CN104903331A - Jnk inhibitors - Google Patents

Abstract

The present invention belongs to the field of pharmaceutical techniques, and in particular relates to JNK inhibitors as shown by general formulae (I), (1a) or (1b), pharmaceutically acceptable salts or stereoisomers thereof, the preparation method of these compounds, pharmaceutical preparations containing these compounds, and use of these compounds in the preparation of drugs for treating and/or preventing ischemia reperfusion injury, diabetes, neurodegenerative disorders, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver or liver cirrhosis.

Description

JNK inhibitors

Jnk inhibitor technical field

The invention belongs to pharmaceutical technology field, specifically related to jnk inhibitor, its pharmaceutically acceptable salt or its stereoisomer, the preparation method of these compounds, pharmaceutical preparation containing these compounds, and purposes of these compounds in preparing treatment and/or preventing the medicine of ischemical reperfusion injury, diabetes, nerve retrograde affection, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver or hepatic sclerosis.

Background technology

JNK is otherwise known as stress activated protein kinase（Stress-activated kinases, SAPK), it is nineteen ninety existing mitogen-activated protein kinase, is one of Major Members of MAPK families.Mitogen-activated protein swashs liquor-saturated (m itogen-activated protein kinase, MAPK；) it is to feed the class serine/threonine protein kitase being widely present in L zooblasts, 4 kinds of family members have been identified at present, are respectively thin！Bag extracellular signal-regulated kinase（Extracellular signal-regu lated kinase 1/2, ERK 1/2), c-Jun J ^ terminal Kinases (c-Jun N-terminal kinase, JNK：), p38 and ERK5.JNK genes have 3 hypotypes, i.e. JNK1, JNK2 and JNK3, are formed by alternative splicing.JNK1 and JNK2 wide expression in the tissue, and JNK3 is expressed only in brain, the heart and testis.Each JNKL^ is because that can encode 46 and 54 kD protein product.3 kinds of JNK isomers are activated by different modes, with reference to the protein substrate different with phosphorylation.

JNK signal paths can be by cell factor [such as TNFa (tumor necrosis factor α, TNFa), interleukin-11 (interleukin 1, IL- 1), EGF（Epidermal growth factor, EGF)], some g protein coupled receptors, stress the activation of (such as ionising radiation, osmotic pressure, heat shock and oxidative damage) many factors, participate in that cell propagation is maintained with differentiation, cellular morphology, the various biological such as cytoskeleton is built, Apoptosis and malignant change of cell is reacted.JNK signal paths functional disturbance can cause a variety of diseases such as ischemical reperfusion injury, chronic inflammation, neurodegeneration, diabetes and tumour.

Typical mitogen-activated protein kinase (MAPK) signal path includes 3 continuous enzymatic reaction, i.e. MAPKKKs → MAPKKs → MAPKs.Only MKK4 and MKK7, the TXY sequence that the JNKs MAPKKs of kinases immediately upstream confirms at present are the dual phosphorylation site that MKK activates JNK, MKK4 and MKK⁷Pass through the 183rd threonine residues of phosphorylation TXY sequences（) and the 185th tyrosine residue Thrl83（Tyrl85 JNK) is activated, causes the various biologicals such as cell propagation and differentiation, Apoptosis and malignant change of cell to be reacted.

The regulation of signal path is an extremely complex system, and the regulation of JN signal paths mainly has two kinds of different mechanism, and one is to recognize the sequence between MKKK and MKK and MKK and MAPK；Two be that scaffolding protein makes MKKK-MKK-MAPK module assembleds into albumen composition.MAPK is by guarding sequence Row and specific upstream molecule MKK and substrate（Such as c-Jun, ATF2 etc.）Achieve a butt joint.In all MAPK（Including J K), there is one group of negatively charged c-terminus atmosphere base acid to be connected to the domain sequence of kinases, this site is referred to as docking domain jointly（Common dock ing doma in, CD), for Μ Κ Κ, Μ Α Ρ Κ, the docking of specific substrate and scaffolding protein.Another conserved sequence is referred to as glutamic acid-aspartic acid domain, is equally used for MAPK docking.Docking site in MKK, substrate, MAPK and scaffolding protein has a common conserved sequence R/K-X4A-0A-X- 0B (0A and 0B are the hydrophobic residues of leucine, isoleucine and valine).When docking site（Docking doma in, DD) in alkaline residue when being combined with the acidic residues in MAPK CD domains, hydrophobic residue is located in docking groove so that 0A-X-0B hydrophobic sequences are combined with DD sequences.Interaction between these docking sites is played an important role in MAPK specific binding and activation.Except the effect of docking between MAPK and MKK, substrate and regulatory factor, also specific sequence regulates and controls the interaction between MKKK and MKK.Research is found, in some MKK, includes regulation JNK MKK4/7, there is a kind of multi-functional docking domain, be referred to as multi-functional docking site（Doma in for versatile dock ing, DVD), DVD sites are located at MKK c-terminus, connection MKKK [including MEKK 1, MEKK4 (MTK 1), ASK1, Tao2 and Takl], it is all these to activate JNK signal paths.N shape kinases binding domain in MKKK is combined with MKK DVD sites.

The another aspect for controlling J K signal paths is by scaffolding protein composite signal path compound.Scaffolding protein can encode docking site in itself without catalysis, connection MAPK module members MKKK, MKK and MAPK.Generally, scaffolding protein by and the interaction of the binding domain such as SH2, SH3, PTB and other protein bindings, and these domains cause the MAPK signal path compounds in cell to position to different loci.Different activators causes scaffolding protein and specificity MKKK Selective activation MAPK, and with space-time dynamic.In different scaffolding proteins, JNK interaction proteins (J K-interacting prote ins, JIPs) binding specificity driving albumen and MKKK 々 mixing lineage kinases（M ixed lineage k inase, MLK) race；Suppress the confactor that albumen β-arrestin are the bony acidifying of g protein coupled receptor；Many binding domain protein POSH (plenty of SH3s) contain multiple SH3 domains, participate in the JNK signal paths in mammal and drosophila cell apoptosis；Adaptor protein C rk II are combined by adhesion factor with JNK signal paths.This sunset is foretold, and MEKK1 can not only be combined with MKK4, moreover it is possible to be combined with JNK1/2, this manifests itself as the effect with similar scaffolding protein.

Target homologous recombination gene in knock-out mice model, so that different JNK or its upstream regulation developed by molecule missing, so as to influence it to be played a role in physiology and disease, important function of the JNK signal paths in various disease has been also further demonstrated that by jnk inhibitor.Jnk inhibitor can suppress the cell death caused by ischemic and other stress-induced apoptotic responses, and this show huge treatment potentiality.Existing document proves that jnk inhibitor can be used for treating or preventing respiratory disease（Such as pulmonary fibrosis）, fat Fat liver, liver fibrosis, hepatic sclerosis, ischemia/reperfusion injury, chronic inflammation disease, nerve degenerative diseases, diabetes and tumour etc..

The more jnk inhibitor of research is mainly in polypeptide and small molecule class compound, WO2005025567 and WO2006076595, effect of the new JNK small molecules class inhibitor in multiple therapy fields of Jun Caigen roads.At present, temporarily without the listing of jnk inhibitor class medicine, accordingly, it would be desirable to research and develop more jnk inhibitor structure types, effectiveness of selection and the preferable compound of security, for respiratory disease, fatty liver, liver fibrosis, hepatic sclerosis, chronic inflammation disease treatment.

AS-602801 is the medicine for being used to treat fibrosis of Merck companies exploitation, is currently under clinical II and has arrived the compound, structural formula is as follows：

The content of the invention

The invention provides following technical proposals

1st, formula（ I )、 （L a) or（L b) shown in compound, its pharmaceutically acceptable salt or its stereoisomer：

(I) (la) (lb)

Wherein,

X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

R¹, R²Independently for hydrogen, sulfonyl, halogen, C_1-6Alkyl, halo C alkyl, C_1-6Alkoxy, amino, hydroxyl, C₂-₆Alkenyl, C_2-6Alkynyl, 6-14 members aryl, 5-14 unit's heteroaryls, 3-14 members cycloalkyl, 3-14 circle heterocycles alkyl；

N is selected from 0,1,2 or 3;

L is C_1-6Alkyl, C_1-6Alkoxy ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted 6-14 members aryl, 5-14 unit's heteroaryls, 3-14 members cycloalkyl, 3-14 circle heterocycles alkyl, 7-12 member loop coils base, 7-12 member bridged ring bases, wherein the cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be with other 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed； O

_R3 be/^！^ or ^：、_r4, wherein m be selected from 0,1,2 or 3,

R⁴For sulfonyl, halogen, C_1-6Alkyl, halo C_1-6Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b)、 C_1-6Alkoxy, amino, cyano group, hydroxyl, C_2-6Alkenyl, C₂_₆It is alkynyl, unsubstituted or at least by a R⁵Substituted 6-14 members aryl, 5-14 unit's heteroaryls, 3-14 members cycloalkyl, 3-14 circle heterocycles alkyl, 7-12 member loop coils base, 7-12 member bridged ring bases, wherein described cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be with other 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed, any CH of 3-14 circle heterocycles alkyl₂It can be replaced by C (O)；

R⁵For sulfonyl, halogen, C_1-6Alkyl, halo C₆Alkyl, _₆Alkoxy,-C (0) -0-Ci_-6Alkyl ,-C-Cw alkyl ,-(CHz C-O-Cw alkyl ,-(CH p-O-C^ alkyl ,-(C)_p-C(0)N(R^aR^b)、 -(CH₂)_p- OH,, hydroxyl, C₂_₆Alkenyl, C_2-6Alkynyl, 3-14 members cycloalkyl, 6-14 members aryl or 3-14 circle heterocycles alkyl；

R^a、 R^bIndependently for hydrogen, d.₆Alkyl ,-(C)_p-OC_1-6Alkyl or 6-14 member aryl C^₆Alkyl,

P is selected from 1,2,3 or 4.

2nd, as any one of preceding solution compound, its pharmaceutically acceptable salt or its stereoisomer：

Wherein,

X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

R¹ , R²Independently for hydrogen, sulfonyl, halogen, d_₆Alkyl, C_1-6Alkoxy, cyano group, hydroxyl, C₂_₆Alkenyl, C₂_₆Alkynyl, 6-14 member aryl；

N is selected from 0,1,2 or 3;

L is d.₆Alkyl, d.₆Alkoxy ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted 6-14 members aryl, 5-14 unit's heteroaryls, 3-14 members cycloalkyl, 3-14 circle heterocycles alkyl, wherein the cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be with other 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed；

0 wherein m is selected from 0,1,2 or 3, R⁴For sulfonyl, halogen, C_1-6Alkyl, halo C_1-6Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b)、 d_₆It is alkoxy, amino, cyano group, hydroxyl, unsubstituted or at least by a R⁵Substituted 6-14 members aryl, 5-14 unit's heteroaryls, 3-14 members cycloalkyl, 3-14 circle heterocycles alkyl, 7-12 member loop coils base, 7-12 member bridged ring bases, wherein described cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be with other 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed, any CH of 3-14 circle heterocycles alkyl₂It can be replaced by C (O)；

R⁵For sulfonyl, halogen, C_1-6Alkyl, halo C^₆Alkyl, C_1-6Alkoxy,-C (0) -0-C_1-6Alkyl ,-C O C^ alkyl ,-(CH₂)_p-C(0)-0-C_1-6Alkyl ,-(CH₂)_p-0-C_1-6Alkyl ,-(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p- OH, amino, cyano group, hydroxyl, C_2-6Alkenyl, C₂.₆Alkynyl, 3-14 members cycloalkyl, 6-14 members aryl or 3-14 circle heterocycles alkyl；

R^A、 R^BIndependently for hydrogen, C₆Alkyl ,-(CH₂)_P-OC_1-6Alkyl, phenyl C_1-6Alkyl, p is selected from 1,2,3 or 4.

3rd, as any one of preceding solution compound, its pharmaceutically acceptable salt or its stereoisomer：

Wherein,

X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

R¹, R²Independently for hydrogen, sulfonyl, halogen, d.₆Alkyl, C^₆Alkoxy, amino, cyano group, hydroxyl；

N is selected from 0,1,2 or 3;

L is d_₆Alkyl, d-6 alkoxies ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted phenyl, quinolyl, 5-6 unit's heteroaryls, 3-8 members cycloalkyl or 3-8 circle heterocycles alkyl；

0

R³" ^ or/R for ^⁴ ,

Wherein m is selected from 0,1,2 or 3,

R⁴For sulfonyl, halogen, C_1-6Alkyl, halo C_1-6Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b), it is alkoxy, amino, cyano group, hydroxyl, unsubstituted or at least by a R⁵Substituted 6-14 members aryl, 5-14 unit's heteroaryls, 3-14 members cycloalkyl, 3-14 circle heterocycles alkyl, wherein described cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be replaced with other 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed, any C of 3-14 circle heterocycles alkyl by C (O)；

R⁵For sulfonyl, halogen, _₆Alkyl, halo d.₆Alkyl, C_1-6Alkoxy,-C (0) -0-Ci_-6 Alkyl ,-ccc-c^ alkyl ,-(CH₂)_p-C(0)-0- d.₆Alkyl ,-(CH₂)_p-0-C_1-6Alkyl ,-(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p- OH, amino, hydroxyl, C_2-6Alkenyl, C_2-6Alkynyl, 3-14 members cycloalkyl, 6-14 members aryl or 3-14 circle heterocycles alkyl；

R^a、 R^bIndependently for hydrogen, ^₆Alkyl ,-(CH^p-OCw alkyl, benzyl or phenylethyl, p are selected from 1,2,3 or 4.

4th, as any one of preceding solution compound, its pharmaceutically acceptable salt or its stereoisomer：

Wherein,

X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

R¹, R²Independently for hydrogen, alkyl；

N is selected from 0,1,2 or 3;

L is d_₆Alkyl, C^₆Alkoxy ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted phenyl, quinolyl, 5-6 unit's heteroaryls, 3-8 members cycloalkyl or 3-8 circle heterocycles alkyl；

o

_R3 for/or/C,_R4, wherein m be selected from 0,1,2 or 3,

R⁴For sulfonyl, halogen, C_1-6Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b)、 d_₆It is alkoxy, amino, cyano group, hydroxyl, unsubstituted or at least by a R⁵Substituted phenyl, 5-6 unit's heteroaryls, 3-8 members cycloalkyl, 3-8 circle heterocycles alkyl, wherein described cycloalkyl, Heterocyclylalkyl, phenyl or heteroaryl can be with other 1 cycloalkyl, Heterocyclylalkyl, phenyl or heteroaryl-condensed, any CH of 3-8 circle heterocycles alkyl₂It can be replaced by C (O)；

R⁵For C_1-6Alkyl, C_1-6Alkoxy,-C (0) -0-C_1-6Alkyl ,-C (0)-C_1-6Alkyl ,-(CH₂)_p-C(0)-0-C_1-6Alkyl ,-(C)_p-0-C_1-6Alkyl ,-(CH₂)_p-C(0)N(R^aR^b)、 -(C¾)_p- OH, amino, cyano group, hydroxyl, 3-8 yuan of rings protective embankments base, phenyl, the circle heterocycles protective embankment bases of 3- 8；

R^A、 R^BIndependently for hydrogen, C alkyl ,-(C)_P-OC_1-6Alkyl, benzyl or phenylethyl；P is selected from 1,2,3 or 4.

5th, as any one of preceding solution compound, its pharmaceutically acceptable salt or its stereoisomer：

Wherein, X, Y are separately N or CR¹, wherein X, Y at least 1 is N;Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

R¹, R²Independently for hydrogen, C^₆Alkyl；

N is selected from 0,1,2 or 3;

1^ is（^₆Alkyl,₆Alkoxy ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted phenyl, quinolyl, 6 unit's heteroaryls, 3-8 members cycloalkyl or 3-8 circle heterocycles alkyl；

R³For

Wherein m is selected from 0,1,2 or 3,

R⁴For sulfonyl, halogen,（^-₃Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b)、 C_1-6It is alkoxy, amino, cyano group, hydroxyl, unsubstituted or at least by a R⁵Substituted phenyl, 5-6 unit's heteroaryls, 3-8 members cycloalkyl, 3-8 circle heterocycles alkyl or 1, wherein 2,3,4- tetrahydroisoquinoline -2- bases, any CH of 3-8 circle heterocycles alkyl₂It can be replaced by C (O)；

R⁵For c_1-6Alkyl, c_1-6Alkoxy ,-c (o)-o-c_1-6Alkyl ,-c ^-c^ alkyl, Alkyl ,-(CH₂)_p-0-C_1-6Alkyl ,-(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p- OH, amino, cyano group or hydroxyl；

R^A、 R^BIndependently for hydrogen, C alkyl ,-(CH₂)_P-OC_1-3Alkyl or benzyl, p are selected from 1,2 or 3.

6th, as any one of preceding solution compound, its pharmaceutically acceptable salt or its stereoisomer：

Wherein,

X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

R¹, R²Independently for hydrogen, d.₆Alkyl；

N is selected from 0,1,2 or 3;

！^ is.^ alkyl, d.₆Alkoxy ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted phenyl, quinolyl, 6 unit's heteroaryls, 3-8 members cycloalkyl or 3-8 circle heterocycles alkyl；

0

_R3 be ^_R4Or,

Wherein m is selected from 0,1,2 or 3, R⁴For sulfonyl, halogen, C_1-3Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b)、 C_1-6It is alkoxy, amino, cyano group, hydroxyl, unsubstituted or at least by a R⁵Substituted 5-6 unit's heteroaryls, 3-8 circle heterocycles alkyl or 1, wherein 2,3,4- tetrahydroisoquinoline -2- bases, any CH of 3-8 circle heterocycles alkyl₂It can be replaced by C (O)；

R⁵For Ci_-3Alkyl, Ci_-6Alkoxy,-C (0) -0-Ci.₆Alkyl ,-C (0)-Ci_-3Alkyl ,-(CH₂)p-C(0)-0-Ci.₃Alkyl ,-(CH₂)_p-0-C_1-3Alkyl ,-(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p- OH, amino, ^J^ or hydroxyl；

R^a、 R^bIndependently for hydrogen,（^₆Alkyl ,-(CH₂)_p- OCw alkyl or benzyl,

P is selected from 1,2 or 3.

7th, as any one of preceding solution compound, its pharmaceutically acceptable salt or its stereoisomer：

Wherein,

X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

R¹ , R²Independently for hydrogen, methyl or ethyl；

N is selected from 0,1,2 or 3;

L is alkyl ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted phenyl, quinolyl, pyridine radicals, pyrimidine radicals, cyclohexyl, piperidyl, THP trtrahydropyranyl, piperazinyl or morpholinyl；

0

_R3 be ^ R₄Or^e、_R4,

Wherein m is selected from 0 or 1,

R⁴For sulfonyl, halogen, C_1-3Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b), it is unsubstituted or at least by a R⁵Substituted pyridine radicals, pyrazolyl, imidazole radicals, pyrimidine radicals, 1,2,3,4- tetrahydroisoquinoline -2- bases, morpholinyl, piperidyl, piperazinyl, nafoxidine 2- ketone groups；

R⁵For C_1-3Alkyl, C_1-6Alkoxy,-C (0) -0-C_1-6Alkyl ,-C (0)-C_1-3Alkyl ,-(CH₂)p-C(0)-0-C₁_₃Alkyl ,-(CH₂)_p-0-C_1-3Alkyl ,-(C)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH;

R^a、 R^bIndependently for hydrogen, C_1-6Alkyl ,-(CH^-OCw alkyl or benzyl,

P is selected from 1,2 or 3.

8. compound, its pharmaceutically acceptable salt as any one of technical scheme 1-7 or it is vertical Body isomers,

One wherein in X and Y is N, and another is 0¹。

9. compound, its pharmaceutically acceptable salt or its stereoisomer as any one of technical scheme 1-8,

Wherein Z represents CH, and W represents CH;

U represents N, and G represents N.

10th, selected from following compound, its pharmaceutically acceptable salt or its stereoisomer:

01

M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

II

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680

n

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98i / 0Z OAV

91

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

LI

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

81

680000/1-lOiN3/X3d 98\m/noz OAV

61

680000/ίΊ01Μ3/Χ3<Ι 98ΐ Ϊ/Π0ε ΟΛ\

oz

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

11st, selected from following compound, its pharmaceutically acceptable salt or its stereoisomer, the compound is selected from：

12nd, a kind of pharmaceutical composition, it includes compound, its pharmaceutically acceptable salt or its stereoisomer and one or more pharmaceutical carriers described in any one of technical scheme 1 ~ 11.

13rd, described in any one of technical scheme 1 ~ 11 pharmaceutical composition of compound, its pharmaceutically acceptable salt or its stereoisomer or technical scheme 12 is preparing treatment and/or prevention ischemical reperfusion injury, diabetes, nerve retrograde affection, chronic inflammation（Such as allergy, asthma, rheumatoid class arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, PVR, glaucoma）, pulmonary fibrosis, liver fibrosis, the purposes in the medicine of fatty liver or hepatic sclerosis.

14th, a kind for the treatment of and/or prevention ischemical reperfusion injury, diabetes, nerve retrograde affection, chronic inflammation（Such as allergy, asthma, rheumatoid class arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, PVR, glaucoma）, pulmonary fibrosis, liver fibrosis, the method for fatty liver or hepatic sclerosis, including give the pharmaceutical composition of compound described in any one of technical scheme 1-12 for needing its bacterium, its pharmaceutically acceptable salt or its stereoisomer or technical scheme 13. 15th, for treating and/or preventing ischemical reperfusion injury, diabetes, nerve retrograde affection, chronic inflammation（Such as allergy, asthma, rheumatoid class arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, PVR, glaucoma）, pulmonary fibrosis, liver fibrosis, the compound described in any one of technical scheme 1 ~ 12 of fatty liver or hepatic sclerosis, the pharmaceutical composition of its pharmaceutically acceptable salt or its stereoisomer or technical scheme 13.Embodiment

In the present invention, term " halogen, refer to fluorine atom, chlorine atom, bromine atoms or iodine atom.

In the present invention, term " C^₆Alkyl " refers to the alkyl of the straight or branched containing 1-6 carbon atom, including such as " d_₅Alkyl ", " CM alkyl ", " Cw alkyl " etc.；The example includes but is not limited to such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, 2- methyl-propyls, 1- Yue base propyl group, 1, the Yue base ethyls of 1- bis-, n-pentyl, 3- methyl butyls, 2- methyl butyls, 1- Yue base butyl, 1- ethyl propyls, n-hexyl, 4- Yue base amyl groups, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 3, the Yue base butyl of 3- bis-, 2, 2- dimethylbutyls, 1, 1- dimethylbutyls, 1, 2- dimethylbutyls, 1, 3- dimethylbutyls, 2, the Yue base butyl of 3- bis-, 2- ethyl-butyls, 1, Yue base propyl group of 2- bis- etc..Term " C_1-5Alkyl ", " CM alkyl ", " C_1-3Alkyl " refer in examples detailed above respectively containing 1-5 carbon atom, 1-4 carbon atom, 1-3 carbon atom instantiation.

In the present invention, term "<^₆Alkenyl " refers to the straight or branched that the carbon number containing double bond is 26 or the alkyl of ring-type, including such as " C_2-5Alkenyl ", " CM alkenyls ", " C_2-3Alkenyl ", " C_3-6Cycloalkenyl group, etc.；The example include but is not limited to for example vinyl, the third Xis of 1- base, 2- acrylic, 1- Yue bases vinyl, 1- cyclobutenyls, 2- cyclobutenyls, 3- cyclobutenyls, 1- Yue base -1- Bing Women bases, the small acrylic of 2- methyl,

1- Yue bases the third honeybees of -2- base, 2- methyl -2- acrylic, 1- pentenyls, 2- pentenyls, 3- pentenyls, 4- pentenyls, the small cyclobutenyl of 1- Yue bases, 2-methyl-1-butene alkenyl, 3-methyl-1-butene base, 1- Yue base -2- cyclobutenyls,

₂- Yue bases _₂_ cyclobutenyl,3- methyl-2-butene bases,1- Yue base -3- cyclobutenyls,2- Yue base -3- cyclobutenyls,3- Yue base -3- cyclobutenyls, 1,1- dimethyl -2- acrylic, 1 ,2- dimethyl -1- acrylic, 1,Yue base -2- the acrylic of 2- bis-,Ethyl -1- acrylic,1- ethyl -2- acrylic,1- hexenyls,2- hexenyls,3- hexenyls,4- hexenyls,5- hexenyls,1- methyl isophthalic acid-Wu Women bases,2- Yue base -1- pentenyls,3- methyl-1-pentene alkenyls,4- Yue base -1- pentenyls,1- Yue base -2- pentenyls,2- methyl -2- pentenyls,3- methyl -2- pentenyls,4- methyl -2- pentenyls,1- methyl -3- Wu Women bases,2- Yue base -3- pentenyls,3- methyl-3-pentenyls,4- methyl-3-pentenyls,1- Yue base -4- pentenyls,2- methyl -4- pentenyls,3- Yue base -4- pentenyls,The Xi bases of 4- Yue bases -4- penta, 1 ,1- dimethyl -2- cyclobutenyls, 1,1- dimethyl -3- cyclobutenyls, 1,Yue base -1- Ding Women the bases of 2- bis-, 1,2- dimethyl -2- cyclobutenyls, 1 ,2- dimethyl -3- cyclobutenyls, 1,3- dimethyl -1- cyclobutenyls, 1,3- dimethyl -2- cyclobutenyls, 1 ,Yue base -3- the cyclobutenyls of 3- bis-, 2,2- dimethyl -3- fourths Xi base, 2,The small butylene of 3- dimethyl Base, 2, Yue base -2- the cyclobutenyls of 3- bis-, 2, Yue base -3- the cyclobutenyls of 3- bis-, 3, 3- dimethyl -1- cyclobutenyls, 3, Yue base -2- fourths Xi the bases of 3- bis-, 1- ethyl -1- cyclobutenyls, 1- ethyl -2- cyclobutenyls, 1- ethyl -3- cyclobutenyls, 2- ethyl -1- cyclobutenyls, 2- ethyl -2- cyclobutenyls, 2- ethyl -3- cyclobutenyls, 1, 1, 2- trimethyl -2- acrylic, 1- ethyl -1- methyl -2- acrylic, 1- ethyl -2- Yue base -1- acrylic, 1- Ethyl-2-Methyl -2- acrylic, 1, 3- butadiene, 1, 3- pentadienes, 1, 4- pentadienes, 1, 4- hexadienes etc.；" the C₃_₆Cycloalkenyl group " the example includes but is not limited to such as cyclopropanyl, cyclobutane base, cyclopentenyl, 1,3- cyclopentadienyl groups, hexamethylene Xi base, 1,4- cyclohexadienyls.

In the present invention, term " alkynyl " refers to the alkyl for the straight or branched that the carbon number containing three keys is 3-6, including for example " (₂_₅Alkynyl ", " Cw alkynyls ", " C₂_₃Alkynyl " etc.；The example includes but is not limited to such as acetenyl, 2-propynyl, 2- butynyls, 3- butynyls, 1- Yue bases -2-propynyl, valerylene base, 3- pentynyls, 4- pentynyls, 1- methyl -2- butynyls, 1- Yue base -3- butynyls, 2- methyl -3- butynyls, 1, the Yue bases of 1- bis- -2-propynyl, 1- ethyls -2-propynyl, 2- hexin bases, 3- hexin bases, 4- hexin bases, 5- hexin bases, 1- methyl-valerylene base, 1- methyl -3- pentynyls, 1- Yue base -4- pentynyls, 2- methyl -3- pentynyls, 2- Yue base -4- pentynyls, 3- Yue base -4- pentynyls, 4- methyl-valerylene base, 1, 1- dimethyl -2- butynyls, 1, 1- dimethyl -3- butynyls, 1, Yue base -3- the butynyls of 2- bis-, 2, Yue base -3- the butynyls of 2- bis-, 1- ethyl -2- butynyls, 1- ethyl -3- butynyls, 2- ethyl -3- butynyls, small Yue bases -2-propynyl of 1- ethyls etc..

In the present invention, term " C_1-6Alkoxy " refers to " C_1-6Alkyl -0- " groups, wherein " Q_₆Alkyl " is as defined hereinabove, including such as " Cw alkoxies ", " CM alkoxies ", " Cw alkoxies "；The example includes but is not limited to such as Yue epoxides, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, amoxy, neopentyl oxygen, hexyloxy.

In the present invention, term " 3-14 members cycloalkyl " refers to the group of naphthene base with 3-14 carbon atom, including such as " 3-12 members cycloalkyl ", " 3-10 members cycloalkyl ", " 3-8 members cycloalkyl ", " 3-6 members cycloalkyl ", " 5-10 members cycloalkyl ", " 5-8 members cycloalkyl ", " 5-10 members cycloalkyl ", " 4-6 members cycloalkyl "；Also include " 3-8 unit monocycles cycloalkyl " and " 6-14 member condensed ring cycloalkyl ".

" the 3-8 unit monocycles cycloalkyl " refers to the monocyclic cycloalkyl with 3-8 carbon atom, including such as " 3-6 unit monocycles cycloalkyl ", " 5-8 unit monocycles cycloalkyl ", " 5-6 unit monocycles cycloalkyl "；The example includes but is not limited to：Cyclopropane base, cyclobutane base, the protective embankment base of ring penta, cyclohexyl, cycloheptyl alkyl, cyclooctane base etc.；It is described " 3-8 unit monocycle cycloalkyl, can also further be replaced by C alkyl, include but is not limited to：Yue basic rings propyl, dimethylcyclopropane base, methyl cyclobutane base, two Yue basic rings butane groups, Yue cyclopentanes base, dimethylcyclopentane base, Yue butylcyclohexanes base, two Yue butylcyclohexane bases etc..

" the 6-14 member condensed ring cycloalkyl " refers to the condensed ring and shares the condensed ring group of naphthene base that two adjacent carbon atoms are formed, " the 6-12 member condensed ring cycloalkanes including for example each other by two or more cyclic structures Base ", " 8-12 member condensed ring cycloalkyl ", " 7-10 member condensed ring cycloalkyl " etc.；The example includes but is not limited to：Two rings [3.1.0] hexyl, two rings [4.1.0] heptane base, two rings [2.2.0] hexyl, two rings [3.2.0] heptane base, two rings [4.2.0] octyl, octahydro indenyl, decahydronaphthalene naphthyl, ten tetrahydrochysene phenanthryl etc..

In the present invention, term " 6-14 members aryl " refers to the aromatic group with 6-14 carbon atom, including such as " 6-10 members aryl "；Also include " 6-8 unit monocycles aryl " and " 8-14 members fused ring aryl ".

It is described " 6-8 unit monocycle aryl, including such as phenyl.

" the 8-14 members fused ring aryl " refers to be shared that two adjacent carbon atoms are formed has the condensed ring group of 8-14 carbon atom and at least one ring for armaticity each other by two or more cyclic structures, including the fused ring aryl that the whole rings of 10-14 members are aromatic ring, such as naphthalene, phenanthrene.

In the present invention, term " 3-14 circle heterocycles alkyl " refers to containing 3-14 annular atom（Wherein at least contains a hetero atom）Cyclic group, including such as " 3-10 circle heterocycles alkyl ", " 4-12 circle heterocycles alkyl ", " 3-8 circle heterocycles alkyl ", " 5-10 circle heterocycles alkyl ", " 5-8 circle heterocycles alkyl ", " 5-6 circle heterocycles alkyl ", also include " 3-8 unit monocycles Heterocyclylalkyl " and " 6-14 member fused ring heterocycles alkyl ", described hetero atom has nitrogen, oxygen and sulphur etc., and annular atom is CH₂When can be by oxo.

" the 3-8 unit monocycles Heterocyclylalkyl ", refers to containing 3-8 annular atom（Wherein at least contains a hetero atom）Monocyclic heterocycloalkyl, including such as " 5-8 unit monocycles Heterocyclylalkyl ", " 5-6 unit monocycles Heterocyclylalkyl ", " 3-6 member saturations monocyclic heterocycloalkyl "；Its instantiation is included but are not limited to：Aziridine base, azetidinyl, Thietane base, tetrahydrofuran base, nafoxidine base, imidazolidinyl, pyrazolidinyl, tetrahydrofuran base, 1,4- dioxanes base, 1,3- dioxanes base, 1,3- dithians base, piperidyl, morpholinyl, piperazinyl etc.；Further, annular atom is CH₂When can be by oxo, such as piperidines -2- ketone.

" the 6-14 member fused ring heterocycles alkyl " refers to containing 6-14 annular atom（Wherein at least contains a hetero atom）Share two adjacent atoms each other by two or more cyclic structures and connect the fused ring heterocycle groups formed, including such as " 8-12 member fused ring heterocycles alkyl ", " 7-10 member fused ring heterocycles alkyl ", " 9-10 member fused ring heterocycles alkyl ", " 9-12 member fused ring heterocycle alkyl;, etc.；Its instantiation is included but are not limited to：Cyclobutane and nafoxidine base, pentamethylene and nafoxidine base, azetidine and imidazolidinyl etc..

" 5-14 unit's heteroaryls " of the present invention, its annular atom is in addition to carbon atom, in addition to one or more hetero atoms, " hetero atom " include but is not limited to oxygen atom, nitrogen-atoms and<Atom.Heteroaryl can be bonded by carbon or heteroatom.Including 5-8 unit monocycles heteroaryl and 8-14 member condensed hetero ring aryl.

" 5-8 unit monocycles heteroaryl " refer to armaticity contain heteroatomic cyclic group, including such as " 5-6 unit monocycles heteroaryl ", " 5-7 unit monocycles heteroaryl "；Its instantiation includes but are not limited to furyl, thiophene¹¹Point base, pyrrole radicals, imidazole radicals, thiazolyl, 1,2,3- thiadiazolyl groups, 1,2,4- thiadiazolyl groups, 1, 3, 4- thiadiazolyl groups, pyrazolyl, 1, 2, 3- triazolyls, 1, 2, 4- triazolyls, pyridine radicals, oxazolyl, isoxazolyl, isothiazolyl, 1, 2, 3- oxadiazolyls, 1, 2, 4- oxadiazolyls, 1, 2, the saliva bases of 5- Evil bis-, 1, 2, 3- triazine radicals, 1, 2, 4- triazine radicals, tetrazole radical, oxatriazole base, 2H-1, 2- oxazinyls, 4H-1, 2- oxazinyls, 6H-1, 2- oxazinyls, 2H-1, 3- oxazinyls, 4H-1, 3- oxazinyls, 611-1, 3- Evil bases, 2H-1, 4- oxazinyls, 4H-1, 4- oxazinyls, Yi oxazinyls, 1, 3, 5- triazine radicals, 1, 2, 4, 5- tetrazine bases, pyridazinyl, pyrimidine radicals and pyrrole are made an uproar base.

It is the condensed hetero ring group of armaticity ring that " the 8-14 member condensed hetero rings aryl ", which refers to whole rings, including such as " 8-12 member condensed hetero rings aryl ", " 9-10 member condensed hetero rings aryl ", " 10-14 member condensed hetero rings aryl ", such as the condensed hetero ring aryl of benzo 5-8 unit monocycles heteroaryl formation, 5-8 unit monocycles heteroaryl and the condensed hetero ring aryl of 5-8 unit monocycles heteroaryl formation etc., its instantiation includes but is not limited to：Benzofuranyl, benzisoxa furyl, benzo thiophene cry of certain animals base, indyl, benzoxazolyl, benzimidazolyl, indazolyl, BTA base, can drench base, it is different can quinoline base, pyrrole, fixed and pyrazolyl, pyrrole¹It is fixed and pyrrole Lip river base, phonetic¹It is fixed and pyrazolyl, phonetic¹Fixed and pyrrole radicals, p reach, the Qin and pyrazolyl,.The Qin and pyrrole radicals, a word used for translation¹⁷Determine base, phenanthridinyl, benzo to rattle away.Qin Ji, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, iso-indoles, isoindolyl, indolizine base, benzodiazine base, benzoisoxazole base, benzoxazinyl, pyrazolo [3,4-b] pyridine radicals etc..

In the present invention, term " 7-12 member bridged rings base " refers to that any two ring shares the aliphatic group containing 7-12 annular atom of two atom not being joined directly together formation, the annular atom with all carbon atoms or can contain hetero atom, and described hetero atom has nitrogen, oxygen and sulphur etc.." the 7-12 members bridged ring " includes " 7-12 member saturation bridged rings base " and " the unsaturated bridged ring base of 7-12 members ".

" the 7-12 member saturation bridged rings base ", it is the cyclic group of saturation to refer to all rings in the bridged ring,

" 7-10 member saturation bridged rings base ", " 7-8 member saturation bridged rings base " etc., its instantiation includes

It is described " the unsaturated bridged ring base of 7-12 members,, refer to there is at least one ring to be undersaturated cyclic group in the bridged ring base, including such as " the unsaturated bridged ring base of 7-10 members ", " the unsaturated bridged ring base of 7-8 members ", Its instantiation includes but is not limited to：

In the present invention, term " 7-12 member loop coils base " refers to that a class shares the aliphatic group containing 7-12 annular atom that an atom is formed by least two rings, the annular atom with all carbon atoms or can contain hetero atom, and described hetero atom is selected from nitrogen, oxygen and sulphur etc..Including such as " 7-11 member loop coils base ", " 8-11 member loop coils base ", " 9-10 member loop coils base ", also including " 7-12 member saturation loop coils base " and " the unsaturated loop coil base of 7-12 members ".

" the 7-12 member saturation loop coils base ", refers to that all rings in the loop coil base are saturated rings, including such as " 7-11 member saturation loop coils base ", " 8- ", " 9-10 members are full "

" the unsaturated loop coil base of 7-12 members ", refers to that at least one ring is undersaturated ring in the loop coil base, including such as " the unsaturated loop coil base of 7-11 members ", " the unsaturated loop coil base of 8-11 members ", " 9-10 members

In the present invention, hetero atom refers to 0, N, S, SO and SO:

The part of compounds of the present invention：

Structural formula structural formula

HZ

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

It

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OW

6£

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

The formula of 2 raw material of intermediate 3（I compound shown in)

(la) (lb)

Reactions steps

(1) raw material 1 and the third two eyeballs are mixed in absolute ethyl alcohol, add glacial acetic acid, heating, 30-100.C reacts 5-24 hours, reaction solution concentration, silica gel column chromatography (petroleum ether → petroleum ether:Ethyl acetate=1:0.5-2) obtain yellow solid；

(2) intermediate 1 is dissolved in tetrahydrofuran, nitrogen protection, Slow adds sodium hydride, 0-30 slowly.Stirred 10-120 minutes under C, add raw material 2,0-30.React 5-24 hours, add water under C, faintly acid is tuned into hydrochloric acid, separate out solid, filtering, filter cake washing, dry cake obtains solid, is directly used in next step；

(3) sodium hydride is added in A^V- dimethyl acetamides, add raw material 3,0-30 °C reaction 10-120 minute after add intermediate 2, be warming up to afterwards 50-150 °C reaction 3-15 hours, it is spin-dried for reaction solution, silica gel column chromatography (dichloromethane → dichloro Yue alkane:Yue alcohol=20:0.1- 5), obtain formula（I compound shown in).

X, Y, G, U, Z, W, L, R in upper reaction equation¹, R²With n as defined hereinabove, formula（I compound shown in) can be its isomers such as formula（I ＆) or（I b) shown in compound.If necessary, blocking group can be sloughed thereafter through conventional method with conventional protective agent to needing functional group to be protected to protect；If necessary, some compounds can also be prepared, for example the preparation of raw material 1.

Claimed formula（ I )、 （L a) or（L b) shown in compound " pharmaceutically acceptable salt,, including alkali metal salt, such as sodium salt, sylvite, lithium salts；Alkali salt, such as calcium salt, magnesium salts；Other metal salts, such as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt；Inorganic base salts, such as ammonium salt；Organic alkali salt, such as t-octyl amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N- Yue bases glucosamine salt, guanidinesalt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, Ν, Ν '-dibenzyl ethylenediamine salt, chloroprocanine salt, procaine salt, diethanolamine salt, Ν-benzyl-phenethyl amine salt, piperazine salt, four Yue bases amine salt, three (hydroxyl Yue yls) aminomethane salt；Halogen acid salt, Such as hydrofluoride, hydrochloride, hydrobromate, hydriodate；Inorganic acid salt, such as nitrate, perchlorate, sulfate, phosphate；The horizontal hydrochlorate of lower alkyl, such as mesylate, fluoroform sulphonate, esilate；Arylsulphonate, such as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt；Acylate, such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalates, maleate；Amino-acid salt, such as glycinate, trimethylglycine salt, arginine salt, ornithine salt, glutamate, aspartate.

Claimed formula（ I )、 （L a) or（L b) shown in compound " stereoisomer ", when there is one or more asymmetric carbon atoms in compound structure, enantiomter can be produced；When compound contains alkenyl or cyclic structure, cis/trans isomers can be produced；When compound there are ketone or oxime, dynamic isomer etc. can be produced.All these isomers and mixture all scope of the invention.

Formula（ I )、 （L a) or（L b) shown in compound, its pharmaceutically acceptable salt or its stereoisomer pharmaceutical preparation can be made with one or more pharmaceutical carriers.The pharmaceutical preparation refers to the conventional formulation clinically used, and can be applied in modes such as oral and parenteral administrations needs the patient of this treatment.Such as tablet, particle, glue Nang, powder, injection, inhalant, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, nasal cavity drop, eye drops, spray, preparation capable of permeating skin.These preparations can be added pharmaceutical carrier such as excipient, binder, humidizer, disintegrant, thickener etc. and be prepared from by conventional method.

Formula（ I )、 （L a) or（L b) shown in compound, its pharmaceutically acceptable salt or its stereoisomer can be used for treating and/or prevent ischemical reperfusion injury, diabetes, nerve retrograde affection, chronic inflammation, pulmonary fibrosis, liver fibrosis, the disease of fatty liver or hepatic sclerosis etc..

Chronic inflammation includes allergy, asthma, rheumatoid class arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, PVR, glaucoma.

Herein, abbreviation has following implications below：

HOAc:Acetic acid

THF:Tetrahydrofuran

DMA:N, N- bis- Jia Ji Yi Ugly amine

TLC:Thin-layer chromatography

DCM:Dichloromethane

MeOH:Methanol

DMSO:Dimethyl sulfoxide (DMSO)

Ac:Acetyl group

Me:Yue bases

PE:Petroleum ether EA:Ethyl acetate

HATU:2- (7- azos BTA)-N, N, N, N ,-four Yue base urea hexafluorophosphoric acid esters

TBS:The Yue base silicon substrates of the tert-butyl group two

TBSC1:Tert-butyl chloro-silicane

DIPEA:DIPEA

Boc:Tertbutyloxycarbonyl

Hepes:4- hydroxyethyl piperazineethanesulfonic acids

Brij-35:Brij-35

DTT:Two ^ Τ υ threitols

FAM:Fluoresceincarboxylic acid

ΑΤΡ:Atriphos

ALT:Glutamic-pyruvic transaminase

AST:Glutamic-oxalacetic transaminease

The beneficial effect of the compounds of this invention is expanded on further below by way of the external the enzyme activity of the compounds of this invention, other compounds of the invention have identical beneficial effect with the compounds of this invention cited in experiment, but this should not be interpreted as to the compounds of this invention only with following beneficial effect.

The external pharmacological activity of the compounds of this invention of experimental example 1

Test sample：Part of compounds of the present invention, is prepared according to embodiment method；Comparison medicine AS-602801, self-control.

Experimental method：Zymetology tests (enzyme assay)

Caliper Mobility- Shift J K2 Assay:

It is accurate to weigh test sample, DMSO dissolvings are added, fully mixes, is made into 10 mM.50 times of final concentrations are diluted to DMSO.Ι Ο Ο μ Ι compounds are shifted into % orifice plates, 3 times is carried out and is serially diluted, totally 10 concentration.Shift Ι Ο μ Ι compounds and 90ul kinases Slow fliud flushings are added per hole into 96 new orifice plates, then to 96 orifice plate（ 50mM Hepes pH 7.5, 10 mM MgCl₂, 0.0015% Brij-35, 2mM DTT ) .The final concentration of compound is 10 μ Μ to the maximum.After transferase 45 ul is into 384 orifice plates, add the kinases Slow fliud flushings that Ι Ο μ Ι include JNK2, it is incubated at room temperature after 30min, add the peptide Slow fliud flushings that Ι Ο μ Ι include FAM-labeled peptide and ATP, 28 °C are incubated after special time, add 25 μ 1 terminate liquid, terminating reaction.Detection substrate and product is separated by electrophoresis, Caliper's Reviewer softwares calculate conversion ratio, inhibiting rate is calculated by below equation, inhibiting rate calculates IC with Prism 5.0₅Q values.

Inhibiting rate=[conversion ratio (ZPE)-conversion ratio (sample)] χ 100/ [conversion ratio (ZPE)-conversion ratio (HPE)] notes： ΗΡΕ:Not enzyme-added blank control； ΖΡΕ:It is not added with the blank control of compound.

Experimental result and conclusion： IC of the compounds of this invention of table 1 to JNK2₅₀Value

Compound JNK2 zymetology inhibitory activity IC₅Q ( nM )

AS-602801 320

Compound 1 177

Compound 2 309

Conclusion：From table 1, the compounds of this invention has a certain degree of inhibitory activity to JNK2 enzymes.The external pharmacological activity of the compounds of this invention of experimental example 2

Test sample：Part of compounds of the present invention, is prepared according to embodiment method；Comparison medicine AS-602801, makes by oneself according to WO2003047570 method.

Experimental method：It is liquor-saturated to learn experiment（enzyme assay )

(homogeneous phase time discrimination fluorescence technology determines the activity experiment of JNK2 enzymes to HTRF JNK2 Assay）：This experiment uses HTRF methods（Cisbio inhibitory activity of the compound to JNK2) is determined.It is accurate to weigh test sample, DMSO dissolvings are added, fully mixes, is made into 10 mM.50 times of final concentrations are diluted to DMSO.The compounds of 30 μ 1 are shifted into 96 orifice plates, 4 times is carried out and is serially diluted, totally 7 concentration.Take 2 μ 1 to be transferred to containing in the Kinase buffer of 38 μ 1 respectively again, obtain final concentration and be to the maximum

25 μ Μ working solution.The compound is added in 384 orifice plates respectively, per the μ 1 of hole 4.Adding concentration is

The 0.04n^l μ 1 of JNK2 kinases 2, is incubated after lOmin, adds ATP and substrate A TF-2 (Cell

Signaling) the μ 1 of mixed liquor 4.25 °C are incubated after 30min, add Anti-GST-XL665 monoclonal antibodies（) and anti-phospho ATF2 Antibody-Cryptate (Cisbio) mixed liquor Cisbio.25 °C are incubated after lh, detect fluorescent value of the sample at 615nm and 665nm respectively with ELIASA.Data processing is as follows：

Ratio=(665nm fluorescent values/615nm fluorescent values) θ⁴

,, Ratio (Positive)-Ratio (Sample)

% inhibiting rates=----^---- xl 00%

Ratio ( Positive ) -Ratio ( negative )

STDEV ( Positive ) +STDEV ( negative )

Z'=l-3x

AVERAGE ( Positive ) - AVERAGE ( negative )

Carried out curve fitting using the softwares of GraphPad 5.0, fit equation is

Y=Bottom + (Top-Bottom)/(l+10^A((LogIC₅₀- X) * HillSlope)), draw IC₅₀Value ' the compounds of this invention of table 2 is to JNK2 IC₅O values

Compound

AS-602801 995

Compound 3 539 Compound 5 275

Compound 29 214

Compound 31 881

Compound 93 844

Compound 89 358

Compound 119 231

Compound 217 527.6

Compound 222 810.8

Conclusion：From table 2, there is the compounds of this invention preferable inhibitory activity to be better than comparison medicine AS-602801 to JNK2.

The Rats pharmacokinetics feature of the compounds of this invention of experimental example 3

Test sample：Part of compounds of the present invention, is prepared according to embodiment method

Real face method：PK tests (in vivo PK evaluation in rats) in rat body

1. zoopery

Normal SD rats, intravenous injection administration (iv) and gastric infusion (po), 3/method of administration.Test sample dosage is respectively 2 mg/kg and 4 mg/kg, and administration concentration is all 1 mg/ml, and administered volume is respectively 2 ml/kg and 4 ml/kg.Iv (intravenous injections）The SD rats of administration, in 0.083h after administration, 0.25h, 0.5h, lh, 2h, 4h, 6h, 8h, 24h is by tail vein blood；Po is (oral）The SD rats of administration, in 0.17h after administration, 0.5h, lh, 2h, 4h, 6h, 8h, 24h is by tail vein blood.Resulting whole blood is placed in heparinised tubes.Low-speed centrifugal（3500 revs/min）Separated plasma after 8 min, 4.C is kept in dark place.Wait after the completion of testing, all blood plasma samples are placed in -70.C refrigerators are preserved.

2. sample analysis

From water tank（- 70 °C) in take out testing sample, room temperature is vortexed 3 min after melting naturally.Precision pipettes 20 μ samples into 1.5 ml centrifuge tubes.Add 200 μ containing the internal standard solution（AS-602801 50ng/ml Yue alcoholic solutions）It is vortexed after 3 min, centrifuges (12000 revs/min of 5 min）.Precision pipettes 50 μ supernatants and adds the water of 150 μ 1, and the laggard LC-MS/MS systems of 3 min that are vortexed carry out sample analysis.Tested material concentration uses the Analyst 1.6.1 output results of AB companies.Microsoft Excel calculate the parameters such as average, standard deviation, the coefficient of variation（Analyst 1.6.1 directly export without calculate）, PK parameters are using the non-compartment model of the softwares of Pharsight Phoenix 6.2 (NCA) calculating. 3. experimental result

PK parameter of the compounds of this invention of table 3 in rat body is summarized

tl/2_iv (h)/ AUC_inflv(h*ng/ml)/

Compound F%

tl/2_po (h) AUC_infpo(h*ng/ml)

1.19 ± 0.12 2422 scholars 310

AS-602801 68±12

1.32 ± 0.55 3277 scholars 603

1.08±0.10 5305±357

Compound 5 78 ± 42

2.97 ± 1.16 8228 scholars 4424

6.75 ± 4.88 11411 scholars 1155

Compound 29 119 ± 56

4.17±0.67 26345±12318

2.65±0.97 6230±1162

Compound 89 83 ± 14

8.17±1.24

3.52 ± 0.16 11986 scholars 1525

Compound 93 109 ± 18

3.00±0.18

3.27 ± 0.60 100340 scholars 16494

Compound 217 97 ± 7

2.75±0.23

2.30±0.56 11893±4267

Compound 218 100 ± 21

4.95 scholar 1.65

Remarks：Tl/2 is half-life period, and AUC is exposed amount, and F% is bioavilability.

The half-life period of the compounds of this invention 5 is when iv is administered, half-life period is suitable with AS-602801, and when po is administered, half-life period is AS-602801 more than twice, the exposed amount and bioavilability of the compounds of this invention 5 are better than AS-602801, half-life period, exposed amount and the bioavilability army of the compounds of this invention 29 are better than AS-602801, therefore the compounds of this invention is compared in terms of PK with stronger advantage with AS-602801.

The internal pharmacological activity of the compounds of this invention of experimental example 4

Test sample：Part of compounds of the present invention, is prepared according to embodiment method

Experimental method：The oxyhepatitis model of canavaline induction

C57BL/6 mouse are randomly divided into model group and each administration group after SPF grades of Animal Houses are adapted to 1 week according to body weight；Is marked before experiment in mouse tail using marking pen, and marks in cage tool test number, group and date of test；Model group animal is given after solvent 30min（10ml/kg), tail vein gives canavaline（Concanavalin A, ConA, 15mg/kg)；Tail vein gives same dose ConA after each administration group administration 30min, gives after ConA 7h, mouse is anaesthetized by yellow Jackets（Intraperitoneal injection 45mg/kg), intraocular corner of the eyes venous sinus takes blood 30, and (^1 (SOP-DS-200024-A), is placed in 1.5ml and is not added with the centrifuge tube of anti-coagulants, be stored at room temperature lh, blood sample uses eppendorf 5424R centrifuges Centrifugal condition is 3500rpm, and 4 °C, lOmin extracts serum afterwards, and wherein Ι Ο Ο μ Ι serum determines ALT and AST content, remaining serum keeping to -80 °C of refrigerators using automatic clinical chemistry analyzer.

Mouse Serum ALT and AST inhibitory action in the oxyhepatitis model that the compound of table 4 is induced ConA

Compound ALT 7h are reduced⁰ /₀AST 7h are reduced⁰ /₀

The conclusion of 59 67 compounds of AS-602801 119 79 74:The compounds of this invention can significantly reduce oxyhepatitis model mouse ALT and AST level, and effect is better than AS-602801.

The embodiment of form, is described in further detail to the above of the invention by the following examples.But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following examples.All technologies realized based on the above of the present invention belong to the scope of the present invention.Embodiment 1:(thiazole is simultaneously by -2- by 2- (2- (4- (morpholinomethyl) benzyloxy) pyrimidine-4-yl)【5,4-W pyridine -2- bases) acetonitrile（Compound 1) preparation

(1) 2- (thiazole simultaneously [5,4-] pyridine -2- bases）The preparation of acetonitrile

In dry round-bottomed flask, it is separately added into 10 mL ethanol, 1.26 g (10 mmol) dredge alcohol than pyridine -1-, 660 mg (10 mmol) malononitrile, 720 mg (12 mmol) glacial acetic acid, heating reflux reaction 15 h, TLC monitoring reaction terminates.It is spin-dried for solvent, column chromatography（DCM:MeOH=500:L), the g of yellow solid 1.01, yield 57.7% are obtained.

- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）The preparation of acetonitrile

In dry reaction bulb, 20 mL THF, 1.01 g (5.77 mmol) 2- (thiazole simultaneously [5,4-) are separately added into] pyridine -2- bases）Acetonitrile, 346 mg (8.66 mmol) 60% NaH, 860 mg (5.77 mmol) 2,4- dichloro pyrimidines, react 15 h at room temperature.Add frozen water to be quenched, add watery hydrochloric acid and adjust to faintly acid, separate out solid, suction filtration washs filter cake with water, Yue alcohol, ethyl acetate respectively, dry, obtain the mg of yellow solid 860, yield 51.8%.

(3) 2- (2- (4- (morpholino Yue yls) benzyloxy) pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases) acetonitrile

1.24 g (6 mmol) 4- (morpholino Yue yls) benzylalcohol is dissolved in 20 mL DMA, add 480 mg (12 mmol) 60% NaH, 1 h is stirred at room temperature, add 860 mg (2.99 mmol) 2- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）Acetonitrile, is heated to 100 °C of 15 h of reaction.Reaction solution is poured into water water, watery hydrochloric acid is added and adjusts to acidity, solid crude product, suction filtration, column chromatography purifying is separated out（DCM:MeOH=20:L), the mg of yellow solid 600, yield 43.8% are obtained.

Molecular formula： C₂₄H₂₂N₆0₂S;Molecular weight： 458.15;Mass spectrum (M+H): 458.9

400 MHz):δ 11.70 (IH, br s), 8.29 (IH, d), 7.99 (1H, d)_:7.79 (IH, d), 7.59 (2H, d), 7.50 (2H, d), 7.37 (IH, dd), 6.64 (IH, m), 5.70 (2H, s), 4.15-3.93 (2H, m), 3.77-3.62 (4H, m), 2.93-2.77 (4H, m).

Embodiment 2:2- (2- (4- (morpholino Yue yls) benzyloxy) pyrimidine-4-yl) -2- (thiazoles simultaneously [4,5-c】Pyridine -2- bases)

The preparation of 3- aminopyridine -4- mercaptan

Weigh chloro- 3- nitropyridines (4.74 g of 4-, 30.0 mmol) with NaHS (5.04 g, 90.0 mmol) it is dissolved in 300 mL ethanol solutions, stirring reaction 1 hour at room temperature, take a policy powder (sodium dithionite) (15.66 g afterwards, 90.0 mmol) the mL of aqueous solution 100,80 °C are warming up to react 12 hours, filtering, filtrate concentrates, silica gel column chromatography (petroleum ether → petroleum ether:Ethyl acetate=3:1) obtain yellowish green The g of color solid 3.3, yield 87%.

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

3- J^ are mixed in 150 mL absolute ethyl alcohols than pyridine -4- mercaptan (2.52 g, 20.0 mmol) and the third two eyeballs (1.32 g, 20.0 mmol), 2.0 mL glacial acetic acids is added, is warming up to 80.C reacts 12 hours, reaction solution concentration, silica gel column chromatography (Shi You Mi → petroleum ether:Ethyl acetate=1:1) g of yellow solid 2.6, yield 74% are obtained.

The preparation of-(2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [4,5-c] pyridine -2- bases) acetonitrile

Weigh 2- (thiazole simultaneously [4,5-c] pyridine -2- bases）Acetonitrile (1.75 g; 10.0 mmol) it is dissolved in the tetrahydrofuran of 15 mL dryings; nitrogen is protected, and Slow adds sodium hydride (60%, 0.8 g slowly; 20 mmol); stir at room temperature half an hour, 2,4- dichloro pyrimidines (1.49 g are added afterwards; 10.0 mmol); react 12 hours at room temperature, add water, faintly acid is tuned into 1N hydrochloric acid; separate out solid; filtering, filter cake washing, dry cake; the g of solid 3.0 is obtained, next step is directly used in.

(4) 2- (2- (4- (morpholinomethyl) benzyloxy) pyrimidine-4-yl) -2- (thiazole simultaneously [4,5-c] pyridine -2- bases) acetonitrile

Weigh sodium hydride (60%, 0.4 g, 10 mmol) it is added in 5 mL A^N- dimethyl acetamides, add 4- (morpholino Yue yls) benzylalcohol (1.04 g, 5.0 mmol), room temperature reaction adds 2- (2- chlorine pyrimidine -4- bases) -2- (thiazole simultaneously [4,5-c] pyridine -2- bases) acetonitrile (0.719 g after 1 hour, 2.5 mmol), 100 are warming up to afterwards.C reacts 8 hours, is spin-dried for reaction solution, silica gel column chromatography (dichloromethane → dichloromethane:Methanol=20:1) g of product 0.6, yield 52.4%, are obtained.

Molecular formula： C₂₄H₂₂N₆0₂S;Molecular weight： 458.15;Mass spectrum (M+H): 458.9

^-NMRiDMSO-^, 400 MHz):δ 8.89 (1 Η, s), 8.22 (1H, m), 7.99 (1H, m), 7.84 (1H, m), 7.55 (2H, d), 7.42 (2H, d), 6.63 (1H, m), 5.61 (2H, s), 3.81 (2H, s), 3.67-3.58 (4H, m), 2.72-2.58 (4H, m).

Embodiment 3:((thiazole is simultaneously by -2- by 2- (4- ((2,6- bis- Yue bases morpholino) Yue yls) benzyl pyrimidine-4-yl) by 2-【5,4-W pyridine -2- bases）Acetonitrile（Compound 3) preparation

- two Yue bases morpholinoes) methyl) benzene Yue acid Yue esters preparation

In dry reaction bulb, 30mL methanol, the Yue base morpholines of 576 mg (5.0 mmol) 2,6- bis-, 2.46 g (15 mmol) p formylbenzoic acid Yue esters, lmL glacial acetic acids, 40 °C of reaction 18h are separately added into.Slow adds 4.24 g (20 mmol) sodium triacetoxy borohydride slowly again, continues to react 10 h.It is spin-dried for solvent, column chromatography (PE:EA=10:1-5:1) the g white solids of crude product 1.9, are obtained.

Methyl morpholine generation) Yue yls) phenyl) and Yue alcohol preparation

The 1.9 g crude products that upper step is obtained are dissolved in 40 mL tetrahydrofurans, and 760 mg (20 mmol) Lithium Aluminium Hydride is added portionwise in Slow slowly, react at room temperature 1 h.Add aqueous ammonium chloride solution to be quenched, suction filtered through kieselguhr, Yue alcohol washing filter cake is spin-dried for filtrate, preparative liquid chromatography purifying（Methanol:Water=50:50w/w) obtain the mg of white solid 700, the step yield 59.5% of the above two.

(3) 2- (2- (4- ((the Yue base morpholinoes of 2,6- bis-）Yue yls) benzyloxy) pyrimidine-4-yl) -2- (thiazole simultaneously [5,⁴-

By 470 mg (2 mmol) (4- ((2,6- thebaine generations) Yue yls) phenyl) Yue alcohol is dissolved in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, 1 h is stirred at room temperature, add 288 mg (1 mmol) 2- (2- chlorine pyrimidine-4-yl) -2- (thiazoles simultaneously [5,4-] pyridine -2- bases）Acetonitrile, Ν₂Protection, 100 °C of 18 h of reaction.Add water, neutrality is adjusted to watery hydrochloric acid, the extraction of dichloro Yue alkane is washed, dries, be spin-dried for, column chromatography（DCM→DCM:MeOH=100:L), the mg of yellow solid 140 is obtained, is dissolved in 4mL dichloromethane, Slow adds 8mL ether slowly, solid is separated out, centrifugation obtains yellow solid 40mg, yield 8.2%

Molecular formula： C₂₆H₂₆N₆0₂S;Molecular weight： 486.2;Matter praseodymium (M+H): 486.9 'H-NM CDMSO-^, 400 MHz):δ 8.25 (IH, d), 7.95 (1H, d), 7.80 (IH, d), 7.55 (2H, d), 7.42 (2H, d), 7.34 (1H, dd), 6.63 (IH, s), 5.66 (2H, s), 3.80 (2H, s), 3.68-3.55 (2H, m), 2.94-2.83 (2H, m), 2.15-1.98 (2H, m), 1.02 (6H, d).

Embodiment 4:((thiazole is simultaneously by -2- by 2- (4- (piperidin-1-yl methyl) benzyl pyrimidine-4-yl) by 2-【5,4-6】Pyridine -2-

(1) preparation of 4- (piperidin-1-yl methyl) methyl benzoate

In the reaction bulb that ^CQzMe is dried, 30 mL Yue alcohol, 852 mg (10 mmol) piperidines, 1.64 g (lO mmol) p formylbenzoic acid methyl esters, I mL glacial acetic acids, 40 °C of 18 h of reaction are separately added into.Slow adds 2.54 g (12 mmol) sodium triacetoxy borohydride slowly again, continues to react 10 h.It is spin-dried for, column chromatography (PE:EA=5:1 → 100%EA), obtain the g white solids of crude product 1.4.

(2) preparation of (4- (the small ylmethyl of piperidines) phenyl) methanol

The 1.4 g crude products that upper step is obtained are dissolved in 40 mL tetrahydrofurans, and 600 mg (15.8 mmol) Lithium Aluminium Hydride is added portionwise in Slow slowly, react at room temperature 1 h.Add aqueous ammonium chloride solution to be quenched, suction filtered through kieselguhr, Yue alcohol washing filter cake is spin-dried for filtrate, preparative liquid chromatography purifying（Methanol：Water=50:50w/w) obtain the mg of white solid 850, the step yield 41.4% of the above two.

(3) 2- (2- (4- (piperidin-1-yl Yue yls) benzyloxy) pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases)

410 mg (2 mmol) (4- (piperidin-1-yl methyl) phenyl) Yue alcohol is dissolved in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, 1 h is stirred at room temperature, add 288 mg (1 mmol) 2- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）Acetonitrile, N₂Protection, 100 °C of 18 h of reaction.Add water, neutrality, suction filtration, dry cake, column chromatography are adjusted to watery hydrochloric acid ( DCM→DCM:MeOH=10:L), the mg of yellow solid 220, yield 48.2% are obtained.

Molecular formula： C₂₅H₂₄N₆OS;Molecular weight： 456.2;Mass spectrum (M+H 456.9

^- MR (DMSO-i 6+D₂0, 400 MHz):δ 8.32 (IH, d), 8.03 (1H, d), 7.73 (IH, d), 7.62 (2H, d), 7.54 (2H, d), 7.40 (IH, dd), 6.66 (IH, d), 5.75 (2H, s), 4.24 (2H, s), 3.30-3.20 (2H, m), 2.88-2.76 (2H, m), 1.82-1.47 (4H, m), 1.35-1.21 (2H, m).

Embodiment 5:(thiazole is simultaneously by -2- by 2- (2- (4- ((2- oxo-pyrrolidine -1- bases) methyl) benzyloxy) pyrimidine-4-yl)

[5,4- -2- bases) acetonitrile（Compound 29) preparation

The preparation of-((2- oxo-pyrrolidine -1- bases) Yue yls) benzoic acid Yue esters

By pyrrolidones（1.7 g, 20 mmol), in the DMA for being added to 10 mL, 60% NaH (800 mg, 20 mmol) is added, 1 h is stirred at room temperature, is added to bromomethyl-benzoic acid methyl ester（2.28 g, 9.95 mmol), react at room temperature 3 h.System is poured into 100 mL water, watery hydrochloric acid is neutralized to neutrality, ethyl acetate is extracted three times, is washed, and is dried, is spin-dried for, column chromatography（PE:EA=5:1→1:2) g of product 1.11, yield, are obtained： 47.8%.

The preparation of-(4- (hydroxyl Yue yls) benzyl) pyrrolidin-2-one

By 4- ((2- oxo-pyrrolidine -1- bases) methyl) benzene Yue acid Yue esters（1.11 g, 4.76 mmol) it is added in 10 mL THF, the mL of Lithium Aluminium Hydride 1.9 that -25 °C of lower Slow ' ft instill 2.5 mol/L reacts 3 h.It is sufficiently stirred for after instilling 180 mg water, 180 mg 10% NaOH solution to system, suction filtration, filtrate is spin-dried for, preparative liquid chromatography purifying（Methanol：Water=50:50w/w) obtain the mg of product 230, yield： 23.5%.

(3) 2- (2- (4- ((2- oxo-pyrrolidine -1- bases）Yue yls) benzyloxy) pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-] pyridine -2- bases）The preparation of acetonitrile

By l- (4- (hydroxyl Yue yls) benzyl) pyrrolidin-2-one (230 mg, 1.12 mmol) it is dissolved in 2 mL DMA, add 60% NaH (90 mg, 2.25 mmol), finish, 2 h are stirred at room temperature.Again by 2- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）Acetonitrile（161 mg, 0.56 mmol) add, N₂100 °C of 16 h of reaction are warming up under protection.System is poured into water, watery hydrochloric acid adjusts pH to neutrality, and system is spin-dried for, preparative liquid chromatography purifying（Methanol：Water=60:40w/w) obtain the mg of product 40, yield： 15.6%.

Molecular formula： C₂₄H₂₀N₆O₂S;Molecular weight： 456.14;Mass spectrum (M+H): 457.1

^]H-NMR (OMSO-d₆, 400 MHz):δ 8.19 (1 Η, d), 7.87 (1H, d), 7.82 (1H, d),

7.50 (2H, d), 7.30 (1H, dd), 7.25 (2H, d), 6.59 (1H, m), 5.58 (2H, s), 4.36 (2H, s),

3.20 (2H, t), 2.27 (2H, t), 1.89 (2H, t).

The 2- of embodiment 6 (2- (4- ((1-pyrazol-1-yls）Yue yls) benzyloxy) pyrimidine-4-yl) (thiazole is simultaneously by -2-

【5,4- -2- bases）Acetonitrile（Compound 31) preparation

The preparation of-((the small base of 1//- pyrazoles) Yue yls) benzoic acid Yue esters

Will be to bromine Yue yl benzoic acid Yue esters（3.42 g, 14.9 mmol), pyrazoles（2.04 g, 30 mmol), potassium carbonate (4.14 g, 30 mmol) is added separately in 30 mL DMA, 50 °C of 16 h of reaction.System is poured into 100 mL water, ethyl acetate is extracted three times, washed, dried, be spin-dried for, column chromatography (PE:EA=5: 1→1 :1) g of product 2.5, yield, are obtained： 77.9%.

- ((li7- pyrazol-1-yls) methyl) phenyl) methanol preparation

By 4- ((1/-pyrazol-1-yl) Yue yls) benzoic acid Yue esters (2.16 g, 9.99 mmol) it is added in 20 mL THF, the graceful addition Lithium Aluminium Hydrides of Slow ' I " (0.76 g, 20 mmol) react at room temperature 3 h.0.76 g water is instilled to system, 0.76 mL 10%NaOH solution is sufficiently stirred for, suction filtration, filter cake is washed twice with THF, and filtrate is spin-dried for, column chromatography（PE:EA=5:1 → 100%EA), obtain the g of product 1.03, yield： 54.8%.

(3) 2- (2- (4- ((1-pyrazol-1-yl) Yue yls) benzyloxy) pyrimidine-4-yl)-2- (thiazole simultaneously [5,4-6] pyrroles Pyridine -2-

By (4- ((1/-pyrazol-1-yl) methyl) phenyl) methanol（188 mg, 1 mmol) it is dissolved in 2 mL DMA, 60% NaH (80 mg, 2 mmol) is added, finishes, 2 h is stirred at room temperature.Again by 2- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-] pyridine -2- bases）Acetonitrile（144 mg, 0.5 mmol) add, N₂100 °C of 16 h of reaction are warming up under protection.System is poured into water, watery hydrochloric acid adjusts pH to neutrality, and system is spin-dried for, preparative liquid chromatography purifying（Yue alcohol：Water=60:40 w/w) obtain the mg of product 20, yield： 9.1%.

Molecular formula： C₂₃H₁₇N₇OS;Molecular weight： 439.12;Mass spectrum (M+H): 440.1

^-NMR (DMSO- 400 MHz):δ 12.82 (1H, s), 8.34 (1 Η, d), 8.06 (IH, d),

7.81 (1H, d), 7.74 (1H, m), 7.53 (2H, d), 7.45 (IH, dd), 7.41 (IH, dd), 7.25 (2H, d)

6.63 (1H, d), 6.26 (1H, t), 5.68 (2H, s), 5.35 (2H, s).

Embodiment 7:(thiazole is simultaneously by -2- by 2- (2- (4- ethyls benzyloxy) pyrimidine-4-yl)【5,4-b】Pyridine -2- bases) acetonitrile (compound 37) preparation

By 272 mg, (2 mmol H- ethyl benzylalcohols are dissolved in 10 ml DMA, add 160 mg (4 mmol) 60% NaH, 1 h is stirred at room temperature, add 288 mg (1 mmol) 2- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）Acetonitrile, N₂Protection, 100 °C of 18 h of reaction.Add water, faintly acid, suction filtration, dry cake, the further column chromatography of filter cake are adjusted to watery hydrochloric acid（DCM--DCM:MeOH=500:L), obtain the mg of yellow solid 240, yield 61.9%.

Molecular formula： C₂₁H₁₇N₅OS;Molecular weight： 387.12;Mass spectrum (M+H): 388.1

Beautiful R (DMSO-i₆, 400 MHz):δ 12.83 (IH, s), 8.37 (1H, dd), 8.11 (IH, d), 7.69 (1H, s), 7.49 (2H, d), 7.43 (IH, dd), 7.27 (2H, d), 6.64 (IH, d), 5.70 (2H, s), 2.61 (2H, q), 1.17 (3H, t).

Embodiment 8:2- (2- (cyclohexyl methoxy) pyrimidine-4-yl) -2- (thiazole simultaneously " 5,4-bl pyridine -2- bases）Acetonitrile（Compound 89) preparation

228 mg (2 mmol) hexahydrobenzyl alcohol is dissolved in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, 1 h is stirred at room temperature, add 288 mg (1 mmol) 2- (2- chlorine pyrimidine -4- bases) -2- (thiazoles simultaneously [5,4->] pyridine -2- bases) acetonitrile, N₂Protection, 100 °C of 18 h of reaction.Add water, faintly acid is adjusted to watery hydrochloric acid, the extraction of dichloro Yue alkane is washed, dries, be spin-dried for, column chromatography (DCM → DCM:MeOH=500:L), obtain the mg of yellow solid 210, yield 57.5%.

Molecular formula： C₁₉H₁₉N₅OS;Molecular weight： 365.13;Matter is said (M+H): 366.1

'H-NMRiDMSO-^, 400 MHz):δ 12.77 (IH, s), 8.37 (1H, d), 8.09 (IH, d), 7.68 (1H, s), 7.43 (1H, dd), 6.60 (IH, d), 4.50 (2H, d), 1.92-1.79 (3H, m), 1.77-1.59 (4H, m), 1.32-1.05 (4H, m).

Embodiment 9:(thiazole is simultaneously by -2- by 2- (2- ((pyrans -4- of tetrahydrochysene -2 bases) Yue epoxides) pyrimidine-4-yl)【5,4-b】Pyridine -2- acetonitriles（Compound 93) preparation

228 mg (2 mmol) (tetrahydrochysene-2-pyrans-4- bases) Yue alcohol is dissolved in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, 1 h is stirred at room temperature, add 288 mg (1 mmol) 2- (2- chlorine pyrimidine-4-yl)-2- (thiazole simultaneously [5,4-6] pyridine-2- bases）Acetonitrile, N₂Protection, 100 °C of 18 h of reaction.Add water, faintly acid is adjusted to watery hydrochloric acid, dichloro Yue alkane extraction, washing is dried organic phase, is spin-dried for, column chromatography (DCM → DCM:MeOH=100:L), yellow solid 230 mg, yield 62.6%. are obtained

Molecular formula C₁₈H₁₇N₅0₂S;Molecular weight： 367.11 ;Mass spectrum (M+H): 368.1

^- MRiCDCls, 400 MHz):δ 14.55 (IH, s), 8.44 (IH, dd), 7.98-7.90 (2H, m), 7.37 (1H, dd), 6.81 (IH, d), 4.35 (2H, d), 4.06 (2H, dd), 3.53-3.42 (2H, m), 2.26-2.11 (lH, m), 1.81-1.72 (2H, m), 1.56-1.45 (2H, m).

Embodiment 10:2- (5- methylthiazols simultaneously [5,4-6] pyridine -2- bases) -2- (2- (4- (morpholinomethyl) benzyl lJ pyrimidine 4- yls) acetonitriles（Compound 119) preparation

(1) preparation of 3- amino -6- Yue yl pyridines -2- mercaptan

'ΝΗ₂

SH

Weigh chloro- 6- Yue bases -3- nitropyridines (6.90 g of 2-, 40.0 mmol) and NaHS (6.61 g, 0.12 mol) it is dissolved in 500 mL ethanol solutions, stirring reaction 1 hour, the mL of aqueous solution 150 of the powder that takes a policy afterwards (20.89 g, 0.12 mol) at room temperature, 80 °C are warming up to react 12 hours, filtering, filtrate concentration, silica gel column chromatography (100% petroleum ether → petroleum ether：Ethyl acetate=2:1) g of yellow solid 1.95, yield 34.8% are obtained.

(2) 2- (5- methylthiazols simultaneously [5,4-6] pyridine -2- bases）The preparation of acetonitrile

.CN 3- amino -6- Yue yl pyridines -2- mercaptan (1.95 g, 13.9 mmol) and the third two eyeballs (0.92 g, 13.9 mmol) are mixed in 50 mL absolute methanols, add 20 mL glacial acetic acids, be warming up to 90.C is reacted 12 hours, and reaction solution is concentrated, and ethyl acetate dissolving, saturated sodium bicarbonate solution, saturated nacl aqueous solution are washed once respectively, have mesh to dry, be concentrated to give the g of yellow solid 1.45, yield 55.1%.

- (2- chlorine pyrimidine-4-yl) -2- (5- Yue bases thiazoles simultaneously [5,4->] pyridine -2- bases) and acetonitrile preparation

Weigh 2- (5- methylthiazols simultaneously [5,4-6] pyridine -2- bases）Acetonitrile (1.45 g; 7.66 mmol) it is dissolved in the tetrahydrofuran of 20 mL dryings; nitrogen is protected, and Slow adds sodium hydride (60%, 0.612 g slowly; 15.3 mmol); stir at room temperature half an hour, 2,4- dichloro pyrimidines (1.141 g are added afterwards; 7.66 mmol); react 12 hours at room temperature, add water, faintly acid is tuned into 1N hydrochloric acid; separate out solid; filtering, filter cake washing, dry cake; obtain the g of yellow solid 2.3, yield： 99.5%.

(4) preparation of 2- (5- methylthiazols simultaneously [5,4-6] pyridine -2- bases) -2- (2- (4- (morpholinomethyl) benzyloxy) pyrimidine-4-yl) acetonitrile

Weigh sodium hydride (60%, 0.2 g, 5.0 mmol) it is added in the Yue yl acetamides of 5 mL A^V- bis-, add 4- (morpholinomethyl) benzylalcohol (0.52 g, 2.51 mmol), room temperature reaction adds 2- (2- chlorine pyrimidine-4-yl) -2- (5- methylthiazols simultaneously [5,4- after 1 hour>] pyridine -2- bases）Acetonitrile (0.377 g, 1.25 mmol), is warming up to 100 °C and reacts 8 hours, be spin-dried for reaction solution, silica gel column chromatography (dichloro Yue alkane → dichloro Yue alkane afterwards:Yue alcohol=20:1) g of product 0.32, yield 54.2%, are obtained.

Molecular formula： C₂₅H₂₄N₆0₂S;Molecular weight： 472.17;Matter language (M+H): 473.2

^-NMR (CDCl₃, 400 MHz):δ 14.41 (1 Η, s), 7.95 (1H, d), 7.79 (1H, d), 7.46 (2H, d), 7.40 (2H, d), 7.19 (1H, d), 6.81 (1H, d), 5.50 (2H, s), 3.72 (4H, t), 3.53 (2H, s), 2.64 (3H, s), 2.47 (4H, t).

Embodiment 11:2- (4- ((4- (cyano group (thiazole simultaneously [5,4-b】Pyridine -2- bases) methyl) pyrimidine-2-yloxy) methyl-Λ ^ ν-dimethyl acetamide（Compound 39) preparation

The preparation of-(4- (Yue Epoxide carbonyls) phenyl) acetic acid

By 4- (2- methoxyl group -2- oxoethyls) benzene Yue acid Yue esters（4 g, 19.2 mmol), a hydronium(ion) lithia（847 mg, 20.17 mmol) it is dissolved in the mixed solvent of tetrahydrofuran/methanol/water（ 60 mL, 4: 1 :1) in, 24 h are stirred at room temperature, are concentrated under reduced pressure after most of organic solvent, ice bath lowers pH 3, precipitation is separated out, and suction filtration, solid is dried, and obtains the g of white solid 3.4, yield 91.2%.

(2) preparation of 4- (2- (two Yue amino) -2- oxoethyls) benzene Yue acid Yue esters By 2- (4- (Yue epoxides take advantage of base) phenyl) acetic acid（2.89 g, 14.88 mmol) it is dissolved in dichloro Yue alkane（40 mL), add under 3 drop A^V " dimethyl Yue acid amides, ice bath and oxalyl chloride is slowly added dropwise（5.67 g, 44.64 mmol), drop finishes, and 2 h are stirred at room temperature, are dissolved in after being concentrated under reduced pressure standby in 20 mL dichloro Yue alkane.

By two Yue amine hydrochlorates（4.85 g, 59.51 mmol) and triethylamine（9.04 g, 89.3 mmol) it is dissolved in dichloromethane（LOO mL), under ice bath ' I " is graceful is added drop-wise to slowly in the solution of above-mentioned acyl chlorides, drop finishes, and 2 h are stirred at room temperature, and gained solid is dried after washing after being concentrated under reduced pressure, and obtains the g of yellow solid 2.82, yield 85.7%.

The preparation of-(4- (methylol) phenyl)-A^V- dimethyl acetamides

By 4- (2- (dimethylamino) -2- oxoethyls) methyl benzoate（2.82 g, 12.7 mmol) it is dissolved in tetrahydrofuran（80 mL), add sodium borohydride（4.82 g, 127 mmol), the h of heating reflux reaction 36 is concentrated under reduced pressure after most of solvent, adds water, and ethyl acetate extraction, organic phase is dried, concentration, silica gel column chromatography（Petroleum ether:Ethyl acetate=1:1) g of white solid 1.05, yield 42.5%, are obtained.

The preparation of-(4- (chloromethyl) phenyl)-A^-dimethyl acetamide

By the Yue yl acetamides of 2- (4- (methylol) phenyl)-A^V- two（0.41 g, 2.12 mmol) it is dissolved in thionyl chloride（10 mL), 2 h are stirred at room temperature.Next step is directly used in after being concentrated under reduced pressure.

- (2- hydroxy pyrimidine -4- bases) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）The preparation of acetonitrile

By 2- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-b] pyridine -2- bases）Acetonitrile（863 mg, 3 mmol), sodium hydroxide（1.2 g, 30 mmol) it is added to the water（20 mL), 6 h are reacted under 90 °C, are cooled down, pH to 6-7 is adjusted, and separate out yellow solid, suction filtration, silica gel column chromatography after drying（Dichloromethane:Yue alcohol=10:1) mg of yellow solid 595, yield 73.6%, are obtained.

(6) 2- (4- ((4- (cyano group (thiazole simultaneously [5,4-b] pyridine -2- bases）Methyl) pyrimidine-2-yloxy）Yue yls) pheiiyldimetliyl acetamide preparation

By 2- (2- hydroxy pyrimidine -4- bases) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）Acetonitrile（380 mg, 1.41 Mmol), 2- (4- (chloromethyl) phenyl)-N- dimethyl acetamides（448 mg, 2.12 mmol), cesium carbonate (1378 mg, 4.23 mmol), KI（24 mg, 0.141 mmol) add in the Yue yl acetamides of V, N " two（20 mL), 16 h are reacted under 70 °C, cools down, pours into frozen water, separate out yellow solid, suction filtration, silica gel column chromatography (dichloro Yue alkane after drying:Yue alcohol=10:1) mg of yellow solid 147, yield 23.5%, are obtained.

Molecular formula： C₂₃H_2QN₆0₂S;Molecular weight： 444.1 ;Mass spectrum (M+H): 445.1

^-NMR^-DMSO, 400 MHz): δ 12.96 (IH, s), 8.49 (IH, d), 8.25 (IH, d),

7.94 (1H, d), 7.55 (IH, dd), 7.29 (2H, d), 7.20 (2H, d), 6.30 (IH, d), 4.98 (2H, s),

3.66 (2H, s), 2.97 (3H, s), 2.79 (3H, s).

Embodiment 12:2- (2- (4- ((6- Yue yl pyridines -3- bases) Yue yls) benzyl | Λ) pyrimidine-4-yl) (thiazole is simultaneously by -2-

【5,4- -2- bases) acetonitrile（Compound 27) preparation

(1) preparation of (4- iodine benzyloxy) two Yue base t-butylsilanes

Will be to iodine benzylalcohol（9.9 g, 42.3 mmol), imidazoles（5.76 g, 84.6 mmol) it is dissolved in 20 mL DMF, then TBSC1 (7.20 g are slowly added into, 47.3 mmol), 14 h are stirred at normal temperatures, are then added drop-wise to slowly in 100 mL water 0 °C of H is graceful, the solution filtering of gained, wash filter cake in three times with 250 mL water, 45 °C of drying filter cakes obtain the g of white solid 12.1, yield： 82%.

The preparation of-methoxyl group-Λ Γ, 6- dimethyl nicotinamides

By 6- Yue base nicotinic acid（2.00 g, 14.59 mmol), Λ ζ Ο-dimethyl hydroxylamine hydrochloride（1.706 g, 17.51 mmol), DIPEA (4.05 g, 31.7 mmol), HATU (6.665 g, 17.51 mmol) is dissolved in 100 mL dichloro Yue alkane, and solution is stirred overnight, then 100 mL water are added, dichloro Yue alkane is extracted, organic phase, is dried, concentration, crosses silicagel column（PE/EA=4:1) g of light red solid 2.40, yield are obtained： 91.4%

(3) preparation of (4- ((the Yue bases siloxy of the tert-butyl group two) Yue yls) phenyl) (6- picoline -3- bases) Yue ketone

250 mL there-necked flasks are taken, by (4- iodine benzyloxy) two Yue base t-butylsilanes（6.960 g, 20 mmol) dissolved with 50 mL THF, with nitrogen displacement three times, 2.4 N lithium hexane solution is then slowly added into the solution at -30 °C（4.2 mL, 10.08 mmol), -30 °C stir 30 min, be cooled to -78 ° (：.Then by the Yue base niacinamide of iV- methoxyl groups two（1.8 g, 10 mmol) 25 mL anhydrous THF solutions be slowly added dropwise in above-mentioned reaction solution, stir 120 min, TLC monitoring raw material disappear, 50 mL aqueous ammonium chloride solutions are added, is extracted 2 times with 100 mL ethyl acetate, organic phase is dried, filtering, is spin-dried for, and crosses silicagel column（PE:EA=4:1) g of colorless oil 1.40, yield, are obtained： 41.1%

- picoline -3- bases) Yue yls) phenyl) and methanol preparation

By (4- ((tertiary butyl dimethyl Si base) Yue yls) phenyl) (6- picoline -3- bases) Yue ketone（1.40 g, 4.11 mmol) it is dissolved in 20 mL triethylene-glycols, then add 5 mL 40% hydrazine hydrate, solution is in 110 °C of 1 h of open stirring, then KOH (0.690 g, 12.35 mmol) is added, solution is stirred 2 hours at 140 °C, it is subsequently cooled to room temperature, 100 mL ethyl acetate and 50 mL water are added, extracts, organic phase is dried, it is spin-dried for, crosses silicagel column（ PE:EA=2:1) g of colorless oil 0.54, yield 61.6% are obtained.

The preparation of-(4- (chloromethyl) benzyl) -2- picolines

By (4- ((6- Yue yl pyridines -3- bases) Yue yls) phenyl) Yue alcohol（0.54 g, 2.53 mmol) it is dissolved in 20 mL dichloromethane, l mL thionyl chlorides are then slowly added dropwise, solution stirring at normal temperature 2 hours is spin-dried for obtaining the g of colorless oil 0.58, yield 98.8%

(6) preparation of 2- (2- (4- ((6- picoline -3- bases) Yue yls) benzyloxy) pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridin-2-yl) acetonitrile

By 2- (2- hydroxy pyrimidine -4- bases) -2- (thiazole simultaneously [5,4-b] pyridine -2- bases）Acetonitrile（0.326 g, 1.212 mmol), 5- (4- (chlorine Yue yls) benzyl) -2- Yue yl pyridines（0.42 g, 1.818 mmol), cesium carbonate（1.184 g, 3.636 mmol) KI（20 mg, 0.121 mmol) add in the Yue yl acetamides of A ^- bis-（20 mL), 46 h are reacted under 60 °C, cools down, pours into frozen water, yellow solid is separated out, and suction filtration is dried, silica gel column chromatography（Dichloromethane:Methanol=15:1) mg of yellow solid 57, yield 10.1%, are obtained.

Molecular formula： C₂₆H₂。N₆OS;Molecular weight： 464.1 ;Mass spectrum (M+H): 465.1 O-NMR^-DMSO, 400 MHz):δ 12.95 (IH, s), 8.50 (IH, d), 8.33 (IH, d), 8.26 (IH, d), 7.92 (IH, d), 7.59-7.50 (IH, m), 7.47 (IH, dd), 7.29 (2H, d), 7.23 (2H, d), 7.13 (IH, d), 6.29 (IH, d), 4.96 (2H, s), 3.89 (2H, s), 2.38 (3H, s).

Embodiment 13:((thiazole is simultaneously by -2- by 2- (cyclohexyl Yue M pyrimidine-4-yls) by 2-【4,5-c】Pyridine -2- bases）Acetonitrile（

(1) 2- (2- (cyclohexyl methoxy) pyrimidine-4-yl) -2- (thiazole simultaneously [4,5-c] pyridine -2- bases）The preparation of acetonitrile

Weigh sodium hydride (60%, 0.320 g, 8.0 mmol) 6 mL A^V " are added in dimethyl acetamide; add hexahydrobenzyl alcohol (0.457 g; 4.0 mmol); room temperature reaction adds 2- (2- chlorine pyrimidine -4- bases) -2- (thiazole simultaneously [4,5-c] pyridine -2- bases after 1 hour）Acetonitrile (0.575 g, 2.0 mmol), is warming up to 100 afterwards.C reacts 4 hours, is spin-dried for reaction solution, silica gel column chromatography (dichloromethane → dichloromethane:Yue alcohol=100:1) g of product 0.311, yield 42.5%, are obtained.

Molecular formula： C₁₉H₁₉N₅OS;Molecular weight： 365.1;Mass spectrum (M+H): 366.1

-NMR (^-DMSO, 400 MHz):δ 9.02 (1 Η, s), 8.32 (1 Η, d), 8.05 (IH, d), 7.72 (IH, d), 6.61 (IH, d), 4.46 (2H, d), 1.93-1.60 (5H, m), 1.34-1.05 (6H, m).

Embodiment 14:2- (2- (piperidin-4-yl methoxyl group) pyrimidine-4-yl) -2- (thiazole simultaneously " 5,4-W pyridine -2- bases) acetonitrile（Compound 91

(1) 4- ((4- (cyano group (thiazole simultaneously [5,4-6] pyridine-2- bases) Yue yls) pyrimidine-2-yloxy) Yue yls) piperidinyl-1-

300 mg (2 mmol) 4- (hydroxymethyl) piperidines -1- t-butyl formates are dissolved in lO mL DMA, add 160 mg (4 mmol) 60% NaH, 1 h is stirred at room temperature, add 288 mg (1 mmol) 2- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）Acetonitrile, N₂Protection, 100 °C of 18 h of reaction. Add water, faintly acid, suction filtration are adjusted to watery hydrochloric acid, filter cake prepares the purification of color language with high pressure liquid phase and obtains the mg of yellow solid 220, yield 47.2%.

(2) 2- (2- (piperidin-4-yl methoxyl group) pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）The system of acetonitrile

By 220 mg (0.47 mmol) 4- ((4- (thiazoles simultaneously [5,4-6] pyridine-2- bases) Yue yls) pyrimidine-2- bases epoxide) Yue yls) piperidines-1-t-butyl formate is dissolved in the in the mixed solvent of 20 mL dichloro Yue alkane and 1 mL Yue alcohol, dry HC1 gas reactions 2 h, TLC monitoring reaction is passed through under ice bath to terminate.Suction filtration, dry cake obtains the mg of yellow solid 160, yield 93.6%.

Molecular formula： C₁₈H₁₈N₆OS;Molecular weight： 366.1 ;Mass spectrum (M+H): 367.1

^-NMRiDMSO-^, 400 MHz):δ 9.06 (IH, d), 8.80-8.65 (IH, m), 8.43 (IH, d), 8.17 (1H, d), 7.74 (IH, d), 7.50 (IH, dd), 6.65 (IH, d), 4.58 (2H, d), 3.36-3.25 (2H, d), 2.90 (2H, dd), 2.28-2.15 (1H, m), 1.95 (2H, d), 1.56 (2H, dd).

Embodiment 15:2- (4- (cyclohexyl first pyrimidine -2-base) -2- (thiazoles simultaneously [5,4-b】Pyridine -2- bases) acetonitrile（

Chromatographic isolation is prepared after preparation method reference implementation example 8, column chromatography by high pressure liquid phase to produce.

Molecular formula： C₁₉H₁₉N₅OS;Molecular weight： 365.1 ;Matter language (M+H): 366.1

^-NMRCDMSO-^, 400 MHz): δ 13.87 (IH, s), 8.35 (IH, dd), 8.03 (IH, dd),

8.32-8.26 (IH, m), 7.47 (IH, dd), 6.45 (IH, d), 4.25 (2H, d), 1.87-1.60 (7H, m),

1.18-0.99 (4H, m).

Embodiment 16:2- (2- ((6- Yue yl pyridines -3- bases）Methoxyl group) pyrimidine 4- yls) (thiazole is simultaneously by -2-【5,4-b】Pyridine-- yl) acetonitrile（Compound 216) preparation

(1) preparation of (6- picoline -3- bases) methanol

1.51 g (10 mmol) 6- Yue base methyl nicotinates are dissolved in 50 ml THF, Slow adds 570 mg (15 mmol) Lithium Aluminium Hydride slowly under ice bath, react at room temperature lh, TLC monitoring reactions terminate.Ten water crystallization sodium sulphate are added, suction filtration is spin-dried for filtrate, column chromatography（PE:EA=3:1→1:1) g of greenish liquid 1.1, yield 89.4% are obtained.

The preparation of-(chlorine Yue yls) -2- picolines

246 mg (2 mmol) (6- Yue yl pyridines -3- bases) methanol is added in 5 mL thionyl chlorides, 5 h are stirred at room temperature, being directly spin-dried for solvent is used for the next step.

(3) 2- (2- ((6- Yue yl pyridines -3- bases) methoxyl group) pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-b] pyridine -2- bases)

By 260 mg (0.97 mmol) 2- (2- hydroxy pyrimidine -4- bases) -2- (thiazoles simultaneously [5,4-6] pyridine -2- bases) acetonitrile is dissolved in 10 mL DMA, adds 1.3 g (4 mmol) cesium carbonates and 5- (chloromethyl) -2- Yue yl pyridines（About 2 mmol), it is eventually adding 20 mg (0.12 mmol) KI, 70 °C of 18 h of reaction.Add water, faintly acid is adjusted to watery hydrochloric acid, dichloromethane extraction is washed, dried, concentration, column chromatography (DCM:MeOH=500:l→ 100:1) mg of yellow solid 105, yield 28.9%, are obtained

Molecular formula： C₁₉H₁₄N₆OS;Molecular weight： 374.1 ;Mass spectrum (M+H): 375.1

^-NMRCDMSO-^, 400 MHz):δ 12.95 (IH, s), 8.52-8.47 (2H, m), 8.26 (1H, d), 7.98 (1H, d), 7.68 (IH, dd), 7.55 (IH, dd), 7.25 (1H, d), 6.31 (1H, d), 5.00 (2H, s), 2.44 (3H, s).

Embodiment 17:2- (2- (cyclohexyloxy) pyrimidine-4-yl) -2- (thiazoles simultaneously [5,4-b】Pyridine -2- bases）Acetonitrile（Compound

200 mg (2 mmol) cyclohexanol is dissolved in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, 1 h is stirred at room temperature, add 288 mg (1 mmol) 2- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-] pyridine -2- bases）Acetonitrile, N₂Protection, 100 °C of 18 h of reaction.Add water, faintly acid is adjusted to watery hydrochloric acid, suction filtration, filter cake prepares chromatographic isolation with high pressure liquid phase and obtains the mg of yellow solid 160, yield 45.5% Molecular formula： C₁₈H₁₇N₅OS;Molecular weight： 351.1 ;Mass spectrum (M+H): 352.1

- wake up R (DMSO-, 400 MHz):δ 12.67 (1 Η, br s), 8.38 (1H, dd), 8.10 (1H, d), 7.69-7.60 (1H, m), 7.43 (1H, dd), 6.59 (1H, d), 5.44-5.32 (1H, m), 2.25-2.15 (2H, m), 1.87-1.76 (2H, m), 1.70-1.42 (5H, m), 1.38-1.25 (1H, m).

Embodiment 18:2- (2- (2- cyclohexylethoxy radicals) pyrimidine-4-yl) -2- (thiazole simultaneously " 5,4-b] pyridine -2- bases) acetonitrile

256 mg (2 mmol) cyclohexyl ethyl alcohol is dissolved in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, 1 h is stirred at room temperature, add 288 mg (1 mmol) 2- (2- chlorine pyrimidine -4- bases) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）Acetonitrile, N₂Protection, 100 °C of 18 h of reaction.Add water, faintly acid is adjusted to watery hydrochloric acid, suction filtration, filter cake prepares chromatographic isolation with high pressure liquid phase and obtains the mg of yellow solid 180, yield 47.4%

Molecular formula： C20H21N5OS;Molecular weight: 379.1；Mass spectrum (M+H): 380.2ο

^-NMRCDMSO-^, 400 MHz):δ 12.72 (1 Η, s), 8.38 (1H, d), 8.09 (1H, d),

7.70-7.61 (1H, m), 7.42 (1H, dd), 6.59 (1H, d), 4.71 (2H, t), 1.82-1.58 (8H, m),

1.31-1.10 (4H, m), 1.07-0.95 (1H, m).

Embodiment 19:((thiazole is simultaneously by -2- by 2- (2- cyclohexyl pyrimethamine -4- bases) by 2-【4,5-c】Pyridine -2- bases) acetonitrile

(1) 2- (2- (2- cyclohexylethoxy radicals) pyrimidine-4-yl) -2- (thiazole simultaneously [4,5-c] pyridine -2- bases）The preparation of acetonitrile

Weigh sodium hydride (60%, 0.211 g, 5.28 mmol) it is added in the Yue yl acetamides of 5 mL TV^N- bis-, add 2- cyclohexyl ethyl alcohols (0.338 g, 2.64 mmol), room temperature reaction adds 2- (2- chlorine pyrimidine -4- bases) -2- (thiazole simultaneously [4,5-c] pyridine -2- bases after 1 hour）Acetonitrile (0.38 g, 1.32 mmol), is warming up to 100 afterwards.C reacts 8 hours, is spin-dried for reaction solution, silica gel column chromatography (dichloro Yue alkane → dichloro Yue alkane:Methanol=100:1) g of product 0.254, yield 50.7%, are obtained.

Molecular formula： C₂。H₂₁N₅OS;Molecular weight： 379.1 ;Mass spectrum (M+H): 380.2 ^-NMR (d₆-OMSO, 400 MHz):δ 9.00 (1H, s), 8.31 (1H, d), 7.98 (1H, d), 7.72 (1H, d), 6.60 (1H, d), 4.68 (2H, t), 1.82-1.34 (8H, m), 1.32-0.92 (5H, m).

Embodiment 20:2- (2- ((l- methyl isophthalic acid H- pyrazole-3-yls) methoxyl group) pyrimidine-4-yl) -2- (thiazole [5,4-W pyridine -2- bases) second

The preparation of-Yue base pyrazoles -3- Yue acid Yue esters

1.26 g (10 mmol) 1- Yue base pyrazoles -3- Yue acid is added in 30 mL absolute methanols, 2.38 g (20 mmol) thionyl chloride is added under ice bath, move to 18 h of room temperature reaction, solvent is spin-dried for, white solid is obtained and is directly used in the next step.

- Yue bases pyrazole-3-yl) Yue alcohol preparation

By upper step product（About 10 mmol) it is added in 40 mL tetrahydrofurans, Slow adds 570 mg (15 mmol) Lithium Aluminium Hydride slowly under ice bath, finishes and moves to room temperature reaction 3h, add ten water crystallization sodium sulphate, suction filtration is spin-dried for filtrate, column chromatography（PE:EA=3: 1→1 :1) mg of colorless oil 800, the step yield 71.4% of the above two, are obtained.

(3) preparation of 2- (2- ((1- Yue base -177- pyrazole-3-yls) methoxyl group) pyrimidine-4-yl) -2- (thiazole [5,4-b] pyridine -2- bases) acetonitrile

By 2²4 mg (2 mmol) (1- methyl-li/- pyrazole-3-yls) methanol is dissolved in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, 1 h is stirred at room temperature, add 288 mg (1 mmol) 2- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）Acetonitrile, N₂Protection, 100 °C of 18 h of reaction.Add water, faintly acid is adjusted to watery hydrochloric acid, suction filtration, filter cake prepares chromatographic isolation with high pressure liquid phase and obtains not sterling, and DMSO is recrystallized to give the mg of yellow solid 20, yield 5.5% Molecular formula： C₁₇H₁₃N₇OS;Molecular weight： 363.1 ;Mass spectrum (M+H): 364.1

^-NMRCDMSO-^, 400 MHz):δ 12.81 (1H, br s), 8.37 (IH, d), 8.14-8.07

(IH, m), 7.74-7.62 (2H, m), 7.43 (IH, dd), 6.68-6.60 (IH, m), 6.42 (1H, d), 5.66

(2H, s), 3.85 (3H, s).

Embodiment 21:²-(2-(²_(²_ oxo-pyrrolidine -1- bases）Ethyoxyl) pyrimidine _⁴_ yl) (thiazole is simultaneously by -2-

【5,4- -2- bases）Acetonitrile（Compound 221) preparation

258 mg (2 mmol) 1- (2- hydroxyethyls) pyrrolidin-2-one is dissolved in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, 1 h is stirred at room temperature, add 288 mg (1 mmol) 2- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）Acetonitrile, N₂Protection, 100 °C of 18 h of reaction.Add water, faintly acid is adjusted to watery hydrochloric acid, suction filtration, filter cake prepares chromatographic isolation with high pressure liquid phase and obtains the mg of yellow solid 160, yield 42.1%

Molecular formula： C₁₈H₁₆N₆0₂S;Molecular weight： 380.42;Mass spectrum (M+H): 381.1

^-NMRCDMSO-^, 400 MHz):δ 8.39 (IH, dd), 8.10 (IH, d), 7.73-7.66 (IH, m), 7.44 (IH, dd), 6.62 (1H, d), 4.78 (2H, t), 3.70 (2H, t), 3.49 (2H, t), 2.22 (2H, t) 1.92 (2H, quintet).

Embodiment 22:(thiazole is simultaneously by -2- by 2- (2- ((4,4- difiuorocyclohexyl) methoxyl group) pyrimidine-4-yl)【5,4-b】Pyridine -2- bases) acetonitrile（

(1) preparation of (4,4- difiuorocyclohexyl) Yue alcohol

By 1.92 g (10 mmol) 4,4- difiuorocyclohexyl Ethyl formates are added in 40 mL tetrahydrofurans, Slow adds 570 mg (15 mmol) Lithium Aluminium Hydride slowly under ice bath, finish and move to 3 h of room temperature reaction, add ten water crystallization sodium sulphate, suction filtration, is spin-dried for filtrate.Add water, ethyl acetate extraction is dried, is spin-dried for obtaining the g of light yellow oil 1.1, yield 73.3%.

(2) 2- (2- ((4,4- difiuorocyclohexyls）Yue epoxides) pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases) acetonitrile preparation

By 3000 (2 01) (4,4- difiuorocyclohexyls) Yue alcohol is dissolved in lOmLDMA, add 160 mg (4 mmol) 60% NaH, 1 h is stirred at room temperature, add 288 mg (1 mmol) 2- (2- chlorine pyrimidine-4-yl) -2- (thiazole simultaneously [5,4-6] pyridine -2- bases）Acetonitrile, N₂Protection, 100 °C of 18 h of reaction.Add water, faintly acid is adjusted to watery hydrochloric acid, suction filtration, the dry DMSO of filter cake thousand dissolves, add a small amount of Yue alcohol, separate out yellow solid 140mg, yield 34.9%

Molecular formula: Ci₉H₁₇F₂N₅OS;Molecular weight： 401.1;Mass spectrum (M+H): 402.1

^-NMRCDMSO-^, 400 MHz):δ 12.79 (1 Η, s 8.38 (1H, d), 8.09 (1H, d), 7.68 (1H, s), 7.43 (1H, dd), 6.69-6.55 (1H, m), 4.59 (2H, d), 2.14-1.74 (9H, m

Claims (13)

1. Claims

   1st, formula（ I )、 （L a) or（L b) shown in compound, its pharmaceutically acceptable salt or

   (I) (la) (!b)

   Wherein,

   X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

   Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

   R¹ , R²Independently for hydrogen, sulfonyl, halogen, alkyl, halo _₆Alkyl, d.6 alkoxy, amino, cyano group, hydroxyl, C_2-6Alkenyl, C₂_₆Alkynyl, 6-14 members aryl, 5-14 unit's heteroaryls, 3-14 members cycloalkyl, 3-14 circle heterocycles alkyl；

   N is selected from 0,1,2 or 3;

   ！^ is.^ alkyl, alkoxy ,-N (R^aR^b), it is unsubstituted or at least by a R³Substitution

   14 yuan of aryl of 6-, 5-14 unit's heteroaryls, 3-14 members cycloalkyl, 3-14 circle heterocycles alkyl, 7-12 member loop coils base, 7-12 member bridged ring bases, wherein the cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be with other 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed；

   Wherein m is selected from 0,1,2 or 3,

   R⁴For sulfonyl, halogen, C^₆Alkyl, halo C_1-6Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b)、 ^₆Alkoxy, amino, cyano group, hydroxyl, C^₆Alkenyl, C^₆It is alkynyl, unsubstituted or at least by a R⁵Substituted 6-14 members aryl, 5-14 unit's heteroaryls, 14 yuan of cycloalkyl of 3-, 3-14 circle heterocycles alkyl,

   12 yuan of loop coil bases of 7-, 7-12 member bridged ring bases, wherein the cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be with other 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed, any CH of 3-14 circle heterocycles alkyl₂It can be replaced by C (O)；

   R⁵For sulfonyl, halogen, C_1-6Alkyl, halo C!—₆Alkyl, C_1-6Alkoxy,-C (0) -0-C_1-6Alkyl ,-C (0)-C_1-6Alkyl ,-(CH₂)_p-C(0)-0-C_1-6Alkyl ,-(CH₂)_p-0-C_1-6Alkyl ,-(C)_p-C(0)N(R^aR^b)、 -(CH₂)_p- OH, amino, hydroxyl, C_2-6Alkenyl, C_2-6Alkynyl, 3-14 members cycloalkyl, 6-14 members aryl or 3-14 circle heterocycles bases；

   R^a、 R^bIndependently for hydrogen, C_1-6Alkyl ,-(C)_p-OC_1-6Alkyl or 6-14 member aryl C_1-6Alkyl,

   P is selected from 1,2,3 or 4.

   2nd, compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer：Wherein,

   X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

   Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

   R¹, R²Independently for hydrogen, sulfonyl, halogen,（^₆Protective embankment base, d.₆Alkoxy, amino, fj^. hydroxyls, C_2-6Alkenyl, C_2-6Alkynyl, 6-14 member aryl；

   N is selected from 0,1,2 or 3;

   L is C_1-6Protective embankment base, d_6 alkoxies ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted 6-14 members aryl, 5-14 unit's heteroaryls, 3-14 members cycloalkyl, 3-14 circle heterocycles alkyl, wherein the cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be with other 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed；

   0

   R³For or^e、R⁴ ,

   Wherein m is selected from 0,1,2 or 3,

   R⁴For sulfonyl, halogen, alkyl, halo d.₆Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b)、 C_1-6It is alkoxy, amino, cyano group, hydroxyl, unsubstituted or at least by a R⁵Substituted 6-14 members aryl, 5-14 unit's heteroaryls, 3-14 members cycloalkyl, 3-14 circle heterocycles alkyl, 7-12 member loop coils base, 7-12 member bridged ring bases, wherein described cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can be with other 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed, any CH of 3-14 circle heterocycles alkyl₂It can be replaced by C (O)；

   R⁵For sulfonyl, halogen, C_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkoxy,-C (0) -0-C_1-6Alkyl ,-C (0)-C_1-6Alkyl ,-(CH₂)_p-C(0)-0-C_1-6Alkyl ,-(CH₂)_p-0-C_1-6Alkyl ,-(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p- OH,, hydroxyl, C_2-6Alkenyl, C_2-6Alkynyl, 3-14 members cycloalkyl, 6-14 members aryl or 3-14 circle heterocycles bases；

   R^a、 R^bIndependently for hydrogen, C_1-6Alkyl ,-(CH₂)_p-OC_1-6Alkyl, phenyl C_1-6Alkyl, p is selected from 1,2,3 or 4. 3rd, compound as claimed in claim 2, its pharmaceutically acceptable salt or its stereoisomer：Wherein,

   X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

   Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

   R¹ , R²Independently for hydrogen, sulfonyl, halogen, d_₆Alkyl, C_1-6Alkoxy, amino, atmosphere base, select base

   N is selected from 0,1,2 or 3;

   ！^ is ^^ alkyl, alkoxy ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted phenyl, quinoline pouring base, 5-6 unit's heteroaryls, 3-8 members cycloalkyl or 3-8 circle heterocycles alkyl；

   0

   _R3 be/^_R4Or/e,_R4, wherein m be selected from 0,1,2 or 3,

   R⁴For sulfonyl, halogen, C_1-6Alkyl, halo C_1-6Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b), it is alkoxy, amino, cyano group, hydroxyl, unsubstituted or at least by a R⁵Substituted 6-14 members aryl, 5-14 unit's heteroaryls, 3-14 members cycloalkyl, 3-14 circle heterocycles alkyl, wherein described cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can slightly be closed with other 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, any CH of 3-14 circle heterocycles alkyl₂It can be replaced by C (O)；

   R⁵For sulfonyl, halogen, C_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkoxy,-C (0) -0-C_1-6Alkyl ,-C (0)-C_1-6Alkyl ,-(CH₂)_p-C(0)-0-C_1-6Alkyl ,-(CH₂)_p-0-C_1-6Alkyl ,-(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p- OH,, hydroxyl, C₂_₆Alkenyl, C_2-6Alkynyl, 3-14 members cycloalkyl, 6-14 members aryl or 3-14 circle heterocycles bases；

   R^a、 R^bIndependently for hydrogen, C_1-6Alkyl ,-(C)_p-OC_1-6Alkyl, benzyl or phenylethyl, p are selected from 1,2,3 or 4.

   4th, compound as claimed in claim 3, its pharmaceutically acceptable salt or its stereoisomer：Wherein,

   X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

   Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

   R¹, R²Independently for hydrogen, d_₆Alkyl；

   N is selected from 0,1,2 or 3;

   L is ^₆Alkyl,（^₆Alkoxy ,-N (R^aR^b), it is unsubstituted or at least by a R³Substitution Phenyl, quinolyl, 5-6 unit's heteroaryls, 3-8 members cycloalkyl or 3-8 circle heterocycles alkyl；

   0

   _R3 be/^ or/^：、_r4, wherein m be selected from 0,1,2 or 3,

   R⁴For sulfonyl, halogen, C_1-6Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b)、 ₆It is alkoxy, amino, cyano group, hydroxyl, unsubstituted or at least by a R⁵Substituted phenyl, 5-6 unit's heteroaryls, 3-8 members cycloalkyl, 3-8 circle heterocycles alkyl, wherein described cycloalkyl, Heterocyclylalkyl, phenyl or heteroaryl can be with other 1 cycloalkyl, Heterocyclylalkyl, phenyl or heteroaryl-condensed, any CH of 3-8 circle heterocycles alkyl₂It can be replaced by C (O)；

   R⁵For C_1-6Alkyl, C_1-6Alkoxy,-C (0) -0-C_1-6Alkyl ,-C (0)-C_1-6Alkyl ,-(CH₂)_p-C(0)-0-C_1-6Alkyl ,-(CH₂)_p-0-C_1-6Alkyl ,-(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p- OH, amino, cyano group, hydroxyl, 3-8 members cycloalkyl, phenyl, 3-8 circle heterocycles bases；

   R^a、 R^bIndependently for hydrogen, C_1-6Alkyl ,-(CH₂)_p-OC_1-6Alkyl, benzyl or phenylethyl；P is selected from 1,2,3 or 4.

   5th, compound as claimed in claim 4, its pharmaceutically acceptable salt or its stereoisomer：Wherein,

   X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

   Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

   R¹, R²Independently for hydrogen, C alkyl；

   N is selected from 0,1,2 or 3;

   ！^ be ^-₆Alkyl, d.6 alkoxy ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted phenyl, quinolyl, 6 unit's heteroaryls, 3-8 members cycloalkyl or 3-8 circle heterocycles alkyl；

   0

   R³For ^^ or/^e、R⁴ ,

   Wherein m is selected from 0,1,2 or 3,

   R⁴For sulfonyl, halogen,₃Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b)、 C_1-6It is alkoxy, amino, cyano group, hydroxyl, unsubstituted or at least by a R⁵Substituted phenyl, 5-6 unit's heteroaryls, 3-8 members cycloalkyl, 3-8 circle heterocycles alkyl or piperidines and any CH of phenyl, wherein 3-8 circle heterocycles alkyl₂It can be replaced by C (O)；

   R⁵For d.₆Alkyl, C_1-6Alkoxy ,-c c-o-c^ alkyl ,-C ^-C^ alkyl ,-(CH₂)_p-C(0)-0-C_1-6Alkyl ,-(C)_p-0-C_1-6Alkyl ,-(CH₂)_p-C(0)N(R^aR^b)、 -(C¾)_P- OH, amino, cyano group or hydroxyl；

   R^A、 R^BIndependently for hydrogen, d_₆Alkyl ,-(CH^-OC alkyl or benzyl, p are selected from 1,2 or 3.

   6th, compound as claimed in claim 5, its pharmaceutically acceptable salt or its stereoisomer：Wherein,

   X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

   Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

   R¹ , R²Independently for hydrogen, alkyl；

   N is selected from 0,1,2 or 3;

   For ^ alkyl, ^₆Alkoxy ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted phenyl, quinolyl, 6 unit's heteroaryls, 3-8 members cycloalkyl or 3-8 circle heterocycles alkyl；

   0

   R³For or, R⁴,

   Wherein m is selected from 0,1,2 or 3,

   R⁴For sulfonyl, halogen, C_1-3Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b)、 C_1-6It is alkoxy, amino, cyano group, hydroxyl, unsubstituted or at least by a R⁵Substituted 5-6 unit's heteroaryls, 3-8 circle heterocycles alkyl or piperidines and any CH of phenyl, wherein 3-8 circle heterocycles alkyl₂It can be replaced by C (O)；

   R⁵For d_₃Alkyl, C_1-6Alkoxy,-C (0) -0-C_1-6Alkyl ,-C (0)-Cw alkyl ,-(CH₂)_p-C(0)-0-C_1-3Alkyl ,-(CH p-O-Cw alkyl ,-(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p- OH, or hydroxyl；

   R^a、 R^bIndependently for hydrogen, C_1-6Alkyl ,-(CH₂)_p- OCw alkyl or benzyl, p are selected from 1,2 or 3.

   7th, compound as claimed in claim 6, its pharmaceutically acceptable salt or its stereoisomer：Wherein,

   X, Y are separately N or CR¹, wherein X, Y at least 1 is N;

   Z, W, U, G are separately N or CR¹, wherein Z, W, U, G at least 1 is N;

   R¹ , R²Independently for hydrogen, methyl or ethyl；

   N is selected from 0,1,2 or 3;

   L is d_₆Alkyl ,-N (R^aR^b), it is unsubstituted or at least by a R³Substituted phenyl, quinoline Base, pyridine radicals, pyrimidine radicals, cyclohexyl, piperidyl, THP trtrahydropyranyl, piperazinyl or morpholinyl；

   0

   _R3 be/(R₄Or^e、_R4 ,

   Wherein m is selected from 0 or 1,

   R⁴For sulfonyl, halogen, C_1-3Alkyl ,-C (0) N (R^aR^b)、 -N(R^aR^b), it is unsubstituted or at least by a R⁵Substituted pyrrole¹¹Determine base, it is pyrazolyl, imidazole radicals, phonetic⁵¹Determine base, piperidines and phenyl, morpholinyl, piperazine¹¹Determine base, piperazine.Qin Ji, nafoxidine 2- ketone groups；

   R⁵For Ci_-3Alkyl, C_1-6Alkoxy,-C (0) -0-C_1-6Alkyl ,-C (0)-C_1-3Alkyl ,-(CH₂)_p-C(0)-0-C_1-3Alkyl ,-(CH p-O-Cw alkyl ,-(CH₂)_p-C(0)N(R^aR^b)、 -(CH₂)_p-OH;

   R^a、 R^bIndependently for hydrogen,₆Alkyl ,-(CH p-OCw alkyl or benzyl,

   P is selected from 1,2 or 3.

   8. compound, its pharmaceutically acceptable salt or its stereoisomer as any one of claim 1-7,

   One wherein in X and Y is N, and another is CR

   9. compound, its pharmaceutically acceptable salt or its stereoisomer as any one of claim 1-8,

   Wherein Z represents CH, and W represents CH;

   U represents N, and G represents N.

   10. selected from following compound, its pharmaceutically acceptable salt or its stereoisomer：

   680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

   680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

   9L

   680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

   LL

   680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

   680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

   08

   680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

   18

   680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

   680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

   C8

   680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

   680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

   11st, selected from following compound, its pharmaceutically acceptable salt or its stereoisomer, the compound is selected from：

   12nd, a kind of pharmaceutical composition, it includes compound, its pharmaceutically acceptable salt or its stereoisomer and one or more pharmaceutical carriers described in any one of claim 1 ~ 11.

   13rd, described in any one of claim 1 11 pharmaceutical composition of compound, its pharmaceutically acceptable salt or its stereoisomer or claim 12 is preparing treatment and/or prevention ischemical reperfusion injury, diabetes, nerve retrograde affection, chronic inflammation（Such as allergy, asthma, rheumatoid class arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, PVR, glaucoma）, pulmonary fibrosis, liver fibrosis, the purposes in the medicine of fatty liver or hepatic sclerosis.

   14th, a kind for the treatment of and/or prevention ischemical reperfusion injury, diabetes, nerve retrograde affection, chronic inflammation（Such as allergy, asthma, rheumatoid class arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, PVR, glaucoma）, pulmonary fibrosis, liver fibrosis, the method for fatty liver or hepatic sclerosis, including give the pharmaceutical composition of compound described in any one of claim 1 ~ 12 for needing its bacterium, its pharmaceutically acceptable salt or its stereoisomer or claim 13. 15th, for treating and/or preventing ischemical reperfusion injury, diabetes, nerve retrograde affection, chronic inflammation（Such as allergy, asthma, rheumatoid class arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, PVR, glaucoma）, pulmonary fibrosis, liver fibrosis, the compound described in any one of claim 1 ~ 12 of fatty liver or hepatic sclerosis, the pharmaceutical composition of its pharmaceutically acceptable salt or its stereoisomer or claim 13.