (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA replacement 3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA makes target compound, productive rate 64%.MSm/z[ESI]：520.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.93(1H，s)，7.70(1H，s)，7.28-7.31(1H，m)，7.07(1H，t，J＝8.0Hz)，6.97(1H，s)，6.04-6.13(2H，m)，4.98(2H，s)，4.43-4.52(1H，m)，3.98(1H，d，J＝12.4Hz)，3.76(3H，s)，3.24(1H，td，J＝12.4Hz，2.8Hz)，2.93(1H，d，J＝10.8Hz)，2.78(1H，d，J＝10.4Hz)，2.29-2.34(4H，m)，2.09-2.14(1H，m)，1.84(3H，d，J＝6.8Hz)，1.29(3H，d，J＝6.8Hz)。
Embodiment 26: 5-((R)-1-(the chloro-3-fluorophenyl of 26-bis-) oxyethyl group)-5 '-methoxyl group-6 '-((S)-2,4-lupetazin-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for embodiment 17, with (S)-1-(the bromo-3-Methoxy Pyridine-2-of 5-yl)-2, 4-lupetazin replaces the bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine, with (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA replacement 3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA makes target compound, productive rate 64%.MSm/z[ESI]：520.2[M+1]。 1H-NMR(400MHz，DMSO-d 6)：δ＝7.89(s，1H)，7.78(s，1H)，7.33(dd，J＝8.8，4.8Hz，1H)，7.09(t，J＝8.4Hz，1H)，7.01(s，1H)，6.95(s，1H)，6.13(q，J＝6.6Hz，1H)，5.50(s，2H)，4.47(m，1H)，3.88(s，3H)，3.85(t，J＝4.2Hz，1H)，3.79(d，J＝11.8Hz，1H)，3.40(m，1H)，3.25(m，2H)，3.12(m，1H)，2.85(s，3H)，1.89(d，J＝6.6Hz，3H)，1.26(d，J＝6.5Hz，3H)。
Embodiment 27: 5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methylpiperazine-1-yl)-3,3 '-dipyridyl-6-amine
Universal synthesis method:
Step 1:5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine
By (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (106mg, 0.275mmol), (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA (140mg, 0.33mmol), tetrakis triphenylphosphine palladium (32mg, 0.0275mmol) and cesium carbonate (179mg, 0.55mmol) be added in diox (10mL) and water (1.5mL), nitrogen replacement, 100 DEG C of reactions are spent the night.Cooling rear silica gel column chromatography separates, obtain 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine (70mg), yield: 42%.MS m/z[ESI]：606.2[M+1]。
Step 2:5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methylpiperazine-1-yl)-3,3 '-dipyridyl-6-amine
Under stirring to 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3, 3 '-dipyridyl-6-amine (67mg, in dichloromethane solution 0.11mmol), (10mL) adds trifluoroacetic acid (1mL), stir 1 hour, be greater than 13 with sodium hydroxide solution adjust pH, with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filter, filtrate is concentrated, column chromatography separating purification (taking dichloromethane methanol=8: 1 is eluent), obtain 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methylpiperazine-1-yl)-3, 3 '-dipyridyl-6-amine (30mg), yield: 55%, MS m/z[ESI]: 506.1[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝7.94(1H，s)，7.71(1H，s)，7.28-7.32(1H，m)，7.07(1H，t，J＝8.4Hz)，6.97(1H，s)，6.04-6.13(2H，m)，4.86(2H，s)，4.57-4.59(1H，m)，4.03(1H，d，J＝14Hz)，3.76(3H，s)，3.07-3.33(4H，m)，2.88-3.00(1H，m)，1.84(3H，d，J＝6.8Hz)，1.34(3H，d，J＝6.8Hz)。
Embodiment 28: 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-(1-methyl piperidine-4-yl) piperazine-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for embodiment 17, with (S)-1-(the bromo-4-methoxypyridine-2-of 5-yl)-2-methyl-4-(1-methyl piperidine-4-yl) piperazine replacement bromo-2-of 5-(4-sec.-propyl piperazine-1-yl)-4-methoxy pyrimidine, with (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA replacement 3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA makes target compound, productive rate 27%.MS m/z[ESI]：603.2[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.88(1H，s)，7.66(1H，s)，7.26-7.28(1H，m)，7.03(1H，t，J＝8.0Hz)，6.93(1H，s)，5.99-6.02(2H，m)，4.83(2H，s)，4.43-4.46(1H，m)，3.98(1H，d，J＝12.4Hz)，3.72(3H，s)，3.21-3.30(2H，m)，3.12(1H，t，J＝11.6Hz)，2.92(1H，d，J＝9.6Hz)，2.79(1H，d，J＝10.8Hz)，2.64-2.80(4H，m)，2.44-2.47(3H，m)，2.29-2.34(1H，m)，2.06-2.14(4H，m)，1.79(3H，d，J＝6.8Hz)，1.21(3H，d，J＝6.4Hz)。
Embodiment 29: (R)-5-(1-(the chloro-3-fluorophenyl of 26-bis-) oxyethyl group)-4 '-methoxyl group-6 '-(1,2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-6-amine
Step 1:(R)-4-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4-methoxyl group-3,3 '-dipyridyl-6-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with 4-(the bromo-4-methoxypyridine-2-of 5-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester replaces (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 20%.MS m/z[ESI]：589.2[M+1]。
Step 2:(R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-(1,2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for step 2 in embodiment 27, with (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4-methoxyl group-3,3 '-dipyridyl-6-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester replaces 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 41%, MS m/z[ESI]: 489.1[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝8.21(1H，s)，7.60(1H，s)，7.26-7.29(1H，m)，7.04(1H，t，J＝8.0Hz)，6.96(1H，s)，6.87(1H，s)，6.49(1H，s)，6.01(1H，q，J＝6.8Hz)，5.33(2H，s)，3.94(2H，s)，3.74(3H，s)，3.49(2H，t，J＝4.2Hz)，3.00(2H，dt，J＝4.2Hz)，1.81(3H，d，J＝6.8Hz)。
Embodiment 30: (R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-methoxyl group-6 '-(1,2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-6-amine
Universal synthesis method:
Step 1:(R)-6 '-chloro-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-methoxyl group-3,3 '-dipyridyl-6-amine
By chloro-bromo-5-2-3-Methoxy Pyridine (244mg, 1.1mmol), (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-PA (427mg, 1.0mmol), tetrakis triphenylphosphine palladium (116mg, 0.1mmol) and cesium carbonate (652mg, 2.0mmol) are added in diox (10mL) and water (1.5mL), nitrogen replacement, 100 DEG C of reactions are spent the night.Cooling rear silica gel column chromatography separates, and obtains (R)-6 '-chloro-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-methoxyl group-3,3 '-dipyridyl-6-amine (252mg), yield: 57%.MS m/z[ESI]：442.0[M+1]。
Step 2:(R)-4-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-3,3 '-dipyridyl-6-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
By (R)-6 '-chloro-5-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5 '-methoxyl group-3,3 '-dipyridyl-6-amine (243mg, 0.55mmol), 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (204mg, 0.66mmol), tetrakis triphenylphosphine palladium (64mg, 0.055mmol) and cesium carbonate (359mg, 1.1mmol) are added in diox (6mL) and water (1mL), nitrogen replacement, 100 DEG C of reactions are spent the night.Cooling rear silica gel column chromatography separates, obtain (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-methoxyl group-3,3 '-dipyridyl-6-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (65mg), yield: 20%.MS m/z[ESI]：589.2[M+1]。
Step 3:(R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-methoxyl group-6 '-(1,2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for step 2 in embodiment 27, with (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-methoxyl group-3,3 '-dipyridyl-6-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester replaces 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 41%, MS m/z[ESI]: 489.1[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝8.21(1H，s)，7.84(1H，s)，7.28-7.32(1H，m)，7.04-7.08(2H，m)，6.93(1H，s)，6.52(1H，s)，6.10(1H，q，J＝6.4Hz)，5.21(2H，s)，3.86(3H，s)，3.74(2H，s)，3.28(2H，t，J＝4.2Hz)，2.77(2H，t，J＝4.2Hz)，1.87(3H，d，J＝6.8Hz)。
Embodiment 31: 5-(1-(2-(1,1-, bis-fluoro ethyls)-5-fluorophenyl) oxyethyl group)-4 '-methoxyl group-6 '-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)-3,3 '-dipyridyl-6-amine
Universal synthesis method:
The bromo-1-of step 1:2-(1,1-, bis-fluoro ethyls)-4-fluorobenzene
By bromo-2-4-fluoro acetophenone (3.5g, 16mmol) and diethylin sulfur trifluoride (DAST) (20mL) put into tube sealing, at 60 DEG C, react and spend the night, in cooling rear careful impouring trash ice, extract with Skellysolve A, dry, silica gel column chromatogram separating purification obtains target compound (2.3g), yield: 60%.
Step 2:1-(2-(1,1-, bis-fluoro ethyls)-5-fluorophenyl) ethyl ketone
By bromo-2-1-(1,1-bis-fluoro ethyls)-4-fluorobenzene (717mg, 3mmol), vinyl n-butyl ether (3.0g, 30mmol), palladium (67mg, 0.3mmol), 1, two (diphenylphosphine) propane (the DPPP) (248mg of 3-, 0.6mmol) and triethylamine (909mg, 9mmol) and DMF (10mL) add in tube sealing, nitrogen replacement, 120 DEG C of reactions are spent the night.After cooling, pour in 10% hydrochloric acid (50mL) and stir 1 hour, with saturated sodium bicarbonate solution neutralization, dichloromethane extraction, silica gel column chromatography separates, and obtains target compound, yield: 33%.
Step 3:1-(2-(1,1-, bis-fluoro ethyls)-5-fluorophenyl) ethanol
With reference to the method for step 4 in intermediate 40, with 1-(2-(1,1-, bis-fluoro ethyls)-5-fluorophenyl) ethyl ketone replacement 2-(dimethylamino)-chloro-5-fluoro acetophenone of 4-, obtain target compound, yield: 30%.
Step 4:2-(1-bromotrifluoromethane)-1-(1,1-, bis-fluoro ethyls)-4-fluorobenzene
With reference to the method for step 5 in intermediate 40, with 1-(2-(1,1-bis-fluoro ethyls)-5-fluorophenyl) ethanol replacement 1-(the chloro-5-fluorophenyl of 2-(dimethylamino)-4-) ethanol, obtain target compound, yield: 50%.
The bromo-3-of step 5:5-(1-(2-(1,1-, bis-fluoro ethyls)-5-fluorophenyl) oxyethyl group) pyridine-2-amine
With reference to the method for step 6 in intermediate 40, with the fluoro-DMA of 2-(1-bromotrifluoromethane)-1-(1,1-, bis-fluoro ethyls)-4-fluorobenzene replacement 2-(1-bromotrifluoromethane) the chloro-4-of-5-, obtain target compound, yield: 41%.MS m/z[ESI]：375.0[M+1]。
Step 6:5-(1-(2-(1,1-, bis-fluoro ethyls)-5-fluorophenyl) oxyethyl group)-4 '-methoxyl group-6 '-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for step 1 in embodiment 27, with the bromo-3-of 5-(1-(2-(1, 1-bis-fluoro ethyls)-5-fluorophenyl) oxyethyl group) pyridine-2-amine replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, with 1-(1-(4-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) pyridine-2-yl) piperidin-4-yl)-4-methylpiperazine replacement (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA) obtain target compound, yield: 32%, MS m/z[ESI]: 585.3[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝7.59-7.65(2H，m)，7.12-7.18(2H，m)，6.98(1H，d，J＝7.6Hz)，6.47(1H，d，J＝6.4Hz)，6.42(1H，s)，5.86(2H，s)，5.36(1H，q，J＝6.8Hz)，3.72-3.79(2H，m)，3.64(3H，s)，2.95-3.08(4H，m)，2.75(2H，t，J＝12.4Hz)，2.56-2.68(4H，m)，2.22(1H，m)，2.07(3H，s)，2.027(3H，t，J＝18.8Hz)，1.93-1.83(4H，m)，1.67(3H，d，J＝6.0Hz)。Embodiment 32: (R)-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-6-(piperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
Step 1:(R)-4-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-2,3 '-dipyridyl-6-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with 4-(the bromo-3-Methoxy Pyridine-2-of 6-yl) piperazine-1-carboxylic acid tert-butyl ester replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 53%.MS m/z[ESI]：592.2[M+1]。
Step 2:(R)-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-6-(piperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
With reference to the method for step 2 in embodiment 27, with (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-methoxyl group-2,3 '-dipyridyl-6-yl) piperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 65%, MSm/z[ESI]: 492.1[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝8.09(1H，s)，7.57-7.62(1H，m)，7.43(1H，t，J＝8.0Hz)，7.22-7.30(2H，m)，7.16(1H，s)，6.01(1H，q，J＝6.4Hz)，5.90(2H，s)，3.78(3H，s)，3.40-3.42(4H，m)，3.05-3.17(4H，m)，1.77(3H，d，J＝6.4Hz)。
Embodiment 33: 5-(1-(the chloro-5-fluorophenyl of 2-)-2,2,2-trifluoro ethoxy)-5 '-(piperazine-1-yl)-3,3 '-dipyridyl-6-amine
Universal synthesis method:
Step 1:1-(the chloro-5-fluorophenyl of 2-)-2,2,2-trifluoro ethyl ketone
By chloro-2-5-fluorophenyl carbamate (18.8g, 0.1mol), trifluoromethyl trimethyl silicane (15.6g, 0.11mol) and cesium fluoride (2.0g, 0.013mmol) stirring at room temperature 30 minutes under nitrogen atmosphere, adding 5M hydrochloric acid (50mL) to stir spends the night, add again glycol dimethyl ether (50mL), at 120 DEG C, stir and spend the night, cooling neutralize with sodium hydroxide solution afterwards, with dichloromethane extraction, dry, silica gel column chromatogram separating purification obtains target compound (3.5g), yield: 15%.
Step 2:1-(the chloro-5-fluorophenyl of 2-)-2,2,2 tfifluoroethyl alcohol
With reference to the method for step 4 in intermediate 40, with 1-(the chloro-5-fluorophenyl of 2-)-2,2,2-trifluoro ethyl ketone replaces 2-(dimethylamino)-chloro-5-fluoro acetophenone of 4-, obtains target compound, yield: 85%.
Step 3:2-(1-bromo-2,2,2-trifluoroethyl) the chloro-4-fluorobenzene of-1-
By 1-(the chloro-5-fluorophenyl of 2-)-2,2,2-trifluoroethanol (2.0g, 8.75mmol) and phosphorus pentabromide (5.0g, 11.6mmol) add in tube sealing, at 140 DEG C, reaction is spent the night, and adds trash ice, neutralizes with sodium hydroxide solution, with dichloromethane extraction, dry, silica gel column chromatogram separating purification obtains target compound, yield: 33%.
The bromo-3-of step 4:5-(1-(the chloro-5-fluorophenyl of 2-)-2,2,2-trifluoro ethoxy) pyridine-2-amine
With reference to the method for step 6 in intermediate 40, replace the fluoro-DMA of 2-(1-bromotrifluoromethane) the chloro-4-of-5-with the chloro-4-fluorobenzene of 2-(1-bromo-2,2,2-trifluoroethyl)-1-, obtain target compound, yield: 27%.MS m/z[ESI]：400.9[M+1]。
Step 5:4-(6 '-amino-5 '-(1-(the chloro-5-fluorophenyl of 2-)-2,2,2-trifluoro ethoxy)-3,3 '-dipyridyl-5-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with the bromo-3-of 5-(1-(the chloro-5-fluorophenyl of 2-)-2, 2, 2-trifluoro ethoxy) pyridine-2-amine replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, with 4-(5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester replacement (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA, obtain target compound, yield: 41%.MS m/z[ESI]：582.2[M+1]。
Step 6:5-(1-(the chloro-5-fluorophenyl of 2-)-2,2,2-trifluoro ethoxy)-5 '-(piperazine-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for step 2 in embodiment 27, with 4-(6 '-amino-5 '-(1-(the chloro-5-fluorophenyl of 2-)-2,2,2-trifluoro ethoxy)-3,3 '-dipyridyl-5-yl) piperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 32%, MS m/z[ESI]: 482.1[M+1]. 1H-NMR(400MHz，CD 3OD)：δ＝8.07(1H，s)，7.97(1H，s)，7.80(1H，s)，7.40-7.50(2H，m)，7.27(1H，s)，7.15(1H，s)7.07(1H，s)，6.43(1H，m)，3.20(4H，m)，3.06(4H，m)。Embodiment 34: (R)-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-3-methoxyl group-6-(piperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
Step 1:(R)-4-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-3-methoxyl group-2,3 '-dipyridyl-6-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with 4-(the bromo-5-methoxypyridine-2-of 6-yl) piperazine-1-carboxylic acid tert-butyl ester replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：592.2[M+1]。
Step 2:(R)-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-3-methoxyl group-6-(piperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
With reference to the method for step 2 in embodiment 27, with (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-3-methoxyl group-2,3 '-dipyridyl-6-yl) piperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 67%, MSm/z[ESI]: 492.1[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝，8.20(1H，s)，7.54-7.58(1H，m)，7.45(1H，t，J＝8.8Hz)，7.41(1H，d，J＝9.2Hz)，7.22(1H，s)，6.77(1H，d，J＝9.2Hz)，6.04(2H，s)，5.98(1H，q，J＝6.6Hz)，3.66(3H，s)，3.53-3.58(4H，m)，3.14-3.17(4H，m)，1.76(3H，d，J＝6.4Hz)。
Embodiment 35: (R)-4-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 26-bis-) oxyethyl group)-4-methoxyl group-3,3 '-dipyridyl-6-yl) piperazine-2-ketone
With reference to the method for step 1 in embodiment 27, with 4-(the bromo-4-methoxypyridine-2-of 5-yl) piperazine-2-ketone replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：506.1[M+1]。 1H-NMR(400MHz，CDCl 3)：δ＝7.16(1H，s)，7.59(1H，s)，7.46(1H，dd，J＝9.2Hz，4.8Hz)，7.26(1H，t，J＝8.4Hz)，6.93(1H，s)，6.32(1H，s)，6.10(1H，q，J＝6.8Hz)，4.14(2H，s)，3.81(2H，t，J＝5.2Hz)，3.77(3H，s)，3.45(2H，t，J＝5.6Hz)，1.85(3H，d，J＝6.4Hz)。
Embodiment 36: (R)-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4-methoxyl group-6-(piperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
Step 1:(R)-4-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4-methoxyl group-2,3 '-dipyridyl-6-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with 4-(6-chloro-4-methoxy pyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：592.2[M+1]。
Step 2:(R)-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4-methoxyl group-6-(piperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
With reference to the method for step 2 in embodiment 27, with (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4-methoxyl group-2,3 '-dipyridyl-6-yl) piperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 67%, MSm/z[ESI]: 492.1[M+1]. 1H-NMR(400MHz，CD 3OD)：δ＝8.15(s，1H)，7.87(s，1H)，7.46(dd，J＝9.4，4.6Hz，1H)，7.25(t，J＝8.5Hz，1H)，6.62(d，J＝1.6Hz，1H)，6.29(d，J＝1.6Hz，1H)，6.17(q，J＝6.3Hz，1H)，3.86(s，3H)，3.82(m，4H)，3.29(m，4H)，1.88(d，J＝6.6Hz，3H)。
Embodiment 37: (R)-5 '-(1-(the chloro-3-fluorophenyl of 26-bis-) oxyethyl group)-4-methoxyl group-6-(piperazine-1-yl)-3,3 '-dipyridyl-6 '-amine
Step 1:(R)-4-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4-methoxyl group-3,3 '-dipyridyl-6-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with 4-(the bromo-4-methoxypyridine-2-of 5-yl) piperazine-1-carboxylic acid tert-butyl ester replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：592.2[M+1]。
Step 2:(R)-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4-methoxyl group-6-(piperazine-1-yl)-3,3 '-dipyridyl-6 '-amine
With reference to the method for step 2 in embodiment 27, with (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4-methoxyl group-2,3 '-dipyridyl-6-yl) piperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 67%, MSm/z[ESI]: 492.1[M+1]. 1h-NMR (400MHz, CDCl 3): δ=7.91 (1H, s), 7.68 (1H, s), 7.26-7.30 (1H, m), 7.05 (1H, t, J=8.4Hz), 6.94 (1H, s), 6.12 (1H, s), 6.04 (1H, q, J=6.8Hz), 4.9 (2H, s), 3.66-3.75 (7H, m), 3.11-3.18 (4H, m), 1.83 (3H, d, J=6.8Hz).
Embodiment 38: (R)-5-(1-(the chloro-3-fluorophenyl of 26-bis-) oxyethyl group)-5 '-methoxyl group-2 '-(piperazine-1-yl)-3,4 '-dipyridyl-6-amine
Step 1:(R)-4-(6-amino-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-methoxyl group-3,4 '-dipyridyl-2 '-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with 4-(the bromo-5-methoxypyridine-2-of 4-yl) piperazine-1-carboxylic acid tert-butyl ester replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：592.2[M+1]。
Step 2:(R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-methoxyl group-2 '-(piperazine-1-yl)-3,4 '-dipyridyl-6-amine
With reference to the method for step 2 in embodiment 27, with (R)-4-(6-amino-5-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5 '-methoxyl group-3,4 '-dipyridyl-2 '-yl) piperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 67%, MSm/z[ESI]: 492.1[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝7.89(1H，s)，7.85(1H，s)，7.30(1H，dd，J＝8.8Hz，4.8Hz)，7.08(1H，t，J＝8.0Hz)，7.01(1H，s)，6.51(1H，s)，6.05(1H，q，J＝6.8Hz)，5.13(2H，s)，3.72-3.80(4H，m)，3.70(3H，s)，3.25-3.31(4H，m)，1.84(3H，d，J＝6.4Hz)。
Embodiment 39: (R)-5 '-(1-(the chloro-3-fluorophenyl of 26-bis-) oxyethyl group)-5-methoxyl group-4-(piperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
Step 1:(R)-4-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-2,3 '-dipyridyl-4-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with 4-(the bromo-5-methoxypyridine-4-of 2-yl) piperazine-1-carboxylic acid tert-butyl ester replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：592.2[M+1]。
Step 2:(R)-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-4-(piperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
With reference to the method for step 2 in embodiment 27, with (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-methoxyl group-2,3 '-dipyridyl-4-yl) piperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 67%, MSm/z[ESI]: 492.1[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝8.18(1H，s)， 8.11(1H，s)，7.35(1H，s)，7.30-7.32(1H，m)，7.06(1H，t，J＝8.4Hz)，6.88(1H，s)，6.15(1H，q，J＝6.8Hz)，5.04-
5.20(2H，brs)，3.93(3H，s)，3.41-3.48(4H，m)，3.28-3.32(4H，m)，1.85(3H，d，J＝6.4Hz)。
Embodiment 40: 3-(1-(2-(difluoromethyl)-5-fluorophenyl) oxyethyl group)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl) pyridine-2-amine
Step 1:4-(4-(6-amino-5-(1-(2-(difluoromethyl)-5-fluorophenyl) oxyethyl group) pyridin-3-yl)-3-p-methoxy-phenyl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with 4-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester replacement (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA, with the bromo-3-of 5-(1-(2-(difluoromethyl)-5-fluorophenyl) oxyethyl group)-PA replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：573.3[M+1]。
Step 2:3-(1-(2-(difluoromethyl)-5-fluorophenyl) oxyethyl group)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl) pyridine-2-amine
With reference to the method for step 2 in embodiment 27, with 4-(4-(6-amino-5-(1-(2-(difluoromethyl)-5-fluorophenyl) oxyethyl group) pyridin-3-yl)-3-p-methoxy-phenyl) piperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 67%, MSm/z[ESI]: 473.2[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝7.68(1H，s)，7.56(1H，dd，J＝8.8Hz，5.2Hz)，7.21-7.23(1H，m)，7.16(1H，t，J＝9.6Hz)，7.03(1H，d，J＝8.0Hz)，6.99(1H，s)，6.81(1H，t，J＝54.8Hz)，6.48(1H，dd，J＝8.4Hz，1.6HZ)，6.42(1H，d，J＝2.0Hz)，5.64(1H，q，J＝6.4Hz)，5.08(2H，s)，3.61(3H，s)，3.43-3.46(4H，m)，3.32-3.35(4H，m)，1.67(3H，d，J＝6.4Hz)。
Embodiment 41: 5-(the chloro-2-methoxyl group-4-of 5-(piperazine-1-yl) phenyl)-3-(1-(2-(difluoromethyl)-5-fluorophenyl) oxyethyl group) pyridine-2-amine
With reference to the preparation method of embodiment 40, column chromatography separates and obtains target compound 41, yield: 7%, MS m/z[ESI]: 507.2[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝7.72(1H，s)，7.60(1H，dd，J＝8.4Hz，5.6Hz)，7.26(1H，d，J＝8.8Hz)，7.20(1H，t，J＝8.4Hz)，7.17(1H，s)，6.98(1H，s)，6.84(1H，t，J＝52.0Hz)，6.59(1H，s)，5.68(1H，q，J＝6.4Hz)，5.08(2H，s)，3.65(3H，s)，3.30-3.50(8H，m)，1.72(3H，d，J＝6.4Hz)。
Embodiment 42: (R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-methoxyl group-6 '-(piperidin-4-yl)-3,3 '-dipyridyl-6-amine
By embodiment 30:(R)-5-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5 '-methoxyl group-6 '-(1,2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-6-amine (98mg, 0.2mmol) and palladium carbon (10mg) add in methyl alcohol (20mL), stir 6 hours under hydrogen atmosphere.Remove by filter palladium carbon, concentrated, prepare target compound (12mg), yield with high performance liquid chromatography: 12%, MS m/z[ESI]: 491.1[M+1]. 1H-NMR(400MHz，CDCl 3)：δ＝8.00(d，J＝1.8Hz，1H)，7.70(d，J＝1.7Hz，1H)，7.37(dd，J＝9.0，4.9Hz，1H)，7.18(s，1H)，7.14(d，J＝8.5Hz，1H)，6.90(d，J＝1.7Hz，1H)，6.14(q，J＝6.5Hz，1H)，4.46(m，1H)，3.83(s，3H)，3.41(m，2H)，3.11-2.99(m，2H)，1.95(dd，J＝9.6，3.6Hz，4H)，1.81(d，J＝6.7Hz，3H)。
Embodiment 43: (R)-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-6-(1,2,3,6-tetrahydropyridine-4-yl)-2,3 '-dipyridyl-6 '-amine
Step 1:(R)-4-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-2,3 '-dipyridyl-6-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with 4-(the bromo-3-Methoxy Pyridine-2-of 6-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester replaces (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：589.2[M+1]。
Step 2:(R)-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-6-(1,2,3,6-tetrahydropyridine-4-yl)-2,3 '-dipyridyl-6 '-amine
With reference to the method for step 2 in embodiment 27, with (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-methoxyl group-2,3 '-dipyridyl-6-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester replaces 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 67%, MS m/z[ESI]: 489.1[M+1]. 1H NMR(400MHz，CDCl 3)：δ＝8.09(1H，s)， 7.40-7.42(2H，m)，7.28-7.30(1H，s)，7.13(1H，d，J＝8.8Hz)，7.00(1H，t，J＝8.8Hz)，6.73(1H，s)，6.10(1H，q，J＝6.8Hz)，5.16(2H，s)，3.99(2H，t，J＝5.6Hz)，3.84(2H，m)，3.52(2H，t，J＝5.6Hz)，3.49(3H，s)，1.83(3H，d，J＝6.8Hz)。
Embodiment 44: 5 '-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-3-methoxyl group-6-((S)-2-methylpiperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
Step 1:(S)-4-(6 '-amino-5 '-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-3-methoxyl group-2,3 '-dipyridyl-6-yl)-3-
Methylpiperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with (S)-4-(the bromo-5-methoxypyridine-2-of 6-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：606.2[M+1]。
Step 2:5 '-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-3-methoxyl group-6-((S)-2-methylpiperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
With reference to the method for step 2 in embodiment 27, with (S)-4-(6 '-amino-5 '-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-3-methoxyl group-2,3 '-dipyridyl-6-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 67%, MS m/z[ESI]: 506.1[M+1]. 1H NMR(400MHz，CDCl 3)：δ＝8.38(d，J＝1.4Hz，1H)，7.45(d，J＝1.5Hz，1H)，7.30(dd，J＝8.9，4.8Hz，1H)，7.21(d，J＝9.0Hz，1H)，7.11-7.01(m，1H)，6.53(d，J＝9.0Hz，1H)，6.08(d，J＝6.7Hz，1H)，5.23(s，2H)，4.62(m，1H)，4.03(d，J＝14.0Hz， 1H)，3.73(s，3H)，3.59(d，J＝12.3Hz，1H)，3.45-3.29(m，3H)，3.11(m，1H)，1.82(d，J＝6.7Hz，3H)，1.38(d，J＝6.9Hz，3H)。
Embodiment 45: (R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-methoxyl group-5 '-(piperazine-1-yl)-3,3 '-dipyridyl-6-amine
Step 1:(R)-4-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4-methoxyl group-3,3 '-dipyridyl-5-yl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with 4-(the bromo-4-methoxypyridine-3-of 5-yl) piperazine-1-carboxylic acid tert-butyl ester replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：592.2[M+1]。
Step 2:(R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-methoxyl group-5 '-(piperazine-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for step 2 in embodiment 27, with (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4-methoxyl group-3,3 '-dipyridyl-5-yl) piperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield 67%, MS m/z[ESI]: 492.1[M+1]. 1H NMR(400MHz，CDCl 3)：δ＝8.13(s，1H)，8.10(s，1H)，7.75(s，1H)，7.29(d，J＝5.0Hz，1H)，7.07(t，J＝8.4Hz，1H)，6.96(s，1H)，6.04(q，J＝6.8Hz，1H)，4.89(s，2H)，3.43(s，3H)，3.21(d，J＝7.3Hz，2H)，3.07(m，6H)，1.85(d，J＝6.7Hz，3H)。
Embodiment 46: 3-(1-(2-(1,1-, bis-fluoro ethyls)-5-fluorophenyl) oxyethyl group)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl) pyridine-2-amine
Step 1:4-(4-(6-amino-5-(1-(2-(1,1-, bis-fluoro ethyls)-5-fluorophenyl) oxyethyl group) pyridin-3-yl)-3-p-methoxy-phenyl) piperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with the bromo-3-of 5-(1-(2-(1, 1-bis-fluoro ethyls)-5-fluorophenyl) oxyethyl group) pyridine-2-amine replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, with 4-(3-methoxyl group-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl) phenyl) piperazine-1-carboxylic acid tert-butyl ester replacement (R)-3-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxane pentaborane-2-yl)-PA, obtain target compound, yield: 46%.MS m/z[ESI]：587.3[M+1]。
Step 2:3-(1-(2-(1,1-, bis-fluoro ethyls)-5-fluorophenyl) oxyethyl group)-5-(2-methoxyl group-4-(piperazine-1-yl) phenyl) pyridine-2-amine
With reference to the method for step 2 in embodiment 27, with 4-(4-(6-amino-5-(1-(2-(1,1-bis-fluoro ethyls)-5-fluorophenyl) oxyethyl group) pyridin-3-yl)-3-p-methoxy-phenyl) piperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield 67%, MSm/z[ESI]: 487.2[M+1]. 1H NMR(400MHz，CDCl 3)：δ＝7.63(t，J＝9.0Hz，2H)，7.54(s，1H)，7.23(t，J＝8.2Hz，1H)，6.99(d，J＝4.3Hz，2H)，6.57(s，1H)，6.52(d，J＝8.4Hz，1H)，5.86(s，2H)，5.81(d，J＝5.7Hz，1H)，3.60(s，3H)，3.17(s，4H)，3.12(s，4H)，2.08(t，J＝19.6Hz，3H)，1.61(d，J＝6.1Hz，3H)。
Embodiment 47: (R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-morpholine-3,3 '-dipyridyl-6-amine
With reference to the method for step 1 in embodiment 27, with 4-(the bromo-4-methoxypyridine-2-of 5-yl) morpholino for (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：493.1[M+1]。 1H NMR(400MHz，CDCl 3)：δ＝7.93(s，1H)，7.70(s，1H)，7.31-7.26(m，1H)，7.05(t，J＝8.4Hz，1H)，6.95(s，1H)，6.10(s，1H)，6.04(q，J＝6.7Hz，1H)，4.94(s，2H)，3.86-3.81(m，4H)，3.75(s，3H)，3.56-3.50(m，4H)，1.83(d，J＝6.7Hz，3H)。
Embodiment 48: 5 '-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-6-((S)-2-methylpiperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
Step 1:(S)-4-(6-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl)-3-Methoxy Pyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with (S)-4-(the bromo-3-Methoxy Pyridine-2-of 6-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：606.2[M+1]。
Step 2:5 '-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-6-((S)-2-methylpiperazine-1-yl)-2,3 '-dipyridyl-6 '-amine
With reference to the method for step 2 in embodiment 27, with (S)-4-(6-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-3-Methoxy Pyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield 67%, MS m/z[ESI]: 506.1[M+1]. 1H NMR(400MHz，CDCl 3)：δ＝8.13(1H，s)，7.73(1H，m)，7.55(1H，m)，7.32(1H，s)，7.20-7.09(2H，m)，6.12(1H，d，J＝6.6Hz)，5.21(2H，s)，4.54(1H，m)，3.86(3H，s)，3.77(1H，m)，3.67(1H，m)，3.51(2H，m)，3.43(1H，d，J＝9.3Hz)，3.24(3H，d，J＝11.9Hz)，1.87(3H，d，J＝6.6Hz)，1.38(3H，d，J＝6.9Hz)。
Embodiment 49: 5-(the chloro-2-methoxyl group-4-of 5-(piperazine-1-yl) phenyl)-3-(1-(2-(1,1-, bis-fluoro ethyls)-5-fluorophenyl) oxyethyl group) pyridine-2-amine
With reference to the preparation method of embodiment 46, silica gel column chromatogram separating purification has obtained target compound 49, yield: 67%, MSm/z[ESI]: 521.2[M+1]. 1H NMR(400MHz，CDCl 3)：δ＝7.65(d，J＝10.7Hz，2H)，7.59(d，J＝13.4Hz，1H)，7.24(s，1H)，7.13(s，1H)，6.99(s，1H)，6.71(s，1H)，6.01(s，2H)，5.83(d，J＝5.8Hz，1H)，3.64(s，3H)，3.17(s，4H)，3.11(s，4H)，2.09(t，J＝19.6Hz，3H)，1.62(d，J＝6.1Hz，3H)。
Embodiment 50: (R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-oxyethyl group-6 '-(1,2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-6-amine
Step 1:5-(the chloro-5-ethoxy pyridine-3-of 6-yl)-3-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridine-2-amine
With reference to the method for step 1 in embodiment 30, with the chloro-3-Methoxy Pyridine of the bromo-2-chloro-3-ethoxy of the 5-pyridine replacement bromo-2-of 5-, obtain target compound, yield: 46%.MS m/z[ESI]：456.0[M+1]。
Step 2:4-(5-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-3-ethoxy pyridine-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With reference to the method for step 2 in embodiment 30, with 5-(the chloro-5-ethoxy pyridine-3-of 6-yl)-3-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine replacement (R)-6 '-chloro-5-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5 '-methoxyl group-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 46%.MS m/z[ESI]：603.2[M+1]。
Step 3:(R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-oxyethyl group-6 '-(1,2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for step 3 in embodiment 30, with 4-(5-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-3-ethoxy pyridine-2-yl)-5, 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester replaces (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-methoxyl group-3, 3 '-dipyridyl-6-yl)-5, 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester, obtain target compound, yield: 67%, MS m/z[ESI]: 503.1[M+1]. 1H NMR(400MHz，CD 3OD)：δ＝8.06(s，1H)，7.73(s，1H)，7.36(dd，J＝9.0，4.9Hz，1H)，7.23(s，1H)，7.16(t，J＝8.6Hz，1H)，6.90(s，1H)，6.48(s，1H)，6.13(d，J＝6.7Hz，1H)，4.08(q，J＝6.8Hz，2H)，3.79(d，J＝2.7Hz，2H)，3.34(t，J＝6.1Hz，2H)，2.82(s，2H)，1.80(d，J＝6.6Hz，3H)，1.38(t，J＝6.9Hz，3H)。
Embodiment 51: 5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-methoxyl group-6 '-(3-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-6-amine
Step 1:4-(5-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-3-Methoxy Pyridine-2-yl)-5-methyl-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With reference to the method for step 2 in embodiment 30, with 5-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester replaces 4-(4,4,5,5-tetramethyl--1,3,2-dioxane pentaborane-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester, obtains target compound, yield: 46%.MS m/z[ESI]：603.2[M+1]。
Step 2:5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-methoxyl group-6 '-(3-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for step 3 in embodiment 30, with 4-(5-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-3-Methoxy Pyridine-2-yl)-5-methyl-5, 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester replaces (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-methoxyl group-3, 3 '-dipyridyl-6-yl)-5, 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester, obtain target compound, yield: 67%, MS m/z[ESI]: 503.1[M+1]. 1H NMR(400MHz，CD 3OD)：δ＝8.16(dd，J＝4.4，1.7Hz，1H)，7.86(s，1H)，7.46(d，J＝2.3Hz，1H)，7.38(s，1H)，7.25(m，1H)，7.03(s，1H)，6.25(q，J＝6.5Hz，1H)，6.12(s，1H)，3.92(s，3H)，3.84(dd，J＝5.9，3.0Hz，2H)，3.54(dd，J＝12.3，5.4Hz，1H)，3.48(s，1H)，3.10(dd，J＝12.3，7.6Hz，1H)，1.91(d，J＝6.7Hz，3H)，0.96(d，J＝7.0Hz，3H)。
Embodiment 52: (R)-2-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-6-(1,2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-5-base oxygen base) ethanol
Step 1:2-(5-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl)-2-chloropyridine-3-base oxygen base) ethanol
With reference to the method for step 1 in embodiment 30, with the chloro-3-Methoxy Pyridine of the chloro-3-hydroxyethyl of the bromo-2-of the 5-pyridine replacement bromo-2-of 5-, obtain target compound, yield: 46%.MS m/z[ESI]：472.0[M+1]。
Step 2:4-(5-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-3-(2-hydroxyl-oxethyl) pyridine-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With reference to the method for step 2 in embodiment 30, with 2-(5-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-2-chloropyridine-3-base oxygen base) ethanol replacement (R)-6 '-chloro-5-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5 '-methoxyl group-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 46%.MS m/z[ESI]：619.2[M+1]。
Step 3:(R)-2-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-6-(1,2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-5-base oxygen base) ethanol
With reference to the method for step 3 in embodiment 30, with 4-(5-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-3-(2-hydroxyl-oxethyl) pyridine-2-yl)-5, 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester replaces (R)-4-(6 '-amino-5 '-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5-methoxyl group-3, 3 '-dipyridyl-6-yl)-5, 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester, obtain target compound, yield 67%, MS m/z[ESI]: 519.1[M+1]. 1H NMR(400MHz，CDCl 3)：δ＝8.23(s，1H)，7.87(d，J＝1.1Hz，1H)，7.31(dd，J＝8.9，4.7Hz，1H)，7.11(s，1H)，7.07(t，J＝8.4Hz，1H)，6.94(s，1H)，6.41(s，1H)，6.11(q，J＝6.6Hz，1H)，4.96(s，2H)，4.18-4.04(m，2H)，4.01(d，J＝4.3Hz，2H)，3.64(d，J＝2.6Hz，2H)，3.16(t，J＝5.7Hz，2H)，2.68(s，2H)，1.88(d，J＝6.7Hz，3H)。
Embodiment 53: 5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-oxyethyl group-6 '-((S)-2-methylpiperazine-1-yl)-3,3 '-dipyridyl-6-amine
Step 1:(S)-4-(5-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl)-4-ethoxy pyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with (S)-4-(the bromo-4-ethoxy pyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：620.2[M+1]。
Step 2:5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-4 '-oxyethyl group-6 '-((S)-2-methylpiperazine-1-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for step 2 in embodiment 27, with (S)-4-(5-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-4-ethoxy pyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 67%.MS m/z[ESI]：520.2[M+1]。 1H NMR(400MHz，CDCl 3)：δ＝7.91(s，1H)，7.78(d，J＝1.0Hz，1H)，7.31-7.26(m，1H)，7.03(dd，J＝17.1，8.9Hz，2H)，6.05(m，2H)，4.77(s，2H)，4.41(m，1H)，4.05(q，J＝6.8Hz，2H)，3.99-3.85(m，1H)，3.20-3.02(m，3H)，2.98-2.77(m，2H)，1.82(d，J＝6.7Hz，3H)，1.36(t，J＝7.0Hz，3H)，1.23(s，3H)。
Embodiment 54: (R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-6 '-morpholinyl-5 '-(2-morpholinyl oxyethyl group)-3,3 '-dipyridyl-6-amine
With reference to the method for step 1 in embodiment 27, with 4-(2-(the bromo-2-morpholinyl of 5-pyridin-3-yl oxygen) ethyl) morpholino for (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield 46%, MSm/z[ESI]: 592.2[M+1]. 1H NMR(400MHz，CDCl 3)：δ＝7.93(d，J＝1.8Hz，1H)，7.81(d，J＝1.4Hz，1H)，7.31(dd，J＝8.9，4.8Hz，1H)，7.11-7.03(m，1H)，6.99(d，J＝1.6Hz，1H)，6.91(s，1H)，6.10(q，J＝6.7Hz，1H)，4.91(s，2H)，4.19-4.06(m，2H)，3.88-3.83(m，4H)，3.74-3.69(m，4H)，3.48-3.38(m，4H)，2.85(t，J＝5.6Hz，2H)，2.60(d，J＝4.3Hz，4H)，1.87(d，J＝6.7Hz，3H)。
Embodiment 55: (R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-(2-morpholinyl oxyethyl group)-6 '-(1,2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-6-amine
Step 1:5-(the chloro-5-of 6-(2-morpholinyl oxyethyl group) pyridin-3-yl)-3-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridine-2-amine
With reference to the method for step 1 in embodiment 30, for the chloro-3-Methoxy Pyridine of the bromo-2-of 5-, obtain target compound, yield: 46% with 4-(2-(the bromo-2-chloropyridine-3-of 5-base oxygen base) ethyl) morpholino.MS m/z[ESI]：543.1[M+1]。
Step 2:4-(5-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-3-(2-morpholinyl oxyethyl group) pyridine-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With reference to the method for step 2 in embodiment 30, with 5-(the chloro-5-of 6-(2-morpholinyl oxyethyl group) pyridin-3-yl)-3-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine replacement (R)-6 '-chloro-5-(1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-5 '-methoxyl group-3,3 '-dipyridyl-6-amine, obtain target compound, yield: 46%.MS m/z[ESI]：688.2[M+1]。
Step 3:(R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5 '-(2-morpholinyl oxyethyl group)-6 '-(1,2,3,6-tetrahydropyridine-4-yl)-3,3 '-dipyridyl-6-amine
With reference to the method for step 3 in embodiment 30, with 4-(5-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-3-(2-morpholinyl oxyethyl group) pyridine-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester replaces (R)-4-(6 '-amino-5 '-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-methoxyl group-3,3 '-dipyridyl-6-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester,obtain target compound, yield: 67%, MS m/z[ESI]: 588.2[M+1]. 1H NMR(400MHz，CDCl 3)：δ＝8.20(s，1H)，7.85(s，1H)，7.30(dd，J＝8.9，4.8Hz，1H)，7.12-7.00(m，2H)，6.93(s，1H)，6.55(s，1H)，6.09(d，J＝6.7Hz，1H)，4.95(s，2H)，4.11(dd，J＝14.4，5.8Hz，2H)，3.76-3.66(m，4H)，3.59(d，J＝2.6Hz，2H)，3.11(t，J＝5.6Hz，2H)，2.83(t，J＝5.7Hz，2H)，2.65-2.51(m，6H)，1.86(d，J＝6.7Hz，3H)。
Embodiment 56: 5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-6 '-((S)-2-methylpiperazine-1-yl)-4 '-(2-morpholinyl oxyethyl group)-3,3 '-dipyridyl-6-amine
Step 1:(S)-4-(5-(6-amino-5-((R)-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridin-3-yl)-4-(2-morpholinyl oxyethyl group) pyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester
With reference to the method for step 1 in embodiment 27, with (S)-4-(the bromo-4-of 5-(2-morpholine oxyethyl group) pyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement (S)-4-(the bromo-4-methoxypyridine-2-of 5-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, obtain target compound, yield: 46%.MS m/z[ESI]：705.3[M+1]。
Step 2:5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-6 '-((S)-2-methylpiperazine-1-yl)-4 '-(2-morpholinyl oxyethyl group)-3,3 '-dipyridyl-6-amine
With reference to the method for step 2 in embodiment 27, with (S)-4-(5-(6-amino-5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridin-3-yl)-4-(2-morpholinyl oxyethyl group) pyridine-2-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester replacement 5-((R)-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group)-4 '-methoxyl group-6 '-((S)-2-methyl-4-tert-butoxycarbonyl-piperazine-1-yl)-3, 3 '-dipyridyl-6-amine, obtain target compound, yield 67%, MS m/z[ESI]: 605.2[M+1]. 1H NMR(400MHz，CDCl 3)：δ＝7.89(s，1H)，7.76(d，J＝1.5Hz，1H)，7.32-7.27(m，1H)，7.08-7.01(m，1H)，6.93(d，J＝1.5Hz，1H)，6.07(s，1H)，6.05(d，J＝6.7Hz，1H)，4.82(s，2H)，4.45-4.36(m，1H)，4.10(dd，J＝10.3，6.1Hz，2H)，3.99-3.89(m，1H)，3.68-3.64(m，4H)，3.08(dd，J＝10.8，7.5Hz，3H)，2.94(d，J＝12.1Hz，1H)，2.85(dd，J＝13.5，10.0Hz，1H)，2.72(dd，J＝10.1，6.1Hz，2H)，2.49-2.44(m，4H)，1.82(d，J＝6.7Hz，3H)，1.24(d，J＝6.7Hz，3H)。
the mensuration of ALK kinase inhibiting activity
Adopt following methods to measure compound of the present invention active to the kinase whose inhibition of ALK, the active IC that adopts of this inhibition 50this index represents, IC 50the concentration of the compound while being the kinase whose activity inhibited 50% of ALK.This patent takes even phase time resolved fluorescence (HTRF, Cisbio) method to set up and optimized the kinase activity detection platform of ALK (buying in Millipore), carries out the mensuration of compound activity.
Materials and methods:
Material:
A. white 384 orifice plates (Perkin Elmer, Catalog No.607290/99)
B.HEPES damping fluid: with 1M HEPES damping fluid (Invitrogen, Catalog No.15630-080) preparation 50ml0.05MHEPES damping fluid, get 1M HEPES damping fluid 2.5ml, add appropriate redistilled water (ddH 2o),, with NaOH adjusting pH to 7.0, finally add ddH 2o (redistilled water) is to 50ml.
C.ALK kinases (Millipore).
d.0.1M Na 3VO 4
e.1M MgCl 2
f.0.2M DTT
g.10％BAS
h.DMSO
i.ddH 2O
J. testing compound: embodiment compound
Undertaken by following working order:
1. preparation ALK enzyme reaction buffer solution: 50mM HEPES (pH=7.0), 0.1mM Na 3vO 4, 0.01%BAS, 5mMMgCl2,1mM DTT, is positioned over for subsequent use on ice;
2. compound is started to carry out with 100%DMSO the gradient dilution of 3 times from 1mM, each concentration is got 4 μ l and is joined in the reaction buffer of 96 μ l, get 2.5 μ l and join 384 orifice plate (OptiPlate-384, PerkinElmer), then add the kinases of 5 μ l, centrifugal mixing, then add the ATP of 2.5 μ l to start and react with TKpeptide mixed solution (ATP final concentration is Km value).
3. 384 orifice plates being put in to 23 degree in incubator reacts 120 minutes.
4. add the TK Antibody-Cryptate antibody of 5 μ l, the XL-665 stopped reaction of the marked by streptavidin of 5 μ l.
5. in incubator (22-23 DEG C), hatch 1 hour;
6. use microplate reader Envision (PerkinElmer) to read the fluorescent signal of reaction: 320nm excites, and reads the emmission spectrum of 665nm wavelength;
7. compound suppresses IC to ALK enzyme 50generation: the IC that uses GraFit6 computerized compound 50value.
It is active that the ALK of table 1 embodiment compound suppresses
The testing data of table 1 shows, compound provided by the invention has good ALK and suppresses active.
Table 2 has been listed the ALK kinase inhibiting activity after 30,53 pairs of sudden changes of embodiment compound.Wherein F1174L, L1196M,
The ALK kinases of G1269S, R1275Q sudden change can be bought acquisition by commercial sources.
The ALK kinase inhibiting activity of table 2 embodiment compound after to four kinds of sudden changes
Compound provided by the invention has extraordinary internal metabolism level.Table 3 listed embodiment of the present invention compound 27,
30 and 53 pharmacokinetic datas in SD rat body.
The pharmacokinetic parameter of table 3 embodiment compound
CYP-3A4 is the metabolic enzyme CYP-3A that body weight for humans is wanted, and this enzyme is produced and suppresses may cause drug combination time, the metabolism of other medicines to be had a negative impact.Table 4 has been listed the restraining effect of 27,30 couples of CYP-3A4 of embodiment compound, visible not obviously inhibition, thus when reducing or avoiding drug combination, the metabolism of other medicines is exerted an influence.
The inhibition of 27,30 couples of CYP-3A4 of table 4 embodiment compound
* KETOKONAZOL.

Claims (17)

1. the compound of formula I or its pharmacy acceptable salt,
Wherein:
A 1be selected from hydrogen ,-O-(CHR 1)-A 4,-CH 2oR 2, by one or more R 3the aryl replacing;
R 1the methyl that is selected from methyl, is replaced by 1-3 halogen;
A 4being selected from can be by one or more R 4the aryl replacing;
R 2being selected from can be by one or more R 3the aryl replacing;
R 3be selected from halogen ,-SO 2(C 1-6alkyl) ,-SO 2nR 6r 7,-NR 6r 7,-NHSO 2(C 1-6alkyl) ,-P (O) R 6r 7;
R 4be selected from halogen, C 1-6alkyl ,-NR 6r 7,-P (O) R 6r 7;
R 6, R 7independently be selected from respectively hydrogen, C 1-6alkyl, or form 3-12 unit heterolipid cyclic group be connected atom;
A 2be selected from phenyl, pyridyl, pyrimidyl, pyrazolyl, can be selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group;
A 5for 3-12 unit heterolipid cyclic group, can be selected from following group and replace by one or more :=zero, unsubstituted C 1-6alkyl, is independently selected from by one or more C that hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group replace 1-6alkyl, 3-12 unit heterolipid cyclic group;
A 3be selected from the heteroaryl that hydrogen ,-NH aryl, aryl replaces, the heteroaryl that heteroaryl replaces, the heteroaryl that arylalkyl replaces, the heteroaryl that heteroarylalkyl replaces, the heteroaryl ethynyl that arylalkyl replaces, the heteroaryl ethynyl that heteroarylalkyl replaces, described aryl, heteroaryl can be replaced by one or more following groups: halogen, optionally can be by the C of halogen, hydroxyl or the heterolipid cyclic group replacement of 3-12 unit 1-6alkyl ,-OH ,-OC 1-6alkyl ,-CN ,-COOH ,-C 1-6alkyl NH 2,-C 1-6alkyl NH (C 1-6alkyl) ,-C 1-6alkyl N (C 1-6alkyl) 2,-COOC 1-6alkyl ,-SO 2(C 1-6alkyl) ,-SO 2n (C 1-6alkyl) 2,-SO 2nH (C 1-6alkyl) ,-NR 6r 7,-NHSO 2(C 1-6alkyl) ,-P (O) R 6r 7; Condition is: A 1and A 3when different, be hydrogen, and A 1and A 3one of them must be hydrogen.
2. compound claimed in claim 1 or its pharmacy acceptable salt, wherein A 3the heteroaryl that be selected from-NH phenyl, phenyl replace, the heteroaryl that heteroaryl replaces, the heteroaryl that phenyl methyl replaces, the heteroaryl that hetervaromatic methyl replaces, the heteroaryl ethynyl that phenyl methyl replaces, the heteroaryl ethynyl that hetervaromatic methyl replaces, described phenyl, heteroaryl can be replaced by one or more following groups: halogen, the C that can be replaced by halogen, hydroxyl or 3-12 unit heterolipid cyclic group 1-6alkyl ,-OH ,-OC 1-6alkyl ,-CN ,-COOH ,-C 1-6alkyl NH 2,-C 1-6alkyl NH (C 1-6alkyl) ,-C 1-6alkyl N (C 1-6alkyl) 2,-COOC 1-6alkyl ,-SO 2(C 1-6alkyl) ,-SO 2n (C 1-6alkyl) 2,-SO 2nH (C 1-6alkyl) ,-NR 6r 7,-NHSO 2(C 1-6alkyl) ,-P (O) R 6r 7; Preferably, A 3the heteroaryl that be selected from-NH phenyl, phenyl replace, the heteroaryl that heteroaryl replaces, the heteroaryl that phenyl methyl replaces, the heteroaryl that hetervaromatic methyl replaces, the heteroaryl ethynyl that phenyl methyl replaces, the heteroaryl ethynyl that hetervaromatic methyl replaces, wherein phenyl, heteroaryl can be replaced by one or more following groups: halogen, and can be by halogen, hydroxyl or 5 or 6 yuan of C that heterolipid cyclic group replaces 1-4alkyl ,-OH ,-OC 1-4alkyl ,-CN ,-COOH ,-C 1-4alkyl NH 2,-C 1-4alkyl NH (C 1-4alkyl) ,-C 1-4alkyl N (C 1-4alkyl) 2,-COOC 1-4alkyl ,-SO 2(C 1-4alkyl) ,-SO 2n (C 1-4alkyl) 2,-SO 2nH (C 1-4alkyl) ,-NH 2,-NH (C 1-4alkyl) ,-N (C 1-4alkyl) 2,-NHSO 2(C 1-4alkyl) ,-P (O) (C 1-4alkyl) 2; Preferred, A 3the pyrazolyl ethynyl of the pyrazolyl that be selected from-NH phenyl, phenyl replace, the pyrazolyl that phenyl methyl replaces, phenyl methyl replacement, wherein phenyl can be replaced by one or more following groups: halogen, by the C of halogen or hydroxyl replacement 1-4alkyl ,-OH ,-OC 1-4alkyl ,-CN ,-COOH ,-C 1-4alkyl NH 2,-C 1-4alkyl NH (C 1-4alkyl) ,-C 1-4alkyl N (C 1-4alkyl) 2,-COOC 1-4alkyl ,-SO 2(C 1-4alkyl) ,-NH 2,-NH (C 1-4alkyl) ,-N (C 1-4alkyl) 2,-NHSO 2(C 1-4alkyl) ,-SO 2n (C 1-4alkyl) 2,-SO 2nH (C 1-4alkyl) ,-P (O) (C 1-4alkyl) 2; Most preferred, A 3the pyrazolyl ethynyl of the pyrazolyl that be selected from-NH phenyl, phenyl replace, the pyrazolyl that phenyl methyl replaces, phenyl methyl replacement, wherein phenyl can be replaced by one or more following groups: F, Cl, trifluoromethyl ,-COOH ,-CH 2oH ,-OCH 3,-OC 2h 5,-CN ,-SO 2nHCH (CH 3) 2,-COOCH 3,-SO 2cH 3,-NH 2,-P (O) (CH 3) 2.
3. compound claimed in claim 1 or its pharmacy acceptable salt, wherein A 3for hydrogen.
4. compound claimed in claim 3 or its pharmacy acceptable salt, wherein work as A 1for by one or more R 3the aryl and the R that replace 3for-NR 6r 7time, R 6, R 7independently be selected from respectively C 1-6alkyl, or form 3-12 unit heterolipid cyclic group be connected atom.
5. the compound described in claim 3 or 4 or its pharmacy acceptable salt, wherein R 2being selected from can be by one or more R 3the phenyl replacing; Preferably, R 2being selected from can be by one or more R 3the phenyl replacing, R 3be selected from halogen ,-SO 2(C 1-6alkyl) ,-SO 2n (C 1-6alkyl) 2,-SO 2nH (C 1-6alkyl) ,-NH (C 1-6alkyl) ,-N (C 1-6alkyl) 2,-NHSO 2(C 1-6alkyl) ,-P (O) (C 1-6alkyl) 2; More preferably, R 2be selected from by one or more R 3the phenyl replacing, R 3be selected from F, Cl ,-SO 2cH 3,-SO 2n (CH 3) C 2h 5,-SO 2nHCH (CH 3) 2,-NHCH 3,-N (CH 3) C 2h 5,-NHSO 2cH 3,-P (O) (CH 3) 2.
6. arbitrary described compound or its pharmacy acceptable salt, wherein A of claim 3-5 4be selected from by one or more R 4the phenyl replacing; Preferably, A 4be selected from by one or more R 4the phenyl replacing, wherein R 4be selected from the C of halogen, halogen replacement 1-6alkyl ,-NR 6r 7,-P (O) R 6r 7, wherein R 6, R 7independently be selected from respectively C 1-6alkyl; More preferably, A 4be selected from by one or more R 4the phenyl replacing, wherein R 4be selected from the methyl of F, Cl, halogen replacement, ethyl, the-N (CH that halogen replaces 3) 2,-P (O) (CH 3) 2; Preferred, A 4be selected from by one or more R 4the phenyl replacing, wherein R 4be selected from F, Cl ,-CHF 2,-CF 3,-CF 2cH 3,-N (CH 3) 2,-P (O) (CH 3) 2, A 4at least replaced by a F atom.
7. the compound of formula III or its pharmacy acceptable salt:
R 4 'independently be selected from hydrogen, halogen, C 1-6alkyl ,-NR 6r 7,-P (O) R 6r 7;
R 6, R 7independently be selected from respectively hydrogen, C 1-6alkyl, or form 3-12 unit heterolipid cyclic group be connected atom;
A 2be selected from phenyl, pyridyl, pyrimidyl, can be independently selected from halogen ,-OC by 1,2,3 or 4 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group;
A 5for 3-12 unit heterolipid cyclic group, can be selected from following group and replace by one or more :=zero, unsubstituted C 1-6alkyl, 3-12 unit heterolipid cyclic group, independently is selected from the C of hydroxyl, carboxyl, the heterolipid cyclic group replacement of 3-12 unit by one or more 1-6alkyl.
8. compound claimed in claim 7 or its pharmacy acceptable salt, wherein R 4 'can be identical or different, and be not all hydrogen; Preferably, the R of 3 4 'substituting group is halogen; Further preferred, the R of 3 4 'substituting group is F, remaining R 4 'substituting group is independently selected from the C of hydrogen, halogen, halogen replacement 1-6alkyl ,-NR 6r 7,-P (O) R 6r 7, wherein R 6, R 7independently be selected from C 1-6alkyl; More preferably, the R of 3 4 'substituting group is F, remaining R 4 'substituting group is independently selected from the methyl of hydrogen, halogen, halogen replacement, ethyl, the-N (CH that halogen replaces 3) 2,-P (O) (CH 3) 2; Further more preferably, the R of 3 4 'substituting group is F, remaining R 4 'substituting group is independently selected from hydrogen, F, Cl ,-CHF 2,-CF 2cH 3,-N (CH 3) 2,-P (O) (CH 3) 2; Preferred, the R of 3 4 'substituting group is F, 2 and 6 s' R 4 'substituting group is Cl, the R of 4 4 'for hydrogen.
9. arbitrary described compound or its pharmacy acceptable salt, wherein A of claim 1-8 2can be selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, described C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, 3-12 unit heterolipid cyclic group; More preferably, A 2can be selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, morpholinyl, tetrahydrofuran base, piperidyl, piperazinyl, tetrahydro pyridyl, dihydropyridine base, tetrahydro-thienyl, pyrrolidyl, oxazolidinyl, thiazolidyl, imidazolidyl, isoxazole alkyl, isothiazole alkyl, pyrazolidyl, thio-morpholinyl, piperazine-2-ketone group, pyrrolinyl, dihydrofuran base, dihydro-thiophene base; Preferred, A2 can be selected from halogen ,-OC by one or more 1-6the group of alkyl replaces, wherein C 1-6hydrogen atom in alkyl can be replaced by hydroxyl, carboxyl, morpholinyl; Most preferred, A 2can be selected from F, Cl, methoxyl group, oxyethyl group ,-OCH by one or more 2cH 2oH, group replace.
10. arbitrary described compound or its pharmacy acceptable salt of claim 1-9, A 5be 5 or 6 yuan of heterolipid cyclic groups; More preferably, A 5for morpholinyl, tetrahydrofuran base, piperidyl, piperazinyl, tetrahydro pyridyl, dihydropyridine base, tetrahydro-thienyl, pyrrolidyl, oxazolidinyl, thiazolidyl, imidazolidyl, isoxazole alkyl, isothiazole alkyl, pyrazolidyl, thio-morpholinyl, piperazine-2-ketone group, pyrrolinyl, dihydrofuran base, dihydro-thiophene base; Preferred, A 5for morpholinyl, 1,2,3,4-tetrahydro pyridyl, 1,2,3,6-tetrahydro pyridyl, 2,3,4,5-tetrahydro pyridyl, piperazinyl, piperazine-2-ketone group, piperidyl; Preferred, A5 is piperazine-1-base, piperazine-2-base, piperazine-3-base, piperidin-4-yl, piperidin-1-yl, piperidin-2-yl, piperidines-3-base, morpholine-4-base, morpholine-2-Ji, morpholine-3-base, 1,2,3,4-tetrahydropyridine-4-base, 1,2,3,6-tetrahydropyridine-4-base, 2,3,4,5-tetrahydropyridine-4-base, piperazine-2-ketone group; Most preferred, A 5for
11. claim 1-10 arbitrary described compound or its pharmacy acceptable salt, A 5can be selected from following group and replace by one or more :=zero, unsubstituted C 1-6alkyl, 3-12 unit heterolipid cyclic group, independently be selected from the C of hydroxyl, carboxyl, the heterolipid cyclic group replacement of 3-12 unit by one or more 1-6alkyl, wherein 3-12 unit heterolipid cyclic group can be replaced by following group further: C 1-6alkyl ,=zero ,-OH ,-COOH ,-CN, halogen ,-NH (C 1-6alkyl) ,-N (C 1-6alkyl) 2; Preferably, A 5can be selected from following group and replace by one or more :=zero, methyl, ethyl, n-propyl, sec.-propyl, 5 or 6 yuan of heterolipid cyclic groups, be independently selected from by one or more-OH ,-COOH, 5 or 6 yuan of methyl, ethyl, n-propyl or sec.-propyls that heterolipid cyclic group replaces, wherein 5 or 6 yuan of heterolipid cyclic groups can be selected from further following group and be replaced: methyl, ethyl, n-propyl, sec.-propyl ,=zero ,-OH ,-COOH ,-CN, halogen ,-NH (C 1-3alkyl) ,-N (C 1-3alkyl) 2; Preferred, A 5can be selected from following group and replace by one or more: methyl, ethyl, n-propyl, sec.-propyl ,=zero, piperidyl, piperazinyl, wherein piperidyl, piperazinyl can be by methyl substituted.
12. claims 1 or 3-11 arbitrary described compound or its pharmacy acceptable salt, work as A 1for-O-(CHR 1)-A 4, R 1during for methyl, A 2at least by one-OC 1-6the group of alkyl replaces.
13. following compounds or its pharmacy acceptable salt:
14.. a pharmaceutical composition, it contains the arbitrary described compound of claim 1-13 or its pharmacy acceptable salt as active ingredient, and one or more pharmaceutically acceptable carriers.
The purposes of pharmaceutical composition described in 15. claim 1-13 arbitrary described compound or its pharmacy acceptable salt or claim 14 in the medicine for the preparation of the treatment disease relevant to protein kinase.
The purposes of pharmaceutical composition described in 16. claim 1-13 arbitrary described compound or its pharmacy acceptable salt or claim 14 in the medicine of the disease being mediated by ALK for the preparation for the treatment of.
Purposes described in 17. claims 16, the disease of wherein said ALK mediation comprises nonsmall-cell lung cancer, primary cutaneous type, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, mammary cancer, colorectal cancer, Diffuse Large B-Cell Lymphoma, body tissue's cellular proliferative disorder and the neuroblastoma of the ALK positive.
CN201310051825.1A 2013-02-02 2013-02-02 Substituted 2-aminopyridine inhibitor for protein kinase Pending CN103965161A (en)

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RU2015136909A RU2671212C2 (en) 2013-02-02 2014-01-27 Substituted 2-aminopyridine protein kinase inhibitor
US14/765,313 US9708295B2 (en) 2013-02-02 2014-01-27 Substituted 2-aminopyridine protein kinase inhibitor
ES14746385T ES2716617T3 (en) 2013-02-02 2014-01-27 Substituted 2-aminopyridine protein kinase inhibitor
CN201480007081.6A CN104968654B (en) 2013-02-02 2014-01-27 Substituted 2-aminopyridine albuminoid kinase inhibitor
KR1020157023826A KR101791762B1 (en) 2013-02-02 2014-01-27 Substituted 2-aminopyridine protein kinase inhibitor
JP2015555577A JP6200520B2 (en) 2013-02-02 2014-01-27 Substituted 2-aminopyridine protein kinase inhibitor
AU2014211856A AU2014211856C1 (en) 2013-02-02 2014-01-27 Substituted 2-aminopyridine protein kinase inhibitor
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PCT/CN2014/071595 WO2014117718A1 (en) 2013-02-02 2014-01-27 Substituted 2-aminopyridine protein kinase inhibitor
CA2899968A CA2899968C (en) 2013-02-02 2014-01-27 Substituted 2-aminopyridine protein kinase inhibitor
PT14746385T PT2952510T (en) 2013-02-02 2014-01-27 Substituted 2-aminopyridine protein kinase inhibitor
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WO2017016514A1 (en) * 2015-07-30 2017-02-02 正大天晴药业集团股份有限公司 Pyridine substituted 2-aminopyridine protein kinase inhibitor crystal
WO2019206049A1 (en) * 2018-04-25 2019-10-31 Zhuhai Yufan Biotechnologies Co., Ltd Hpk1 inhibitors, preparation method and application thereof
CN110396088A (en) * 2018-04-25 2019-11-01 珠海宇繁生物科技有限责任公司 HPK1 kinase inhibitor, preparation method and applications
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CN110283161B (en) * 2015-07-30 2021-09-03 正大天晴药业集团股份有限公司 Crystal of pyridine substituted 2-aminopyridine protein kinase inhibitor
US10385038B2 (en) 2015-07-30 2019-08-20 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Pyridine substituted 2-aminopyridine protein kinase inhibitor crystal
WO2017016514A1 (en) * 2015-07-30 2017-02-02 正大天晴药业集团股份有限公司 Pyridine substituted 2-aminopyridine protein kinase inhibitor crystal
CN107949560B (en) * 2015-07-30 2019-08-16 正大天晴药业集团股份有限公司 The crystallization for the 2-aminopyridine albuminoid kinase inhibitor that pyridine replaces
CN107949560A (en) * 2015-07-30 2018-04-20 正大天晴药业集团股份有限公司 The crystallization of 2 aminopyridines kinases inhibitors of pyridine substitution
CN110283161A (en) * 2015-07-30 2019-09-27 正大天晴药业集团股份有限公司 The crystallization for the 2-aminopyridine albuminoid kinase inhibitor that pyridine replaces
CN110330483A (en) * 2015-07-30 2019-10-15 正大天晴药业集团股份有限公司 The crystallization for the 2-aminopyridine albuminoid kinase inhibitor that pyridine replaces
TWI707848B (en) * 2015-07-30 2020-10-21 大陸商正大天晴藥業集團股份有限公司 Crystallization of pyridine-substituted 2-aminopyridine protein kinase inhibitors
CN106083708A (en) * 2016-06-30 2016-11-09 浙江大学 2 aminopyrazole derivatives containing 2 pyridone ring side chains and preparation and application
CN110396087A (en) * 2018-04-25 2019-11-01 珠海宇繁生物科技有限责任公司 HPK1 kinase inhibitor, preparation method and applications
CN110396088A (en) * 2018-04-25 2019-11-01 珠海宇繁生物科技有限责任公司 HPK1 kinase inhibitor, preparation method and applications
WO2019206049A1 (en) * 2018-04-25 2019-10-31 Zhuhai Yufan Biotechnologies Co., Ltd Hpk1 inhibitors, preparation method and application thereof
IL278036B1 (en) * 2018-04-25 2023-10-01 Zhuhai Yufan Biotechnologies Co Ltd Hpk1 inhibitors, preparation method and application thereof
IL278036B2 (en) * 2018-04-25 2024-02-01 Zhuhai Yufan Biotechnologies Co Ltd Hpk1 inhibitors, preparation method and application thereof
CN110396088B (en) * 2018-04-25 2024-03-12 珠海宇繁生物科技有限责任公司 HPK1 kinase inhibitor, preparation method and application thereof
US11999725B2 (en) 2018-04-25 2024-06-04 Zhuhai Yufan Biotechnologies Co., Ltd. HPK1 inhibitors, preparation method and application thereof
CN112552293A (en) * 2019-09-25 2021-03-26 珠海宇繁生物科技有限责任公司 PROTAC small molecular compound and application thereof

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