CN108373476B - Kinase inhibitor and preparation and application thereof - Google Patents

Abstract

The present invention provides a compound of formula (I), or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament or pharmaceutical composition for the treatment of a disease mediated by Pim kinase.

Description

Kinase inhibitor and preparation and application thereof

Technical Field

The invention relates to a compound of formula (I) as a Pim kinase inhibitor and application thereof in preparing medicaments or medicinal compositions for treating Pim kinase mediated diseases such as cancers and immune related diseases.

Background

The Pim (Proviral Integration Moloney virus) gene is a family of proto-oncogenes that encode a group of silk/threonine kinases, namely Pim1, Pim2 and Pim 3. Pim kinases belong to the calcium ion/calmodulin-dependent protein kinase superfamily and are highly conserved in the process of multicellular evolution. Pim1^-/-Pim2^-/-Pim3^-/-Mice survive normally and have fertility, but they have a significantly reduced size and impaired response to hematopoietic growth factors; however, there was no significant phenotypic difference in mice with only a single Pim subtype deletion, indicating a certain degree of functional redundancy among Pim protein family members (Mikkers, H. et al, mol. cell. biol.2004,24(13), 6104-.

Pim1 kinase has increased expression levels in human myeloid and lymphoid leukemias and lymphomas (Wang, Z. et al, J.Vet.Sci. 2001,2(3), 167-. In Acute Myeloid Leukemia (AML), the mRNA level of Pim1 is increased with genetic alterations in the MLL gene (Chen, W., et al, Cancer Cell 2008,13(5), 432-. It has been reported that increased expression of Pim1 or Pim3 may be a key factor in the development of some B-cell diseases associated with Kaposi's Sarcoma Herpes Virus (KSHV) or Epstein Barr Virus (EBV) (Cheng, F. et al, PLoS Patholog.2009, 5(3), e 1000324; Bajaj, B. G. et al, Virology 2006,351(1), 18-28). Recently, overexpression of Pim1 has also been observed in a variety of solid tumors, including pancreatic, prostate, squamous cell, gastric, colorectal, liver, liposarcoma, and bladder (Bachmann, M. et al, int.J.biochem.cell.biol.2005,37(4), 726-.

It was found that elevated levels of Pim2 kinase were detected in AML patients (tambourini, j. et al, Blood 2009, 114(8), 1618-. In addition, Pim2 expression levels were elevated in Prostate cancer and were associated with decreased cell hyperproliferation and apoptosis (Dai, H., et al, Prostate 2005,65(3), 276-. Several in vitro studies have shown that Pim2 kinase is also associated with liver cancer (Brault, L., et al, Haematologica 2010,95(6), 1004-.

Abnormal expression of Pim3 was observed in malignancies such as liver Cancer, pancreatic Cancer and Ewing's sarcoma (Brault, L. et al, Haematologica 2010,95(6), 1004-. It was found that Pim3 was highly expressed at the site of human hepatocellular carcinoma and pancreatic carcinoma lesions, but Pim3 overexpression was not observed in normal liver cells and pancreatic tissues (Li, Y.Y., et al, Cancer Res.2006,66(13), 6741-6747; Fujii, C. et al, int.J.cancer 2005,114(2), 209-218); furthermore, Pim3mRNA is also overexpressed in human Ewing sarcoma Cell lines and nasopharyngeal carcinoma Cell lines (Deneen, B. et al, mol. Cell. biol.2003,23 (11)), 3897-.

Therefore, the overexpression of the Pim kinase is closely related to the occurrence and development of various tumors, and Pim kinase inhibitors have special significance for treating cancers related to Pim kinase activity. Research shows that dominant negative mutation Pim1 can reduce the tumorigenicity of a pancreatic cancer cell and Hela cell xenograft mouse model (Chen, J. et al, am.J.Pathol.2009,175(1), 400-11). In vivo experiments showed that the Pim2 and Pim3 deletions significantly inhibited the growth of 3-methylcholanthrene-induced sarcomas with tumor-inhibiting effects comparable to those of all Pim kinase deletions (Narlik-Grassow, M. et al, Carcinogenesis 2012,33(8), 1479-1486). The migration inhibition rate of siRNA interference targeting Pim1 and Pim2 on PC3 cells is 50%; when all Pim family kinases were inhibited with DHPCC-9, the mobility inhibition increased to 90% (Santio, N.M. et al, mol. cancer 2010,9, 279-291). In vivo and in vitro studies have shown that the Pim inhibitor DHPCC-9 can inhibit the migration and invasion of solid tumor cells such as prostate cancer and head and neck squamous cell carcinoma (pause, n.m., et al, mol. cancer 2010,9, 279-289); the compound CX-4945 shows dose-dependent anticancer activity on various solid tumors and blood tumors (Pierre, F. et al, mol. cell. biochem.2011,6 (1-2), 37-3; Pierre, F. et al, bioorg. Med. chem. Lett.2011,21(22), 6687-. Compound CXR1002 has cytotoxic effects on a variety of human ovarian, pancreatic and sarcoma cells, while CXR1002 has synergistic anticancer effects with a variety of anticancer drugs (especially gemcitabine, doxorubicin, geldanamycin, MAPK inhibitors and AKT/PI3K inhibitors) (Barnett, a. et al, EJC suppl.2010,8(7), 45-46). In addition, Pim inhibitors have chemotherapeutic or radiosensitizing effects (Xu, D. et al, Cardinogenesis 2011,32(4), 488-28495; Mumenthaler, S.M. et al, mol. cancer ther.2009,8(10), 2882-2893).

Pim kinase also has a certain immunomodulatory effect. It was found that Pim2 has increased expression levels in various inflammatory conditions (Li, j, et al, US patent,20030125231a 1); pim2 has a positive regulatory effect on IL-6, i.e., an increase in kinase levels stimulates increased IL-6 levels (Yang, J. et al, Immunology 2010,131, 174-182). Meanwhile, Pim1 and Pim2 are also associated with cytokine-induced T-cell growth and survival (Fox, J. et al, J.Exp.Med.2005,201(2), 259-66). Therefore, Pim inhibitors are useful as therapeutic agents for immune-related diseases such as inflammation, autoimmune diseases, allergy, and immunosuppression in organ transplantation.

Currently, several small molecule Pim inhibitors (e.g., CX-4945, AZD-1208, CXR1002, LGH447, etc.) have entered clinical research. The small molecule Pim inhibitor LGH447 with the fastest research progress has entered clinical phase II research, but the synthetic route of the compound is long and can be obtained only through 15 steps of reaction (US2010056576a1, CN 102203079A); and the molecule of the compound has three chiral centers, and chiral separation is needed to obtain a single optical isomer. The small molecule inhibitor of Pim, SGI-1776, has terminated further development of this molecule due to its cardiotoxic response. Therefore, there is an urgent need to develop small molecule Pim inhibitors that are easier to prepare, have better activity and have good drug-like properties.

Disclosure of Invention

The present invention relates to novel small molecule inhibitor compounds of Pim, pharmaceutically acceptable salts, solvates and prodrugs thereof. The invention also relates to compositions of these compounds, alone or in combination with at least one other therapeutic agent and optionally a pharmaceutically acceptable carrier. The invention further relates to methods of using these compounds, alone or in combination with at least one other therapeutic agent, in the prevention or treatment of a disease mediated by Pim kinase. Such Pim inhibitors are not only easier to prepare (only 9 steps are required) but also possess only one chiral centre and can be prepared as single optical isomers without chiral separation by starting with commercially available chiral compounds.

The present invention also provides a compound of formula (I):

wherein:

a is selected from 5-6 membered heteroaryl and phenyl, wherein said heteroaryl and phenyl may be selected from halogen, trifluoromethyl, difluoromethyl, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

x is selected from 5-6 membered heterocycloalkyl, -NH-C_3-6Cycloalkyl, -NH-C_1-4Alkylamino, 5-6 membered heteroaryl and 5-6 membered cycloalkyl, wherein said heterocycloalkyl, heteroaryl and cycloalkyl groups may be selected from halogen, -NH₂、C_1-6Alkyl, cyano, hydroxy, mercapto, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, C_1-4Substituent substitution of alkoxy, acyl and ester group;

Z₁when is N, Z₂S, NH or O;

Z₁when is S, Z₂Is N;

Z₁when-N ═ CH-or-CH ═ CH-, Z₂Is N;

r is selected from hydrogen, halogen, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, C_3-6Cycloalkyl radical, C_1-6Alkyl radicals and

wherein said phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, C_3-6Cycloalkyl and C_1-6Alkyl may be selected from halogen, -NH₂Hydroxy, mercapto, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, carboxy, acyl, ester, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4Substituted by a substituent of a haloalkyl group.

In some specific embodiments, the present invention provides compounds of formula (I), wherein a is selected from:

wherein is the point of attachment to X,

is the point of attachment to NH;

each R¹Each independently selected from halogen, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4A haloalkyl group;

R²is selected from C_1-4An alkyl group;

or a stereoisomer, tautomer, nitroxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof.

In other specific embodiments, the present invention provides compounds of formula (I), wherein:

x is selected from:

wherein is the point of attachment to a;

or a stereoisomer, tautomer, nitroxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof.

In other embodiments, the invention provides compounds of formula (I), wherein:

selected from:

wherein is the point of attachment to NH,

is the point of attachment to R;

each R³Each independently selected from hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4A haloalkyl group;

R⁴selected from hydrogen and C_1-4An alkyl group;

or a stereoisomer, tautomer, nitroxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof.

In other specific embodiments, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrogen oxides, metabolites, prodrugs, pharmaceutically acceptable salts, or solvates thereof, wherein:

r is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclopentyl, cyclohexyl, and phenyl, wherein said cyclopropyl, cyclopentyl, cyclohexyl, and phenyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, acyl, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy; or

R is selected from furan, pyridine, thiophene, thiazole, isothiazole, pyrimidine, pyrazole, imidazole, oxazole, isoxazole, pyrazine, and mixtures thereof,

Wherein each of said R is optionally substituted with one or more groups independently selected from fluoro, chloro, bromo, iodo, nitro, acyl, and C_1-4Alkyl substituents.

The present invention provides a compound as described herein, or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof, and use thereof for the preparation of a medicament or pharmaceutical composition for the treatment of a disease mediated by Pim kinase. The disease mediated by Pim kinase includes cancer and/or immune related diseases.

The present invention relates to the use of a compound or pharmaceutical composition of the invention for modulating protein kinase activity in a biological sample in the manufacture of a medicament. The invention further relates to the use of the compounds of the invention for inhibiting Pim kinase activity in a biological sample.

In each embodiment of the invention, the compound, such as a compound of formula (I), may be used to prepare a medicament or pharmaceutical composition for inhibiting Pim kinase.

Detailed Description

Throughout this application, various embodiments of the compounds and methods of the present invention are referenced herein. The described embodiments are intended to provide illustrative examples and should not be construed as descriptions of alternatives. It should also be noted that the embodiments discussed herein (including the various methods and parameters) are merely illustrative of the present invention and do not limit the scope of the invention in any way.

A Compounds

The present invention also provides a compound of formula (I), or a stereoisomer, tautomer, nitroxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof:

wherein:

a is selected from 5-6 membered heteroaryl and phenyl, wherein said heteroaryl and phenyl may be selected from halogen, trifluoromethyl, difluoromethyl, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

x is selected from 5-6 membered heterocycloalkyl, -NH-C_3-6Cycloalkyl, -NH-C_1-4Alkylamino, 5-6 membered heteroaryl and 5-6 membered cycloalkyl, wherein said heterocycloalkyl, heteroaryl and cycloalkyl groups may be selected from halogen, -NH₂、C_1-6Alkyl, cyano, hydroxy, mercapto, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, C_1-4Substituent substitution of alkoxy, acyl and ester group;

Z₁when is N, Z₂S, NH or O;

Z₁when is S, Z₂Is N;

Z₁when-N ═ CH-or-CH ═ CH-, Z₂Is N;

r is selected from hydrogen, halogen, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, C_3-6Cycloalkyl radical, C_1-6Alkyl radicals and

wherein said phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, C_3-6Cycloalkyl and C_1-6Alkyl may be selected from halogen, -NH₂Hydroxy, mercapto, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, diFluoromethoxy group, carboxyl group, acyl group, ester group, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4Substituted by a substituent of a haloalkyl group.

In some specific embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, nitric oxide, metabolite, prodrug, pharmaceutically acceptable salt, or solvate thereof, wherein a is selected from:

wherein is the point of attachment to X,

is the point of attachment to NH;

each R¹Each independently selected from halogen, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4A haloalkyl group;

R²is selected from C_1-4An alkyl group.

In other specific embodiments, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrogen oxides, metabolites, prodrugs, pharmaceutically acceptable salts, or solvates thereof, wherein:

x is selected from:

wherein is the point of attachment to a.

In other embodiments, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrogen oxides, metabolites, prodrugs, pharmaceutically acceptable salts, or solvates thereof, wherein:

selected from:

wherein is the point of attachment to NH,

is the point of attachment to R;

each R³Each independently selected from hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4A haloalkyl group;

R⁴selected from hydrogen and C_1-4An alkyl group.

In other specific embodiments, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrogen oxides, metabolites, prodrugs, pharmaceutically acceptable salts, or solvates thereof, wherein:

r is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclopentyl, cyclohexyl, and phenyl, wherein said cyclopropyl, cyclopentyl, cyclohexyl, and phenyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, acyl, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy; or

R is selected from furan, pyridine, thiophene, thiazole, isothiazole, pyrimidine, pyrazole, imidazole, oxazole, isoxazole, pyrazine, and mixtures thereof,

Wherein each of said R is optionally substituted with one or more groups independently selected from fluoro, chloro, bromo, iodo, nitro, acyl, and C_1-4Alkyl substituents.

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

the invention provides a compound shown in a formula (I), or a stereoisomer, a tautomer, an oxynitride, a metabolite, a prodrug, a pharmaceutically acceptable salt or a solvate thereof,

wherein X is amino-substituted piperidyl or difluoro-substituted piperidyl, A is X-group-substituted pyridyl or X group and trifluoromethyl-substituted pyridyl; more preferably, X is a 3-amino-substituted-piperidine 1-yl group (R or S configuration), A is a pyridyl group substituted with the X group;

z1 is N; z2 is S; or Z1 is S; z2 is N; preferably, Z1 is N; z2 is S;

r is phenyl, or phenyl is selected from halogen and C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Phenyl substituted by one or more than two of alkoxy, hydroxyl, sulfydryl, nitro, cyano, carboxyl, acyl and ester group; or

R is selected from furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, or pyrazinyl; or any one of furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and pyrazinyl is selected from halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4A benzo group substituted with one or two or more substituents selected from alkoxy, hydroxyl, mercapto, nitro, cyano, carboxyl, acyl, and ester groups;

wherein said halogen and C_1-4Halogen in the halogenated alkyl is one or more of fluorine, chlorine, bromine or iodine.

In a more preferred embodiment of the present invention, the present invention provides said compound of formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,

wherein X is amino-substituted piperidyl or difluoro-substituted piperidyl, A is X-group-substituted pyridyl or X group and trifluoromethyl-substituted pyridyl; more preferably, X is a 3-amino-substituted-piperidine 1-yl group (R or S configuration), A is a pyridyl group substituted with the X group;

z1 is N; z2 is S; or Z1 is S; z2 is N; preferably, Z1 is N; z2 is S;

r is one selected from phenyl, furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl; or R is one selected from phenyl, furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl and is selected from halogen and C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4And one or more of alkoxy, hydroxyl, sulfydryl, carboxyl, acyl and ester groups.

In a still more preferred embodiment of the present invention, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, nitroxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof, wherein R is one selected from phenyl, furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazolyl; or R is selected from halogen, C_1-4Alkyl, or C_1-4One or more substituted halogenated alkyl groups selected from phenyl, furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl.

In a still more preferred embodiment of the present invention, there is provided a compound of formula (I), or a stereoisomer, tautomer, nitroxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof, wherein R is phenyl, or phenyl substituted with halogen, methyl, ethyl, or halomethyl, haloethyl, or furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazolyl; or one of furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl substituted with halogen, methyl, ethyl, halomethyl or haloethyl;

preferably wherein said halogen is fluorine, said C_1-4The halogenated alkyl is fluoromethyl, difluoromethyl or trifluoromethyl; fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethylOr hexafluoroethyl.

In a still more preferred embodiment of the present invention, there is provided said compound of formula (I), or a stereoisomer, tautomer, nitroxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof, wherein R is phenyl, or monofluorophenyl, or difluorophenyl, or fluoro-p-methylphenyl, or di (fluoromethyl) phenyl or di (trifluoromethyl) phenyl; or furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazolyl; or a group selected from furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl substituted with methyl, fluoro, and/or fluoromethyl.

In a still more preferred embodiment of the present invention, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, pharmaceutically acceptable salt or solvate thereof, wherein,

selected from the following formula B1 or formula B2:

wherein is the point of attachment to NH,

is the point of attachment to R; each of said R³Each independently selected from hydrogen, halogen, C_1-4Alkyl and C_1-4One or more halogenated alkyl groups; preferably, the halogen or halogen in the C1-4 haloalkyl group is selected from one or more of fluorine, chlorine, bromine or iodine.

In still a more preferred embodiment of the present invention, the present invention provides a compound of formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof, wherein R is³Independently selected from one or more of hydrogen, fluorine, methyl or trifluoromethyl; wherein R is phenyl or difluorophenyl; or furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazolyl; or any of methylfuryl, fluorofuryl, methylfluorofuryl, methylpyridyl, fluoropyridyl, methylfluoropyridyl, methylthiazolyl, fluorothiazolyl, methylfluorothiazolyl, methylisothiazolyl, fluoroisothiazolyl, methylfluoroisothiazolyl, methylthiothienyl, fluorothienyl, methylfluorothienyl, methylpyrazolyl, fluoropyrazolyl, methylfluoropyrazolyl, methylimidazolyl, fluoroimidazolyl or methylfluoroimidazolyl.

The present invention relates to typical compounds of formula (I) as shown in table 1, but not limited to the following examples:

TABLE 1

The compounds in table 1 were named using ChemDraw Ultra 11.0, performing IUPAC standard nomenclature.

Definition of B

As used above and elsewhere herein, the following terms and abbreviations have the meanings defined below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

The term "hydrogen" refers herein to-H.

The term "halogen" refers herein to-F, -Cl, -Br, and-I.

The term "fluoro" refers herein to-F.

The term "chloro" refers herein to-Cl.

The term "bromine" refers herein to-Br.

The term "iodine" refers herein to-I.

The term "nitro" refers herein to the group-NO₂。

The term "trifluoromethyl" refers herein to the group-CF₃。

The term "difluoromethyl" refers herein to the group-CHF₂。

The term "trifluoromethoxy" as used herein refers to the group-OCF₃。

The term "difluoromethoxy" as used herein refers to the group-OCHF₂。

The term "hydroxy" refers herein to the group-OH.

The term "mercapto" refers herein to the group-SH.

The term "carboxy" refers herein to the group-COOH or a salt thereof.

The term "cyano" refers herein to the group-CN.

The term "methyl" refers herein to the group-CH₃。

The term "alkyl" refers herein to a saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms, and this term includes straight chain and branched chain hydrocarbon groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and the like.

The term "cycloalkyl" refers herein to cyclic alkyl groups having 3 to 8 carbon atoms, with single or multiple rings (including fused, bridged, and spiro ring systems). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "heterocycloalkyl" refers herein to a non-aromatic cycloalkyl group containing at least one heteroatom selected from O, N and S, and optionally containing one or more double or triple bonds. The heterocycloalkyl group as a whole may have 3 to 8 ring atoms. The heterocycloalkyl group can be covalently attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. One or more of the N or S atoms on the heterocycloalkyl group may be oxidized (e.g., morpholine N-oxide, thiomorpholine S, S-dioxide). Heterocycloalkyl may also contain one or more oxo groups, such as phthalimido, piperidinonyl, oxazolidinonyl, 2,4(1H,3H) -dioxo-pyrimidinyl, pyridine-2 (1H) -onyl, and the like. Non-limiting examples of heterocycloalkyl also include morpholinyl, thiomorpholinyl, pyranyl, imidazolidinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiazolyl, piperidinyl, azetidinyl, piperazinyl, and the like.

The term "aryl" refers herein to a 6-to 8-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group having a conjugated pi-electron system. The aryl group may be covalently linked to the defined chemical structure at any carbon atom that results in a stable structure. In some non-limiting examples, the aryl group may have only aromatic carbocyclic rings, such as phenyl and the like.

The term "heteroaryl" refers herein to an aromatic group consisting of 5 to 8 atoms and containing at least one heteroatom selected from N, O or S. The term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, m-diazepine, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.).

The term "alkoxy" refers herein to a substituted or unsubstituted alkyl-O-group, wherein the alkyl is as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and the like.

The term "acyl" refers herein to the groups H-C (O) -, substituted or unsubstituted alkyl-C (O) -, substituted or unsubstituted cycloalkyl-C (O) -, substituted or unsubstituted heterocycloalkyl-C (O) -, substituted or unsubstituted aryl-C (O) -, and substituted or unsubstituted heteroaryl-C (O) -. Wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and like groups are as defined herein.

The term "ester group" refers herein to the groups substituted or unsubstituted alkyl-O-c (O) -, substituted or unsubstituted alkenyl-O-c (O) -, substituted or unsubstituted alkynyl-O-c (O) -, substituted or unsubstituted cycloalkyl-O-c (O) -, substituted or unsubstituted cycloalkenyl-O-c (O) -, substituted or unsubstituted heterocycloalkyl-O-c (O) -, substituted or unsubstituted aryl-O-c (O) -, and substituted or unsubstituted heteroaryl-O-c (O) -.

The term "substituted" as used herein means that any group is mono-or polysubstituted with the indicated substituent(s) to the extent that such mono-or polysubstitution is chemically permissible, including multiple substitutions on the same moiety, each substituent may be at any available position on the group and may be attached through any available atom on the substituent. "any available position" refers to any position on the group that is chemically accessible by methods known in the art or taught herein and that does not result in an overly labile molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and thus may be the same or different. The substituent refers to a group consisting of the following groups: hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, alkyl, acyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of said groups is as defined herein.

At various positions in this specification, substituents of the compounds of the invention are groups or rangesThe enclosed form is disclosed. This specifically means that the invention includes each member of such groups and ranges or subcombinations of each individual member of the members. Such as the term "C_1-4Alkyl "specifically means that methyl, ethyl, C are disclosed separately₃Alkyl and C₄An alkyl group.

The term "compounds of the invention" (unless specifically indicated otherwise) refers herein to compounds of formula (I) and all pure and mixed stereoisomers, geometric isomers, tautomers, nitrogen oxides, sulfur oxides, solvates, metabolites, prodrugs and isotopically labeled compounds and any pharmaceutically acceptable salts thereof. Solvates of the compounds of the invention refer to compounds or salts thereof, such as hydrates, ethanolates, methanolates, and the like, in combination with stoichiometric and non-stoichiometric amounts of solvent. The compounds may also exist in one or more crystalline states, i.e., as co-crystals, polymorphs, or they may exist as amorphous solids. All such forms are intended to be covered by the claims.

The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith.

The term "stereoisomer" refers herein to compounds of different chirality having one or more stereocenters, including the enantiomers and diastereomers.

The term "tautomer" refers herein to structural isomeric forms having different energies that may cross the low energy barrier, thereby converting each other. Such as proton tautomers include tautomers that undergo interconversion by proton migration, such as enol-ketone tautomers and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to ring-NH-moieties and ring-N-moieties, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Valence tautomers include interconversion by recombination of some of the bond-forming electrons.

The term "prodrug" refers herein to any derivative of a compound of the present invention that, when administered to a subject, is capable of providing, directly or indirectly, a compound of the present invention, an active metabolite or residue thereof. Particularly preferred are those derivatives or prodrugs that increase the bioavailability, metabolic stability and tissue targeting of the compounds of the present invention. Prodrugs include ester derivatives of the compounds of the present invention. Examples of ester prodrugs include formate, acetate, propionate, butyrate, acrylate, and ethylsuccinate derivatives, but are not limited to these ester derivatives.

The compounds of the present invention may be used in the form of salts, such as "pharmaceutically acceptable salts" derived from inorganic or organic acids. These include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, hydrochloride, 2-naphthalenesulfonate, oxalate, pectinate, sulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and decanoate. In addition, the basic nitrogen-containing groups can be quaternized with the following agents to form quaternary ammonium salts: such as lower alkyl halides including methyl, ethyl, propyl and butyl chlorides, bromides and iodides; such as dialkyl sulfates, including dimethyl, diethyl, dibutyl, and diamyl sulfates; such as long chain halides including chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl groups; such as aralkyl halides, such as benzyl and phenethyl bromides, and the like.

The term "metabolite" refers herein to the product of a specific compound or salt thereof produced by metabolism in vivo. Metabolites of compounds may be identified by conventional techniques known in the art, and their activity may be determined using the assays described herein. The above products can be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

Protecting Groups in relation to hydroxy, amino, mercapto, carboxy and the like are those which protect hydroxy, amino, mercapto, carboxy and the like from undesired reactions by means of functional Groups, and the protecting Groups used are well known to the person skilled in the art, such as those mentioned in Protective Groups in Organic Synthesis (John Wiley & Sons, New York, third edition, 1999).

The invention also includes isotopically-labelled compounds of the invention, i.e. those structures disclosed above in which one or more atoms are replaced by an atom having the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, oxygen, sulfur, fluorine, chlorine, and iodine, respectively²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、 ¹⁷O、³⁵S、¹⁸F、³⁶Cl and¹³¹i, and the like. The compounds of the present invention, stereoisomers, tautomers, nitrogen oxides, sulfur oxides, prodrugs, pharmaceutically acceptable salts or solvates thereof, as well as compounds of the above forms containing the aforementioned isotopes and/or other atomic isotopes, are within the scope of the present invention. Certain isotopically-labelled compounds of the invention, e.g. by³H or¹⁴Those labeled with C can be used in drug tissue distribution assays, and thus, these³H or¹⁴The C isotope is particularly preferred because of its ease of preparation and detection. In addition, by heavier isotopes such as²Some of the compounds of the invention substituted with H have certain therapeutic advantages due to their greater metabolic stability, such as increased in vivo half-life and lower dosages, and, therefore,²h is also preferred in some cases.

The compounds of the invention have Pim inhibitory activity and can be used for the preparation of medicaments or pharmaceutical compositions for human or veterinary use in the treatment of Pim kinase mediated diseases such as cancer or immune related diseases. In particular, the compounds can be used for treating human or animal cancers, including epithelial cell cancer, hematological tumors, solid tumors, germ cell cancer or blastoma selected from breast cancer, lung cancer, prostate cancer, liver cancer, pancreatic cancer, colorectal cancer, bone cancer, lymphoma, leukemia, myeloma, ovarian cancer, cervical cancer, testicular cancer, endometrial cancer, gastric cancer, renal cancer, esophageal cancer, nasopharyngeal cancer, brain cancer and/or neural cancer, and the like. In particular, the compounds of the present invention may be used for the treatment of immune related diseases in humans or animals, including inflammation, autoimmune diseases, allergy and/or immunosuppression of organ transplantation, among others.

Process for producing compound C or intermediate

Specific examples are set forth below to illustrate the invention. It is to be understood that the invention is not limited to these examples, which are provided solely to provide methods of practicing the invention and are not intended to limit the scope of the invention in any way.

The compounds provided herein can be prepared by standard synthetic methods well known in the art, and the general methods for preparing the compounds of the invention are provided herein. The starting materials are generally commercially available, for example, via Alfa

TCI、

Shaoyuan chemical, Annaige chemical, Aister biopharmaceutical and Chengdesque reagents, or prepared by methods well known to those skilled in the art.

The following reaction methods and synthetic steps provide possible routes for the synthesis of the compounds of the invention as well as key intermediates. For a more detailed description of the individual reaction steps, reference is made to the following examples. It will be appreciated by those skilled in the art that the compounds of the invention may also be obtained by other synthetic routes. Although specific starting materials and reagents are used in the reaction schemes below, these starting materials and reagents may be substituted with other similar starting materials or reagents to provide various derivatives. In addition, many of the compounds prepared by the methods described below can be further modified by conventional chemical methods well known to those skilled in the art, given the benefit of this disclosure.

In the preparation of the compounds of the present invention, it may be desirable to protect certain interfering functional groups (e.g., primary or secondary amines) of the intermediates. The requirements for such protecting groups vary depending on the nature of the particular functional group and the conditions of the preparation process. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), and the like. Suitable hydroxy protecting groups include allyl, acetyl, silyl, benzyl, trityl, p-methoxybenzyl and the like. Such protecting Groups can be readily determined by those skilled in the art (see in particular Protective Groups in Organic Synthesis, John Wiley & Sons, New York, third edition, 1999).

The following reaction scheme 1 provides a representative procedure for the preparation of compounds of formula (I). It will be appreciated that these reaction steps and conditions are not limiting and that the process described can be used to prepare compounds of formula (I) by judicious variation of the reaction conditions.

Method 1

Method 1 illustrates a general process for the preparation of compounds of formula (I) within the scope of the present invention. Wherein, A, X, Z₁，Z₂And R has the meaning as defined in the description of the invention. And (3) carrying out amination reaction on the intermediate I and the intermediate II under an alkaline condition by using palladium to catalyze halogenated aromatic hydrocarbon to obtain the compound shown in the formula (I). Wherein the solvent used in the reaction is selected from toluene, THF, dioxane, etc(ii) a The base used in the reaction is selected from potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate and the like; the palladium catalyst used in the reaction is selected from Pd₂(dba)₃、Pd(OAc)₂、Pd(dppf)Cl₂、Pd(Ph₃)₄Etc.; the ligand used in the reaction is selected from BINAP, Xantphos and the like.

In a preferred embodiment of the process 1 of the present invention, the process for the preparation of a compound of formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a metabolite, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, according to the present invention, wherein the compound is obtained by a process comprising the following steps:

(1) step 1: preparation of 4-chloro-2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine comprising the steps of:

step 1: preparing 3-amino-4-mercapto-pyridine,

step 2: preparing thiazolo [4,5-c ] pyridine,

and step 3: preparing 2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine,

and 4, step 4: preparation of 2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine-5-oxide, and

and 5: preparing 4-chloro-2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine;

(2) and a step 2: (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine

-preparation of 4-amine comprising the following steps:

step 1, preparation of tert-butyl (S) -1- (3- (2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridin-4-yl-amino) pyridin-4-yl) piperidine-3-carbamate, and

step 2, preparing (S) -N- (4- (3-aminopiperidin-1-yl) pyridine-3-yl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridin-4-amine.

In another preferred embodiment of the method 1 of the present invention, the compound of formula (I) according to the present invention, or a stereoisomer, a tautomer, a nitrogen oxide, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof, is obtained by a production method comprising the following steps:

(1) step 1: preparation of 4-chloro-2- (thiazol-2-yl) thiazolo [4,5-c ] pyridine comprising the following steps:

step 1: preparation of 2- (thiazol-2-yl) -thiazolo [4,5-c ] pyridine,

step 2: preparing 2- (thiazol-2-yl) -thiazolo [4,5-c ] pyridine-5-oxide; and

and step 3: preparation of 4-chloro-2- (thiazol-2-yl) -thiazolo [4,5-c ] pyridine; and

(2) and a step 2: preparation of (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thiazol-2-yl) thiazolo [4,5-c ] pyridin-4-amine comprising the steps of: reacting 4-chloro-2- (thiazol-2-yl) -thiazolo [4,5-c ] pyridine with (S) -tert-butyl (1- (3-aminopyridin-4-yl) piperidin-3-yl) carbamate, followed by removal of the protecting group for the amino-tert-butoxycarbonyl group to give (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thiazol-2-yl) thiazolo [4,5-c ] pyridin-4-amine.

In another preferred embodiment of method 1 of the present invention, the compound of formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof, according to the present invention is obtained by a preparation method comprising the following steps:

(1) step 1: preparation of 4-chloro-2- (thiophen-2-yl) thiazolo [4,5-c ] pyridine comprising the steps of:

step 1: preparation of 2- (thien-2-yl) -thiazolo [4,5-c ] pyridine,

step 2: preparation of 2- (thien-2-yl) -thiazolo [4,5-c ] pyridine-5-oxide, and

and step 3: preparing 4-chloro-2- (thiophen-2-yl) -thiazolo [4,5-c ] pyridine; and

(2) and a step 2: preparation of (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thiophen-2-yl) thiazolo [4,5-c ] pyridin-4-amine comprising the steps of: reaction of 4-chloro-2- (thien-2-yl) -thiazolo [4,5-c ] pyridine with (S) -tert-butyl (1- (3-aminopyridin-4-yl) piperidin-3-yl) carbamate followed by removal of the amino protecting group tert-butoxycarbonyl gives (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thien-2-yl) thiazolo [4,5-c ] pyridin-4-amine.

The compounds of the invention and the corresponding preparation processes are further illustrated and exemplified below by means of examples and preparations. It will be appreciated that although typical or preferred reaction conditions (e.g., reaction temperature, time, molar ratios of reactants, reaction solvent, and pressure, etc.) are given in the specific examples, other reaction conditions may be used by one skilled in the art. The optimal reaction conditions may vary with the particular reaction substrate or solvent used, but can be determined by one of skill in the art through routine optimization.

The structures of the compounds of the following examples were characterized by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The compound was dissolved in appropriate deuterated reagent using a Bruker Ascend 400MHz NMR spectrometer, performed at ambient temperature with TMS as internal standard¹H-NMR analysis. NMR chemical shifts (δ) are in ppm and are abbreviated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad singlet. MS by Waters UPLC-Vevo^TMTQ MS mass spectrometry (ESI) measurements.

The starting materials, intermediates and compounds of the examples can be isolated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (e.g., column chromatography, TLC separation and purification).

TLC uses a tobacco yellow sea HSGF254 thin layer chromatography silica gel plate (0.2 +/-0.03 mm), and TLC separation and purification uses a tobacco yellow sea HSGF254 thin layer chromatography thick preparation plate (0.9-1 mm), which are purchased from Qingdao ocean chemical plants.

The column chromatography is carried out by taking 300-400 mesh silica gel of Taiwan Huanghai as a carrier and purchased from Qingdao oceanic chemical plants.

Commercial solvents and reagents used in the test were used without specific indication, and were used without further purification or treatment after purchase. The reaction conditions (reaction temperature, reaction solvent, molar ratio of reactants, or/and reaction duration) may be different when referring to other examples or synthetic methods. In general, the progress of the reaction can be monitored by TLC, whereby the reaction is terminated at a suitable time and is followedAnd (6) processing. The purification conditions of the compounds may also vary, generally speaking, according to R of TLC_fThe appropriate column chromatography eluent is selected for the values, or the corresponding compound is isolated and purified by preparative TLC.

Example 1, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c]Pyridin-4-amines

Preparation of (S) -1- (3-aminopyridin-4-yl) piperidin-3-yl-carbamic acid tert-butyl ester

Step 1 preparation of (S) -1- (3-nitropyridin-4-yl) piperidin-3-yl-carbamic acid tert-butyl ester

4-chloro-3-nitropyridine (475.6mg, 3mmol), (S) -3-tert-butyloxycarbonylaminopiperidine (600.8mg, 3mmol) and DIPEA (387.7mg, 3.0mmol) were added successively to a 50mL round-bottomed flask, followed by addition of 10mL ethanol and stirring at room temperature for 5 h. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, the ethyl acetate phase (50 mL. times.3) was washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give (S) -1- (3-nitropyridin-4-yl) piperidin-3-yl-carbamic acid tert-butyl ester (840 mg, 87%) as a yellow solid.

Step 2, preparation of (S) -1- (3-aminopyridin-4-yl) piperidin-3-yl-carbamic acid tert-butyl ester

(S) -1- (3-Nitropyridin-4-yl) piperidin-3-yl-carbamic acid tert-butyl ester (841.3mg, 2.61mmol) was dissolved in 20mL ethanol, then iron powder (1.17g, 20.88mmol), ammonium chloride (837.8mg, 15.66mmol) and 3mL water were added in that order and refluxed at 90 ℃ for 4 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, an appropriate amount of water was added to the residue, ethyl acetate extraction (50mL × 3) was performed, the organic phases were combined and washed with water (50mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give tert-butyl (S) -1- (3-aminopyridin-4-yl) piperidin-3-yl-carbamate (724mg, 95%) as a yellow solid.

4-chloro-2- (2, 6-difluorophenyl) thiazolo [4,5-c]Preparation of pyridine

Step 1, preparation of 3-amino-4-mercapto-pyridine

Dissolving 4-chloro-3-nitro-pyridine (7.93g, 50mmol) in 50mL ethanol, slowly adding 50mmol concentrated hydrochloric acid, and stirring at room temperature; weighing NaHS. H₂O (13.7g, 185mmol) is added to the reaction solution and stirred for 40min at room temperature; sodium hydrosulfite (32.21g, 185mmol) was then weighed out and dissolved in water, and the aqueous sodium hydrosulfite solution was added to the reaction mixture and stirred at 80 ℃ for 12 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with dichloromethane: methanol ═ 5:1 to elute impurities first, and then with dichloromethane: methanol ═ 1:1 to give a crude product), to give a crude 3-amino-4 mercapto-pyridine as a brown yellow solid. The crude 3-amino-4-mercapto-pyridine was used directly in the next reaction without further purification.

Step 2, preparation of Thiazolo [4,5-c ]]Pyridine compound

Dissolving the crude 3-amino-4-mercaptopyridine in 100mL formic acid, refluxing for 4h, adding saturated NaHCO₃And (5) quenching the solution for reaction. The reaction solution was extracted with ethyl acetate (200 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to give thiazolo [4,5-c as a white solid]Pyridine (2.52g, 37% yield over two steps).

Step 3, preparing 2- (2, 6-difluorophenyl) thiazolo [4,5-c]Pyridine compound

Reacting thiazolo [4,5-c ]]Pyridine (2.0g, 14.7mmol), 2, 6-difluoroiodobenzene (4.2g, 17.6mmol), Pd(PPh₃)₄(849mg, 0.735mmol), CuI (140mg, 0.735mmol), and Cs₂CO₃(14.4g, 44.1mmol) was dissolved in 50mL DMF, stirred at 120 deg.C (tube-sealed reaction for 4h) and TLC monitored to completion. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and extracted with ethyl acetate (50 mL. times.2), the organic phase was washed with water (50 mL. times.1) and saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separating and purifying by silica gel column chromatography (petroleum ether: ethyl acetate: 3:1) to obtain 2- (2, 6-difluorophenyl) thiazolo [4,5-c ] as white powdery solid]Pyridine (2.59g, 71%).

Step 4, preparing 2- (2, 6-difluorophenyl) thiazolo [4,5-c]Pyridine-5-oxides

2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine (2.48g, 10mmol) was dissolved in 30mL of dichloromethane, MCPBA (2.42g, 14mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and the reaction quenched by addition of 50mL of 1M potassium carbonate solution. To the reaction solution was added 100mL of saturated brine, extracted with dichloromethane (50 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine-5-oxide as a white solid. The crude 2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine-5-oxide was used in the next reaction without further purification.

Step 5, preparing 4-chloro-2- (2, 6-difluorophenyl) thiazolo [4,5-c]Pyridine compound

Reacting 2- (2, 6-difluorophenyl) thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And refluxing for 2 h. The reaction solution is concentrated under reduced pressure, ice water is slowly added to quench the residual POCl₃Adding saturated sodium bicarbonate to adjust pH to neutrality, extracting with ethyl acetate (50 mL. times.3), combining organic phases, drying the organic phases over anhydrous sodium sulfate, filtering and concentrating under reduced pressure, and separating and purifying by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to obtain 4-chloro-2- (2, 6-difluorophenyl) thiazolo [4,5-c ] as a pale yellow solid]Pyridine (2.0g, 71% yield over two steps).

(S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c]Pyridine (II) Preparation of pyridin-4-amines

Step 1, preparing (S) -1- (3- (2- (2, 6-difluorophenyl) thiazolo [4, 5-c)]Pyridin-4-yl-amino) pyridines- 4-yl) piperidine-3-carbamic acid tert-butyl ester

Tert-butyl (S) -1- (3-aminopyridin-4-yl) piperidin-3-yl-carbamate (210mg, 0.72mmol), 4-chloro-2- (2, 6-difluorophenyl) thiazolo [4,5-c]Pyridine (170mg, 0.6mmol) was dissolved in 5mL of toluene, and Pd was added successively₂(dba)₃(16mg, 0.018mmol), Xantphos (21mg, 0.036mmol) and potassium tert-butoxide (101mg, 0.9mmol), stirring at 80 ℃ under nitrogen (lock tube reaction) and monitoring by TLC until no more reaction of starting material is achieved. The reaction solution was filtered, the filter cake was thoroughly washed with a dichloromethane/methanol mixture (1:1), the filtrate was concentrated under reduced pressure, and the filtrate was purified by preparative TLC to give (S) -1- (3- (2- (2, 6-difluorophenyl) thiazolo [4,5-c ] as a yellow solid]pyridin-4-Yl-amino) pyridin-4-Yl) piperidin-3-carbamic acid tert-butyl ester (85mg, 26%).

Step 2, preparing (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c]Pyridin-4-amines

Reacting (S) -1- (3- (2- (2, 6-difluorophenyl) thiazolo [4, 5-c)]Pyridine-4-yl-amino) pyridine-4-yl) piperidine-3-carbamic acid tert-butyl ester (85mg, 0.16mmol) is dissolved in 4mL dichloromethane, the reaction flask is placed in an ice bath for cooling, 1mL trifluoroacetic acid is added, stirring is carried out for 20min under the ice bath condition, then the temperature is raised to room temperature for continuous reaction, and TLC detection is carried out until the reaction is complete. The reaction solution was concentrated under reduced pressure, 150mL of a saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (50 mL. times.3), the organic phases were washed with water (25 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is passed throughPreparative TLC separation purification to give (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (2, 6-difluorophenyl) thiazolo [4, 5-c) as a yellow solid]Pyridin-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]⁺。

Example 2, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2-phenylthiazolo [4,5-c]Pyridine- 4-amines

4-chloro-2-phenylthiazolo [4,5-c]Preparation of pyridine

Step 1, preparation of 3-amino-4-mercaptopyridine

Dissolving 4-chloro-3-nitro-pyridine (7.9g, 49.8mmol) in 50mL ethanol, slowly adding 50mmol concentrated hydrochloric acid, and stirring at room temperature; then weighing NaHS. H₂O (13.69g, 184.8mmol) was added to the reaction solution, and stirred at room temperature for 40 min; sodium hydrosulfite (32.21g, 185.1mmol) was then weighed out and dissolved in water and the aqueous sodium hydrosulfite solution was added to the reaction mixture and stirred at 80 ℃ for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluting with dichloromethane/methanol 5:1 to elute impurities and then with dichloromethane/methanol 1:1 to obtain a crude product) to obtain a crude 3-amino-4-mercaptopyridine product as a brown yellow solid. The crude product of 3-amino-4-mercaptopyridine was used directly in the next reaction without further purification.

Step 2, preparation of Thiazolo [4,5-c ]]Pyridine compound

The crude 3-amino-4-mercaptopyridine product is dissolved in 100mL formic acid, refluxed for 4h, and added with saturated sodium bicarbonate solution to quench the reaction. The reaction solution was extracted with ethyl acetate (200 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) gave thiazolo [4,5-c ] pyridine as a white solid (2.52g, 37% yield over two steps).

Step 3, preparing 2-phenylthiazolo [4,5-c]Pyridine compound

Reacting thiazolo [4,5-c ]]Pyridine (2.0g, 14.7mmol), iodobenzene (3.7g, 17.9mmol), Pd (PPh)₃)₄(849mg, 0.735mmol), CuI (140mg, 0.735mmol), and Cs₂CO₃(14.4g, 44.1mmol) was dissolved in 50mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and extracted with ethyl acetate (50 mL. times.2), the organic phase was washed with water (50 mL. times.1) and saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography on silica gel (petroleum ether: ethyl acetate ═ 3:1) to give 2-phenylthiazolo [4,5-c ] as a white solid powder]Pyridine (2.26 g, 72%).

Step 4, preparing 2-phenylthiazolo [4,5-c]Pyridine-5-oxides

2-Phenylthiazolo [4,5-c ] pyridine (2.25g, 10.6mmol) was dissolved in 30mL of dichloromethane, MCPBA (2.56mg, 14.8mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and the reaction was quenched by addition of 50mL of 1M potassium carbonate solution. To the reaction solution was added 100mL of saturated brine, extracted with dichloromethane (50 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2-phenylthiazolo [4,5-c ] pyridine-5-oxide as a white solid. The crude product of 2-phenylthiazolo [4,5-c ] pyridine-5-oxide was used in the next reaction without further purification.

Step 5, preparation of 4-chloro-2-phenylthiazolo [4,5-c ]]Pyridine compound

2-phenylthiazolo [4,5-c ]]The crude pyridine-5-oxide was dissolved in 10mL of POCl₃And refluxing for 2 h. Concentrating the reaction solution under reduced pressure, slowly adding ice water to quench the residualPOCl of₃Adding saturated sodium bicarbonate to adjust the pH to be neutral, extracting with ethyl acetate (50mL multiplied by 3), combining organic phases, drying the organic phases through anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to obtain 4-chloro-2-phenylthiazolo [4,5-c ] as a light yellow solid]Pyridine (2.0g, 76% yield over two steps).

The compound of example 2 of the invention was prepared according to method 1, the other preparative procedures were prepared according to example 1, ESI-MS m/z: 403.4[ M + H]⁺。

Example 3, (S) -N- (5- (3-Aminopiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenylthiazolo [4,5-c]Pyridin-4-amines

Preparation of (S) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-3-yl-carbamic acid tert-butyl ester

Step 1, preparation of 1-methyl-4-nitro-1H-pyrazole

4-Nitro-1H-pyrazole (1.13g, 9.99mmol) was dissolved in 15mL of anhydrous THF, the reaction flask was placed in an ice bath to cool, NaH (600mg, 25mmol) was added slowly, the mixture was warmed to room temperature and stirred for 2.5H, methyl iodide (3.84g, 20mmol) was then added slowly, stirring was continued for 1.5H, and the reaction was quenched by the slow addition of 15mL of saturated saline. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (50 mL. times.3), and the organic phase was separated, washed with water and saturated brine (50 mL. times.2) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-methyl-4-nitro-1H-pyrazole as a pale yellow solid (826mg, 65%).

Step 2, preparing 1-methyl-4-nitro-5-chloro-1H-pyrazole

Dissolving 1-methyl-4-nitro-1H-pyrazole (1g, 7.87mmol) in 12mL of anhydrous THF, cooling to-78 ℃ under nitrogen atmosphere, slowly dropwise adding 6mL of LDA with the concentration of 2mol/L, and continuously stirring for 1H at-78 ℃ under nitrogen atmosphere; hexachloroethane (2.42g, 10.2mmol) was dissolved in 12mL of anhydrous THF, slowly added dropwise to the above reaction solution, stirred at-78 ℃ for 2h, then warmed to room temperature and stirred for 1h, and the reaction was quenched with saturated aqueous ammonium chloride. The organic phase was washed with aqueous ammonium chloride (20 mL. times.1), extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) gave 1-methyl-4-nitro-5-chloro-1H-pyrazole (691mg, 54%) as a yellow solid.

Step 3, preparing (S) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidine-3-yl-carbamic acid tert-butyl Esters

1-methyl-4-nitro-5-chloro-1H-pyrazole (485mg, 3.0mmol) and (S) -3-tert-butyloxycarbonylaminopiperidine (781 mg, 3.9mmol) were dissolved in 15mL ethanol, DIPEA (3.1g, 24mmol) was added, heated to reflux, and TLC was monitored to completion of the reaction. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to give (S) -tert-butyl 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-3-yl-carbamate as a yellow oily liquid (620mg, 63%).

Step 4, preparing (S) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-3-yl-carbamic acid tert-butyl Esters

(S) -tert-butyl 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) piperidin-3-yl-carbamate (600mg, 1.84mmol), iron powder (824mg, 14.7mmol), ammonium chloride (591mg, 11mmol) were added to a 100mL round-bottomed flask, 14mL of ethanol and 2mL of water were added, and stirring was carried out at 60 ℃ for 8H; iron powder (101mg, 1.81mmol) was then added, stirred at 60 ℃ and monitored by TLC until the reaction was complete. The reaction solution was filtered, the filtrate was diluted with 60mL of ethyl acetate and 60mL of 10% potassium phosphate solution, the organic phase was separated and extracted with ethyl acetate (50 mL. times.2), the organic phases were combined and washed with water (25 mL. times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) gave tert-butyl (S) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-3-yl-carbamate (380 mg, 70%) as a brown oily liquid.

The compound of the invention example 3 was prepared according to method 1, the other preparation steps were prepared according to example 1. ESI-MS m/z: 406.6[ M + H]⁺。

Example 4, (S) -N- (5- (3-aminopiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridin-4-amine

The compound of the invention example 4 was prepared according to method 1, with specific synthesis of reference example 1.¹H NMR(400MHz, CDCl₃)δ8.02(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]^-。

Example 5, (S) -N- (2- (3-Aminopiperidin-1-yl) phenyl) -2-phenylthiazolo [4,5-c]Pyridin-4-amines

Preparation of (S) -1- (2-aminophenyl) piperidin-3-yl-carbamic acid tert-butyl ester

Step 1, preparation of (S) -1- (2-nitrophenyl) piperidin-3-yl-carbamic acid tert-butyl ester

1-chloro-2-nitrobenzene (470mg, 2.98mmol), (S) -3-tert-butyloxycarbonylaminopiperidine (600mg, 2.99mmol) was dissolved in DMF, Pd/C (70mg) was added, stirring was performed at 80 ℃ under nitrogen atmosphere, and TLC was performed until the reaction was complete. The reaction was cooled to room temperature, filtered, the filtrate was poured into water, extracted with ethyl acetate (50mL × 3), the organic phases were combined and washed with water (25mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude (S) -tert-butyl 1- (2-nitrophenyl) piperidin-3-yl-carbamate as a dark brown oily liquid. The crude (S) -1- (2-nitrophenyl) piperidin-3-yl-carbamic acid tert-butyl ester was used in the next reaction without further purification.

Step 2,Preparation of (S) -1- (2-aminophenyl) piperidin-3-yl-carbamic acid tert-butyl ester

The crude (S) -tert-butyl 1- (2-nitrophenyl) piperidin-3-yl-carbamate was dissolved in 70mL of ethanol, iron powder (1.3g, 23.84mmol), ammonium chloride (957mg, 17.88mmol) and 3mL of water were added in that order, heated to reflux and monitored by TLC to completion of the reaction. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, an appropriate amount of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined and washed with water (25mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane: methanol ═ 20:1) gave (S) -1- (2-aminophenyl) piperidin-3-yl-carbamic acid tert-butyl ester (322mg, two-step yield 37%) as a yellow solid.

(S) -N- (2- (3-aminopiperidin-1-yl) phenyl) -2-phenylthiazolo [4,5-c]Preparation of pyridin-4-amines

Step 1, preparation of (S) -1- (2- (2-phenylthiazolo [4, 5-c)]Pyridin-4-yl-amino) phenyl) piperidin-3-yl- Carbamic acid tert-butyl ester

(S) -1- (2-aminophenyl) piperidin-3-yl-carbamic acid tert-butyl ester (76mg, 0.26mmol), 4-chloro-2-phenylthiazo [4, 5-c)]Pyridine (64mg, 0.26mmol) was dissolved in THF, Pd was added sequentially₂(dba)₃(7.6mg, 0.008mmol), BINAP (10mg, 0.016mmol) and t-BuOK (44mg, 0.39mmol), stirred at 80 ℃ under nitrogen and monitored by TLC until the reaction was complete. The reaction solution was filtered, the filter cake was thoroughly washed with a dichloromethane/methanol mixture (1:1), and the filtrate was concentrated under reduced pressure. Purification by TLC separation (dichloromethane: methanol ═ 20:1) gave (S) -1- (2- (2-phenylthiazolo [4, 5-c) as a yellow solid]Pyridin-4-yl-amino) phenyl) piperidin-3-yl-carbamic acid tert-butyl ester (78mg, 60%).

Step 2, preparation of (S) -N- (2- (3-aminopiperidin-1-yl) phenyl) -2-phenylthiazolo [4,5-c]Pyridine-4- Amines as pesticides

Reacting (S) -1- (2- (2-phenylthiazolo [4, 5-c)]Pyridin-4-yl-amino) phenyl) piperidin-3-yl-carbamic acid tert-butyl ester (78mg, 0.15mmol) was dissolved in 4mL of dichloromethane, the reaction flask was placed in an ice bath to cool, 1mL of trifluoroacetic acid was added, stirring was performed for 20min under ice bath conditions, then the temperature was raised to room temperature to continue the reaction, and TLC was monitored until the reaction was complete. The reaction solution was concentrated under reduced pressure, 50mL of a saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (50mL × 3), and the organic phases were combined and washed with water (25mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative TLC affording (S) -N- (2- (3-aminopiperidin-1-yl) phenyl) -2-phenylthiazolo [4, 5-c) as a yellow solid]Pyridin-4-amine (40mg, 66%).¹H NMR(400MHz,d₆-DMSO)δ9.47(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]⁺。

Example 6, (S) -N- (2- (3-aminopiperidin-1-yl) phenyl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c] Pyridin-4-amines

The compound of the invention example 6 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ9.47(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]⁺。

Example 7, (S) -N- (4- (3-Aminopiperidin-1-yl) pyrimidin-5-yl) -2-phenylthiazolo [4,5-c]Pyridine- 4-amines

Preparation of tert-butyl (S) -1- (5-aminopyrimidin-4-yl) piperidin-3-yl-carbamate

Step 1, preparation of 5-amino-6-chloropyrimidine-4 (1H) -thione hydrochloride

5-amino-4, 6-dichloropyrimidine (2g, 12.2mmol) was dissolved in 7mL of DMSO and Na was added₂S·9H₂O (3.221g, 13.4mmol), stirred at room temperature and monitored by TLC to completion. The reaction flask was placed in an ice bath, 10mL of water was added to the reaction solution, concentrated hydrochloric acid was slowly added dropwise to adjust the pH of the reaction solution to weak acidity, a large amount of precipitate was generated in the reaction solution, the reaction solution was filtered, the filter cake was sufficiently washed with water, and a solid was collected and dried to obtain a crude product of 5-amino-6-chloropyrimidine-4 (1H) -thione hydrochloride (2.67g, about 100%). The crude product of 5-amino-6-chloropyrimidine-4 (1H) -thione hydrochloride is directly used for the next reaction without further purification.

Step 2, preparing 4-chloro-5-aminopyrimidine

The hydrochloride compound of 5-amino-6-chloropyrimidine-4 (1H) -thione (2.67g) was dissolved in 25mL of dry methanol, 25% aqueous ammonia (2.5mL) and Raney Ni (2mL) were added, and the mixture was stirred at 80 ℃ under a nitrogen atmosphere and monitored by TLC until the reaction was complete. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure and purified by preparative TLC to give 4-chloro-5-aminopyrimidine (156mg, 9.9%) as a yellow solid.

Step 3 preparation of (S) -1- (5-aminopyrimidin-4-yl) piperidin-3-yl-carbamic acid tert-butyl ester

4-chloro-5-aminopyrimidine (156mg, 1.2mmol) and (S) -3-tert-butoxycarbonylaminopiperidine (288mg, 1.44mmol) were dissolved in 8mL of methanol, DIPEA (186mg, 1.44mmol) was added, stirring under reflux, and TLC was monitored to completion. The reaction solution was concentrated under reduced pressure, 150mL of a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (25 mL. times.3), and the organic phases were combined and washed with water (25 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC separation (dichloromethane: methanol ═ 20:1) to give tert-butyl (S) -1- (5-aminopyrimidin-4-yl) piperidin-3-yl-carbamate as a tan oily liquid (240mg, 68%).

The compound of the invention example 7 was prepared according to method 1, the other preparation steps were prepared according to example 1. ESI-MS m/z: 404.3[ M + H]⁺。

Example 8, (S) -N- (4- (3-Aminopiperidin-1-yl) pyrimidin-5-yl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c]Pyridin-4-amines

The compound of the invention example 8 was prepared according to method 1, the other preparation steps were prepared according to example 1.¹H NMR (400MHz,CDCl₃)δ9.72(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]^-。

Example 9, (S) -N- (4- (3-Aminopyrrolidin-1-yl) pyridin-3-yl) -2-phenylthiazolo [4,5-c]Pyridine (II) Pyridin-4-amines

Preparation of (S) -1- (3-aminopyridin-4-yl) pyrrolidin-3-yl-carbamic acid tert-butyl ester

Step 1, preparation of (S) -1- (3-nitropyridin-4-yl) pyrrolidin-3-yl-carbamic acid tert-butyl ester

4-chloro-3-nitropyridine (475mg, 3.0mmol), (S) -3-tert-butyloxycarbonylpyrrolidine (558mg, 3.0mmol) and DIPEA (464mg, 3.59mmol) were dissolved in 20mL ethanol and stirred at room temperature for 12 h. After the reaction solution was concentrated under reduced pressure, it was dissolved in ethyl acetate, and the ethyl acetate phase (25 mL. times.3) was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography separation and purification (petroleum ether: ethyl acetate ═ 3:1) gave (S) -1- (3-nitropyridin-4-yl) pyrrolidin-3-yl-carbamic acid tert-butyl ester as a yellow solid (758mg, 82%).

Step 2, preparation of (S) -1- (3-aminopyridin-4-yl) pyrrolidin-3-yl-carbamic acid tert-butyl ester

(S) -1- (3-Nitropyridin-4-yl) pyrrolidin-3-yl-carbamic acid tert-butyl ester (616mg, 2.0mmol) was dissolved in 20mL ethanol, then iron powder (896mg, 16mmol), ammonium chloride (642mg, 12mmol) and 2mL water were added in that order and refluxed at 90 ℃ for 4 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was added with an appropriate amount of water, extracted with ethyl acetate (50mL × 3), the organic phases were combined and washed with water (25mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane: methanol ═ 20:1) gave (S) -1- (3-aminopyridin-4-yl) pyrrolidin-3-yl-carbamic acid tert-butyl ester (528mg, 95%) as a yellow solid.¹H NMR(400MHz,d₆-DMSO)δ7.83(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)。

The compound of the invention example 9 was prepared according to method 1, the other preparation steps were prepared according to example 1.¹H NMR (400MHz,d₆-DMSO)δ8.80(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]⁺。

Example 10, (S) -N- (4- (3-Aminopyrrolidin-1-yl) pyridin-3-yl) -2- (2, 6-difluorophenyl) thiazole And [4,5-c ]]Pyridin-4-amines

The compound of the invention example 10 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,d₆-DMSO)δ8.79(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]⁺。

Example 11, (S) -N- (5- (3-Aminopyrrolidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenylthiazole And [4,5-c ]]Pyridin-4-amines

Preparation of (S) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) pyrrolidin-3-yl-carbamic acid tert-butyl ester

Step 1, preparation of 1-methyl-4-nitro-1H-pyrazole

4-Nitro-1H-pyrazole (1130mg, 9.99mmol) was dissolved in 15mL of anhydrous THF, the reaction flask was placed in an ice bath to cool, NaH (600mg, 25mmol) was slowly added, the mixture was warmed to room temperature and stirred for 2.5H, methyl iodide (3.84g, 20mmol) was then slowly added, stirring was continued for 1.5H, and the reaction was quenched by the addition of 15mL of saturated saline. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (50 mL. times.3), and the organic phase was separated and washed with water, saturated brine (50 mL. times.2) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-methyl-4-nitro-1H-pyrazole as a pale yellow solid (826mg, 65%).¹H NMR(400MHz,CDCl₃)δ8.14(s,1H),8.07(s,1H),3.99(s,3H)。

Step 2, preparing 1-methyl-4-nitro-5-chloro-1H-pyrazole

Dissolving 1-methyl-4-nitro-1H-pyrazole (1.0g, 7.87mmol) in 12mL of anhydrous THF, cooling to-78 ℃ under nitrogen atmosphere, slowly dropwise adding 6mL of LDA with the concentration of 2mol/L, and continuously stirring for 1H under nitrogen atmosphere at-78 ℃; hexachloroethane (2.41g, 10.2mmol) was dissolved in 12mL of anhydrous THF, slowly added dropwise to the reaction mixture, stirred at-78 ℃ for 2h, warmed to room temperature and stirred for 1h, and quenched with saturated aqueous ammonium chloride. The organic phase was washed by adding 20mL of aqueous ammonium chloride solution, extracted with ethyl acetate (10 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (petroleum ether: ethyl acetate 3:1) to give 1-methyl-4-nitro-5-chloro-1H-pyrazole (691mg, 54%)。¹H NMR(400MHz,CDCl₃)δ8.33(s,1H),3.82(s,3H)。

Step 3, preparing (S) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) pyrrolidine-3-yl-carbamic acid tert-butyl ester Esters of phenyl or naphthyl

1-methyl-4-nitro-5-chloro-1H-pyrazole (485mg, 3.0mmol) and (S) -3-tert-butoxycarbonylaminopyrrolidine (725mg, 3.89mmol) were dissolved in 15mL ethanol, DIPEA (3.1g, 24mmol) was added, heating to reflux and TLC was monitored to completion of the reaction. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to give (S) -tert-butyl 1- (1-methyl-4-nitro-1H-pyrazol-5-yl) pyrrolidin-3-yl-carbamate as a yellow oily liquid (560mg, 60%).

Step 4, preparing (S) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) pyrrolidine-3-yl-carbamic acid tert-butyl ester Esters of phenyl or naphthyl

(S) -1- (1-methyl-4-nitro-1H-pyrazol-5-yl) pyrrolidin-3-yl-carbamic acid tert-butyl ester (311mg, 1.0mmol), iron powder (448mg, 8mmol), ammonium chloride (321mg, 6mmol) were added to a 100mL round-bottomed flask, followed by addition of 14mL ethanol and 2mL water, stirring at 60 ℃ and TLC monitoring to completion of the reaction. The reaction solution was filtered, the filtrate was diluted with 60mL of ethyl acetate and 60mL of 10% potassium phosphate solution, the organic phase was separated, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined and washed with water (25 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography on silica gel (petroleum ether: ethyl acetate ═ 1:1) gave tert-butyl (S) -1- (4-amino-1-methyl-1H-pyrazol-5-yl) pyrrolidin-3-yl-carbamate (199mg, 71%) as a brown oily liquid. ESI-MS m/z: 282.3[ M + H]⁺。

The compound of the invention example 11 was prepared according to method 1, the other preparation steps were prepared according to example 1.¹H NMR (400MHz,CDCl₃)δ9.24(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]⁺。

Example 12, (S) -N- (5- (3-Aminopyrrolidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2- (2, 6-bis Fluorophenyl) thiazolo [4,5-c]Pyridin-4-amines

The compound of the invention example 12 was prepared according to method 1, the other preparation steps were prepared according to example 1.¹H NMR (400MHz,CDCl₃)δ10.27(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]⁺。

Example 13, (S) -N- (2- (3-Aminopyrrolidin-1-yl) phenyl) -2-phenylthiazolo [4,5-c]Pyridine-4- Amines as pesticides

Preparation of (S) -1- (2-aminophenyl) pyrrolidin-3-yl-carbamic acid tert-butyl ester

Step 1, preparation of (S) -1- (2-nitrophenyl) pyrrolidin-3-yl-carbamic acid tert-butyl ester

1-chloro-2-nitrobenzene (470mg, 3mmol), (S) -3-tert-butyloxycarbonylpyrrolidine (558mg, 3mmol) was dissolved in DMF and then Pd/C (70mg) was added, stirred at 80 ℃ under nitrogen and monitored by TLC until the reaction was complete. The reaction was cooled to room temperature, poured into water, extracted with ethyl acetate (50mL × 3), the organic phases were combined and washed with water (25mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude (S) -1- (2-nitrophenyl) pyrrolidin-3-yl-carbamic acid tert-butyl ester as a dark brown oily liquid. The crude product of the (S) -1- (2-nitrophenyl) pyrrolidine-3-yl-carbamic acid tert-butyl ester is directly used for the next reaction without further purification.

Step 2, preparing (S) -1- (2-aminophenyl) pyrrolidine-3-yl-carbamic acid tert-butyl ester

The crude (S) -1- (2-nitrophenyl) pyrrolidin-3-yl-carbamic acid tert-butyl ester was dissolved in 70mL of ethanol, iron powder (1.3g, 24mmol), ammonium chloride (963mg, 18mmol) and 2mL of water were added in that order, heated to reflux, and TLC monitored to completion of the reaction. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, an appropriate amount of water was added to the filtrate, extracted with ethyl acetate (50mL × 3), the organic phases were combined and washed with water (25mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane: methanol ═ 20:1) gave tert-butyl (S) -1- (2-aminophenyl) pyrrolidin-3-yl-carbamate as a yellow solid (390mg, 47% yield over two steps). ESI-MS m/z: 278.3[ M + H]⁺。

The compound of the invention example 13 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ8.57(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]⁺。

Example 14, (S) -N- (2- (3-aminopyrrolidin-1-yl) phenyl) -2- (2, 6-difluorophenyl) thiazolo [4, 5-c]pyridin-4-amines

The compound of the invention example 14 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ8.98(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]⁺。

Example 15, (S) -N- (4- (3-Aminopyrrolidin-1-yl) pyrimidin-5-yl) -2-phenylthiazolo [4,5-c]Pyridine (II) Pyridin-4-amines

Preparation of tert-butyl (S) -1- (5-aminopyrimidin-4-yl) pyrrolidin-3-yl-carbamate

Step 1, preparation of 5-amino-6-chloropyrimidine-4 (1H) -thione hydrochloride

5-amino-4, 6-dichloropyrimidine (2.0g, 12.2mmol) was dissolved in 7mL of DMSO and Na was added₂S·9H₂O (3.221g, 13.4mmol), stirred at room temperature and monitored by TLC to completion. The reaction flask was placed in an ice bath, 10mL of water was added, concentrated hydrochloric acid was slowly added dropwise to adjust the pH of the reaction solution to weak acidity, a large amount of precipitate was generated in the reaction solution, the reaction solution was filtered, the filter cake was sufficiently washed with water, the solid was collected, and dried to obtain 5-amino-6-chloropyrimidine-4 (1H) -thione hydrochloride (2.67g, ca. 100%) as a pale yellow solid.

Step 2, preparing 4-chloro-5-aminopyrimidine

The crude 5-amino-6-chloropyrimidine-4 (1H) -thione hydrochloride (2.67g) was dissolved in 25mL of dry methanol, 2.5mL of 25% aqueous ammonia and 2mL of Raney Ni were added, and the mixture was stirred at 80 ℃ under a nitrogen atmosphere and monitored by TLC until the reaction was complete. The reaction solution was filtered, the filter cake was washed with methanol, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative TLC to give 4-chloro-5-aminopyrimidine (156mg, 9.9%) as a yellow solid.

Step 3, preparation of (S) -1- (5-aminopyrimidin-4-yl) pyrrolidin-3-yl-carbamic acid tert-butyl ester

4-chloro-5-aminopyrimidine (156mg, 1.2mmol) and (S) -3-tert-butoxycarbonylaminopyrrolidine (268mg, 1.44mmol) were dissolved in 8mL of methanol, DIPEA (186mg, 1.44mmol) was added, stirring under reflux, and TLC was monitored to completion. The reaction solution was concentrated under reduced pressure, 150mL of a saturated sodium bicarbonate solution was added, the reaction solution was extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and washed with water (25 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by TLC separation (dichloromethane: methanol ═ 20:1) to give tert-butyl (S) -1- (5-aminopyrimidin-4-yl) pyrrolidin-3-yl-carbamate as a tan oily liquid (262mg, 78%).

The compound of the invention example 15 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ8.55(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]^-。

Example 16, (S) -N- (4- (3-Aminopyrrolidin-1-yl) pyrimidin-5-yl) -2- (2, 6-difluorophenyl) thiazole And [4,5-c ]]Pyridin-4-amines

The compound of the invention example 16 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ8.44(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]⁺。

Example 17, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2-phenyl-1H-imidazo [4,5-c] Pyridin-4-amines

4-chloro-2-phenyl-1H-imidazo [4,5-c]Preparation of pyridine

2-chloro-3, 4-diaminopyridine (1.4g, 9.75mmol), benzaldehyde (1.24g, 11.68mmol) and 14mL of nitrobenzene were charged into a three-necked flask and reacted at 175 ℃ under a nitrogen atmosphere until the color of the reaction system changed from reddish brown to blackish green. Cooling the reaction to room temperature, adding montmorillonite (7g), heating to 175 deg.C, continuing the reaction, and detecting by TLC until the reaction is finishedAnd (4) completing. The reaction solution was cooled to room temperature, the reaction solution was filtered, the filter cake was sufficiently washed with methanol, and the filtrate was concentrated under reduced pressure. Column chromatography on silica gel (dichloromethane: methanol ═ 40:1) gave 4-chloro-2-phenyl-1H-imidazo [4,5-c ] as a yellow solid]Pyridine (691mg, 31%). ESI-MS m/z: 228.2[ M-H]^-。

The compound of the invention example 17 was prepared according to method 1, the other preparation steps were prepared according to example 1.¹H NMR (400MHz,CDCl₃)δ10.17(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]⁺。

Example 18, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2-phenylthiazolo [5,4-c]Pyridine (II) Pyridin-4-amines

4-chloro-2-phenylthiazolo [5,4-c]Preparation of pyridine

Step 1, preparation of 4- (chloromethyl) -2-phenyl-1, 3-thiazole

Thiobenzamide (400mg, 2.9mmol) was dissolved in a mixed solution of ethanol/tetrahydrofuran (mass ratio ═ 10 g: 8g), heated to 65 ℃,1, 3-dichloroacetone (405mg, 3.19mmol) was added, the mixture was heated to 85 ℃ and refluxed overnight, and the reaction was monitored by TLC. The solvent was removed under reduced pressure and the residue was taken up in 50mL ethyl acetate and NaHCO₃Washing with aqueous solution, and passing the organic phase through anhydrous NaSO₄Dried, filtered and concentrated under reduced pressure. Separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) gave 4- (chloromethyl) -2-phenyl-1, 3-thiazole (264mg, 43%) as a pale yellow clear liquid.¹H NMR(400MHz, CDCl₃)δ7.97(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, preparation of 4- (iodomethyl) -2-phenyl-1, 3-thiazole

4- (chloromethyl) -2-phenyl-1, 3-thiazole (257mg, 1.22mmol) was dissolved in 5g of dimethyl carbonate (DMC), NaI (202mg, 1.35mmol) was added, and the reaction was refluxed at 90 ℃ for 5 h. The reaction was cooled to room temperature, concentrated under reduced pressure, the residue was dissolved in ethyl acetate (20mL) and washed with saturated sodium chloride solution, the organic phase was separated and the organic phase was washed with anhydrous NaSO₄Dried, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) gave 4- (iodomethyl) -2-phenyl-1, 3-thiazole (194mg, 53%) as a pale yellow solid. ESI-MS m/z: 302.1[ M + H]⁺。

Step 3, preparing 2-phenyl-1, 3-thiazole-4-formaldehyde

4- (iodomethyl) -2-phenyl-1, 3-thiazole (415mg, 1.38mmol) and urotropin (213mg, 1.52mmol) were added to a single-neck round-bottom flask, followed by addition of 50% aqueous acetic acid (5g) and reaction at 115 ℃ under reflux for 4 h. Cooling the reaction solution to 80 deg.C, adding 2mL concentrated hydrochloric acid, heating for reaction for 15min, cooling the reaction solution to room temperature, extracting with dichloromethane (50mL × 3), sequentially adding NaHCO into organic phase₃Washing with aqueous solution (50 mL. times.1) and pure water (50 mL. times.1), anhydrous NaSO₄Dried, filtered and concentrated under reduced pressure. Separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) gave 2-phenyl-1, 3-thiazole-4-carbaldehyde (114mg, 44%) as a yellow solid.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, preparing 3- (2-phenyl-1, 3-thiazole-4-yl) acrylic acid

Adding 2-phenyl-1, 3-thiazole-4-formaldehyde (107mg, 0.56mmol) and malonic acid (118mg, 1.13mmol) into a single-neck round-bottom flask, adding pyridine (2mL) and piperidine (0.2mL), and stirring at 85 ℃ for reacting for 30 min; the temperature is increased to 110 ℃ and the reflux reaction is carried out for 3 h. Pouring the reaction solution into 20mL of ice water, adjusting the pH value to 1-2, extracting with ethyl acetate (50mL multiplied by 3), separating an organic phase, and using anhydrous NaSO for the organic phase₄Dried, filtered and concentrated under reduced pressure.Purification by silica gel column chromatography (dichloromethane: methanol ═ 10:1) gave 3- (2-phenyl-1, 3-thiazol-4-yl) acrylic acid (110mg, 85%) as a yellow solid.¹H NMR(400MHz,DMSO-d6)δ7.97(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, preparing 3- (2-phenyl-1, 3-thiazole-4-yl) acrylic azide

3- (2-phenyl-1, 3-thiazol-4-yl) acrylic acid (92.4mg, 0.40mmol) was dissolved in 2mL of acetone, triethylamine (54mg, 0.53mmol) was added, the reaction mixture was cooled to 0 deg.C, ethyl chloroformate (54.2mg, 0.50mmol) was slowly added, and after stirring for 30min, NaN was slowly added₃(24.2mg, 0.37mmol), the reaction was stirred at 0 ℃ for 2 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give 3- (2-phenyl-1, 3-thiazol-4-yl) azidoacrylic acid (53mg, 52%) as a yellow solid.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, preparation of 2-phenylthiazolo [5,4-c ]]Pyridin-4 (5H) -ones

3- (2-phenyl-1, 3-thiazol-4-yl) acrylic azide (348mg, 1.36mmol) was dissolved in diphenyl ether (3g, 17.6mmol), and reacted at 220 ℃ for 15 hours with nitrogen exchange. The reaction solution was filtered, and the filter cake was washed with a small amount of ethyl acetate to give 2-phenylthiazolo [5,4-c ] as a white solid]Pyridin-4 (5H) -one (63mg, 20%).¹H NMR(400MHz,DMSO-d6) δ8.11(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, preparation of 4-chloro-2-phenylthiazolo [5,4-c ]]Pyridine compound

2-phenylthiazolo [5,4-c ]]Pyridin-4 (5H) -one (200mg, 0.88mmol) and phosphorus oxychloride (5mL) were added to a dry, single-neck round bottom flask, purged with nitrogen, and reacted at 135 ℃ for 2H. Cooling downThe reaction mixture was poured into 20mL of ice water at room temperature, extracted with dichloromethane (50 mL. times.3), and the organic phase was washed with saturated aqueous sodium chloride and dried over anhydrous NaSO₄Dry, filter and concentrate the organic phase under reduced pressure. Separation and purification by silica gel column chromatography (dichloromethane: methanol ═ 100:1) to give 4-chloro-2-phenylthiazolo [5,4-c ] as a yellow solid]Pyridine (66mg, 30%).¹H NMR(400MHz,MeOD)δ8.44(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) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2-phenylthiazolo [5,4-c]Preparation of pyridin-4-amines Prepare for

Step 1, preparation of (S) -tert-butyl (1- (3- ((2-phenylthiazolo [5, 4-c))]Pyridin-4-yl) amino) pyridine-4- Yl) piperidin-3-yl) carbamates

Reacting 4-chloro-2-phenylthiazolo [5,4-c ]]Pyridine (145mg, 0.59mmol), (S) -tert-butyl (1- (3-aminopyridin-4-yl) piperidin-3-yl) carbamate (172mg, 0.59mmol) and Pd₂(dba)₃(16mg，0.018mmol)、BINAP (22mg，0.036mmol)、K₂CO₃(326mg, 2.36mmol) was added to the lock tube and dissolved with tetrahydrofuran. Ventilating with nitrogen, sealing, stirring at 80 deg.C for 16h, and monitoring by TLC for reaction completion. Filtering the reaction solution, washing the filter cake with dichloromethane/methanol mixed solution (1:1), collecting filtrate, distilling off the solvent under reduced pressure, separating the crude product by preparative TLC to obtain (S) -tert-butyl (1- (3- ((2-phenylthiazolo [5, 4-c) as yellow solid]Pyridin-4-yl) amino) pyridin-4-yl) piperidin-3-yl) carbamate (36mg, 12% yield).

Step 2, preparation of (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2-phenylthiazolo [5,4-c]Pyridine (II) Pyridin-4-amines

Reacting (S) -tert-butyl (1- (3- ((2-phenylthiazolo [5, 4-c))]Pyridine compound-4-yl) amino) pyridin-4-yl) piperidin-3-yl) carbamate (36mg, 0.07mmol) was dissolved in 4mL dichloromethane and placed in an ice bath, trifluoroacetic acid (1mL) was added, the ice bath was removed after stirring for 20min, the ice bath was stirred at room temperature for 1h and the reaction was monitored by TLC for completion. The solvent was evaporated under reduced pressure, 150mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (50mL x 3), washed with clear water (50mL x 1), the organic phase was collected, evaporated to dryness under reduced pressure and the crude product was isolated by preparative TLC to give (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2-phenylthiazolo [5, 4-c) as a yellow solid]Pyridin-4-amine (15mg, 52% yield).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]⁺。

Example 19, (S) -N- (5- (3-Aminopiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenyl-1H-imidazole Azolo [4,5-c]Pyridin-4-amines

Step 1 preparation of (S) -tert-butyl (1- (1-methyl-4- ((2-phenyl-1H-imidazo [4, 5-c))]Pyridin-4-yl) Amino) -1H-pyrazol-5-yl) piperidin-3-yl) carbamates

Reacting 4-chloro-2-phenyl-3H-imidazo [4, 5-c)]Pyridine (230mg, 1mmol), (S) -tert-butyl (1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-3-yl) carbamate (295mg, 1mmol) and Pd₂(dba)₃(27mg, 0.03mmol), Xantphos (35mg, 0.06mmol), t-BuOK (168mg, 1.5mmol) were added to the vial and dissolved in toluene. The mixture was purged with nitrogen, stirred at 80 ℃ for 14h, and monitored by TLC for no further reaction of starting materials. The reaction mixture was filtered with suction, the filter cake was washed with a dichloromethane/methanol mixture (1:1), the filtrate was collected, the solvent was evaporated under reduced pressure, and the crude product was separated by preparative TLC (dichloromethane: methanol ═ 10:1) to give (S) -tert-butyl (1- (1-methyl-4- ((2-phenyl-1H-) -1) as a yellow solidImidazo [4, 5-c)]Pyridin-4-yl) amino) -1H-pyrazol-5-yl) piperidin-3-yl) carbamate (160mg, yield 32.8%).

Step 2, preparation of (S) -N- (5- (3-aminopiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenyl-1H- Imidazo [4, 5-c)]Pyridin-4-amines

Reacting (S) -tert-butyl (1- (1-methyl-4- ((2-phenyl-1H-imidazo [4, 5-c))]Pyridin-4-yl) amino) -1H-pyrazol-5-yl) piperidin-3-yl) carbamate (160mg, 0.3mmol) was dissolved in 4mL of dichloromethane, placed in an ice bath, trifluoroacetic acid (1mL) was added, the ice bath was removed after stirring for 20min, the mixture was stirred at room temperature for 1H, and the completion of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure, saturated sodium bicarbonate solution 150mL was added, extracted with ethyl acetate (50mL x 3), washed with clear water (50mL x 1), the organic phase was collected, the solvent was evaporated and the crude product was separated by preparative TLC (dichloromethane: methanol ═ 5:1) to give (S) -N- (5- (3-aminopiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenyl-1H-imidazo [4, 5-c) as a yellow solid]Pyridin-4-amine (23mg, 18.1% yield).¹H NMR(400MHz,d₆-DMSO)δ8.18-8.14(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]⁺。

Example 20, (S) -N- (5- (3-aminopiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenylthiazolo [5,4-c]Pyridin-4-amines

Step 1, preparation of (S) -tert-butyl (1- (1-methyl-4- ((2-phenylthiazolo [4, 5-c))]Pyridin-4-yl) amino 1H-pyrazol-5-yl) piperidin-3-yl) carbamate

Reacting 4-chloro-2-phenylthiazolo [5,4-c ]]Pyridine (160mg, 0.65mmol), (S) -tert-butyl (1- (4-amino-1-methyl-1H-pyrazol-5-yl) piperidin-3-yl) carbamate (192mg, 0.65mmol) and Pd₂(dba)₃(18mg，0.02mmol)、 Xantphos(23mg，0.04mmol)、K₂CO₃(269mg, 1.95mmol) was added to the vial and dissolved in tetrahydrofuran. The reaction mixture was purged with nitrogen, sealed, stirred at 80 ℃ for 16h, and monitored by TLC for no further reaction of starting materials. Filtering the reaction solution, washing the filter cake with dichloromethane/methanol mixed solution (1:1), collecting filtrate, distilling off the solvent under reduced pressure, separating the crude product by preparative TLC to obtain (S) -tert-butyl (1- (1-methyl-4- ((2-phenylthiazolo [4,5-c ]) as brown solid]Pyridin-4-yl) amino) -1H-pyrazol-5-yl) piperidin-3-yl) carbamate (54mg, 16.5% yield).

Step 2, preparation(S) -N- (5- (3-aminopiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenylthiazole And [5,4-c ]]Pyridin-4-amines

Reacting (S) -tert-butyl (1- (1-methyl-4- ((2-phenylthiazolo [4, 5-c))]Pyridin-4-yl) amino) -1H-pyrazol-5-yl) piperidin-3-yl) carbamate (54mg, 0.11mmol) was dissolved in 4mL of dichloromethane, placed in an ice bath, trifluoroacetic acid (1mL) was added, the ice bath was removed after stirring for 20min, the mixture was stirred at room temperature for 1H, and the completion of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure, 150mL of saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (50mL x 3), the mixture was washed with clear water (50mL x 1), the organic phase was collected, the solvent was evaporated, and the crude product was isolated by preparative TLC to give (S) -N- (5- (3-aminopiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenylthiazolo [5, 4-c) as a yellow solid]Pyridin-4-amine (29mg, 67% yield).¹H NMR(400MHz,MeOD) δ8.11-8.05(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]⁺。

Example 21, (S) -N- (2- (3-Aminopiperidin-1-yl) phenyl) -2-phenyl-1H-imidazo [4,5-c]Pyridine- 4-amines

The compound of the invention example 21 was prepared according to method 1, the other preparation steps were prepared according to example 5. ESI-MS m/z: 385.3[ M + H]⁺。

Example 22, (S) -N- (2- (3-)Aminopiperidin-1-yl) phenyl) -2-phenylthiazolo [5,4-c]Pyridin-4-amines

The compound of the invention example 22 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ8.38-8.32(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]⁺。

Example 23, (S) -N- (4- (3-Aminopiperidin-1-yl) pyrimidin-5-yl) -2-phenyl-1H-imidazo [4,5-c] Pyridin-4-amines

The compound of the invention example 23 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,MeOD)δ8.83(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]⁺。

Example 24, (S) -N- (4- (3-Aminopiperidin-1-yl) pyrimidin-5-yl) -2-phenylthiazolo [5,4-c]Pyridine (II) Pyridin-4-amines

The compound of the invention example 24 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,MeOD)δ8.58(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]⁺。

Example 25, (S) -N- (4- (3-Aminopyrrolidin-1-yl) pyridin-3-yl) -2-phenyl-1H-imidazo [4,5- c]Pyridin-4-amines

The compound of the invention example 25 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,MeOD)δ8.35(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]⁺。

Example 26, (S) -N- (4- (3-Aminopyrrolidin-1-yl) pyridin-3-yl) -2-phenylthiazolo [5,4-c]Pyridine (II) Pyridin-4-amines

The compound of the invention example 26 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,MeOD)δ8.23-8.17(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]⁺。

Example 27, (S) -N- (5- (3-Aminopyrrolidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenyl-1H- Imidazo [4, 5-c)]Pyridin-4-amines

The compound of the invention example 27 was prepared according to method 1, the other preparation steps were prepared according to example 19.¹H NMR (400MHz,d₆-DMSO)δ8.18-8.14(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]⁺。

Example 28, (S) -N- (5- (3-Aminopyrrolidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenylthiazole And [5,4-c ]]Pyridin-4-amines

The compound of the invention example 28 was prepared according to method 1, the other preparation steps were prepared according to example 20.¹H NMR (400MHz,CDCl₃)δ8.06(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]⁺。

Example 29, (S) -N- (2- (3-Aminopyrrolidin-1-yl) phenyl) -2-phenyl-1H-imidazo [4,5-c]Pyridine (II) Pyridin-4-amines

The compound of the invention example 29 was prepared according to method 1, the other preparation steps were prepared according to example 5. ESI-MS m/z: 371.0[ M + H]⁺。

Example 30, (S) -N- (2- (3-Aminopyrrolidin-1-yl) phenyl) -2-phenylthiazolo [5,4-c]Pyridine-4- Amines as pesticides

The compound of the invention example 30 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ8.23(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]⁺。

Example 31, (S) -N- (4- (3-Aminopyrrolidin-1-yl) pyrimidin-5-yl) -2-phenyl-1H-imidazo [4,5- c]Pyridin-4-amines

Step 1: (S) -1- (5-Aminopyrimidin-4-yl) pyrrolidin-3-yl-carbamic acid tert-butyl ester (257mg, 0.92mmol), 4-chloro-2-phenyl-3H-imidazo [4, 5-c)]Pyridine (212mg, 0.92mmol) in tetrahydrofuran, followed by addition of Pd (OAc)₂(6mg, 0.028mmol), Xantphos (32mg, 0.056mmol) and t-BuOK (155mg, 1.38mmol), stirred at 80 ℃ under nitrogen and monitored by TLC until the reaction was complete. The reaction solution was filtered, the filter cake was thoroughly washed with a dichloromethane/methanol mixture (1:1), and the filtrate was concentrated under reduced pressure. Purification by TLC separation (dichloromethane: methanol ═ 10:1) gave (S) - {1- [ (5- (2-phenyl-1H-imidazo [4, 5-c) as a yellow powdery solid]Pyridin-4-yl-amine) -pyrimidin-4-yl]-pyrrol-3-yl } -ammoniaTert-butyl benzoate (80mg, 18.4%).

Step 2: reacting (S) - {1- [ (5- (2-phenyl-1H-imidazo [4, 5-c))]Pyridin-4-yl-amine) -pyrimidin-4-yl]-pyrrol-3-yl } -carbamic acid tert-butyl ester (80mg, 0.17mmol) is dissolved in 6mL dichloromethane, the reaction flask is placed in an ice bath to cool, 1.5mL trifluoroacetic acid is added, the mixture is stirred under ice bath conditions for 20min, the reaction is continued by warming to room temperature, and TLC detection is carried out until the reaction is complete. The reaction solution was concentrated under reduced pressure, 50mL of a saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (50 mL. times.3), the combined organic phases were washed with water (10 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by TLC preparative thin layer chromatography gave (S) -N- (4- (3-aminopyrrolidin-1-yl) pyrimidin-5-yl) -2-phenyl-1H-imidazo [4, 5-c) as a yellow solid]Pyridin-4-amine (35mg, 55.3%). ESI-MS m/z: 371.14[ M-H]^-。

Example 32, (S) -N- (4- (3-Aminopyrrolidin-1-yl) pyrimidin-5-yl) -2-phenylthiazolo [5,4-c]Pyridine (II) Pyridin-4-amines

The compound of the invention example 32 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,MeOD)δ8.53(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]⁺。

Example 33, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2-phenyloxazolo [4,5-c]Pyridine (II) Pyridin-4-amines

4-chloro-2-phenyl-oxazolo [4,5-c]Preparation of pyridine

Step 1, preparation of 3-amino-4-hydroxypyridine

4-hydroxy-3-nitropyridine (2.8g, 20.0mmol) was dissolved in 150mL of methanol, 280mg of Pd/C was added, the air in the reaction flask was replaced with hydrogen, hydrogen was continuously introduced, stirring was carried out at room temperature, and TLC was carried out until the reaction was complete. The reaction solution was filtered with suction, the filter cake was washed with methanol, and the filtrate was collected and concentrated under reduced pressure to give 3-amino-4-hydroxypyridine (1.98g, 90%) as a dark orange oily liquid.

Step 2, preparing N- (4-hydroxypyridine-3-yl) benzamide

Dissolving benzoic acid (2.015g, 16.5mmol) in 60mL THF, adding EDCI (3.163g, 16.5mmol), HOAT (2.244g, 16.5mmol) and 3.5mL triethylamine in sequence, and stirring at room temperature for 2h to obtain activated ester; the reaction solution was concentrated under reduced pressure, and the resulting solid residue was dissolved in 15mL of DMF. 3-amino-4-hydroxypyridine was dissolved in 25mL of DMF and slowly added to the DMF solution of the activated ester, stirred at room temperature and monitored by TLC until the reaction was complete. The reaction solution was poured into 350mL of water, extracted with ethyl acetate, the organic phase was washed with 150mL of water, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 10:1) to give N- (4-hydroxypyridin-3-yl) benzamide (2.1g, 59%) as a white solid.

Step 3, preparation of 2-phenyloxazole [4,5-c ]]Pyridine derivatives

N- (4-hydroxypyridin-3-yl) benzamide (2.1g, 9.8mmol) was dissolved in 230mL of dichloromethane and hexachloroethane (5.802g, 24.5mmol), triphenylphosphine (7.714g, 29.4mmol) and 10.9mL of TEA were added sequentially, stirred at room temperature and TLC monitored to completion. To the reaction solution was added 200mL of a saturated sodium bicarbonate solution, allowed to stand for separation, the dichloromethane layer was separated, the aqueous phase was extracted with dichloromethane (150mL × 3), the organic phases were combined and washed with water (200mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) gave 2-phenyloxazolo [4,5-c ] bipyridine (1.4g, 73%) as a pale yellow solid.

Step 4, preparing 2-phenyloxazole [4,5-c ]]5-oxide of pyridine

2-phenyloxazole [4,5-c ]]The pyridine (1.4g, 7.13mmol) was dissolved in 40mL of dichloromethane, MCPBA (1.726g, 10.0mmol) was added slowly, and the mixture was cooled to room temperatureStirring, TLC monitoring to completion of reaction, 100mL of 1M K was added₂CO₃The solution is quenched for reaction. To the reaction solution was added 200mL of a saturated sodium chloride solution, extracted with dichloromethane (150 mL. times.3), the organic phase was separated and washed with water (25 mL. times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-phenyloxazole [4,5-c ] as a pale yellow solid]Crude product of bipyridine-5-oxide. The 2-phenyloxazole [4,5-c ]]The crude product of the bipyridine-5-oxide was directly subjected to the next reaction without further purification.

Step 5, preparation of 4-chloro-2-phenyl-oxazolo [4,5-c]Pyridine compound

The crude 2-phenyloxazolo [4,5-c ] pyridine-5-oxide was dissolved in 20mL of phosphorus oxychloride, stirred at 90 ℃ and monitored by TLC until the reaction was complete. Concentrating the reaction solution under reduced pressure, placing the reaction bottle in an ice bath for cooling, and slowly adding a saturated sodium bicarbonate solution until no bubbles are generated; the reaction solution was extracted with ethyl acetate (150 mL. times.3), the organic phases were combined, the organic phase was washed with water (200 mL. times.2), dried over anhydrous sodium sulfate, the organic phase was filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate 8:1) gave 4-chloro-2-phenyl-oxazolo [4,5-c ] pyridine (1.22g, 74% yield over two steps) as a pale yellow solid.

The compound of the invention example 33 was prepared according to method 1, the other preparation steps were prepared according to example 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]⁺。

Example 34, (S) -N- (5- (3-aminopiperidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenyloxazolo [4,5-c]Pyridin-4-amines

The compound of the invention example 34 was prepared according to method 1, the other preparation steps were prepared according to example 19.¹H NMR (400MHz,CDCl₃)δ8.25-8.20(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]^-。

Example 35, (S) -N- (2- (3-aminopiperidin-1-yl) phenyl) -2-phenyloxazolo [4, 5-c)]Pyridin-4-amines

The compound of the invention example 35 was prepared according to method 1, the other preparation steps were prepared according to example 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]⁺。

Example 36, (S) -N- (4- (3-aminopiperidin-1-yl) pyrimidin-5-yl) -2-phenyloxazolo [4,5-c]Pyridine (II) Pyridin-4-amines

The compound of the invention example 36 was prepared according to method 1, the other preparation steps were prepared according to example 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]⁺。

Example 37, (S) -N- (4- (3-Aminopyrrolidin-1-yl) pyridin-3-yl) -2-phenyloxazolo [4,5-c]Pyridine (II) Pyridin-4-amines

The compound of the invention example 37 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ8.44(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]⁺。

Example 38, (S) -N- (5- (3-amino)Pyrrolidin-1-yl) -1-methyl-1H-pyrazol-4-yl) -2-phenyloxazole And [4,5-c ]]Pyridin-4-amines

The compound of the invention example 38 was prepared according to method 1, the other preparation steps were prepared according to example 19.¹H NMR (400MHz,CDCl₃)δ10.00(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]⁺。

Example 39, (S) -N- (2- (3-Aminopyrrolidin-1-yl) phenyl) -2-phenyloxazolo [4,5-c]Pyridine-4- Amines as pesticides

The compound of the invention example 39 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ8.62(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]⁺。

Example 40, (S) -N- (4- (3-Aminopyrrolidin-1-yl) pyrimidin-5-yl) -2-phenyloxazolo [4,5-c]Pyridine (II) Pyridin-4-amines

The compound of the invention example 40 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ8.55(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]^-。

^{4 3}Example 41N-Cyclohexanyl-N- (2-phenylthiazolo [4, 5-c)]Pyridin-4-yl) pyridine-3, 4-diamines

⁴Preparation of N-cyclohexyl-pyridine-3, 4-diamine

Step 1, preparation of N-cyclohexyl-3-nitropyridin-4-amine

The compound 4-chloro-3-nitropyridine (0.8g, 5.05mmol), cyclohexylamine (0.5g, 5.04mmol) and DIPEA (0.65g, 5.03mmol) were added sequentially to a round-bottomed flask, 18mL of methanol was added, stirred at room temperature under nitrogen, and TLC was monitored to completion of the reaction. To the reaction solution, 20mL of water was added, extracted with ethyl acetate (10 mL. times.3), the organic phases were combined and washed with water (20 mL. times.2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) gave N-cyclohexyl-3-nitropyridin-4-amine (0.66g, 59%) as a dark yellow oily liquid.¹H NMR (400MHz,CDCl3)δ9.20(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]⁺。

⁴Step 2, preparing N-cyclohexyl-pyridine-3, 4-diamine

N-cyclohexyl-3-nitropyridin-4-amine (0.66g, 2.99mmol) was dissolved in 40mL ethanol and iron powder (1.34g, 24.0mmol) and NH were added₄Cl (959mg, 17.92mmol), stirred at 90 ℃ under nitrogen and TLC monitored to completion. The reaction solution was filtered, the filter cake was washed thoroughly with ethanol, and the filtrate was concentrated under reduced pressure. Separation and purification by silica gel column chromatography (dichloromethane: methanol 15:1) gave N as a dark yellow oily liquid⁴-cyclohexyl-pyridine-3, 4-diamine (426mg, 74%). ESI-MS m/z: 192.3[ M + H]⁺。

The compound of the invention example 41 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ8.34(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]⁺。

Example 42N- (4- (4-Aminopiperidin-1-yl) pyridin-3-yl) -2-phenylthiazolo [4,5-c]Pyridine-4- Amines as pesticides

Preparation of tert-butyl 1- (3-aminopyridin-4-yl) piperidin-4-yl-carbamate

Step 1, preparation of tert-butyl 1- (3-nitropyridin-4-yl) piperidine 4-yl-carbamate

4-chloro-3-nitropyridine (800mg, 5.05mmol), piperidine 4-carbamic acid tert-butyl ester (1.01g, 5.04mmol) and DIEPA (652mg, 5.04mmol) were added sequentially to a round bottom flask, followed by 25mL of methanol, stirring at room temperature and TLC monitoring to completion of the reaction. To the reaction solution was added an appropriate amount of water, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and washed with water (20 mL. times.2), dried over anhydrous sodium sulfate, the organic phase was filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) gave tert-butyl 1- (3-nitropyridin-4-yl) piperidin-4-yl-carbamate (1.7g, ca. 100%) as a yellow solid.

Step 2, preparing 1- (3-aminopyridin-4-yl) piperidin-4-yl-carbamic acid tert-butyl ester

1- (3-Nitropyridin-4-yl) piperidin-4-yl-carbamic acid tert-butyl ester (1.7g,5.27mmol) was dissolved in 15mL of ethanol, iron powder (2.3g, 41.18mmol), ammonium chloride (1.7g, 31.78mmol) and 3mL of water were added in that order, stirred at 90 ℃ and monitored by TLC until the reaction was complete. Adding a proper amount of NaHCO into the reaction liquid₃The solution was extracted with ethyl acetate (50 mL. times.3), the organic phases were combined and washed with water (20 mL. times.2), dried over anhydrous sodium sulfate, the organic phase was filtered and concentrated under reduced pressure. Column chromatography on silica gel (dichloromethane: methanol ═ 15:1 with 2% aqueous ammonia) gave tert-butyl 1- (3-aminopyridin-4-yl) piperidin-4-yl-carbamate (1.0g, 65%) as a brown solid. ESI-MS m/z：315.1[M+Na]⁺。

The compound of the invention example 42 was prepared according to method 1, with specific synthesis of reference example 5.¹H NMR(400MHz, CDCl₃)δ9.99(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]⁺。

Example 43N- (4- (piperazin-1-yl) pyridin-3-yl) -2-phenylthiazolo [4,5-c]Pyridin-4-amines

Preparation of tert-butyl 4- (3-aminopyridin-4-yl) piperazine-1-carbamate

Step 1, preparing 4- (3-nitropyridin-4-yl) piperazine-1-carbamic acid tert-butyl ester

4-chloro-3-nitropyridine (1.0g, 6.31mmol), 1-tert-butoxycarbonylpiperazine (1.17g, 6.28mmol) and DIPEA (0.815g, 6.30mmol) were added sequentially to a round-bottomed flask, followed by addition of 20mL EtOH, stirring at room temperature under nitrogen, and TLC detection until the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give tert-butyl 4- (3-nitropyridin-4-yl) piperazine-1-carbamate (1.4g, 72%) as a yellow solid.¹H NMR(400MHz,CDCl₃)δ8.89(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, preparing 4- (3-aminopyridin-4-yl) piperazine-1-carbamic acid tert-butyl ester

Tert-butyl 4- (3-nitropyridin-4-yl) piperazine-1-carbamate (1.94g, 6.30mmol) was dissolved in 40mL ethanol, and iron powder (2.82g, 50.4mmol) and NH were added sequentially₄Cl (2.02g, 37.8mmol), stirred at 90 ℃ under nitrogen and monitored by TLC until the reaction was complete. The reaction solution was filtered, the filter cake was washed thoroughly with ethanol, and the filtrate was concentrated under reduced pressure. Purification by column chromatography on silica gel afforded tert-butyl 4- (3-aminopyridin-4-yl) piperazin-1-carbamate (981mg, 56%) as a yellow solid.¹H NMR(400MHz,CDCl₃)δ8.07(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]⁺。

The compound of the invention example 43 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ10.00(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]⁺。

Example 44N- (4-Morpholinopyridin-3-yl) -2-phenylthiazolo [4,5-c]Pyridin-4-amines

Preparation of 4-morpholinyl-3-aminopyridine

Step 1, preparation of 4- (3-nitropyridin-4-yl) morpholine

4-chloro-3-nitropyridine (1.0g, 6.31mmol), morpholine (0.55g, 6.31mmol) and DIPEA (0.82 g, 6.34mmol) were added sequentially to a round-bottomed flask, 20mL of ethanol was added, stirring was carried out at room temperature under a nitrogen atmosphere, and TLC was monitored until the reaction was complete. The reaction mixture was concentrated under reduced pressure to give crude 4- (3-nitropyridin-4-yl) morpholine (1.25 g). The crude product of 4- (3-nitropyridin-4-yl) morpholine was used in the next reaction without further purification. ESI-MS m/z: 210.2 [ M + H]⁺。

Step 2, preparing 4-morpholinyl-3-aminopyridine

Reacting 4- (3-nitropyridine)Dissolving crude (1.25g, 5.97mmol) of (4-yl) morpholine in 74mL of ethanol, and adding iron powder (2.68g, 47.8mmol) and NH in sequence₄Cl (1.92g, 35.8mmol), stirred at 90 ℃ under nitrogen, and monitored by TLC until the reaction was complete. The reaction solution was filtered, the filter cake was washed thoroughly with ethanol, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane: methanol ═ 15:1) gave 4-morpholinyl-3-aminopyridine (1.02g, 95%) as a black solid. ESI-MS m/z: 180.2[ M + H]⁺。

The compound of the invention example 44 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ10.04(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]⁺。

^{4 3}Example 45N-Cyclopropylalkyl-N- (2-phenylthiazolo [4, 5-c)]Pyridin-4-yl) pyridine-3, 4-diamines

⁴Preparation of N-cyclopropyl-pyridine-3, 4-diamine

Step 1, preparation of N-cyclopropyl-3-nitropyridin-4-amine

4-chloro-3-nitropyridine (1.0g, 6.31mmol), cyclopropylamine (0.36g, 6.30mmol) and DIPEA (0.815g, 6.30mmol) were added sequentially to a round-bottomed flask, followed by 20mL of ethanol, stirring at room temperature under nitrogen, and TLC monitored for completion of the reaction. The reaction solution was filtered, the filter cake was washed thoroughly with methanol, and the filtrate was concentrated under reduced pressure. Column chromatography on silica gel (petroleum ether: ethyl acetate ═ 2:1) gave N-cyclopropyl-3-nitropyridin-4-amine (1.17g, ca. 100%) as a pale yellow solid.¹H NMR(400MHz,CDCl₃)δ9.22(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]⁺。

⁴Step 2, preparing N-cyclopropyl pyridine-3, 4-diamine

Dissolving N-cyclopropyl-3-nitropyridin-4-amine (1.17g, 6.53mmol) in 80mL ethanol, adding iron powder (2.9 g, 52.2mmol) and NH in that order₄Cl (2.1g, 39.2mmol), 8.9mL of water was added, stirring was performed at 90 ℃ under nitrogen, and TLC was performed until the reaction was complete. Filtering the reaction solution, washing the filter cake with ethanol, drying the filtrate over anhydrous magnesium sulfate, filtering and concentrating under reduced pressure to obtain N as a light yellow solid⁴-cyclopropylpyridine-3, 4-diamine (487mg, 51%).¹H NMR(400 MHz,d₆-DMSO)δ7.63(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]⁺。

The compound of the invention example 45 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ8.37(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]^-。

^{4 3}Example 46N-Cyclopentylalkyl-N- (2-phenylthiazolo [4, 5-c)]Pyridin-4-yl) pyridine-3, 4-diamines

⁴Preparation of N-cyclopentyl-pyridine-3, 4-diamine

Step 1, preparation of N-cyclopentyl-3-nitropyridin-4-amine

4-chloro-3-nitropyridine (1.0g, 6.31mmol), cyclopentylamine (537mg, 6.31mmol) and DIPEA (815mg, 6.30mmol) were added to a round-bottomed flask, followed by addition of 20mL of ethanol, stirring at room temperature under nitrogen, and TLCThe reaction was monitored to completion. The reaction solution was filtered, the filter cake was thoroughly washed with methanol, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give N-cyclopentyl-3-nitropyridin-4 amine (1.0g, 76%) as a pale yellow solid.¹H NMR(400MHz,CDCl₃)δ9.17(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]⁺。

⁴Step 2, preparing N-cyclopentyl-pyridine-3, 4-diamine

N-cyclopentyl-3-nitropyridin-4-amine (1.0g, 4.82mmol) was dissolved in 80mL ethanol and 8.9mL H was added₂O, and then iron powder (2.16g, 38.6mmol) and NH were added in this order₄Cl (1.55g, 28.9mmol), stirred at 90 ℃ under nitrogen and monitored by TLC until the reaction was complete. The reaction solution was filtered, the filter cake was washed thoroughly with ethanol, and the filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 15:1) to give N as a pale yellow solid⁴-cyclopentyl-pyridine-3, 4-diamine (800mg, 94%).¹H NMR(400MHz,d₆-DMSO)δ7.76 (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]⁺。

The compound of the invention example 46 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ8.34(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]^-。

Example 47, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2-cyclohexylthiazolo [4, 5-c)] Pyridin-4-amines

4-chloro-2-cyclohexylThiazolo [4,5-c ]]Preparation of pyridine

Step 1, preparation of 3-amino-4-mercaptopyridine

4-chloro-3-nitropyridine (16.5g,104.1mmol) was dissolved in 220mL ethanol, concentrated HCl (8.67mL) was slowly added at room temperature, stirred for 10min, and 70% NaHS. H was slowly added under ice bath₂And (4) O solution. After 1 hour of reaction at room temperature, 40mL of sodium hydrosulfite (24.38g, 140.01mmol) was added and the reaction was carried out overnight at 80 ℃. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (50mL) and filtered, the filtrate was concentrated under reduced pressure, the residue was further dissolved in methanol and filtered, and the filtrate was concentrated under reduced pressure to give a crude product of 3-amino-4-mercaptopyridine (44 g). The crude product of 3-amino-4-mercaptopyridine was used directly in the next reaction without further purification.

Step 2, preparing 2-cyclohexyl thiazolo [4,5-c]Pyridine compound

The crude 3-amino-4-mercaptopyridine (8g) was dissolved in 30mL of cyclohexanecarboxylic acid, refluxed at 120 ℃ overnight and monitored by TLC for completion of the reaction. The reaction was concentrated under reduced pressure and saturated NaHCO was used₃Adjusting the pH value of the aqueous solution to 7-8, extracting with ethyl acetate, combining organic phases, washing the organic phase with water and saturated salt sequentially, drying the organic phase through anhydrous magnesium sulfate, filtering the organic phase, and concentrating the organic phase under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to give 2-cyclohexylthiazolo [4,5-c as a white solid]Pyridine (2.7g, 65% yield over two steps). ESI-MS m/z: 219.3[ M + H]⁺。

Step 3, preparing 2-cyclohexyl thiazolo [4,5-c]Pyridine-5-oxides

2-cyclohexyl thiazolo [4, 5-c)]Pyridine (2.7g, 12.37mmol) was dissolved in 20mL dichloromethane, MCPBA (3.21g, 18.6mmol) was added slowly, stirred overnight at room temperature, and TLC monitored for completion of the reaction. With saturated NaHCO₃Adjusting the pH value of the reaction solution to 7-8, and extracting with dichloromethaneCollecting organic phase, and passing through anhydrous MgSO₄Drying, filtering and concentrating under reduced pressure to obtain 2-cyclohexyl thiazolo [4,5-c]Crude pyridine-5-oxide (860 mg). The 2-cyclohexyl thiazolo [4, 5-c)]The crude pyridine-5-oxide was used in the next reaction without further purification.

Step 4, preparing 4-chloro-2-cyclohexyl thiazolo [4,5-c]Pyridine compound

2-cyclohexyl thiazolo [4, 5-c)]Pyridine-5-oxide (860mg) and POCl₃(15mL) was added to a single glass flask and allowed to react overnight at 90 ℃ with TLC monitoring of the completion of the reaction. The reaction was concentrated under reduced pressure and saturated NaHCO was used₃Adjusting the pH value of the reaction solution to 7-8 by using an aqueous solution, extracting by using ethyl acetate, combining organic phases, washing the organic phases by using water and saturated salt sequentially, and performing anhydrous MgSO (MgSO) treatment₄The organic phase was dried, filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to give 4-chloro-2-cyclohexylthiazolo [4,5-c as a white solid]Pyridine (670mg, 21%). ESI-MS m/z: 253.2[ M + H]⁺。

The compound of the invention example 47 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,DMSO)δ9.66(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]⁺。

Example 48, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2-cyclopropylthiazolo [4, 5-c)] Pyridin-4-amines

4-chloro-2-cyclopropylthiazolo [4,5-c]Preparation of pyridine

Step 1, preparation of 2-cyclopropyl-thiazolo [4,5-c]Pyridine compound

3-amino-4-mercaptopyridine (240mg,1.90mmol) was dissolved in 6mL of cyclopropylcarboxylic acid, placed in a sealed tube, refluxed overnight at 100 ℃ and monitored by TLC for completion of the reaction. With saturated NaHCO₃The reaction was quenched, extracted with ethyl acetate, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to give 2-cyclopropyl-thiazolo [4,5-c ] as a yellow oily liquid]Pyridine (78mg, 23%).¹H NMR(400MHz,CDCl₃)δ9.14(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, preparation of 2-cyclopropyl-thiazolo [4,5-c]Pyridine-5-oxides

2-cyclopropyl-thiazolo [4,5-c ]]Pyridine (5.304g,30.1mmol) and MCPBA (7.7g,44.6mmol) were dissolved in 40mL DCM and reacted for 3h at RT, and the reaction was monitored by TLC. With saturated NaHCO₃Adjusting the pH value of the reaction solution to 7-8, extracting with dichloromethane, separating an organic phase, washing the organic phase with water and saturated sodium chloride aqueous solution in sequence, and performing anhydrous MgSO₄Drying, filtering and concentrating under reduced pressure to give 2-cyclopropyl-thiazolo [4,5-c ] as a yellow solid]Crude pyridine-5-oxide (1.29 g). The 2-cyclopropyl-thiazolo [4, 5-c)]The crude pyridine-5-oxide was used in the next reaction without further purification.

Step 3, preparing 4-chloro-2-cyclohexyl thiazolo [4,5-c]Pyridine compound

2-cyclopropyl-thiazolo [4,5-c ]]Pyridine-5-oxide dissolved in 10mL POCl₃Reflux overnight at 90 ℃ and TLC monitoring of the reaction completion. The reaction was concentrated under reduced pressure and saturated NaHCO was used₃Adjusting the pH value of the reaction liquid to 7-8 by using an aqueous solution, extracting by using ethyl acetate, separating an organic phase, drying by using anhydrous magnesium sulfate, filtering, and concentrating the organic phase under reduced pressure. Separating and purifying by silica gel column chromatography to obtain 4-chloro-2-cyclohexyl thiazolo [4,5-c ] as yellow solid]Pyridine (250mg, 18%).

The compound of the invention example 48 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,DMSO)δ9.72(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]⁺。

Example 49, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2-methylthiazolo [4,5-c]Pyridine (II) Pyridin-4-amines

4-chloro-2-methylthiazolo [4,5-c]Preparation of pyridine

Step 1, preparation of 3-amino-4-mercaptopyridine

4-chloro-3-nitropyridine (6.0g,37.8mmol) was dissolved in 80mL of ethanol, concentrated HCl (3.28mL) was slowly added at room temperature, stirred for 10min, and 70% NaHS. H was slowly added under ice bath₂And (4) O aqueous solution. After 1h reaction at room temperature, 40mL of sodium hydrosulfite (24.38g, 140.01mmol) was added and the reaction was carried out overnight at 80 ℃ and the completion of the reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol and filtered, the filtrate was concentrated under reduced pressure, the residue was further dissolved in methanol and filtered, and the filtrate was concentrated under reduced pressure to give a crude product of 3-amino-4-mercaptopyridine (20 g). The crude product of 3-amino-4-mercaptopyridine was used directly in the next reaction without further purification.

Step 2, preparing 2-methylthiazolo [4,5-c]Pyridine compound

3-amino-4-mercaptopyridine (4g,31.7mmol) was added to the reaction flask followed by 30mL of acetic acid, reflux overnight at 100 ℃ and TLC to monitor completion of the reaction. The reaction was concentrated under reduced pressure and saturated NaHCO was used₃Adjusting the pH of the reaction solution to 7-8 with an aqueous solution, extracting with ethyl acetate, separating an organic phase, washing the organic phase with water and a saturated NaCl aqueous solution in sequence, and carrying out anhydrous MgSO₄Dried, filtered and concentrated under reduced pressure. Disabled personSeparating and purifying the residue by silica gel column chromatography to obtain white solid 2-methylthiazolo [4,5-c]Pyridine (430mg, 9%).

Step 3, preparing 2-methylthiazolo [4,5-c]Pyridine-5-oxides

2-methylthiazolo [4,5-c ]]Pyridine (430mg, 2.87mmol) was dissolved in dichloromethane (20mL), MCPBA (742mg, 4.3mmol) was added slowly, stirred overnight at room temperature, and the reaction was monitored by TLC for completion. With saturated NaHCO₃Adjusting the pH value of the reaction solution to 7-8 by using an aqueous solution, extracting by using dichloromethane, separating an organic phase, and carrying out anhydrous MgSO₄Drying, filtering and concentrating the organic phase under reduced pressure to obtain 2-methylthiazolo [4,5-c]Crude pyridine-5-oxide (320 mg). The 2-methylthiazolo [4, 5-c)]The crude pyridine-5-oxide was used in the next reaction without further purification.

Step 4, preparing 4-chloro-2-methylthiazolo [4.5-c]Pyridine compound

2-methylthiazolo [4,5-c ]]Pyridine-5-oxide (320mg, 1.92mmol) and POCl₃(15mL) was added to the reaction flask, the reaction was allowed to proceed overnight at 90 ℃ and the reaction was monitored by TLC. The reaction was concentrated under reduced pressure and saturated NaHCO was used₃Adjusting the pH of the reaction solution to 7-8 with an aqueous solution, extracting with ethyl acetate, separating an organic phase, washing the organic phase with water and a saturated NaCl aqueous solution in sequence, drying with anhydrous MgSO4, filtering, and concentrating under reduced pressure. The residue was separated and purified by silica gel column chromatography to give 4-chloro-2-methylthiazolo [4.5-c ] as a white solid]Pyridine (209mg, two-step yield 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]⁺。

The compound of the invention example 49 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,MeOD)δ9.61(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]⁺。

Practice ofExample 50, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2-ethylthiazolo [4,5-c]Pyridine (II) Pyridin-4-amines

4-chloro-2-ethylthiazolo [4,5-c]Preparation of pyridine

Step 1, preparation of 2-ethylthiazolo [4,5-c]Pyridine compound

3-amino-4-mercaptopyridine (2.625g,20.8mmol) was dissolved in 50mL of propionic acid and refluxed at 100 ℃ overnight with TLC monitoring of the completion of the reaction. The filtrate was concentrated under reduced pressure and taken up with saturated NaHCO₃Adjusting the pH of the reaction solution to 7-8 with an aqueous solution, extracting with ethyl acetate, separating an organic phase, washing the organic phase with water and a saturated NaCl aqueous solution in sequence, and carrying out anhydrous MgSO₄The organic phase was dried, filtered and concentrated under reduced pressure. The residue was separated and purified by means of a silica gel column chromatography to give 2-ethylthiazolo [4,5-c ] as a yellow oily liquid]Pyridine (694mg, 20%).¹H NMR(400MHz,CDCl₃)δ9.24(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, preparing 2-ethylthiazolo [4,5-c]Pyridine-5-oxides

2-ethylthiazolo [4,5-c ]]Pyridine (430mg, 2.62mmol) was dissolved in 20mL dichloromethane, MCPBA (495mg, 2.87mmol) was added slowly, stirred overnight at room temperature, and TLC monitored for reaction completion. With saturated NaHCO₃Adjusting the pH value of the reaction solution to 7-8, extracting with dichloromethane, separating an organic phase, and carrying out anhydrous MgSO (MgSO) treatment₄Drying, filtering the organic phase and concentrating under reduced pressure to give 2-ethylthiazolo [4,5-c ] as a yellow solid]Crude pyridine-5-oxide (625 mg). The 2-ethylthiazolo [4, 5-c)]The crude pyridine-5-oxide was used in the next reaction without further purification.

Step 3, preparing 4-chloro-2-ethylthiazolo [4,5-c]Pyridine compound

2-ethylthiazolo [4,5-c ]]Pyridine-5-oxide (625mg) and POCl₃(15mL) was added to the flask and allowed to react overnight at 90 ℃ and TLC monitored for completion. The reaction was concentrated under reduced pressure and saturated NaHCO was used₃Adjusting the pH of the reaction solution to 7-8, extracting with ethyl acetate, combining organic phases, washing the organic phases with water and saturated NaCl aqueous solution in sequence, drying with anhydrous MgSO4, filtering and concentrating under reduced pressure. The residue was separated and purified by silica gel column chromatography to give 4-chloro-2-ethylthiazolo [4,5-c ] as a white solid]Pyridine (369mg, 71% yield over two steps).¹H NMR(400MHz,CDCl₃)δ8.27(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]^-。

The compound of the invention example 50 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR(400MHz,MeOD)δ9.66(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]⁺。

Example 51N- (4- (4, 4-Difluoropiperidin-1-yl) pyridin-3-yl) -2-phenylthiazolo [4,5-c]Pyridine- 4-amines

Preparation of 4- (4, 4-difluoropiperidin-1-yl) -3-aminopyridine

Step 1, preparation of 4, 4-difluoropiperidine 1-carboxylic acid tert-butyl ester

Tert-butyl 4-oxo-1-piperidinecarboxylate (199mg, 1.0mmol) was dissolved in dry DCM, DAST (507mg, 3.14mmol) was added under ice bath conditions, the reaction was carried out at room temperature for 1.5h, and the reaction was monitored by TLC for completion. Cooling the reaction solution under ice bath condition, adding saturated sodium bicarbonate solution to quench the reaction, and extracting with dichloromethaneThe organic phases were combined and washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 4, 4-difluoropiperidine 1-carboxylate (210mg, 95%). ESI-MS m/z: 244.1[ M + Na ]]⁺。

Step 2, preparing 4, 4-difluoropiperidine

Tert-butyl 4, 4-difluoropiperidine 1-carboxylate (221mg, 1.0mmol) was dissolved in 5mL of DCM/THF mixture (volume ratio 1:1), 5mL of trifluoroacetic acid was added, the reaction was carried out at room temperature for 15min, and the completion of the reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure to give 4, 4-difluoropiperidine. The title compound was used in the next reaction without further purification.

Step 3, preparation of 4- (4, 4-difluoro-piperidin-1-yl) -3-nitropyridine

Adding DIPEA into the crude product of 4, 4-difluoropiperidine to neutralize residual TFA, concentrating under reduced pressure, and dissolving the residue in ethanol; 4-chloro-3-nitropyridine (158mg, 1.0mmol) was added and the reaction was allowed to proceed overnight at room temperature, followed by TLC to monitor completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 30:1) to give 4- (4, 4-difluoro-piperidin-1-yl) -3-nitropyridine.

Step 4, preparation of 4- (4, 4-difluoro-piperidin-1-yl) -3-aminopyridine

4- (4, 4-difluoro-piperidin-1-yl) -3-nitropyridine (634mg, 2.61mmol) was dissolved in 20mL of ethanol, iron powder (293mg, 5.23mmol), ammonium chloride (280mg, 5.23mmol) and 5mL of water were added in this order, and the reaction was refluxed at 80 ℃ for 4 hours and monitored by TLC for completion. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, an appropriate amount of water was added to the residue, extracted with ethyl acetate (15mL × 3), the organic phases were combined and washed with water (10mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane: methanol ═ 20:1) to give 4- (4, 4-difluoro-piperidin-1-yl) -3-aminopyridine (528mg, 95%) as a pale yellow solid.

The compound of the invention example 51 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ10.12(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]⁺。

Example 52, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (4-bromophenyl) thiazolo [4,5- c]Pyridin-4-amines

2- (4-bromophenyl-1-yl) -4-chloro-thiazolo [4,5-c]Preparation of pyridine

Step 1, preparation of 2- (4-bromophenyl-1-yl) thiazolo [4,5-c]Pyridine compound

Reacting thiazolo [4,5-c ]]Pyridine (2.0g, 14.69mmol), p-bromoiodobenzene (4.2g, 14.85mmol), Pd (PPh)₃)₄(855mg, 0.74mmol), CuI (142mg, 0.74mmol), and Cs₂CO₃(14.7g, 45mmol) was dissolved in 25mL DMF and the reaction was stirred at 120 ℃ and monitored by TLC to completion. The reaction mixture was cooled to room temperature, the reaction mixture was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated, the organic phase was washed successively with water (25 mL. times.1) and saturated brine (25 mL. times.2), dried over anhydrous sodium sulfate, the organic phase was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give 2- (4-bromophenyl-1-yl) thiazolo [4, 5-c) as a yellow solid powder]Pyridine (2.93g, 68%).¹H NMR(400MHz,CDCl₃)δ9.36(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, preparation of 2- (4-bromophenyl-1-yl) thiazolo [4,5-c]Pyridine-5-oxides

2- (4-bromophenyl-1-yl) thiazolo [4,5-c ] pyridine (2.93g, 10.1mmol) was dissolved in 10mL of dichloromethane, MCPBA (2.49g, 14.4mmol) was slowly added, stirring was performed at room temperature, TLC was monitored for completion of the reaction, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 2- (4-bromophenyl-1-yl) thiazolo [4,5-c ] pyridine-5-oxide (3.1g) as a yellow solid. The crude 2- (4-bromophenyl-1-yl) thiazolo [4,5-c ] pyridine-5-oxide was used in the next reaction without further purification.

Step 3, preparation of 2- (4-bromophenyl-1-yl) -4-chloro-thiazolo [4,5-c]Pyridine compound

Reacting 2- (4-bromophenyl-1-yl) thiazolo [4,5-c]The crude pyridine-5-oxide was dissolved in 5mL of POCl₃And refluxing for 2 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (25 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (4-bromophenyl-1-yl) -4-chloro-thiazolo [4,5-c ] as a pale pink solid]Pyridine (1.58g, 48% yield over two steps).¹H NMR (400MHz,CDCl₃)δ8.31(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]⁺。

The compound of the invention example 52 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,MeOD)δ8.37(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]⁺。

Example 53, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (pyridin-2-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (2-pyridyl) thiazolo [4,5-c]Preparation of pyridine

Step 1, preparation of 2- (pyridin-2-yl) thiazolo [4,5-c]Pyridine compound

Reacting thiazolo [4,5-c ]]Pyridine (1g, 7.34mmol), 2-bromopyridine (1392mg, 8.81mmol), Pd (PPh)₃)₄(424mg，0.37mmol)、CuI(71mg，0.37mmol)、Cs₂CO₃(7.17g, 22.0mmol) and DMF (100mL) were added sequentially to the single-neck flask, reacted at 120 ℃ for 6h, and the completion of the reaction was monitored by TLC. The reaction solution was cooled to room temperature, the reaction solution was filtered, the filtrate was poured into water, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, washed with saturated brine (50 mL. times.3), and then anhydrous MgSO₄The organic phase was dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give 2- (pyridin-2-yl) thiazolo [4, 5-c) as a pale yellow solid]Pyridine (1370mg, 88%).¹H NMR(400MHz,CDCl₃)δ9.37(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, preparation of 2- (pyridin-2-yl) thiazolo [4,5-c]Pyridine-5-oxides

Reacting 2- (pyridin-2-yl) thiazolo [4,5-c]Pyridine (1370mg, 6.42mmol) was dissolved in 60mL DCM and MCPBA (1551mg, 8.99mmol) was added slowly and reacted overnight at RT with TLC monitoring of the completion of the reaction. NaHCO is slowly added to the reaction solution₃Solution (90 mL. times.2), filtration of the reaction mixture, separation of the organic phase, and passage over anhydrous Na₂SO₄Drying, filtering the organic phase and concentrating under reduced pressure to give 2- (pyridin-2-yl) thiazolo [4, 5-c) as a yellowish-brown solid]Crude pyridine-5-oxide (1355 mg). The 2- (pyridine-2-yl) thiazolo [4,5-c]The crude pyridine-5-oxide was used in the next reaction without further purification.

Step 3, preparing 4-chloro-2- (pyridine-2-yl) thiazolo [4,5-c]Pyridine compound

Reacting 2- (pyridin-2-yl) thiazolo [4,5-c]Pyridine-5-oxide (1355mg) and POCl₃Adding the mixture into a single-neck flask, reacting for 6 hours at 100 ℃, cooling the reaction liquid to room temperature, slowly dropwise adding 50mL of water into the reaction liquid, and continuously stirring for 0.5 hour. Adjusting pH of the reaction solution to about 8 with 30% NaOH aqueous solution, extracting with DCM (100mL), separating organic phase, and passing through anhydrous Na₂SO₄The organic phase was dried, filtered and concentrated under reduced pressure. Separating and purifying the residue with silica gel column chromatography to obtain 4-chloro-2- (pyridin-2-yl) thiazolo [4,5-c as white solid]Pyridine (944mg, two-step yield 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]⁺。

The compound of the invention example 53 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ9.74(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]⁺。

Example 54, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thiophen-3-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (thien-3-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: dissolving 4-chloro-3-nitro-pyridine (7950mg, 50mmol) in 50mL ethanol, slowly adding 50mmol concentrated hydrochloric acid, and stirring at room temperature; weighing NaHS. H₂O (13.69g, 185mmol) is added to the reaction solution and stirred for 40min at room temperature; sodium hydrosulfite (32.21g, 185mmol) was weighed out and dissolved in water and the aqueous sodium hydrosulfite solution was added to the reaction mixture and stirred at 80 ℃ for 12 h. Filtering the reaction solution, concentrating the filtrate under reduced pressure, and performing column chromatographySeparation and purification (eluting with dichloromethane: methanol ═ 5:1 and then dichloromethane: methanol ═ 1:1 to give crude product) gave crude 3-amino-4-mercaptopyridine as a brownish yellow solid. It was not purified and used directly in the next reaction.

Step 2: the crude product of 3-amino-4-mercaptopyridine was dissolved in 100mL of formic acid, refluxed for 4h, and quenched by addition of saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate (200 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave thiazolo [4,5-c ] pyridine (2.52g, 37% yield in two steps) as a white powdery solid.

And step 3: reacting thiazolo [4,5-c ]]Pyridine (2g, 14.7mmol), 3-bromothiophene (2.876g, 17.6mmol), Pd (PPh)₃)₄(855mg, 0.74mmol), CuI (141mg, 0.74mmol), and Cs₂CO₃(14.5g, 44.1mmol) was dissolved in 40mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 200mL of water and 100mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 100mL of water, the organic phase was washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separation and purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave 2-thiophen-3-yl-thiazolo [4,5-c ] as a pale yellow solid]Pyridine (2g, 62.4%).¹H NMR (400MHz,CDCl₃)δ9.33(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]⁺。

And 4, step 4: 2-Thiophen-3-yl-thiazolo [4,5-c ] pyridine (3.2g, 14.7mmol) was dissolved in 20mL of dichloromethane, MCPBA (3.445g, 19.96mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 20mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 100mL of saturated brine, extracted with dichloromethane (100mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2-thiophen-3-yl-thiazolo [4,5-c ] pyridine-5-oxide as a white solid. It was not purified and used directly in the next reaction.

And 5: reacting 2-thiophen-3-yl-thiazolo [4,5-c ]]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Adding saturated sodium bicarbonate to adjust pH to neutrality, extracting with ethyl acetate (100 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure to obtain a pale yellow powder solid 4-chloro-2- (thiophen-3-yl) thiazolo [4,5-c ]]Pyridine (1.1g, 30% yield over two steps).¹H NMR(400 MHz,CDCl₃)δ8.29(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]⁺。

The compound of the invention example 54 was prepared according to method 1, with the other steps being prepared according to example 18.¹H NMR(400 MHz,CDCl₃)δ10.01(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]⁺。

Example 55, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (furan-2-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (furan-2-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (1g, 7.3mmol), 2-bromofuran (1.3g, 8.8mmol), Pd (PPh)₃)₄(428mg, 0.37mmol), CuI (70mg, 0.37mmol) and Cs₂CO₃(7.18g, 22mmol) was dissolved in 20mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction mixture was cooled to room temperature, filtered, and 200mL of water and 100m of water were addedTo the filtrate was added L ethyl acetate, the organic phase was separated and washed with 100mL water, the organic phase was washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separation and purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave 2-furan-2-yl-thiazolo [4,5-c ] as a pale yellow powdery solid]Pyridine (2g, 93.9%).¹H NMR (400MHz,CDCl₃)δ9.35(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: 2-Furan-2-yl-thiazolo [4,5-c ] pyridine (1.5g, 7.43mmol) was dissolved in 10mL of dichloromethane, MCPBA (1.96g, 11.14mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 20mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 100mL of saturated brine, extracted with dichloromethane (100mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2-furan-2-yl-thiazolo [4,5-c ] pyridine-5-oxide as a yellow solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2-furan-2-yl-thiazolo [4,5-c ]]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And refluxing for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (100 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (furan-2-yl) thiazolo [4,5-c ] as a pale yellow solid]Pyridine (900mg, two-step yield 51.5%).

(S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (furan-2-yl) thiazolo [4,5-c]Pyridine- Preparation of 4-amines

Step 1: (S) -1- (3-Aminopyridin-4-yl) piperidin-3-yl-carbamic acid tert-butyl ester (292mg, 1mmol), 4-chloro-2-furan-2-yl-thiazolo [4, 5-c)]Pyridine (237 mg)1mmol) in tetrahydrofuran, successively adding Pd₂(dba)₃(27mg, 0.03mmol), BINAP (37mg, 0.06mmol) and K₂CO₃(414mg, 3mmol), stirred at 80 ℃ under nitrogen and monitored by TLC until the reaction was complete. The reaction solution was filtered, the filter cake was sufficiently washed with a dichloromethane/methanol mixture (1:1), and the filtrate was concentrated under reduced pressure. Purification by TLC separation (dichloromethane: methanol ═ 20:1) gave (S) - [3' - (2-furan-2-yl-thiazolo [4, 5-c) as a yellow solid]Pyridin-4-yl-amine) -3,4,5, 6-tetrahydro-2H- [1,4']Bispyridyl-3-yl]Tert-butyl carbamate (202mg, 41%).

Step 2: mixing (S) - [3' - (2-furan-2-yl-thiazolo [4, 5-c)]Pyridin-4-yl-amine) -3,4,5, 6-tetrahydro-2H- [1,4']Bispyridin-3-yl]Tert-butyl carbamate (202mg, 0.41mmol) was dissolved in 6mL dichloromethane, the reaction flask was placed in an ice bath to cool, 1.5mL trifluoroacetic acid was added, the mixture was stirred under ice bath conditions for 20min, the reaction was continued by warming to room temperature, and TLC detection was performed until the reaction was complete. The reaction solution was concentrated under reduced pressure, 50mL of a saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (50 mL. times.3), the combined organic phases were washed with water (10 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by TLC preparative thin layer chromatography gave (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (furan-2-yl) thiazolo [4, 5-c) as a yellow solid]Pyridin-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]⁺。

Example 56, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (pyridin-4-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (pyridin-4-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (500mg, 3.67mmol), 4-bromopyridine hydrochloride (855mg, 4.4mmol), Pd (PPh)₃)₄(212mg, 0.183mmol), CuI (35mg, 0.183mmol) and Cs₂CO₃(4.3g, 13.2mmol) was dissolved in 20mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 50mL of water, the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To obtain 2-pyridin-4-yl-thiazolo [4,5-c]Crude pyridine product is directly reacted in the next step.¹H NMR(400MHz,CDCl₃)δ9.44(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: the crude 2-pyridin-4-yl-thiazolo [4,5-c ] pyridine was dissolved in 20mL of dichloromethane, MCPBA (887mg, 5.14mmol) was added slowly, stirred at room temperature, TLC monitored for completion of the reaction, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2-pyridin-4-yl-thiazolo [4,5-c ] pyridine-5-oxide as a yellow solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2-pyridin-4-yl-thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And refluxing for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Adding saturated sodium bicarbonate to adjust pH to neutrality, extracting with ethyl acetate (100 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure to give 4-chloro-2-pyridin-4-yl-thiazolo [4,5-c ] as a yellow solid powder]Pyridine (270mg, 29.7% yield in three steps).

The compound of the invention example 56 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.58(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]^-。

Example 57, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (pyrimidin-2-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (pyrimidin-2-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (136mg, 1mmol), 2-bromopyrimidine (191mg, 4.4mmol), Pd (PPh)₃)₄(58mg, 0.05mmol), CuI (10mg, 0.05mmol) and Cs₂CO₃(977mg, 3mmol) was dissolved in 5mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 50mL of water, the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (dichloromethane: methanol ═ 20:1) gave 2- (pyrimidin-2-yl) thiazolo [4,5-c as a pale yellow solid]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: 2- (pyrimidin-2-yl) thiazolo [4,5-c ] pyridine (197mg, 0.92mmol) was dissolved in 5mL of dichloromethane, MCPBA (222mg, 1.92mmol) was added slowly, stirred at room temperature, TLC monitored for reaction completion, and 5mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2-pyrimidin-2-yl-thiazolo [4,5-c ] pyridine-5-oxide as a yellow solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (pyrimidin-2-yl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 8mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (pyrimidin-2-yl) -thiazolo [4,5-c as a pale yellow solid]Pyridine (109mg, two-step yield 52.4%).¹H NMR(400 MHz,CDCl₃)δ8.98(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)。

The compound of the invention example 57 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ9.68(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]⁺。

Example 58, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thiazol-2-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (thiazol-2-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (2.0g, 14.79mmol), 2-bromothiazole (2.89g, 17.75mmol), Pd (PPh)₃)₄(854mg, 0.740mmol), CuI (141mg, 0.740mmol), and Cs₂CO₃(14.4g, 44.37mmol) was dissolved in 40mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 200mL of water and 100mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 100mL of water, the organic phase was washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By passingColumn chromatography separation and purification (petroleum ether: ethyl acetate ═ 2:1) afforded 2- (thiazol-2-yl) -thiazolo [4,5-c ] as a pale yellow solid]Pyridine (2.98g, 92%).¹H NMR(400MHz,CDCl₃)δ9.40(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: 2- (Thiazol-2-yl) -thiazolo [4,5-c ] pyridine (2.98g, 13.607mmol) was dissolved in 50mL dichloromethane, MCPBA (3.188g, 18.476mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 20mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 100mL of saturated brine, extracted with dichloromethane (100 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (thiazol-2-yl) -thiazolo [4,5-c ] pyridine-5-oxide as a yellow solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (thiazol-2-yl) -thiazolo [4,5-c ]]Pyridine-5-oxide crude product dissolved in 20mL POCl₃And refluxing for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (100 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (thiazol-2-yl) -thiazolo [4,5-c ] as a yellow solid powder]Pyridine (1.08g, 38.7% yield over two steps).¹H NMR(400MHz, CDCl₃)δ8.35(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)。

The compound of the invention example 58 was prepared according to method 1, the other preparation steps were prepared according to example 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]^-。

Example 59, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thiophen-2-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (thien-2-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (1.0g, 7.34mmol), 2-bromothiophene (1436mg, 8.81mmol), Pd (PPh)₃)₄(424mg, 0.367mmol), cuprous iodide (70mg, 0.367mmol), cesium carbonate (7174mg, 22.02mmol) and DMF (100mL) were sequentially added to a 250mL single-neck flask, and stirred at 120 ℃ for 6 h. TLC monitored the reaction complete and cooled to room temperature. Filtering, adding 200ml EA and 100ml H into the filtrate₂O, the layers were separated, the aqueous phase was extracted with EA (50 mL. times.3), the organic phases were combined, washed with saturated NaCl solution (100 mL. times.3), and the organic layer was over anhydrous MgSO₄Drying, suction filtering, rotary evaporating to remove solvent, and separating residue by column chromatography (P: E ═ 3:1) to obtain light yellow solid 2- (thiophene-2-yl) -thiazolo [4,5-c]Pyridine (1.2g, 75%).¹H NMR(400MHz,CDCl₃)δ9.29(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: reacting 2- (thien-2-yl) -thiazolo [4,5-c]Pyridine (1.2g, 5.5mmol), DCM (55mL) and MCPBA (1329mg, 7.7mmol) were put into a 250mL single-neck flask in sequence, stirred overnight at room temperature, 30% NaOH solution was slowly added dropwise, filtered, the filtrate was separated into layers, and the organic phase was purified with anhydrous Na₂SO₄Drying, filtering, and rotary evaporating to remove solvent to obtain yellowish green solid 2- (thiophene-2-yl) -thiazolo [4,5-c]Pyridine-5-oxide. Directly feeding the mixture into the next step for reaction.

And step 3: reacting 2- (thien-2-yl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 20mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Adding saturated sodium bicarbonate to adjust pH to neutrality, extracting with ethyl acetate (100 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure to give a light solutionYellow solid powder of 4-chloro-2- (thien-2-yl) thiazolo [4,5-c]Pyridine (486mg, two-step yield 35.0%).¹H NMR(400 MHz,CDCl₃)δ8.28(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]⁺。

The compound of the invention example 59 was prepared according to method 1, the other preparation steps were prepared according to example 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]⁺。

Example 60, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (4-methylphenyl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (4-methylphenyl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (460mg, 11.01mmol), 4-methyliodobenzene (883mg, 4.05mmol), Pd (PPh)₃)₄(195mg, 0.169mmol), CuI (32mg, 0.169mmol) and Cs₂CO₃(3.3mg, 10.14mmol) was dissolved in 20mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 50mL of water, the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separation and purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave 2- (4-methylphenyl) thiazolo [4,5-c ] as a white solid]Pyridine (550mg, 72%).

Step 2: 2- (4-methylphenyl) thiazolo [4,5-c ] pyridine (550mg, 2.43mmol) was dissolved in 15mL dichloromethane, MCPBA (630mg, 3.65mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution, 50mL of saturated brine was added, and extraction was performed with methylene chloride (50 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC separation to obtain 2- (4-methylphenyl) thiazolo [4,5-c ] pyridine-5-oxide as a white solid, which was directly subjected to the next reaction without purification.

And step 3: reacting 2- (4-methylphenyl) thiazolo [4,5-c ]]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And refluxing for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Adding saturated sodium bicarbonate to adjust pH to neutrality, extracting with ethyl acetate (100 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure to give 4-chloro-2- (4-methylphenyl) thiazolo [4,5-c ] as off-white solid]Pyridine (350mg, 46.3%). ESI-MS m/z: 261.02[ M + H]⁺。

(S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (4-methylphenyl) thiazolo [4,5-c]Pyridine- Preparation of 4-amines

Step 1: (S) -1- (3-Aminopyridin-4-yl) piperidin-3-yl-carbamic acid tert-butyl ester (134mg, 0.46mmol), 4-chloro-2-p-tolyl-thiazolo [4,5-c]Pyridine (120mg, 0.46mmol) was dissolved in tetrahydrofuran, followed by the addition of Pd₂(dba)₃(13mg, 0.014mmol), Xantphos (16mg, 0.028mmol) and t-BuOK (77mg, 0.69mmol), stirred at 80 ℃ under nitrogen and monitored by TLC until the reaction was complete. The reaction solution was filtered, the filter cake was thoroughly washed with a dichloromethane/methanol mixture (1:1), and the filtrate was concentrated under reduced pressure. Purification by TLC separation (dichloromethane: methanol ═ 20:1) afforded (S) - [3' - (2-p-tolyl-thiazolo [4, 5-c) as a yellow-brown solid]Pyridin-4-yl-amine) -3,4,5, 6-tetrahydro-2H- [1,4']Bis-pyridin-3-yl]-carbamic acid tert-butyl ester (60mg, 25.2%).

Step 2: mixing (S) - [3' - (2-p-tolyl-thiazolo [4, 5-c)]Pyridine-4-yl-amine) -3,4,5, 6-tetrahydro-2H- [1,4']Bis-pyridin-3-yl]Tert-butyl carbamate (60mg, 0.12mmol) was dissolved in 4mL dichloromethane, the reaction flask was cooled in an ice bath, 1mL trifluoroacetic acid was added, the mixture was stirred for 20min under ice bath conditions, warmed to room temperature for further reaction, and checked by TLC until the reaction was complete. The reaction solution was concentrated under reduced pressure, 50mL of a saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate (50 mL. times.3), the combined organic phases were washed with water (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by TLC preparative thin layer separation gave 27mg of compound 60 as a yellow solid in 54% yield.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]⁺。

Example 61, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2- (4-methoxyphenyl) thiazolo [4,5-c]Pyridin-4-amines

4-chloro-2- (4-methoxyphenyl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (200mg, 1.469mmol), 4-methoxyiodobenzene (413mg, 1.763 mmol), Pd (PPh)₃)₄(86mg, 0.074mmol), CuI (14mg, 0.074mmol) and Cs₂CO₃(1.436mg, 4.407mmol) was dissolved in 10mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 50mL of water, the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave 2- (4-methoxy-phenyl) as a white solid) Thiazolo [4,5-c]Pyridine (249mg, 70%).¹H NMR(400MHz,CDCl₃)δ9.32(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: 2- (4-methoxy-phenyl) -thiazolo [4,5-c ] pyridine (225mg, 0.93mmol) was dissolved in 10mL of dichloromethane, MCPBA (224mg, 1.3mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (4-methoxy-phenyl) -thiazolo [4,5-c ] pyridine-5-oxide.

And step 3: reacting 2- (4-methoxy-phenyl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And then flows back for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (100mL × 3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (4-methoxy-phenyl) -thiazolo [4,5-c ] as a white solid]Pyridine (136mg, 52.8%).¹H NMR(400 MHz,CDCl₃)δ8.28(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]⁺。

The compound of the invention example 61 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,d₆-DMSO)δ9.66(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]⁺。

Example 62, 2-phenyl-N- (4- (piperidin-1-yl) pyridin-3-yl) thiazolo [4,5-c]Pyridin-4-amines

Preparation of 4- (piperidin-1-yl) -3-aminopyridine

Step 1, preparation of 3-nitro-4- (piperidin-1-yl) pyridine

4-chloro-3-nitropyridine (1g,6.31mmol), piperidine (536mg,6.31mmol) and DIPEA (812mg,6.28 mmol) were dissolved in 25mL of methanol, stirred at room temperature for 5h, and the reaction was monitored by TLC for completion. Pouring the reaction solution into water, extracting with ethyl acetate, combining organic phases, washing the organic phase with saturated sodium chloride aqueous solution, and performing anhydrous MgSO₄Drying, filtration of the organic phase and concentration under reduced pressure gave 3-nitro-4- (piperidin-1-yl) pyridine (1.304g, ca. 100%) as a yellow oil.¹H NMR (400MHz,CDCl₃)δ8.79(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, preparing 4- (piperidine-1-yl) -3-aminopyridine

3-Nitro-4- (piperidin-1-yl) pyridine (1.3g,6.27mmol), iron powder (2.822g, 50.4mmol) and ammonium chloride (2.022g,37.8mmol) were added to a reaction flask, followed by 15mL EtOH and 3mL H₂O, reflux overnight at 90 ℃, TLC monitored completion of the reaction. Filtering the reaction solution to remove iron powder, adding saturated NaHCO into the filtrate₃Extracting the solution with ethyl acetate, mixing the organic phases, washing the organic phase with water for 2 times, and purifying with anhydrous MgSO₄The organic phase was dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane: methanol 15:1, 2% aqueous ammonia was added) to give 4- (piperidin-1-yl) -3-aminopyridine as a brown oily liquid (799mg, 72%).¹H NMR(400MHz,CDCl₃)δ8.00(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]⁺。

The compound of the invention example 62 was prepared according to method 1, the other preparation steps were prepared according to example 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]⁺。

Example 63, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2- (2-acetylthiophen-5-yl) thia-ne Azolo [4,5-c]Pyridin-4-amines

4-chloro-2- (2-acetylthiophen-5-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 2- (2-acetylthiophen-5-yl) thiazolo [4,5-c ] pyridine (190mg, 0.73mmol) was dissolved in 10mL of dichloromethane, MCPBA (176mg, 1.02mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 5mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (2-acetylthiophen-5-yl) thiazolo [4,5-c ] pyridine-5-oxide, which was not purified and directly reacted in the next step.

Step 2: 2- (2-acetylthiophen-5-yl) thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 5mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (100 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (2-acetylthiophen-5-yl) thiazolo [4,5-c ] as a yellow solid]Pyridine (85mg, 39.5%).¹H NMR (400MHz,CDCl₃)δ8.35(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)。

The compound of the invention example 63 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.77(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]⁺。

Example 64, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) Thiazolo [4,5-c ]]Pyridin-4-amines

4-chloro-2- (1-methyl-1H-pyrazol-4-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (1.071g, 8.5mmol) and 1-methyl-1H-pyrazole-4-carboxylic acid (2.144g, 17mmol) were dissolved in polyphosphoric acid (PPA) and subjected to tube sealing reaction at 140 ℃. The reaction was complete by TLC. The reaction was terminated and quenched by addition of saturated sodium bicarbonate solution. The reaction was extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) gave 2- (1-methyl-1H-pyrazol-4-yl) -thiazolo [4,5-c ] pyridine (483mg, 26.3%) as a yellow solid.

Step 2: 2- (1-methyl-1H-pyrazol-4-yl) -thiazolo [4,5-c ] pyridine (483mg, 2.2mmol) was dissolved in 30mL of dichloromethane, MCPBA (535mg, 3.1mmol) was slowly added, stirred at room temperature, TLC monitored for completion of the reaction, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (1-methyl-1H-pyrazol-4-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (1-methyl-1H-pyrazol-4-yl) -thiazolo [4,5-c]Crude pyridine-5-oxideThe product was dissolved in 8mL POCl₃And refluxing for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (1-methyl-1H-pyrazol-4-yl) -thiazolo [4, 5-c) as a pale yellow solid]Pyridine (328mg, two-step yield 59.6%).

The compound of the invention example 64 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.84(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]^-。

Example 65, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-imidazol-4-yl) thia-ne Azolo [4,5-c]Pyridin-4-amines

4-chloro-2- (1-methyl-1H-imidazol-4-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (252mg, 2mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (504mg, 4mmol) were dissolved in polyphosphoric acid (PPA) and subjected to a tube-sealing reaction at 140 ℃. The reaction was complete by TLC. The reaction was terminated and quenched by addition of saturated sodium bicarbonate solution. The reaction was extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) afforded 2- (1-methyl-1H-imidazol-4-yl) -thiazolo [4, 5-c) as a yellow solid]Pyridine (225mg, 52%).¹H NMR(400MHz, CDCl₃)δ9.28(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: 2- (1-methyl-1H-imidazol-4-yl) -thiazolo [4,5-c ] pyridine (225mg, 1mmol) was dissolved in 10mL dichloromethane, MCPBA (251mg, 1.4mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 5mL 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (1-methyl-1H-imidazol-4-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (1-methyl-1H-imidazol-4-yl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 8mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (1-methyl-1H-imidazol-4-yl) -thiazolo [4,5-c as a pale yellow solid]Pyridine (130mg, 52% yield over two steps).

The compound of the invention example 65 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.62(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]⁺。

Example 66, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-imidazol-5-yl) Thiazolo [4,5-c ]]Pyridin-4-amines

4-chloro-2- (1-methyl-1H-imidazol-5-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (1.0g, 7.9mmol) and 1-methyl-1H-imidazole-5-carboxylic acid (2.0g, 15.8mmol) were dissolved in polyphosphoric acid (PPA) and the reaction was blocked at 140 ℃. The reaction was complete by TLC. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench the reaction. The reaction solution was extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) gave 2- (1-methyl-1H-imidazol-5-yl) -thiazolo [4,5-c ] pyridine (520mg, 30.5%) as a yellow solid.

And step 3: 2- (1-methyl-1H-imidazol-5-yl) -thiazolo [4,5-c ] pyridine (520mg, 2.4mmol) was dissolved in 30mL dichloromethane, MCPBA (582mg, 3.4mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 100mL of saturated brine, extracted with dichloromethane (100mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (1-methyl-1H-imidazol-5-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And 4, step 4: reacting 2- (1-methyl-1H-imidazol-5-yl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 8mL POCl₃And refluxing for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (100mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (1-methyl-1H-imidazol-5-yl) -thiazolo [4, 5-c) as a yellow solid]Pyridine (331mg, 55% yield over two steps).

The compound of the invention example 66 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.51(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]^-。

Example 67, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (pyrimidin-5-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (pyrimidin-5-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (280mg, 2mmol), 5-bromopyrimidine (392mg, 2.4mmol), Pd (PPh)₃)₄(116mg, 0.1mmol), CuI (19mg, 0.1mmol) and Cs₂CO₃(1.965g, 6mmol) was dissolved in 10mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 50mL of water, the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (dichloromethane: methanol ═ 20:1) gave 2- (pyrimidin-5-yl) -thiazolo [4, 5-c) as a pale yellow solid]Pyridine (349mg, 81.5%).

Step 2: 2- (pyrimidin-5-yl) -thiazolo [4,5-c ] pyridine (349mg, 1.6mmol) was dissolved in 10mL of dichloromethane, MCPBA (394mg, 2.3mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 5mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude 2- (pyrimidin-5-yl) -thiazolo [4,5-c ] pyridine-5-oxide as a yellow solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (pyrimidin-5-yl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 8mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Adding saturated sodium bicarbonate to adjust pH to neutrality, extracting with ethyl acetate (50 mL. times.3), combining organic phases, and passing through anhydrous sulfurSodium acid drying, filtration and concentration under reduced pressure to give 4-chloro-2- (pyrimidin-5-yl) -thiazolo [4,5-c as a pale yellow solid]Pyridine (122mg, two-step yield 39.3%).

The compound of the invention example 67 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.60(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]⁺。

Example 68, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thiazol-4-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (thiazol-4-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (730mg, 5.8mmol) and thiazole-4-carboxylic acid (1.5g, 11.6mmol) were dissolved in polyphosphoric acid (PPA) and subjected to tube sealing reaction at 140 ℃. The reaction was complete by TLC. The reaction was terminated and quenched by addition of saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) gave 2- (thiazol-4-yl) -thiazolo [4,5-c ] pyridine (600mg, 47.2%) as a brown solid.

Step 2: 2- (Thiazol-4-yl) -thiazolo [4,5-c ] pyridine (600mg, 2.74mmol) was dissolved in 40mL dichloromethane, MCPBA (662mg, 3.84mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (thiazol-4-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (thiazol-4-yl) -thiazolo [4,5-c ]]Pyridine-5-oxide crude product dissolved in 8mL POCl₃And refluxing for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (thiazol-4-yl) -thiazolo [4,5-c ] as an off-white solid]Pyridine (455mg, 65.4% yield over two steps).

The compound of the invention example 68 was prepared according to method 1, the other preparation steps were prepared according to example 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]^-。

Example 69, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thiazol-5-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (thiazol-5-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (1g, 7.9mmol) and thiazole-5-carboxylic acid (2.04g, 15.8mmol) were dissolved in polyphosphoric acid (PPA) and subjected to tube sealing reaction at 140 ℃. The reaction was complete by TLC. The reaction was terminated and quenched by addition of saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) afforded 2- (thiazol-5-yl) -thiazolo [4, 5-c) as an off-white solid]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: 2- (Thiazol-5-yl) -thiazolo [4,5-c ] pyridine (420mg, 2mmol) was dissolved in 40mL dichloromethane, MCPBA (482mg, 2.8mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product of 2- (thiazol-5-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (thiazol-5-yl) -thiazolo [4,5-c ]]Pyridine-5-oxide crude product dissolved in 5mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (thiazol-5-yl) -thiazolo [4,5-c ] as a yellow solid]Pyridine (170mg, 35% yield over two steps).¹H NMR(400MHz, CDCl₃)δ9.03(s,1H),8.51(s,1H),8.37(d,J＝5.4Hz,1H),7.80(d,J＝5.4Hz,1H)。

The compound of the invention example 69 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.75(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]^-。

Example 70, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2- (benzo [ b ]]Thien-3-yl) thia Azolo [4,5-c]Pyridin-4-ylamine H

4-chloro-2- (benzo [ b ]]Thien-3-yl) thiazolo [4,5-c]Preparation of pyridine

Step one, adding thiazolo [4,5-c ] into a 50ml sealed tube]Pyridine (100mg, 0.734mmol), 3-bromobenzo [ b ]]Thiophene (188mg, 0.881mmol), cesium carbonate (717mg, 2.2mmol), copper iodide (7mg, 0.0367mmol) and tetrakis (triphenylphosphine) palladium (42mg, 0.0367mmol) were dissolved in 8ml DMF after the addition was complete, the reaction was stirred with nitrogen, the tube was sealed, the reaction was heated in a 120 ℃ oil bath and stirred, and after 14h, the reaction was complete by TLC and stopped. And (3) post-treatment: adding water, extracting with ethyl acetate, backwashing the organic phase with water, spin-drying the organic phase, and purifying the residue with thin layer plate to obtain light yellow powder solid 2- (benzo [ b)]Thien-3-yl) thiazolo [4,5-c]Pyridine (67mg, 34%).¹H NMR (400MHz,CDCl₃)δ9.42(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 two, 2- (benzo [ b ]]Thien-3-yl) thiazolo [4,5-c]Pyridine (680mg, 2.53mmol) was dissolved in 20mL dichloromethane, MCPBA (595mg, 3.45mmol) was added slowly, stirred at room temperature, TLC monitored for completion, and 10mL 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (benzo [ b ] b as a yellow solid]Thien-3-yl) thiazolo [4,5-c]Pyridine-5-oxide (480mg, 66%). ESI-MS m/z: 302.83[ M + H ]]⁺。

And step 3: 2- (benzo [ b ]]Thien-3-yl) thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 5mL POCl₃And then flows back for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (benzo [ b ] b as a yellow solid]Thien-3-yl) thiazolo [4,5-c]Pyridine (120mg, 20%).¹H NMR(400 MHz,CDCl₃)δ9.04(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]⁺。

The compound of the invention example 70 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ10.04(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)。

Example 71, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2-cyclopentylthiazolo [4,5-c]Pyridine (II) Pyridin-4-amines

4-chloro-2- (cyclopentyl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (582mg, 4.62mmol) and cyclopentylcarboxylic acid (1.05g, 9.24mmol) were dissolved in polyphosphoric acid (PPA) and subjected to a tube-sealing reaction at 140 ℃. The reaction was complete by TLC. The reaction was terminated and quenched by addition of saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) gave 2- (cyclopentyl) -thiazolo [4,5-c ] pyridine as a brown solid (880mg, 80%).

Step 2: 2- (cyclopentyl) -thiazolo [4,5-c ] pyridine (880mg, 4.31mmol) was dissolved in 40mL dichloromethane, MCPBA (482mg, 6.03mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product of 2- (cyclopentyl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (cyclopentyl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 5mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (cyclopentyl) -thiazolo [4,5-c ] as a yellow oil]Pyridine (450mg, two-step yield 43.9%).¹H NMR(400MHz, CDCl₃)δ8.25(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]⁺。

The compound of the invention example 71 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ9.84(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]⁺。

Example 72, (S) -N- (2- (3-aminopiperidin-1-yl) -5-methoxyphenyl) -2-phenylthiazolo [4,5-c] Pyridin-4-amines

Preparation of (S) -tert-butyl 1- (2-amino-4-methoxyphenyl) piperidin-3-yl-carbamate

Step 1, preparation of (S) -1- (2-nitro-4-methoxyphenyl) piperidin-3-yl-carbamic acid tert-butyl ester

1-fluoro-4-methoxy-3-nitrobenzene (3g, 16mmol), (S) -3-tert-butyloxycarbonylpiperidine (3.84g, 19.2mmol) and triethylamine (3.23g, 32mmol) were added to 40ml of methanol in this order, and the reaction was blocked at 130 ℃ and was difficult to complete by TLC detection. The reaction solution was evaporated to dryness under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give (S) -tert-butyl 1- (2-nitro-4-methoxyphenyl) piperidin-3-yl-carbamate (487mg, 8.7%) as a yellow solid.

Step 2, preparation of (S) -1- (2-amino-4-methoxyphenyl) piperidin-3-yl-carbamic acid tert-butyl ester

Tert-butyl (S) -1- (2-nitro-4-methoxyphenyl) piperidin-3-yl-carbamate (487mg, 1.38mmol), iron powder (620mg, 11.08mmol) and NH₄Cl (445mg, 8.31mmol) was dissolved in 20mL of methanol, 2mL of water was added, the reaction was carried out at 60 ℃ and the completion of the reaction was checked by TLC. The reaction solution was evaporated to dryness under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give (S) -tert-butyl 1- (2-amino-4-methoxyphenyl) piperidin-3-yl-carbamate as a brown oil (255mg, 55.8%).

The compound of the invention example 72 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,d₆-DMSO)δ9.73(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]⁺。

Example 73, (S) -N- (2- (3-Aminopiperidin-1-yl) -5-fluorophenyl) -2-phenylthiazolo [4,5-c]Pyridine (II) Pyridin-4-amines

Preparation of (S) -1- (2-amino-4-fluorophenyl) piperidin-3-yl-carbamic acid tert-butyl ester

Step 1:1, 4-difluoro-2-nitrobenzene (3g, 18.86mmol), (S) -3-tert-butyloxycarbonylpiperidine (5.28g, 26.4mmol) and triethylamine (3.8g, 37.7mmol) were added in this order to 40ml of methanol, and the reaction was stopped at 130 ℃ and checked by TLC. The reaction solution was evaporated to dryness under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give (S) - [1- (4-fluoro-2-nitrophenyl) -piperidin-3-yl ] -carbamic acid tert-butyl ester (3.538g, 55.3%) as a yellow solid.

Step 2: reacting (S) - [1- (4-fluoro-2-nitrophenyl) -piperidin-3-yl]Tert-butyl-carbamate (3.538g, 10.4mmol) was dissolved in 40mL of methanol, 15% mass fraction Pd/C was added, hydrogen was introduced, the reaction was carried out at room temperature, and the completion of the reaction was detected by TLC. The reaction solution was filtered, the filter cake was thoroughly washed with a dichloromethane/methanol mixture (1:1), the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate 4: 1) to give (S) -tert-butyl 1- (2-amino-4-fluorophenyl) piperidin-3-yl-carbamate as a brown oil (3.10g, 96%).¹H NMR(400MHz,CDCl₃)δ6.88(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)。

The compound of the invention example 73 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ9.68(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]⁺。

Example 74, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2- (2- (trifluoromethyl) phenyl) thia-ne Azolo [4,5-c]Pyridin-4-amines

4-chloro-2- (2- (trifluoromethyl) phenyl) -thiazolo [4,5-c]Preparation of pyridine

Step 1:reacting thiazolo [4,5-c ]]Pyridine (400mg, 2.93mmol), 1-iodo-2-trifluoromethylbenzene (960mg, 3.52mmol), Pd (PPh)₃)₄(170mg, 0.146mmol), CuI (30mg, 0.146mmol) and Cs₂CO₃(2.86g, 8.79mmol) was dissolved in 20mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 25mL of water, the organic phase was washed with saturated brine (25mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separation and purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave 2- (2-trifluoromethylphenyl) thiazolo [4,5-c ] as a white solid powder]Pyridine (636mg, 77%).¹H NMR(400MHz,CDCl₃)δ9.43(s,1H),8.59(d,J＝5.5Hz,1H),7.96-7.82 (m,2H),7.73-7.67(m,3H)。

Step 2: 2- (2- (trifluoromethyl) phenyl) -thiazolo [4,5-c ] pyridine (636mg, 2.271mmol) was dissolved in 10mL dichloromethane, MCPBA (532mg, 3.084mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and the reaction quenched by addition of 10mL 1M potassium carbonate solution. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (2- (trifluoromethyl) phenyl) -thiazolo [4,5-c ] pyridine-5-oxide as a white solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (2- (trifluoromethyl) phenyl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And refluxing for 2 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (25mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (2- (trifluoromethyl) phenyl) -thiazolo [4,5-c ] as a yellow solid]Pyridine (313mg, 50%).¹H NMR (400MHz,CDCl₃)δ8.38(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]⁺。

Compounds of the invention example 74Prepared according to method 1, and the other preparation steps were prepared according to example 5. ESI-MS m/z: 471.3[ M + H]⁺。

Example 75, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2- (4- (trifluoromethyl) phenyl) thia-ne Azolo [4,5-c]Pyridin-4-amines

4-chloro-2- (4- (trifluoromethyl) phenyl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (200mg, 1.47mmol), 1-iodo-4-trifluoromethylbenzene (480mg, 1.76 mmol), Pd (PPh)₃)₄(86mg, 0.074mmol), CuI (14mg, 0.074mmol) and Cs₂CO₃(1.436g, 4.407mmol) was dissolved in 20mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 25mL of water, the organic phase was washed with saturated brine (25mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separation and purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave 2- (4- (trifluoromethyl) phenyl) thiazolo [4,5-c ] as a white solid powder]Pyridine (295mg, 71.8%).¹H NMR(400MHz,CDCl₃)δ9.40(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: 2- (4- (trifluoromethyl) phenyl) thiazolo [4,5-c ] pyridine (225mg, 0.803mmol) was dissolved in 10mL dichloromethane, MCPBA (193mg, 1.12mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (4- (trifluoromethyl) phenyl) thiazolo [4,5-c ] pyridine-5-oxide as a white solid. It was not purified and used directly in the next reaction.

And step 3: 2- (4- (trifluoromethyl) phenyl) thiazolo [4, 5-c) obtained by the reaction in the previous step]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And refluxing for 2 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (25 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (4- (trifluoromethyl) phenyl) thiazolo [4,5-c ] as a yellow solid]Pyridine (149mg, 59%).¹H NMR(400MHz,CDCl₃)δ9.29(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]⁺。

The compound of the invention example 75 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CD₃OD)δ9.61(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]⁺。

Example 76, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2- (3- (trifluoromethyl) phenyl) thia-ne Azolo [4,5-c]Pyridin-4-amines

4-chloro-2- (3- (trifluoromethyl) phenyl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (400mg, 2.94mmol), 1-iodo-3-trifluoromethylbenzene (960mg, 3.53mmol), Pd (PPh)₃)₄(169.8mg, 0.147mmol), CuI (28mg, 0.147mmol) and Cs₂CO₃(2.87g, 8.82mmol) was dissolved in 20mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction mixture was cooled to room temperature, filtered, and 100mL of water and 50mL of ethyl acetate were addedThe ester was added to the filtrate, the organic phase was separated and washed with 25mL of water, the organic phase was washed with saturated brine (25 mL. times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separation and purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave 2- (3- (trifluoromethyl) phenyl) thiazolo [4,5-c ] as a white solid powder]Pyridine (572mg, 69.5%).¹H NMR(400MHz,CDCl3)δ9.39(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: 2- (3- (trifluoromethyl) phenyl) thiazolo [4,5-c ] pyridine (520mg, 1.86mmol) was dissolved in 12mL dichloromethane, MCPBA (435mg, 2.52mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (3- (trifluoromethyl) phenyl) thiazolo [4,5-c ] pyridine-5-oxide as a white solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (3- (trifluoromethyl) phenyl) thiazolo [4, 5-c)]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And refluxing for 2 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (25 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (3- (trifluoromethyl) phenyl) thiazolo [4,5-c ] as a white solid powder]Pyridine (230mg, 46%).¹H NMR(400MHz,CDCl₃)δ8.38-8.32(m,3H),7.83-7.81(m,2H),7.68(t,J＝7.9Hz,1H)。 ESI-MS m/z：315.07[M+H]⁺。

The compound of the invention example 76 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,d₆-DMSO)δ9.72(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]⁺。

Example 77, (S) -N- (2- (3-aminopiperidin-1-yl) -5- (trifluoromethyl) phenyl) -2-phenylthiazolo [4, 5-c]pyridin-4-amines

Preparation of (S) -1- (2-amino-4- (trifluoromethyl) phenyl) piperidin-3-yl-carbamic acid tert-butyl ester

Step 1: 4-fluoro-3-nitro-trifluorotoluene (2g, 9.56mmol), (S) -3-tert-butyloxycarbonylpiperidine (2.49g, 12.43mmol) and triethylamine (7.74g, 76.52mmol) were added sequentially to the tube, 40ml of methanol was added, the reaction was carried out at 130 ℃ in the tube, and the reaction was completed by TLC. The reaction solution was evaporated to dryness under reduced pressure, and the obtained residue was separated by column chromatography (petroleum ether: ethyl acetate: 5:1) to give (S) -tert-butyl 1- (2-nitro-4- (trifluoromethyl) phenyl) piperidin-3-yl-carbamate (3.7g, 99.4%) as a yellow solid.

Step 2: (S) -1- (2-Nitro-4- (trifluoromethyl) phenyl) piperidin-3-yl-carbamic acid tert-butyl ester (3.72g, 9.88 mmol), iron powder (4.27g, 76.43mmol) and NH₄Cl (3.07g, 57.32mmol) was dissolved in 60mL of methanol, 2mL of water was added, the reaction was carried out at 60 ℃ and the reaction was completed by TLC. The reaction solution was evaporated under reduced pressure and the resulting residue was separated by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give tert-butyl (S) -1- (2-amino-4- (trifluoromethyl) phenyl) piperidin-3-yl-carbamate (3.4g, 95.8%) as a pink solid.

The compound of the invention example 77 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,d₆-DMSO)δ9.31(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]⁺。

Example 78, (S) -N- (4- (3-aminopiperidin-1-yl) -pyridin-3-yl) -1, 6-naphthyridin-5-amine

The compound of the invention example 78 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CD₃OD)δ9.00(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]⁺。

Example 79, (S) -N- (4- (3-Aminopiperidin-1-yl) -pyridin-3-yl) pyrido [4,3-b]Pyrazin-5-amines

5-chloro-pyridine [3,4-b ]]Preparation of pyrazines

The method comprises the following steps: 2-chloro-3, 4-diaminopyridine (200mg, 1.4mmol) was dissolved in 20ml of ethanol, and 40% aqueous solution of hexanedial (200mg, 1.4mmol) was added, and the mixture was refluxed at 75 ℃ and reacted for 12 hours. The reaction was complete by TLC. Evaporating to dryness under reduced pressure, and separating by column chromatography to obtain white solid powder 5-chloro-pyrido [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)。

The compound of the invention example 79 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CD₃OD)δ10.04(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]^-。

Example 80, 2-phenyl-N- (4- (thien-2-yl) -pyridin-3-yl) thiazolo [4,5-c]Pyridin-4-amines

Preparation of 4- (thien-2-yl) pyridin-3-amine

Step 1, dissolving 2-bromothiophene (300mg, 1.84mmol) in 5ml THF in a 25ml double-mouth bottle, placing at-78 ℃ for nitrogen protection, slowly adding n-BuLi (809 mu L,2.024mmol) after 5min, and reacting for 1h at-78 ℃ under nitrogen protection. Finally, pinacol diboron (465mg and 1.84mmol) is added dropwise and dissolved in 2.9ml of THF mixed solution, the reaction temperature is-78 ℃, the temperature is changed to normal temperature after 1h, the reaction is carried out overnight, and the reaction is completely detected by TLC. Concentration under reduced pressure, column chromatography (petroleum ether: ethyl acetate/20: 1) to give 2-thiopheneboronic acid pinacol ester (200mg, 63%) as a white solid.¹H NMR(400MHz, CDCl₃)δ7.65(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: 2-Thiopheneboronic acid pinacol ester (200mg,0.95mmol), sodium carbonate (201mg,1.9mmol), 4-chloro-3-nitropyridine (180mg,1.14mmol), and palladium tetrakistriphenylphosphine (55mg,0.047mmol) were dissolved in 10ml of a1, 4-dioxane solution and reacted at 120 ℃ overnight. The reaction was spun dry and isolated by column chromatography to give 3-nitro-4- (thiophen-2-yl) -pyridine as a brown oil (98mg, 50%).¹H NMR(400MHz,CDCl₃)δ8.92(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)。

And step 3: 3-Nitro-4- (thien-2-yl) -pyridine (1.7g,8.25mmol), iron powder (3.687g, 66mmol), ammonium chloride (2.647g,49.5mmol) were dissolved in a mixed solvent of ethanol and water (30ml EtOH +5ml H)₂O), the reaction was refluxed at 90 ℃ overnight and checked by TLC for completion after overnight. Adding saturated NaHCO into the reaction solution₃The solution is prepared by mixing a solvent and a solvent,extracting with ethyl acetate, mixing the organic phases, backwashing with water, anhydrous MgSO₄The filtrate was dried by rotary drying under reduced pressure, and the residue was separated by column chromatography (dichloromethane: methanol/20: 1) to give 4- (thiophen-2-yl) pyridin-3-amine (1.04 g, 72%) as a brown solid.¹H NMR(400MHz,CDCl₃)δ8.15(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]⁺。

The compound of the invention example 80 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ9.98(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]⁺。

Example 81, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2- (3-methoxyphenyl) thiazolo [4,5-c]Pyridin-4-amines

4-chloro-2- (3- (methoxy) phenyl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (700mg, 5.14mmol), 1-iodo-3-methoxybenzene (1.446g, 6.18mmol), Pd (PPh)₃)₄(297mg, 0.257mmol), CuI (49mg, 0.257mmol), and Cs₂CO₃(5.024g, 15.42mmol) was dissolved in 40mL DMF, the reaction was stirred at 120 ℃ and monitored by TLC to completion. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 25mL of water, the organic phase was washed with saturated brine (25mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate 3:1) and reacted directly to the next step.

Step 2: theoretical amount of crude 2- (3-methoxyphenyl) thiazolo [4,5-c ] pyridine (1.245g, 5.14mmol) was dissolved in 20mL of dichloromethane, MCPBA (1.33g, 7.71mmol) was added slowly, stirred at room temperature, TLC monitored for completion of the reaction, and 20mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 2- (3- (methoxy) phenyl) thiazolo [4,5-c ] pyridine-5-oxide as a white solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (3- (methoxy) phenyl) thiazolo [4, 5-c)]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And then the flow returns for 2 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (25 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (3- (methoxy) phenyl) thiazolo [4,5-c ] as a yellow solid]Pyridine (414mg, 29%).¹H NMR(400 MHz,CDCl₃)δ8.29(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]⁺。

The compound of the invention example 81 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.64(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]⁺。

Example 82, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) thiazolo [4,5-c]Pyridin-4-amines

4-chloro-thiazolo [4,5-c]Preparation of pyridine

Step 1: thiazolo [4,5-c ] pyridine (800mg, 5.88mmol) was dissolved in 10mL of dichloromethane, MCPBA (1.52g, 8.82mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 20mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude thiazolo [4,5-c ] pyridine-5-oxide as a white solid. It was not purified and used directly in the next reaction.

Step 2: reacting thiazolo [4,5-c ]]Pyridine-5-oxide crude product dissolved in 15mL POCl₃And refluxing for 2 h. Concentrating the reaction solution under reduced pressure, slowly adding ice water to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-thiazolo [4,5-c ] as a white solid]Pyridine (507mg, 50.8%).¹H NMR(400MHz,CDCl₃)δ9.13(s,1H),8.38(d,J ＝5.4Hz,1H),7.87(d,J＝5.5Hz,1H)。ESI-MS m/z：171.08[M+H]⁺。

The compound of the invention example 82 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.61(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]⁺。

Example 83, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2- (2- (methoxy) phenyl) thiazole And [4,5-c ]]Pyridin-4-amines

4-chloro-2- (2- (methoxy) phenyl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (400mg, 2.93mmol), 1-iodo-2-methoxybenzene (825mg, 3.52mmol), Pd (PPh)₃)₄(170mg, 0.146mmol), CuI (30mg, 0.146mmol) and Cs₂CO₃(2.86g, 8.79mmol) was dissolved in 20mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 25mL of water, the organic phase was washed with saturated brine (25mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separation and purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave 2- (2- (methoxy) phenyl) thiazolo [4,5-c ] as a white solid powder]Pyridine (619mg, 87.2%).¹H NMR(400MHz,CDCl₃)δ9.37(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: 2- (2- (methoxy) phenyl) thiazolo [4,5-c ] pyridine (619mg, 2.554mmol) was dissolved in 10mL dichloromethane, MCPBA (599mg, 3.47mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (2- (methoxy) phenyl) -thiazolo [4,5-c ] pyridine-5-oxide as a white solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (2- (methoxy) phenyl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And then the flow returns for 2 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutrality, extracted with ethyl acetate (25 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (2- (methoxy) phenyl) -thiazolo [4,5-c ] as a pale yellow solid]Pyridine (260mg, 50%).

The compound of the invention example 83 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,d⁶-DMSO)δ9.65(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]⁺。

Example 84, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (4-nitrophenyl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- ((4-nitro) phenyl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (400mg, 2.94mmol), 1-iodo-4-nitrobenzene (875mg, 3.53mmol), Pd (PPh)₃)₄(170mg, 0.147mmol), CuI (28mg, 0.147mmol) and Cs₂CO₃(2.87g, 8.82mmol) was dissolved in 20mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 25mL of water, the organic phase was washed with saturated brine (25mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separation and purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave 2- ((4-nitro) phenyl) thiazolo [4,5-c ] as a yellow solid powder]Pyridine (242mg, 32%).

Step 2: 2- ((4-Nitro) phenyl) thiazolo [4,5-c ] pyridine (360mg, 1.4mmol) was dissolved in 20mL dichloromethane, MCPBA (363mg, 2.1mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and the reaction quenched by addition of 10mL 1M potassium carbonate solution. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- ((4-nitro) phenyl) thiazolo [4,5-c ] pyridine-5-oxide as a white solid. It was not purified and used directly in the next reaction.

And step 3: 2- ((4-nitro) phenyl) thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And refluxing for 2 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (25 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- ((4-nitro) phenyl) thiazolo [4,5-c ] as a yellow solid]Pyridine (168mg, 41% over two steps).¹H NMR(400 MHz,CDCl₃)δ8.43-8.30(m,5H),7.87(d,J＝5.4Hz,1H)。

The compound of the invention example 84 was prepared according to method 1, the other preparation steps were prepared according to example 5. ESI-MS m/z: 448.22[ M + H]⁺。

^{4 3}Example 85N- (2-aminoethyl) -N- (2-phenyl-thiazolo [4, 5-c)]Pyridin-4-yl) pyridine-3, 4-bis Amines as pesticides

[2- (3-amino-pyridin-4-yl-amino) -ethyl]Preparation of tert-butyl (E) -carbamate

Step 1: 4-chloro-3-nitropyridine (1.16g, 7.3mmol), (2-amino-ethyl) -carbamic acid tert-butyl ester (1.169 g, 7.3mmol) and DIPEA (945mg, 7.3mmol) were added successively to a 100mL round-bottomed flask, 50mL of ethanol was added, and stirring was carried out at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, the ethyl acetate phase (50 mL. times.3) was washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (petroleum ether: ethyl acetate 1:1) gave [2- (3-nitro-pyridin-4-yl-amino) -ethyl as a yellow solid]Tert-butyl carbamate (1.75g, 85%).¹H NMR(400MHz,CDCl₃)δ9.21(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: reacting [2- (3-nitro-pyridin-4-yl-amino) -ethyl]Tert-butyl carbamate (1.751g, 6.21mmol) was dissolved in 50mL ethanol, then iron powder (2.774g, 49.67mmol), ammonium chloride (1.993g, 37.26mmol) and 5mL water were added sequentially and refluxed at 90 ℃ for 4 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was added with an appropriate amount of water, extracted with ethyl acetate (50mL × 3), the organic phases were combined and washed with water (20mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (dichloromethane: methanol ═ 20:1) gave [2- (3-amino-pyridin-4-yl-amino) -ethyl ] -ethyl as a yellow solid]-carbamic acid tert-butyl ester (800mg, 51%). ESI-MS m/z: 253.15[ M + H]⁺。

The compound of the invention example 85 was prepared according to method 1, the other preparation steps were prepared according to example 31.¹H NMR (400MHz,CD₃OD)δ8.50(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]⁺。

Example 86N- (4- (-3-amino-5-methylcyclohexyl) pyridin-3-yl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c]Pyridin-4-amines

Preparation of Compound 86-11

Step 1: a500 ml three-necked flask was charged with the compound 5-methyl-1, 3-cyclohexanedione (10.0g,79.37mmol), pyridine (12.5g,158.74mmol) and DCM (168ml), N₂Displacement, T ═ 0 ℃, clear solution, triflic anhydride (33.57g, 119.05mmol) dissolved slowly dropwise in 100ml DCM, after about 1h the solution turned red, after complete addition, the reaction was switched toReacting for 1h at normal temperature. TLC (petroleum ether: ethyl acetate 1:1) detection, and the product point gradually changes from light to thick under an ultraviolet lamp of 254 nm. After the reaction was complete, 100ml of H was added₂O, separating the layers, extracting the water phase with DCM, combining the DCM phases, and adding saturated NaHCO₃Washing with water for three times to remove pyridine, washing with saturated brine, and MgSO₄The mixture was dried and filtered, and the filtrate was spin-dried to give 86-122.0 g (yield 107.47%) of a product as a pale red oil. The product is unstable and immediately put into the next reaction.

Step 2: a500 ml single-neck flask was charged with 86-1(22.0g,93.22mmol), dissolved in dioxane to give a pale red transparent solution (0.3M), and then sequentially charged with pinacol diborate (45.23g, 186.44mmol), potassium acetate (25.2 g, 279.66mmol), Pd (dppf) Cl₂(3.11g，4.25mmol)，N₂The mixture was replaced four times, and reacted at 80 ℃ for 5 hours, whereby the solution became black. After 5h, TLC detection reaction is finished, filtering is carried out, washing is carried out by using dioxane solution, and a product 86-2 is obtained, wherein the filtrate is directly put into the next step of reaction without purification.

And step 3: a500 ml single-neck flask was charged with a solution of crude 86-2(21.99g, 93.18mmol) in dioxane and N₂Bubbling, then adding Na₂CO₃Solution (19.76g, 186.36mmol, 2M) was added with 4-chloro-3-nitropyridine (17.67g, 111.82mmol), Pd (dppf) Cl₂(3.41g，4.66mmol)，N₂After three replacements, the reaction was carried out at 120 ℃. TLC detection till the reaction is finished. After the reaction was complete, 200ml of H was added₂O and 200ml ethyl acetate, adding diatomite into the funnel, filtering the obtained filtrate repeatedly for three times to obtain black filtrate, extracting with ethyl acetate in small amount for preventing emulsification, combining organic phases, washing with water, washing with saturated salt water, and MgSO₄Drying, filtration, spin-drying of the filtrate under reduced pressure and column chromatography of the residue gave the purer product 86-3, 12.9g of a yellow solid in 70% yield. ESI-MS m/z: 233.21[ M + H]⁺。

And 4, step 4: a250 ml single neck flask was charged with product 86-3(3.2g, 13.7mmol) dissolved in 66ml EtOH solution followed by CeCl₃.7H₂O (6.62g, 17.7mmol), was placed in an ice bath at 0 ℃ and NaBH was added slowly in portions₄(672 mg17.7mmol) to form a yellow solution, the reaction was stirred and after 3h the reaction was complete by TLC. 100ml of H are added₂O, extracting with ethyl acetate, washing the organic phase with water, washing with saturated salt solution, and MgSO₄Drying and column chromatography gave 2.6g of 86-4 as a white solid powder in 81% yield.¹H NMR(400MHz,CDCl₃)δ9.08(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)。

And 5: a250 ml single neck flask was charged with product 86-4(2.6g, 11.11mmol) dissolved in 66ml DMF and then imidazole (3.02g, 44.43mmol), TBDMsCl (4.2g, 27.77mmol) was added and stirred at room temperature overnight. The reaction was complete by TLC. 500ml of H are added₂O, extracting with ethyl acetate, washing the organic phase with water, washing with saturated salt solution, and MgSO₄Drying and column chromatography gave 3.8g of 86-5 in 98.3% yield.¹H NMR(400MHz,CDCl₃)δ9.09(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: a250 ml single-neck flask was charged with 86-5(3.8g, 10.92mmol) dissolved in 50ml of anhydrous methanol, followed by addition of 10% Pd/C (1.16g, 1.092mmol), and introduction of H₂By replacement with H₂Sealed and stirred at room temperature overnight. The reaction was complete by TLC. Filtration (celite on filter paper) and washing with methanol gave a yellow filtrate which was spin dried to give 2.8g of the product 86-6 as a yellow liquid in 80% yield. ESI-MS m/z: 321.22[ M + H]⁺。

And 7: a250 ml single neck flask was charged with product 86-6(2.8g, 8.75mmol) dissolved in 40ml CH₂Cl₂Then benzyloxycarbonyl succinimide (7.82g, 30.63mmol), DMAP (243mg, 1.925mmol) were added thereto, and N was passed through₂The reaction was stirred at room temperature for 3 d. TLC detection (dichloromethane: methanol: 30:1) the starting material was not reacted completely, and 0.5eq benzyloxycarbonylsuccinimide, 0.31eq DMAP were added and the reaction was continued until the reaction was completed. Column chromatography to obtain 1.5g productSubstance 86-7, yield 38.5%. ESI-MS m/z: 455.29[ M + H]⁺。

And 8: a100 ml single neck flask was charged with 86-7(1.5g, 3.30mmol) dissolved in 33.63ml of a combined solution (V (6N HCl): V (MeOH): V (THF): 1:2) in a clear yellow solution, stirred at room temperature for reaction, TLC checked for completion of the starting material reaction, adjusted to pH 7 with 6N NaOH solution, added 50ml of water, extracted with ethyl acetate, the organic phase washed with water, saturated brine, MgSO 2₄Drying, filtering, spin-drying and column chromatography gave 857mg of 86-8, 76.5% yield. ESI-MS m/z: 341.57[ M + H]⁺。

And step 9: a100 mL single neck flask was charged with 86-8(771mg, 2.27mmol) dissolved in 16.5mL CH₂Cl₂After placing in an ice bath at 0 ℃, a Dess-Martin reagent (1.44g, 3.40mmol) solution is added to become turbid and stirred at room temperature. After 5h, TLC detects that the raw materials are completely reacted, and 10% Na is added₂S₂O₃：NaHCO₃1: washing with 1 volume ratio solution, using CH₂Cl₂Extracting, and adding 10% Na to the organic phase₂S₂O₃：NaHCO₃1: washing with 1 volume ratio solution, washing with water, washing with saturated salt solution, MgSO₄Drying, filtering, spin-drying and column chromatography gave 230mg of 86-9, 30.0% yield. ESI-MS m/z: 339.21 [ M + H]⁺。

Step 10: a50 ml single neck flask was charged with 86-9(230mg, 0.68mmol) dissolved in 10ml CH₂Cl₂Benzylamine (273.99mg, 2.72mmol), acetic acid (489.6mg, 8.16mmol) were added, the reaction was allowed to proceed overnight at 30 ℃, then TLC (dichloromethane: methanol 15:1) showed no new product, and NaBH (OAc) was added₃(1.73g, 8.16mmol), and the reaction was continued at ordinary temperature. TLC (dichloromethane: methanol 15:1) starting material reacted completely and new spots formed. The reaction was stopped and the reaction solution was saturated NaHCO₃Washing, extracting with ethyl acetate, and extracting the organic phase with saturated NaHCO₃The solution, water, saturated brine washing, MgSO₄Drying, filtering, spin-drying and column chromatography gave 69mg of 86-10, 23.7% yield. ESI-MS m/z: 429.84[ M + H]⁺。

Step 11: a50 ml single neck flask was charged with 86-10(69mg, 0.16mmol) of product dissolved in 10ml CH₃OH, 20% Pd (OH) is added₂(22.5mg，0.032mmol)，H₂Replacement at H₂And reacting at normal temperature in a sealed environment overnight. TLC (dichloromethane: methanol ═ 5:1+ NH)₃.H₂O) shows the starting material has reacted to completion and product spots are visible. Filtration, methanol washing, spin-drying to give a yellow viscous liquid, thin layer silica gel preparation of plate to give 29.9mg, then dissolve the product in 6ml methanol and add Boc₂O(30.72mg，0.141mmol)，N₂Replacement, yellow transparent solution, reaction at room temperature for 5h, and TLC detection (dichloromethane: methanol: 10:1+ NH)₃.H₂O) the raw material is reacted completely, and a new point is generated. The solution was spun down and purified on thin silica gel plates to give 30mg of 86-11 in 69.38% yield. ESI-MS m/z: 306.28[ M + H]⁺。

The compound of the invention example 86 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CDCl₃)δ9.29(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]⁺。

Example 87N- (4- (-3-amino-5-methylcyclohexyl) pyridin-3-yl) -2-phenylthiazolo [4,5-c]Pyridine (II) Pyridin-4-amines

The compound of the invention example 87 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,d⁶-DMSO)δ8.82(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]⁺。

Example 88N- (4- (3-amino-5-methylcyclohexyl) pyridin-3-yl) -2- (thiazol-2-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (thiazol-2-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (1.5g, 11mmol), 2-bromothiazole (2.166g, 13.2mmol), Pd (PPh)₃)₄(636mg, 0.549mmol), CuI (105mg, 0.549mmol), and Cs₂CO₃(19.2g, 39.6mmol) was dissolved in 40mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 200mL of water and 100mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 50mL of water, the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave 2- (thiazol-2-yl) thiazolo [4, 5-c) as a yellow solid]Pyridine (2.98g, 92%).¹H NMR(400MHz,CDCl₃)δ9.40(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: 2- (Thiazol-2-yl) thiazolo [4,5-c ] pyridine (2.98g, 13.6mmol) was dissolved in 50mL of dichloromethane, MCPBA (3.188g, 18.5mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 20mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 100mL of saturated brine, extracted with dichloromethane (100 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 2- (thiazol-2-yl) thiazolo [4,5-c ] pyridine-5-oxide as a white solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (thiazol-2-yl) thiazolo [4,5-c ]]Pyridine-5-oxide crude product dissolved in 20mL POCl₃And refluxing for 9 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Adding saturated sodium bicarbonate to adjust pH to neutrality, extracting with ethyl acetate (100 mL. times.3), combining organic phases, drying over anhydrous sodium sulfate, and filteringFiltering and concentrating under reduced pressure to obtain 4-chloro-2- (thiazol-2-yl) thiazolo [4, 5-c) as a yellow solid]Pyridine (1.08g, 31.4% yield over two steps).¹H NMR(400 MHz,CDCl₃)δ8.35(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]⁺。

The compound of the invention example 88 was prepared according to method 1, the other preparation steps were according to example 18.¹H NMR (400MHz,CDCl₃)δ9.25(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]^-。

Example 89, (R) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c]Pyridin-4-amines

Preparation of tert-butyl (R) - (1- (3-aminopyridin-4-yl) piperidin-3-yl) carboxylate

Step 1: 4-chloro-3-nitropyridine (1.268g, 8mmol), (R) -3-tert-butyloxycarbonylpiperidine (1.602g, 8mmol) and DIPEA (1.034g, 8mmol) were added successively to a 100mL round-bottomed flask, 20mL ethanol was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, the ethyl acetate phase (50 mL. times.3) was washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product is directly reacted.

Step 2: the crude (R) -1- (3-nitropyridin-4-yl) piperidin-3-yl-carbamic acid tert-butyl ester was dissolved in 40mL of ethanol, followed by addition of iron powder (3.584g, 64mmol), ammonium chloride (2.568g, 48mmol) and 4mL of water in that order and refluxing at 80 ℃ for 4 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was added with an appropriate amount of water, extracted with ethyl acetate (100mL × 3), the organic phases were combined and washed with water (50mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (dichloromethane: methanol ═ 20:1) gave (R) -tert-butyl 1- (3-aminopyridin-4-yl) piperidin-3-yl-carbamate (1.823g, 78% yield in two steps) as a yellow solid.

The compound of the invention example 89 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CD₃OD)δ9.66(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]⁺。

Example 90N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2-phenylthiazolo [4,5-c]Pyridine-4- Amines as pesticides

Preparation of 1- (3-aminopyridin-4-yl) piperidin-3-yl-carboxylic acid tert-butyl ester

Step 1: 4-chloro-3-nitropyridine (1.1g, 7mmol), 3-tert-butyloxycarbonylpiperidine (1.402g, 7mmol) and DIPEA (905mg, 7mmol) were added successively to a 50mL round-bottomed flask, 10mL ethanol was added, and the mixture was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, the ethyl acetate phase (50mL × 3) was washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product is directly reacted.

Step 2: the crude tert-butyl 1- (3-nitropyridin-4-yl) piperidin-3-yl-carbamate was dissolved in 30mL of ethanol, followed by addition of iron powder (3.25g, 58mmol), ammonium chloride (2.327g, 43.5mmol) and 3mL of water in that order and refluxing at 80 ℃ for 4 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was added with an appropriate amount of water, extracted with ethyl acetate (100mL × 3), the organic phases were combined and washed with water (50mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (dichloromethane: methanol ═ 20:1) gave tert-butyl 1- (3-aminopyridin-4-yl) piperidin-3-yl-carbamate (1.75g, 82.7%) as a yellow solid.

The compound of the invention example 90 was prepared according to method 1, the other preparation steps were prepared according to example 5.¹H NMR (400MHz,CD₃OD)δ9.65(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]⁺。

Example 91, N- (2,4 '-bipyridin-3' -yl) -2-phenylthiazolo [4,5-c]Pyridin-4-amines

[2,4' -Bipyridinyl]Preparation of (E) -3' -amines

Step 1: 2-bromopyridine (500mg, 3.165mmol) was dissolved in 5ml dry THF, N₂Replacement, reaction temperature-78 deg.C, adding n-BuLi (1.4ml, 2.5M), keeping-78 deg.C, reacting for 1h, then adding (Bu)₃SnCl (1.03g, 3.165mmol), after 1h of reaction, the temperature was slowly raised to room temperature and the reaction was allowed to proceed overnight at room temperature, and the reaction was complete by TLC. Addition of saturated NH₄Cl solution, ethyl acetate extraction, washing organic phase with water, MgSO₄Drying, filtration, spin-drying of the filtrate, and purification by column chromatography gave 2-tributylstannyl pyridine (652mg, 55.8%). ESI-MS m/z: 369.98[ M + H]⁺。

Step 2: 2-Tributylstannyl-pyridine (2.5g, 6.77mmol), 4-chloro-3-nitropyridine (1.283g, 8.13 mmol), Pd (PPh)₃)₄(454mg, 0.392mmol) and CuI (74.4mg, 0.392mmol) were dissolved in 70ml DMF, N₂Replacement, reaction at 115 ℃ for 18h, and TLC detection of reaction completion. Adding appropriate amount of water after reaction, extracting with ethyl acetate, washing with water, MgSO₄Drying, filtering, spin-drying the filtrate, separating and purifying by column chromatography to obtain the product 3' -nitro- [2,4']bipyridine (360mg, 26.5%).¹H NMR(400MHz,CDCl₃)δ9.13(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, mixing 3 '-nitro- [2,4']Bipyridine (360mg, 1.79mmol), iron powder (802mg, 14.33mmol), NH₄Cl (574.5mg, 10.74mmol) and 1mL of water were dissolved in 10mL of ethanol and reacted at 90 ℃ for 11h, and the TLC detection was complete. Filtering the reaction solution, concentrating the filtrate under reduced pressure, and separating and purifying by column chromatography to obtain the product [2,4' -bipyridine]-3' -amine (210mg, 68.8%).

The compound of the invention example 91 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ12.61(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]^-。

Example 92, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (pyrazin-2-yl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (pyrazin-2-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (517mg, 3.8mmol), 2-iodopyrazine (939mg, 4.56mmol), Pd (PPh)₃)₄(220mg, 0.19mmol), CuI (36mg, 0.19mmol) and Cs₂CO₃(3.714g, 11.4mmol) was dissolved in 10mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 25mL of water, the organic phase was washed with saturated brine (25mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separating and purifying by column chromatography (dichloromethane: methanol)40:1) to give 2- (pyrazin-2-yl) thiazolo [4,5-c as a yellow solid]Pyridine (637mg, 78.3%).

Step 2: 2- (pyrazin-2-yl) thiazolo [4,5-c ] pyridine (637mg, 3mmol) was dissolved in 20mL dichloromethane, MCPBA (718mg, 4.2mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and the reaction quenched by addition of 10mL 1M potassium carbonate solution. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (pyrazin-2-yl) thiazolo [4,5-c ] pyridine-5-oxide as a yellow solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (pyrazin-2-yl) thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Adding saturated sodium bicarbonate to adjust pH to neutrality, extracting with ethyl acetate (50 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure to give 4-chloro-2- (pyrazin-2-yl) thiazolo [4,5-c ] as a yellow solid]Pyridine (150mg, 35.4%).¹H NMR(400MHz,CDCl₃) δ9.73(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]⁺。

The compound of the invention example 92 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ10.01(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]⁺。

Example 93, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2- (3-fluoro-6-methylpyridin-2- Yl) thiazolo [4,5-c]Pyridin-4-amines

4-chloro-2- (3-fluoro-6-methylpyridin-2-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (500mg, 3.67mmol), 2-bromo-3-fluoro-6-methylpyridine (838mg, 4.4mmol), Pd (PPh)₃)₄(213mg, 0.18mmol), CuI (36mg, 0.19mmol) and Cs₂CO₃(3.6g, 11mmol) was dissolved in 8mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 100mL of water and 50mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 25mL of water, the organic phase was washed with saturated brine (25mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (dichloromethane: acetone ═ 10:1) gave 2- (3-fluoro-6-methyl-pyridin-2-yl) thiazolo [4, 5-c) as a yellow powdery solid]Pyridine (569mg, 63.3%).

Step 2: 2- (3-fluoro-6-methyl-pyridin-2-yl) thiazolo [4,5-c ] pyridine (569mg, 2.33mmol) was dissolved in 50mL of dichloromethane, MCPBA (604mg, 3.5mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (3-fluoro-6-methyl-pyridin-2-yl) thiazolo [4,5-c ] pyridine-5-oxide as a crude product as a yellow solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (3-fluoro-6-methyl-pyridin-2-yl) thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And refluxing for 3 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Adding saturated sodium bicarbonate to adjust pH to neutrality, extracting with ethyl acetate (50 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure to obtain 4-chloro-2- (3-fluoro-6-methyl-pyridin-2-yl) thiazolo [4,5-c]Pyridine (322mg, 49.5%).¹H NMR (400MHz,CDCl₃)δ8.36(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)。

The compound of the invention example 93 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.79(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]⁺。

Example 94, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (6-fluoropyridin-3-yl) thiazolo [4,5-c]Pyridin-4-amines

4-chloro-2- (6-fluoropyridin-3-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: reacting thiazolo [4,5-c ]]Pyridine (2g, 14.69mmol), 5-bromo-2-fluoropyridine (3.103g, 17.63mmol), Pd (PPh)₃)₄(849mg, 0.735mmol), CuI (140mg, 0.735mmol), and Cs₂CO₃(14.36g, 44.07 mmol) was dissolved in 80mL DMF, stirred at 120 ℃ and monitored by TLC until the reaction was complete. The reaction solution was cooled to room temperature, the reaction solution was filtered, 200mL of water and 100mL of ethyl acetate were added to the filtrate, the organic phase was separated and washed with 100mL of water, the organic phase was washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separation and purification by column chromatography (petroleum ether: ethyl acetate ═ 3:1) gave 2- (6-fluoro-pyridin-3-yl) thiazolo [4, 5-c) as a yellow solid]Pyridine (3.01g, 88.7%).¹H NMR(400MHz,CDCl₃)δ9.39(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: 2- (6-fluoro-pyridin-3-yl) thiazolo [4,5-c ] pyridine (3.01g, 13.01mmol) was dissolved in 120mL of dichloromethane, MCPBA (3.144g, 18.22mmol) was added slowly, stirred at room temperature, TLC monitored for completion, and 30mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 100mL of saturated brine, extracted with dichloromethane (50mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (6-fluoro-pyridin-3-yl) thiazolo [4,5-c ] pyridine-5-oxide as a crude product as a yellow solid. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (6-fluoro-pyridin-3-yl) thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 10mL POCl₃And then flows back for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (100 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (6-fluoropyridin-3-yl) thiazolo [4,5-c ] as an off-white solid]Pyridine (350mg, 19% over two steps).¹H NMR(400MHz,CDCl₃)δ9.08(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)。

The compound of the invention example 94 was prepared according to method 1, the other preparation steps were prepared according to example 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]⁺。

Example 95, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (5-methylthiophen-2-yl) thiazole And [4,5-c ]]Pyridin-4-amines

4-chloro-2- (5-methylthiophen-2-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 4-chloro-3-nitro-pyridine (7950mg, 50mmol) was dissolved in 50mL ethanol and stirred slowly at room temperatureAdding 50mmol of concentrated hydrochloric acid; then weighing NaHS.H₂O (13.69g, 185mmol) is added into the reaction solution and stirred for 40min at room temperature; next, sodium hydrosulfite (32.21g, 185mmol) was weighed out and dissolved in water, and the aqueous sodium hydrosulfite solution was added to the reaction mixture and stirred at 80 ℃ for 12 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the filtrate was purified by column chromatography (dichloromethane: methanol: 5:1 to 1:1 elution) to give a crude product of 3-amino-4-mercaptopyridine as a tan solid. It was not purified and used directly in the next reaction.

Step 2: 3-amino-4-mercaptopyridine (446mg, 3.54mmol) and 5-methyl-thiophene-2-carboxylic acid (1005mg, 7.08mmol) were dissolved in polyphosphoric acid (PPA) and subjected to a tube-sealing reaction at 140 ℃. The reaction was complete by TLC. The reaction was terminated and quenched by addition of saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate (50 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) gave 2- (5-methyl-thiophen-2-yl) -thiazolo [4,5-c ] pyridine as a pale yellow solid (561mg, two step yield 71%).

And step 3: 2- (5-methyl-thiophen-2-yl) -thiazolo [4,5-c ] pyridine (561mg, 2.4mmol) was dissolved in 20mL of dichloromethane, MCPBA (580mg, 3.36mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 2- (5-methyl-thiophen-2-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And 4, step 4: reacting 2- (5-methyl-thiophen-2-yl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 8mL POCl₃And refluxing for 2 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (25mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (5-methyl-thiophen-2-yl) -thiazolo [4,5-c ] as a pale yellow solid]Pyridine (525mg, 82.2%).

The compound of the invention example 95 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ9.91(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]^-。

Example 96, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (5-methylisoxazol-3-yl) thia-ne Azolo [4,5-c]Pyridin-4-amines

4-chloro-2- (5-methylisoxazol-3-yl) -thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (252mg, 2mmol) and 5-methyl-isoxazole-3-carboxylic acid (508mg, 4mmol) were dissolved in polyphosphoric acid (PPA) and the reaction was blocked at 140 ℃. The reaction was complete by TLC. The reaction was terminated and quenched by addition of saturated sodium bicarbonate solution. The reaction was extracted with ethyl acetate (50mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) gave 2- (5-methylisoxazol-3-yl) -thiazolo [4,5-c ] pyridine (194mg, 44.6%) as a brown solid.

Step 2: 2- (5-Methylisoxazol-3-yl) -thiazolo [4,5-c ] pyridine (194mg, 0.89mmol) was dissolved in 20mL dichloromethane, MCPBA (216mg, 1.25mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (5-methylisoxazol-3-yl) -thiazolo [4,5-c ] pyridine-5-oxide as a crude product. It was not purified and used directly in the next reaction.

And 4, step 4: reacting 2- (5-methylisoxazol-3-yl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 6mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust pH to neutrality, extracted with ethyl acetate (25 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (5-methylisoxazol-3-yl) -thiazolo [4,5-c ] as a pale yellow solid]Pyridine (132mg, 58.9% over two steps).

The compound of the invention example 96 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.65(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]^-。

Example 97, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (2-methylthiazol-4-yl) thiazole And [4,5-c ]]Pyridin-4-amines

4-chloro-2- (2-methylthiazol-4-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (252mg, 2mmol) and 2-methyl-thiazole-4-carboxylic acid (573mg, 4mmol) were dissolved in polyphosphoric acid (PPA) and subjected to a tube-sealing reaction at 140 ℃. The reaction was complete by TLC. The reaction was terminated and quenched by addition of saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate (50mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) gave 2- (2-methyl-thiazol-4-yl) -thiazolo [4,5-c ] pyridine (213mg, 45.6%) as a yellow solid.

Step 2: 2- (2-methyl-thiazol-4-yl) -thiazolo [4,5-c ] pyridine (213mg, 0.91mmol) was dissolved in 20mL dichloromethane, MCPBA (220mg, 1.27mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 2- (2-methyl-thiazol-4-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (2-methyl-thiazol-4-yl) -thiazolo [4, 5-c)]Pyridine-5-oxide crude product dissolved in 6mL POCl₃And refluxing for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (25mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (2-methyl-thiazol-4-yl) -thiazolo [4,5-c ] as a pale yellow solid]Pyridine (243mg, two-step yield 99.6%).

The compound of the invention example 97 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CD₃OD)δ9.63(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]^-。

Example 98, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (3-fluoro-benzyl) thiazolo [4, 5-c]pyridin-4-amines

4-chloro-2- (3-fluoro-benzyl) -thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (1g, 8mmol) was reacted with 3-fluoro-phenylacetic acid (3).7g, 24mmol) was dissolved in polyphosphoric acid (PPA) and the tube was sealed at 140 ℃. The reaction was complete by TLC. And (4) finishing the reaction, and adding a saturated sodium bicarbonate solution to quench the reaction. The reaction solution was extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) afforded 2- (3-fluoro-benzyl) -thiazolo [4,5-c]Pyridine (489mg, 25%).¹H NMR(400MHz,CDCl₃)δ9.31(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: 2- (3-fluoro-benzyl) -thiazolo [4,5-c ] pyridine (489mg, 2mmol) was dissolved in 15mL dichloromethane, MCPBA (483mg, 2.8mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (3-fluoro-benzyl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (3-fluoro-benzyl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 6mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Adding saturated sodium bicarbonate to adjust pH to neutrality, extracting with ethyl acetate (50 mL. times.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure to give 4-chloro-2- (3-fluoro-benzyl) -thiazolo [4,5-c]Pyridine (145mg, 26% over two steps).

The compound of the invention example 98 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ9.96(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]^-。

Example 99, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (4-methylthiophen-2-yl) thiazole And [4,5-c ]]Pyridin-4-amines

4-chloro-2- (4-methylthiophen-2-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (441mg, 3.5mmol) and 4-methyl-thiophene-2-carboxylic acid (995mg, 7mmol) were dissolved in polyphosphoric acid (PPA) and the reaction was blocked at 140 ℃. The reaction was complete by TLC. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench the reaction. The reaction solution was extracted with ethyl acetate (50mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) gave 2- (4-methyl-thiophen-2-yl) -thiazolo [4,5-c ] pyridine (650mg, 80%) as a pale yellow solid.

Step 2: 2- (4-methyl-thiophen-2-yl) -thiazolo [4,5-c ] pyridine (600mg, 2.6mmol) was dissolved in 10mL of dichloromethane, MCPBA (625mg, 3.6mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (25mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (4-methyl-thiophen-2-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (4-methyl-thiophen-2-yl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 6mL POCl₃And refluxing for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (4-methyl-thia-zyl) as a yellow solid powderPhen-2-yl) -thiazolo [4,5-c]Pyridine (492mg, two-step yield 76.5%).

The compound of the invention example 99 was prepared according to method 1, the other preparation steps were prepared according to example 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]⁺。

Example 100, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (5-nitrothiophen-2-yl) thia-ne Azolo [4,5-c]Pyridin-4-amines

4-chloro-2- (5-nitrothiophen-2-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (850mg, 6.75mmol) and 5-nitro-thiophene-2-carboxylic acid (2.336g, 13.5mmol) were dissolved in polyphosphoric acid (PPA) and the reaction was blocked at 140 ℃. The reaction was complete by TLC. The reaction was terminated and quenched by addition of saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) gave 2- (5-nitro-thiophen-2-yl) -thiazolo [4,5-c ] pyridine (110mg, 6.2%) as a yellow solid.

Step 2: 2- (5-Nitro-thiophen-2-yl) -thiazolo [4,5-c ] pyridine (110mg, 0.42mmol) was dissolved in 10mL of dichloromethane, MCPBA (101mg, 0.59mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 25mL of saturated brine, extracted with dichloromethane (50 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 2- (5-nitro-thiophen-2-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (5-nitro-thiophen-2-yl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 5mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (5-nitro-thiophen-2-yl) -thiazolo [4,5-c ] as a yellow solid]Pyridine (65mg, 52% yield over two steps).

The compound of the invention example 100 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ10.01(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]⁺。

Example 101, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (4-methylthiazol-5-yl) thi-azol-e Azolo [4,5-c]Pyridin-4-amines

4-chloro-2- (4-methylthiazol-5-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (819mg, 6.5mmol) and 4-methyl-thiazole-5-carboxylic acid (1.86g, 13mmol) were dissolved in polyphosphoric acid (PPA) and reacted at 140 ℃ with a tube sealer. The reaction was complete by TLC. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench the reaction. The reaction was extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) afforded 2- (4-methyl-thiazole as a yellow solid-5-yl) -thiazolo [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: 2- (4-methyl-thiazol-5-yl) -thiazolo [4,5-c ] pyridine (677mg, 2.9mmol) was dissolved in 40mL of dichloromethane, MCPBA (702mg, 4.1mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (4-methyl-thiazol-5-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (4-methyl-thiazol-5-yl) -thiazolo [4,5-c]Pyridine-5-oxide crude product dissolved in 8mL POCl₃And refluxing for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (4-methyl-thiazol-5-yl) -thiazolo [4,5-c ] as a pale yellow solid]Pyridine (482mg, 62% over two steps).

The compound of the invention example 101 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ10.03(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]^-。

Example 102, (S) -N- (4- (3-Aminopiperidin-1-yl) pyridin-3-yl) -2- (2-methylthiazol-5-yl) thia-ne Azolo [4,5-c]Pyridin-4-amines

4-chloro-2- (2-methylthiazol-4-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (500mg, 4mmol) and 2-methyl-thiazole-5-carboxylic acid (1.145g, 8mmol) were dissolved in polyphosphoric acid (PPA) and the reaction was blocked at 140 ℃. The reaction was complete by TLC. The reaction was terminated and quenched by addition of saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) afforded 2- (2-methyl-thiazol-5-yl) -thiazolo [4, 5-c) as a yellow solid]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: 2- (2-methyl-thiazol-5-yl) -thiazolo [4,5-c ] pyridine (400mg, 1.72mmol) was dissolved in 30mL of dichloromethane, MCPBA (416mg, 2.41mmol) was added slowly, stirred at room temperature, TLC monitored to completion, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (2-methyl-thiazol-5-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (2-methyl-thiazol-5-yl) -thiazolo [4, 5-c)]Pyridine-5-oxide crude product dissolved in 8mL POCl₃And refluxing for 5 h. Concentrating the reaction solution under reduced pressure, slowly adding borneol to quench the residual POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (2-methyl-thiazol-5-yl) -thiazolo [4,5-c ] as a pale yellow solid]Pyridine (120mg, 26% over two steps).

The compound of the invention example 102 was prepared according to method 1, the other preparation steps were prepared according to example 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]⁺。

Example 103, (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazole-5- Yl) thiazolo [4,5-c]Pyridin-4-amines

4-chloro-2- (1-methyl-1H-pyrazol-5-yl) thiazolo [4,5-c]Preparation of pyridine

Step 1: 3-amino-4-mercaptopyridine (500mg, 4mmol) and 1-methyl-1H-pyrazole-5-carboxylic acid (1g, 8mmol) were dissolved in polyphosphoric acid (PPA) and subjected to a tube-sealing reaction at 140 ℃. The reaction was complete by TLC. The reaction was terminated and quenched by addition of saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate (100mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative TLC separation (petroleum ether: ethyl acetate ═ 1:1) afforded 2- (1-methyl-1H-pyrazol-5-yl) -thiazolo [4, 5-c) as a yellow solid]Pyridine (432mg, 50%).¹H NMR(400MHz,CDCl₃) δ9.38(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: 2- (1-methyl-1H-pyrazol-5-yl) -thiazolo [4,5-c ] pyridine (432mg, 2mmol) was dissolved in 30mL of dichloromethane, MCPBA (483mg, 2.8mmol) was slowly added, stirring was performed at room temperature, TLC was performed until the reaction was complete, and 10mL of 1M potassium carbonate solution was added to quench the reaction. To the reaction solution was added 50mL of saturated brine, extracted with dichloromethane (50mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of 2- (1-methyl-1H-pyrazol-5-yl) -thiazolo [4,5-c ] pyridine-5-oxide. It was not purified and used directly in the next reaction.

And step 3: reacting 2- (1-methyl-1H-pyrazol-5-yl) -thiazolo [4,5-c]Pyridine-5-oxide crude product solutionIn 8mL of POCl₃And refluxing for 5 h. The reaction solution was concentrated under reduced pressure, and ice water was slowly added to quench the remaining POCl₃Saturated sodium bicarbonate was added to adjust the pH to neutral, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-2- (1-methyl-1H-pyrazol-5-yl) -thiazolo [4, 5-c) as a yellow solid]Pyridine (342mg, 68.4% yield over two steps).

The compound of the invention example 103 was prepared according to method 1, the other preparation steps were prepared according to example 18.¹H NMR (400MHz,CDCl₃)δ9.88(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]⁺。

Example 104, 2-amino-6-methyl-4- (3- (2- (thiophen-2-yl) thiazolo [4, 5-c)]Pyridin-4-ylamines Yl) pyridin-4-yl) cyclohexyl acetate

The compound of the invention example 104 was prepared according to method 1, example 18. ESI-MS m/z: 480.95 [ M + H]⁺。

Example 105, 2-amino-6-methyl-4- (3- (2- (thiazol-2-yl) thiazolo [4, 5-c)]Pyridin-4-ylamines Yl) pyridin-4-yl) cyclohexyl acetate

The compound of the invention example 105 was prepared according to method 1, the other preparation steps were prepared according to example 18. ESI-MS m/z: 482.11[ M + H]⁺。

D biological assay

Test example 1 Pim1ATP loss test

To evaluate the effect of compounds on the activity of the kinase Pim1, ADP-Glo was used^TMThe kinase activity was measured by the kit (promega corporation) by measuring ATP consumption in the enzymatic reaction. The samples to be tested were dissolved in DMSO. In a microplate, Pim1 kinase and reaction buffer are added into each wellLiquid (containing Tris-HCl pH 7.5, MgCl)₂DTT and BSA), ATP, kinase substrate (S6K substrate) and sample (25 μ L total volume per well) while a blank control (no enzyme and sample) and a negative control (no sample) were set; reacting at room temperature for 60min, adding ADP-Glo Reagent, and reacting at room temperature for 40min to inactivate excessive ATP; then, a Kinase Detection Reagent was added, and after reaction at room temperature for 30min, the chemiluminescence intensity L of each well was measured. Calculating the inhibition rate of the compound according to the value L of the chemiluminescence intensity, wherein the inhibition rate is [1- (L)_{Sample (I)}-L_{Blank space})/(L_{Negative of} -L_{Blank space})]X 100%. Each sample is subjected to primary screening under the specific single concentration condition, and at least 6 different concentration gradients are further arranged on the sample with the inhibition rate of more than 50% to determine the IC of the sample₅₀Values, as shown in table 2.

Test example 2 Pim2ATP loss test

To evaluate the effect of compounds on the activity of the kinase Pim2, ADP-Glo was used^TMThe kinase activity was measured by the kit (promega corporation) by measuring ATP consumption in the enzymatic reaction. The samples to be tested were dissolved in DMSO. Pim2 kinase, reaction buffer (containing Tris-HCl pH 7.5, MgCl) were added to each well of the plate₂DTT and BSA), ATP, kinase substrate (S6K substrate) and sample (25 μ L total volume per well) while a blank control (no enzyme and sample) and a negative control (no sample) were set; reacting at room temperature for 60min, adding ADP-Glo Reagent, and reacting at room temperature for 40min to inactivate excessive ATP; then, a Kinase Detection Reagent was added, and after reaction at room temperature for 30min, the chemiluminescence intensity L of each well was measured. Calculating the inhibition rate of the compound according to the value L of the chemiluminescence intensity, wherein the inhibition rate is [1- (L)_{Sample (I)}-L_{Blank space})/(L_{Negative of} -L_{Blank space})]X 100%. Each sample is subjected to primary screening under the specific single concentration condition, and at least 6 different concentration gradients are further arranged on the sample with the inhibition rate of more than 50% to determine the IC of the sample₅₀Values, as shown in table 2.

Test example 3 Pim3ATP loss test

To evaluateEffect of Compounds on kinase Pim3 Activity Using ADP-Glo^TMThe kinase activity was measured by the kit (promega corporation) by measuring ATP consumption in the enzymatic reaction. The samples to be tested were dissolved in DMSO. Pim3 kinase, reaction buffer (containing Tris-HCl pH 7.5, MgCl) were added to each well of the plate₂DTT and BSA), ATP, kinase substrate (S6K substrate) and sample (25 μ L total volume per well) while a blank control (no enzyme and sample) and a negative control (no sample) were set; reacting at room temperature for 60min, adding ADP-Glo Reagent, and reacting at room temperature for 40min to inactivate excessive ATP; then, a Kinase Detection Reagent was added, and after reaction at room temperature for 30min, the chemiluminescence intensity L of each well was measured. Calculating the inhibition rate of the compound according to the value L of the chemiluminescence intensity, wherein the inhibition rate is [1- (L)_{Sample (I)}-L_{Blank space})/(L_{Negative of} -L_{Blank space})]X 100%. Each sample is subjected to primary screening under the specific single concentration condition, and at least 6 different concentration gradients are further arranged on the sample with the inhibition rate of more than 50% to determine the IC of the sample₅₀Values, as shown in table 2.

The IC of the example compound was determined using the procedures of test example 1(Pim1ATP loss test), test example 2(Pim2ATP loss test) and test example 3(Pim 3ATP loss test)₅₀The values are specifically shown in table 2 below.

TABLE 2

The results of the Pim kinase activity test show that a plurality of examples have significant inhibitory activity on three subtypes of Pim kinases, wherein examples 1, 58, 59, 68 and 95 all show inhibitory activity on the nM level on Pim 1/2/3.

Claims (26)

1. A compound of formula (I), or a tautomer or pharmaceutically acceptable salt thereof,

wherein:

a is selected from pyridyl as defined below as a 1:

wherein is the point of attachment to X,

is the point of attachment to NH; each R¹Each independently selected from hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4A haloalkyl group;

x is selected from the following X1, X4, X10, X14 and X15, and can be selected from halogen, -NH₂、C_1-6Alkyl, hydroxy, mercapto, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, or C_1-4The substituent of the alkoxy group is substituted,

wherein is the point of attachment to a;

Z₁is N, Z₂Is S;

wherein the content of the first and second substances,

selected from the following formulas B1:

wherein is the point of attachment to NH,

is the point of attachment to R; each of said R³Each independently selected from hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4One or more halogenated alkyl groups; r is selected from the group consisting of phenyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, wherein said phenyl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl may be selected from the group consisting of halogen, -NH₂Hydroxy, mercapto, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4Substituted by a substituent of a haloalkyl group.

2. A compound of formula (I) as claimed in claim 1, or a tautomer or a pharmaceutically acceptable salt thereof, wherein: each R in the pyridyl as defined by A1¹Each independently selected from trifluoromethyl or difluoromethyl.

3. A compound of formula (I) as claimed in claim 1, or a tautomer or a pharmaceutically acceptable salt thereof, wherein:

r is selected from phenyl, wherein said phenyl is substituted with one or more substituents independently selected from fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy; or

R is selected from furan, pyridine, thiophene, thiazole, isothiazole, pyrimidine, pyrazole, imidazole, oxazole, isoxazole and pyrazine, wherein each of said R is optionally substituted with one or more groups independently selected from fluorine, chlorine, bromine, iodine, nitro and C_1-4Alkyl substituents.

4. A compound of formula (I) as defined in claim 1, or a tautomer or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

5. a compound of formula (I) according to claim 1, or a tautomer or a pharmaceutically acceptable salt thereof,

wherein X is an amino-substituted piperidinyl group selected from X1, X4, X14 and X15, and each R1 is independently selected from trifluoromethyl or hydrogen;

r is phenyl, or phenyl is selected from halogen and C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Phenyl substituted by one or more of alkoxy, hydroxyl, sulfydryl, nitro and cyano; or

R is selected from furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl or pyrazinyl; or any one of furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and pyrazinyl is selected from halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, hydroxyl, mercapto, nitro, cyano, or a group substituted with two or more substituents;

wherein said halogen and C_1-4Halogen in the halogenated alkyl is one or more of fluorine, chlorine, bromine or iodine.

6. A compound of formula (I) according to claim 5, or a tautomer or a pharmaceutically acceptable salt thereof,

r is one selected from phenyl, furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl; or R is one selected from phenyl, furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl and selected from halogen and C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4And (3) a group substituted with one or more of alkoxy, hydroxyl and mercapto.

7. A compound of formula (I), or a tautomer or pharmaceutically acceptable salt thereof, according to claim 6, wherein R is selected from halogen, C_1-4Alkyl, or C_1-4One or more substituted halogenated alkyl groups selected from phenyl, furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl.

8. A compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, according to claim 7, wherein R is phenyl, or phenyl substituted with halogen, methyl, ethyl, or halomethyl, haloethyl, or furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl, or imidazolyl; or one of furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl and imidazolyl substituted with halogen, methyl, ethyl, halomethyl or haloethyl.

9. The compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, according to claim 6, wherein the halogen in the R group is fluorine, the C_1-4The halogenated alkyl is fluoromethyl, difluoromethyl or trifluoromethyl; fluoroethyl and difluoroethylA trifluoroethyl group, a tetrafluoroethyl group, a pentafluoroethyl group or a hexafluoroethyl group.

10. A compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, according to claim 8, wherein R is phenyl, or monofluorophenyl, or difluorophenyl, or fluoro-p-methylphenyl, or di (fluoromethyl) phenyl or di (trifluoromethyl) phenyl; or furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazolyl; or a group selected from furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazolyl substituted with methyl, fluoro and/or fluoromethyl.

11. A compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3 or according to any one of claims 5 to 10, X being X1 or X14, i.e. a 3-amino-substituted piperidine 1-yl group in the R or S configuration.

12. A compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3 or any one of claims 5 to 10, wherein R is³Halogen or C in (1)_1-4The halogen in the halogenated alkyl is selected from one or more of fluorine, chlorine, bromine or iodine.

13. A compound of formula (I), or a tautomer or pharmaceutically acceptable salt thereof, according to claim 12, wherein R³Independently selected from one or more of hydrogen, fluorine, methyl or trifluoromethyl; wherein R is phenyl or difluorophenyl; or furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl or imidazolyl; or methylfuryl, fluorofuryl, methylfluorofuryl, methylpyridyl, fluoropyridyl, methylfluoropyridyl, methylthiazolyl, fluorothiazolyl, methylfluorothiazolyl, methylisothiazolyl, fluoroisothiazolyl, methylfluoroisothiazolyl, methylthiothienyl, fluorothienyl, methylfluorothienyl, methyl-fluorothienyl,Any one of methyl pyrazolyl, fluoro pyrazolyl, methyl imidazolyl, fluoro imidazolyl or methyl fluoro imidazolyl.

14. A process for the preparation of a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 10, wherein a compound represented by the following intermediate I and intermediate II is subjected to an amination reaction with a halogenated aromatic hydrocarbon to obtain

15. The process for producing a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, according to claim 11, wherein the compound represented by the following intermediate I and intermediate II is subjected to amination reaction of halogenated aromatic hydrocarbon to obtain

16. The process for producing a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, according to claim 12, wherein the compound represented by the following intermediate I and intermediate II is subjected to amination reaction of halogenated aromatic hydrocarbon to obtain

17. The process for producing a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, according to claim 13, wherein the compound represented by the following intermediate I and intermediate II is subjected to amination reaction of halogenated aromatic hydrocarbon to obtain

18. The process for producing a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is produced by a production process comprising the steps of:

(1) step 1: preparation of 4-chloro-2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine comprising the steps of:

step 1: preparing 3-amino-4-mercapto-pyridine,

step 2: preparing thiazolo [4,5-c ] pyridine,

and step 3: preparing 2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine,

and 4, step 4: preparation of 2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine-5-oxide, and

and 5: preparing 4-chloro-2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridine;

(2) and a step 2: preparation of (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridin-4-amine comprising the following steps:

step 1, preparation of tert-butyl (S) -1- (3- (2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridin-4-yl-amino) pyridin-4-yl) piperidine-3-carbamate, and

step 2, preparing (S) -N- (4- (3-aminopiperidin-1-yl) pyridine-3-yl) -2- (2, 6-difluorophenyl) thiazolo [4,5-c ] pyridin-4-amine.

19. The process for producing a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is produced by a production process comprising the steps of:

(1) step 1: preparation of 4-chloro-2- (thiazol-2-yl) thiazolo [4,5-c ] pyridine comprising the following steps:

step 1: preparation of 2- (thiazol-2-yl) -thiazolo [4,5-c ] pyridine,

step 2: preparing 2- (thiazol-2-yl) -thiazolo [4,5-c ] pyridine-5-oxide; and

and step 3: preparation of 4-chloro-2- (thiazol-2-yl) -thiazolo [4,5-c ] pyridine; and

(2) and a step 2: preparation of (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thiazol-2-yl) thiazolo [4,5-c ] pyridin-4-amine comprising the steps of: reacting 4-chloro-2- (thiazol-2-yl) -thiazolo [4,5-c ] pyridine with (S) -tert-butyl (1- (3-aminopyridin-4-yl) piperidin-3-yl) carbamate, followed by removal of the protecting group for the amino, tert-butyloxycarbonyl, to give (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thiazol-2-yl) thiazolo [4,5-c ] pyridin-4-amine.

20. The process for producing a compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is produced by a production process comprising the steps of:

(1) step 1: preparation of 4-chloro-2- (thiophen-2-yl) thiazolo [4,5-c ] pyridine comprising the steps of:

step 1: preparation of 2- (thien-2-yl) -thiazolo [4,5-c ] pyridine,

step 2: preparation of 2- (thien-2-yl) -thiazolo [4,5-c ] pyridine-5-oxide, and

and step 3: preparing 4-chloro-2- (thiophen-2-yl) -thiazolo [4,5-c ] pyridine; and

(2) and a step 2: preparation of (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thiophen-2-yl) thiazolo [4,5-c ] pyridin-4-amine comprising the steps of: reacting 4-chloro-2- (thien-2-yl) -thiazolo [4,5-c ] pyridine with (S) -tert-butyl (1- (3-aminopyridin-4-yl) piperidin-3-yl) carbamate, followed by removal of the protecting group for the amino-tert-butoxycarbonyl group to give (S) -N- (4- (3-aminopiperidin-1-yl) pyridin-3-yl) -2- (thien-2-yl) thiazolo [4,5-c ] pyridin-4-amine.

21. Use of a compound according to any one of claims 1 to 13, or a tautomer or a pharmaceutically acceptable salt thereof, or a compound prepared by a process according to any one of claims 14 to 20, or a tautomer or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease mediated by Pim kinase.

22. Use of a compound according to any one of claims 1 to 13, or a tautomer or a pharmaceutically acceptable salt thereof, or a compound prepared by a process according to any one of claims 14 to 20, or a tautomer or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of a disease mediated by Pim kinase.

23. A medicament comprising a compound according to any one of claims 1 to 13, or a tautomer or a pharmaceutically acceptable salt thereof, or a compound prepared by a process according to any one of claims 14 to 20, or a tautomer or a pharmaceutically acceptable salt thereof.

24. A medicament according to claim 23 for the treatment of cancer and/or immune related diseases.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a tautomer or a pharmaceutically acceptable salt thereof, or a compound produced by the production process of any one of claims 14 to 20, or a tautomer or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition of claim 25 for use in the treatment of cancer and/or immune-related diseases.