CN108373476A

CN108373476A - A kind of kinase inhibitor and its preparation and application

Info

Publication number: CN108373476A
Application number: CN201810029135.9A
Authority: CN
Inventors: 郭娜; 何倩; 邓塔; 代川; 杨巧; 陈爽; 范波
Original assignee: Chengdu Diao Pharmaceutical Group Co Ltd
Current assignee: Chengdu Diao Pharmaceutical Group Co Ltd
Priority date: 2017-01-13
Filing date: 2018-01-12
Publication date: 2018-08-07
Anticipated expiration: 2038-01-12
Also published as: CN108373476B

Abstract

The present invention provides formula (I) compound, or its stereoisomer, tautomer, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate, treatment is being prepared by the application in the drug or pharmaceutical composition of Pim kinase mediated diseases.

Description

A kind of kinase inhibitor and its preparation and application

Technical field

The present invention relates to formula (I) compounds as Pim kinase inhibitors, and its is preparing treatment by the kinase mediated diseases of Pim The drug or the application in pharmaceutical composition of disease such as cancer and immune correlated disease.

Background technology

Pim (Proviral Integration Moloney virus) gene is to encode one group of serine/threonine kinases (i.e. Pim1, Pim2 and Pim3) proto-oncogene family.Pim kinases belongs to calcium ion/calmodulin-dependent protein kinase superfamily, It is highly conserved in many cells evolutionary process.Pim1^-/-Pim2^-/-Pim3^-/-Mouse energy normal existence simultaneously has fecundity, but It is that their builds are obviously reduced, while being damaged to the reaction of hemopoieticgrowth factor；But the mouse that only some Pim hypotype lacks There is no apparent phenotypic difference, illustrate to a certain extent to exist between Pim protein family members functional redundancy (Mikkers, H. etc., Mol. Cell.Biol.2004,24 (13), 6104-6115；Laird, P.W. etc., Nucleic Acids Res.1993,21(20), 4750-4755)。

Pim1 kinases in people's bone marrow and leukemic lymphoblastoid and lymthoma expression increase (Wang, Z. etc., J.Vet.Sci. 2001,2(3),167-179；Cuypers, H.T. etc., Hum.Genet.1986,72 (3), 262-265； Selten, G. etc., Cell 1986,46 (4), 603-611).In acute myeloid leukaemia (AML), the mRNA level in-site of Pim1 increases Add, while changing (Chen, W. etc., Cancer Cell 2008,13 (5), 432-440) with mll gene development genetics. It is reported that Pim1 or Pim3 expression increases may be and Kaposi sarcoma herpesviral (KSHV) or Epstein-Barr virus (EBV) phase Key factor (Cheng, F. etc., the PLoS Pathog.2009,5 (3), e1000324 for some the B- cell diseases development closed； Bajaj, B. G. etc., Virology 2006,351 (1), 18-28).Recently, it also observed Pim1's in a variety of solid tumors It is overexpressed phenomenon, including cancer of pancreas, prostate cancer, squamous cell carcinoma, gastric cancer, colorectal cancer, liver cancer, embryonal-cell lipoma and bladder Cancer (Bachmann, M. etc., Int.J.Biochem.Cell.Biol.2005,37 (4), 726-730；Guo, S. etc., J.Exp.Clin.Cancer Res. 2010,29,161-1；Nga, M.E. etc., Int.J.Exp.Pathol.2010,91 (1), 34-43；Shah, N. etc., Eur.J. Cancer 2008,44 (15), 2144-2151).

The study found that detected in AML patient Pim2 Kinase levels increase (Tamburini, J. etc., Blood 2009, 114 (8), 1618-1627), in the cell-derived malignant tumours of B-, such as diffusivity large B cell lymphoid tumor (DLBLC), follicularis leaching Bar tumor (FL), lymphoma mantle cell (MCL), chronic lymphocytic leukemia (CLL), MALT- type marginal zone lymphomas (MZL-MALT), it also observed the overexpression phenomenon of Pim2 in the evolution of lymph node marginal zone lymphoma (NMZL) etc. (Cohen, A.M. etc., Leuk.Lymphoma 2004,45 (5), 951-955；Huttmann, A. etc., Leukemia 2006, 20(10),1774-1782).In addition, Pim2 expressions in prostate cancer increase, and subtract with cell hyperproliferation and apoptosis Rare pass (Dai, H. etc., Prostate 2005,65 (3), 276-286).Some in vitro studies show Pim2 kinases and liver cancer Also related (Brault, L. etc., Haematologica 2010,95 (6), 1004-1015).

It observed unconventionality expression (Brault, the L. of Pim3 in the malignant tumours such as liver cancer, cancer of pancreas and ewing's sarcoma Deng Haematologica 2010,95 (6), 1004-1015；Mukaida, N. etc., Cancer Sci.2011,102 (8), 1437-1442).The study found that Pim3 is expressed in human hepatocellular carcinoma and cancer of pancreas diseased region height, but it is thin in normal hepatocytes Pim3 overexpressions (Li, Y.Y. etc., Cancer Res.2006,66 (13), 6741- is not observed in born of the same parents and pancreatic tissue 6747；Fujii, C. etc., Int.J.Cancer 2005,114 (2), 209-218)；In addition, Pim3mRNA is in people's You Wenshi meat There is also be overexpressed phenomenon (Deneen, B. etc., Mol.Cell.Biol.2003,23 in tumor cell strain and human nasopharyngeal epithelioma 1 (11),3897-3908；Yang, X.Y. etc., Cell Oncol.2005,27 (4), 215-223).

Therefore, the occurrence and development of the overexpression and kinds of tumors of Pim kinases are closely related, and Pim kinase inhibitors are to treatment It acquires a special sense with the relevant cancer of Pim kinase activities.Studies have shown that dominant negative mutations Pim1 can reduce pancreatic cancer cell With oncogenicity (Chen, J. etc., the Am.J.Pathol.2009,175 (1), 400- of Hela cell xenograft mouse models 11).In vivo studies shows that Pim2 and Pim3 missings can significantly inhibit the growth of the sarcoma of 3-MECA induction, tumor killing effect Suitable with the effect of all Pim kinases missing (Narlik-Grassow, M. etc., Carcinogenesis 2012,33 (8), 1479-1486).The siRNA interference for targeting Pim1 and Pim2 is 50% to the inhibition of metastasis rate of PC3 cells；When with DHPCC-9 When inhibiting the kinases of all Pim families, inhibition of metastasis rate increase to 90% (Santio, N.M. etc., Mol.Cancer 2010, 9,279-291).Body is inside and outside studies have shown that Pim inhibitor DHPCC-9 can inhibit prostate cancer and head and neck squamous cell carcinoma It waits the migration of solid tumor cells and invades profit (Santio, N.M. etc., Mol.Cancer 2010,9,279-289)；Compound CX- The active anticancer of 4945 pairs of a variety of solid tumors and neoplastic hematologic disorder be in dose dependent (Pierre, F. etc., Mol.Cell.Biochem.2011,6(1–2), 37-3；Pierre, F. etc., Bioorg.Med.Chem.Lett.2011,21 (22),6687-6692).Compound CXR1002 has cytotoxicity to a variety of human ovarian cancers, cancer of pancreas and sarcoma cell, CXR1002 and a variety of anticarcinogens (especially gemcitabine, adriamycin, geldanamycin, MAPK inhibitor and AKT/ simultaneously PI3K inhibitor) there is Synergistic anti-cancer effect (Barnett, A. etc., EJC Suppl.2010,8 (7), 45-46).In addition, Pim Inhibitor also has chemotherapy or radiosensitizing effect (Xu, D. etc., Carcinogenesis 2011,32 (4), 488-495； Mumenthaler, S.M. etc., Mol.Cancer Ther.2009,8 (10), 2882-2893).

Pim kinases also has certain immunoregulation effect.The study found that Pim2 expressions in inflammation increase (Li, J. etc., US patent, 20030125231A1)；Pim2 has Pasitive Regulation Effect of Genseng, i.e. kinases amount increase that can pierce IL-6 Swash IL-6 levels and increases (Yang, J. etc., Immunology 2010,131,174-182).Meanwhile Pim1 and Pim2 also with carefully The T- cell growths of intracellular cytokine induction are related with existence (Fox, J. etc., J.Exp.Med.2005,201 (2), 259-66).Cause This, the immune related disease such as immunosupress that Pim inhibitor can be as inflammation, autoimmune disease, allergy and organ transplant The medicine of disease.

Currently, some small molecules Pim inhibitor (such as CX-4945, AZD-1208, CXR1002, LGH447) has been enter into Clinical investigation phase.The most fast small molecule Pim inhibitor LGH447 of research progress has been enter into the clinical II phases and studies, but the change It is longer to close object synthetic route, (US2010056576A1, CN102203079A) can just be obtained by the reaction of 15 steps；And the change There are three chiral centres for adduct molecule tool, need progress chiral separation that can just obtain single optical isomer.Pim small molecules Inhibitor SGI-1776 has terminated the further exploitation to the molecule due to its cardiotoxicity.Therefore, it is badly in need of development more It easily prepares, activity is more preferable and small molecule Pim inhibitor with good quasi-medicated property.

Invention content

The present invention relates to novel Pim molecule inhibitor compounds, pharmaceutically acceptable salt, solvate and preceding Medicine.There is at least one other therapeutic agent alone or in combination the present invention also relates to these compounds and optionally can pharmaceutically connect The composition for the supporting agent received.The present invention, which further relates to these compounds alone or in combination, has at least one other therapeutic agent preventing Or treatment is by the application method in disease kinase mediated Pim.This kind of Pim inhibitor is not only easier to prepare (only to need 9 steps anti- Should can be obtained), and only tool is not needed there are one chiral centre by doing raw material to be commercialized available chipal compounds It carries out chiral separation and can be obtained single optical isomer.

The present invention also provides the compounds of formula (I) a kind of：

Wherein：

A is selected from 5-6 unit's heteroaryls and phenyl, wherein the heteroaryl and phenyl can be by selected from halogen, trifluoromethyl, difluoros Methyl, C_1-4Alkyl and C_1-4The substituent group of alkoxy is replaced；

X is selected from 5-6 membered heterocycloalkyls ,-NH-C_3-6Naphthenic base ,-NH-C_1-4Alkyl amino, 5-6 unit's heteroaryls and 5-6 membered rings Alkyl, wherein the Heterocyclylalkyl, heteroaryl and naphthenic base can be by selected from halogen ,-NH₂、C_1-6Alkyl, cyano, hydroxyl, mercapto Base, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoro-methoxy, C_1-4The substituent group substitution of alkoxy, acyl group, ester group；

Z₁For N when, Z₂For S, NH or O；

Z₁For S when, Z₂For N；

Z₁For-N=CH- or-CH=CH- when, Z₂For N；

R is selected from hydrogen, halogen, phenyl, 5-6 unit's heteroaryls, 5-6 membered heterocycloalkyls, C_3-6Naphthenic base, C_1-6Alkyl andThe wherein described phenyl, 5-6 unit's heteroaryls, 5-6 membered heterocycloalkyls, C_3-6Naphthenic base and C_1-6Alkyl can by selected from Halogen ,-NH₂, hydroxyl, sulfydryl, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoro-methoxy, carboxyl, Acyl group, ester group, C_1-4Alkyl, C_1-4Alkoxy and C_1-4The substituent group of halogenated alkyl is replaced.

In some specific embodiments, the present invention provides formula (I) compound, and wherein A is selected from：

Wherein, * is the tie point with X,It is the tie point with NH；

Each R¹Separately it is selected from halogen, C_1-4Alkyl, C_1-4Alkoxy and C_1-4Halogenated alkyl；

R²Selected from C_1-4Alkyl；

Or its stereoisomer, tautomer, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvent Close object.

In some other specific embodiment, the present invention provides formula (I) compound, wherein：

X is selected from：

Wherein, * is the tie point with A；

In some other embodiment, the present invention provides formula (I) compound, wherein：

It is selected from：

Wherein, * is the tie point with NH,It is the tie point with R；

Each R³Separately it is selected from hydrogen, halogen, C_1-4Alkyl, C_1-4Alkoxy and C_1-4Halogenated alkyl；

R⁴Selected from hydrogen and C_1-4Alkyl；

In some other specific embodiment, the present invention provides formula (I) compound or its stereoisomer, change Isomers, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate, wherein：

R is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclopenta, cyclohexyl And phenyl, wherein the cyclopropyl, cyclopenta, cyclohexyl and phenyl optionally by one or more be independently selected from fluorine, chlorine, bromine, Iodine, nitro, trifluoromethyl, acyl group, C_1-4Alkyl and C_1-4The substituent group of alkoxy is replaced；Or

R be selected from furans, pyridine, thiophene, thiazole, isothiazole, pyrimidine, pyrazoles, imidazoles, oxazole, isoxazole, pyrazine,Wherein each described R optionally by one or more be independently selected from fluorine, chlorine, bromine, iodine, nitro, acyl group and C_1-4The substituent group of alkyl is replaced.

The present invention provides compound described herein or its stereoisomer, tautomer, nitrogen oxides, metabolin, preceding Medicine, pharmaceutically acceptable salt or solvate, and its preparing drug or drug of the treatment by disease kinase mediated Pim Application in composition.The disease kinase mediated by Pim includes cancer and/or immune correlated disease.

The present invention relates to the purposes of the compounds of this invention or pharmaceutical composition in medicine preparation, the compound or drug Composition is used for the regulatory protein kinase activity in biological sample.The invention further relates to the compounds of this invention to be used in life Inhibit Pim kinase activities in object sample.

In each specific embodiment of the present invention, the compound of compound such as formula (I), which can be used for preparing, inhibits Pim kinases Drug or pharmaceutical composition.

Specific implementation mode

Through the application, multiple embodiments of the compound of the present invention and method are mentioned above.Multiple embodiments Multiple illustrative examples are intended to provide, it should not be constructed as the description of substitute.Also, it is noted that discussed herein Embodiment (including various methods and parameter) is only for illustrating the present invention, the protection model not limiting the invention in any way It encloses.

A compounds

The present invention also provides the compounds of formula (I) a kind of, or its stereoisomer, tautomer, nitrogen oxides, metabolism Object, prodrug, pharmaceutically acceptable salt or solvate：

Wherein：

Z₁For N when, Z₂For S, NH or O；

Z₁For S when, Z₂For N；

Z₁For-N=CH- or-CH=CH- when, Z₂For N；

In some specific embodiments, the present invention provides formula (I) compound or its stereoisomer, tautomerism Body, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate, wherein A are selected from：

Wherein, * is the tie point with X,It is the tie point with NH；

R²Selected from C_1-4Alkyl.

X is selected from：

Wherein, * is the tie point with A.

In some other embodiment, the present invention provide formula (I) compound or its stereoisomer, tautomer, Nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate, wherein：

It is selected from：

Wherein, * is the tie point with NH,It is the tie point with R；

R⁴Selected from hydrogen and C_1-4Alkyl.

In a preferred embodiment of the invention, the present invention provides following technical solutions：

The present invention provides formula (I) compound represented or its stereoisomer, tautomer, nitrogen oxides, metabolism Object, prodrug, pharmaceutically acceptable salt or solvate,

Wherein, X be amino substituted piperidine base, difluoro substituted piperidine base, A be X group substitution pyridyl group or X group and The pyridyl group of trifluoromethyl substitution；It is highly preferred that X is 3- amino substituted piperidine 1- bases (R or S configurations), A is X group substitution Pyridyl group；

Z1 is N；Z2 is S；Or Z1 is S；Z2 is N；Preferably, Z1 N；Z2 is S；

R is phenyl or phenyl by selected from halogen, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, hydroxyl, sulfydryl, nitre One or two or more the phenyl replaced in base, cyano, carboxyl, acyl group, ester group；Or

R is selected from furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrimidine radicals, pyrazolyl, imidazole radicals, oxazole Base, isoxazolyl or pyrazinyl；Or furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrimidine radicals, pyrazolyl, miaow Any one of oxazolyl, oxazolyl, isoxazolyl, pyrazinyl are by selected from halogen, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alcoxyl In base, hydroxyl, sulfydryl, nitro, cyano, carboxyl, acyl group, ester group one or two or more substituent group substitution group or The benzo groups of either of which kind；

The wherein described halogen and C_1-4Halogen in halogenated alkyl be any one of fluorine, chlorine, bromine or iodine or it is a kind of with On.

In preferred embodiment of the invention, the present invention provides formula (I) compound or its alloisomerism Body, tautomer, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate,

Z1 is N；Z2 is S；Or Z1 is S；Z2 is N；Preferably, Z1 N；Z2 is S；

R is in phenyl, furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazole radicals It is a kind of；Or R is in phenyl, furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrazolyl, imidazole radicals It is a kind of by selected from halogen, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4It is any in alkoxy, hydroxyl, sulfydryl, carboxyl, acyl group, ester group Kind or the group of more than one group substitution.

The present invention even more preferably from embodiment in, the present invention provides formula (I) compound or its alloisomerism Body, tautomer, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate, wherein R is selected from benzene One kind in base, furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazole radicals；Or R be by selected from Halogen, C_1-4Alkyl or C_1-4The substitution of any one or more groups is selected from phenyl, furyl, pyridine in halogenated alkyl One kind in base, thienyl, thiazolyl, isothiazolyl, pyrazolyl, imidazole radicals.

The present invention even more preferably from embodiment in, the present invention provides formula (I) compound or its alloisomerism Body, tautomer, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate, wherein R be phenyl, Or phenyl or furyl, pyridyl group, thienyl, the thiazole replaced by halogen, methyl, ethyl or halogenated methyl, halogenated ethyl Base, isothiazolyl, pyrazolyl or imidazole radicals；Or selected from furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrazoles A kind of group replaced by halogen, methyl, ethyl, halogenated methyl or halogenated ethyl in base, imidazole radicals；

The halogen is fluorine, the C preferably wherein_1-4Halogenated alkyl is fluoromethyl, difluoromethyl, trifluoromethyl；Fluoro Ethyl, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group or hexafluoro ethyl.

The present invention even more preferably from embodiment in, the present invention provides formula (I) compound or its alloisomerism Body, tautomer, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate, wherein R be phenyl, Or phenyl-monofluoride base or difluorophenyl or fluoro p-methylphenyl or two (fluoromethyl) phenyl or two (trifluoromethies) Phenyl；Or furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazole radicals；Or selected from furyl, A kind of in pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrazolyl, imidazole radicals is taken by methyl, fluorine, and/or fluoromethyl The group in generation.

The present invention even more preferably from embodiment in, the present invention provides formula (I) compound or its alloisomerism Body, tautomer, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate, wherein

Selected from following formula B1 or formula B2：

Wherein, * is the tie point with NH,It is the tie point with R；Each R³Independently selected from hydrogen, halogen, C_1-4Alkyl and C_1-4It is one or more than one kinds of in halogenated alkyl；It is preferred that the halogen in the halogen or C1-4 halogenated alkyls One or more in fluorine, chlorine, bromine or iodine.

The present invention even more preferably from embodiment in, the present invention provides formula (I) compound or its alloisomerism Body, tautomer, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate, wherein the R³Solely Vertical the one or more in hydrogen, fluorine, methyl or trifluoromethy；Wherein, the R is phenyl or difluorophenyl； Or furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazole radicals；Or methylfuran base, fluoro Furyl, fluoromethane are for furyl, picolyl, fluorinated pyridine base, fluoromethane for pyridyl group, methyl thiazolium oxazolyl, fluoro thiophene Oxazolyl, fluoromethane are for thiazolyl, methyl-isothiazol base, fluoro isothiazolyl, fluoromethane for isothiazolyl, methylthiophene base, fluorine For thienyl, fluoromethane for thienyl, methylpyrazole base, fluoro pyrazolyl, fluoromethane for pyrazolyl, methylimidazolyl, fluoro Imidazole radicals or fluoromethane are for any one of imidazole radicals.

The present invention relates to the typical compound of formula (I) is as shown in table 1, but it is not limited to following embodiment：

Table 1

Compound in table 1 uses ChemDraw Ultra 11.0, executes IUPAC standardized denominations to be named.

B is defined

As used above and elsewhere in this article, following term and abbreviation have meaning defined below.As undefined, Then all technical and scientific terms used in this specification all have those of ordinary skill in the art institute and normally understood contain Justice.

Term " hydrogen " in this article refers to-H.

Term " halogen " in this article refers to-F ,-Cl ,-Br and-I.

Term " fluorine " in this article refers to-F.

Term " chlorine " in this article refers to-Cl.

Term " bromine " in this article refers to-Br.

Term " iodine " in this article refers to-I.

Term " nitro " in this article refers to group-NO₂。

Term " trifluoromethyl " in this article refers to group-CF₃。

Term " difluoromethyl " in this article refers to group-CHF₂。

Term " trifluoromethoxy " in this article refers to group-OCF₃。

Term " difluoro-methoxy " in this article refers to group-OCHF₂。

Term " hydroxyl " in this article refers to group-OH.

Term " sulfydryl " in this article refers to group-SH.

Term " carboxyl " in this article refers to group-COOH or its salt.

Term " cyano " in this article refers to group-CN.

Term " methyl " in this article refers to group-CH₃。

Term " alkyl " in this article refers to the saturated aliphatic hydrocarbons group with 1 to 6 carbon atom, which includes Straight chain and branched hydrocarbyl.The non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Sec-butyl, tertiary butyl, n-pentyl, neopentyl, n-hexyl etc..

Term " naphthenic base " in this article refers to have 3 to 8 carbon atoms, has monocycle or changes (including condensed ring, bridged ring more And spiral ring system) cyclic alkyl.The non-limiting examples of naphthenic base include cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..

Term " Heterocyclylalkyl " in this article refers at least containing there are one be selected from the hetero atoms such as O, N and S and optionally contain one Item or a plurality of double or triple bonds non aromatic cycloalkyl.Heterocyclylalkyl can have 3 to 8 annular atoms as a whole.Heterocyclylalkyl It can be covalently attached with defined chemical constitution in any heteroatom or carbon atom for generating rock-steady structure.Heterocyclylalkyl On one or more N or S atom can be by oxidation (such as morpholine N-Oxide, thiomorpholine S- oxides, thiomorpholine S, S- Dioxide).Heterocyclylalkyl can also contain one or more oxo groups, such as phthalimido group, piperidone base, evil Oxazolidine ketone group, 2,4 (1H, 3H)-dioxo-pyrimidine radicals, pyridine -2 (1H) -one base etc..The non-limiting examples of Heterocyclylalkyl are also Including morpholinyl, thiomorpholine base, pyranose, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrole Cough up alkyl, pyrrolinyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro-thiazoles base, piperidyl, azetidinyl, piperazinyl Deng.

Term " aryl " in this article refers to 6 to 8 yuan of full carbon monocycles or fused polycycle (shares adjacent carbon pairs Ring) group, there is polycyclic (ring for the carrying adjacent carbon pairs) group of the pi-electron system of conjugation.Aryl can generate It is covalently attached with defined chemical constitution on the arbitrary carbon atom of rock-steady structure.In some non-limiting examples, aryl can Only to have aromatic carbocyclic, such as phenyl.

It is that term " heteroaryl " in this article refers to be made of 5 to 8 atoms and containing it is at least one selected from N, O or The heteroatomic aromatic group such as S.The term can have single ring, and (non-limiting examples include furans, thiophene, imidazoles, pyrrole Azoles, pyridine, pyrazine, oxazole, thiazole, metadiazine etc.) or multiple condensed ring (non-limiting examples include benzothiophene, benzo Furans, indoles, iso-indoles etc.).

Term " alkoxy " in this article refers to the substituted or unsubstituted alkyl-O- of group, wherein the alkyl is as herein Defined in.The non-limiting examples of alkoxy include methoxyl group, ethyoxyl, trifluoromethoxy, difluoro-methoxy, positive third oxygen Base, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy etc..

Term " acyl group " in this article refers to group H-C (O)-, substituted or unsubstituted alkyl-C (O)-, substitution or does not take Naphthenic base-C (O)-, substituted or unsubstituted Heterocyclylalkyl-C (O)-, substituted or unsubstituted aryl-C (O)-and the substitution in generation Or unsubstituted heteroaryl-C (O)-.The groups such as the wherein described alkyl, naphthenic base, Heterocyclylalkyl, aryl and heteroaryl are as herein Defined in.

Term " ester group " in this article refers to the substituted or unsubstituted alkyl-O-C of group (O)-, substituted or unsubstituted alkene Base-O-C (O)-, substituted or unsubstituted alkynyl-O-C (O)-, substituted or unsubstituted naphthenic base-O-C (O)-, substitution or not Substituted cycloalkenyl group-O-C (O)-, substituted or unsubstituted Heterocyclylalkyl-O-C (O)-, substituted or unsubstituted aryl-O-C (O)-and substituted or unsubstituted heteroaryl-O-C (O)-.

It is monosubstituted or polysubstituted to this monosubstituted by specified substituent group that term " substitution " in this article refers to any group Or the degree that polysubstituted (the multiple substitution for being included in same section) allows in chemistry, each substituent group can be located at the base Any available position in group, and can be connected by any available atom on the substituent group.It is " any available Position " refer to the method instructed by methods known in the art or herein can chemistry obtain, and do not generate excessive shakiness Any position on the group of fixed molecule.When on any group there are two or when multiple substituent groups, each substituent group It is defined independently of any other substituent group, therefore can be identical or different.The substituent group refers to by following each group The group of composition：Hydrogen, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoro-methoxy, methoxy Base, alkyl, acyl group, alkoxy, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl, wherein each group as determined herein Justice.

In each position of this specification, the substituent group of the compounds of this invention carries out disclosure in the form of group or range. This specifically means that the present invention includes the sub-combination of each of each member or member of such group and range individual. Such as term " C_1-4Alkyl " specifically means to separately disclose methyl, ethyl, C₃Alkyl and C₄Alkyl.

Term " the compounds of this invention " in this article refers to formula (I) compound and its all pure (unless otherwise particularly pointing out) And mixed stereoisomer, geometric isomer, tautomer, nitrogen oxides, oxysulfide, solvate, metabolism Object, the compound of prodrug and isotope labelling and any pharmaceutically acceptable salt.The solvate of the compounds of this invention refers to The compound or its salt combined with stoichiometry and non-stoichiometric solvent, such as hydrate, ethanolates, methanol solvate. Compound can also one or more crystalline states exist, that is, be used as eutectic, polymorph or its can be with amorphous solid In the presence of.All such form is covered by the claims.

" pharmaceutically acceptable " the expression substance of term or composition chemically and/or toxicologically must be with composition preparations Other ingredients and/or with its treatment mammal it is compatible.

Term " stereoisomer " in this article refers to the different compound of the chirality with one or more Stereocenters, Including corresponding isomers and diastereoisomer.

Term " tautomer " in this article refers to different energy structural isomerism and carries that low energy can be crossed It builds, to mutual inversion of phases.Such as proton tautomer includes carrying out change, such as enol-keto tautomerism by proton transfer Body and imine-enamine tautomers, or the heteroaryl containing the annular atom for being connected to the parts ring-NH- and ring=parts N- The tautomeric form of group, such as pyrazoles, imidazoles, benzimidazole, triazole and tetrazolium.Valence tautomers include Bonding electrons recombinates and carries out change.

Term " prodrug " in this article refers to when to snibject, can directly or indirectly provide the change of the present invention Close any derivative of the compounds of this invention of object, its active metabolite or residue.Especially preferably those can increase this hair Bright compound bioavailability, the derivative or prodrug for improving metabolic stability and tissue-targeting.Prodrug includes the present inventionization Close the ester derivant of object.The example of ester prodrug includes formic acid esters, acetic acid esters, propionic ester, butyrate, acrylate and ethyl Succinate derivative, but it is not limited to these ester derivatives.

The compounds of this invention can be used in a salt form, such as derive from inorganic acid or organic acid " pharmaceutically Acceptable salt ".These are including but not limited to what follows：Acetate, adipate, alginates, citrate, asparagus fern Propylhomoserin salt, benzoate, benzene sulfonate, disulfate, butyrate, camphor hydrochlorate, camsilate, digluconate, ring Pentane propionate, lauryl sulfate, esilate, glucose enanthate, glycerophosphate, Hemisulphate, enanthate, oneself Hydrochlorate, fumarate, hydrochloride, hydrobromate, hydriodate, 2- isethionates, lactate, maleate, first Sulfonate, hydrochloride, 2- naphthalene sulfonates, oxalates, pectinic acid salt, sulfate, 3- phenylpropionic acids salt, picrate, front three Guanidine-acetic acid salt, propionate, succinate, tartrate, rhodanate, tosilate and caprate.In addition, alkalinity contains Nitrogen groups can occur quaternization reaction with following reagent and generate quaternary ammonium salt：Such as low-carbon alkyl halide, including methyl, ethyl, The chloride of propyl and butyl, bromide and iodide；Such as dialkyl sulfate, including dimethyl, diethyl, dibutyl and The sulfate of diamyl；Such as long chain halide, include chloride, the bromide of decyl, lauryl, myristyl and stearyl And iodide；Such as aralkyl halide, such as the bromide of benzyl and phenethyl.

The product that term " metabolin " in this article refers to particular compound or its salt is generated by metabolism in vivo.Change Closing the metabolin of object can be identified by routine techniques known in the art, and their activity can use the application It is described to test to determine.Above-mentioned product can be by passing through oxidation to drug compound, reduction, hydrolysis, amidation, taking off The methods of amide effect, esterification, enzymatic lysis obtain.Correspondingly, the present invention includes the metabolite of compound, including this is sent out Bright compound comes into full contact with metabolite caused by a period of time with mammal.

Refer to that hydroxyl, amino, sulfydryl, carboxyl etc. are passed through into official with the relevant protecting group such as hydroxyl, amino, sulfydryl, carboxyl Protection can be rolled into a ball, avoids its that undesirable reaction occurs, and protecting group used is well-known to those skilled in the art, is such as existed Protective Groups in Organic Synthesis (John Wiley＆Sons, New York, the third edition, 1999) In those of refer to protecting group.

The invention also includes the compounds of this invention of isotope labelling, i.e., identical as above-mentioned disclosed structure, but the knot One or more atoms are substituted from its atom with identical proton number but different neutron populations in structure.In conjunction with the present inventionization The isotope embodiment for closing object includes the isotope of hydrogen, carbon, oxygen, sulphur, fluorine, chlorine, iodine, respectively such as²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³⁵S、¹⁸F、³⁶Cl and¹³¹I etc..The compound of the present invention, stereoisomer, tautomer, nitrogen oxides, sulphur oxidation Object, prodrug, pharmaceutically acceptable salt or solvate, and the institute containing above-mentioned isotope and/or other atom isotopes The compound of the above form is stated, within the scope of the present invention.The compounds of this invention of certain isotope labellings, such as quilt³H or¹⁴C Compound those of is marked to can be used in drug entities distribution experiment, therefore, these³H or¹⁴C isotopes are easy due to it It prepares and detection is particularly preferred.In addition, such as by heavier isotope²Certain the compounds of this invention that H is substituted are due to tool There is better metabolic stability and there are certain treatment advantages, such as Half-life in vivo and less dosage can be increased, therefore,²H is also preferred in some cases.

The compounds of this invention has Pim inhibiting effect, can be used for application and preparation in the drug or medicine group of the mankind or animal doctor Object is closed, for treating the kinase mediated diseases of Pim such as cancer or immune correlated disease.Specifically, the compound can be used In the cancer for the treatment of mankind or animal, including cell carcinoma, neoplastic hematologic disorder, solid tumor, germinocarcinoma or enblastoma choosing From breast cancer, lung cancer, prostate cancer, liver cancer, cancer of pancreas, colorectal cancer, osteocarcinoma, lymthoma, leukaemia, myeloma, ovary Cancer, cervical carcinoma, carcinoma of testis, carcinoma of endometrium, gastric cancer, kidney, cancer of the esophagus, nasopharyngeal carcinoma, the cancer of the brain and/or neural cancer etc..Specifically Ground, the compounds of this invention can be used for treat mankind or animal immune correlated disease, including inflammation, autoimmune disease, The immunosupress etc. of allergy and/or organ transplant.

C compounds or intermediate preparation

For the description present invention, it is listed below specific embodiment.But it is to be understood that the present invention is not limited to these Examples, Following embodiment is only to provide the method for the practice present invention, the scope not limiting the invention in any way.

Compound provided by the invention can be prepared by Standard synthetic methods well known in the art, and this specification provides Prepare the conventional method of the compounds of this invention.Starting material can usually be obtained by being commercialized, such as pass through Alfa TCI、Splendid remote chemistry, the resistance to Jilin Chemical of peace, special (Chengdu) bio-pharmaceuticals of Ace and Chengdu bass spy examination Ji Deng companies are commercially available, or are prepared by method well-known to those skilled in the art.

Following reaction methods and synthesis step provide the possibility for synthesizing the compounds of this invention and key intermediate Approach.About being described in more detail for individual reaction steps, referring to following embodiments.It will be understood by those skilled in the art that of the invention Compound can also be obtained by other route of synthesis.Although hereafter used in reaction process specific starting material and Reagent, but these starting materials can be replaced with reagent by other similar starting materials or reagent, to provide various spread out Biology.In addition, under the guidance of this specification, art technology can be passed through by many compounds made from following methods Conventional chemical processes known to personnel are further modified.

In the preparation of the compounds of this invention, it may be necessary to protect intermediate certain interference functional groups (for example, primary amine or Secondary amine).Requirement for such protecting group changes depending on the property of specific functional group and the condition of preparation method.Ammonia appropriate Base protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (Cbz), 9- fluorenes methylene oxygen carbonyls (Fmoc) etc..Hydroxyl protection base appropriate include allyl, acetyl group, silylation, benzyl, trityl, to methoxybenzene Methyl etc..Such protecting group can be easily determined by by those skilled in the art and (specifically refer to Protective Groups in Organic Synthesis, John Wiley＆Sons, New York, the third edition, 1999).

Following reaction methods 1 provide the exemplary steps for preparing formula (I) compound.It will be appreciated that these reaction steps and Condition is not restrictive, described method can be used to prepare formula (I) compound by reasonable change reaction condition.

Method 1

Method 1 shows the conventional method for being used to prepare formula in the scope of the invention (I) compound.Wherein, A, X, Z₁, Z₂And R With definition as described in the present invention.Intermediate compound I under alkaline condition, passes through the amine of palladium chtalyst halogenated aryl hydrocarbon with intermediate II Formula (I) compound is obtained by the reaction in change.Wherein, reaction solvent for use is selected from toluene, THF, dioxane etc.；Reaction alkali choosing used From potassium tert-butoxide, tert-butyl alcohol lithium, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate etc.；Reaction palladium catalyst used is selected from Pd₂ (dba)₃、Pd(OAc)₂、Pd(dppf)Cl₂、Pd(Ph₃)₄Deng；Reaction ligand used is selected from BINAP, Xantphos etc..

In the preferred embodiment of the method 1 of the present invention, formula (I) compound of the present invention or its alloisomerism The preparation method of body, tautomer, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate, In, it is obtained by the preparation method comprising following processes：

(1) process 1：The preparation of the chloro- 2- of 4- (2,6- difluorophenyl) thiazole simultaneously [4,5-c] pyridine, it includes following step：

Step 1：- 4 mercapto-pyridine of 3- amino is prepared,

Step 2：Thiazole simultaneously [4,5-c] pyridine is prepared,

Step 3：2- (2,6- difluorophenyl) thiazole simultaneously [4,5-c] pyridine is prepared,

Step 4：2- (2,6- difluorophenyl) thiazole simultaneously [4,5-c] pyridine -5- oxides are prepared, and

Step 5：Prepare 4- chloro- 2- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyridine；

(2) process 2：(S) thiazole is simultaneously by -2- (2,6- difluorophenyls) by-N- (- 3 base of 4- (3- amino piperidine -1- bases) pyridine) [4,5-c] pyridine

The preparation of -4- amine, it includes following step：

Step 1 prepares (S) -1- (3- (2- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyridin-4-yl-amido) pyridine - 4- yls) piperidines -3- amidocarbonic acid tertiary butyl esters, and

Step 2, preparing (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl), thiazole is simultaneously by -2- (2,6- difluorophenyls) [4,5-c] pyridine -4- amine.

In another preferred embodiment of the method 1 of the present invention, formula (I) compound of the present invention or it is vertical The preparation side of body isomers, tautomer, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate Method, wherein obtained by the preparation method comprising following processes：

(1) process 1：Prepare 4- chloro- 2- (thiazol-2-yl) thiazole simultaneously [4,5-c] pyridine comprising following step：

Step 1：2- (thiazol-2-yl)-thiazole simultaneously [4,5-c] pyridine is prepared,

Step 2：Prepare 2- (thiazol-2-yl)-thiazole simultaneously [4,5-c] pyridine -5- oxides；With

Step 3：Prepare the chloro- 2- of 4- (thiazol-2-yl)-thiazole simultaneously [4,5-c] pyridine；And

(2) process 2：Preparing (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl), -2- (thiazol-2-yl) thiazole is simultaneously [4,5-c] pyridine -4- amine comprising following step：Make the chloro- 2- of 4- (thiazol-2-yl)-thiazole simultaneously [4,5-c] pyridine and (S)- Tertiary butyl (1- (3- aminopyridine -4- bases) piperidines -3- bases) urethane reaction, the blocking group uncle for then removing amino Butoxy carbonyl obtains (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl), and -2- (thiazol-2-yl) thiazole is simultaneously [4,5-c] Pyridine -4- amine.

(1) process 1：Prepare 4- chloro- 2- (thiophene -2- bases) thiazole simultaneously [4,5-c] pyridine comprising following step：

Step 1：2- (thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine is prepared,

Step 2：2- (thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine -5- oxides are prepared, and

Step 3：Prepare 4- chloro- 2- (thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine；And

(2) process 2：Preparing (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl), thiazole is simultaneously by -2- (thiophene -2- bases) [4,5-c] pyridine -4- amine comprising following step：Make the chloro- 2- of 4- (thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine and (S) - Tertiary butyl (1- (3- aminopyridine -4- bases) piperidines -3- bases) urethane reaction, the blocking group uncle for then removing amino Butoxy carbonyl base obtains (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (thiophene -2- bases) thiazole simultaneously [4,5- C] pyridine -4- amine.

The compounds of this invention and corresponding preparation method are hereafter explained further and enumerated with preparation by embodiment.Ying Liao Solution, although given in specific embodiment typical or preferred reaction condition (such as reaction temperature, the time, reactant mole Than, reaction dissolvent and pressure etc.), but those skilled in the art can also use other reaction conditions.Optimum reaction condition It can change with specific reaction substrate used or solvent, but the condition can be passed through by those skilled in the art Optimization routine and determine.

The structure of following embodiment compounds is characterized by nuclear magnetic resonance (NMR) and/or mass spectrum (MS).Use Bruker Ascend 400MHz NMR spectra instrument, compound is dissolved in deuterated reagent appropriate, under environment temperature using TMS as internal standard into Row¹H-NMR is analyzed.Nmr chemical displacement (δ) is used hereinafter referred to as unit of ppm：S, it is unimodal；D, doublet；T, it is triple Peak；Q, quartet；M, multiplet；Brs, width unimodal.MS passes through Waters UPLC-Vevo^TMTQ MS mass spectrographs (ESI) measure.

React starting material, intermediate and embodiment compound can by precipitation, filtering, crystallization, evaporation, distillation with And the routine techniques such as chromatography (such as column chromatography, TLC isolates and purifies) carry out isolation and purification.

TLC uses Yantai Huanghai Sea HSGF254 tlc silica gels plate (0.2 ± 0.03mm), and TLC is isolated and purified using cigarette Platform Huanghai Sea HSGF254 thin-layer chromatography thickness prepares plate (0.9~1mm), is purchased from Haiyang Chemical Plant, Qingdao.

Column chromatography is purchased from Haiyang Chemical Plant, Qingdao using 300~400 mesh silica gel of the Yantai Huanghai Sea as carrier.

The commercialization solvent and reagent used in experiment is not necessarily to be further purified or handle unless otherwise specified, after purchase Directly use.When with reference to other embodiments or synthetic method, reaction condition (reaction temperature, reaction dissolvent, reactant molar ratio Or/and duration of the reaction) may be different.In general, reaction process can be monitored by TLC, the suitable time is selected accordingly It terminates and reacts and post-processed.The purification condition of compound is it can also happen that variation, it is however generally that, the R according to TLC_fValue choosing Suitable column chromatography eluant, eluent is selected, or respective compound is isolated and purified by preparing TLC.

Embodiment 1, thiazole is simultaneously by -2- (2,6- difluorophenyls) by (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) [4,5-c] pyridine -4- amine

(S) preparation of -1- (3- aminopyridine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

Step 1 prepares (S) -1- (3- nitropyridine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

By the chloro- 3- nitropyridines (475.6mg, 3mmol) of 4-, and (S) -3- tertbutyloxycarbonyls piperidines (600.8mg, 3 Mmol) and DIPEA (387.7mg, 3.0mmol) sequentially adds 50mL round-bottomed flasks, adds 10mL ethyl alcohol, 5h is stirred at room temperature. Reaction solution is concentrated under reduced pressure, ethyl acetate dissolves residue, ethyl acetate phase (50mL × 3) is washed with water, organic phase is through anhydrous slufuric acid Sodium is dried, and is filtered and is concentrated under reduced pressure.Residue isolates and purifies (petroleum ether by silica gel column chromatography：Ethyl acetate=3:1), Obtain for yellow solid (S) -1- (3- nitropyridine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (840 mg, 87%).

Step 2 prepares (S) -1- (3- aminopyridine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

By (S) -1- (3- nitropyridine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (841.3mg, 2.61mmol) Be dissolved in 20mL ethyl alcohol, then sequentially add iron powder (1.17g, 20.88mmol), ammonium chloride (837.8mg, 15.66mmol) and 3mL water, 90 DEG C of reflux 4h.Filtrate is concentrated under reduced pressure in filtering reacting liquid, and suitable quantity of water, ethyl acetate extraction are added into residue (50mL × 3) merge organic phase and are washed with water (50mL × 3), and organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure. Residue isolates and purifies (dichloromethane by silica gel column chromatography：Methanol=20:1) (S) -1- for yellow solid, is obtained (3- aminopyridine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (724mg, 95%).

The preparation of the chloro- 2- of 4- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyridine

Step 1 prepares -4 mercapto-pyridine of 3- amino

The chloro- 3- nitro-pyridines (7.93g, 50mmol) of 4- are dissolved in 50mL ethyl alcohol, are slowly added to 50mmol concentrated hydrochloric acids, room Temperature stirring；Weigh NaHSH₂O (13.7g, 185mmol) is added in reaction solution, and 40min is stirred at room temperature；Sodium hydrosulfite is weighed again (32.21g, 185mmol) is soluble in water, and insurance amidin is added in reaction mixture, 80 DEG C of stirring 12h.Filtering reaction Liquid, is concentrated under reduced pressure filtrate, and residue is isolated and purified by silica gel column chromatography and (first uses dichloromethane：Methanol=5:1 elution is miscellaneous Matter, then use dichloromethane：Methanol=1:1 affords crude product), obtain -4 mercapto-pyridine of 3- amino for yellow-brown solid Crude product.- 4 mercapto-pyridine crude product of 3- amino is directly used in and reacts in next step without being further purified.

Step 2 prepares thiazole simultaneously [4,5-c] pyridine

3- amino -4- mercaptopyridine crude products are dissolved in 100mL formic acid, flow back 4h, and saturation NaHCO is added₃Solution is quenched instead It answers.Reaction solution is extracted with ethyl acetate (200mL × 3), merges organic phase, and organic phase is dried over anhydrous sodium sulfate, filters and subtract Pressure concentration.Residue isolates and purifies (petroleum ether by silica gel column chromatography：Ethyl acetate=3：1) it, obtains as white solid Thiazole simultaneously [4,5-c] pyridine (2.52g, two step yields 37%).

Step 3 prepares 2- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyridine

By thiazole simultaneously [4,5-c] pyridine (2.0g, 14.7mmol), 2,6- difluoros iodobenzene (4.2g, 17.6mmol), Pd (PPh₃)₄(849mg, 0.735mmol), CuI (140mg, 0.735mmol) and Cs₂CO₃(14.4g, 44.1mmol) is dissolved in 50mL DMF, 120 DEG C of stirrings (tube sealing reaction 4h), TLC are monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering reaction Liquid is added in 100mL water and 50mL ethyl acetate to filtrate, detaches organic phase, then (50mL × 2) are extracted with ethyl acetate, has Machine is mutually washed with water (50mL × 1), saturated salt solution (50mL × 2) successively, and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Silicon Plastic column chromatography isolates and purifies (petroleum ether：Ethyl acetate=3：1) 2- (2, the 6- difluorobenzenes for white powdery solids, are obtained Base) thiazole simultaneously [4,5-c] pyridine (2.59g, 71%).

Step 4 prepares 2- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyridine -5- oxides

By 2- (2,6- difluorophenyl) thiazole, simultaneously [4,5-c] pyridine (2.48g, 10mmol) is dissolved in 30mL dichloromethane, delays It is slow that MCPBA (2.42g, 14mmol) is added, it is stirred at room temperature, TLC is monitored to the reaction was complete, and 50mL 1M solution of potassium carbonate is added Reaction is quenched.100mL saturated salt solutions are added into reaction solution, (50mL × 3) are extracted with dichloromethane, merge organic phase, warp Anhydrous sodium sulfate dry, filter and be concentrated under reduced pressure, obtain for white solid 2- (2,6- difluorophenyl) thiazole simultaneously [4,5-c] Pyridine -5- oxide crude products.2- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyridine -5- oxides crude product without It is further purified, is directly used in and reacts in next step.

Step 5 prepares 4- chloro- 2- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyridine

By 2- (2,6- difluorophenyls) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, reflux 2h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, addition saturated sodium bicarbonate adjusting pH to neutrality, It is extracted with ethyl acetate (50mL × 3), merges organic phase, organic phase is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, silicon Plastic column chromatography isolates and purifies (petroleum ether：Ethyl acetate=3:1) 4- chloro- 2- (2, the 6- difluorobenzenes for light yellow solid, are obtained Base) thiazole simultaneously [4,5-c] pyridine (2.0g, two step yields 71%).

(S)-N- (- 3 base of 4- (3- amino piperidine -1- bases) pyridine) -2- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyrrole The preparation of pyridine -4- amine

Step 1 prepares (S) -1- (3- (2- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyridin-4-yl-amido) pyridine - 4- yls) piperidines -3- amidocarbonic acid tertiary butyl esters

By (S) -1- (3- aminopyridine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (210mg, 0.72mmol), Simultaneously [4,5-c] pyridine (170mg, 0.6mmol) is dissolved in 5mL toluene to the chloro- 2- of 4- (2,6- difluorophenyl) thiazole, sequentially adds Pd₂ (dba)₃(16mg, 0.018mmol), Xantphos (21mg, 0.036mmol) and potassium tert-butoxide (101mg, 0.9mmol), nitrogen Atmosphere encloses lower 80 DEG C of stirrings (tube sealing reaction), and TLC, which is monitored to raw material, no longer to react.Filtering reacting liquid uses methylene chloride/methanol Mixed liquor (1:1) filter cake is fully washed, filtrate is concentrated under reduced pressure, is isolated and purified, is obtained as yellow solid by preparing TLC (S) -1- (3- (2- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyridin-4-yl-amido) pyridin-4-yl) piperidines -3- amido first Sour tertiary butyl ester (85mg, 26%).

Step 2, preparing (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl), thiazole is simultaneously by -2- (2,6- difluorophenyls) [4,5-c] pyridine -4- amine

By (S) -1- (3- (2- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyridin-4-yl-amido) pyridin-4-yl) piperazine Pyridine -3- amidocarbonic acids tertiary butyl ester (85mg, 0.16mmol) is dissolved in 4mL dichloromethane, and reaction bulb is placed in cooling in ice bath, 1mL trifluoracetic acids are added, stir 20min under condition of ice bath, are then warmed to room temperature that the reaction was continued, TLC is detected to the reaction was complete. Reaction solution is concentrated under reduced pressure, 150mL saturated sodium bicarbonate solutions are added in residue, (50mL × 3), water is extracted with ethyl acetate Organic phase (25mL × 3) is washed, organic phase is merged, organic phase is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure.Residue is logical Preparation TLC is crossed to isolate and purify, obtain for yellow solid (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (2, 6- difluorophenyls) thiazole simultaneously [4,5-c] pyridine -4- amine (50mg, 71%).¹H NMR(400MHz,CDCl₃)δ10.00(s, 1H), 8.68 (brs, 1H), 8.26 (d, J=5.2Hz, 1H), 8.22 (d, J=5.6Hz, 1H), 7.52-7.45 (m, 1H), 7.33 (d, J=5.6Hz, 1H), 7.14 (t, J=8.8Hz, 2H), 7.00 (d, J=5.2Hz, 1H), 3.29-3.19 (m, 2H), 3.14-3.06(m,1H), 2.80-2.72(m,1H),2.64-2.59(m,1H),2.06-1.97(m,1H),1.96-1.89(m, 2H),1.41-1.32(m,1H). ESI-MS m/z：461.2[M+Na]⁺。

Embodiment 2, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine - 4- amine

The preparation of the chloro- 2- phenyl thiazoles of 4- simultaneously [4,5-c] pyridine

Step 1 prepares 3- amino -4- mercaptopyridines

The chloro- 3- nitro-pyridines (7.9g, 49.8mmol) of 4- are dissolved in 50mL ethyl alcohol, are slowly added to 50mmol concentrated hydrochloric acids, It is stirred at room temperature；NaHSH is weighed again₂O (13.69g, 184.8mmol) is added in reaction solution, and 40min is stirred at room temperature；Then claim It takes sodium hydrosulfite (32.21g, 185.1mmol) soluble in water, and insurance amidin is added in reaction mixture, 80 DEG C of stirrings 12h.Filtering reacting liquid concentrates filtrate decompression, and silica gel column chromatography separating purification (first uses dichloromethane：Methanol=5:1 elution Impurity, then use dichloromethane：Methanol=1:1 affords crude product), obtain the 3- amino -4- sulfydryl pyrroles for yellow-brown solid Pyridine crude product.3- amino -4- mercaptopyridines the crude product is directly used in and reacts in next step without being further purified.

Step 2 prepares thiazole simultaneously [4,5-c] pyridine

3- amino -4- mercaptopyridine crude products are dissolved in 100mL formic acid, flow back 4h, and saturated sodium bicarbonate solution is added and is quenched Reaction.Reaction solution is extracted with ethyl acetate (200mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, filters and depressurize dense Contracting.Silica gel column chromatography separating purification (petroleum ether：Ethyl acetate=3：1) thiazole simultaneously [4, the 5-c] pyridine for white solid, is obtained (2.52g, two step yields 37%).

Step 3 prepares 2- phenyl thiazoles simultaneously [4,5-c] pyridine

By thiazole simultaneously [4,5-c] pyridine (2.0g, 14.7mmol), iodobenzene (3.7g, 17.9mmol), Pd (PPh₃)₄ (849mg, 0.735mmol), CuI (140mg, 0.735mmol) and Cs₂CO₃(14.4g, 44.1mmol) is dissolved in 50mL DMF, 120 DEG C of stirrings, TLC are monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering reacting liquid, 100mL water and 50mL is added In ethyl acetate to filtrate, organic phase is detached, then (50mL × 2) are extracted with ethyl acetate, organic phase washed with water (50mL × 1), saturated salt solution (50mL × 2) is washed, and is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Silica gel column chromatography separating purification (petroleum ether：Ethyl acetate=3：1), obtain for white solid powder 2- phenyl thiazoles simultaneously [4,5-c] pyridine (2.26 g, 72%).

Step 4 prepares 2- phenyl thiazoles simultaneously [4,5-c] pyridine -5- oxides

By 2- phenyl thiazoles, simultaneously [4,5-c] pyridine (2.25g, 10.6mmol) is dissolved in 30mL dichloromethane, is slowly added to MCPBA (2.56mg, 14.8mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 50mL 1M solution of potassium carbonate is added and is quenched Reaction.100mL saturated salt solutions are added into reaction solution, extracts (50mL × 3) with dichloromethane, merges organic phase, anhydrous sulphur The drying of sour sodium, filters and is concentrated under reduced pressure, and simultaneously [4,5-c] pyridine -5- oxides slightly produce the 2- phenyl thiazoles for obtaining as white solid Object.Simultaneously [4,5-c] pyridine -5- oxides crude product is directly used in next step the 2- phenyl thiazoles without being further purified Reaction.

Step 5 prepares the chloro- 2- phenyl thiazoles of 4- simultaneously [4,5-c] pyridine

By 2- phenyl thiazoles, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, flow back 2h.It is concentrated under reduced pressure Reaction solution is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH to neutrality, is extracted with ethyl acetate It takes (50mL × 3), merges organic phase, organic phase is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, silica gel column chromatography separation Purify (petroleum ether：Ethyl acetate=3：1) the chloro- 2- phenyl thiazoles of 4- simultaneously [4, the 5-c] pyridine for light yellow solid, is obtained (2.0g, two step yields 76%).

2 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 1, ESI-MS m/z：403.4[M+H]⁺。

Embodiment 3, -2- phenyl thiazoles are simultaneously by (S)-N- (5- (3- amino piperidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) [4,5-c] pyridine -4- amine

(S) preparation of -1- (4- amino -1- methyl-1 H- pyrazoles -5- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

Step 1 prepares 1- methyl -4- nitro -1H- pyrazoles

4- nitro -1H- pyrazoles (1.13g, 9.99mmol) is dissolved in the anhydrous THF of 15mL, reaction bulb is placed in cold in ice bath But, be slowly added to NaH (600mg, 25mmol), be warmed to room temperature stirring 2.5h, be then slowly added into iodomethane (3.84 g, 20mmol), continue to stir 1.5h, be slowly added to 15mL saturated salt solutions and reaction is quenched.Reaction solution, ethyl acetate is concentrated under reduced pressure It extracts (50mL × 3), detaches organic phase, washed successively with water, saturated salt solution (50mL × 2), anhydrous sodium sulfate drying, filtering And be concentrated under reduced pressure, obtain the 1- methyl -4- nitro -1H- pyrazoles (826mg, 65%) for light yellow solid.

Step 2 prepares the chloro- 1H- pyrazoles of 1- methyl -4- nitros -5-

1- methyl -4- nitro -1H- pyrazoles (1g, 7.87mmol) is dissolved in the anhydrous THF of 12mL, is cooled under nitrogen atmosphere - 78 DEG C, the LDA of a concentration of 2mol/L of 6mL is slowly added dropwise, continues to stir 1h under -78 DEG C, nitrogen atmosphere；By carbon trichloride (2.42g, 10.2mmol) is dissolved in the anhydrous THF of 12mL, is slowly added dropwise into the above reaction solution, then -78 DEG C of stirring 2h rise to Room temperature continues to stir 1h, and reaction is quenched with saturated aqueous ammonium chloride.Organic phase washes (20mL × 1), second with aqueous ammonium chloride solution Acetoacetic ester extracts (10mL × 3), merges organic phase, and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Silica gel column chromatography detaches Purify (petroleum ether：Ethyl acetate=3:1), obtain for yellow solid the chloro- 1H- pyrazoles of 1- methyl -4- nitros -5- (691mg, 54%).

Step 3 prepares (S) -1- (1- methyl -4- nitro -1H- pyrazoles -5- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl Ester

By the chloro- 1H- pyrazoles (485mg, 3.0mmol) of 1- methyl -4- nitros -5- and (S) -3- tertbutyloxycarbonyl piperazines Pyridine (781 mg, 3.9mmol) is dissolved in 15mL ethyl alcohol, and DIPEA (3.1g, 24mmol) is added, is heated to reflux, TLC is monitored to reaction Completely.Reaction solution is cooled to room temperature, is concentrated under reduced pressure, silica gel column chromatography separating purification (petroleum ether：Ethyl acetate=3:1) it, obtains To (S) -1- (1- methyl -4- nitro -1H- pyrazoles -5- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl for yellow oily liquid Ester (620 mg, 63%).

Step 4 prepares (S) -1- (4- amino -1- methyl-1 H- pyrazoles -5- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl Ester

By (S) -1- (1- methyl -4- nitro -1H- pyrazoles -5- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (600mg, 1.84 mmol), iron powder (824mg, 14.7mmol), ammonium chloride (591mg, 11mmol) be added 100mL round-bottomed flasks in, be added 14mL ethyl alcohol and 2mL water, 60 DEG C of stirring 8h；Then iron powder (101mg, 1.81mmol), 60 DEG C of stirrings are added, TLC is monitored to anti- It should be complete.Filtering reacting liquid, filtrate 60mL ethyl acetate and the dilution of 10% potassium phosphate solutions of 60mL, detach organic phase, then It is extracted with ethyl acetate (50mL × 2), merges organic phase and is washed with water (25mL × 2), be dried over anhydrous sodium sulfate, filtering is simultaneously It is concentrated under reduced pressure.Silica gel column chromatography separating purification (petroleum ether：Ethyl acetate=1：1) (S) -1- for brown oil liquid, is obtained (4- amino -1- methyl-1 H- pyrazoles -5- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (380 mg, 70%).

3 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 1.ESI-MS m/z：406.6[M+H]⁺。

Embodiment 4, (S)-N- (5- (3- amino piperidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) -2- (2,6- difluorobenzenes Base) thiazole simultaneously [4,5-c] pyridine -4- amine

4 compound of the embodiment of the present invention is prepared according to method 1, specific synthesized reference embodiment 1.¹H NMR(400MHz, CDCl₃) δ 8.02 (d, J=5.6Hz, 1H), 7.48-7.41 (m, 2H), 7.17 (d, J=6.0Hz, 1H), 7.10 (t, J= 8.6Hz, 2H),3.82(s,3H),3.48-3.38(m,2H),3.33-3.25(m,1H),3.15-3.03(m,2H),2.02- 1.90(m,1H), 1.89-1.74(m,2H),1.68-1.56(m,1H).ESI-MS m/z：439.8[M-H]^-。

Embodiment 5, (S)-N- (2- (3- amino piperidine -1- bases) phenyl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine -4- amine

(S) preparation of -1- (2- aminophenyls) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

Step 1 prepares (S) -1- (2- nitrobenzophenones) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

By the chloro- 2- nitrobenzenes (470mg, 2.98mmol) of 1-, (S) -3- tertbutyloxycarbonyls piperidines (600mg, 2.99 Mmol it) is dissolved in DMF, Pd/C (70mg) is added, is stirred under 80 DEG C, nitrogen atmosphere, TLC is monitored to the reaction was complete.By reaction solution It is cooled to room temperature, filters, filtrate is poured into water, is extracted with ethyl acetate (50mL × 3), merge organic phase and be washed with water (25mL × 3), organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure, and (S) -1- for dark brown oil liquid is obtained (2- nitrobenzophenones) piperidines -3- bases-amidocarbonic acid tertiary butyl ester crude product.Described (S) -1- (2- nitrobenzophenones) piperidines -3- Base-amidocarbonic acid tertiary butyl ester crude product is directly used in and reacts in next step without being further purified.

Step 2 prepares (S) -1- (2- aminocarbonyl phenyls) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

(S) -1- (2- nitrobenzophenones) piperidines -3- bases-amidocarbonic acid tertiary butyl ester crude product is dissolved in 70mL ethyl alcohol, is added successively Enter iron powder (1.3g, 23.84mmol), ammonium chloride (957mg, 17.88mmol) and 3mL water, is heated to reflux, TLC is monitored to anti- It should be complete.Reaction solution is cooled to room temperature, is filtered, filtrate is concentrated under reduced pressure, suitable quantity of water is added, be extracted with ethyl acetate (50 mL × 3), merge organic phase and be washed with water (25mL × 3), anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Silica gel column chromatography detaches Purify (dichloromethane：Methanol=20:1) (S) -1- (2- aminocarbonyl phenyls) piperidines -3- bases-amido first for yellow solid, is obtained Sour tertiary butyl ester (322mg, two step yields 37%).

(S) preparation of-N- (2- (3- amino piperidine -1- bases) phenyl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine -4- amine

Step 1 prepares (S) -1- (2- (2- phenyl thiazoles simultaneously [4,5-c] pyridin-4-yl-amido) phenyl) piperidines -3- bases - Amidocarbonic acid tertiary butyl ester

By (S) -1- (2- aminophenyls) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (76mg, 0.26mmol), the chloro- 2- of 4- Simultaneously [4,5-c] pyridine (64mg, 0.26mmol) is dissolved in THF to phenyl thiazole, sequentially adds Pd₂(dba)₃(7.6mg, 0.008mmol), BINAP (10mg, 0.016mmol) and t-BuOK (44mg, 0.39mmol), under nitrogen atmosphere, 80 DEG C of stirrings, TLC is monitored to the reaction was complete.Filtering reacting liquid, with methylene chloride/methanol mixed liquor (1:1) filter cake is fully washed, is concentrated under reduced pressure Filtrate.(dichloromethane is isolated and purified by TLC：Methanol=20:1) (S) -1- (2- (2- phenyl thiophenes for yellow solid, are obtained Azoles simultaneously [4,5-c] pyridin-4-yl-amido) phenyl) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (78mg, 60%).

Step 2 prepares (S)-N- (2- (3- amino piperidine -1- bases) phenyl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine -4- Amine

By (S) -1- (2- (2- phenyl thiazoles simultaneously [4,5-c] pyridin-4-yl-amido) phenyl) piperidines -3- bases-amidocarbonic acid Tertiary butyl ester (78 mg, 0.15mmol) is dissolved in 4mL dichloromethane, and reaction bulb is placed in ice bath to cooling, addition 1mL trifluoro vinegar Acid stirs 20min under condition of ice bath, is then warmed to room temperature that the reaction was continued, and TLC is monitored to the reaction was complete.Reaction is concentrated under reduced pressure 50mL saturated sodium bicarbonate solutions are added into residue, are extracted with ethyl acetate (50mL × 3) for liquid, merge organic phase and are used in combination It washes (25mL × 2), anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.It is isolated and purified, is obtained as yellow solid with TLC is prepared (S)-N- (2- (3- amino piperidine -1- bases) phenyl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine -4- amine (40mg, 66%).¹H NMR(400MHz,d₆- DMSO) δ 9.47 (s, 1H), 8.81 (dd, J=8.0,1.2Hz, 1H), 8.17-8.14 (m, 3H), 7.67-7.63 (m, 2H), 7.58 (d, J=5.6Hz, 1H), 7.27 (dd, J=7.6,1.2Hz, 1H), 7.21 (td, J=7.6, 1.2 Hz, 1H), 7.01 (td, J=7.6,1.6Hz, 1H), 3.25-3.17 (m, 2H), 2.99-2.93 (m, 1H), 2.75-2.66 (m,2H), 2.18-2.11(m,1H),2.02-1.90(m,2H),1.51-1.41(m,1H).ESI-MS m/z：424.0[M+ Na]⁺。

Embodiment 6, -2- (2,6- difluorophenyls) thiazole is simultaneously [4,5-c] by (S)-N- (2- (3- amino piperidine -1- bases) phenyl) Pyridine -4- amine

6 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 9.47 (s, 1H), 8.88 (d, J=7.6Hz, 1H), 8.20 (d, J=5.6Hz, 1H), 7.46-7.38 (m, 1H), 7.27-7.11 (m, 4H), 7.00 (t, J=7.6Hz, 1H), 3.34-3.28 (m, 1H), 3.23-3.15 (m, 1H), 2.99-2.90 (m,1H),2.80-2.64(m,2H),2.06-1.97(m,1H),1.97-1.87(m,2H),1.48-1.36(m, 1H).ESI-MS m/z：460.1[M+Na]⁺。

Embodiment 7, (S)-N- (4- (3- amino piperidine -1- bases) pyrimidine -5- bases) -2- phenyl thiazoles simultaneously [4,5-c] pyridine - 4- amine

(S) preparation of -1- (5- aminopyrimidine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

Step 1 prepares -4 (1H)-thioketones hydrochloride of 5- amino -6- chlorine pyrimidine

5- amino -4,6- dichloro pyrimidine (2g, 12.2mmol) is dissolved in 7mL DMSO, Na is added₂S·9H₂O (3.221g, 13.4mmol), it is stirred at room temperature, TLC is monitored to the reaction was complete.Reaction bulb is placed in ice bath, 10mL is added into reaction solution Water is slowly added dropwise concentrated hydrochloric acid and reaction solution pH is adjusted to faintly acid, a large amount of precipitations generated in reaction solution, filtering reacting liquid is filled with water Point washing filter cake, collects solid and drying, obtain -4 (1H)-thioketones hydrochloride, crude of 5- amino -6- chlorine pyrimidine (2.67g, About 100%).- 4 (1H)-thioketones hydrochloride, crude of 5- amino -6- chlorine pyrimidine is directly used in without being further purified It reacts in next step.

Step 2 prepares 4- chlorine-5-amido pyrimidines

The hydrochloride compound (2.67g) of -4 (1H)-thioketones of 5- amino -6- chlorine pyrimidine is dissolved in 25mL and dries methanol, is added Enter 25% ammonium hydroxide (2.5mL) and Raney Ni (2mL), stirred under 80 DEG C, nitrogen atmosphere, TLC is monitored to the reaction was complete.Instead It answers liquid to filter, washs filter cake with methanol, filtrate is concentrated under reduced pressure, isolated and purified, obtained chloro- for the 4- of yellow solid with TLC is prepared 5- aminopyrimidines (156mg, 9.9%).

Step 3 prepares (S) -1- (5- aminopyrimidine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

By 4- chlorine-5-amido pyrimidines (156mg, 1.2mmol) and (S) -3- t-butoxycarbonyl aminos piperidines (288mg, 1.44 Mmol it) is dissolved in 8mL methanol, DIPEA (186mg, 1.44mmol), return stirring is added, TLC is monitored to the reaction was complete.It depressurizes dense Contracting reaction solution is added 150mL saturated sodium bicarbonate solutions, is extracted with ethyl acetate (25mL × 3), merges organic phase and uses water It washes (25mL × 2), anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Residue isolates and purifies (dichloromethane by preparing TLC Alkane：Methanol=20:1) (S) -1- (5- aminopyrimidine -4- bases) piperidines -3- bases-amido first for yellowish-brown oily liquids, are obtained Sour tertiary butyl ester (240mg, 68%).

7 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 1.ESI-MS m/z：404.3[M+H]⁺。

Embodiment 8, thiazole is simultaneously by -2- (2,6- difluorophenyls) by (S)-N- (4- (3- amino piperidine -1- bases) pyrimidine -5- bases) [4,5-c] pyridine -4- amine

8 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 1.¹H NMR (400MHz,CDCl₃) δ 9.72 (s, 1H), 8.61 (s, 1H), 8.20 (d, J=5.6Hz, 1H), 7.55-7.47 (m, 1H), 7.38 (d, J=5.6Hz, 1H), 7.15 (t, J=8.8Hz, 2H), 3.68-3.61 (m, 1H), 3.58-3.50 (m, 1H), 3.23-3.07 (m, 2H),2.96-2.89(m,1H),2.07-1.98(m,1H),1.94-1.80(m,2H),1.47-1.38(m,1H)。ESI- MS m/z： 438.0[M-H]^-。

Embodiment 9, (S)-N- (4- (3- amino-pyrrolidine -1- bases) pyridin-3-yl) -2- phenyl thiazoles simultaneously [4,5-c] pyrrole Pyridine -4- amine

(S) preparation of -1- (3- amidos pyridin-4-yl) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester

Step 1 prepares (S) -1- (3- nitropyridine -4- bases) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester

By the chloro- 3- nitropyridines (475mg, 3.0mmol) of 4-, (S) -3- tertiary butyl oxycarbonyls pyrrolidines (558mg, 3.0mmol) and DIPEA (464mg, 3.59mmol) is dissolved in 20mL ethyl alcohol, and 12h is stirred at room temperature.It is concentrated under reduced pressure after reaction solution, It is dissolved with ethyl acetate, washing ethyl acetate phase (25mL × 3) is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure.Silica gel Column chromatographic isolation and purification (petroleum ether：Ethyl acetate=3:1) (S) -1- (3- nitropyridine -4- bases) for yellow solid, is obtained Pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester (758mg, 82%).

Step 2 prepares (S) -1- (3- aminopyridine -4- bases) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester

(S) -1- (3- nitropyridine -4- bases) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester (616mg, 2.0mmol) is molten In 20mL ethyl alcohol, iron powder (896mg, 16mmol), ammonium chloride (642mg, 12mmol) and 2mL water are then sequentially added, 90 DEG C Flow back 4h.Reaction solution filters, and filtrate is concentrated under reduced pressure, and suitable quantity of water is added in residue, and ethyl acetate extracts (50mL × 3), merges Organic phase is simultaneously washed with water (25mL × 3), is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure.It is detached by silica gel column chromatography Purify (dichloromethane：Methanol=20:1) (S) -1- (3- aminopyridine -4- bases) pyrrolidines -3- for yellow solid, is obtained Base-amidocarbonic acid tertiary butyl ester (528mg, 95%).¹H NMR(400MHz,d₆- DMSO) δ 7.83 (d, J=6.4Hz, 1H), 7.73 (s, 1H), 7.25 (d, J=6.0Hz, 1H), 6.66 (d, J=6.4Hz, 1H), 4.14-4.03 (m, 1H), 3.93-3.84 (m,1H),3.78-3.66(m,1H),3.65-3.56(m,1H),3.54-3.48(m,1H),2.11-1.99(m,1H), 1.94- 1.82(m,1H),1.39(s,9H)。

9 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 1.¹H NMR (400MHz,d₆- DMSO) δ 8.80 (s, 1H), 8.16-8.13 (m, 2H), 8.07 (s, 1H), 8.05 (d, J=5.6Hz, 1H), 7.89 (d, J=5.6Hz, 1H), 7.62-7.58 (m, 3H), 7.36 (d, J=5.6Hz, 1H), 6.63 (d, J=5.6Hz, 1H), 3.69-3.65(m,1H),3.60-3.55(m,3H),2.05-1.95(m,2H),1.79-1.70(m,1H).ESI-MS m/z： 388.8 [M+H]⁺。

Embodiment 10, (S)-N- (4- (3- amino-pyrrolidine -1- bases) pyridin-3-yl) -2- (2,6- difluorophenyls) thiazole And [4,5-c] pyridine -4- amine

10 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,d₆- DMSO) δ 8.79 (s, 1H), 8.02 (s, 1H), 8.00 (d, J=5.6Hz, 1H), 7.94 (d, J= 5.6Hz, 1H), 7.75-7.67 (m, 1H), 7.41-7.37 (m, 3H), 6.57 (d, J=6.0Hz, 1H), 3.59-3.52 (m, 4H),3.09-3.03 (m,1H),1.91-1.84(m,1H),1.60-1.52(m,1H).ESI-MS m/z：425.3[M+H]⁺。

Embodiment 11, (S)-N- (5- (3- amino-pyrrolidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) -2- phenyl thiazoles And [4,5-c] pyridine -4- amine

(S) preparation of -1- (4- amino -1- methyl-1 H- pyrazoles -5- bases) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester

Step 1 prepares 1- methyl -4- nitro -1H- pyrazoles

4- nitro -1H- pyrazoles (1130mg, 9.99mmol) is dissolved in the anhydrous THF of 15mL, reaction bulb is placed in ice bath It is cooling, be slowly added to NaH (600mg, 25mmol), be warmed to room temperature stirring 2.5h, be then slowly added into iodomethane (3.84 g, 20mmol), continue to stir 1.5h, 15mL saturated salt solutions are added, reaction is quenched.Reaction solution is concentrated under reduced pressure, is extracted with ethyl acetate It takes (50mL × 3), detaches organic phase, and washed successively with water, saturated salt solution (50mL × 2), anhydrous sodium sulfate drying, filtering And be concentrated under reduced pressure, obtain the 1- methyl -4- nitro -1H- pyrazoles (826mg, 65%) for light yellow solid.¹H NMR (400MHz,CDCl₃)δ8.14(s,1H),8.07(s,1H),3.99(s,3H)。

Step 2 prepares the chloro- 1H- pyrazoles of 1- methyl -4- nitros -5-

1- methyl -4- nitro -1H- pyrazoles (1.0g, 7.87mmol) is dissolved in the anhydrous THF of 12mL, is cooled down under nitrogen atmosphere To -78 DEG C, the LDA of a concentration of 2mol/L of 6mL is slowly added dropwise, continues to stir 1h under -78 DEG C, nitrogen atmosphere；By carbon trichloride (2.41g, 10.2mmol) is dissolved in the anhydrous THF of 12mL, is slowly added dropwise into above-mentioned reaction solution, and -78 DEG C of stirring 2h are warmed to room temperature Continue to stir 1h, reaction is quenched with saturated aqueous ammonium chloride.20mL aqueous ammonium chloride solutions are added and wash organic phase, use acetic acid Ethyl ester extracts (10mL × 3), merges organic phase, and anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure.Pass through silica gel column chromatography point From purifying (petroleum ether：Ethyl acetate=3:1) the chloro- 1H- pyrazoles of 1- methyl -4- nitros -5- for yellow solid, is obtained (691mg, 54%).¹H NMR(400MHz,CDCl₃)δ8.33(s,1H),3.82(s,3H)。

Step 3 prepares (S) -1- (1- methyl -4- nitro -1H- pyrazoles -5- bases) tertiary fourth of pyrrolidin-3-yl-amidocarbonic acid Base ester

By the chloro- 1H- pyrazoles (485mg, 3.0mmol) of 1- methyl -4- nitros -5- and (S) -3- t-butoxycarbonyl amino pyrroles Alkane (725mg, 3.89mmol) is dissolved in 15mL ethyl alcohol, and DIPEA (3.1g, 24mmol) is added, is heated to reflux, TLC is monitored to anti- It should be complete.Reaction solution is cooled to room temperature, is concentrated under reduced pressure, silica gel column chromatography separating purification (petroleum ether：Ethyl acetate=3:1), Obtain (S) -1- (1- methyl -4- nitro -1H- pyrazoles -5- bases) pyrrolidin-3-yl-amidocarbonic acid uncle for yellow oily liquid Butyl ester (560mg, 60%).

Step 4 prepares (S) -1- (4- amino -1- methyl-1 H- pyrazoles -5- bases) tertiary fourth of pyrrolidin-3-yl-amidocarbonic acid Base ester

By (S) -1- (1- methyl -4- nitro -1H- pyrazoles -5- bases) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester (311mg, 1.0 mmol), iron powder (448mg, 8mmol), ammonium chloride (321mg, 6mmol) are added in 100mL round-bottomed flasks, then 14mL ethyl alcohol and 2mL water, 60 DEG C of stirrings is added, TLC is monitored to the reaction was complete.Filtering reacting liquid, filtrate 60mL ethyl acetate It is diluted with 10% potassium phosphate solutions of 60mL, detaches organic phase, then (50mL × 2) are extracted with ethyl acetate, merge organic phase simultaneously (25mL × 2) are washed with water, organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Silica gel column chromatography separating purification (stone Oily ether：Ethyl acetate=1：1) (S) -1- (4- amino -1- methyl-1 H- pyrazoles -5- bases) pyrrole for brown oil liquid, is obtained Cough up alkane -3- bases-amidocarbonic acid tertiary butyl ester (199mg, 71%).ESI-MS m/z：282.3[M+H]⁺。

11 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 1.¹H NMR (400MHz,CDCl₃) δ 9.24 (brs, 1H), 8.06 (d, J=5.6Hz, 1H), 8.02-7.99 (m, 3H), 7.54-7.51 (m, 3H), 7.13 (d, J=5.6Hz, 1H), 3.79 (s, 3H), 3.72-3.68 (m, 1H), 3.62-3.55 (m, 1H), 3.48 (dd, J=10.4,4.4Hz, 1H), 3.34 (td, J=8.8,3.2Hz, 1H), 3.09 (dt, J=10.4,1.6Hz, 1H), 2.15-2.06(m,1H), 1.83-1.78(m,1H).ESI-MS m/z：392.1[M+H]⁺。

Embodiment 12, (S)-N- (5- (3- amino-pyrrolidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) -2- (2,6- bis- Fluorophenyl) thiazole simultaneously [4,5-c] pyridine -4- amine

12 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 1.¹H NMR (400MHz,CDCl₃) δ 10.27 (brs, 1H), 8.17 (s, 1H), 8.12 (d, J=5.6Hz, 1H), 7.50-7.43 (m, 1H), 7.16-7.10 (m, 3H), 3.79 (s, 3H), 3.74-3.68 (m, 1H), 3.64-3.58 (m, 1H), 3.43 (dd, J= 10.8,3.6Hz, 1H), 3.31 (dt, J=8.8,2.0Hz, 1H), 3.03 (d, J=10.8Hz, 1H), 2.11-2.02 (m, 1H),1.88-1.81(m, 1H).ESI-MS m/z：428.2[M+H]⁺。

Embodiment 13, (S)-N- (2- (3- amino-pyrrolidine -1- bases) phenyl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine -4- Amine

(S) preparation of -1- (2- aminophenyls) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester

Step 1 prepares (S) -1- (2- nitrobenzophenones) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester

By the chloro- 2- nitrobenzenes (470mg, 3mmol) of 1-, (S) -3- t-butyloxycarbonyls pyrrolidines (558mg, 3mmol) It is dissolved in DMF, Pd/C (70mg) is then added, under nitrogen atmosphere, 80 DEG C of stirrings, TLC is monitored to the reaction was complete.Liquid cooling will be reacted But it to room temperature, is poured into water, is extracted with ethyl acetate (50mL × 3), merge organic phase and (25mL × 3) are washed with water, through anhydrous Sodium sulphate is dried, and is filtered and is concentrated under reduced pressure, obtains (S) -1- (2- nitrobenzophenones) pyrrolidines -3- for dark brown oil liquid Base-amidocarbonic acid tertiary butyl ester crude product.Described (S) -1- (2- nitrobenzophenones) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl Ester crude product is directly used in and reacts in next step without being further purified.

Step 2 prepares (S) -1- (2- aminocarbonyl phenyls) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester

(S) -1- (2- nitrobenzophenones) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester crude product is dissolved in 70mL ethyl alcohol, successively Iron powder (1.3g, 24mmol), ammonium chloride (963mg, 18mmol) and 2mL water is added, is heated to reflux, TLC is monitored to having reacted Entirely.Reaction solution is cooled to room temperature, is filtered, filtrate is concentrated under reduced pressure, suitable quantity of water is added into filtrate, is extracted with ethyl acetate (50mL × 3) merge organic phase and are washed with water (25mL × 3), and organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure. Silica gel column chromatography separating purification (dichloromethane：Methanol=20:1) (S) -1- (2- aminocarbonyl phenyls) pyrrole for yellow solid, is obtained Cough up alkane -3- bases-amidocarbonic acid tertiary butyl ester (390mg, two step yields 47%).ESI-MS m/z：278.3[M+H]⁺。

13 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 8.57 (d, J=8.0Hz, 1H), 8.10 (d, J=6.0Hz, 1H), 8.05-8.01 (m, 2H), 7.58-7.49 (m, 3H), 7.22 (d, J=5.6Hz, 1H), 7.17-7.13 (m, 2H), 7.02 (t, J=7.6Hz, 1H), 3.76- 3.68 (m,1H),3.45-3.39(m,1H),3.30-3.26(m,1H),3.09-3.03(m,2H),2.47-2.40(m,1H), 1.88-1.79 (m,1H).ESI-MS m/z：388.3[M+H]⁺。

Embodiment 14, (S)-N- (2- (3- amino-pyrrolidine -1- bases) phenyl) -2- (2,6- difluorophenyls) thiazole simultaneously [4, 5-c] pyridine -4- amine

14 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 8.98 (brs, 1H), 8.75 (d, J=8.0Hz, 1H), 8.18 (d, J=5.6Hz, 1H), 7.46- 7.39 (m, 1H), 7.26 (d, J=5.6Hz, 1H), 7.22-7.12 (m, 4H), 7.01 (t, J=7.6Hz, 1H), 3.88-3.81 (m,1H), 3.50-3.44(m,1H),3.32-3.25(m,1H),3.17-3.10(m,1H),2.98-2.90(m,1H),2.48- 2.38(m,1H), 1.98-1.89(m,1H).ESI-MS m/z：424.3[M+H]⁺。

Embodiment 15, (S)-N- (4- (3- amino-pyrrolidine -1- bases) pyrimidine -5- bases) -2- phenyl thiazoles simultaneously [4,5-c] pyrrole Pyridine -4- amine

(S) preparation of -1- (5- aminopyrimidine -4- bases) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester

5- amino -4,6- dichloro pyrimidine (2.0g, 12.2mmol) is dissolved in 7mL DMSO, Na is added₂S·9H₂O(3.221 G, 13.4mmol), it is stirred at room temperature, TLC is monitored to the reaction was complete.Reaction bulb is placed in ice bath, 10mL water is added, slowly drips Reaction solution pH is adjusted to faintly acid by enriching hydrochloric acid, and a large amount of precipitations are generated in reaction solution, and filtering reacting liquid fully washs filter with water Cake collects solid, dry, obtain for faint yellow solid -4 (1H)-thioketones hydrochloride of 5- amino -6- chlorine pyrimidine (2.67 g, about 100%).

Step 2 prepares 4- chlorine-5-amido pyrimidines

- 4 (1H)-thioketones hydrochloride, crude (2.67g) of 5- amino -6- chlorine pyrimidine is dissolved in 25mL and dries methanol, is added 25% ammonium hydroxide of 2.5mL and 2mL Raney Ni, are stirred, TLC is monitored to the reaction was complete under 80 DEG C, nitrogen atmosphere.Filtering reaction Liquid washs filter cake with methanol, and filtrate is concentrated under reduced pressure, and crude product is isolated and purified with TLC is prepared, obtained chloro- for the 4- of yellow solid 5- aminopyrimidines (156mg, 9.9%).

Step 3 prepares (S) -1- (5- aminopyrimidine -4- bases) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester

By 4- chlorine-5-amido pyrimidines (156mg, 1.2mmol) and (S) -3- t-butoxycarbonyl aminos pyrrolidines (268mg, 1.44 mmol) it is dissolved in 8mL methanol, DIPEA (186mg, 1.44mmol), return stirring is added, TLC is monitored to the reaction was complete. Reaction solution is concentrated under reduced pressure, 150mL saturated sodium bicarbonate solutions are added, reaction solution (50mL × 3) is extracted with ethyl acetate, merges Organic phase is simultaneously washed with water (25mL × 2), and organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Residue passes through TLC Isolate and purify (dichloromethane：Methanol=20:1) (S) -1- (5- aminopyrimidine -4- bases) for yellowish-brown oily liquids, is obtained Pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester (262mg, 78%).

15 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 8.55 (s, 1H), 8.37 (s, 1H), 8.10-8.06 (m, 2H), 8.03 (d, J=5.6Hz, 1H), 7.56-7.53 (m, 3H), 7.23 (d, J=5.6Hz, 1H), 3.95-3.85 (m, 2H), 3.80-3.73 (m, 1H), 3.65-3.59 (m, 1H), 3.49 (dd, J=11.2,4.4Hz, 1H), 2.11-2.02 (m, 1H), 1.74-1.67 (m, 1H).ESI-MS m/z： 388.1 [M-H]^-。

Embodiment 16, (S)-N- (4- (3- amino-pyrrolidine -1- bases) pyrimidine -5- bases) -2- (2,6- difluorophenyls) thiazole And [4,5-c] pyridine -4- amine

16 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 8.44 (s, 1H), 8.25 (s, 1H), 7.94 (d, J=5.6Hz, 1H), 7.51-7.42 (m, 1H), 7.26 (d, J=5.6Hz, 1H), 7.10 (m, 2H), 3.88-3.80 (m, 2H), 3.79-3.71 (m, 1H), 3.71-3.66 (m, 2H), 2.17-2.08(m,1H),1.96-1.86(m,1H).ESI-MS m/z：426.3[M+H]⁺。

Embodiment 17, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- phenyl -1H- imidazos [4,5-c] Pyridine -4- amine

The preparation of chloro- 2- phenyl -1H- imidazos [4,5-c] pyridines of 4-

By chloro- 3, the 4- diamino-pyridines (1.4g, 9.75mmol) of 2-, benzaldehyde (1.24g, 11.68mmol) and 14mL nitre Base benzene is added in there-necked flask, and reacted under 175 DEG C, nitrogen atmosphere becomes blackish green to reaction system color from rufous.It will be anti- It should be cooled to room temperature, montmorillonite (7g) be added, being warming up to 175 DEG C, the reaction was continued, and TLC is detected to the reaction was complete.Liquid cooling will be reacted But to room temperature, filtering reacting liquid fully washs filter cake with methanol, filtrate is concentrated under reduced pressure.Silica gel column chromatography separating purification (dichloro Methane:Methanol=40:1), obtain for yellow solid chloro- 2- phenyl -1H- imidazos [4, the 5-c] pyridines of 4- (691mg, 31%).ESI-MS m/z：228.2[M-H]^-。

17 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 1.¹H NMR (400MHz,CDCl₃) δ 10.17 (s, 1H), 8.23 (d, J=5.2Hz, 1H), 8.15 (d, J=6.4Hz, 2H), 8.05 (d, J=5.6Hz, 1H), 7.52-7.43 (m, 3H), 7.20 (d, J=5.2Hz, 1H), 6.99 (d, J=4.8Hz, 1H), 3.39-3.28(m, 1H),3.23-2.79(m,4H),2.14-1.89(m,3H),1.67-1.49(m,1H).ESI-MS m/z： 408.1[M+Na]⁺。

Embodiment 18, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- phenyl thiazoles simultaneously [5,4-c] pyrrole Pyridine -4- amine

The preparation of the chloro- 2- phenyl thiazoles of 4- simultaneously [5,4-c] pyridine

Step 1 prepares 4- (chloromethyl) -2- phenyl -1,3- thiazoles

Thiobenzamide (400mg, 2.9mmol) is dissolved in ethyl alcohol/tetrahydrofuran (mass ratio=10g：It 8g) mixes molten Liquid is heated to 65 DEG C, and 1,3-DCA (405mg, 3.19mmol) is added, is warming up to 85 DEG C and is refluxed overnight, and TLC monitorings are anti- It should finish.Solvent is removed under reduced pressure, residue is dissolved with 50mL ethyl acetate and uses NaHCO₃Aqueous solution is washed, and organic phase is through anhydrous NaSO₄It is dry, it filters and is concentrated under reduced pressure.Silica gel column chromatography separating purification (petroleum ether：Ethyl acetate=20:1) it, obtains being shallow 4- (the chloromethyl) -2- phenyl of yellow clarified solution body -1,3-thiazoles (264mg, 43%).¹H NMR(400MHz, CDCl₃)δ 7.97 (dd, J=6.8,2.8Hz, 2H), 7.48-7.45 (m, 3H), 7.33 (s, 1H), 4.78 (s, 2H).ESI-MS m/z： 210.0[M+H]⁺。

Step 2 prepares 4- (iodomethyl) -2- phenyl -1,3- thiazoles

4- (chloromethyl) -2- phenyl -1,3-thiazoles (257mg, 1.22mmol) is dissolved in 5g dimethyl carbonates (DMC), is added Enter NaI (202mg, 1.35mmol), is warming up to 90 DEG C of back flow reaction 5h.Reaction solution is cooled to room temperature, is concentrated under reduced pressure, it is remaining Object dissolves (20mL) with ethyl acetate and is washed with saturated nacl aqueous solution, detaches organic phase, organic phase is through anhydrous Na SO₄It is dry, It filters and is concentrated under reduced pressure.Silica gel column chromatography separating purification (petroleum ether：Ethyl acetate=20:1) it, obtains as light yellow solid 4- (iodomethyl) -2- phenyl -1,3-thiazoles (194mg, 53%).ESI-MS m/z：302.1[M+H]⁺。

Step 3 prepares 2- phenyl -1,3- thiazole-4-formaldehydes

By 4- (iodomethyl) -2- phenyl -1,3-thiazoles (415mg, 1.38mmol) and methenamine (213mg, Single necked round bottom flask 1.52mmol) is added, adds 50% acetic acid aqueous solution (5g), 115 DEG C of back flow reaction 4h.By reaction solution 80 DEG C are cooled to, 2mL concentrated hydrochloric acids are added, continues heating reaction 15min, then reaction solution is cooled to room temperature, uses dichloromethane It extracts (50 mL × 3), organic phase uses NaHCO successively₃Aqueous solution (50mL × 1) and pure water (50mL × 1) are washed, anhydrous Na SO₄It is dry It is dry, it filters and is concentrated under reduced pressure.Silica gel column chromatography separating purification (petroleum ether：Ethyl acetate=20:1) it, obtains as yellow solid 2- phenyl -1,3-thiazoles -4- formaldehyde (114mg, 44%).¹H NMR(400MHz,CDCl₃)δ10.12(s,1H),8.19(s, 1H),8.04-7.99(m,2H),7.53-7.48(m,3H).ESI-MS m/z：227.9[M+K]⁺。

Step 4 prepares 3- (2- phenyl -1,3- thiazole-4-yls) acrylic acid

2- phenyl -1,3-thiazoles -4- formaldehyde (107mg, 0.56mmol) and malonic acid (118mg, 1.13mmol) are added Single necked round bottom flask adds pyridine (2mL) and piperidines (0.2mL), and 85 DEG C are stirred to react 30min；It is warming up to 110 DEG C of reflux React 3h.Reaction solution is poured into 20mL ice water, pH value is adjusted to 1~2, (50mL × 3) is extracted with ethyl acetate, separation has Machine phase, organic phase anhydrous Na SO₄It is dry, it filters and is concentrated under reduced pressure.Silica gel column chromatography separating purification (dichloromethane：Methanol= 10:1) 3- (2- phenyl -1,3-thiazoles -4- bases) acrylic acid (110mg, 85%) for yellow solid, is obtained.¹H NMR (400MHz, DMSO-d6) δ 7.97 (dd, J=7.3,2.3Hz, 2H), 7.84 (s, 1H), 7.57-7.49 (m, 3H), 7.27 (d, J=15.5Hz, 1H), 6.67 (d, J=15.6Hz, 1H).ESI-MS m/z：230.1[M-H]^-。

Step 5 prepares 3- (2- phenyl -1,3- thiazole-4-yls) Azide acrylic acid

3- (2- phenyl -1,3-thiazoles -4- bases) acrylic acid (92.4mg, 0.40mmol) is dissolved in 2mL acetone, and triethylamine is added Reaction solution is cooled to 0 DEG C by (54 mg, 0.53mmol), is slowly added to ethyl chloroformate (54.2mg, 0.50mmol), stirring NaN is slowly added to after 30min₃(24.2mg, 0.37mmol), 0 DEG C is stirred to react 2h.Filtrate is concentrated under reduced pressure in filtering reacting liquid, Residue isolates and purifies (petroleum ether by silica gel column chromatography：Ethyl acetate=20:1) 3- (2- for yellow solid, are obtained Phenyl -1,3-thiazoles -4- bases) Azide acrylic acid (53mg, 52%).¹H NMR(400MHz,CDCl₃)δ8.05-7.98 (m, 2H), 7.71 (d, J=15.3Hz, 1H), 7.53 (s, 1H), 7.52-7.47 (m, 3H), 6.90 (d, J=15.3Hz, 1H). ESI-MS m/z：255.2[M-H]^-。

Step 6 prepares 2- phenyl thiazoles simultaneously [5,4-c] pyridine -4 (5H) -one

By 3- (2- phenyl -1,3-thiazoles -4- bases) Azide acrylic acid (348mg, 1.36mmol) be dissolved in diphenyl ether (3g, 17.6 mmol), lead to nitrogen ventilation, 220 DEG C of reaction 15h.Filtering reacting liquid, filter cake are washed with a small amount of ethyl acetate, obtain being white The 2- phenyl thiazoles of color solid simultaneously [5,4-c] pyridine -4 (5H) -one (63mg, 20%).¹H NMR(400MHz,DMSO-d6) δ 8.11 (dd, J=7.9,1.6Hz, 2H), 8.01 (s, 1H), 7.66-7.56 (m, 3H), 7.49 (d, J=7.1Hz, 1H), 6.92 (d, J=7.1Hz, 1H).ESI-MS m/z：251.4[M+Na]⁺。

Step 7 prepares the chloro- 2- phenyl thiazoles of 4- simultaneously [5,4-c] pyridine

By 2- phenyl thiazoles, simultaneously [5,4-c] pyridine -4 (5H) -one (200mg, 0.88mmol) and phosphorus oxychloride (5mL) are added Dry single necked round bottom flask leads to nitrogen ventilation, 135 DEG C of reaction 2h.It is cooled to room temperature, reaction solution is poured into 20mL ice water, (50mL × 3) are extracted with dichloromethane, organic phase is washed with saturated sodium-chloride water solution and through anhydrous Na SO₄It is dry, it filters and subtracts Pressure concentration organic phase.Silica gel column chromatography separating purification (dichloromethane：Methanol=100:1) it, obtains chloro- for the 4- of yellow solid 2- phenyl thiazoles simultaneously [5,4-c] pyridine (66mg, 30%).¹H NMR (400MHz, MeOD) δ 8.44 (d, J=5.6 Hz, 1H), 8.23-8.16 (m, 2H), 7.96 (d, J=5.6Hz, 1H), 7.69-7.55 (m, 3H).ESI-MS m/z：247.1 [M+H]⁺。

(S) system of-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- phenyl thiazoles simultaneously [5,4-c] pyridine -4- amine It is standby

Step 1 prepares (S)-tertiary butyl (1- (3- ((2- phenyl thiazoles simultaneously [5,4-c] pyridin-4-yl) amino) pyridine -4- Base) piperidines -3- bases) carbamate

By the chloro- 2- phenyl thiazoles of 4- simultaneously [5,4-c] pyridine (145mg, 0.59mmol), (S)-tertiary butyl (1- (3- amino pyrroles Pyridine -4- bases) piperidines -3- bases) carbamate (172mg, 0.59mmol) and Pd₂(dba)₃(16mg, 0.018mmol), BINAP (22mg, 0.036mmol), K₂CO₃(326mg, 2.36mmol) is added in tube sealing, and tetrahydrofuran is used in combination to dissolve.Nitrogen is taken a breath, Sealing is placed in 80 DEG C of stirring 16h, TLC monitoring reactions and completes.Reaction solution filters, with methylene chloride/methanol mixed liquor (1:1) it washes Filter cake is washed, filtrate is collected, decompression steams solvent, and crude product obtains (S)-tertiary butyl for yellow solid with TLC separation is prepared (1- (3- ((2- phenyl thiazoles simultaneously [5,4-c] pyridin-4-yl) amino) pyridin-4-yl) piperidines -3- bases) carbamate (36mg, yield 12%).

Step 2 prepares (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- phenyl thiazoles simultaneously [5,4-c] pyrrole Pyridine -4- amine

By (S)-tertiary butyl (1- (3- ((2- phenyl thiazoles simultaneously [5,4-c] pyridin-4-yl) amino) pyridin-4-yl) piperidines- 3- yls) carbamate (36mg, 0.07mmol) is dissolved in 4mL dichloromethane, is placed in ice bath, trifluoroacetic acid (1mL) is added, Ice bath is removed after stirring 20min, stirs 1h at room temperature, TLC monitoring reactions are completed.Decompression steams solvent, and unsaturated carbonate hydrogen is added Sodium solution 150mL is extracted with ethyl acetate (50mL x 3), and clear water washs (50mL x 1), collection organic phase, evaporated under reduced pressure, Crude product obtains (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- for yellow solid with TLC separation is prepared Phenyl thiazole simultaneously [5,4-c] pyridine -4- amine (15mg, yield 52%).¹H NMR(400MHz,CDCl₃)δ8.71(s,1H), 8.19 (d, J=5.6Hz, 1H), 8.12 (d, J=5.7Hz, 1H), 8.03 (d, J=7.6Hz, 2H), 7.57-7.38 (m, 4H), 6.92 (d, J=5.6 Hz, 1H), 3.42-3.19 (m, 4H), 2.85-2.77 (m, 1H), 2.03-1.76 (m, 4H), 1.54- 1.44(m,1H).ESI-MS m/z：403.4[M+H]⁺。

Embodiment 19, (S)-N- (5- (3- amino piperidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) -2- phenyl -1H- miaows Azoles simultaneously [4,5-c] pyridine -4- amine

Step 1 prepares (S)-tertiary butyl (1- (1- methyl -4- ((2- phenyl -1H- imidazos [4,5-c] pyridin-4-yl) Amino) -1H- pyrazoles -5- bases) piperidines -3- bases) carbamate

By chloro- 2- phenyl -3H- imidazos [4, the 5-c] pyridines (230mg, 1mmol) of 4-, (S)-tertiary butyl (1- (4- amino - 1- methyl-1 H- pyrazoles -5- bases) piperidines -3- bases) carbamate (295mg, 1mmol) and Pd₂(dba)₃(27mg, 0.03mmol), Xantphos (35mg, 0.06mmol), t-BuOK (168mg, 1.5mmol) are added in tube sealing, and toluene is used in combination Dissolving.Nitrogen is taken a breath, and is placed in 80 DEG C of stirring 14h, TLC monitoring raw materials and is no longer reacted.Reaction solution filters, with dichloromethane/first Alcohol mixed liquor (1:1) filter cake is washed, filtrate is collected, decompression steams solvent, and crude product detaches (dichloromethane with TLC is prepared：First Alcohol=10:1) (S)-tertiary butyl (1- (1- methyl -4- ((2- phenyl -1H- imidazos [4,5-c] pyrroles for yellow solid, are obtained Pyridine -4- bases) amino) -1H- pyrazoles -5- bases) piperidines -3- bases) carbamate (160mg, yield 32.8%).

Step 2 prepares (S)-N- (5- (3- amino piperidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) -2- phenyl -1H- Imidazo [4,5-c] pyridine -4- amine

By (S)-tertiary butyl (1- (1- methyl -4- ((2- phenyl -1H- imidazos [4,5-c] pyridin-4-yl) amino) -1H- Pyrazoles -5- bases) piperidines -3- bases) carbamate (160mg, 0.3mmol) is dissolved in 4mL dichloromethane, is placed in ice bath, it is added Trifluoroacetic acid (1 mL) removes ice bath after stirring 20min, stirs 1h at room temperature, and TLC monitoring reactions are completed.Decompression steams solvent, Saturated sodium bicarbonate solution 150mL is added, is extracted with ethyl acetate (50mL x 3), clear water washs (50mL x 1), and collection has Machine phase, steams solvent, and crude product detaches (dichloromethane with TLC is prepared：Methanol=5:1) (S)-N- for yellow solid, is obtained (5- (3- amino piperidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) -2- phenyl -1H- imidazos [4,5-c] pyridine -4- amine (23mg, yield 18.1%).¹H NMR(400MHz,d₆- DMSO) δ 8.18-8.14 (m, 2H), 7.69 (d, J=5.6Hz, 1H), 7.60-7.54 (m, 2H), 7.53-7.48 (m, 1H), 7.29 (s, 1H), 6.85 (d, J=6.0Hz, 1H), 3.66 (s, 3H), 3.25-3.15(m,1H),3.18-2.78(m,4H),1.77-1.45(m,2H),1.28-1.14(m,2H).ESI-MS m/z： 389.5 [M+H]⁺。

Embodiment 20, -2- phenyl thiazoles are simultaneously by (S)-N- (5- (3- amino piperidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) [5,4-c] pyridine -4- amine

Step 1 prepares (S)-tertiary butyl (1- (1- methyl -4- ((2- phenyl thiazoles simultaneously [4,5-c] pyridin-4-yl) ammonia Base) -1H- pyrazoles -5- bases) piperidines -3- bases) carbamate

By the chloro- 2- phenyl thiazoles of 4- simultaneously [5,4-c] pyridine (160mg, 0.65mmol), (S)-tertiary butyl (1- (4- amino- 1- methyl-1 H- pyrazoles -5- bases) piperidines -3- bases) carbamate (192mg, 0.65mmol) and Pd₂(dba)₃(18mg, 0.02mmol), Xantphos (23mg, 0.04mmol), K₂CO₃(269mg, 1.95mmol) is added in tube sealing, and tetrahydrochysene is used in combination Furans dissolves.Nitrogen is taken a breath, sealing, is placed in 80 DEG C of stirring 16h, TLC monitoring raw materials and is no longer reacted.Reaction solution filters, with two Chloromethanes/methyl alcohol mixed liquor (1:1) filter cake is washed, filtrate is collected, decompression steams solvent, and crude product is obtained with TLC separation is prepared To (S)-tertiary butyl (1- (1- methyl -4- ((2- phenyl thiazoles simultaneously [4,5-c] pyridin-4-yl) amino) -1H- for brown solid Pyrazoles -5- bases) piperidines -3- bases) carbamate (54mg, yield 16.5%).

It is prepared by step 2(S)-N- (5- (3- amino piperidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) -2- phenyl thiazoles And [5,4-c] pyridine -4- amine

By (S)-tertiary butyl (1- (1- methyl -4- ((2- phenyl thiazoles simultaneously [4,5-c] pyridin-4-yl) amino) -1H- pyrroles Azoles -5- bases) piperidines -3- bases) carbamate (54mg, 0.11mmol) is dissolved in 4mL dichloromethane, is placed in ice bath, it is added three Fluoroacetic acid (1mL) removes ice bath after stirring 20min, stirs 1h at room temperature, and TLC monitoring reactions are completed.Decompression steams solvent, adds Enter saturated sodium bicarbonate solution 150mL, be extracted with ethyl acetate (50mL x 3), clear water washs (50mL x 1), collects organic Phase, steams solvent, and crude product obtains (S)-N- (5- (3- amino piperidine -1- bases)-for yellow solid with TLC separation is prepared 1- methyl-1 H- pyrazoles -4- bases) -2- phenyl thiazoles simultaneously [5,4-c] pyridine -4- amine (29mg, yield 67%).¹H NMR (400MHz, MeOD) δ 8.11-8.05 (m, 3H), 7.63-7.54 (m, 3H), 7.44 (s, 1H), 7.37 (d, J=5.6Hz, 1H),3.83(s,3H), 3.44-3.35(m,2H),3.17-3.11(m,1H),3.08-2.99(m,2H),2.03-1.81(m, 2H),1.77-1.69(m,1H), 1.55-1.44(m,1H).ESI-MS m/z：406.3[M+H]⁺。

Embodiment 21, (S)-N- (2- (3- amino piperidine -1- bases) phenyl) -2- phenyl -1H- imidazos [4,5-c] pyridine - 4- amine

21 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.ESI- MS m/z：385.3[M+H]⁺。

Embodiment 22, (S)-N- (2- (3- amino piperidine -1- bases) phenyl) -2- phenyl thiazoles simultaneously [5,4-c] pyridine -4- amine

22 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 8.38-8.32 (m, 1H), 8.29 (d, J=5.6Hz, 1H), 8.14-9.11 (m, 2H), 7.58- 7.50 (m, 3H), 7.47 (d, J=5.6Hz, 1H), 7.20-7.14 (m, 2H), 7.02 (td, J=7.6,1.2Hz, 1H), 3.30-3.21(m,1H), 3.20-3.13(m,1H),2.96-2.87(m,1H),2.83-2.68(m,2H),2.10-2.00(m, 1H), 1.99-1.90 (m, 1H), 1.82-1.71 (m, 1H), 1.55-1.41 (m, 1H).ESI-MS m/z：402.3[M+H]⁺。

Embodiment 23, (S)-N- (4- (3- amino piperidine -1- bases) pyrimidine -5- bases) -2- phenyl -1H- imidazos [4,5-c] Pyridine -4- amine

23 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz, MeOD) δ 8.83 (s, 1H), 8.56 (s, 1H), 8.20-8.13 (m, 2H), 7.86 (d, J=6.0Hz, 1H), 7.64-7.55 (m, 3H), 7.15 (d, J=6.0Hz, 1H), 4.13-4.02 (m, 1H), 3.74-3.41 (m, 4H), 2.14-2.01 (m, 1H),1.90-1.71(m,2H),1.64-1.51(m,1H).ESI-MS m/z：387.2[M+H]⁺。

Embodiment 24, (S)-N- (4- (3- amino piperidine -1- bases) pyrimidine -5- bases) -2- phenyl thiazoles simultaneously [5,4-c] pyrrole Pyridine -4- amine

24 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz, MeOD) δ 8.58 (s, 1H), 8.34 (s, 1H), 8.18-8.15 (m, 2H), 8.10 (d, J=6.0Hz, 1H), 7.66-7.58 (m, 3H), 7.49 (d, J=6.0Hz, 1H), 4.38-4.31 (m, 1H), 4.07-3.99 (m, 1H), 3.48-3.41 (m, 1H),3.31-3.23(m,2H),2.23-1.98(m,2H),1.67-1.57(m,2H).ESI-MS m/z：404.3[M+H ]⁺。

Embodiment 25, (S)-N- (4- (3- amino-pyrrolidine -1- bases) pyridin-3-yl) -2- phenyl -1H- imidazos [4,5- C] pyridine -4- amine

25 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz, MeOD) δ 8.35 (d, J=0.8Hz, 1H), 8.24 (dd, J=7.2,1.2Hz, 1H), 8.16 (dd, J= 7.8,1.8 Hz, 2H), 7.78 (d, J=6.0Hz, 1H), 7.63-7.55 (m, 3H), 7.14-7.12 (m, 2H), 4.20-4.15 (m,1H), 4.01-3.84(m,4H),2.46-2.37(m,1H),2.23-2.12(m,1H).ESI-MS m/z：372.8[M+H ]⁺。

Embodiment 26, (S)-N- (4- (3- amino-pyrrolidine -1- bases) pyridin-3-yl) -2- phenyl thiazoles simultaneously [5,4-c] pyrrole Pyridine -4- amine

26 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz, MeOD) δ 8.23-8.17 (m, 2H), 8.16-8.12 (m, 2H), 8.06 (d, J=5.6Hz, 1H), 7.65- 7.55 (m, 3H), 7.43 (d, J=5.6Hz, 1H), 6.98 (d, J=6.8Hz, 1H), 4.02 (q, J=6.0Hz, 1H), 3.94- 3.85(m,2H), 3.80-3.71(m,2H),2.39-2.30(m,1H),2.13-2.05(m,1H).ESI-MS m/z：389.3 [M+H]⁺。

Embodiment 27, (S)-N- (5- (3- amino-pyrrolidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) -2- phenyl -1H- Imidazo [4,5-c] pyridine -4- amine

27 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 19.¹H NMR (400MHz,d₆- DMSO) δ 8.18-8.14 (m, 2H), 7.94 (s, 1H), 7.79 (d, J=5.6Hz, 1H), 7.59-7.52 (m, 2H), 7.52-7.45 (m, 1H), 6.82 (d, J=5.6Hz, 1H), 3.66 (s, 3H), 3.61-3.55 (m, 1H), 3.42- 3.31(m, 2H),3.27-3.20(m,2H),1.98-1.89(m,1H),1.87-1.79(m,1H).ESI-MS m/z：375.1 [M+H]⁺。

Embodiment 28, (S)-N- (5- (3- amino-pyrrolidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) -2- phenyl thiazoles And [5,4-c] pyridine -4- amine

28 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 20.¹H NMR (400MHz,CDCl₃) δ 8.06 (d, J=5.6Hz, 1H), 8.03-7.99 (m, 2H), 7.55 (s, 1H), 7.52-7.43 (m, 3H), 7.32 (d, J=6.0Hz, 1H), 3.79 (s, 3H), 3.78-3.72 (m, 1H), 3.61-3.51 (m, 2H), 3.26- 3.17(m,2H), 2.13-2.03(m,1H),1.96-1.84(m,1H).ESI-MS m/z：392.3[M+H]⁺。

Embodiment 29, (S)-N- (2- (3- amino-pyrrolidine -1- bases) phenyl) -2- phenyl -1H- imidazos [4,5-c] pyrrole Pyridine -4- amine

29 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.ESI- MS m/z：371.0[M+H]⁺。

Embodiment 30, (S)-N- (2- (3- amino-pyrrolidine -1- bases) phenyl) -2- phenyl thiazoles simultaneously [5,4-c] pyridine -4- Amine

30 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 8.23 (d, J=5.7Hz, 1H), 8.09-7.97 (m, 2H), 7.78 (dd, J=7.9,1.6Hz, 1H), 7.59-7.39 (m, 4H), 7.15 (ddd, J=8.5,7.3,1.6Hz, 1H), 7.07-6.94 (m, 2H), 3.65-3.57 (m, 1H), 3.44-3.34 (m, 2H), 3.24-3.14 (m, 1H), 2.99 (dd, J=9.5,4.4Hz, 1H), 2.27-2.15 (m, 1H),1.72-1.56 (m,3H).ESI-MS m/z：388.3[M+H]⁺。

Embodiment 31, (S)-N- (4- (3- amino-pyrrolidine -1- bases) pyrimidine -5- bases) -2- phenyl -1H- imidazos [4,5- C] pyridine -4- amine

Step 1：By (S) -1- (5- aminopyrimidine -4- bases) pyrrolidin-3-yl-amidocarbonic acid tertiary butyl ester (257mg, 0.92 mmol), chloro- 2- phenyl -3H- imidazos [4, the 5-c] pyridines (212mg, 0.92mmol) of 4- be dissolved in tetrahydrofuran, successively Pd (OAc) is added₂(6mg, 0.028mmol), Xantphos (32mg, 0.056mmol) and t-BuOK (155mg, 1.38mmol), under nitrogen atmosphere, 80 DEG C of stirrings, TLC are monitored to the reaction was complete.Filtering reacting liquid, it is mixed with methylene chloride/methanol Close liquid (1:1) filter cake is fully washed, filtrate is concentrated under reduced pressure.(dichloromethane is isolated and purified by TLC：Methanol=10:1) it, obtains For (S)-{ 1- [(5- (2- phenyl -1H- imidazos [4,5-c] pyridin-4-yl-amine)-pyrimidine -4- of yellow powder solid Base)]-pyrroles -3- bases }-t-butyl carbamate (80mg, 18.4%).

Step 2：By (S)-{ 1- [(5- (2- phenyl -1H- imidazos [4,5-c] pyridin-4-yl-amine)-pyrimidine-4-yl)] - Pyrroles -3- bases }-t-butyl carbamate (80mg, 0.17mmol) is dissolved in 6mL dichloromethane, reaction bulb is placed in cold in ice bath But, 1.5mL trifluoracetic acids are added, condition of ice bath stirs 20min, is warmed to room temperature that the reaction was continued, and TLC is detected to the reaction was complete.Subtract Concentration of reaction solution is pressed, 50mL saturated sodium bicarbonate solutions are added in residue, are extracted with ethyl acetate (50mL × 3), wash Merge organic phase (10mL × 2), is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure.Thin layer is prepared by TLC to isolate and purify, Obtain (S)-N- (4- (3- amino-pyrrolidine -1- bases) pyrimidine -5- bases) -2- phenyl -1H- imidazos [4,5- for yellow solid C] pyridine -4- amine (35mg, 55.3%).ESI-MS m/z：371.14[M-H]^-。

Embodiment 32, (S)-N- (4- (3- amino-pyrrolidine -1- bases) pyrimidine -5- bases) -2- phenyl thiazoles simultaneously [5,4-c] pyrrole Pyridine -4- amine

32 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz, MeOD) δ 8.53 (s, 1H), 8.18-8.14 (m, 3H), 8.06 (d, J=6.0Hz, 1H), 7.65-7.56 (m, 3H), 7.43 (d, J=5.6Hz, 1H), 4.14-4.03 (m, 1H), 3.97-3.82 (m, 4H), 2.37-2.86 (m, 1H), 2.09-1.99(m, 1H).ESI-MS m/z：390.2[M+H]⁺。

Embodiment 33, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- oxazolyl phenyls simultaneously [4,5-c] pyrrole Pyridine -4- amine

The preparation of the chloro- 2- phenyl-oxazoles of 4- simultaneously [4,5-c] pyridine

Step 1 prepares 3- amino-4-hydroxy pyridines

4- hydroxy-3-nitropyridines (2.8g, 20.0mmol) are dissolved in 150mL methanol, 280mg Pd/C, hydrogen is added The air in reaction bulb is replaced, hydrogen is continually fed into, is stirred at room temperature, TLC is monitored to the reaction was complete.Reaction solution is filtered, methanol is washed Wash filter cake, collect filtrate and be simultaneously concentrated under reduced pressure, obtain for deep orange oily liquids 3- amino-4-hydroxies pyridine (1.98g, 90%).

Step 2 prepares N- (4- pyridone -3- bases) benzamide

Benzoic acid (2.015g, 16.5mmol) is dissolved in 60mL THF, sequentially add EDCI (3.163g, 16.5mmol), HOAT (2.244g, 16.5mmol) and 3.5mL triethylamines, are stirred at room temperature 2h, obtain Acibenzolar；Reaction solution is concentrated under reduced pressure, is obtained To solid residue be dissolved in 15mL DMF.3- amino-4-hydroxy pyridines are dissolved in 25mL DMF, are slowly added to Acibenzolar It in DMF solution, is stirred at room temperature, TLC is monitored to the reaction was complete.Reaction solution is poured into 350mL water, is extracted with ethyl acetate, is had Machine is mutually washed with 150mL, and organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Residue passes through silica gel column chromatography Isolate and purify (dichloromethane：Methanol=10:1) N- (4- pyridone -3- bases) benzamide for white solid, is obtained (2.1g, 59%).

Step 3 prepares 2- oxazolyl phenyls [4,5-c] and pyridine

N- (4- pyridone -3- bases) benzamide (2.1g, 9.8mmol) is dissolved in 230mL dichloromethane, then is added successively Enter carbon trichloride (5.802g, 24.5mmol), triphenylphosphine (7.714g, 29.4mmol) and 10.9mL TEA, be stirred at room temperature, TLC is monitored to the reaction was complete.200mL saturated sodium bicarbonate solutions are added into reaction solution, stratification detaches dichloromethane Layer is merged organic phase and is washed with water (200mL × 2) with dichloromethane aqueous phase extracted (150mL × 3), dry through anhydrous sodium sulfate It is dry, it filters and is concentrated under reduced pressure.Silica gel column chromatography separating purification (petroleum ether：Ethyl acetate=1:1) it, obtains as light yellow solid 2- oxazolyl phenyls [4,5-c] and pyridine (1.4g, 73%).

Step 4 prepares 2- oxazolyl phenyls [4,5-c] and pyridine -5- oxides

2- oxazolyl phenyls [4,5-c] and pyridine (1.4g, 7.13mmol) are dissolved in 40mL dichloromethane, are slowly added to MCPBA (1.726g, 10.0mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 100mL 1M K are added₂CO₃Solution is quenched Reaction.200mL saturated nacl aqueous solutions are added into reaction solution, (150mL × 3) are extracted with dichloromethane, separation organic phase is simultaneously It is washed with water (25mL × 2), anhydrous sodium sulfate drying is filtered and is concentrated under reduced pressure, obtains the 2- oxazolyl phenyls for light yellow solid [4,5-c] and pyridine -5- oxide crude products.The 2- oxazolyl phenyls [4,5-c] and pyridine -5- oxides crude product is not Through being further purified, direct plunges into and react in next step.

Step 5 prepares the chloro- 2- phenyl-oxazoles of 4- simultaneously [4,5-c] pyridine

2- oxazolyl phenyls [4,5-c] and pyridine -5- oxide crude products are dissolved in 20mL phosphorus oxychloride, 90 DEG C of stirrings, TLC prisons It surveys to the reaction was complete.Reaction solution is concentrated under reduced pressure, reaction bulb is placed in cooling in ice bath, is slowly added to saturated sodium bicarbonate solution, Until bubble-free generates；Reaction solution (150mL × 3) is extracted with ethyl acetate, merges organic phase, (200mL is washed with water in organic phase × 2) it, is dried over anhydrous sodium sulfate, filters organic phase and is concentrated under reduced pressure.Silica gel column chromatography separating purification (petroleum ether：Acetic acid second Ester=8:1) the chloro- 2- phenyl-oxazoles of 4- simultaneously [4,5-c] pyridine (1.22g, the two step yields 74%) for light yellow solid, are obtained.

33 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃)δ9.88(s,1H),8.24-8.18(m,4H),7.95(brs,1H),7.56-7.55(m,3H), 7.07 (d, J=6.0Hz, 1H), 6.96 (d, J=5.2Hz, 1H), 3.34-3.25 (m, 1H), 3.21-3.12 (m, 1H), 3.11-3.03(m,1H), 2.89-2.81(m,1H),2.79-2.68(m,1H),2.07-1.97(m,2H),1.94-1.86(m, 1H),1.59-1.45(m,1H). ESI-MS m/z：387.4[M+H]⁺。

Embodiment 34, -2- oxazolyl phenyls are simultaneously by (S)-N- (5- (3- amino piperidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) [4,5-c] pyridine -4- amine

34 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 19.¹H NMR (400MHz,CDCl₃) δ 8.25-8.20 (m, 2H), 8.08 (d, J=6.0Hz, 1H), 7.60 (s, 1H), 7.58-7.53 (m, 3H), 6.96 (d, J=5.6Hz, 1H), 6.73 (brs, 1H), 3.76 (s, 3H), 3.27 (dd, J=11.2,3.6Hz, 1H), 3.15-3.07 (m, 1H), 3.05-2.95 (m, 2H), 2.81 (dd, J=11.2,4.0Hz, 1H), 1.92-1.78 (m, 2H),1.69-1.58(m,1H), 1.25-1.17(m,1H).ESI-MS m/z：388.2[M-H]^-。

Embodiment 35, (S)-N- (2- (3- amino piperidine -1- bases) phenyl) -2- oxazolyl phenyls simultaneously [4,5-c] pyridine -4- amine

35 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃)δ8.86-8.74(m,2H),8.29-8.14(m,3H),7.63-7.48(m,3H),7.26-7.12 (m,2H), 7.10-6.95(m,2H),3.38-3.24(m,1H),3.20-3.06(m,1H),3.04-2.91(m,1H),2.88- 2.78(m,1H), 2.75-2.64(m,1H),2.10-1.86(m,3H),1.64-1.44(m,1H).ESI-MS m/z：386.4 [M+H]⁺。

Embodiment 36, (S)-N- (4- (3- amino piperidine -1- bases) pyrimidine -5- bases) -2- oxazolyl phenyls simultaneously [4,5-c] pyrrole Pyridine -4- amine

36 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃)δ9.55(s,1H),8.60(s,1H),8.23-8.18(m,3H),7.62-7.54(m,3H),7.11 (d, J=6.0Hz, 1H), 3.56-3.46 (m, 2H), 3.31-3.19 (m, 2H), 3.14-3.07 (m, 1H), 2.03-1.91 (m, 2H), 1.83-1.74(m,1H),1.58-1.50(m,1H).ESI-MS m/z：388.4[M+H]⁺。

Embodiment 37, (S)-N- (4- (3- amino-pyrrolidine -1- bases) pyridin-3-yl) -2- oxazolyl phenyls simultaneously [4,5-c] pyrrole Pyridine -4- amine

37 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 8.44 (s, 1H), 8.22-8.17 (m, 3H), 8.07 (d, J=6.0Hz, 1H), 7.61-7.52 (m, 3H), 6.99 (d, J=5.6Hz, 1H), 6.61 (d, J=5.6Hz, 1H), 3.71-3.59 (m, 3H), 3.52-3.46 (m, 1H),3.30-3.22 (m,1H),2.15-2.04(m,1H),1.75-1.66(m,1H).ESI-MS m/z：373.3[M+H]⁺。

Embodiment 38, (S)-N- (5- (3- amino-pyrrolidine -1- bases) -1- methyl-1 H- pyrazoles -4- bases) -2- oxazolyl phenyls And [4,5-c] pyridine -4- amine

38 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 19.¹H NMR (400MHz,CDCl₃) δ 10.00 (brs, 1H), 8.22-8.08 (m, 4H), 7.59-7.50 (m, 3H), 6.90 (d, J= 6.0Hz, 1H), 3.79 (s, 3H), 3.61-3.45 (m, 2H), 3.38-3.29 (m, 1H), 3.10 (d, J=10.8Hz, 1H), 2.19-2.05 (m, 2H), 1.93-1.84 (m, 1H).ESI-MS m/z：376.1[M+H]⁺。

Embodiment 39, (S)-N- (2- (3- amino-pyrrolidine -1- bases) phenyl) -2- oxazolyl phenyls simultaneously [4,5-c] pyridine -4- Amine

39 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 8.62 (d, J=8.4Hz, 1H), 8.45 (brs, 1H), 8.24-8.15 (m, 3H), 7.59-7.51 (m, 3H),7.20-7.12(m,2H),7.03-6.98(m,2H),3.81-3.72(m,1H),3.42-3.35(m,1H),3.16- 3.02(m, 3H),2.53-2.41(m,1H),1.94-1.82(m,1H).ESI-MS m/z：372.4[M+H]⁺。

Embodiment 40, (S)-N- (4- (3- amino-pyrrolidine -1- bases) pyrimidine -5- bases) -2- oxazolyl phenyls simultaneously [4,5-c] pyrrole Pyridine -4- amine

40 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 8.55 (s, 1H), 8.31 (s, 1H), 8.23-8.17 (m, 2H), 8.06 (d, J=6.0Hz, 1H), 7.60-7.52 (m, 3H), 7.02 (d, J=5.6Hz, 1H), 6.83 (brs, 1H), 3.93-3.84 (m, 2H), 3.77-3.70 (m, 1H), 3.64-3.58 (m, 1H), 3.47 (dd, J=11.2,4.4Hz, 1H), 2.10-2.01 (m, 1H), 1.73-1.66 (m, 1H).ESI-MS m/z：372.2[M-H]^-。

Embodiment 41, N⁴Cyclohexyl-N³(2- phenyl thiazoles simultaneously [4,5-c] pyridin-4-yl) pyridine -3,4- diamines

N⁴The preparation of cyclohexyl-pyridine -3,4- diamines

Step 1 prepares N- cyclohexyl -3- nitropyridine -4- amine

Successively by -3 nitropyridine of compound 4-chloro (0.8g, 5.05mmol), cyclohexylamine (0.5g, 5.04mmol) and Round-bottomed flask is added in DIPEA (0.65g, 5.03mmol), adds 18mL methanol, is stirred at room temperature under nitrogen atmosphere, TLC prisons It surveys to the reaction was complete.20mL water is added into reaction solution, is extracted with ethyl acetate (10mL × 3), merge organic phase and is washed with water (20mL × 2), are dried through anhydrous magnesium sulfate, are filtered and are concentrated under reduced pressure.Silica gel column chromatography separating purification (petroleum ether：Ethyl acetate =1:1) the N- cyclohexyl -3- nitropyridine -4- amine (0.66g, 59%) for buff oily liquids, is obtained.¹H NMR (400MHz, CDCl3) δ 9.20 (s, 1H), 8.24 (d, J=6.0Hz, 1H), 8.19 (brs, 1H), 6.71 (d, J=6.0Hz, 1H),3.57-3.48(m,1H),2.08-1.99(m,2H),1.88-1.77(m,2H),1.48-1.30(m,6H)。ESI-MS m/ z： 222.7[M+H]⁺。

Step 2 prepares N⁴Cyclohexyl-pyridine -3,4- diamines

N- cyclohexyl -3- nitropyridine -4- amine (0.66g, 2.99mmol) is dissolved in 40mL ethyl alcohol, iron powder is added (1.34g, 24.0mmol) and NH₄Cl (959mg, 17.92mmol), is stirred under 90 DEG C, nitrogen atmosphere, and TLC is monitored to anti- It should be complete.Filtering reacting liquid fully washs filter cake with ethyl alcohol, filtrate is concentrated under reduced pressure.Silica gel column chromatography separating purification (dichloromethane Alkane：Methanol=15:1) it, obtains as the N of buff oily liquids⁴Cyclohexyl-pyridine -3,4- diamines (426mg, 74%).ESI- MS m/z：192.3[M+H]⁺。

41 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 8.34 (s, 1H), 8.20 (d, J=5.6Hz, 1H), 8.14-8.08 (m, 2H), 8.01 (d, J= 5.6Hz, 1H), 7.58-7.51 (m, 3H), 7.24 (d, J=5.6Hz, 1H), 6.66 (d, J=5.6Hz, 1H), 4.94 (d, J= 6.8Hz,1H), 3.48-3.38(m,1H),2.09-2.00(m,2H),1.80-1.70(m,2H),1.69-1.60(m,1H), 1.47-1.33(m,2H), 1.26-1.16(m,3H).ESI-MS m/z：402.3[M+H]⁺。

Embodiment 42, N- (4- (4- amino piperidine -1- bases) pyridin-3-yl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine -4- Amine

The preparation of 1- (3- amidos pyridin-4-yl) piperidines 4- bases-amidocarbonic acid tertiary butyl ester

Step 1 prepares 1- (3- nitropyridine -4- bases) piperidines 4- bases-amidocarbonic acid tertiary butyl ester

Successively by the chloro- 3- nitropyridines (800mg, 5.05mmol) of 4-, piperidines 4- amidocarbonic acids tertiary butyl ester (1.01g, 5.04 mmol) and DIEPA (652mg, 5.04mmol) addition round-bottomed flasks, 25mL methanol is added, is stirred at room temperature, TLC prisons It surveys to the reaction was complete.Suitable quantity of water is added into reaction solution, is extracted with ethyl acetate (50mL × 3), merge organic phase and is washed with water (20mL × 2), are dried over anhydrous sodium sulfate, and filter organic phase and are concentrated under reduced pressure.Silica gel column chromatography separating purification (petroleum ether：Second Acetoacetic ester=1:1) 1- (3- nitropyridine -4- bases) piperidines 4- bases-amidocarbonic acid tertiary butyl ester for yellow solid, are obtained (1.7g, it is nearly 100%).

Step 2 prepares 1- (3- amidos pyridin-4-yl) piperidin-4-yl-amidocarbonic acid tertiary butyl ester

1- (3- nitropyridine -4- bases) piperidines 4- bases-amidocarbonic acid tertiary butyl ester (1.7g, 5.27mmol) is dissolved in 15mL Ethyl alcohol sequentially adds iron powder (2.3g, 41.18mmol), ammonium chloride (1.7g, 31.78mmol) and 3mL water, and 90 DEG C are stirred, TLC is monitored to the reaction was complete.Appropriate NaHCO is added in reaction solution₃Solution is extracted with ethyl acetate (50mL × 3), is associated with Machine phase is simultaneously washed with water (20mL × 2), is dried over anhydrous sodium sulfate, and filters organic phase and is concentrated under reduced pressure.Silica gel column chromatography separation is pure Change (dichloromethane：Methanol=15:1, contain 2% ammonium hydroxide), obtain 1- (3- amidos pyridin-4-yl) piperidines -4- for brown solid Base-amidocarbonic acid tertiary butyl ester (1.0g, 65%).ESI-MS m/z：315.1[M+Na]⁺。

42 compound of the embodiment of the present invention is prepared according to method 1, specific synthesized reference embodiment 5.¹H NMR(400MHz, CDCl₃) δ 9.99 (s, 1H), 8.64 (brs, 1H), 8.26 (d, J=5.2Hz, 1H), 8.18 (d, J=5.6Hz, 1H), 8.12- 8.05 (m, 2H), 7.57-7.50 (m, 3H), 7.29 (d, J=7.2Hz, 1H), 7.00 (d, J=5.2Hz, 1H), 3.33-3.24 (m,2H), 3.20-3.11(m,1H),2.83-2.74(m,1H),2.69-2.59(m,1H),2.12-2.03(m,1H),2.03- 1.93(m,2H), 1.47-1.34(m,1H).ESI-MS m/z：403.2[M+H]⁺。

Embodiment 43, N- (4- (piperazine -1- bases) pyridin-3-yl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine -4- amine

The preparation of 4- (3- aminopyridine -4- bases) piperazine -1- amidocarbonic acid tertiary butyl esters

Step 1 prepares 4- (3- nitropyridine -4- bases) piperazine -1- amidocarbonic acid tertiary butyl esters

Successively by chloro- 3 nitropyridines (1.0g, 6.31mmol) of 4-, 1- tert-butoxycarbonyl-piperazines (1.17g, 6.28mmol) Round-bottomed flask is added with DIPEA (0.815g, 6.30mmol), adds 20mL EtOH, under nitrogen atmosphere, stirring at normal temperature, TLC is detected to the reaction was complete.Reaction solution, silica gel column chromatography separating purification (petroleum ether is concentrated under reduced pressure：Ethyl acetate=2：1) it, obtains To 4- (3- nitropyridine -4- bases) piperazine -1- amidocarbonic acids tertiary butyl ester (1.4g, 72%) for yellow solid.¹H NMR (400MHz,CDCl₃) δ 8.89 (s, 1H), 8.42 (d, J=6.0Hz, 1H), 6.87 (d, J=6.0Hz, 1H), 3.68-3.59 (m,4H),3.32-3.18(m,4H),1.50(s,9H).ESI-MS m/z：309.1[M+H]⁺。

Step 2 prepares 4- (3- aminopyridine -4- bases) piperazine -1- amidocarbonic acid tertiary butyl esters

4- (3- nitropyridine -4- bases) piperazine -1- amidocarbonic acids tertiary butyl ester (1.94g, 6.30mmol) is dissolved in 40mL Ethyl alcohol sequentially adds iron powder (2.82g, 50.4mmol) and NH₄Cl (2.02g, 37.8mmol), under 90 DEG C, nitrogen atmosphere Stirring, TLC are monitored to the reaction was complete.Filtering reacting liquid fully washs filter cake with ethyl alcohol, filtrate is concentrated under reduced pressure.Silica gel column chromatography Isolate and purify, obtain for yellow solid 4- (3- aminopyridine -4- bases) piperazine -1- amidocarbonic acids tertiary butyl ester (981mg, 56%).¹H NMR(400MHz,CDCl₃) δ 8.07 (s, 1H), 8.00 (d, J=5.2Hz, 1H), 6.80 (d, J=5.2Hz, 1H),3.75(m,2H),3.63-3.57(m,4H),3.01-2.91(m,4H),1.51(s,9H).ESI-MS m/z：301.2 [M +Na]⁺。

43 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 10.00 (s, 1H), 8.64 (brs, 1H), 8.27 (d, J=5.2Hz, 1H), 8.17 (d, J= 5.6Hz, 1H), 8.12-8.09 (m, 2H), 7.58-7.52 (m, 3H), 7.29 (d, J=6.0Hz, 1H), 7.02 (d, J= 5.6Hz,1H), 3.25-3.17(m,4H),3.09-3.01(m,4H).ESI-MS m/z：389.2[M+H]⁺。

Embodiment 44, N- (4- morpholinyls pyridin-3-yl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine -4- amine

The preparation of 4- morpholinyl -3- aminopyridines

Step 1 prepares 4- (3- nitropyridine -4- bases) morpholine

Successively by the chloro- 3- nitropyridines (1.0g, 6.31mmol) of 4-, morpholine (0.55g, 6.31mmol) and DIPEA (0.82 G, 6.34mmol) round-bottomed flask is added, 20mL ethyl alcohol is added, is stirred under room temperature, nitrogen atmosphere, TLC is monitored to having reacted Entirely.Reaction solution is concentrated under reduced pressure, obtains 4- (3- nitropyridine -4- bases) morpholine crude product (1.25g).4- (the 3- nitro pyrroles Pyridine -4- bases) morpholine crude product without being further purified, is directly used in and reacts in next step.ESI-MS m/z：210.2 [M+H]⁺。

Step 2 prepares 4- morpholinyl -3- aminopyridines

4- (3- nitropyridine -4- bases) morpholine crude product (1.25g, 5.97mmol) is dissolved in 74mL ethyl alcohol, sequentially adds iron Powder (2.68g, 47.8mmol) and NH₄Cl (1.92g, 35.8mmol), is stirred under 90 DEG C, nitrogen atmosphere, and TLC is monitored to anti- It should be complete.Filtering reacting liquid fully washs filter cake with ethyl alcohol, filtrate is concentrated under reduced pressure.Silica gel column chromatography separating purification (dichloromethane Alkane：Methanol=15:1) the 4- morpholinyl -3- aminopyridines (1.02g, 95%) for black solid, are obtained.ESI-MS m/z： 180.2[M+H]⁺。

44 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 10.04 (s, 1H), 8.65 (brs, 1H), 8.30 (d, J=5.2Hz, 1H), 8.18 (d, J= 5.6Hz, 1H), 8.13-8.08 (m, 2H), 7.59-7.54 (m, 3H), 7.30 (d, J=5.6Hz, 1H), 7.03 (d, J= 5.2Hz,1H), 4.08-3.99(m,4H),3.14-3.05(m,4H).ESI-MS m/z：390.1[M+H]⁺。

Embodiment 45, N⁴Cyclopropane base-N³(2- phenyl thiazoles simultaneously [4,5-c] pyridin-4-yl) pyridine -3,4- diamines

N⁴The preparation of cyclopropyl-pyridine -3,4- diamines

Step 1 prepares N- cyclopropyl -3- nitropyridine -4- amine

Successively by the chloro- 3- nitropyridines (1.0g, 6.31mmol) of 4-, cyclopropylamine (0.36g, 6.30mmol) and DIPEA (0.815g, 6.30mmol) be added round-bottomed flask, add 20mL ethyl alcohol, stirred under room temperature, nitrogen atmosphere, TLC monitor to The reaction was complete.Filtering reacting liquid fully washs filter cake with methanol, filtrate is concentrated under reduced pressure.Silica gel column chromatography separating purification (oil Ether：Ethyl acetate=2:1), obtain for faint yellow solid N- cyclopropyl -3- nitropyridine -4- amine (1.17g, it is nearly 100%) 。¹H NMR(400MHz,CDCl₃) δ 9.22 (s, 1H), 8.37 (d, J=6.0Hz, 1H), 8.20 (brs, 1H), 7.17 (d, J= 6.4Hz,1H),2.68-2.62(m,1H),1.04-0.98(m,2H),0.77-0.70(m,2H).ESI-MS m/z：180.7 [M +H]⁺。

Step 2 prepares N⁴Cyclopropyl pyridine -3,4- diamines

N- cyclopropyl -3- nitropyridine -4- amine (1.17g, 6.53mmol) is dissolved in 80mL ethyl alcohol, sequentially adds iron powder (2.9 g, 52.2mmol) and NH₄Cl (2.1g, 39.2mmol), adds 8.9mL water, is stirred under 90 DEG C, nitrogen atmosphere, TLC is monitored to the reaction was complete.Filtering reacting liquid fully washs filter cake with ethyl alcohol, and filtrate is dried through anhydrous magnesium sulfate, and filtering is simultaneously It is concentrated under reduced pressure, obtains the N for faint yellow solid⁴Cyclopropyl pyridine -3,4- diamines (487mg, 51%).¹H NMR(400 MHz, d₆- DMSO) δ 7.63 (s, 1H), 7.62 (d, J=5.2Hz, 1H), 6.66 (d, J=5.2Hz, 1H), 5.77 (s, 1H), 4.52 (s,2H),2.42-2.36(m,1H),0.77-0.72(m,2H),0.45-0.40(m,2H).ESI-MS m/z：172.2 [M+ Na]⁺。

45 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 8.37 (s, 1H), 8.28 (d, J=5.6Hz, 1H), 8.12-8.07 (m, 2H), 8.01 (d, J= 5.6Hz, 1H), 7.59-7.51 (m, 3H), 7.26-7.21 (m, 2H), 7.06 (d, J=5.6Hz, 1H), 5.36 (brs, 1H), 2.60-2.53(m, 1H),0.84-0.79(m,2H),0.59-0.55(m,2H).ESI-MS m/z：358.1[M-H]^-。

Embodiment 46, N⁴Pentamethylene base-N³(2- phenyl thiazoles simultaneously [4,5-c] pyridin-4-yl) pyridine -3,4- diamines

N⁴The preparation of cyclopenta-pyridine -3,4- diamines

Step 1 prepares -4 amine of N- cyclopenta -3- nitropyridines

Successively by the chloro- 3- nitropyridines (1.0g, 6.31mmol) of 4-, cyclopenta amine (537mg, 6.31mmol) and DIPEA (815mg, 6.30mmol) be added round-bottomed flask, add 20mL ethyl alcohol, stirred under room temperature, nitrogen atmosphere, TLC monitor to The reaction was complete.Filtering reacting liquid fully washs filter cake with methanol, filtrate, silica gel column chromatography separating purification (oil is concentrated under reduced pressure Ether：Ethyl acetate=2:1) -4 amine (1.0g, 76%) of N- cyclopenta -3- nitropyridines for faint yellow solid, is obtained.¹H NMR(400MHz,CDCl₃) δ 9.17 (s, 1H), 8.25 (d, J=6.0Hz, 1H), 8.16 (brs, 1H), 6.72 (d, J= 6.2Hz,1H),4.01-3.94(m,1H),2.16-2.07(m,2H),1.86-1.58(m,6H).ESI-MS m/z：208.2 [M +H]⁺。

Step 2 prepares N⁴Cyclopenta-pyridine -3,4- diamines

- 4 amine (1.0g, 4.82mmol) of N- cyclopenta -3- nitropyridines is dissolved in 80mL ethyl alcohol, 8.9mL H are added₂O, Sequentially add iron powder (2.16g, 38.6mmol) and NH₄Cl (1.55g, 28.9mmol), is stirred under 90 DEG C, nitrogen atmosphere, TLC is monitored to the reaction was complete.Filtering reacting liquid fully washs filter cake with ethyl alcohol, and filtrate is dried through anhydrous magnesium sulfate, and filtering is simultaneously It is concentrated under reduced pressure.Residue purifies (dichloromethane by silica gel column chromatography：Methanol=15：1) it, obtains as faint yellow solid N⁴Cyclopenta-pyridine -3,4- diamines (800mg, 94%).¹H NMR(400MHz,d₆- DMSO) δ 7.76 (d, J=6.4Hz, 1H), 7.57 (s, 1H), 7.52 (d, J=6.4Hz, 1H), 6.71 (d, J=6.4Hz, 1H), 6.03 (brs, 2H), 4.19 (s, 1H),4.04-3.93(m,1H),2.04-1.94(m,2H),1.78-1.62(m,4H),1.62-1.52(m,2H)。ESI-MS m/ z：178.9[M+H]⁺。

46 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 8.34 (s, 1H), 8.22 (d, J=5.6Hz, 1H), 8.15-8.08 (m, 2H), 8.00 (d, J= 6.0Hz, 1H), 7.58-7.52 (m, 3H), 7.31 (s, 1H), 7.24 (d, J=5.6Hz, 1H), 6.68 (d, J=5.6Hz, 1H), 5.00 (d, J=6.0Hz, 1H), 3.97-3.89 (m, 1H), 2.10-1.99 (m, 2H), 1.76-1.59 (m, 4H), 1.58-1.48(m,2H). ESI-MS m/z：386.1[M-H]^-。

Embodiment 47, -2- cyclohexyls thiazole is simultaneously [4,5-c] by (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) Pyridine -4- amine

The preparation of the chloro- 2- cyclohexyl thiazoles of 4- simultaneously [4,5-c] pyridine

Step 1 prepares 3- amino -4- mercaptopyridines

The chloro- 3- nitropyridines (16.5g, 104.1mmol) of 4- are dissolved in 220mL ethyl alcohol, are slowly added under room temperature dense HCl (8.67mL) is slowly added to 70% NaHSH after stirring 10min under condition of ice bath₂O solution.After reacting at room temperature 1h, 40mL sodium hydrosulfites (24.38g, 140.01mmol) aqueous solution is added, 80 DEG C of reactions are overnight.Reaction solution is concentrated under reduced pressure, it is molten with methanol Solution residue (50mL) simultaneously filters, and filtrate is concentrated under reduced pressure, and continues to dissolve residue with methanol and filter, filtrate is concentrated under reduced pressure, obtains To 3- amino -4- mercaptopyridines crude products (44g).3- amino -4- mercaptopyridine the crude products without being further purified, It is directly used in and reacts in next step.

Step 2 prepares 2- cyclohexyl thiazole simultaneously [4,5-c] pyridine

3- amino -4- mercaptopyridines crude products (8g) are dissolved in 30mL hexahydrobenzoid acids, 120 DEG C are refluxed overnight, TLC prisons Reaction is surveyed to finish.Reaction solution is concentrated under reduced pressure, with saturation NaHCO₃PH is adjusted to 7~8 by aqueous solution, is extracted with ethyl acetate, and is merged Organic phase, organic phase washed with water and saturated common salt washing, are dried through anhydrous magnesium sulfate, are filtered organic phase and are concentrated under reduced pressure.It is residual Excess isolates and purifies (petroleum ether by silica gel column chromatography：Ethyl acetate=3:1) the 2- cyclohexyl for white solid, is obtained Thiazole simultaneously [4,5-c] pyridine (2.7g, two step yields 65%).ESI-MS m/z：219.3[M+H]⁺。

Step 3 prepares 2- cyclohexyl thiazole simultaneously [4,5-c] pyridine -5- oxides

By 2- cyclohexyl thiazole, simultaneously [4,5-c] pyridine (2.7g, 12.37mmol) is dissolved in 20mL dichloromethane, is slowly added to MCPBA (3.21g, 18.6mmol), is stirred overnight at room temperature, and TLC monitoring reactions finish.With saturation NaHCO₃Solution is by reaction solution PH is adjusted to 7~8, and dichloromethane extraction, organic phase is through anhydrous MgSO₄It is dry, it filters and is concentrated under reduced pressure, obtain 2- cyclohexyl thiophenes Azoles simultaneously [4,5-c] pyridine -5- oxides crude product (860mg).Simultaneously [4,5-c] pyridine -5- is aoxidized the 2- cyclohexyl thiazole Object crude product is directly used in and reacts in next step without being further purified.

Step 4 prepares the chloro- 2- cyclohexyl thiazoles of 4- simultaneously [4,5-c] pyridine

By 2- cyclohexyl thiazole simultaneously [4,5-c] pyridine -5- oxides (860mg) and POCl₃Single port glass is added in (15mL) Flask, overnight, TLC monitoring reactions finish for 90 DEG C of reactions.Reaction solution is concentrated under reduced pressure, with saturation NaHCO₃Aqueous solution is by reaction solution PH is adjusted to 7~8, is extracted with ethyl acetate, and merges organic phase, organic phase washed with water and saturated common salt washing, through anhydrous MgSO₄Dry organic phase, filters and is concentrated under reduced pressure.Residue is isolated and purified by silica gel column chromatography, is obtained as white solid The chloro- 2- cyclohexyl thiazoles of 4- simultaneously [4,5-c] pyridine (670mg, 21%).ESI-MS m/z：253.2[M+H]⁺。

47 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz, DMSO) δ 9.66 (s, 1H), 8.55 (brs, 1H), 8.18 (d, J=5.2Hz, 1H), 8.09 (d, J= 5.6Hz, 1H), 7.51 (d, J=5.6Hz, 1H), 7.12 (d, J=5.2Hz, 1H), 3.36-3.26 (m, 2H), 3.23-3.13 (m,1H), 3.06-2.95(m,1H),2.86-2.67(m,2H),2.20-2.10(m,2H),2.09-2.00(m,1H),1.95- 1.38(m,10H), 1.33-1.88(m,1H).ESI-MS m/z：409.2[M+H]⁺。

Embodiment 48, -2- cyclopropane bases thiazole is simultaneously [4,5-c] by (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) Pyridine -4- amine

The preparation of the chloro- 2- cyclopropyl thiazoles of 4- simultaneously [4,5-c] pyridine

Step 1 prepares 2- cyclopropyl-thiazole simultaneously [4,5-c] pyridine

3- amino -4- mercaptopyridines (240mg, 1.90mmol) are dissolved in 6mL ethylene-acetic acids, are placed in tube sealing, 100 DEG C It is refluxed overnight, TLC monitoring reactions finish.With saturation NaHCO₃Reaction is quenched, ethyl acetate extraction, organic phase is through anhydrous slufuric acid Magnesium is dried, and is filtered and is concentrated under reduced pressure.Residue is isolated and purified by silica gel column chromatography, obtains the 2- for yellow oily liquid Cyclopropyl-thiazole simultaneously [4,5-c] pyridine (78mg, 23%).¹H NMR(400MHz,CDCl₃) δ 9.14 (d, J=0.8Hz, 1H), 8.46 (d, J=5.2Hz, 1H), 7.76 (dd, J=5.4,1.0Hz, 1H), 2.45-2.38 (m, 1H), 1.63-1.56 (m, 2H), 1.30-1.25(m,2H).ESI-MS m/z：177.1[M+H]⁺。

Step 2 prepares 2- cyclopropyl-thiazole simultaneously [4,5-c] pyridine -5- oxides

By 2- cyclopropyl-thiazole, simultaneously [4,5-c] pyridine (5.304g, 30.1mmol) and MCPBA (7.7g, 44.6mmol) are molten In 40mL DCM, 3h is reacted at room temperature, TLC monitoring reactions finish.With saturation NaHCO₃Reaction solution pH is adjusted to 7~8, two by solution Chloromethanes extracts, and detaches organic phase, organic phase washed with water and saturated sodium-chloride water solution are washed, through anhydrous MgSO₄It is dry, filtering And be concentrated under reduced pressure, obtain 2- cyclopropyl-thiazole simultaneously [4,5-c] pyridine -5- oxides crude product (1.29 g) for yellow solid. Simultaneously [4,5-c] pyridine -5- oxides crude product is directly used in next step the 2- cyclopropyl-thiazole without being further purified Reaction.

Step 3 prepares the chloro- 2- cyclohexyl thiazoles of 4- simultaneously [4,5-c] pyridine

By 2- cyclopropyl-thiazole, simultaneously [4,5-c] pyridine -5- oxides are dissolved in 10mL POCl₃, 90 DEG C are refluxed overnight, TLC Monitoring reaction finishes.Reaction solution is concentrated under reduced pressure, with saturation NaHCO₃Reaction solution pH is adjusted to 7~8 by aqueous solution, then with acetic acid second Ester extracts, and detaches organic phase and is dried through anhydrous magnesium sulfate, filter and organic phase is concentrated under reduced pressure.Silica gel column chromatography separating purification, Obtain the chloro- 2- cyclohexyl thiazoles of 4- simultaneously [4,5-c] pyridine (250mg, 18%) for yellow solid.

48 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz, DMSO) δ 9.72 (s, 1H), 8.45 (brs, 1H), 8.16 (d, J=5.2Hz, 1H), 8.07 (d, J= 5.6Hz, 1H), 7.47 (d, J=6.0Hz, 1H), 7.10 (d, J=5.2Hz, 1H), 3.26-3.12 (m, 2H), 3.03-2.94 (m,1H), 2.74-2.57(m,3H),2.05-1.94(m,1H),1.93-1.82(m,1H),1.78-1.65(m,1H),1.49- 1.36(m,1H), 1.33-1.25(m,2H),1.24-1.17(m,2H).ESI-MS m/z：367.3[M+H]⁺。

Embodiment 49, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- methylthiazols simultaneously [4,5-c] pyrrole Pyridine -4- amine

The preparation of 4- chloro-2-methyls thiazole simultaneously [4,5-c] pyridine

Step 1 prepares 3- amino -4- mercaptopyridines

The chloro- 3- nitropyridines (6.0g, 37.8mmol) of 4- are dissolved in 80mL ethyl alcohol, are slowly added to dense HCl under room temperature (3.28mL) is slowly added to 70% NaHSH after stirring 10min under condition of ice bath₂O aqueous solutions.After reacting at room temperature 1h, add Enter 40mL sodium hydrosulfites (24.38g, 140.01mmol) aqueous solution, overnight, TLC monitoring reactions finish for 80 DEG C of reactions.It is concentrated under reduced pressure Reaction solution dissolves residue with methanol and filters, filtrate is concentrated under reduced pressure, and continues to dissolve residue with methanol and filter, decompression is dense Contracting filtrate obtains 3- amino -4- mercaptopyridines crude products (20g).3- amino -4- mercaptopyridines the crude product without into One step purifies, and is directly used in and reacts in next step.

Step 2 prepares 2- methylthiazols simultaneously [4,5-c] pyridine

Reaction bulb is added in 3- amino -4- mercaptopyridines (4g, 31.7mmol), 30mL acetic acid, 100 DEG C of reflux are then added Overnight, TLC monitorings reaction finishes.Reaction solution is concentrated under reduced pressure, with saturation NaHCO₃Aqueous solution tune reaction solution pH to 7~8, acetic acid Ethyl ester extracts, and detaches organic phase, organic phase washed with water and saturation NaCl aqueous solutions are washed, through anhydrous MgSO₄Dry, filtering is simultaneously It is concentrated under reduced pressure.Residue is isolated and purified by silica gel column chromatography, obtain for white solid 2- methylthiazols simultaneously [4,5-c] Pyridine (430mg, 9%).

Step 3 prepares 2- methylthiazols simultaneously [4,5-c] pyridine -5- oxides

By 2- methylthiazols, simultaneously [4,5-c] pyridine (430mg, 2.87mmol) is dissolved in dichloromethane (20mL), is slowly added to MCPBA (742mg, 4.3mmol), is stirred overnight at room temperature, and TLC monitoring reactions finish.With saturation NaHCO₃Aqueous solution tune reaction solution PH to 7~8, dichloromethane extraction detach organic phase and through anhydrous MgSO₄It is dry, organic phase is filtered and be concentrated under reduced pressure, is obtained 2- methylthiazols simultaneously [4,5-c] pyridine -5- oxides crude product (320mg).The 2- methylthiazols simultaneously [4,5-c] pyridine- 5- oxides crude product is directly used in and reacts in next step without being further purified.

Step 4 prepares 4- chloro-2-methyls thiazole simultaneously [4.5-c] pyridine

By 2- methylthiazols simultaneously [4,5-c] pyridine -5- oxides (320mg, 1.92mmol) and POCl₃(15mL) is added anti- Bottle is answered, overnight, TLC monitoring reactions finish for 90 DEG C of reactions.Reaction solution is concentrated under reduced pressure, with saturation NaHCO₃Aqueous solution adjusts reaction Liquid pH to 7~8, is extracted with ethyl acetate, and detaches organic phase, organic phase washed with water and saturation NaCl aqueous solutions are washed, through anhydrous MgSO4 is dried, and is filtered and is concentrated under reduced pressure.Residue is isolated and purified by silica gel column chromatography, obtains the 4- for white solid Chloro-2-methyl thiazole simultaneously [4.5-c] pyridine (209mg, two step yields 40%).¹H NMR(400MHz,CDCl₃)δ 8.28(d,J =5.6Hz, 1H), 7.72 (d, J=5.2Hz, 1H), 2.93 (s, 3H).ESI-MS m/z：185.1[M+H]⁺。

49 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz, MeOD) δ 9.61 (s, 1H), 8.13 (d, J=5.6Hz, 1H), 8.02 (d, J=5.6Hz, 1H), 7.35 (d, J =5.6Hz, 1H), 7.16 (d, J=5.6Hz, 1H), 3.46-3.35 (m, 2H), 3.15-3.10 (m, 1H), 2.93-2.86 (m, 5H), 2.17-2.06(m,1H),2.02-1.83(m,2H),1.67-1.58(m,1H).ESI-MS m/z：341.3[M+H]⁺。

Embodiment 50, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- ethyl thiazoles simultaneously [4,5-c] pyrrole Pyridine -4- amine

The preparation of the chloro- 2- ethyl thiazoles of 4- simultaneously [4,5-c] pyridine

Step 1 prepares 2- ethyl thiazoles simultaneously [4,5-c] pyridine

3- amino 4- mercaptopyridines (2.625g, 20.8mmol) are dissolved in 50mL propionic acid, 100 DEG C are refluxed overnight, TLC prisons Reaction is surveyed to finish.Filtrate is concentrated under reduced pressure, with saturation NaHCO₃Aqueous solution adjusts reaction solution pH to 7~8, and ethyl acetate extraction divides From organic phase, organic phase washed with water and saturation NaCl aqueous solutions are washed, through anhydrous MgSO₄It is dry, it filters organic phase and depressurizes dense Contracting.Residue is isolated and purified by silica gel column chromatography method, obtains 2- ethyl thiazoles simultaneously [4, the 5-c] pyrrole for yellow oily liquid Pyridine (694mg, 20%).¹H NMR(400MHz,CDCl₃) δ 9.24 (s, 1H), 8.49 (d, J=5.6Hz, 1H), 7.80 (dd, J =5.4,0.6Hz, 1H), 3.18 (q, J=7.5Hz, 2H), 1.48 (t, J=7.4Hz, 3H).ESI-MS m/z：165.1 [M+ H]⁺。

Step 2 prepares 2- ethyl thiazoles simultaneously [4,5-c] pyridine -5- oxides

By 2- ethyl thiazoles, simultaneously [4,5-c] pyridine (430mg, 2.62mmol) is dissolved in 20mL dichloromethane, is slowly added to MCPBA (495mg, 2.87mmol), is stirred overnight at room temperature, and TLC monitoring reactions finish.With saturation NaHCO₃Solution adjusts reaction Liquid pH to 7~8, dichloromethane extraction, detaches organic phase, through anhydrous MgSO₄It is dry, it filters organic phase and is concentrated under reduced pressure, obtain For 2- ethyl thiazoles simultaneously [4,5-c] pyridine -5- oxides crude product (625mg) of yellow solid.The 2- ethyl thiazoles are simultaneously [4,5-c] pyridine -5- oxides crude product is directly used in and reacts in next step without being further purified.

Step 3 prepares the chloro- 2- ethyl thiazoles of 4- simultaneously [4,5-c] pyridine

By 2- ethyl thiazoles simultaneously [4,5-c] pyridine -5- oxides (625mg) and POCl₃(15mL) addition reaction bulb, 90 DEG C Overnight, TLC monitoring reactions finish for reaction.Reaction solution is concentrated under reduced pressure, with saturation NaHCO₃Solution adjusts reaction solution pH to 7~8, It being extracted with ethyl acetate, merges organic phase, organic phase washed with water and saturation NaCl aqueous solutions are washed, are dried through anhydrous MgSO4, It filters and is concentrated under reduced pressure.Residue is isolated and purified by silica gel column chromatography, obtains the chloro- 2- ethyls thiophenes of 4- for white solid Azoles simultaneously [4,5-c] pyridine (369mg, two step yields 71%).¹H NMR(400MHz,CDCl₃) δ 8.27 (d, J=5.6 Hz, 1H), 7.73 (d, J=5.2Hz, 1H), 3.23 (q, J=7.6Hz, 2H), 1.50 (t, J=7.6Hz, 3H).ESI-MS m/z： 197.0 [M-H]^-。

50 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz, MeOD) δ 9.66 (s, 1H), 8.12 (d, J=5.6Hz, 1H), 8.01 (d, J=5.6Hz, 1H), 7.33 (d, J =5.6Hz, 1H), 7.14 (d, J=5.2Hz, 1H), 3.42-3.34 (m, 2H), 3.20 (q, J=7.7Hz, 2H), 3.15-3.06 (m,1H),2.89-2.77(m,2H),2.22-2.06(m,1H),1.99-1.84(m,2H),1.64-1.55(m,1H),1.50 (t, J=7.4Hz, 3H).ESI-MS m/z：355.2[M+H]⁺。

Embodiment 51, N- (4- (4,4- difluoropiperdin -1- bases) pyridin-3-yl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine - 4- amine

The preparation of 4- (4,4- difluoropiperdin -1- bases) -3- aminopyridines

Step 1 prepares 4,4- difluoropiperdin 1- carboxylates

4- oxo -1- piperidine carboxylates (199mg, 1.0mmol) are dissolved in dry DCM, are added under condition of ice bath DAST (507mg, 3.14mmol), reacts at room temperature 1.5h, and TLC monitoring reactions finish.Cooling reaction solution, is added under condition of ice bath Reaction is quenched in saturated sodium bicarbonate solution, is extracted with dichloromethane, merges organic phase and is washed with water, is dried through anhydrous magnesium sulfate, It filters and is concentrated under reduced pressure, obtain 4,4- difluoropiperdin 1- carboxylates (210mg, 95%).ESI-MS m/z：244.1[M+ Na]⁺。

Step 2 prepares 4,4- difluoropiperdins

4,4- difluoropiperdin 1- carboxylates (221mg, 1.0mmol) are dissolved in 5mL DCM/THF mixed liquor (bodies Product is than being 1:1) 5mL trifluoracetic acids are added, react at room temperature 15min, TLC monitoring reactions finish.Reaction solution is concentrated under reduced pressure, obtains 4,4- difluoropiperdins.The title compound is directly used in and reacts in next step without being further purified.

Step 3 prepares 4- (4,4- difluoro-piperidin -1- bases) -3- nitropyridines

It is added in 4,4- difluoropiperdin crude products in DIPEA and remaining TFA, reduced pressure, residue is dissolved in ethyl alcohol；Again Chloro- 3 nitropyridines (158mg, 1.0mmol) of 4- are added, overnight, TLC monitoring reactions finish for room temperature reaction.Reaction is concentrated under reduced pressure Liquid, residue isolate and purify (dichloromethane by silica gel column chromatography：Methanol=30:1) 4- (4,4- difluoro-piperidins-, are obtained 1- yls) -3- nitropyridines.

Step 4 prepares 4- (4,4- difluoro-piperidin -1- bases) -3- aminopyridines

4- (4,4- difluoro-piperidin -1- bases) -3- nitropyridines (634mg, 2.61mmol) are dissolved in 20mL ethyl alcohol, successively Iron powder (293mg, 5.23mmol), ammonium chloride (280mg, 5.23mmol) and 5mL water is added, 80 DEG C of reflux 4h, TLC monitorings are anti- It should finish.Filtering reacting liquid is concentrated under reduced pressure filtrate, suitable quantity of water is added in residue, is extracted with ethyl acetate (15mL × 3), closes And organic phase and be washed with water (10mL × 3), organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure.Residue passes through silicon Gel column chromatography isolates and purifies (dichloromethane：Methanol=20:1) 4- (4, the 4- difluoro-piperidins-for faint yellow solid, are obtained 1- yls) -3- aminopyridines (528mg, 95%).

51 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 10.12 (s, 1H), 8.64 (s, 1H), 8.34 (d, J=4.0Hz, 1H), 8.14 (d, J= 5.6Hz, 1H), 8.08-7.99 (m, 2H), 7.58-7.47 (m, 3H), 7.07 (d, J=4.4Hz, 1H), 3.25-3.12 (m, 4H),2.45-2.28(m, 4H).ESI-MS m/z：424.2[M+H]⁺。

Embodiment 52, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (4- bromophenyls) thiazole simultaneously [4,5- C] pyridine -4- amine

The preparation of 2- (4- bromophenyl -1- bases) chloro- thiazoles of -4- simultaneously [4,5-c] pyridine

Step 1 prepares 2- (4- bromophenyl -1- bases) thiazole simultaneously [4,5-c] pyridine

By thiazole simultaneously [4,5-c] pyridine (2.0g, 14.69mmol), to bromo-iodobenzene (4.2g, 14.85mmol), Pd (PPh₃)₄ (855mg, 0.74mmol), CuI (142mg, 0.74mmol) and Cs₂CO₃(14.7g, 45mmol) is dissolved in 25 mL DMF, 120 DEG C It is stirred to react, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering reacting liquid, 100mL water and 50mL second is added In acetoacetic ester to filtrate, organic phase, organic phase washed with water (25mL × 1) and saturated common salt washing (25mL × 2), warp are detached Anhydrous sodium sulfate is dried, and is filtered organic phase and is concentrated under reduced pressure.Residue isolates and purifies (petroleum ether by silica gel column chromatography：Second Acetoacetic ester=3：1), obtain for yellow solid powder 2- (4- bromophenyl -1- bases) thiazole simultaneously [4,5-c] pyridine (2.93g, 68%).¹H NMR(400MHz,CDCl₃) δ 9.36 (s, 1H), 8.52 (d, J=5.2Hz, 1H), 8.12-8.08 (m, 2H), 7.85 (d, J=5.6Hz, 1H), 7.55-7.51 (m, 2H).ESI-MS m/z：292.9[M+H]⁺。

Step 2 prepares 2- (4- bromophenyl -1- bases) thiazole simultaneously [4,5-c] pyridine -5- oxides

By 2- (4- bromophenyl -1- bases) thiazole, simultaneously [4,5-c] pyridine (2.93g, 10.1mmol) is dissolved in 10mL dichloromethane, It is slowly added to MCPBA (2.49g, 14.4mmol), is stirred at room temperature, TLC is monitored to the reaction was complete, and 10mL 1M potassium carbonate is added Reaction is quenched in solution.25mL saturated salt solutions are added into reaction solution, extracts (25mL × 2) with dichloromethane, merges organic Phase, organic phase are dried over anhydrous sodium sulfate, and are filtered and are concentrated under reduced pressure, and 2- (4- bromophenyl -1- bases) thiophene for yellow solid is obtained Azoles simultaneously [4,5-c] pyridine -5- oxides crude product (3.1g).Described 2- (4- bromophenyl -1- bases) thiazole simultaneously [4,5-c] pyrrole Pyridine -5- oxides crude product is directly used in and reacts in next step without being further purified.

Step 3 prepares 2- (4- bromophenyl -1- bases) chloro- thiazoles of -4- simultaneously [4,5-c] pyridine

By 2- (4- bromophenyl -1- bases) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 5mL POCl₃, reflux 2h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, addition saturated sodium bicarbonate adjusting pH to neutrality, It is extracted with ethyl acetate (25mL × 3), merges organic phase, be dried over anhydrous sodium sulfate, filter organic phase and be concentrated under reduced pressure, obtain To simultaneously [4,5-c] pyridine (1.58g, the two step yields of 2- (4- bromophenyl -1- bases) chloro- thiazoles of -4- for light pink solid 48%).¹H NMR (400MHz,CDCl₃) δ 8.31 (d, J=5.2Hz, 1H), 8.03-7.99 (m, 2H), 7.79 (d, J= 5.2Hz,1H), 7.69-7.65(m,2H).ESI-MS m/z：327.0[M+H]⁺。

52 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz, MeOD) δ 8.37 (s, 1H), 8.24-8.22 (m, 2H), 8.08-8.04 (m, 2H), 8.01 (d, J=5.2Hz, 1H), 7.20 (d, J=6.0Hz, 1H), 7.04-7.01 (m, 2H), 3.95-3.89 (m, 1H), 3.58-3.48 (m, 1H), 3.21-3.11(m, 1H),3.04-2.88(m,5.9Hz,2H),2.08-1.97(m,1H),1.93-1.83(m,1H),1.66- 1.50(m,2H).ESI-MS m/z：483.2[M+H]⁺。

Embodiment 53, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (pyridine -2- bases) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (2- pyridyl groups) thiazole simultaneously [4,5-c] pyridine

Step 1 prepares 2- (pyridine -2- bases) thiazole simultaneously [4,5-c] pyridine

By thiazole simultaneously [4,5-c] pyridine (1g, 7.34mmol), 2- bromopyridines (1392mg, 8.81mmol), Pd (PPh₃)₄ (424mg, 0.37mmol), CuI (71mg, 0.37mmol), Cs₂CO₃(7.17g, 22.0mmol) and DMF (100mL) add successively Enter in single-necked flask, 120 DEG C of reaction 6h, TLC monitoring reactions finish.Reaction solution is cooled to room temperature, filtering reacting liquid, will be filtered Liquid is poured into water, is extracted with ethyl acetate (50mL × 3), and organic phase is merged, and organic phase washes (50mL × 3) with saturated common salt, Through anhydrous MgSO₄It is dry, it filters organic phase and is concentrated under reduced pressure.Residue isolates and purifies (petroleum ether by silica gel column chromatography： Ethyl acetate=3:1) 2- (pyridine -2- bases) thiazole of faint yellow solid simultaneously [4,5-c] pyridine (1370mg, 88%), is obtained.¹H NMR(400MHz,CDCl₃) δ 9.37 (d, J=0.4Hz, 1H), 8.71-8.69 (m, 1H), 8.54 (d, J=5.6Hz, 1H), 8.39 (dt, J=8.0,1.0Hz, 1H), 7.91-7.86 (m, 2H), 7.46-7.42 (m, 1H). ESI-MS m/z：214.3[M+ H]⁺。

Step 2 prepares 2- (pyridine -2- bases) thiazole simultaneously [4,5-c] pyridine -5- oxides

By 2- (pyridine -2- bases) thiazole, simultaneously [4,5-c] pyridine (1370mg, 6.42mmol) is dissolved in 60mL DCM, slowly adds Enter MCPBA (1551mg, 8.99mmol), overnight, TLC monitoring reactions finish for room temperature reaction.It is slowly added into reaction solution NaHCO₃Solution (90mL × 2), filtering reacting liquid detach organic phase, through anhydrous Na₂SO₄It is dry, it filters organic phase and depressurizes dense Contracting obtains 2- (pyridine -2- bases) thiazole simultaneously [4,5-c] pyridine -5- oxides crude product (1355mg) for khaki solid. Simultaneously [4,5-c] pyridine -5- oxide crude products are directly used in down described 2- (pyridine -2- bases) thiazole without being further purified Single step reaction.

Step 3 prepares 4- chloro- 2- (pyridine -2- bases) thiazole simultaneously [4,5-c] pyridine

By 2- (pyridine -2- bases) thiazole simultaneously [4,5-c] pyridine -5- oxides (1355mg) and POCl₃Single-necked flask is added In, 100 DEG C of reaction 6h, reaction solution is cooled to room temperature, is slowly added dropwise in 50mL water to reaction solution, continues to stir 0.5h.With 30% NaOH aqueous solutions adjust reaction solution pH to 8 or so, extract (100mL) with DCM, organic phase are detached, through anhydrous Na₂SO₄It is dry, Filtering organic phase is simultaneously concentrated under reduced pressure.Residue is isolated and purified by silica gel column chromatography, obtains the chloro- 2- of 4- for off-white powder (pyridine -2- bases) thiazole simultaneously [4,5-c] pyridine (944mg, two step yields 59%).¹H NMR(400MHz,CDCl₃)δ8.70(d, J=4.8Hz, 1H), 8.50 (d, J=7.6Hz, 1H), 8.32 (d, J=4.8Hz, 1H), 7.93-7.87 (m, 1H), 7.83 (d, J=5.2Hz, 1H), 7.49-7.45 (m, 1H).ESI-MS m/z：248.0[M+H]⁺。

53 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 9.74 (s, 1H), 8.65 (d, J=4.8Hz, 1H), 8.25 (d, J=8.0Hz, 1H), 8.15 (d, J=5.2Hz, 1H), 8.11 (d, J=5.6Hz, 1H), 7.95 (t, J=7.2Hz, 1H), 7.45-7.36 (m, 1H), 7.31 (d, J=5.6 Hz, 1H), 6.99 (d, J=5.2Hz, 1H), 3.43-3.25 (m, 2H), 3.11-3.06 (m, 1H), 2.93-2.79 (m,2H), 2.14-1.81(m,3H),1.67-1.52(m,1H).ESI-MS m/z：404.3[M+H]⁺。

Embodiment 54, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (thiene-3-yl) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of 4- chloro- 2- (thiene-3-yl) thiazole simultaneously [4,5-c] pyridine

Step 1：The chloro- 3- nitro-pyridines (7950mg, 50mmol) of 4- are dissolved in 50mL ethyl alcohol, it is dense to be slowly added to 50mmol Hydrochloric acid is stirred at room temperature；Weigh NaHSH₂O (13.69g, 185mmol) is added in reaction solution, and 40min is stirred at room temperature；Weigh guarantor Dangerous powder (32.21g, 185mmol) is soluble in water, and insurance amidin is added in reaction mixture, 80 DEG C of stirring 12h.It crosses Reaction solution is filtered, filtrate is concentrated under reduced pressure, is isolated and purified by column chromatography and (first uses dichloromethane：Methanol=5:1 elution impurity, then Use dichloromethane：Methanol=1:1 affords crude product), obtain 3- amino -4- mercaptopyridine crude products, yellow-brown solid. It does not purify, is directly used in and reacts in next step.

Step 2：3- amino -4- mercaptopyridine crude products are dissolved in 100mL formic acid, flow back 4h, and saturated sodium bicarbonate is added Reaction is quenched in solution.Reaction solution is extracted with ethyl acetate (200mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, and filters And it is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography：Ethyl acetate=3：1) it, obtains as white powdery solids Thiazole simultaneously [4,5-c] pyridine (2.52g, two step yields 37%).

Step 3：By thiazole simultaneously [4,5-c] pyridine (2g, 14.7mmol), 3 bromo thiophene (2.876g, 17.6mmol), Pd (PPh₃)₄(855mg, 0.74mmol), CuI (141mg, 0.74mmol) and Cs₂CO₃(14.5g, 44.1mmol) is dissolved in 40mL DMF, 120 DEG C of stirrings, TLC are monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering reacting liquid, be added 200mL water and In 100mL ethyl acetate to filtrate, detaches organic phase and washed with 100mL, saturated common salt water washing organic phase (100mL × 2) it, is dried over anhydrous sodium sulfate, filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography：Ethyl acetate=3： 1) 2- thiene-3-yls-thiazole simultaneously [4,5-c] pyridine (2g, 62.4%) for faint yellow solid, is obtained.¹H NMR (400MHz, CDCl₃) δ 9.33 (s, 1H), 8.52 (d, J=5.4Hz, 1H), 8.07 (dd, J=2.9,1.1Hz, 1H), 7.83 (d, J= 5.4Hz, 1H), 7.72 (dd, J=5.1,1.1Hz, 1H), 7.47 (dd, J=5.1,3.0Hz, 1H).ESI-MS m/z： 219.05[M+H]⁺。

Step 4：By 2- thiene-3-yls-thiazole, simultaneously [4,5-c] pyridine (3.2g, 14.7mmol) is dissolved in 20mL dichloromethane, It is slowly added to MCPBA (3.445g, 19.96mmol), is stirred at room temperature, TLC is monitored to the reaction was complete, and 20mL 1M potassium carbonate is added Reaction is quenched in solution.100mL saturated salt solutions are added into reaction solution, extracts (100mL × 2) with dichloromethane, merges organic Phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure, and obtaining 2- thiene-3-yls-thiazole, simultaneously [4,5-c] pyridine -5- is aoxidized Object crude product, white solid.It does not purify, is directly used in and reacts in next step.

Step 5：By 2- thiene-3-yls-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, return Flow 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, it is extracted with ethyl acetate (100mL × 3), merges organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain Pale yellow powder shape solid 4- chloro- 2- (thiene-3-yl) thiazole simultaneously [4,5-c] pyridine (1.1g, two step yields 30%).¹H NMR(400 MHz,CDCl₃) δ 8.29 (d, J=5.4Hz, 1H), 8.14 (dd, J=2.9,1.2Hz, 1H), 7.76 (d, J= 5.4Hz, 1H), 7.74 (dd, J=5.1,1.2Hz, 1H), 7.47 (dd, J=5.1,3.0Hz, 1H).ESI-MS m/z： 252.90[M+H]⁺。

54 compound of the embodiment of the present invention is prepared according to method 1, other steps are prepared with reference to embodiment 18.¹H NMR (400 MHz,CDCl₃) δ 10.01 (s, 1H), 8.57 (br s, 1H), 8.24 (d, J=5.2Hz, 1H), 8.17 (d, J= 5.6Hz, 1H), 8.01 (m, 1H), 7.70 (dd, J=5.0,1.0Hz, 1H), 7.50 (m, 1H), 7.28 (d, J=5.8Hz, 1H), 7.00 (d, J=5.2 Hz, 1H), 3.31-3.22 (m, 2H), 3.15-3.10 (m, 1H), 2.82-2.76 (m, 1H), 2.69-2.64(m,1H),2.08-1.97 (m,3H),1.50-1.37(m,1H).ESI-MS m/z：409.04[M+H]⁺。

Embodiment 55, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (furans -2- bases) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (furans -2- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously [4,5-c] pyridine (1g, 7.3mmol), 2- bromines furans (1.3g, 8.8mmol), Pd (PPh₃)₄ (428mg, 0.37mmol), CuI (70mg, 0.37mmol) and Cs₂CO₃(7.18g, 22mmol) is dissolved in 20mL DMF, and 120 DEG C are stirred It mixes, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering reacting liquid, 200mL water and 100mL acetic acid second is added In ester to filtrate, detaches organic phase and washed with 100mL, saturated common salt water washing organic phase (100 mL × 2), through anhydrous slufuric acid Sodium is dried, and is filtered and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography：Ethyl acetate=3：1) it, obtains being yellowish 2- furans -2- bases-thiazole of color pulverulent solids simultaneously [4,5-c] pyridine (2g, 93.9%).¹H NMR (400MHz,CDCl₃)δ 9.35 (s, 1H), 8.54 (d, J=5.4Hz, 1H), 7.87 (d, J=5.4Hz, 1H), 7.67 (d, J=1.2Hz, 1H), 7.29 (d, J=3.5Hz, 1H), 6.67 (dd, J=3.5,1.8Hz, 1H).

Step 2：By 2- furans -2- bases-thiazole, simultaneously [4,5-c] pyridine (1.5g, 7.43mmol) is dissolved in 10mL dichloromethane, It is slowly added to MCPBA (1.96g, 11.14mmol), is stirred at room temperature, TLC is monitored to the reaction was complete, and 20mL 1M potassium carbonate is added Reaction is quenched in solution.100mL saturated salt solutions are added into reaction solution, extracts (100mL × 2) with dichloromethane, merges organic Phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure, and obtaining 2- furans -2- bases-thiazole, simultaneously [4,5-c] pyridine -5- is aoxidized Object crude product, yellow solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- furans -2- bases-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, return Flow 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, it is extracted with ethyl acetate (100mL × 3), merges organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain For the chloro- 2- of 4- (furans -2- bases) thiazole simultaneously [4,5-c] pyridine (900mg, two step yields 51.5%) of light yellow solid.

(S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (furans -2- bases) thiazole simultaneously [4,5-c] pyridine - The preparation of 4- amine

Step 1：By (S) -1- (3- aminopyridine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (292mg, 1mmol), simultaneously [4,5-c] pyridine (237mg, 1mmol) is dissolved in tetrahydrofuran to the chloro- 2- furans -2- bases-thiazoles of 4-, sequentially adds Pd₂(dba)₃(27mg, 0.03mmol), BINAP (37mg, 0.06mmol) and K₂CO₃(414mg, 3mmol), nitrogen atmosphere Under, 80 DEG C of stirrings, TLC monitors to the reaction was complete.Filtering reacting liquid, with methylene chloride/methanol mixed liquor (1:1) fully washing Filtrate is concentrated under reduced pressure in filter cake.(dichloromethane is isolated and purified by TLC：Methanol=20:1) (S)-for yellow solid, is obtained [3'- (2- furans -2- bases-thiazole simultaneously [4,5-c] pyridin-4-yl-amine) double pyridyl group -3- of -3,4,5,6- tetrahydrochysenes -2H- [1,4'] Base]-t-butyl carbamate (202mg, 41%).

Step 2：By (S)-[3'- (2- furans -2- bases-thiazole simultaneously [4,5-c] pyridin-4-yl-amine) -3,4,5,6- tetrahydrochysenes - Double pyridyl group -3- the bases of 2H- [Isosorbide-5-Nitrae ']]-t-butyl carbamate (202mg, 0.41mmol) is dissolved in 6mL dichloromethane, it will react Bottle is placed in ice bath cooling, and 1.5mL trifluoracetic acids are added, and condition of ice bath stirs 20min, is warmed to room temperature that the reaction was continued, TLC inspections It surveys to the reaction was complete.Reaction solution is concentrated under reduced pressure, 50mL saturated sodium bicarbonate solutions are added in residue, are extracted with ethyl acetate (50 mL × 3), washing merge organic phase (10mL × 2), are dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure.Pass through TLC systems Standby thin layer isolates and purifies, and obtains (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (furans-for yellow solid 2- yls) thiazole simultaneously [4,5-c] pyridine -4- amine (119mg, 74%).¹H NMR(400MHz,CD₃OD)δ9.64(s,1H),8.21 (d, J=5.0 Hz, 1H), 8.10 (dd, J=5.6,2.2Hz, 1H), 7.87 (d, J=1.2Hz, 1H), 7.48-7.46 (m, 1H), 7.34 (d, J=3.4Hz, 1H), 7.24 (d, J=5.4Hz, 1H), 6.78-6.77 (m, 1H), 3.66-3.62 (m, 1H), 3.48-3.45(m,1H), 3.25-3.17(m,1H),3.12-2.99(m,2H),2.25-2.11(m,1H),2.07-1.91(m, 2H),185-1.73(m,1H). ESI-MS m/z：393.12[M+H]⁺。

Embodiment 56, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (pyridin-4-yl) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of 4- chloro- 2- (pyridin-4-yl) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously [4,5-c] pyridine (500mg, 3.67mmol), 4- bromopyridine hydrochlorides (855mg, 4.4mmol)、 Pd(PPh₃)₄(212mg, 0.183mmol), CuI (35mg, 0.183mmol) and Cs₂CO₃(4.3g, It 13.2mmol) is dissolved in 20mL DMF, 120 DEG C of stirrings, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering is anti- Liquid is answered, is added in 100mL water and 50mL ethyl acetate to filtrate, organic phase is detached and is washed with 50mL, saturated common salt water washing Organic phase (50mL × 2), is dried over anhydrous sodium sulfate, and filters and is concentrated under reduced pressure.Obtain 2- pyridin-4-yls-thiazole simultaneously [4,5-c] Pyridine crude product is directly reacted in next step.¹H NMR(400MHz,CDCl₃) δ 9.44 (s, 1H), 8.83 (d, J=4.7Hz, 2H), 8.60 (d, J=5.4Hz, 1H), 7.97 (m, 2H), 7.92 (d, J=5.4Hz, 1H).

Step 2：By 2- pyridin-4-yls-thiazole, simultaneously [4,5-c] pyridine crude product is dissolved in 20mL dichloromethane, is slowly added to MCPBA (887mg, 5.14mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 10mL 1M solution of potassium carbonate is added and is quenched Reaction.50mL saturated salt solutions are added into reaction solution, extracts (50mL × 2) with dichloromethane, merges organic phase, through anhydrous Sodium sulphate is dried, and is filtered and is concentrated under reduced pressure, obtains 2- pyridin-4-yls-thiazole simultaneously [4,5-c] pyridine -5- oxide crude products, Yellow solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- pyridin-4-yls-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, return Flow 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, it is extracted with ethyl acetate (100mL × 3), merges organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain For 4- Chloro-2-Pyridyles -4- bases-thiazole simultaneously [4,5-c] pyridine (270mg, three step yields 29.7%) of yellow solid powder.

56 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.58 (s, 1H), 8.77 (d, J=5.8Hz, 2H), 8.19 (d, J=5.4Hz, 1H), 8.10- 8.06 (m, 3H), 7.46-7.44 (m, 1H), 7.19 (d, J=5.4Hz, 1H), 3.50-3.45 (m, 2H), 3.24-3.19 (m, 1H), 2.93-2.85(m,2H),2.22-2.17(m,1H),2.00-1.86(m,2H),1.67-1.58(m,1H)。ESI-MS m/z：402.2 [M-H]^-。

Embodiment 57, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (pyrimidine -2-base) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of 4- chloro- 2- (pyrimidine -2-base) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously [4,5-c] pyridine (136mg, 1mmol), 2- Bromopyrimidines (191mg, 4.4mmol), Pd (PPh₃)₄(58mg, 0.05mmol), CuI (10mg, 0.05mmol) and Cs₂CO₃(977mg, 3mmol) is dissolved in 5mL DMF, and 120 DEG C stirring, TLC monitors to the reaction was complete.Reaction solution is cooled to room temperature, filtering reacting liquid, 100mL water and 50mL acetic acid is added In ethyl ester to filtrate, detaches organic phase and washed with 50mL, saturated common salt water washing organic phase (50 mL × 2), through anhydrous slufuric acid Sodium is dried, and is filtered and is concentrated under reduced pressure.(dichloromethane is isolated and purified by column chromatography：Methanol=20：1) it, obtains being faint yellow 2- (pyrimidine -2-base) thiazole of solid simultaneously [4,5-c] pyridine (202mg, 94.3%).¹H NMR(400MHz, CDCl₃)δ9.53 (s, 1H), 8.96 (d, J=4.9Hz, 2H), 8.60 (d, J=5.1Hz, 1H), 7.93 (d, J=5.4Hz, 1H), 7.44 (t, J =4.9Hz, 1H).

Step 2：By 2- (pyrimidine -2-base) thiazole, simultaneously [4,5-c] pyridine (197mg, 0.92mmol) is dissolved in 5mL dichloromethanes Alkane is slowly added to MCPBA (222mg, 1.92mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 5mL 1M carbonic acid is added Reaction is quenched in potassium solution.50mL saturated salt solutions are added into reaction solution, extracts (50mL × 2) with dichloromethane, merges organic Phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure, and obtaining 2- pyrimidine -2-bases-thiazole, simultaneously [4,5-c] pyridine -5- is aoxidized Object crude product, yellow solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (pyrimidine -2-base)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 8mL POCl₃, Flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, be extracted with ethyl acetate (50mL × 3), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain for The chloro- 2- of 4- (pyrimidine -2-base)-thiazole of faint yellow solid simultaneously [4,5-c] pyridine (109mg, two step yields 52.4%).¹H NMR(400 MHz,CDCl₃) δ 8.98 (d, J=4.9Hz, 2H), 8.39 (d, J=5.4Hz, 1H), 7.86 (d, J=5.4Hz, 1H), 7.46 (t, J=4.9Hz, 1H).

57 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 9.68 (br s, 1H), 8.93 (d, J=4.8Hz, 2H), 8.40 (brs, 1H), 8.25 (d, J= 5.3Hz, 1H), 8.20 (d, J=5.6Hz, 1H), 7.26-7.18 (m, 1H), 6.94 (d, J=5.2Hz, 1H), 3.60-3.42 (m,1H), 3.28-3.21(m,1H),3.11-2.97(m,3H),2.09-1.61(m,4H).ESI-MS m/z：427.00[M+ Na]⁺。

Embodiment 58, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (thiazol-2-yl) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of 4- chloro- 2- (thiazol-2-yl) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously [4,5-c] pyridine (2.0g, 14.79mmol), 2- bromo thiazoles (2.89g, 17.75mmol), Pd(PPh₃)₄(854mg, 0.740mmol), CuI (141mg, 0.740mmol) and Cs₂CO₃(14.4g, 44.37mmol) is dissolved in 40mL DMF, 120 DEG C of stirrings, TLC are monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering reacting liquid, 200mL is added In water and 100mL ethyl acetate to filtrate, detaches organic phase and washed with 100mL, saturated common salt water washing organic phase (100mL × 2) it, is dried over anhydrous sodium sulfate, filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography：Ethyl acetate= 2：1) 2- (thiazol-2-yl)-thiazole simultaneously [4,5-c] pyridine (2.98g, 92%) for faint yellow solid, is obtained.¹H NMR (400MHz,CDCl₃) δ 9.40 (s, 1H), 8.59 (s, 1H), 8.02 (d, J=3.1Hz, 1H), 7.91 (d, J=5.3 Hz, 1H), 7.62 (d, J=3.1Hz, 1H).

Step 2：By 2- (thiazol-2-yl)-thiazole, simultaneously [4,5-c] pyridine (2.98g, 13.607mmol) is dissolved in 50mL dichloros Methane is slowly added to MCPBA (3.188g, 18.476mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 20mL is added Reaction is quenched in 1M solution of potassium carbonate.100mL saturated salt solutions are added into reaction solution, (100 mL × 2) are extracted with dichloromethane, Merge organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, obtain 2- (thiazol-2-yl)-thiazole simultaneously [4,5-c] pyrrole Pyridine -5- oxide crude products, yellow solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (thiazol-2-yl)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 20mL POCl₃, Flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, it is extracted with ethyl acetate (100mL × 3), merges organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain The chloro- 2- of yellow solid powder 4- (thiazol-2-yl)-thiazole simultaneously [4,5-c] pyridine (1.08g, two step yields 38.7%).¹H NMR(400MHz, CDCl₃) δ 8.35 (d, J=5.4Hz, 1H), 8.02 (d, J=3.1Hz, 1H), 7.82 (d, J=5.4Hz, 1H), 7.65 (d, J=3.1Hz, 1H).

58 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD)δ9.76(br s,1H),8.20-8.11(m,2H),8.06-8.01(m,1H),7.92-7.88(m, 1H), 7.48-7.40(m,1H),7.24-7.19(m,1H),3.46-3.33(m,2H),3.25-3.14(m,1H),2.92- 2.83(m,1H), 2.78-2.69(m,1H),2.24-2.14(m,1H),2.06-1.97(m,2H),1.58-1.46(m,1H)。 ESI-MS m/z： 408.13[M-H]^-。

Embodiment 59, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (thiophene -2- bases) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (thiophene -2- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously [4,5-c] pyridine (1.0g, 7.34mmol), 2- bromothiophenes (1436mg, 8.81mmol), Pd (PPh₃)₄(424mg, 0.367mmol), cuprous iodide (70mg, 0.367mmol), cesium carbonate (7174mg, 22.02mmol), DMF (100mL) is sequentially added in 250mL single-necked flasks, and 6h is stirred under 120 DEG C of heating conditions.The reaction was complete for TLC monitorings, cold But to room temperature.It filters, 200ml EA and 100ml H is added in filtrate₂O, layering, water phase are extracted with EA (50mL × 3), are associated with Machine phase is washed, the anhydrous MgSO of organic layer with saturation NaCl solution (100mL × 3)₄It is dry, it filters, revolving removes solvent, residue Pillar layer separation (P:E=3:1) faint yellow solid 2- (thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine (1.2g, 75%), is obtained 。¹H NMR(400MHz,CDCl₃) δ 9.29 (s, 1H), 8.50 (d, J=5.4Hz, 1H), 7.80 (dd, J=5.4,0.7Hz, 1H), 7.70 (dd, J=3.7,1.1Hz, 1H), 7.57 (dd, J=5.0,1.0Hz, 1H), 7.16 (dd, J=5.0,3.8Hz, 1H).ESI-MS m/z：219.09[M+H]⁺。

Step 2：By 2- (thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine (1.2g, 5.5mmol), DCM (55mL) and MCPBA (1329mg, 7.7mmol) is put into 250mL single-necked flasks successively, is stirred overnight at room temperature, 30%NaOH is slowly added dropwise Liquid, filtering, filtrate layered, organic phase anhydrous Na₂SO₄Dry, filtering, revolving removes solvent, obtains class greenish yellow solid 2- (thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine -5- oxides.Directly throw the next step.

Step 3：By 2- (thiophene -2- bases)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 20mL POCl₃, Flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, it is extracted with ethyl acetate (100mL × 3), merges organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain The chloro- 2- of faint yellow solid powder 4- (thiophene -2- bases) thiazole simultaneously [4,5-c] pyridine (486mg, two step yields 35.0%).¹H NMR(400 MHz,CDCl₃) δ 8.28 (d, J=5.4Hz, 1H), 7.74-7.73 (m, 2H), 7.60 (dd, J=5.0,0.9Hz, 1H), 7.17 (dd, J=4.9,3.8Hz, 1H).ESI-MS m/z：274.91[M+Na]⁺。

59 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD)δ9.77(s,1H),8.18-8.13(m,1H),8.09-8.04(m,1H),7.78-7.70(m, 2H), 7.39-7.34(m,1H),7.25-7.16(m,2H),3.24-3.13(m,1H),2.94-2.76(m,2H),2.28- 2.196(m,1H), 2.08-1.95(m,2H),1.90-1.87(m,1H),1.67-1.57(m,2H).ESI-MS m/z： 409.12[M+H]⁺。

Embodiment 60, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (4- aminomethyl phenyls) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (4- aminomethyl phenyls) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously [4,5-c] pyridine (460mg, 11.01mmol), 4- methyl iodobenzene (883mg, 4.05mmol)、 Pd(PPh₃)₄(195mg, 0.169mmol), CuI (32mg, 0.169mmol) and Cs₂CO₃(3.3mg, It 10.14mmol) is dissolved in 20mL DMF, 120 DEG C of stirrings, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering is anti- Liquid is answered, is added in 100mL water and 50mL ethyl acetate to filtrate, organic phase is detached and is washed with 50mL, saturated common salt water washing Organic phase (50mL × 2), is dried over anhydrous sodium sulfate, and filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography： Ethyl acetate=3：1) white solid 2- (4- aminomethyl phenyls) thiazole simultaneously [4,5-c] pyridine (550mg, 72%), is obtained.

Step 2：By 2- (4- aminomethyl phenyls) thiazole, simultaneously [4,5-c] pyridine (550mg, 2.43mmol) is dissolved in 15mL dichloromethanes Alkane is slowly added to MCPBA (630mg, 3.65mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 10mL 1M potassium carbonate is added Reaction is quenched in solution.50mL saturated salt solutions are added into reaction solution, extracts (50mL × 2) with dichloromethane, merges organic Phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure, and TLC is isolated and purified, and obtains white solid 2- (4- aminomethyl phenyls) thiophene Simultaneously [4,5-c] pyridine -5- oxides direct plunge into the next step to azoles without further purification.

Step 3：By 2- (4- aminomethyl phenyls) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, Flow back 5 h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, it is extracted with ethyl acetate (100mL × 3), merges organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain The chloro- 2- of off-white powder 4- (4- aminomethyl phenyls) thiazole simultaneously [4,5-c] pyridine (350mg, 46.3%).ESI-MS m/z： 261.02[M+H]⁺。

(S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (4- aminomethyl phenyls) thiazole simultaneously [4,5-c] pyridine - The preparation of 4- amine

Step 1：By (S) -1- (3- aminopyridine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (134mg, 0.46mmol), simultaneously [4,5-c] pyridine (120mg, 0.46mmol) is dissolved in tetrahydrofuran to the chloro- 2- ρ-tolyl-thiazoles of 4-, successively Pd is added₂(dba)₃(13mg, 0.014mmol), Xantphos (16mg, 0.028mmol) and t-BuOK (77mg, 0.69mmol), under nitrogen atmosphere, 80 DEG C of stirrings, TLC are monitored to the reaction was complete.Filtering reacting liquid, it is mixed with methylene chloride/methanol Close liquid (1:1) filter cake is fully washed, filtrate is concentrated under reduced pressure.(dichloromethane is isolated and purified by TLC：Methanol=20:1) it, obtains For (S)-[3'- (2-p- tolyls-thiazole simultaneously [4,5-c] pyridin-4-yl-amine) -3,4,5,6- tetrahydrochysenes-of brown solid 2H- [Isosorbide-5-Nitrae '] double pyridin-3-yls]-t-butyl carbamate (60mg, 25.2%).

Step 2：By (S)-[3'- (2-p- tolyls-thiazole simultaneously [4,5-c] pyridin-4-yl-amine) -3,4,5,6- tetrahydrochysenes - 2H- [Isosorbide-5-Nitrae '] double pyridin-3-yls]-t-butyl carbamate (60mg, 0.12mmol) is dissolved in 4mL dichloromethane, by reaction bulb Be placed in ice bath cooling, 1mL trifluoracetic acids be added, condition of ice bath stirs 20min, is warmed to room temperature that the reaction was continued, TLC detect to The reaction was complete.Reaction solution is concentrated under reduced pressure, 50mL saturated sodium bicarbonate solutions are added in residue, (50mL is extracted with ethyl acetate × 3), washing merges organic phase (50mL × 2), is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure.Thin layer is prepared by TLC It isolates and purifies, obtains 27mg compounds 60, yellow solid, yield 54%.¹H NMR(400MHz,d₆-DMSO)δ9.73 (s, 1H), 8.75 (brs, 1H), 8.19 (d, J=5.2Hz, 1H), 8.12 (d, J=5.6Hz, 1H), 8.02 (d, J=8.0Hz, 2H), 7.56 (d, J=5.6Hz, 1H), 7.42 (d, J=8.1Hz, 2H), 7.14 (d, J=5.2Hz, 1H), 3.24-3.12 (m, 2H), 3.08-2.99(m,1H),2.78-2.70(m,1H),2.64-2.56(m,1H),2.40(s,3H),2.02-1.73(m,3H), 1.40-1.22(m,1H).ESI-MS m/z：417.26[M+H]⁺。

Embodiment 61, thiazole is simultaneously by -2- (4- methoxyphenyls) by (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (4- methoxyphenyls) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously [4,5-c] pyridine (200mg, 1.469mmol), 4- methoxyl groups iodobenzene (413mg, 1.763 mmol)、Pd(PPh₃)₄(86mg, 0.074mmol), CuI (14mg, 0.074mmol) and Cs₂CO₃(1.436mg, It 4.407mmol) is dissolved in 10mL DMF, 120 DEG C of stirrings, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering is anti- Liquid is answered, is added in 100mL water and 50mL ethyl acetate to filtrate, organic phase is detached and is washed with 50mL, saturated common salt water washing Organic phase (50mL × 2), is dried over anhydrous sodium sulfate, and filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography： Ethyl acetate=3：1), obtain for white solid 2- (4- methoxyl groups-phenyl)-thiazole simultaneously [4,5-c] pyridine (249mg, 70%).¹H NMR(400MHz,CDCl₃) δ 9.32 (s, 1H), 8.51 (d, J=4.6Hz, 1H), 8.07 (d, J=8.3Hz, 2H), 7.84 (d, J=4.9Hz, 1H), 7.04 (d, J=8.3Hz, 2H), 3.92 (s, 3H).ESI-MS m/z： 243.16[M+ H]⁺。

Step 2：By 2- (4- methoxyl groups-phenyl)-thiazole, simultaneously [4,5-c] pyridine (225mg, 0.93mmol) is dissolved in 10mL bis- Chloromethanes is slowly added to MCPBA (224mg, 1.3mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 10mL 1M carbon is added Reaction is quenched in sour potassium solution.50mL saturated salt solutions are added into reaction solution, extracts (50 mL × 2) with dichloromethane, is associated with Machine phase, is dried over anhydrous sodium sulfate, and filters and is concentrated under reduced pressure, and obtains 2- (4- methoxyl groups-phenyl)-thiazole simultaneously [4,5-c] pyrrole Pyridine -5- oxide crude products.

Step 3：By 2- (4- methoxyl groups-phenyl)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (100mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and depressurize dense Contracting obtains the chloro- 2- of 4- (4- methoxyl groups-phenyl)-thiazole simultaneously [4,5-c] pyridine (136mg, 52.8%) for white solid.¹H NMR(400 MHz,CDCl₃) δ 8.28 (d, J=5.4Hz, 1H), 8.10 (d, J=9.9Hz, 1H), 7.77 (d, J=5.4Hz, 1H), 7.04 (d, J=9.9Hz, 1H), 3.92 (s, 3H) .ESI-MS m/z：298.98[M+Na]⁺。

61 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,d₆- DMSO) δ 9.66 (s, 1H), 8.17 (d, J=5.4Hz, 1H), 8.05-8.02 (m, 3H), 7.38 (d, J =5.6 Hz, 1H), 7.19 (d, J=5.4Hz, 1H), 7.12-7.08 (m, 2H), 3.91 (s, 3H), 3.51-3.41 (m, 2H), 3.26-3.15 (m,1H),2.94-2.81(m,2H),2.23-2.12(m,1H),2.04-1.87(m,2H),1.66-1.52(m, 1H).ESI-MS m/z：433.13[M+H]⁺。

Embodiment 62,2- phenyl-N- (4- (piperidin-1-yl) pyridin-3-yl) thiazole simultaneously [4,5-c] pyridine -4- amine

The preparation of 4- (piperidin-1-yl) -3- aminopyridines

Step 1 prepares 3- nitros -4- (piperidin-1-yl) pyridine

By the chloro- 3- nitropyridines (1g, 6.31mmol) of 4-, piperidines (536mg, 6.31mmol) and DIPEA (812mg, 6.28 Mmol it) is dissolved in 25mL methanol, 5h is stirred at room temperature, TLC monitoring reactions finish.Reaction solution is poured into water, is extracted with ethyl acetate It takes, merges organic phase, organic phase is washed with saturated sodium-chloride water solution, through anhydrous MgSO₄It is dry, it filters organic phase and depressurizes dense Contracting, obtain for yellow oil 3- nitros -4- (piperidin-1-yl) pyridine (1.304g, it is nearly 100%).¹H NMR (400MHz, CDCl₃) δ 8.79 (s, 1H), 8.30 (d, J=6.4Hz, 1H), 6.84 (d, J=6.0Hz, 1H), 3.23-3.16 (m, 4H), 1.76-1.64(m,6H).ESI-MS m/z：208.2[M+H]⁺。

Step 2 prepares 4- (- 1 base of piperidines) -3- aminopyridines

By 3- nitros -4- (piperidin-1-yl) pyridine (1.3g, 6.27mmol), iron powder (2.822g, 50.4mmol) and chlorination Reaction bulb is added in ammonium (2.022g, 37.8mmol), adds 15mL EtOH and 3mL H₂O, 90 DEG C are refluxed overnight, TLC monitorings Reaction finishes.Filtering reacting liquid removes iron powder, and saturation NaHCO is added into filtrate₃Solution is extracted with ethyl acetate, and is associated with Machine phase, organic phase is washed with water 2 times, through anhydrous MgSO₄It is dry, it filters organic phase and is concentrated under reduced pressure.Residue passes through silica gel column chromatography Column method isolates and purifies (dichloromethane:Methanol=15:1,2% ammonium hydroxide is added), obtain the 4- (piperidines -1 for brown oil liquid Base) -3- aminopyridines (799mg, 72%).¹H NMR(400MHz,CDCl₃) δ 8.00 (s, 1H), 7.94 (d, J=5.2 Hz, 1H), 6.77 (d, J=5.2Hz, 1H), 3.71 (brs, 2H), 2.91 (t, J=5.0Hz, 4H), 1.73-1.66 (m, 4H), 1.62-1.57(m,2H)。ESI-MS m/z:177.7[M+H]⁺。

62 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃)δ10.12(s,1H),8.60(s,1H),8.44-8.41(m,1H),8.14-8.04(m,3H), 7.58-7.53 (m, 3H), 7.24 (d, J=5.6Hz, 1H), 7.09 (d, J=5.6Hz, 1H), 3.15-3.01 (m, 4H), 1.99-1.78(m,4H), 1.79-1.65(m,2H)。ESI-MS m/z:388.3[M+H]⁺。

Embodiment 63, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (2- acetyl thiophene -5- bases) thiophene Azoles simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (2- acetyl thiophene -5- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By 2- (2- acetyl thiophene -5- bases) thiazole, simultaneously [4,5-c] pyridine (190mg, 0.73mmol) is dissolved in 10mL dichloromethane is slowly added to MCPBA (176mg, 1.02mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 5mL 1M solution of potassium carbonate.Into reaction solution be added 50mL saturated salt solutions, with dichloromethane extraction (50mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (2- acetyl thiophene -5- bases) thiazole And [4,5-c] pyridine -5- oxide crude products, it does not purify, directly reacts in next step.

Step 2：By 2- (2- acetyl thiophene -5- bases) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 5mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (100mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and depressurize dense Contracting obtains the chloro- 2- of 4- (2- acetyl thiophene -5- bases) thiazole simultaneously [4,5-c] pyridine (85mg, 39.5%) for yellow solid 。¹H NMR (400MHz,CDCl₃) δ 8.35 (d, J=5.4Hz, 1H), 7.79 (d, J=5.4Hz, 1H), 7.77 (d, J= 4.0Hz, 1H), 7.73 (d, J=4.0Hz, 1H), 2.65 (s, 3H).

63 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.77 (s, 1H), 8.18 (d, J=5.3Hz, 1H), 8.14 (d, J=5.7Hz, 1H), 7.86 (d, J=4.0Hz, 1H), 7.75 (d, J=4.0Hz, 1H), 7.42 (d, J=5.6Hz, 1H), 7.21 (d, J=5.4Hz, 1H), 3.45-3.36 (m,1H),3.33(s,3H),3.26-3.17(m,1H),2.87-2.68(m,2H),2.27-2.17(m,1H), 2.12-1.96(m,2H), 1.57-1.46(m,1H),1.36-1.26(m,1H).ESI-MS m/z：451.27[M+H]⁺。

Embodiment 64, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (1- methyl-1 H- pyrazoles -4- bases) Thiazole simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (1- methyl-1 H- pyrazoles -4- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By 3- amino -4- mercaptopyridines (1.071g, 8.5mmol) and 1- methyl-1 H- pyrazoles -4- formic acid (2.144g, 17mmol) is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, adds Enter saturated sodium bicarbonate solution and reaction is quenched.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, through anhydrous Sodium sulphate is dried, and is filtered and is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1), obtain for 2- (1- methyl-1 H- pyrazoles -4- bases)-thiazole of yellow solid simultaneously [4,5-c] pyridine (483mg, 26.3%).

Step 2：By 2- (1- methyl-1 H- pyrazoles -4- bases), simultaneously [4,5-c] pyridine (483mg, 2.2mmol) is dissolved in-thiazole 30mL dichloromethane is slowly added to MCPBA (535mg, 3.1mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 10mL 1M solution of potassium carbonate.Into reaction solution be added 50mL saturated salt solutions, with dichloromethane extraction (50 mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (1- methyl-1 H- pyrazoles -4- bases)-thiophene Azoles simultaneously [4,5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (1- methyl-1 H- pyrazoles -4- bases), simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in-thiazole 8mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added PH is adjusted to neutrality, is extracted with ethyl acetate (50mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, filters and depressurize Concentration, obtain for faint yellow solid the chloro- 2- of 4- (1- methyl-1 H- pyrazoles -4- bases)-thiazole simultaneously [4,5-c] pyridine (328mg, Two step yields 59.6%).

64 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.84 (s, 1H), 8.17 (d, J=5.2Hz, 1H), 8.09 (d, J=5.6Hz, 1H), 8.03 (s, 1H), 7.99 (s, 1H), 7.23 (d, J=5.6Hz, 1H), 6.97 (d, J=5.3Hz, 1H), 4.02 (s, 3H), 3.37-3.29 (m,1H), 3.29-3.18(m,1H),3.06-2.98(m,1H),2.92-2.86(m,1H),2.84-2.76(m,1H),2.07- 1.93(m,2H), 1.92-1.78(m,1H),1.66-1.54(m,1H).ESI-MS m/z：404.91[M-H]^-。

Implement 65, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (1- methyl-1 H- imidazol-4 yls) thiophene Azoles simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (1- methyl-1 H- imidazol-4 yls) thiazole simultaneously [4,5-c] pyridine

Step 1：By 3- amino -4- mercaptopyridines (252mg, 2mmol) and 1- methyl-1 H- imidazoles -4- formic acid (504mg, It 4mmol) is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and saturated carbon is added Reaction is quenched in sour hydrogen sodium solution.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, dry through anhydrous sodium sulfate It is dry, it filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) it, obtains as yellow solid 2- (1- methyl-1 H- imidazol-4 yls)-thiazole simultaneously [4,5-c] pyridine (225mg, 52%).¹H NMR(400MHz, CDCl₃)δ 9.28 (s, 1H), 8.50 (d, J=5.4Hz, 1H), 7.87 (d, J=5.4Hz, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 3.84(s,3H)。

Step 2：By 2- (1- methyl-1 H- imidazol-4 yls)-thiazole, simultaneously [4,5-c] pyridine (225mg, 1mmol) is dissolved in 10mL dichloromethane is slowly added to MCPBA (251mg, 1.4mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 5mL 1M solution of potassium carbonate.Into reaction solution be added 50mL saturated salt solutions, with dichloromethane extraction (50 mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (1- methyl-1 H- imidazol-4 yls)-thiophene Azoles simultaneously [4,5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (1- methyl-1 H- imidazol-4 yls)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 8mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added PH is adjusted to neutrality, is extracted with ethyl acetate (50mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, filters and depressurize Concentration, obtain for faint yellow solid the chloro- 2- of 4- (1- methyl-1 H- imidazol-4 yls)-thiazole simultaneously [4,5-c] pyridine (130mg, Two step yields 52%).

65 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.62 (s, 1H), 8.17 (d, J=5.4Hz, 1H), 8.05 (d, J=5.6Hz, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.42 (dd, J=5.7,1.4Hz, 1H), 7.19 (d, J=5.4Hz, 1H), 3.88 (s, 3H), 3.40- 3.35(m, 2H),3.22-3.13(m,1H),3.01-2.92(m,1H),2.91-2.82(m,1H),2.15-1.97(m,2H), 1.95-1.83(m, 1H),1.66-1.54(m,1H).ESI-MS m/z：407.10[M+H]⁺。

Embodiment 66, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (1- methyl-1 H- imidazoles -5- bases) Thiazole simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (1- methyl-1 H- imidazoles -5- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By 3- amino -4- mercaptopyridines (1.0g, 7.9mmol) and 1- methyl-1 H- imidazoles -5- formic acid (2.0g, 15.8 mmol) it is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, is added full Reaction is quenched with sodium bicarbonate solution.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, through anhydrous slufuric acid Sodium is dried, and is filtered and is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) it, obtains consolidating for yellow 2- (1- methyl-1 H- imidazoles -5- bases)-thiazole of body simultaneously [4,5-c] pyridine (520mg, 30.5%).

Step 3：By 2- (1- methyl-1 H- imidazoles -5- bases), simultaneously [4,5-c] pyridine (520mg, 2.4mmol) is dissolved in-thiazole 30mL dichloromethane is slowly added to MCPBA (582mg, 3.4mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 10mL 1M solution of potassium carbonate.100mL saturated salt solutions are added into reaction solution, (100mL is extracted with dichloromethane × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (1- methyl-1 H- imidazoles -5- bases) - Thiazole simultaneously [4,5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 4：By 2- (1- methyl-1 H- imidazoles -5- bases), simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in-thiazole 8mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added PH is adjusted to neutrality, is extracted with ethyl acetate (100mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, filters and depressurize Concentration, obtain for yellow solid the chloro- 2- of 4- (1- methyl-1 H- imidazoles -5- bases)-thiazole simultaneously [4,5-c] pyridine (331mg, two Walk yield 55%).

66 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.51 (s, 1H), 8.18 (d, J=5.4Hz, 1H), 8.09 (d, J=5.7Hz, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.43 (d, J=5.7Hz, 1H), 7.19 (d, J=5.4Hz, 1H), 4.20 (s, 3H), 3.46-3.38 (m,1H), 3.28-3.18(m,1H),3.13-3.03(m,1H),2.87-2.77(m,1H),2.69-2.60(m,1H),2.12- 2.01(m,1H), 1.92-1.84(m,1H),1.76-1.65(m,1H),1.45-1.34(m,1H).ESI-MS m/z：405.21 [M-H]^-。

Embodiment 67, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (pyrimidine -5- bases) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (pyrimidine -5- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously [4,5-c] pyridine (280mg, 2mmol), 5- Bromopyrimidines (392mg, 2.4mmol), Pd (PPh₃)₄(116mg, 0.1mmol), CuI (19mg, 0.1mmol) and Cs₂CO₃(1.965g, 6mmol) is dissolved in 10mL DMF, 120 DEG C of stirrings, TLC are monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering reacting liquid, 100mL water and 50mL is added In ethyl acetate to filtrate, detaches organic phase and washed with 50mL, saturated common salt water washing organic phase (50 mL × 2), through anhydrous Sodium sulphate is dried, and is filtered and is concentrated under reduced pressure.(dichloromethane is isolated and purified by column chromatography：Methanol=20：1) it, obtains being shallow Yellow solid 2- (pyrimidine -5- bases)-thiazole simultaneously [4,5-c] pyridine (349mg, 81.5%).

Step 2：By 2- (pyrimidine -5- bases)-thiazole, simultaneously [4,5-c] pyridine (349mg, 1.6mmol) is dissolved in 10mL dichloromethanes Alkane is slowly added to MCPBA (394mg, 2.3mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 5mL 1M potassium carbonate is added Reaction is quenched in solution.50mL saturated salt solutions are added into reaction solution, extracts (50mL × 2) with dichloromethane, merges organic Phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure, and 2- (pyrimidine -5- bases)-thiazole simultaneously [4,5-c] pyridine -5- oxygen is obtained Compound crude product, yellow solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (pyrimidine -5- bases)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 8mL POCl₃, Flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, be extracted with ethyl acetate (50mL × 3), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain for The chloro- 2- of 4- (pyrimidine -5- bases)-thiazole of light yellow solid simultaneously [4,5-c] pyridine (122mg, two step yields 39.3%).

67 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.60 (s, 1H), 9.46 (s, 2H), 9.32 (s, 1H), 8.18 (d, J=5.4Hz, 1H), 8.14 (d, J=5.7Hz, 1H), 7.49 (d, J=5.7Hz, 1H), 7.20 (d, J=5.4Hz, 1H), 3.44-3.36 (m, 1H), 3.28-3.20(m, 1H),3.19-3.11(m,1H),2.88-2.79(m,1H),2.73-2.64(m,1H),2.15-2.06(m, 1H),1.98-1.79(m, 2H),1.49-1.38(m,1H).ESI-MS m/z：404.94[M+H]⁺。

Embodiment 68, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (thiazole-4-yl) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of 4- chloro- 2- (thiazole-4-yl) thiazole simultaneously [4,5-c] pyridine

Step 1：By 3- amino -4- mercaptopyridines (730mg, 5.8mmol) and 4-thiazolecarboxylic acid (1.5g, 11.6mmol) It is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and saturated sodium bicarbonate is added Reaction is quenched in solution.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, and filters And it is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) 2- (thiophenes for brown solid, are obtained Azoles -4- bases)-thiazole simultaneously [4,5-c] pyridine (600mg, 47.2%).

Step 2：By 2- (thiazole-4-yl)-thiazole, simultaneously [4,5-c] pyridine (600mg, 2.74mmol) is dissolved in 40mL dichloromethanes Alkane is slowly added to MCPBA (662mg, 3.84mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 10mL 1M potassium carbonate is added Reaction is quenched in solution.50mL saturated salt solutions are added into reaction solution, extracts (50mL × 2) with dichloromethane, merges organic Phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure, and 2- (thiazole-4-yl)-thiazole simultaneously [4,5-c] pyridine -5- oxygen is obtained Compound crude product.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (thiazole-4-yl)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 8mL POCl₃, Flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, be extracted with ethyl acetate (50mL × 3), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain for The chloro- 2- of 4- (thiazole-4-yl)-thiazole of off-white powder simultaneously [4,5-c] pyridine (455mg, two step yields 65.4%).

68 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃)δ9.82(s,1H),8.93(s,1H),8.21(s,1H),8.18-8.07(m,2H),7.31-7.28 (m,1H), 7.03-6.95(m,1H),3.29-3.18(m,2H),2.90-2.77(m,1H),2.76-2.62(m,1H),2.05- 1.78(m,3H), 1.54-1.41(m,1H),1.27-1.14(m,1H).ESI-MS m/z：408.16[M-H]^-。

Embodiment 69, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (thiazole -5- bases) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (thiazole -5- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：3- amino -4- mercaptopyridines (1g, 7.9mmol) and thiazole -5- formic acid (2.04g, 15.8mmol) is molten In polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and it is molten that saturated sodium bicarbonate is added Reaction is quenched in liquid.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, and filtering is simultaneously It is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) it, obtains as off-white powder 2- (thiazoles- 5- yls)-thiazole simultaneously [4,5-c] pyridine (420mg, 24%).¹H NMR(400MHz,CDCl₃)δ9.37(s,1H), 9.01(s, 1H), 8.59 (d, J=5.4Hz, 1H), 8.50 (s, 1H), 7.88 (d, J=5.4Hz, 1H).

Step 2：By 2- (thiazole -5- bases)-thiazole, simultaneously [4,5-c] pyridine (420mg, 2mmol) is dissolved in 40mL dichloromethane, It is slowly added to MCPBA (482mg, 2.8mmol), is stirred at room temperature, TLC is monitored to the reaction was complete, and it is molten that 10mL 1M potassium carbonate is added Reaction is quenched in liquid.50mL saturated salt solutions are added into reaction solution, extracts (50mL × 2) with dichloromethane, merges organic phase, It is dried over anhydrous sodium sulfate, filters and is concentrated under reduced pressure, obtain 2- (thiazole -5- bases)-thiazole simultaneously [4,5-c] pyridine -5- oxides Crude product.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (thiazole -5- bases)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 5mL POCl₃, Flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, be extracted with ethyl acetate (50mL × 3), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain for The chloro- 2- of 4- (thiazole -5- bases)-thiazole of yellow solid simultaneously [4,5-c] pyridine (170mg, two step yields 35%).¹H NMR (400MHz, CDCl₃) δ 9.03 (s, 1H), 8.51 (s, 1H), 8.37 (d, J=5.4Hz, 1H), 7.80 (d, J=5.4Hz, 1H)。

69 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.75 (s, 1H), 9.21 (s, 1H), 8.55 (s, 1H), 8.16 (d, J=5.4Hz, 1H), 8.12 (d, J=5.7Hz, 1H), 7.42 (d, J=5.7Hz, 1H), 7.20 (d, J=5.4Hz, 1H), 3.40-3.30 (m, 2H), 3.22-3.14(m, 1H),2.90-2.80(m,1H),2.74-2.65(m,1H),2.22-2.13(m,1H),2.01-1.94(m, 2H),1.55-1.43(m, 1H).ESI-MS m/z：408.13[M-H]^-。

Embodiment 70, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (benzo [b] thiene-3-yl) thiophene Azoles simultaneously [4,5-c] pyridine -4- amine H

The preparation of the chloro- 2- of 4- (benzo [b] thiene-3-yl) thiazole simultaneously [4,5-c] pyridine

Step 1:In the tube sealing of 50ml, thiazole simultaneously [4,5-c] pyridine (100mg, 0.734mmol) is added, 3- bromobenzenes are simultaneously [b] thiophene (188mg, 0.881mmol), cesium carbonate (717mg, 2.2mmol), cuprous iodide (7mg, 0.0367mmol) and four (triphenylphosphine) palladium (42mg, 0.0367mmol) after addition, is dissolved, nitrogen protection, tube sealing with the DMF of 8ml, until Heating stirring is reacted in 120 DEG C of oil bath pan, and after 14h, the reaction was complete for TLC detections, stops reaction.Post-processing：Water is added, It is extracted with ethyl acetate, organic phase uses water backwash, organic phase to be spin-dried for again, and residue purifies to obtain yellowish toner through preparing lamellae 2- (benzo [b] thiene-3-yl) thiazole of last shape solid simultaneously [4,5-c] pyridine (67mg, 34%).¹H NMR (400MHz, CDCl₃) δ 9.42 (s, 1H), 9.01 (d, J=8.2Hz, 1H), 8.55 (d, J=5.2Hz, 1H), 8.17 (s, 1H), 7.94 (d, J=8.1Hz, 1H), 7.87 (d, J=5.3Hz, 1H), 7.63-7.58 (m, 1H), 7.52-7.46 (m, 1H).ESI-MS m/z： 269.10[M+H]⁺。

Step 2:By 2- (benzo [b] thiene-3-yl) thiazole, simultaneously [4,5-c] pyridine (680mg, 2.53mmol) is dissolved in 20mL dichloromethane is slowly added to MCPBA (595mg, 3.45mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 10mL 1M solution of potassium carbonate.Into reaction solution be added 50mL saturated salt solutions, with dichloromethane extraction (50 mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (benzo [b] thiophenes for yellow solid Pheno -3- bases) thiazole simultaneously [4,5-c] pyridine -5- oxides (480mg, 66%).ESI-MS m/z：302.83[M+H]⁺。

Step 3：By 2- (benzo [b] thiene-3-yl) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 5mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (50mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- (benzo [b] thiene-3-yl) thiazole simultaneously [4,5-c] pyridine (120mg, 20%) for yellow solid.¹H NMR(400 MHz,CDCl₃) δ 9.04 (d, J=8.2Hz, 1H), 8.33 (d, J=5.4Hz, 1H), 8.21 (s, 1H), 7.94 (d, J=8.1Hz, 1H), 7.80 (d, J=5.4Hz, 1H), 7.66-7.58 (m, 1H), 7.54-7.48 (m, 1H).ESI-MS m/z： 302.83 [M+H]⁺。

70 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 10.04 (s, 1H), 9.04 (d, J=7.2Hz, 1H), 8.61 (brs, 1H), 8.28 (d, J= 5.2Hz, 1H), 8.22 (d, J=5.6Hz, 1H), 8.14 (s, 1H), 7.97 (d, J=7.2Hz, 1H), 7.60-7.49 (m, 2H), 7.32 (d, J=5.6Hz, 1H), 7.04 (d, J=5.2Hz, 1H), 3.36-3.16 (m, 3H), 2.78-2.66 (m, 1H), 2.59-2.51(m,1H), 2.07-1.86(m,3H),1.39-1.30(m,1H)。

Embodiment 71, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- cyclopenta thiazole simultaneously [4,5-c] pyrrole Pyridine -4- amine

The preparation of 4- chloro- 2- (cyclopenta) thiazole simultaneously [4,5-c] pyridine

Step 1：By 3- amino -4- mercaptopyridines (582mg, 4.62mmol) and cyclopenta formic acid (1.05g, 9.24mmol) It is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and saturated sodium bicarbonate is added Reaction is quenched in solution.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, and filters And it is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) 2- (rings penta for brown solid, are obtained Base)-thiazole simultaneously [4,5-c] pyridine (880mg, 80%).

Step 2：By 2- (cyclopenta)-thiazole, simultaneously [4,5-c] pyridine (880mg, 4.31mmol) is dissolved in 40mL dichloromethane, It is slowly added to MCPBA (482mg, 6.03mmol), is stirred at room temperature, TLC is monitored to the reaction was complete, and it is molten that 10mL 1M potassium carbonate is added Reaction is quenched in liquid.50mL saturated salt solutions are added into reaction solution, extracts (50mL × 2) with dichloromethane, merges organic phase, It is dried over anhydrous sodium sulfate, filters and is concentrated under reduced pressure, obtaining 2- (cyclopenta)-thiazole, simultaneously [4,5-c] pyridine -5- oxides are thick Product.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (cyclopenta)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 5mL POCl₃, reflux 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, addition saturated sodium bicarbonate adjusting pH to neutrality, It is extracted with ethyl acetate (50mL × 3), merges organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain as Huang The chloro- 2- of 4- (cyclopenta)-thiazole of color grease simultaneously [4,5-c] pyridine (450mg, two step yields 43.9%).¹H NMR (400MHz, CDCl₃) δ 8.25 (d, J=5.4Hz, 1H), 7.71 (d, J=5.4Hz, 1H), 3.71-3.56 (m, 1H), 2.38- 2.19(m,2H), 1.98-1.82(m,4H),1.79-1.68(m,2H).ESI-MS m/z：238.65[M+H]⁺。

71 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 9.84 (s, 1H), 8.15 (d, J=5.3Hz, 1H), 8.09 (d, J=5.6Hz, 1H), 7.23 (d, J=5.6Hz, 1H), 6.97 (d, J=5.3Hz, 1H), 3.60-3.50 (m, 1H), 3.34-3.17 (m, 2H), 3.10-2.99 (m, 1H), 2.88-2.69 (m, 2H), 2.33-2.20 (m, 2H), 2.07-1.72 (m, 9H), 1.58-1.44 (m, 1H).ESI- MS m/z：417.10 [M+Na]⁺。

Embodiment 72, -2- phenyl thiazoles are simultaneously [4,5-c] by (S)-N- (2- (3- amino piperidine -1- bases) -5- methoxyphenyls) Pyridine -4- amine

(S) preparation of -1- (2- amino-4-methoxyls phenyl) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

Step 1 prepares (S) -1- (2- nitro -4- methoxyphenyls) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

By the fluoro- 4- methoxyl groups -3- nitrobenzenes (3g, 16mmol) of 1-, (S) -3- t-butyloxycarbonyls piperidines (3.84g, It 19.2mmol) is sequentially added in 40ml methanol with triethylamine (3.23g, 32mmol), 130 DEG C of tube sealing reactions, TLC detections are difficult to The reaction was complete.Evaporated under reduced pressure reaction solution, crude product use column chromatography (petroleum ether：Ethyl acetate=10：1) it, obtains consolidating for yellow (S) -1- (2- nitro -4- methoxyphenyls) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (487mg, 8.7%) of body.

Step 2 prepares (S) -1- (2- amino-4-methoxyls phenyl) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

By (S) -1- (2- nitro -4- methoxyphenyls) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (487mg, 1.38mmol), iron powder (620mg, 11.08mmol) and NH₄Cl (445mg, 8.31mmol) is dissolved in 20mL methanol, and 2mL is added Water reacts at 60 DEG C, and TLC detection reactions are completed.Evaporated under reduced pressure reaction solution, crude product use column chromatography (petroleum ether：Acetic acid second Ester=5：1) (S) -1- (2- amino-4-methoxyls phenyl) piperidines -3- bases-tertiary fourth of amidocarbonic acid for brown oil, is obtained Base ester (255mg, 55.8%).

72 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,d₆- DMSO) δ 9.73 (s, 1H), 8.49 (d, J=2.8Hz, 1H), 8.19-8.09 (m, 3H), 7.65-7.56 (m, 3H), 7.52 (d, J=5.6Hz, 1H), 7.14 (d, J=8.6Hz, 1H), 6.51 (dd, J=8.6,2.9Hz, 1H), 3.75 (s,3H), 3.10-3.06(m,1H),2.98-2.93(m,1H),2.83-2.74(m,1H),2.66-2.56(m,1H),2.44- 2.39(m,1H), 2.00-1.92(m,1H),1.90-1.79(m,2H),1.29-1.16(m,1H).ESI-MS m/z：432.21 [M+H]⁺。

Embodiment 73, (S)-N- (2- (3- amino piperidine -1- bases) -5- fluorophenyls) -2- phenyl thiazoles simultaneously [4,5-c] pyrrole Pyridine -4- amine

(S) preparation of -1- (2- amino -4- fluorophenyls) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

Step 1：By the fluoro- 2- nitrobenzenes (3g, 18.86mmol) of Isosorbide-5-Nitrae-two, (S) -3- t-butyloxycarbonyl piperidines (5.28g, 26.4mmol) is sequentially added with triethylamine (3.8g, 37.7mmol) in 40ml methanol, 130 DEG C of tube sealing reactions, TLC The reaction was complete for detection.Evaporated under reduced pressure reaction solution, crude product use column chromatography (petroleum ether：Ethyl acetate=10：1) it, obtains as Huang (S)-[1- (the fluoro- 2- nitrobenzophenones of 4-)-piperidines -3- bases]-amidocarbonic acid tertiary butyl ester (3.538g, 55.3%) of color solid.

Step 2：By (S)-[1- (the fluoro- 2- nitrobenzophenones of 4-)-piperidines -3- bases]-amidocarbonic acid tertiary butyl ester (3.538g, It 10.4mmol) is dissolved in 40mL methanol, the Pd/C of 15% mass fraction is added, is passed through hydrogen, reacts at room temperature, TLC detections are anti- It should complete.Filtering reacting liquid, with methylene chloride/methanol mixed liquor (1:1) filter cake is fully washed, filtrate is concentrated under reduced pressure, crude product is used Column chromatography for separation (petroleum ether：Ethyl acetate=4：1) (S) -1- (2- amino -4- fluorophenyls) piperazine for brown oil, is obtained Pyridine -3- bases-amidocarbonic acid tertiary butyl ester (3.10g, 96%).¹H NMR(400MHz,CDCl₃) δ 6.88 (dd, J=8.6, 5.8Hz, 1H),6.47-6.35(m,2H),4.79(brs,1H),3.93-3.78(m,1H),3.22-3.04(m,1H),2.94- 2.44(m,3H), 2.01-1.62(m,3H),1.46(s,10H)。

73 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 9.68 (s, 1H), 8.78 (dd, J=11.6,3.0Hz, 1H), 8.18 (d, J=5.6Hz, 1H), 8.12-8.09 (m, 2H), 7.56-7.52 (m, 3H), 7.27 (d, J=5.5Hz, 1H), 7.12 (dd, J=8.6,5.8Hz, 1H), 6.66 (td, J=8.3,3.0Hz, 1H), 3.34-3.28 (m, 1H), 3.18-3.14 (m, 1H), 3.03-2.92 (m, 1H), 2.80-2.69(m, 1H),2.65-2.54(m,1H),2.15-1.94(m,3H),1.50-1.33(m,1H).ESI-MS m/z： 420.21[M+H]⁺。

Embodiment 74, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (2- (trifluoromethyl) phenyl) thiophene Azoles simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (2- (trifluoromethyl) phenyl)-thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously the iodo- 2- trifluoromethylbenzenes of [4,5-c] pyridine (400mg, 2.93mmol), 1- (960mg, 3.52 mmol)、Pd(PPh₃)₄(170mg, 0.146mmol), CuI (30mg, 0.146mmol) and Cs₂CO₃(2.86g, It 8.79mmol) is dissolved in 20mL DMF, 120 DEG C of stirrings, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering is anti- Liquid is answered, is added in 100mL water and 50mL ethyl acetate to filtrate, organic phase is detached and is washed with 25mL, saturated common salt water washing Organic phase (25mL × 2), is dried over anhydrous sodium sulfate, and filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography： Ethyl acetate=3：1) 2- (2- trifluoromethyls) thiazole simultaneously [4,5-c] pyridine for white solid powder, is obtained (636mg, 77%).¹H NMR(400MHz,CDCl₃) δ 9.43 (s, 1H), 8.59 (d, J=5.5Hz, 1H), 7.96-7.82 (m, 2H),7.73-7.67(m,3H)。

Step 2：By 2- (2- (trifluoromethyl) phenyl)-thiazole, simultaneously [4,5-c] pyridine (636mg, 2.271mmol) is dissolved in 10mL dichloromethane is slowly added to MCPBA (532mg, 3.084mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 10mL 1M solution of potassium carbonate.Into reaction solution be added 25mL saturated salt solutions, with dichloromethane extraction (25mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (2- (trifluoromethyl) phenyl)-thiazole And [4,5-c] pyridine -5- oxide crude products, white solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (2- (trifluoromethyl) phenyl)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, flow back 2h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (25mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- (2- (trifluoromethyl) phenyl)-thiazole simultaneously [4,5-c] pyridine (313mg, 50%) for yellow solid.¹H NMR (400MHz,CDCl₃) δ 8.38 (d, J=5.4Hz, 1H), 7.88-7.86 (m, 1H), 7.83 (d, J=5.4Hz, 1H), 7.75-7.72(m,1H),7.70-7.68(m,2H).ESI-MS m/z：315.02[M+H]⁺。

74 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.ESI- MS m/z：471.3[M+H]⁺。

Embodiment 75, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (4- (trifluoromethyl) phenyl) thiophene Azoles simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (4- (trifluoromethyl) phenyl) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously the iodo- 4- trifluoromethylbenzenes of [4,5-c] pyridine (200mg, 1.47mmol), 1- (480mg, 1.76 mmol)、Pd(PPh₃)₄(86mg, 0.074mmol), CuI (14mg, 0.074mmol) and Cs₂CO₃(1.436g, It 4.407mmol) is dissolved in 20mL DMF, 120 DEG C of stirrings, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering is anti- Liquid is answered, is added in 100mL water and 50mL ethyl acetate to filtrate, organic phase is detached and is washed with 25mL, saturated common salt water washing Organic phase (25mL × 2), is dried over anhydrous sodium sulfate, and filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography： Ethyl acetate=3：1) 2- (4- (trifluoromethyl) phenyl) thiazole simultaneously [4,5-c] pyridine for white solid powder, is obtained (295mg, 71.8%).¹H NMR(400MHz,CDCl₃) δ 9.40 (s, 1H), 8.56 (d, J=5.4Hz, 1H), 8.22 (d, J= 5.8Hz, 2H), 7.88 (d, J=5.4Hz, 1H), 7.78 (d, J=8.2Hz, 2H),.ESI-MS m/z：281.05 [M+H]⁺。

Step 2：By 2- (4- (trifluoromethyl) phenyl) thiazole, simultaneously [4,5-c] pyridine (225mg, 0.803mmol) is dissolved in 10mL dichloromethane is slowly added to MCPBA (193mg, 1.12mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 10mL 1M solution of potassium carbonate.Into reaction solution be added 25mL saturated salt solutions, with dichloromethane extraction (25 mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtaining 2- (4- (trifluoromethyl) phenyl), thiazole is simultaneously [4,5-c] pyridine -5- oxide crude products, white solid.It does not purify, is directly used in and reacts in next step.

Step 3：By upper step 2- obtained by the reaction (4- (trifluoromethyl) phenyl) thiazole simultaneously [4,5-c] pyridine -5- oxides Crude product is dissolved in 10mL POCl₃, flow back 2h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, it is added full PH is adjusted to neutrality with sodium bicarbonate, is extracted with ethyl acetate (25mL × 3), is merged organic phase, be dried over anhydrous sodium sulfate, It filters and is concentrated under reduced pressure, obtain the chloro- 2- of 4- (4- (trifluoromethyl) phenyl) thiazole simultaneously [4,5-c] pyridine for yellow solid (149mg, 59%).¹H NMR(400MHz,CDCl₃) δ 9.29 (s, 1H), 8.57 (s, 1H), 8.25 (d, J=8.2Hz, 2H), 7.83 (d, J=8.2Hz, 1H).ESI-MS m/z：315.02[M+H]⁺。

75 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CD₃OD) δ 9.61 (s, 1H), 8.25 (d, J=8.2Hz, 2H), 8.15 (d, J=5.4Hz, 1H), 8.05 (d, J=5.7Hz, 1H), 7.86 (d, J=8.2Hz, 2H), 7.39 (d, J=5.7Hz, 1H), 7.16 (d, J=5.4Hz, 1H), 3.48-3.34 (m,2H),3.22-3.14(m,1H),2.86-2.81(m,2H),2.21-2.11(m,1H),2.00-1.84(m, 2H),1.62-1.50 (m,1H).ESI-MS m/z：471.16[M+H]⁺。

Embodiment 76, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (3- (trifluoromethyl) phenyl) thiophene Azoles simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (3- (trifluoromethyl) phenyl) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously the iodo- 3- trifluoromethylbenzenes of [4,5-c] pyridine (400mg, 2.94mmol), 1- (960mg, 3.53 mmol)、Pd(PPh₃)₄(169.8mg, 0.147mmol), CuI (28mg, 0.147mmol) and Cs₂CO₃(2.87g, It 8.82mmol) is dissolved in 20mL DMF, 120 DEG C of stirrings, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering is anti- Liquid is answered, is added in 100mL water and 50mL ethyl acetate to filtrate, organic phase is detached and is washed with 25mL, saturated common salt water washing Organic phase (25mL × 2), is dried over anhydrous sodium sulfate, and filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography： Ethyl acetate=3：1) 2- (3- (trifluoromethyl) phenyl) thiazole simultaneously [4,5-c] pyridine for white solid powder, is obtained (572mg, 69.5%).¹H NMR (400MHz, CDCl3) δ 9.39 (s, 1H), 8.57 (d, J=5.4Hz, 1H), 8.38 (s, 1H), 8.27 (d, J=7.8Hz, 1H), 7.88 (d, J=5.4Hz, 1H), 7.79 (d, J=7.8Hz, 1H), 7.66 (t, J=7.8 Hz,1H).ESI-MS m/z：281.06[M+H]⁺。

Step 2：By 2- (3- (trifluoromethyl) phenyl) thiazole, simultaneously [4,5-c] pyridine (520mg, 1.86mmol) is dissolved in 12mL Dichloromethane is slowly added to MCPBA (435mg, 2.52mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 10mL is added Reaction is quenched in 1M solution of potassium carbonate.25mL saturated salt solutions are added into reaction solution, extracts (25 mL × 2) with dichloromethane, closes And organic phase, it is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, obtain 2- (3- (trifluoromethyl) phenyl) thiazole simultaneously [4,5- C] pyridine -5- oxide crude products, white solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (3- (trifluoromethyl) phenyl) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, flow back 2h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added PH is adjusted to neutrality, is extracted with ethyl acetate (25mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, filters and depressurize Concentration, obtain for white solid powder the chloro- 2- of 4- (3- (trifluoromethyl) phenyl) thiazole simultaneously [4,5-c] pyridine (230mg, 46%).¹H NMR(400MHz,CDCl₃) δ 8.38-8.32 (m, 3H), 7.83-7.81 (m, 2H), 7.68 (t, J=7.9Hz, 1H). ESI-MS m/z：315.07[M+H]⁺。

76 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,d₆- DMSO) δ 9.72 (s, 1H), 8.78 (brs, 1H), 8.49 (s, 1H), 8.33 (d, J=7.8Hz, 1H), 8.20 (d, J=5.2Hz, 1H), 8.16 (d, J=5.6Hz, 1H), 7.97 (d, J=8.0Hz, 1H), 7.85 (t, J=7.8Hz, 1H), 7.60 (d, J=5.6Hz, 1H), 7.14 (d, J=5.2Hz, 1H), 3.29-3.22 (m, 1H), 3.19-3.14 (m, 1H), 3.12-3.03(m,1H), 2.78-2.69(m,1H),2.67-2.60(m,1H),2.02-1.86(m,2H),1.84-1.71(m, 1H),1.45-1.32(m,1H). ESI-MS m/z：471.26[M+H]⁺。

Embodiment 77, (S)-N- (2- (3- amino piperidine -1- bases) -5- (trifluoromethyl) phenyl) -2- phenyl thiazoles simultaneously [4, 5-c] pyridine -4- amine

(S) preparation of -1- (2- amino -4- (trifluoromethyl) phenyl) piperidines -3- bases-amidocarbonic acid tertiary butyl ester

Step 1：By the fluoro- 3- nitros of 4--benzotrifluoride (2g, 9.56mmol), (S) -3- t-butyloxycarbonyl piperidines (2.49g, 12.43mmol) is sequentially added with triethylamine (7.74g, 76.52mmol) in tube sealing, addition 40ml methanol, 130 DEG C Tube sealing reaction, the reaction was complete for TLC detections.Evaporated under reduced pressure reaction solution, obtained residue use column chromatography (petroleum ether：Second Acetoacetic ester=5：1) (S) -1- (2- nitros -4- (trifluoromethyl) phenyl) piperidines -3- bases-amido first for yellow solid, are obtained Sour tertiary butyl ester (3.7g, 99.4%).

Step 2：By (S) -1- (2- nitros -4- (trifluoromethyl) phenyl) piperidines -3- bases-amidocarbonic acid tertiary butyl ester (3.72g, 9.88 mmol), iron powder (4.27g, 76.43mmol) and NH₄Cl (3.07g, 57.32mmol) is dissolved in 60mL methanol In, 2mL water is added, is reacted at 60 DEG C, TLC detection reactions are completed.Evaporated under reduced pressure reaction solution, obtained residue column chromatography Detach (petroleum ether：Ethyl acetate=5：1) (S) -1- (2- amino -4- (trifluoromethyl) phenyl) piperazine for pink solid, is obtained Pyridine -3- bases-amidocarbonic acid tertiary butyl ester (3.4g, 95.8%).

77 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,d₆- DMSO) δ 9.31 (d, J=1.9Hz, 1H), 9.26 (brs, 1H), 8.19 (d, J=5.6Hz, 1H), 8.10-8.06 (m, 2H), 7.54-7.52 (m, 3H), 7.31 (d, J=5.6Hz, 1H), 7.29 (d, J=8.6Hz, 1H), 7.17 (d, J=8.1Hz, 1H), 3.38-3.29 (m, 1H), 3.26-3.19 (m, 1H), 3.10-3.03 (m, 1H), 2.81-2.71 (m, 1H), 2.66-2.56(m,1H),2.16-1.95(m,3H),1.45-1.35(m,1H).ESI-MS m/z：470.27[M+H]⁺。

Embodiment 78, (S)-N- (4- (3- amino piperidine -1- bases)-pyridin-3-yl) -1,6- naphthyridines -5- amine

78 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CD₃OD) δ 9.00 (d, J=3.3Hz, 1H), 8.87 (d, J=8.4Hz, 1H), 8.59 (brs, 1H), 8.23 (d, J=5.6Hz, 1H), 8.07 (brs, 1H), 7.66 (dd, J=8.5,4.4Hz, 1H), 7.28 (brs, 1H), 7.10 (d, J =5.7Hz, 1H), 3.61-3.53 (m, 1H), 3.08-3.00 (m, 1H), 2.94-2.78 (m, 2H), 1.97-1.86 (m, 1H), 1.69-1.59(m, 1H),1.49-1.23(m,3H).ESI-MS m/z：321.41[M+H]⁺。

Embodiment 79, (S)-N- (4- (3- amino piperidine -1- bases)-pyridin-3-yl) pyrido [4,3-b] pyrazine -5- amine

The preparation of the chloro- pyridines of 5- [3,4-b] pyrazine

Step：Chloro- 3, the 4- diamino-pyridines (200mg, 1.4mmol) of 2- are dissolved in 20ml ethyl alcohol, dialdehyde 40% is added Aqueous solution (200mg, 1.4mmol), 75 DEG C of reflux, reacts 12h.TLC detection reactions are completed.Evaporated under reduced pressure, column chromatography for separation, Obtain the chloro- pyridos of white solid powder 5- [3,4-b] pyrazine (210mg, 93%).¹H NMR(400MHz,CDCl₃) δ9.08 (dd, J=12.9,1.7Hz, 2H), 8.62 (d, J=5.7Hz, 1H), 7.94 (d, J=5.7Hz, 1H).

79 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CD₃OD) δ 10.04 (s, 1H), 9.45 (brs, 1H), 9.01 (d, J=1.9Hz, 1H), 8.78 (d, J= 1.9Hz, 1H), 8.42 (d, J=6.0Hz, 1H), 8.29 (d, J=5.2Hz, 1H), 7.34 (d, J=6.0Hz, 1H, 1H), 7.02 (dd, J=5.3Hz, 1H), 4.75 (brs, 1H), 3.27-3.21 (m, 2H), 3.16-3.08 (m, 1H), 2.83-2.74 (m,1H),2.63-2.56 (m,1H),2.11-2.01(m,1H),1.99-1.85(m,2H),1.46-1.32(m,1H)。ESI- MS m/z：320.11[M-H]^-。

Embodiment 80,2- phenyl-N- (4- (thiophene -2- bases)-pyridin-3-yl) thiazole simultaneously [4,5-c] pyridine -4- amine

The preparation of 4- (thiophene -2- bases) pyridine -3- amine

Step 1:In 25ml bottle with two necks, 2- bromothiophenes (300mg, 1.84mmol) are dissolved in 5ml THF, are placed in -78 DEG C, Nitrogen protection is slowly added to n-BuLi (809 μ L, 2.024mmol) reaction 1h, -78 DEG C of reaction temperature, nitrogen protection after 5min. Connection boric acid pinacol ester (465mg, 1.84mmol) is finally added dropwise and is dissolved in 2.9ml THF mixed solutions, -78 DEG C of reaction temperature, 1h After switch to room temperature, overnight, the reaction was complete for TLC detections for reaction.It is concentrated under reduced pressure, column chromatography (petroleum ether：Ethyl acetate/20:1) it, obtains To white solid powder 2- thienyl boric acid pinacols ester (200mg, 63%).¹H NMR(400MHz, CDCl₃) δ 7.65 (d, J= 3.4Hz, 1H), 7.65 (d, J=4.8Hz, 1H), 7.19 (dd, J=4.7,3.4Hz, 1H), 1.35 (s, 12H).

Step 2：By 2- thienyl boric acid pinacol esters (200mg, 0.95mmol), sodium carbonate (201mg, 1.9mmol), 4- Chloro- 3- nitropyridines (180mg, 1.14mmol), tetra-triphenylphosphine palladium (55mg, 0.047mmol) are dissolved in the 1,4- dioxies of 10ml In six ring solution, reacted overnight at 120 DEG C.It is spin-dried for reaction solution, column chromatography for separation obtains the 3- nitros-for brown oil 4- (thiophene -2- bases)-pyridine (98mg, 50%).¹H NMR(400MHz,CDCl₃) δ 8.92 (s, 1H), 8.72 (d, J=5.2 Hz, 1H), 7.54 (dd, J=5.1,0.9Hz, 1H), 7.50 (d, J=5.2Hz, 1H), 7.27 (dd, J=3.7,0.9Hz, 1H), 7.13 (dd, J=5.0,3.8Hz, 1H).

Step 3：By 3- nitros -4- (thiophene -2- bases)-pyridine (1.7g, 8.25mmol), iron powder (3.687g, 66mmol), Ammonium chloride (2.647g, 49.5mmol) is dissolved in the mixed solvent (the 30ml EtOH+5ml H of second alcohol and water₂O), 90 DEG C next time Overnight, the reaction was complete for rear TLC detections overnight for stream reaction.The NaHCO of saturation is added into reaction solution₃Ethyl acetate is used in combination in solution Extraction merges organic phase and with water backwash, anhydrous MgSO₄Dry filter is spin-dried under filtrate decompression, and residue is through column chromatography column (dichloromethane：Methanol/20:1) it detaches, obtains 4- (thiophene -2- bases) pyridine -3- amine (1.04 g, 72%) for brown solid 。¹H NMR(400MHz,CDCl₃) δ 8.15 (s, 1H), 8.00 (d, J=5.0Hz, 1H), 7.41 (dd, J=5.1,0.9Hz, 1H), 7.34 (dd, J=3.6,1.0Hz, 1H), 7.16-7.12 (m, 2H), 4.10 (s, 2H).ESI-MS m/z： 177.11[M+ H]⁺。

80 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 9.98 (s, 1H), 8.47 (brs, 1H), 8.38 (d, J=5.0Hz, 1H), 8.16 (d, J= 5.6Hz, 1H), 8.03-8.00 (m, 2H), 7.57-7.50 (m, 5H), 7.43 (d, J=5.0Hz, 1H), 7.33-7.28 (m, 2H).ESI-MS m/z：387.07[M+H]⁺。

Embodiment 81, thiazole is simultaneously by -2- (3- methoxyphenyls) by (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (3- (methoxyl group) phenyl) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously the iodo- 3- methoxybenzenes of [4,5-c] pyridine (700mg, 5.14mmol), 1- (1.446g, 6.18mmol)、 Pd(PPh₃)₄(297mg, 0.257mmol), CuI (49mg, 0.257mmol) and Cs₂CO₃(5.024g, 40mL DMF 15.42mmol) are dissolved in, 120 DEG C are stirred to react, and TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, mistake Reaction solution is filtered, is added in 100mL water and 50mL ethyl acetate to filtrate, organic phase is detached and is washed with 25mL, saturated salt solution Organic phase (25mL × 2) is washed, is dried over anhydrous sodium sulfate, is filtered and be concentrated under reduced pressure.(stone is isolated and purified by column chromatography Oily ether：Ethyl acetate=3：1) crude product, is obtained, directly reaction next step.

Step 2：By 2- (3- methoxyphenyls) thiazole simultaneously [4,5-c] pyridine crude product theoretical amount (1.245g, It 5.14mmol) is dissolved in 20mL dichloromethane, MCPBA (1.33g, 7.71mmol) is slowly added to, is stirred at room temperature, TLC is monitored to anti- Should be complete, 20mL 1M solution of potassium carbonate is added, reaction is quenched.50mL saturated salt solutions are added into reaction solution, use dichloromethane It extracts (50mL × 2), merges organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain the 2- for white solid (3- (methoxyl group) phenyl) thiazole simultaneously [4,5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (3- (methoxyl group) phenyl) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, flow back 2h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (25mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- (3- (methoxyl group) phenyl) thiazole simultaneously [4,5-c] pyridine (414mg, 29%) for yellow solid.¹H NMR(400 MHz,CDCl₃) δ 8.29 (d, J=5.4Hz, 1H), 7.78 (d, J=5.4Hz, 1H), 7.72-7.64 (m, 2H), 7.42 (t, J=7.9Hz, 1H), 7.09 (ddd, J=8.3,2.6,0.9Hz, 1H), 3.93 (s, 3H).ESI-MS m/z： 277.15[M+H]⁺。

81 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.64 (s, 1H), 8.21 (d, J=5.4Hz, 1H), 8.07 (d, J=5.7Hz, 1H), 7.67- 7.62 (m, 2H), 7.49 (t, J=8.0Hz, 1H), 7.42 (d, J=5.7Hz, 1H), 7.22 (d, J=5.4Hz, 1H), 7.16 (dd, J=8.1,1.8Hz, 1H), 3.93 (s, 3H), 3.58-3.48 (m, 2H), 3.30-3.23 (m, 1H), 3.00-2.86 (m, 2H),2.25-2.16 (m,1H),2.05-1.90(m,2H),1.70-1.59(m,1H).ESI-MS m/z：433.21[M+H]⁺。

Embodiment 82, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) thiazole simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- thiazoles of 4- simultaneously [4,5-c]-pyridine

Step 1：By thiazole, simultaneously [4,5-c] pyridine (800mg, 5.88mmol) is dissolved in 10mL dichloromethane, is slowly added to MCPBA (1.52g, 8.82mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 20mL 1M solution of potassium carbonate is added and is quenched instead It answers.50mL saturated salt solutions are added into reaction solution, extracts (50mL × 2) with dichloromethane, merges organic phase, through anhydrous sulphur The drying of sour sodium, filters and is concentrated under reduced pressure, and obtains thiazole simultaneously [4,5-c] pyridine -5- oxide crude products for white solid.Not Purifying is directly used in and reacts in next step.

Step 2：By thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 15mL POCl₃, flow back 2h.It depressurizes dense Contracting reaction solution is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH to neutrality, uses ethyl acetate It extracts (50mL × 3), merges organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain the 4- for white solid Chloro- thiazole simultaneously [4,5-c] pyridine (507mg, 50.8%).¹H NMR(400MHz,CDCl₃) δ 9.13 (s, 1H), 8.38 (d, J= 5.4Hz, 1H), 7.87 (d, J=5.5Hz, 1H).ESI-MS m/z：171.08[M+H]⁺。

82 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.61 (s, 1H), 9.26 (s, 1H), 8.19 (d, J=5.4Hz, 1H), 8.11 (d, J=5.3Hz, 1H), 7.52 (d, J=5.7Hz, 1H), 7.21 (d, J=5.4Hz, 1H), 3.64-3.58 (m, 1H), 3.49-3.46 (m, 1H), 3.17-3.10 (m,1H),3.06-2.96(m,2H),2.21-2.14(m,1H),2.05-1.96(m,1H),1.94-1.84(m, 1H),1.78-1.70 (m,1H).ESI-MS m/z：349.08[M+Na]⁺。

Embodiment 83, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (2- (methoxyl group) phenyl) thiazole And [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (2- (methoxyl group) phenyl) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously the iodo- 2- methoxybenzenes of [4,5-c] pyridine (400mg, 2.93mmol), 1- (825mg, 3.52mmol)、 Pd(PPh₃)₄(170mg, 0.146mmol), CuI (30mg, 0.146mmol) and Cs₂CO₃(2.86g, It 8.79mmol) is dissolved in 20mL DMF, 120 DEG C of stirrings, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering is anti- Liquid is answered, is added in 100mL water and 50mL ethyl acetate to filtrate, organic phase is detached and is washed with 25mL, saturated common salt water washing Organic phase (25mL × 2), is dried over anhydrous sodium sulfate, and filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography： Ethyl acetate=3：1), obtain white solid powder 2- (2- (methoxyl group) phenyl) thiazole simultaneously [4,5-c] pyridine (619mg, 87.2%).¹H NMR(400MHz,CDCl₃) δ 9.37 (s, 1H), 8.55 (dd, J=7.9,1.6Hz, 1H), 8.49 (d, J= 5.4Hz, 1H), 7.86 (d, J=5.4Hz, 1H), 7.51 (dt, J=8.7,2.6Hz, 1H), 7.16 (t, J=7.3Hz, 1H), 7.09 (d, J=8.3Hz, 1H), 4.08 (s, 3H).ESI-MS m/z：243.10[M+H]⁺。

Step 2：By 2- (2- (methoxyl group) phenyl) thiazole, simultaneously [4,5-c] pyridine (619mg, 2.554mmol) is dissolved in 10mL Dichloromethane is slowly added to MCPBA (599mg, 3.47mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 10mL is added Reaction is quenched in 1M solution of potassium carbonate.25mL saturated salt solutions are added into reaction solution, extracts (25 mL × 2) with dichloromethane, closes And organic phase, it is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, obtain 2- (2- (methoxyl group) phenyl)-thiazole simultaneously [4,5- C] pyridine -5- oxide crude products, white solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (2- (methoxyl group) phenyl)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, flow back 2h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (25mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- (2- (methoxyl group) phenyl)-thiazole simultaneously [4,5-c] pyridine (260mg, 50%) for light yellow solid.

83 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,d⁶- DMSO) δ 9.65 (s, 1H), 8.79 (brs, 1H), 8.53 (dd, J=7.9,1.2Hz, 1H), 8.21 (d, J=5.2Hz, 1H), 8.10 (d, J=5.6Hz, 1H), 7.63-7.56 (m, 2H), 7.35 (d, J=8.4Hz, 1H), 7.28 (t, J=7.6 Hz, 1H), 7.15 (d, J=5.2Hz, 1H), 4.09 (s, 3H), 3.07-2.98 (m, 2H), 2.92-2.80 (m, 2H), 2.12-2.03 (m, 1H), 1.98-1.89 (m, 1H), 1.84-1.74 (m, 1H), 1.65-1.56 (m, 1H), 1.27-1.17 (m, 1H).ESI-MS m/z：433.31[M+H]⁺。

Embodiment 84, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (4- nitrobenzophenones) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- ((4- nitros) phenyl) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously the iodo- 4- nitrobenzenes of [4,5-c] pyridine (400mg, 2.94mmol), 1- (875mg, 3.53mmol)、 Pd(PPh₃)₄(170mg, 0.147mmol), CuI (28mg, 0.147mmol) and Cs₂CO₃(2.87g, It 8.82mmol) is dissolved in 20mL DMF, 120 DEG C of stirrings, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering is anti- Liquid is answered, is added in 100mL water and 50mL ethyl acetate to filtrate, organic phase is detached and is washed with 25mL, saturated common salt water washing Organic phase (25mL × 2), is dried over anhydrous sodium sulfate, and filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography： Ethyl acetate=3：1), obtain for yellow solid powder 2- ((4- nitros) phenyl) thiazole simultaneously [4,5-c] pyridine (242mg, 32%).

Step 2：By 2- ((4- nitros) phenyl) thiazole, simultaneously [4,5-c] pyridine (360mg, 1.4mmol) is dissolved in 20mL dichloros Methane is slowly added to MCPBA (363mg, 2.1mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 10mL 1M carbonic acid is added Reaction is quenched in potassium solution.25mL saturated salt solutions are added into reaction solution, extracts (25mL × 2) with dichloromethane, merges organic Phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure, and 2- ((4- nitros) phenyl) thiazole simultaneously [4,5-c] pyridine -5- oxygen is obtained Compound crude product, white solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- ((4- nitros) phenyl) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, flow back 2h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (25mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- ((4- nitros) phenyl) thiazole simultaneously [4,5-c] pyridine (168mg, two step yields 41%) for yellow solid.¹H NMR(400 MHz,CDCl₃) δ 8.43-8.30 (m, 5H), 7.87 (d, J=5.4Hz, 1H).

84 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.ESI- MS m/z：448.22[M+H]⁺。

Embodiment 85, N⁴(2- amino-ethyls)-N³(2- Phenyl-thiazols simultaneously [4,5-c] pyridin-4-yl) pyridine -3,4- two Amine

The preparation of [2- (3- amino-pyridines -4- bases-amido)-ethyl]-amidocarbonic acid tert-butyl ester

Step 1：By the chloro- 3- nitropyridines (1.16g, 7.3mmol) of 4-, (2- amino-ethyls)-amidocarbonic acid tert-butyl ester (1.169 g, 7.3mmol) and DIPEA (945mg, 7.3mmol) sequentially add 100mL round-bottomed flasks, and 50mL ethyl alcohol, room is added Temperature stirring 12h.Reaction solution is concentrated under reduced pressure, ethyl acetate dissolves residue, washing ethyl acetate phase (50mL × 3), organic phase warp Anhydrous sodium sulfate is dried, and is filtered and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography：Ethyl acetate=1:1) it, obtains To [2- (3- nitro-pyridines -4- bases-amido)-ethyl]-amidocarbonic acid tert-butyl ester (1.75g, 85%) for yellow solid.¹H NMR(400MHz,CDCl₃) δ 9.21 (s, 1H), 8.34 (brs, 1H), 8.30 (d, J=6.1Hz, 1H), 6.82 (d, J= 6.1Hz,1H),3.57-3.35(m,4H),1.45(s,9H).ESI-MS m/z：283.17[M+H]⁺。

Step 2：By [2- (3- nitro-pyridines -4- bases-amido)-ethyl]-amidocarbonic acid tert-butyl ester (1.751g, 6.21mmol) be dissolved in 50mL ethyl alcohol, then sequentially add iron powder (2.774g, 49.67mmol), ammonium chloride (1.993g, 37.26mmol) and 5mL water, 90 DEG C of reflux 4h.Reaction solution filters, and filtrate is concentrated under reduced pressure, suitable quantity of water, acetic acid is added in residue Ethyl ester extracts (50mL × 3), merges organic phase and is washed with water (20mL × 3), is dried over anhydrous sodium sulfate, filters and depressurize dense Contracting.(dichloromethane is isolated and purified by column chromatography：Methanol=20:1) [2- (the 3- amino-pyridines-for yellow solid, are obtained 4- bases-amino)-ethyl]-t-butyl carbamate (800mg, 51%).ESI-MS m/z：253.15[M+H]⁺。

85 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 31.¹H NMR (400MHz,CD₃OD) δ 8.50 (d, J=1.0Hz, 1H), 8.30 (dd, J=1.1,7.1Hz, 1H), 8.24-8.21 (m, 2H), 7.94 (d, J=5.7Hz, 1H), 7.61-7.58 (m, 3H), 7.53 (d, J=5.7Hz, 1H), 7.30 (d, J=7.1Hz, 1H), 3.82 (t, J=6.3Hz, 2H), 3.24 (t, J=6.3Hz, 2H).ESI-MS m/z：363.06[M+H]⁺。

Embodiment 86, thiazole is simultaneously by -2- (2,6- difluorophenyls) by N- (4- (- 3- amino -5- methylcyclohexyls) pyridin-3-yl) [4,5-c] pyridine -4- amine

The preparation of compound 86-11

Step 1：500ml three-necked flasks, sequentially add compound 5- methyl-1s, hydroresorcinol (10.0g, 79.37mmol), pyridine (12.5g, 158.74mmol) and DCM (168ml), N₂Displacement, T=0 DEG C, clear solution slowly drips Trifluoromethanesulfanhydride anhydride (33.57g, 119.05mmol) is added to be dissolved in the DCM of 100ml, 1h or so is dripped off, and solution reddens, and is added dropwise After, go to normal-temperature reaction 1h.TLC (petroleum ethers：Ethyl acetate=1：1) detect, product point under 254nm ultraviolet lamps by It is gradually dense by fading.After completion of the reaction, 100ml H are added₂O, water phase is extracted with DCM after layering, merges DCM phases, with saturation NaHCO₃Solution washs, and water washing removes pyridine, saturated common salt water washing, MgSO three times₄Dry filter, filtrate are spin-dried for obtaining light Red oil product 86-1 22.0g (yield 107.47%).Unstable products throw the next step at once.

Step 2：In 500ml single-necked flasks be added compound 86-1 (22.0g, 93.22mmol), be dissolved in dioxane at Pale red clear solution (0.3M) sequentially adds connection boric acid pinacol ester (45.23g, 186.44mmol), potassium acetate (25.2 G, 279.66mmol), Pd (dppf) Cl₂(3.11g, 4.25mmol), N₂Displacement four times, 80 DEG C of reaction 5h, solution become black. After 5h, TLC detection reactions finish, and filter, are used in combination dioxane solution to wash, obtain product 86-2, do not have to purifying, filtrate is straight It connects and casts single step reaction.

Step 3：The dioxane solution of crude product 86-2 (21.99g, 93.18mmol) is added in 500ml single-necked flasks, Use N₂It is bubbled, Na is then added₂CO₃Solution (19.76g, 186.36mmol, 2M) adds the chloro- 3- nitropyridines of 4- (17.67g, 111.82mmol), Pd (dppf) Cl₂(3.41g, 4.66mmol), N₂After displacement three times, in 120 DEG C of reactions. TLC Detection to reaction terminates.After reaction, 200ml H are added₂Diatomite filtering is added in funnel for O and 200ml ethyl acetate, Obtained filtrate repeatedly filters three times again, obtains black filtrate, is extracted with ethyl acetate in batches on a small quantity, prevents from emulsifying, be associated with Machine phase, is washed with water, saturated common salt washing, MgSO₄Dry, filtering is spin-dried under filtrate decompression, residue through column chromatography obtain compared with Pure product 86-3,12.9g yellow solid, yield 70%.ESI-MS m/z：233.21[M+H]⁺。

Step 4：250ml single-necked flasks are added product 86-3 (3.2g, 13.7mmol) and are dissolved in 66ml EtOH solution, so After CeCl is added₃.7H₂O (6.62g, 17.7mmol) is placed in 0 DEG C of ice bath, NaBH is slowly added portionwise₄(672 mg, 17.7mmol), yellow solution is formed, is stirred to react, the reaction was complete for TLC detections after 3h.100ml H are added₂O uses ethyl acetate Extraction, organic phase are washed with water, saturated common salt washing, MgSO₄Dry, column chromatography obtains the white solid powder product of 2.6g 86-4, yield 81%.¹H NMR(400MHz,CDCl₃) δ 9.08 (s, 1H), 8.72 (d, J=5.0Hz, 1H), 7.27-7.25 (m,1H),5.70(s,1H),4.45-4.42(m,1H),4.14-4.07(m,1H),2.17-2.11(m,2H),2.03 (brs, 1H), 1.99-1.92 (m, 2H), 1.04 (d, J=6.2Hz, 3H).

Step 5：250ml single-necked flasks are added product 86-4 (2.6g, 11.11mmol) and are dissolved in 66ml DMF solutions, so Imidazoles (3.02g, 44.43mmol) is added afterwards, TBDMsCl (4.2g, 27.77mmol) is stirred overnight at room temperature.TLC detection reactions Completely.500ml H are added₂O is extracted with ethyl acetate, and organic phase is washed with water, saturated common salt washing, MgSO₄It is dry, column chromatography Obtain 3.8g product 86-5, yield 98.3%.¹H NMR(400MHz,CDCl₃) δ 9.09 (s, 1H), 8.72 (d, J=5.0Hz, 1H), 7.29 (d, J=5.0Hz, 1H), 5.61 (s, 1H), 4.47-4.43 (m, 1H), 2.16-2.13 (m, 1H), 2.01-1.91 (m, 2H), 1.36-1.23 (m, 2H), 1.03 (d, J=6.2Hz, 3H), 0.90 (s, 9H), 0.09 (d, J=1.9Hz, 6H). ESI-MS m/z：349.05[M+H]⁺。

Step 6：250ml single-necked flasks are added product 86-5 (3.8g, 10.92mmol) and are dissolved in 50ml absolute methanols, so 10%Pd/C (1.16g, 1.092mmol) is added afterwards, is passed through H₂Displacement, is used in combination H₂Sealing, is stirred overnight at room temperature.TLC detections are anti- It should be complete.It filters (diatomite is added on filter paper), methanol washs yellowly filtrate, and filtrate is spin-dried for obtaining the production of 2.8g yellow liquids Object 86-6, yield 80%.ESI-MS m/z：321.22[M+H]⁺。

Step 7：250ml single-necked flasks are added product 86-6 (2.8g, 8.75mmol) and are dissolved in 40ml CH₂Cl₂, then add Enter benzene methoxy carbonyl acyl succinimide (7.82g, 30.63mmol), DMAP (243mg, 1.925mmol) is passed through N₂Displacement, room Temperature is stirred to react 3d.TLC detects (dichloromethane：Methanol=30:1) raw material unreacted is complete, adds 0.5eq benzene methoxy carbonyl acyl ambers Amber acid imide, 0.31eq DMAP, the reaction was continued until reaction terminates.Column chromatography obtains 1.5g product 86-7, yield 38.5%. ESI-MS m/z：455.29[M+H]⁺。

Step 8：In 100ml single-necked flasks, be added product 86-7 (1.5g, 3.30mmol) be dissolved in one group of 33.63ml it is mixed It closes in solution, (V (6N HCl)：V(MeOH)：V (THF)=1:1:2) reaction is stirred at room temperature in, the transparent yellow solution of solution, TLC detects raw material, and the reaction was complete, with 6N NaOH solution tune pH=7, adds 50ml water, is extracted with ethyl acetate, organic phase It is washed with water, saturated common salt washing, MgSO₄Dry, filtering is spin-dried for, and column chromatography obtains 857mg product 86-8, yield 76.5%. ESI-MS m/z：341.57[M+H]⁺。

Step 9：100ml single-necked flasks are added product 86-8 (771mg, 2.27mmol) and are dissolved in 16.5ml CH₂Cl₂, set In 0 DEG C of ice bath, Dess-Martin reagents (1.44g, 3.40mmol) solution is then added and becomes cloudy, is stirred at room temperature.After 5h TLC detects raw material, and the reaction was complete, and 10%Na is added₂S₂O₃：NaHCO₃=1：1 volume ratio solution washs, and uses CH₂Cl₂Extraction, it is organic Mutually 10%Na is used again₂S₂O₃：NaHCO₃=1：1 volume ratio solution washs, washing, saturated common salt washing, MgSO₄It is dry, filtering, It is spin-dried for, column chromatography obtains 230mg product 86-9, yield 30.0%.ESI-MS m/z：339.21 [M+H]⁺。

Step 10：50ml single-necked flasks are added product 86-9 (230mg, 0.68mmol) and are dissolved in 10ml CH₂Cl₂, then add Enter benzylamine (273.99mg, 2.72mmol), acetic acid (489.6mg, 8.16mmol), 30 DEG C of reactions are stayed overnight, then TLC (dichloromethanes Alkane：Methanol=15:1) new product point is not seen, NaBH (OAc) is added₃(1.73g, 8.16mmol) continues normal-temperature reaction. TLC detects (dichloromethane：Methanol=15:1) raw material has reacted, and has new point to generate.Stop reaction, reaction solution saturation NaHCO₃Washing, is extracted with ethyl acetate, organic phase saturation NaHCO₃Solution, water, saturated common salt water washing, MgSO₄It is dry, Filtering, is spin-dried for, column chromatography obtains 69mg product 86-10, yield 23.7%.ESI-MS m/z：429.84[M+H]⁺。

Step 11：50ml single-necked flasks are added product 86-10 (69mg, 0.16mmol) and are dissolved in 10ml CH₃OH is added 20%Pd (OH)₂(22.5mg, 0.032mmol), H₂Displacement, in H₂Normal-temperature reaction is stayed overnight under sealed environment.TLC (dichloromethane： Methanol=5:1+NH₃.H₂O) display raw material has reacted, and sees product point.Filtering, methanol washing, is spin-dried for obtaining yellow mucus, Thin layer silica gel prepares plate and obtains product 29.9mg, and then product is dissolved in 6ml methanol, and Boc is added₂O (30.72mg, 0.141mmol), N₂Displacement, yellow transparent solution, TLC detects (dichloromethane after reacting at room temperature 5h：Methanol=10:1+ NH₃.H₂O) raw material has reacted, and has new point to generate.It is spin-dried for solution, thin layer silica gel prepares plate and purifies to obtain 30mg product 86-11, production Rate 69.38%.ESI-MS m/z：306.28[M+H]⁺。

86 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CDCl₃) δ 9.29 (s, 1H), 8.28 (d, J=4.5Hz, 1H), 8.04 (d, J=5.6Hz, 1H), 7.46- 7.39 (m, 1H), 7.25 (d, J=5.6Hz, 1H), 7.12-7.05 (m, 3H), 3.63 (brs, 2H), 3.50 (t, J= 12.3Hz, 1H), 2.08-1.93 (m, 4H), 1.74 (t, J=12.1Hz, 1H), 1.17-1.08 (m, 1H), 0.89 (d, J= 5.9Hz,3H).ESI-MS m/z：452.17[M+H]⁺。

Embodiment 87, N- (4- (- 3- amino -5- methylcyclohexyls) pyridin-3-yl) -2- phenyl thiazoles simultaneously [4,5-c] pyrrole Pyridine -4- amine

87 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,d⁶- DMSO) δ 8.82 (s, 1H), 8.66 (s, 1H), 8.35 (d, J=5.1Hz, 1H), 8.18-8.16 (m, 2H), 7.94 (d, J=5.6Hz, 1H), 7.61-7.59 (m, 3H), 7.46 (d, J=5.6Hz, 1H), 7.40 (d, J=5.2Hz, 1H), 2.51 (d, J=1.7Hz, 2H), 1.96-1.77 (m, 4H), 1.38-1.08 (m, 3H), 0.86 (d, J=6.0Hz, 3H). ESI-MS m/z：416.19[M+H]⁺。

Embodiment 88, N- (4- (3- amino -5- methylcyclohexyls) pyridin-3-yl) -2- (thiazol-2-yl) thiazole simultaneously [4, 5-c] pyridine -4- amine

Step 1：By thiazole simultaneously [4,5-c] pyridine (1.5g, 11mmol), 2- bromo thiazoles (2.166g, 13.2mmol), Pd (PPh₃)₄(636mg, 0.549mmol), CuI (105mg, 0.549mmol) and Cs₂CO₃(19.2g, 39.6mmol) is dissolved in 40mL DMF, 120 DEG C of stirrings, TLC are monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering reacting liquid, 200mL is added In water and 100mL ethyl acetate to filtrate, detaches organic phase and washed with 50mL, saturated common salt water washing organic phase (50mL × 2) it, is dried over anhydrous sodium sulfate, filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by column chromatography：Ethyl acetate=3： 1) 2- (thiazol-2-yl) thiazole simultaneously [4,5-c] pyridine (2.98g, 92%) for yellow solid, is obtained.¹H NMR(400MHz, CDCl₃) δ 9.40 (brs, 1H), 8.59 (brs, 1H), 8.02 (d, J=3.1Hz, 1H), 7.91 (d, J=5.3Hz, 1H), 7.62 (d, J=3.1Hz, 1H).ESI-MS m/z：220.06[M+H]⁺。

Step 2：By 2- (thiazol-2-yl) thiazole, simultaneously [4,5-c] pyridine (2.98g, 13.6mmol) is dissolved in 50mL dichloromethanes Alkane is slowly added to MCPBA (3.188g, 18.5mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 20mL 1M carbon is added Reaction is quenched in sour potassium solution.100mL saturated salt solutions are added into reaction solution, extracts (100mL × 2) with dichloromethane, merges Organic phase is dried over anhydrous sodium sulfate, and is filtered and is concentrated under reduced pressure, obtain for white solid 2- (thiazol-2-yl) thiazole simultaneously [4,5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (thiazol-2-yl) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 20mL POCl₃, Flow back 9h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, it is extracted with ethyl acetate (100mL × 3), merges organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain For 4- chloro- 2- (thiazol-2-yl) thiazole simultaneously [4,5-c] pyridine (1.08g, two step yields 31.4%) of yellow solid.¹H NMR (400 MHz,CDCl₃) δ 8.35 (d, J=5.4Hz, 1H), 8.02 (d, J=3.1Hz, 1H), 7.82 (d, J=5.4Hz, 1H), 7.65 (d, J=3.1Hz, 1H).ESI-MS m/z：254.00[M+H]⁺。

88 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 9.25 (s, 1H), 8.27 (d, J=5.1Hz, 1H), 7.98 (d, J=5.6Hz, 1H), 7.89 (d, J=3.0 Hz, 1H), 7.47 (d, J=3.0Hz, 1H), 7.18 (d, J=5.6Hz, 1H), 7.06 (d, J=5.0Hz, 1H), 3.66 (d, J=4.0 Hz, 1H), 3.55 (t, J=12.0Hz, 1H), 2.07-1.92 (m, 4H), 1.73-1.67 (m, 1H), 1.27-1.22 (m, 1H), 1.10-1.01 (m, 1H), 0.89 (d, J=6.2Hz, 3H).ESI-MS m/z：421.03[M-H]^-。

Embodiment 89, thiazole is simultaneously by -2- (2,6- difluorophenyls) by (R)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) [4,5-c] pyridine -4- amine

(R)-(1- (3- aminopyridine -4- bases) piperidines -3- bases) preparation of carboxylate

Step 1：By the chloro- 3- nitropyridines (1.268g, 8mmol) of 4-, (R) -3- t-butyloxycarbonyl piperidines (1.602g, 8mmol) and DIPEA (1.034g, 8mmol) sequentially add 100mL round-bottomed flasks, and 20mL ethyl alcohol, room temperature is added Stir 12h.Reaction solution is concentrated under reduced pressure, ethyl acetate dissolves residue, and washing ethyl acetate phase (50mL × 3), organic phase is through nothing Aqueous sodium persulfate is dried, and is filtered and is concentrated under reduced pressure.Crude product is directly reacted.

Step 2：(R) -1- (3- nitropyridine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester crude product is dissolved in 40mL ethyl alcohol, then sequentially adds iron powder (3.584g, 64mmol), ammonium chloride (2.568g, 48mmol) and 4mL water, 80 DEG C Flow back 4h.Reaction solution filters, and filtrate is concentrated under reduced pressure, and suitable quantity of water is added in residue, and ethyl acetate extracts (100mL × 3), closes And organic phase and be washed with water (50mL × 2), it is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure.It is detached by column chromatography pure Change (dichloromethane：Methanol=20:1) (R) -1- (3- aminopyridine -4- bases) piperidines -3- bases-amido for yellow solid, are obtained Carboxylate (1.823g, two step yields 78%).

89 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CD₃OD) δ 9.66 (s, 1H), 8.19-8.09 (m, 4H), 7.60-7.58 (m, 3H), 7.45 (d, J= 5.4Hz, 1H), 7.21 (d, J=5.3Hz, 1H), 3.47-3.41 (m, 1H), 3.26-3.19 (m, 1H), 2.91-2.74 (m, 2H),2.21-2.09(m, 1H),2.01-1.85(m,2H),1.58-1.25(m,2H).ESI-MS m/z：403.07[M+H]⁺。

Embodiment 90, N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine -4- Amine

The preparation of 1- (3- aminopyridine -4- bases) piperidines -3- bases-carboxylate

Step 1：By the chloro- 3- nitropyridines (1.1g, 7mmol) of 4-, 3- t-butyloxycarbonyls piperidines (1.402g, 7mmol) and DIPEA (905mg, 7mmol) sequentially adds 50mL round-bottomed flasks, and 10mL ethyl alcohol is added, 4h is stirred at room temperature.Decompression Concentration of reaction solution, ethyl acetate dissolve residue, washing ethyl acetate phase (50mL × 3), and organic phase is done through anhydrous sodium sulfate It is dry, it filters and is concentrated under reduced pressure.Crude product is directly reacted.

Step 2：1- (3- nitropyridine -4- bases) piperidines -3- bases-amidocarbonic acid tertiary butyl ester crude product is dissolved in 30mL second Then alcohol sequentially adds iron powder (3.25g, 58mmol), ammonium chloride (2.327g, 43.5mmol) and 3mL water, 80 DEG C of reflux 4h.Reaction solution filters, and filtrate is concentrated under reduced pressure, and suitable quantity of water is added in residue, and ethyl acetate extracts (100mL × 3), is associated with Machine phase is simultaneously washed with water (50mL × 2), is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure.It is isolated and purified by column chromatography (dichloromethane：Methanol=20:1) 1- (3- aminopyridine -4- bases) piperidines -3- bases-amidocarbonic acid for yellow solid, are obtained Tertiary butyl ester (1.75g, 82.7%).

90 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 5.¹H NMR (400MHz,CD₃OD) δ 9.65 (s, 1H), 8.20 (d, J=5.4Hz, 1H), 8.16-8.13 (m, 2H), 8.10 (d, J= 5.6 Hz, 1H), 7.61-7.59 (m, 3H), 7.46 (d, J=5.6Hz, 1H), 7.22 (d, J=5.4Hz, 1H), 3.48-3.37 (m,2H), 3.27-3.22(m,1H),2.92-2.81(m,2H),2.19-2.13(m,1H),2.02-1.93(m,2H),1.61- 1.52(m,1H). ESI-MS m/z：403.15[M+H]⁺。

Embodiment 91, N- (2,4 '-two pyridines -3 '-yl) -2- phenyl thiazoles simultaneously [4,5-c] pyridine -4- amine

The preparation of [2,4'- bipyridyls] -3'- amine

Step 1：2- bromopyridines (500mg, 3.165mmol) are dissolved in the THF of 5ml dryings, N₂Displacement, reaction temperature- 78 DEG C, n-BuLi (1.4ml, 2.5M) is added, keeps -78 DEG C of reaction 1h, (Bu) then is added₃SnCl (1.03g, 3.165mmol), after reacting 1h, temperature is slowly increased to room temperature, and overnight, TLC detection reactions are completed for room temperature reaction.Saturation is added NH₄Cl solution, ethyl acetate extraction, washes organic phase, MgSO₄Dry, filtering is spin-dried for filtrate, column chromatographic isolation and purification obtains 2- tributylstannyl pyridines (652mg, 55.8%).ESI-MS m/z：369.98[M+H]⁺。

Step 2：By 2- tributylstannyl-pyridines (2.5g, 6.77mmol), the chloro- 3- nitropyridines of 4- (1.283g, 8.13 mmol)、Pd(PPh₃)₄(454mg, 0.392mmol) and CuI (74.4mg, 0.392mmol) are dissolved in 70ml DMF, N₂It sets It changes, 115 DEG C of reaction 18h, TLC detection reactions are completed.Suitable water, ethyl acetate extraction, washing, MgSO are added after reaction₄It is dry Dry, filtering is spin-dried for filtrate, column chromatographic isolation and purification obtains product 3'- nitros-[2,4']-bipyridyl (360mg, 26.5%) 。¹H NMR(400MHz,CDCl₃) δ 9.13 (s, 1H), 8.89 (d, J=5.0Hz, 1H), 8.70 (d, J=4.3Hz, 1H), 7.86 (td, J=7.8,1.7Hz, 1H), 7.62 (d, J=5.0Hz, 1H), 7.57 (d, J=7.9Hz, 1H), 7.42 (ddd, J= 7.6,4.9,1.0Hz,1H)。

Step 3:By 3'- nitros-[2,4'] bipyridyl (360mg, 1.79mmol), iron powder (802mg, 14.33mmol), NH₄Cl (574.5mg, 10.74mmol) and 1mL is water-soluble to react 11h at 10mL ethyl alcohol, 90 DEG C, and TLC detection reactions are completed.It crosses Reaction solution is filtered, filtrate is concentrated under reduced pressure, is isolated and purified by column chromatography, obtains product [2,4'- bipyridyl] -3'- amine (210mg, 68.8%).

91 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 12.61 (s, 1H), 10.35 (s, 1H), 8.98 (d, J=4.7Hz, 1H), 8.39 (d, J= 5.1Hz, 1H),8.21-8.15(m,3H),7.95-7.88(m,2H),7.62-7.56(m,4H),7.44-7.41(m,1H), 7.30 (d, J=5.6 Hz, 1H).ESI-MS m/z：380.16[M-H]^-。

Embodiment 92, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (pyrazine -2- bases) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (pyrazine -2- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously [4,5-c] pyridine (517mg, 3.8mmol), 2- iodine pyrazine (939mg, 4.56mmol), Pd (PPh₃)₄(220mg, 0.19mmol), CuI (36mg, 0.19mmol) and Cs₂CO₃(3.714g, 11.4mmol) is dissolved in 10mL DMF, 120 DEG C of stirrings, TLC are monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering reacting liquid, be added 100mL water and In 50mL ethyl acetate to filtrate, detaches organic phase and washed with 25mL, saturated common salt water washing organic phase (25mL × 2), passed through Anhydrous sodium sulfate is dried, and is filtered and is concentrated under reduced pressure.(dichloromethane is isolated and purified by column chromatography：Methanol=40：1) it, obtains For 2- (pyrazine -2- bases) thiazole simultaneously [4,5-c] pyridine (637mg, 78.3%) of yellow solid.

Step 2：By 2- (pyrazine -2- bases) thiazole, simultaneously [4,5-c] pyridine (637mg, 3mmol) is dissolved in 20mL dichloromethane, It is slowly added to MCPBA (718mg, 4.2mmol), is stirred at room temperature, TLC is monitored to the reaction was complete, and it is molten that 10mL 1M potassium carbonate is added Reaction is quenched in liquid.25mL saturated salt solutions are added into reaction solution, extracts (25mL × 2) with dichloromethane, merges organic phase, It is dried over anhydrous sodium sulfate, filters and is concentrated under reduced pressure, obtain 2- (pyrazine -2- bases) thiazole simultaneously [4,5-c] pyridine -5- oxides Crude product, yellow solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (pyrazine -2- bases) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, Flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, be extracted with ethyl acetate (50mL × 3), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain for The chloro- 2- of 4- (pyrazine -2- bases) thiazole of yellow solid simultaneously [4,5-c] pyridine (150mg, 35.4%).¹H NMR(400MHz, CDCl₃) δ 9.73 (d, J=1.5Hz, 1H), 8.78 (t, J=2.7Hz, 1H), 8.72-8.67 (m, 1H), 8.39 (d, J= 5.4Hz, 1H), 7.89 (d, J=5.4Hz, 1H).ESI-MS m/z：249.09[M+H]⁺。

92 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 10.01 (s, 1H), 9.58 (s, 1H), 8.71-8.67 (m, 2H), 8.29 (dd, J=5.0Hz, 1H), 8.24 (d, J=5.5Hz, 1H), 7.36 (d, J=5.4Hz, 1H), 7.04 (d, J=5.1Hz, 1H), 3.30-3.28 (m, 2H), 3.19-3.16(m,1H),2.82-2.74(m,1H),2.67-2.59(m,1H),2.15-1.94(m,3H),1.45- 1.37(m,1H). ESI-MS m/z：405.01[M+H]⁺。

Embodiment 93, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (fluoro- 6- picolines -2- of 3- Base) thiazole simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (the fluoro- 6- picolines -2- bases of 3-) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously the fluoro- 6- picolines of [4,5-c] pyridine (500mg, 3.67mmol), the bromo- 3- of 2- (838mg, 4.4mmol)、Pd(PPh₃)₄(213mg, 0.18mmol), CuI (36mg, 0.19mmol) and Cs₂CO₃(3.6g, 11mmol) is molten In 8mL DMF, 120 DEG C of stirrings, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, filtering reacting liquid, is added In 100mL water and 50mL ethyl acetate to filtrate, detaches organic phase and washed with 25mL, saturated common salt water washing organic phase (25mL × 2), are dried over anhydrous sodium sulfate, and filter and are concentrated under reduced pressure.(dichloromethane is isolated and purified by column chromatography：Acetone =10：1) 2- (the fluoro- 6- methvl-pyridiniums -2- bases of 3-) thiazole simultaneously [4,5-c] pyridine for yellow powdery solid, is obtained (569mg, 63.3%).

Step 2：By 2- (the fluoro- 6- methvl-pyridiniums -2- bases of 3-) thiazole, simultaneously [4,5-c] pyridine (569mg, 2.33mmol) is molten In 50mL dichloromethane, it is slowly added to MCPBA (604mg, 3.5mmol), is stirred at room temperature, TLC is monitored to the reaction was complete, is added Reaction is quenched in 10mL 1M solution of potassium carbonate.Into reaction solution be added 25mL saturated salt solutions, with dichloromethane extraction (25 mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (the fluoro- 6- methvl-pyridiniums -2- bases of 3-) Thiazole simultaneously [4,5-c] pyridine -5- oxide crude products, yellow solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (the fluoro- 6- methvl-pyridiniums -2- bases of 3-) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, flow back 3h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added PH is adjusted to neutrality, is extracted with ethyl acetate (50mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, filters and depressurize Concentration, obtains the chloro- 2- of 4- (the fluoro- 6- methvl-pyridiniums -2- bases of 3-) thiazole simultaneously [4,5-c] pyridine (322mg, 49.5%).¹H NMR (400MHz,CDCl₃) δ 8.36 (d, J=5.4Hz, 1H), 7.85 (d, J=5.4Hz, 1H), 7.56 (t, J=9.8Hz, 1H), 7.34 (dd, J=8.6,3.5Hz, 1H), 2.67 (s, 3H).

93 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.79 (s, 1H), 8.17 (d, J=5.3Hz, 1H), 8.07 (d, J=5.6Hz, 1H), 7.69- 7.64 (m, 1H), 7.44-7.40 (m, 2H), 7.21 (d, J=5.4Hz, 1H), 3.56-3.49 (m, 1H), 3.44-3.40 (m, 1H), 3.19-3.11(m,1H),2.94-2.87(m,1H),2.82-2.77(m,1H),2.59(s,3H),2.24-2.14(m, 1H), 2.04-1.96(m,2H),1.64-1.54(m,1H).ESI-MS m/z：436.59[M+H]⁺。

Embodiment 94, thiazole is simultaneously by -2- (6- fluorine pyridin-3-yl) by (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (6- fluorine pyridin-3-yl) thiazole simultaneously [4,5-c] pyridine

Step 1：By thiazole simultaneously the bromo- 2- fluorine pyridine of [4,5-c] pyridine (2g, 14.69mmol), 5- (3.103g, 17.63mmol)、 Pd(PPh₃)₄(849mg, 0.735mmol), CuI (140mg, 0.735mmol) and Cs₂CO₃(14.36g, 44.07 mmol) it is dissolved in 80mL DMF, 120 DEG C of stirrings, TLC is monitored to the reaction was complete.Reaction solution is cooled to room temperature, is filtered Reaction solution is added in 200mL water and 100mL ethyl acetate to filtrate, detaches organic phase and is washed with 100mL, saturated salt solution Organic phase (100mL × 2) is washed, is dried over anhydrous sodium sulfate, is filtered and be concentrated under reduced pressure.(stone is isolated and purified by column chromatography Oily ether：Ethyl acetate=3：1) 2- (the fluoro- pyridin-3-yls of 6-) thiazole simultaneously [4,5-c] pyridine for yellow solid, is obtained (3.01g, 88.7%).¹H NMR(400MHz,CDCl₃) δ 9.39 (s, 1H), 8.92 (d, J=2.4Hz, 1H), 8.60-8.51 (m, 2H), 7.90 (dd, J=5.4,0.7Hz, 1H), 7.13 (dd, J=8.6,2.9Hz, 1H).

Step 2：By 2- (the fluoro- pyridin-3-yls of 6-) thiazole, simultaneously [4,5-c] pyridine (3.01g, 13.01mmol) is dissolved in 120mL Dichloromethane is slowly added to MCPBA (3.144g, 18.22mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 30mL 1M solution of potassium carbonate.100mL saturated salt solutions are added into reaction solution, (50 mL are extracted with dichloromethane × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtaining 2- (the fluoro- pyridin-3-yls of 6-), thiazole is simultaneously [4,5-c] pyridine -5- oxide crude products, yellow solid.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (the fluoro- pyridin-3-yls of 6-) thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 10mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (100mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and depressurize dense Contracting obtains the chloro- 2- of 4- (6- fluorine pyridin-3-yl) thiazole simultaneously [4,5-c] pyridine (350mg, two step yields for off-white powder 19%).¹H NMR(400MHz,CDCl₃) δ 9.08 (d, J=2.4Hz, 1H), 8.48 (dd, J=8.3,2.5Hz, 1H), 8.39 (d, J=5.4Hz, 1H), 7.85 (d, J=5.4Hz, 1H), 7.55 (d, J=8.3Hz, 1H).

94 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃)δ9.99(s,1H),9.20(s,1H),8.67-8.56(m,1H),8.53-8.33(m,1H), 8.33-8.17 (m,2H),7.40-7.24(m,1H),7.07-6.96(m,1H),3.32-3.07(m,3H),2.85-2.73(m, 1H),2.68-2.56 (m,1H),2.15-1.85(m,3H),1.48-1.34(m,1H).ESI-MS m/z：421.96[M+H]⁺。

Embodiment 95, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (5- methylthiophene -2- bases) thiazole And [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (5- methylthiophene -2- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：The chloro- 3- nitro-pyridines (7950mg, 50mmol) of 4- are dissolved in 50mL ethyl alcohol, be stirred at room temperature it is lower slowly plus Enter 50mmol concentrated hydrochloric acids；Then NaHSH is weighed₂O (13.69g, 185mmol) is added in reaction solution, and 40min is stirred at room temperature； Next it is soluble in water to weigh sodium hydrosulfite (32.21g, 185mmol), and insurance amidin is added in reaction mixture, 80 DEG C stirring 12h.Filtering reacting liquid is concentrated under reduced pressure filtrate, (dichloromethane is isolated and purified by column chromatography：Methanol=5:1 arrives 1:1 elution), obtain 3- amino -4- mercaptopyridine crude products, yellow-brown solid.It does not purify, is directly used in and reacts in next step.

Step 2：By 3- amino -4- mercaptopyridines (446mg, 3.54mmol) and 5- methyl-thiophene -2- formic acid (1005mg, It 7.08mmol) is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and saturation is added Reaction is quenched in sodium bicarbonate solution.Reaction solution is extracted with ethyl acetate (50mL × 3), merges organic phase, dry through anhydrous sodium sulfate It is dry, it filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) it, obtains as light yellow solid 2- (5- methyl-thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine (561mg, two step yields 71%).

Step 3：By 2- (5- methyl-thiophene -2- bases)-thiazole, simultaneously [4,5-c] pyridine (561mg, 2.4mmol) is dissolved in 20mL Dichloromethane is slowly added to MCPBA (580mg, 3.36mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 10mL is added Reaction is quenched in 1M solution of potassium carbonate.25mL saturated salt solutions are added into reaction solution, extracts (25 mL × 2) with dichloromethane, closes And organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (5- methyl-thiophene -2- bases)-thiazole simultaneously [4, 5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 4：By 2- (5- methyl-thiophene -2- bases)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 8mL POCl₃, flow back 2h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (25mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- (5- methyl-thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine (525mg, 82.2%) for light yellow solid.

95 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 9.91 (s, 1H), 8.18 (d, J=5.3Hz, 1H), 8.10 (d, J=5.6Hz, 1H), 7.43 (d, J=3.7Hz, 1H), 7.21 (d, J=5.6Hz, 1H), 6.98 (d, J=5.3Hz, 1H), 6.80 (dd, J=3.7,1.0Hz, 1H), 3.44-3.36(m,1H),3.32-3.24(m,1H),3.11-3.03(m,1H),2.88-2.79(m,1H),2.78- 2.67(m,1H), 2.58(s,3H),2.05-1.95(m,3H),1.59-1.48(m,1H).ESI-MS m/z：420.92[M- H]^-。

Embodiment 96, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (5- methyl-isoxazole -3- bases) thiophene Azoles simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (5- methyl-isoxazole -3- bases)-thiazole simultaneously [4,5-c] pyridine

Step 1：By 3- amino -4- mercaptopyridines (252mg, 2mmol) and 5- methyl-isoxazole -3- formic acid (508mg, It 4mmol) is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and saturated carbon is added Reaction is quenched in sour hydrogen sodium solution.Reaction solution is extracted with ethyl acetate (50mL × 3), merges organic phase, dry through anhydrous sodium sulfate It is dry, it filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) it, obtains as brown solid 2- (5- methylisoxazole -3- bases)-thiazole simultaneously [4,5-c] pyridine (194mg, 44.6%).

Step 2：By 2- (5- methylisoxazole -3- bases)-thiazole, simultaneously [4,5-c] pyridine (194mg, 0.89mmol) is dissolved in 20mL dichloromethane is slowly added to MCPBA (216mg, 1.25mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 10mL 1M solution of potassium carbonate.Into reaction solution be added 25mL saturated salt solutions, with dichloromethane extraction (25 mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (5- methylisoxazole -3- bases)-thiazole And [4,5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 4：By 2- (5- methylisoxazole -3- bases)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 6mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (25mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- (5- methylisoxazole -3- bases)-thiazole simultaneously [4,5-c] pyridine (132mg, two step yields for light yellow solid 58.9%).

96 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.65 (s, 1H), 8.18 (d, J=5.4Hz, 1H), 8.14 (dd, J=5.7,1.9Hz, 1H), 7.47-7.43 (m, 1H), 7.19 (d, J=5.4Hz, 1H), 6.74 (s, 1H), 3.40-3.36 (m, 1H), 3.23-3.14 (m, 2H), 2.92-2.82(m,1H),2.75-2.66(m,1H),2.59(s,3H),2.12-2.03(m,1H),2.01-1.81(m, 2H), 1.52-1.39(m,1H).ESI-MS m/z：406.25[M-H]^-。

Embodiment 97, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (2- methylthiazol -4- bases) thiazole And [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (2- methylthiazol -4- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By 3- amino -4- mercaptopyridines (252mg, 2mmol) and 2- methYl-thiazol -4- formic acid (573mg, It 4mmol) is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and saturated carbon is added Reaction is quenched in sour hydrogen sodium solution.Reaction solution is extracted with ethyl acetate (50mL × 3), merges organic phase, dry through anhydrous sodium sulfate It is dry, it filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) it, obtains as yellow solid 2- (2- methYl-thiazol -4- bases)-thiazole simultaneously [4,5-c] pyridine (213mg, 45.6%).

Step 2：By 2- (2- methYl-thiazol -4- bases)-thiazole, simultaneously [4,5-c] pyridine (213mg, 0.91mmol) is dissolved in 20mL dichloromethane is slowly added to MCPBA (220mg, 1.27mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 10mL 1M solution of potassium carbonate.Into reaction solution be added 25mL saturated salt solutions, with dichloromethane extraction (25 mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (2- methYl-thiazol -4- bases)-thiazole And [4,5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (2- methYl-thiazol -4- bases)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 6mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (25mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- (2- methYl-thiazol -4- bases)-thiazole simultaneously [4,5-c] pyridine (243mg, two step yields for light yellow solid 99.6%).

97 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD) δ 9.63 (s, 1H), 8.17 (d, J=5.4Hz, 1H), 8.15 (s, 1H), 8.07 (d, J=5.7Hz, 1H), 7.43 (d, J=5.7Hz, 1H), 7.19 (d, J=5.4Hz, 1H), 3.44-3.35 (m, 1H), 3.23-3.15 (m, 1H), 2.96-2.88 (m,1H),2.85-2.77(m,4H),2.16-2.06(m,1H),2.04-1.85(m,2H),1.60-1.49(m, 1H).ESI-MS m/z：422.26[M-H]^-。

Embodiment 98, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (the fluoro- benzyls of 3-) thiazole simultaneously [4, 5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (the fluoro- benzyls of 3-)-thiazole simultaneously [4,5-c] pyridine

Step 1：3- amino -4- mercaptopyridines (1g, 8mmol) and 3- fluoro-phenyls acetic acid (3.7g, 24mmol) are dissolved in In polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and saturated sodium bicarbonate solution is added Reaction is quenched.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, filters and subtract Pressure concentration.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1), obtain 2- (the fluoro- benzyls of 3-)-thiazole simultaneously [4, 5-c] pyridine (489mg, 25%).¹H NMR(400MHz,CDCl₃) δ 9.31 (s, 1H), 8.51 (d, J=5.4Hz, 1H), 7.78 (d, J=4.8Hz, 1H), 7.39-7.32 (m, 1H), 7.16 (d, J=8.0Hz, 1H), 7.12-7.06 (m, 1H), 7.02 (dt, J=8.6,2.4Hz, 1H), 4.48 (s, 2H).

Step 2：By 2- (the fluoro- benzyls of 3-)-thiazole, simultaneously [4,5-c] pyridine (489mg, 2mmol) is dissolved in 15mL dichloromethane, It is slowly added to MCPBA (483mg, 2.8mmol), is stirred at room temperature, TLC is monitored to the reaction was complete, and it is molten that 10mL 1M potassium carbonate is added Reaction is quenched in liquid.50mL saturated salt solutions are added into reaction solution, extracts (50mL × 2) with dichloromethane, merges organic phase, It is dried over anhydrous sodium sulfate, filters and is concentrated under reduced pressure, obtain 2- (the fluoro- benzyls of 3-)-thiazole simultaneously [4,5-c] pyridine -5- oxides Crude product.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (the fluoro- benzyls of 3-)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 6mL POCl₃, Flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts pH into Property, it is extracted with ethyl acetate (50mL × 3), merges organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 4- Chloro- 2- (the fluoro- benzyls of 3-)-thiazole simultaneously [4,5-c] pyridine (145mg, two step yields 26%).

98 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 9.96 (s, 1H), 8.45 (brs, 1H), 8.24 (d, J=5.2Hz, 1H), 8.14 (d, J= 5.6Hz, 1H), 7.39-7.32 (m, 1H), 7.21 (d, J=5.6Hz, 1H), 7.16 (d, J=7.7Hz, 1H), 7.14-7.08 (m, 1H), 7.03 (dt, J=8.5,2.4Hz, 1H), 6.98 (d, J=5.2Hz, 1H), 4.44 (s, 2H), 3.23-3.03 (m, 3H),2.80-2.70(m, 1H),2.65-2.55(m,1H),2.04-1.95(m,1H),1.94-1.85(m,1H),1.84- 1.78(m,1H),1.42-1.30(m, 1H).ESI-MS m/z：433.32[M-H]^-。

Embodiment 99, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (4- methylthiophene -2- bases) thiazole And [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (4- methylthiophene -2- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By 3- amino -4- mercaptopyridines (441mg, 3.5mmol) and 4- methyl-thiophene -2- formic acid (995mg, 7 Mmol it) is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and unsaturated carbonate is added Reaction is quenched in hydrogen sodium solution.Reaction solution is extracted with ethyl acetate (50mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, It filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) it, obtains as faint yellow solid 2- (4- methyl-thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine (650mg, 80%).

Step 2：By 2- (4- methyl-thiophene -2- bases)-thiazole, simultaneously [4,5-c] pyridine (600mg, 2.6mmol) is dissolved in 10mL Dichloromethane is slowly added to MCPBA (625mg, 3.6mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 10mL is added Reaction is quenched in 1M solution of potassium carbonate.25mL saturated salt solutions are added into reaction solution, extracts (25 mL × 2) with dichloromethane, closes And organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (4- methyl-thiophene -2- bases)-thiazole simultaneously [4, 5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (4- methyl-thiophene -2- bases)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 6mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (50mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- (4- methyl-thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine (492mg, production of two steps for yellow solid powder Rate 76.5%).

99 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CD₃OD)δ9.79(s,1H),8.18-8.13(m,1H),8.10-8.04(m,1H),7.60-7.53(m, 1H), 7.38-7.30(m,1H),7.23-7.16(m,1H),3.46-3.35(m,1H),3.21-3.12(m,1H),2.89- 2.79(m,1H), 2.75-2.67(m,1H),2.66-2.60(m,1H),2.33(s,3H),2.23-2.14(m,1H),2.08- 1.97(m,2H), 1.57-1.43(m,1H).ESI-MS m/z：423.25[M+H]⁺。

Embodiment 100, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (5- nitrothiophene -2- bases) thiophene Azoles simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (5- nitrothiophene -2- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By 3- amino -4- mercaptopyridines (850mg, 6.75mmol) and 5- Nitro-thiophene -2- formic acid (2.336g, It 13.5mmol) is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and saturation is added Reaction is quenched in sodium bicarbonate solution.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, through anhydrous sodium sulfate It is dry, it filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) it, obtains as yellow solid 2- (5- Nitro-thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine (110mg, 6.2%).

Step 2：By 2- (5- Nitro-thiophene -2- bases)-thiazole, simultaneously [4,5-c] pyridine (110mg, 0.42mmol) is dissolved in 10mL dichloromethane is slowly added to MCPBA (101mg, 0.59mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 10mL 1M solution of potassium carbonate.Into reaction solution be added 25mL saturated salt solutions, with dichloromethane extraction (50 mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (5- Nitro-thiophene -2- bases)-thiazole And [4,5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (5- Nitro-thiophene -2- bases)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 5mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (50mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- (5- Nitro-thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine (65mg, two step yields for yellow solid 52%).

100 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 10.01 (s, 1H), 8.73 (br s, 1H), 8.29 (d, J=5.2Hz, 1H), 8.25 (d, J= 5.6Hz, 1H), 7.97 (d, J=4.3Hz, 1H), 7.52 (d, J=4.3Hz, 1H), 7.29 (m, 1H), 7.04 (d, J= 5.2Hz,1H), 3.39-3.31(m,1H),3.30-3.25(m,1H),3.19-3.10(m,1H),2.86-2.78(m,1H), 2.68-2.60(m,1H), 2.20-2.12(m,1H),2.09-1.98(m,2H),1.47-1.38(m,1H).ESI-MS m/z： 407.4[M+H]⁺。

Embodiment 101, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (4- methylthiazol -5- bases) thiophene Azoles simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (4- methylthiazol -5- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By 3- amino -4- mercaptopyridines (819mg, 6.5mmol) and 4- methyl-thiazole-5s-formic acid (1.86g, 13 Mmol it) is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and unsaturated carbonate is added Reaction is quenched in hydrogen sodium solution.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, It filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) 2- for yellow solid, is obtained (4- methyl-thiazole-5s-yl)-thiazole simultaneously [4,5-c] pyridine (677mg, 44.7%).¹H NMR(400MHz, CDCl₃)δ9.38 (s, 1H), 8.87 (s, 1H), 8.57 (d, J=5.4Hz, 1H), 7.89 (dd, J=5.4,0.8Hz, 1H), 2.92 (s, 3H).

Step 2：By 2- (4- methyl-thiazole-5s-yl)-thiazole, simultaneously [4,5-c] pyridine (677mg, 2.9mmol) is dissolved in 40mL Dichloromethane is slowly added to MCPBA (702mg, 4.1mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, and 10mL is added Reaction is quenched in 1M solution of potassium carbonate.50mL saturated salt solutions are added into reaction solution, extracts (50 mL × 2) with dichloromethane, closes And organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (4- methyl-thiazole-5s-yl)-thiazole simultaneously [4, 5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (4- methyl-thiazole-5s-yl)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 8mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (50mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- (4- methyl-thiazole-5s-yl)-thiazole simultaneously [4,5-c] pyridine (482mg, two step yields for light yellow solid 62%).

101 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 10.03 (s, 1H), 8.84 (s, 1H), 8.63 (s, 1H), 8.26 (d, J=5.1Hz, 1H), 8.19 (d, J=5.6Hz, 1H), 7.28 (d, J=5.2Hz, 1H), 7.01 (d, J=5.1Hz, 1H), 3.35-3.22 (m, 2H), 3.17-3.06(m, 1H),2.89(s,3H),2.82-2.72(m,1H),2.64-2.55(m,1H),2.15-2.05(m,1H), 2.03-1.92(m,2H), 1.46-1.33(m,1H).ESI-MS m/z：422.24[M-H]^-。

Embodiment 102, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (2- methylthiazol -5- bases) thiophene Azoles simultaneously [4,5-c] pyridine -4- amine

Step 1：By 3- amino -4- mercaptopyridines (500mg, 4mmol) and 2- methyl-thiazole-5s-formic acid (1.145g, It 8mmol) is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and saturated carbon is added Reaction is quenched in sour hydrogen sodium solution.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, dry through anhydrous sodium sulfate It is dry, it filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) it, obtains as yellow solid 2- (2- methyl-thiazole-5s-yl)-thiazole simultaneously [4,5-c] pyridine (400mg, 43%).¹H NMR(400MHz,CDCl₃)δ 9.32 (d, J=0.5Hz, 1H), 8.54 (d, J=5.4Hz, 1H), 8.21 (s, 1H), 7.84 (dd, J=5.4,0.5Hz, 1H), 2.82 (s,3H)。

Step 2：By 2- (2- methyl-thiazole-5s-yl)-thiazole, simultaneously [4,5-c] pyridine (400mg, 1.72mmol) is dissolved in 30mL dichloromethane is slowly added to MCPBA (416mg, 2.41mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 10mL 1M solution of potassium carbonate.Into reaction solution be added 50mL saturated salt solutions, with dichloromethane extraction (50 mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (2- methyl-thiazole-5s-yl)-thiazole And [4,5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (2- methyl-thiazole-5s-yl)-thiazole, simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in 8mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to borneol and remaining POCl is quenched₃, saturated sodium bicarbonate is added and adjusts PH is extracted with ethyl acetate (50mL × 3) to neutrality, merges organic phase, is dried over anhydrous sodium sulfate, filters and be concentrated under reduced pressure, Obtain the chloro- 2- of 4- (2- methyl-thiazole-5s-yl)-thiazole simultaneously [4,5-c] pyridine (120mg, two step yields for light yellow solid 26%).

102 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃)δ9.82(s,1H),8.22-8.09(m,3H),7.26-7.24(m,1H),7.02-6.94(m, 1H), 3.52-3.43(m,1H),3.40-3.31(m,2H),3.09-3.00(m,2H),2.82(s,3H),2.22-2.11(m, 1H), 2.03-1.91(m,2H),1.72-1.62(m,1H).ESI-MS m/z：424.24[M+H]⁺。

Embodiment 103, (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (1- methyl-1 H- pyrazoles -5- Base) thiazole simultaneously [4,5-c] pyridine -4- amine

The preparation of the chloro- 2- of 4- (1- methyl-1 H- pyrazoles -5- bases) thiazole simultaneously [4,5-c] pyridine

Step 1：By 3- amino -4- mercaptopyridines (500mg, 4mmol) and 1- methyl-1 H- pyrazoles -5- formic acid (1g, It 8mmol) is dissolved in polyphosphoric acids (PPA), 140 DEG C of tube sealing reactions.The reaction was complete for TLC detections.Reaction was completed, and saturated carbon is added Reaction is quenched in sour hydrogen sodium solution.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, dry through anhydrous sodium sulfate It is dry, it filters and is concentrated under reduced pressure.(petroleum ether is isolated and purified by preparing TLC：Ethyl acetate=1：1) it, obtains as yellow solid 2- (1- methyl-1 H- pyrazoles -5- bases)-thiazole simultaneously [4,5-c] pyridine (432mg, 50%).¹H NMR(400MHz,CDCl₃) δ 9.38 (s, 1H), 8.57 (d, J=5.4Hz, 1H), 7.87 (d, J=5.4Hz, 1H), 7.57 (d, J=2.0Hz, 1H), 6.85 (d, J=2.0Hz, 1H), 4.43 (s, 3H).

Step 2：By 2- (1- methyl-1 H- pyrazoles -5- bases), simultaneously [4,5-c] pyridine (432mg, 2mmol) is dissolved in-thiazole 30mL dichloromethane is slowly added to MCPBA (483mg, 2.8mmol), is stirred at room temperature, and TLC is monitored to the reaction was complete, is added Reaction is quenched in 10mL 1M solution of potassium carbonate.Into reaction solution be added 50mL saturated salt solutions, with dichloromethane extraction (50 mL × 2), merge organic phase, be dried over anhydrous sodium sulfate, filter and be concentrated under reduced pressure, obtain 2- (1- methyl-1 H- pyrazoles -5- bases)-thiophene Azoles simultaneously [4,5-c] pyridine -5- oxide crude products.It does not purify, is directly used in and reacts in next step.

Step 3：By 2- (1- methyl-1 H- pyrazoles -5- bases), simultaneously [4,5-c] pyridine -5- oxide crude products are dissolved in-thiazole 8mL POCl₃, flow back 5h.Reaction solution is concentrated under reduced pressure, is slowly added to ice water and remaining POCl is quenched₃, saturated sodium bicarbonate is added PH is adjusted to neutrality, is extracted with ethyl acetate (50mL × 3), merges organic phase, is dried over anhydrous sodium sulfate, filters and depressurize Concentration, obtain for yellow solid the chloro- 2- of 4- (1- methyl-1 H- pyrazoles -5- bases)-thiazole simultaneously [4,5-c] pyridine (342mg, two Walk yield 68.4%).

103 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18.¹H NMR (400MHz,CDCl₃) δ 9.88 (s, 1H), 8.43 (brs, 1H), 8.26 (d, J=5.2Hz, 1H), 8.19 (d, J= 5.6Hz, 1H), 7.56 (d, J=2.1Hz, 1H), 7.29 (d, J=5.6Hz, 1H), 7.01 (d, J=5.3Hz, 1H), 6.81 (d, J=2.1 Hz, 1H), 4.42 (s, 3H), 3.34-3.27 (m, 1H), 3.20-3.09 (m, 2H), 2.78-2.60 (m, 2H), 2.11-2.03(m,1H), 1.97-1.87(m,1H),1.83-1.72(m,1H),1.45-1.34(m,1H).ESI-MS m/z： 407.35[M+H]⁺。

Embodiment 104,2- amino -6- methyl -4- (3- (2- (thiophene -2- bases) thiazole simultaneously [4,5-c] pyridin-4-yl amine Base) pyridin-4-yl) cyclohexyl-acetic acid ester

104 compound of the embodiment of the present invention is prepared according to method 1, specific synthesized reference embodiment 18.ESI-MS m/z： 480.95 [M+H]⁺。

Embodiment 105,2- amino -6- methyl -4- (3- (2- (thiazol-2-yl) thiazole simultaneously [4,5-c] pyridin-4-yl amine Base) pyridin-4-yl) cyclohexyl-acetic acid ester

105 compound of the embodiment of the present invention is prepared according to method 1, other preparation processes are prepared according to embodiment 18. ESI-MS m/z：482.11[M+H]⁺。

D biological tests

Test case 1:Pim1ATP loss tests

It is to assess compound to the active influences of kinases Pim1, utilizes ADP-Glo^TM(promega companies) kit measurement ATP consumes to detect kinase activity in zymetology reaction.Sample to be tested is dissolved in DMSO.In microwell plate, Pim1 is added per hole Kinases, reaction buffer (pH containing Tris-HCl 7.5, MgCl₂, DTT and BSA), ATP, kinase substrate (S6K substrates) and sample Product (per 25 μ L of hole total volume), while setting up blank control (without enzyme and sample) and negative control (being free of sample)；Room temperature is anti- After answering 60min, ADP-Glo Reagent are added, the reaction was continued at ambient temperature, and 40min makes extra ATP inactivate；Then Kinase Detection Reagent are added, after reacting at room temperature 30min, measure the chemiluminescence intensity L per hole.According to change Learn the inhibiting rate that luminous intensity L values calculate compound, inhibiting rate=[1- (L_Sample-L_Blank)/(L_{It is negative} -L_Blank)] × 100%.Each Sample first carries out primary dcreening operation under specific single concentration conditions, and at least six is further arranged in the sample for inhibiting rate more than 50% Different concentration gradients measures its IC₅₀Value, the value are as shown in table 2.

Test case 2:Pim2ATP loss tests

It is to assess compound to the active influences of kinases Pim2, utilizes ADP-Glo^TM(promega companies) kit measurement ATP consumes to detect kinase activity in zymetology reaction.Sample to be tested is dissolved in DMSO.In microwell plate, Pim2 is added per hole Kinases, reaction buffer (pH containing Tris-HCl 7.5, MgCl₂, DTT and BSA), ATP, kinase substrate (S6K substrates) and sample Product (per 25 μ L of hole total volume), while setting up blank control (without enzyme and sample) and negative control (being free of sample)；Room temperature is anti- After answering 60min, ADP-Glo Reagent are added, the reaction was continued at ambient temperature, and 40min makes extra ATP inactivate；Then Kinase Detection Reagent are added, after reacting at room temperature 30min, measure the chemiluminescence intensity L per hole.According to change Learn the inhibiting rate that luminous intensity L values calculate compound, inhibiting rate=[1- (L_Sample-L_Blank)/(L_{It is negative} -L_Blank)] × 100%.Each Sample first carries out primary dcreening operation under specific single concentration conditions, and at least six is further arranged in the sample for inhibiting rate more than 50% Different concentration gradients measures its IC₅₀Value, the value are as shown in table 2.

Test case 3:Pim3ATP loss tests

It is to assess compound to the active influences of kinases Pim3, utilizes ADP-Glo^TM(promega companies) kit measurement ATP consumes to detect kinase activity in zymetology reaction.Sample to be tested is dissolved in DMSO.In microwell plate, Pim3 is added per hole Kinases, reaction buffer (pH containing Tris-HCl 7.5, MgCl₂, DTT and BSA), ATP, kinase substrate (S6K substrates) and sample Product (per 25 μ L of hole total volume), while setting up blank control (without enzyme and sample) and negative control (being free of sample)；Room temperature is anti- After answering 60min, ADP-Glo Reagent are added, the reaction was continued at ambient temperature, and 40min makes extra ATP inactivate；Then Kinase Detection Reagent are added, after reacting at room temperature 30min, measure the chemiluminescence intensity L per hole.According to change Learn the inhibiting rate that luminous intensity L values calculate compound, inhibiting rate=[1- (L_Sample-L_Blank)/(L_{It is negative} -L_Blank)] × 100%.Each Sample first carries out primary dcreening operation under specific single concentration conditions, and at least six is further arranged in the sample for inhibiting rate more than 50% Different concentration gradients measures its IC₅₀Value, the value are as shown in table 2.

Using test case 1 (Pim1ATP loss tests), test case 2 (Pim2ATP loss tests) and 3 (Pim3 of test case ATP loss tests) operation, measure embodiment compound IC₅₀Value, shown in table 2 specific as follows.

Table 2

Pim kinase activity test results show that multiple embodiments significantly inhibit work to three hypotypes of pim kinases Property, wherein embodiment 1,58,59,68 and 95 couples of pim1/2/3 all show the inhibitory activity of nM ranks.

Claims

1. formula (I) compound or its stereoisomer, tautomer, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable Salt or solvate,

Wherein：

A is selected from 5-6 unit's heteroaryls and phenyl, wherein the heteroaryl and phenyl can be by selected from halogen, trifluoromethyl, difluoro first Base, C_1-4Alkyl and C_1-4The substituent group of alkoxy is replaced；

X is selected from 5-6 membered heterocycloalkyls ,-NH-C_3-6Naphthenic base ,-NH-C_1-4Alkyl amino, 5-6 unit's heteroaryls and 5-6 member cycloalkanes Base, wherein the Heterocyclylalkyl, heteroaryl and naphthenic base can be by selected from halogen ,-NH₂、C_1-6Alkyl, cyano, hydroxyl, sulfydryl, three Methyl fluoride, difluoromethyl, trifluoromethoxy, difluoro-methoxy, C_1-4The substituent group substitution of alkoxy, acyl group, ester group；

Z₁For N when, Z₂For S, NH or O；

Z₁For S when, Z₂For N；

Z₁For-N=CH- or-CH=CH- when, Z₂For N；

R is selected from hydrogen, halogen, phenyl, 5-6 unit's heteroaryls, 5-6 membered heterocycloalkyls, C_3-6Naphthenic base, C_1-6Alkyl and The wherein described phenyl, 5-6 unit's heteroaryls, 5-6 membered heterocycloalkyls, C_3-6Naphthenic base and C_1-6Alkyl can be by selected from halogen ,-NH₂, hydroxyl Base, sulfydryl, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoro-methoxy, carboxyl, acyl group, ester group, C_1-4 Alkyl, C_1-4Alkoxy and C_1-4The substituent group of halogenated alkyl is replaced.

2. formula (I) compound as described in claim 1 or its stereoisomer, tautomer, nitrogen oxides, metabolin, Prodrug, pharmaceutically acceptable salt or solvate, wherein：

A is selected from：

Wherein, * is the tie point with X,It is the tie point with NH；

R²Selected from C_1-4Alkyl.

3. formula (I) compound as described in claim 1 or its stereoisomer, tautomer, nitrogen oxides, metabolin, Prodrug, pharmaceutically acceptable salt or solvate, wherein：

X is selected from：

Wherein, * is the tie point with A.

4. formula (I) compound as described in claim 1 or its stereoisomer, tautomer, nitrogen oxides, metabolin, Prodrug, pharmaceutically acceptable salt or solvate, wherein：

It is selected from：

Wherein, * is the tie point with NH,It is the tie point with R；

R⁴Selected from hydrogen and C_1-4Alkyl.

5. formula (I) compound as described in claim 1 or its stereoisomer, tautomer, nitrogen oxides, metabolin, Prodrug, pharmaceutically acceptable salt or solvate, wherein：

R is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclopenta, cyclohexyl and benzene Base, wherein the cyclopropyl, cyclopenta, cyclohexyl and phenyl are optionally independently selected from fluorine, chlorine, bromine, iodine, nitre by one or more Base, trifluoromethyl, acyl group, C_1-4Alkyl and C_1-4The substituent group of alkoxy is replaced；Or

R be selected from furans, pyridine, thiophene, thiazole, isothiazole, pyrimidine, pyrazoles, imidazoles, oxazole, isoxazole, pyrazine, Wherein each described R is optionally independently selected from fluorine, chlorine, bromine, iodine, nitro, acyl group and C by one or more_1-4The substitution of alkyl Base is replaced；

Wherein,R withThe tie point of parent compound, * are the tie points with NH.

6. a kind of compound or its stereoisomer, tautomer, nitrogen oxidation of formula (I) as defined in claim 1 Object, metabolin, prodrug, pharmaceutically acceptable salt or solvate, selected from the group being made of following compounds：

7. compound or its stereoisomer, tautomer, nitrogen oxides, generation as described in any one of claim 1 to 6 Object, prodrug, pharmaceutically acceptable salt or solvate are thanked, drug or drug of the treatment by Pim kinase mediated diseases are being prepared Application in composition.

8. drug as claimed in claim 7 or pharmaceutical composition, it to be used for controlling for treating cancer and/or immune correlated disease It treats.

9. formula (I) compound according to claim 1 or its stereoisomer, tautomer, nitrogen oxides, metabolism Object, prodrug, pharmaceutically acceptable salt or solvate,

Wherein, X is amino substituted piperidine base, difluoro substituted piperidine base, and A is the pyridyl group that X group replaces or X group and trifluoro Methyl substituted pyridyl group；It is highly preferred that X is 3- amino substituted piperidine 1- bases (R or S configurations), A is the pyridine of X group substitution Base；

Z1 is N；Z2 is S；Or Z1 is S；Z2 is N；Preferably, Z1 N；Z2 is S；

R is phenyl or phenyl by selected from halogen, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, hydroxyl, sulfydryl, nitro, cyanogen One or two or more the phenyl replaced in base, carboxyl, acyl group, ester group；Or

R is selected from furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrimidine radicals, pyrazolyl, imidazole radicals, oxazolyl, different Oxazolyl or pyrazinyl；Or furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrimidine radicals, pyrazolyl, imidazole radicals, Any one of oxazolyl, isoxazolyl, pyrazinyl are by selected from halogen, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, hydroxyl In base, sulfydryl, nitro, cyano, carboxyl, acyl group, ester group one or two or more substituent group substitution group or they in Any benzo groups；

The wherein described halogen and C_1-4Halogen in halogenated alkyl be any one of fluorine, chlorine, bromine or iodine or more than one.

10. formula (I) compound according to claim 9 or its stereoisomer, tautomer, nitrogen oxides, metabolism Object, prodrug, pharmaceutically acceptable salt or solvate,

Z1 is N；Z2 is S；Or Z1 is S；Z2 is N；Preferably, Z1 N；Z2 is S；

R is one kind in phenyl, furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazole radicals； Or R is a kind of quilt in phenyl, furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrazolyl, imidazole radicals Selected from halogen, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4It is any or a kind of in alkoxy, hydroxyl, sulfydryl, carboxyl, acyl group, ester group The group of above group substitution.

11. formula (I) compound according to claim 10 or its stereoisomer, tautomer, nitrogen oxides, generation Thank object, prodrug, pharmaceutically acceptable salt or solvate, wherein R is selected from phenyl, furyl, pyridyl group, thienyl, thiophene One kind in oxazolyl, isothiazolyl, pyrazolyl or imidazole radicals；Or R is by selected from halogen, C_1-4Alkyl or C_1-4Halogenated alkyl In any one or more group substitutions selected from phenyl, furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, One kind in pyrazolyl, imidazole radicals.

12. formula (I) compound according to claim 11 or its stereoisomer, tautomer, nitrogen oxides, generation Thank object, prodrug, pharmaceutically acceptable salt or solvate, wherein R is for phenyl or by halogen, methyl, ethyl or halogenated first The phenyl or furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazole radicals that base, halogenated ethyl replace； Or it is a kind of by halogen, first in furyl, pyridyl group, thienyl, thiazolyl, isothiazolyl, pyrazolyl, imidazole radicals Base, ethyl, halogenated methyl or the group of halogenated ethyl substitution；

The halogen is fluorine, the C preferably wherein_1-4Halogenated alkyl is fluoromethyl, difluoromethyl, trifluoromethyl；Fluoro second Base, bis-fluoro ethyls, trifluoroethyl, four fluoro ethyls, pentafluoroethyl group or hexafluoro ethyl.

13. formula (I) compound according to claim 12 or its stereoisomer, tautomer, nitrogen oxides, generation Thank object, prodrug, pharmaceutically acceptable salt or solvate, wherein R be phenyl or phenyl-monofluoride base or difluorophenyl or Fluoro p-methylphenyl or two (fluoromethyl) phenyl or two (trifluoromethy) phenyl；Or furyl, pyridyl group, thiophene Base, thiazolyl, isothiazolyl, pyrazolyl or imidazole radicals；Or selected from furyl, pyridyl group, thienyl, thiazolyl, isothiazole A kind of group replaced by methyl, fluorine, and/or fluoromethyl in base, pyrazolyl, imidazole radicals.

14. according to claim 4 or claim 9-13 any one of them formula (I) compound or its stereoisomer, change Isomers, nitrogen oxides, metabolin, prodrug, pharmaceutically acceptable salt or solvate, wherein

Selected from following formula B1 or formula B2：

Wherein, * is the tie point with NH,It is the tie point with R；Each R³It independently obtains selected from hydrogen, halogen, C_1-4Alkyl And C_1-4It is one or more than one kinds of in halogenated alkyl；It is preferred that the halogen or C_1-4Halogen in halogenated alkyl be selected from fluorine, chlorine, One or more in bromine or iodine.

15. formula (I) compound according to claim 14 or its stereoisomer, tautomer, nitrogen oxides, generation Thank object, prodrug, pharmaceutically acceptable salt or solvate, wherein the R³It is so independent that be selected from hydrogen, fluorine, methyl or three fluoro One or more in methyl；Wherein, the R is phenyl or difluorophenyl；Or furyl, pyridyl group, thienyl, thiophene Oxazolyl, isothiazolyl, pyrazolyl or imidazole radicals；Or methylfuran base, fluoro furyl, fluoromethane are for furyl, methyl pyrrole Piperidinyl, fluorinated pyridine base, fluoromethane are for pyridyl group, methyl thiazolium oxazolyl, fluoro thiazolyl, fluoromethane for thiazolyl, the different thiophene of methyl Oxazolyl, fluoro isothiazolyl, fluoromethane are for isothiazolyl, methylthiophene base, fluoro thienyl, fluoromethane for thienyl, methyl Pyrazolyl, fluoro pyrazolyl, fluoromethane are for pyrazolyl, methylimidazolyl, fluoro imidazole radicals or fluoromethane for appointing in imidazole radicals It is a kind of.

16. formula (I) compound described in claim 1-15 or its stereoisomer, tautomer, nitrogen oxides, metabolism The preparation method of object, prodrug, pharmaceutically acceptable salt or solvate, wherein make shown in following intermediate compound Is and intermediate II Compound carry out halogenated aryl hydrocarbon aminating reaction obtain

17. formula (I) compound according to claim 16 or its stereoisomer, tautomer, nitrogen oxides, generation Thank to the preparation method of object, prodrug, pharmaceutically acceptable salt or solvate, wherein by the preparation side for including following processes Method obtains：

Step 1：- 4 mercapto-pyridine of 3- amino is prepared,

Step 2：Thiazole simultaneously [4,5-c] pyridine is prepared,

(2) process 2：(S)-N- (- 3 base of 4- (3- amino piperidine -1- bases) pyridine) -2- (2,6- difluorophenyls) thiazole simultaneously [4,5- C] pyridine -4- amine preparation, it includes following step：

Step 1 prepares (S) -1- (3- (2- (2,6- difluorophenyls) thiazole simultaneously [4,5-c] pyridin-4-yl-amido) pyridine -4- Base) piperidines -3- amidocarbonic acid tertiary butyl esters, and

Step 2, prepare (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (2,6- difluorophenyls) thiazole simultaneously [4, 5-c] pyridine -4- amine.

18. formula (I) compound according to claim 16 or its stereoisomer, tautomer, nitrogen oxides, generation Thank to the preparation method of object, prodrug, pharmaceutically acceptable salt or solvate, wherein by the preparation side for including following processes Method obtains：

(2) process 2：Prepare (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (thiazol-2-yl) thiazole simultaneously [4, 5-c] pyridine -4- amine comprising following step：Make the chloro- 2- of 4- (thiazol-2-yl)-thiazole simultaneously [4,5-c] pyridine and (S)-tertiary fourth Base (1- (3- aminopyridine -4- bases) piperidines -3- bases) urethane reaction, the blocking group tertiary butyl oxygen for then removing amino Carbonyl obtains (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (thiazol-2-yl) thiazole simultaneously [4,5-c] pyridine - 4- amine.

19. formula (I) compound according to claim 16 or its stereoisomer, tautomer, nitrogen oxides, generation Thank to the preparation method of object, prodrug, pharmaceutically acceptable salt or solvate, wherein by the preparation side for including following processes Method obtains：

(2) process 2：Prepare (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (thiophene -2- bases) thiazole simultaneously [4, 5-c] pyridine -4- amine comprising following step：Make the chloro- 2- of 4- (thiophene -2- bases)-thiazole simultaneously [4,5-c] pyridine and (S)-tertiary fourth Base (1- (3- aminopyridine -4- bases) piperidines -3- bases) urethane reaction, the blocking group tertiary butyloxycarbonyl for then removing amino Base obtains (S)-N- (4- (3- amino piperidine -1- bases) pyridin-3-yl) -2- (thiophene -2- bases) thiazole simultaneously [4,5-c] pyridine -4- Amine.