CN104903331A - Jnk inhibitors - Google Patents

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to JNK inhibitors represented by general formula (I), (Ia) or (Ib), their pharmaceutically acceptable salts or stereoisomers thereof, methods for preparing these compounds, pharmaceutical preparations containing these compounds, and the use of these compounds in the preparation of medicaments for treating and/or preventing ischemia-reperfusion injury, diabetes, neurodegenerative diseases, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver or cirrhosis.

Description

JNK inhibitor Technical field

The present invention belongs to the field of medical technology, and specifically relates to JNK inhibitors, pharmaceutically acceptable salts or stereoisomers thereof, methods for preparing these compounds, pharmaceutical preparations containing these compounds, and the preparation of these compounds for treatment and/or prevention Drug use in ischemia-reperfusion injury, diabetes, neurodegeneration, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver or cirrhosis.

Background technique

JNK, also known as stress-activated protein kinases (stress-activated kinases, SAPK), is a mitogen-activated protein kinase discovered in 1990 and is one of the main members of the MAPK family. Mitogen-activated protein kinase (MAPK;) is a kind of serine/threonine protein kinase widely present in mammalian cells, and four family members have been identified so far, namely cell! Including extracellular signal-regulated kinase 1/2, ERK 1/2), c-Jun J ^ terminal kinase (c-Jun N-terminal kinase, JNK:), p38 and ERK5. The JNK gene has three isoforms, namely JNK1, JNK2 and JNK3, which are formed by alternative splicing. JNK1 and JNK2 are widely expressed in tissues, while JNK3 is only expressed in brain, heart and testis. Each JNKL gene can encode protein products of 46 and 54 kD. The three JNK isoforms activate, bind and phosphorylate different protein substrates in different ways.

The JNK signaling pathway can be activated by cytokines [such as tumor necrosis factor α (tumor necrosis factor α, TNFa), interleukin 1 (interleukin 1, IL- 1 ), epidermal growth factor (epidermal growth factor, EGF) ], some G protein couples Activated by various factors such as receptors, stress (such as ionizing radiation, osmotic pressure, heat shock, and oxidative damage), and participates in various biological processes such as cell proliferation and differentiation, cell shape maintenance, cytoskeleton construction, cell apoptosis, and cell malignant transformation Learn to react. Dysregulation of the JNK signaling pathway can cause various diseases such as ischemia-reperfusion injury, chronic inflammation, neurodegeneration, diabetes and tumors.

A typical mitogen-activated protein kinase (MAPK) signaling pathway includes three consecutive enzymatic reactions, namely MAPKKKs→MAPKKs→MAPKs. The direct upstream kinases of JNKs, MAPKKs, are currently confirmed to be only MKK4 and MKK7. The TXY sequence is the dual phosphorylation site for MKK to activate JNK. MKK4 and MKK ⁷ phosphorylate the 183th threonine residue (Thrl83) and the The 185th tyrosine residue (Tyrl85) activates JNK, causing various biological responses such as cell proliferation and differentiation, cell apoptosis and cell malignant transformation.

The regulation of the signaling pathway is an extremely complex system. There are two main mechanisms for the regulation of the JN signaling pathway. One is to recognize the sequence between MKKK and MKK and MKK and MAPK; the other is to assemble the MKKK-MKK-MAPK module into a scaffold protein protein complex. MAPK through conserved sequence Columns are docked with specific upstream molecules MKK and substrates (such as c-Jun, ATF2, etc.). In all MAPKs (including JK), there is a group of negatively charged carboxy-terminal amino acids connected to the domain sequence of the kinase, this site is called the common docking domain (common docking domain in, CD), for MKK , MAPK, docking of specific substrates and scaffold proteins. Another conserved sequence, called the glutamate-aspartate domain, is also used for MAPK docking. The docking sites in MKK, substrate, MAPK and scaffolding proteins have a common conserved sequence R/K-X4A-0A-X- 0B (0A and 0B are the hydrophobicity of leucine, isoleucine and valine Residues). When the basic residues in the docking site (docking domain in, DD) are combined with the acidic residues of the CD domain of MAPK, the hydrophobic residues are located in the docking groove, so that the OA-X-OB hydrophobic sequence is combined with the DD sequence. The interaction between these docking sites plays an important role in the specific binding and activation of MAPK. In addition to the docking between MAPK and MKK, substrates and regulators, there are also specific sequences that regulate the interaction between MKKK and MKK. Studies have found that in some MKKs, including MKK4/7 that regulates JNK, there is a multifunctional docking domain called a multifunctional docking site (domain in for versatile docking, DVD), and the DVD site is located at the carboxyl group of MKK terminal, connecting MKKK [including MEKK 1, MEKK4 (MTK 1), ASK1, Tao2 and Takl], all of which can activate the JNK signaling pathway. The N-shaped kinase-binding domain within MKKK binds to the DVD site of MKK.

Another aspect of the control of the JK signaling pathway is the assembly of signaling pathway complexes by scaffold proteins. The scaffold protein itself has no catalytic function, but it can encode the docking site and connect the MAPK module members MKKK, MKK and MAPK. In general, scaffolding proteins bind to other proteins by interacting with binding domains such as SH2, SH3, and PTB, and these domains allow the MAPK signaling pathway complex in cells to be positioned to different sites. Different activators allow scaffolding proteins and specific MKKKs to selectively activate MAPKs with temporal and spatial dynamics. Among the different scaffolding proteins, JNK interacting proteins (J K-interacting proteins, JIPs) combine specificity kinesin and MKKK ό々 mixed lineage kinase (mixed lineage kinase, MLK) family; inhibitory protein β-arrestin is Cofactor of phosphorylation of G protein-coupled receptors; multi-binding domain protein POSH (plenty of SH3s) contains multiple SH3 domains, involved in JNK signaling pathway in mammalian and Drosophila cell apoptosis; adapter protein C rk II through Adhesion factors bind to the JNK signaling pathway. In addition, MEKK1 can not only combine with MKK4, but also combine with JNK1/2, which indicates that it itself has a role similar to scaffolding protein.

Knocking out the target homologous recombination gene in the mouse model makes the expression of different JNK or its upstream regulatory molecules missing, thus affecting its function in physiology and disease. JNK inhibitors have further proved that the JNK signaling pathway plays a role in different diseases important role. JNK inhibitors can inhibit cell death caused by ischemia and other stress-induced apoptotic responses, which shows great therapeutic potential. It has been documented that JNK inhibitors can be used to treat or prevent respiratory diseases (such as pulmonary fibrosis), lipid Fatty liver, liver fibrosis, liver cirrhosis, ischemia/reperfusion injury, chronic inflammatory diseases, neurodegenerative diseases, diabetes and tumors, etc.

The JNK inhibitors that have been studied more are mainly polypeptides and small molecule compounds. In WO2005025567 and WO2006076595, the effects of new JNK small molecule inhibitors in multiple therapeutic fields have been discovered. At present, there are no JNK inhibitor drugs on the market. Therefore, it is necessary to develop more structural types of JNK inhibitors, and select compounds with better efficacy and safety for respiratory diseases, fatty liver, liver fibrosis, and liver cirrhosis. , Treatment of chronic inflammatory diseases.

AS-602801 is a drug developed by Merck for the treatment of fibrosis, which is currently in clinical phase II. The compound has the following structural formula:

Contents of the invention

The present invention provides the following technical solutions

1. The compound represented by general formula (I), (la) or (lb), its pharmaceutically acceptable salt or its stereoisomer:

(I) (la) (lb)

in,

X and Y are independently N or CR ¹ , wherein at least one of X and Y is N;

Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N;

R ¹ and R ² are independently hydrogen, sulfonyl, halogen, C _1-6 alkyl, halogenated C alkyl, C _1-6 alkoxy, amino, , hydroxyl, C _{2-6 alkenyl} , C _2-6 alkynyl, 6-14 aryl, 5-14 heteroaryl, 3-14 cycloalkyl, 3-14 heterocycloalkyl;

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

L is C _1-6 alkyl, C _1-6 alkoxy, -N(R ^a R ^b ), unsubstituted or at least one R ³ substituted 6-14 membered aryl, 5-14 membered heteroaryl group, 3-14 membered cycloalkyl group, 3-14 membered heterocycloalkyl group, 7-12 membered spirocyclyl group, 7-12 membered bridged ring group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group or Heteroaryl can be fused with another 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; O

_R 3 for /^! ^ or ^:, _r4 , wherein m is selected from 0, 1, 2 or 3,

R ⁴ is sulfonyl, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), C _1-6 Alkoxy, amino, cyano, hydroxyl, C _2-6 alkenyl, C ₂ _ ₆ alkynyl, unsubstituted or at least one R ⁵ substituted 6-14 membered aryl, 5-14 membered heteroaryl , 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 7-12 membered spirocyclyl, 7-12 membered bridged ring group, wherein the cycloalkyl, heterocycloalkyl, aryl or hetero The aryl group can be fused with another 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, and any CH ₂ of the 3-14 membered heterocycloalkyl group can be substituted by C(O);

R ⁵ is sulfonyl, halogen, C _1-6 alkyl, halogenated C ₆ alkyl, _-6 alkoxy, -C(0)-0-Ci _-6 alkyl, -C -Cw alkyl, - (CHz C -O-Cw alkyl, -(CH pOC^ alkyl, -(C¾) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, , , hydroxyl, C _{2_6} alkenyl, _C2-6 alkynyl, 3-14 membered cycloalkyl, _6-14 membered aryl or 3-14 membered heterocycloalkyl;

R ^a , R ^b are independently hydrogen, d. ₆ alkyl, -(C¾) _p -OC _1-6 alkyl or 6-14 membered aryl C ^ ₆ alkyl,

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

2. The compound as described in any one of the preceding technical schemes, its pharmaceutically acceptable salt or its stereoisomer:

in,

X and Y are independently N or CR ¹ , wherein at least one of X and Y is N;

Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N;

R ¹ and R ² are independently hydrogen, sulfonyl, halogen, _{d_6 alkyl, C 1-6 alkoxy} , cyano, hydroxyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, 6- 14-membered aryl;

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

L is _d.6 alkyl, _d.6 alkoxy, -N(R ^a R ^b ), unsubstituted or at least one R ³ substituted 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be combined with another 1-2 cycloalkyl, heterocycloalkyl , aryl or heteroaryl fused;

0 wherein m is selected from 0, 1, 2 or 3, R ⁴ is sulfonyl, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), _{d_6} alkoxyl group, amino group, cyano group, hydroxyl group, 6-14 membered aryl group, ^5-14 membered heteroaryl group, 3- 14-membered cycloalkyl group, 3-14-membered heterocycloalkyl group, 7-12-membered spirocyclyl group, 7-12-membered bridged ring group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group can be Fused with another 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, any CH ₂ of the 3-14 membered heterocycloalkyl can be replaced by C(O);

R ⁵ is sulfonyl, halogen, C _1-6 alkyl, halogenated C ₆ alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -COC ^ alkane radical, -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0) N(R ^a R ^b ), -( _{CH 2} ) _p -OH, amino, cyano, hydroxyl, C _2-6 alkenyl, C 2.6 alkynyl, 3-14 membered cycloalkyl, _6-14 membered Aryl or 3-14 membered heterocycloalkyl;

R ^A and R ^B are independently hydrogen, C ₆ alkyl, -(CH ₂ ) _P -OC _1-6 alkyl, phenyl C _1-6 alkyl, and p is selected from 1, 2, 3 or 4.

3. The compound as described in any one of the preceding technical schemes, its pharmaceutically acceptable salt or its stereoisomer:

in,

X and Y are independently N or CR ¹ , wherein at least one of X and Y is N;

Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N;

R ¹ and R ² are independently hydrogen, sulfonyl, halogen, _{d.6 alkyl, C^6 alkoxy} , amino, cyano, hydroxyl;

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

L is d_6 alkyl, d- ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or at least one R ³ substituted phenyl, quinolinyl, 5-6 membered heteroaryl, 3 -8-membered cycloalkyl or 3-8-membered heterocycloalkyl;

0

R ³ is ^" ^ or / R ⁴ ,

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

R ⁴ is sulfonyl, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), alkoxy, Amino, cyano, hydroxyl, 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl that are unsubstituted or substituted by at least one R ⁵ , Wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be fused with another 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, 3-14 membered heterocycloalkane Any C2 of the group can be substituted by C(O);

R ⁵ is sulfonyl, halogen, _-6 alkyl, halogenated _{d.6 alkyl, C 1-6 alkoxy} , -C(0)-0-Ci _-6 alkyl, -ccc -c alkyl , -(CH ₂ ) _p -C(0)-0- _d.6 alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N( R ^a R ^b ), -(CH ₂ ) _p -OH, amino, , hydroxyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-14 membered cycloalkyl, 6-14 membered aryl or 3 -14 membered heterocycloalkyl;

R ^a and R ^b are independently hydrogen, ^ ₆ alkyl, -(CH^p-OCw alkyl, benzyl or phenylethyl, and p is selected from 1, 2, 3 or 4.

4. The compound as described in any one of the preceding technical schemes, its pharmaceutically acceptable salt or its stereoisomer:

in,

X and Y are independently N or CR ¹ , wherein at least one of X and Y is N;

Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N;

R ¹ and R ² are independently hydrogen and alkyl;

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

L is d_ ₆ alkyl, C ^ ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or at least one R ³ substituted phenyl, quinolinyl, 5-6 membered heteroaryl, 3 -8-membered cycloalkyl or 3-8-membered heterocycloalkyl;

o

_R 3 is / or / C, _R4 , wherein m is selected from 0, 1, 2 or 3,

R ⁴ is sulfonyl, halogen, C _1-6 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), _{d_6} alkoxy, amino, cyano, hydroxyl, Unsubstituted or substituted by at least one R ⁵ phenyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl , phenyl or heteroaryl can be fused with another cycloalkyl, heterocycloalkyl, phenyl or heteroaryl, any CH ₂ of 3-8 membered heterocycloalkyl can be substituted by C(O);

R ⁵ is C _1-6 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C(0)-C _1-6 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(C¾) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ) , -(C3) _p -OH, amino, cyano, hydroxyl, 3-8 membered cycloalkyl, phenyl, 3-8 membered heterocyclyl;

R ^A and R ^B are independently hydrogen, C alkyl, -(C¾) _P -OC _1-6 alkyl, benzyl or phenylethyl; p is selected from 1, 2, 3 or 4.

5. The compound as described in any one of the preceding technical schemes, its pharmaceutically acceptable salt or its stereoisomer:

Wherein, X, Y are independently N or CR ¹ , wherein at least one of X, Y is N; Z, W, U, G are independently N or CR ¹ , wherein Z, W, U, G are at least There is 1 for N;

R ¹ and R ² are independently hydrogen and C^ ₆ alkyl;

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

1^ is (^ ₆ alkyl, ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or at least one R ³ substituted phenyl, quinolinyl, 6-membered heteroaryl, 3-8 Cycloalkyl or 3-8 heterocycloalkyl;

^R3 is

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

R ⁴ is sulfonyl, halogen, (^ _-3 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), C _1-6 alkoxy, amino, cyano, Hydroxy, unsubstituted or phenyl substituted by at least one R5, ^5-6 membered heteroaryl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl or 1,2,3,4-tetra Hydrogen isoquinolin-2-yl, wherein any _CH of the 3-8 membered heterocycloalkyl can be replaced by C (O);

R ⁵ is C _1-6 alkyl group, C _1-6 alkoxy group, -c(o)-oc _1-6 alkyl group, -c ^-c ^ alkyl group, Alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, amino, cyanide group or hydroxyl group;

R ^A and R ^B are independently hydrogen, C alkyl, -(CH ₂ ) _P -OC _1-3 alkyl or benzyl, and p is selected from 1, 2 or 3.

6. The compound as described in any one of the preceding technical schemes, its pharmaceutically acceptable salt or its stereoisomer:

in,

X and Y are independently N or CR ¹ , wherein at least one of X and Y is N;

Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N;

R ¹ and R ² are independently hydrogen and d. ₆ alkyl;

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

! ^ for. ^ alkyl, d. ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or at least one R ³ substituted phenyl, quinolinyl, 6-membered heteroaryl, 3-8-membered cycloalkane Base or 3-8 membered heterocycloalkyl;

0

_R3 is ^ _R4 or,

wherein m is selected from 0, 1, 2 or 3, R ⁴ is sulfonyl, halogen, C _1-3 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), C _1-6 alkoxy, amino, cyano, hydroxyl, unsubstituted or at least one R ⁵ substituted 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or 1,2,3,4- Tetrahydroisoquinolin-2-yl, wherein any _CH of the 3-8 membered heterocycloalkyl can be replaced by C (O);

R ⁵ is Ci _-3 alkyl, Ci _{- 6} alkoxy, -C(0)-0-Ci.6 alkyl, -C(0)-Ci _-3 alkyl, -(CH ₂ )pC(0 )-0- _Ci.3 alkyl, -(CH ₂ ) _p -0-C _1-3 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, amino, ^J^ or hydroxyl;

R ^a and R ^b are independently hydrogen, (^ ₆ alkyl, -(CH ₂ ) _p -OCw alkyl or benzyl, respectively,

p is selected from 1 , 2 or 3.

7. The compound as described in any one of the preceding technical schemes, its pharmaceutically acceptable salt or its stereoisomer:

in,

X and Y are independently N or CR ¹ , wherein at least one of X and Y is N;

Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N;

R ¹ and R ² are independently hydrogen, methyl or ethyl;

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

L is alkyl, -N(R ^a R ^b ), unsubstituted or phenyl substituted by at least one R ³ , quinolinyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl, tetrahydropyridine Fyl, piperazinyl or morpholinyl;

0

_R 3 is ^R ₄ or ^e , _R4 ,

where m is selected from 0 or 1 ,

R ⁴ is sulfonyl, halogen, C _1-3 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), unsubstituted or at least one pyridyl substituted by R ⁵ , pyrazolyl, imidazolyl, pyrimidinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrole 2-one-yl;

R ⁵ is C _1-3 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C(0)-C _1-3 alkyl, -(CH ₂ )pC(0)-0-C ₁ _ ₃ alkyl, -(CH ₂ ) _p -0-C _1-3 alkyl, -(C¾) _p -C(0)N(R ^a R ^b ), - (CH ₂ ) _p -OH;

R ^a and R ^b are independently hydrogen, C _1-6 alkyl, -(CH^-OCw alkyl or benzyl,

p is selected from 1, 2 or 3.

8. The compound as described in any one of technical schemes 1-7, its pharmaceutically acceptable salt or its immediate body isomers,

One of X and Y is N, and the other is 0 ¹ .

9. The compound described in any one of technical schemes 1-8, its pharmaceutically acceptable salt or its stereoisomer,

Where Z represents CH, W represents CH;

U stands for N and G stands for N.

10. A compound selected from the following, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

01

M0ZN3/X3d 98ΪΪ/ 0Ζ OAV

II

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680

no

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

11. A compound selected from the group consisting of:

12. A pharmaceutical composition comprising the compound described in any one of technical schemes 1 to 11, its pharmaceutically acceptable salt or its stereoisomer and one or more pharmaceutically acceptable carriers.

13. The compound described in any one of technical schemes 1 to 11, its pharmaceutically acceptable salt or its stereoisomer, or the pharmaceutical composition of technical scheme 12 in the preparation of treatment and/or prevention of ischemia-reperfusion injury, diabetes , neurodegeneration, chronic inflammation (eg, allergy, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, allergic keratitis, dry eye, retinopathy, glaucoma), pulmonary Use in medicine for fibrosis, liver fibrosis, fatty liver or cirrhosis.

14. A treatment and/or prevention of ischemia-reperfusion injury, diabetes, neurodegeneration, chronic inflammation (such as allergy, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, Allergic keratitis, dry eye, retinopathy, glaucoma), pulmonary fibrosis, liver fibrosis, fatty liver or liver cirrhosis, including administering any one of the technical schemes 1-12 to patients in need thereof The above-mentioned compound, its pharmaceutically acceptable salt or its stereoisomer or the pharmaceutical composition of technical scheme 13. 15. For the treatment and/or prevention of ischemia-reperfusion injury, diabetes, neurodegeneration, chronic inflammation (such as allergy, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, Allergic keratitis, dry eye, retinopathy, glaucoma), pulmonary fibrosis, liver fibrosis, fatty liver or the compound described in any one of technical schemes 1 to 12 of cirrhosis, its pharmaceutically acceptable salt or Its stereoisomer or the pharmaceutical composition of technical scheme 13. Detailed ways

In the present invention, the term "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present invention, the term "C^ ₆ alkyl" refers to a linear or branched alkyl group containing 1-6 carbon atoms, including, for example, " _{d_5} alkyl", "CM alkyl", "C alkane ", etc.; examples include but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethyl Ethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl base, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The terms "C _1-5 alkyl", "CM alkyl", and "C _1-3 alkyl" refer to those containing 1-5 carbon atoms, 1-4 carbon atoms, and 1-3 carbon atoms in the above examples, respectively. A concrete instance of an atom.

In the present invention, the term "<^ ₆ alkenyl" refers to a straight-chain or branched chain or cyclic hydrocarbon group containing double bonds with carbon atoms of 2 to 6, including for example "C _2-5 alkenyl", " CM alkenyl", "C _2-3 alkenyl", "C _3-6 cycloalkenyl, etc.; examples thereof include but are not limited to vinyl, 1-propenyl, 2-propenyl, 1-methyl yl vinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl small propenyl,

1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methylpentyl Butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl,

₂ -Methyl_2-butenyl, 3-methyl- ₂ -butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3 -butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, ethyl-1-propenyl Base, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl Phenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl Base-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl Base, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl -4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2- Dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butene base, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl Small butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3, 3-Dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl- 1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1- Methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1,3-butadiene, 1,3- Pentadiene, 1,4-pentadiene, 1,4-hexadiene, etc.; Examples of the "C ₃ _ ₆ cycloalkenyl" include but are not limited to, for example, cyclopropenyl, cyclobutenyl, cyclopentyl Alkenyl, 1,3-cyclopentadienyl, cyclohexyl, 1,4-cyclohexadienyl, etc.

In the present invention, the term "alkynyl" refers to a straight _{-chain or branched hydrocarbon group with 3-6 carbon atoms containing a triple bond, including, for example, "(2-5 alkynyl} ", "Cw alkynyl", " C ₂ _ ₃ alkynyl"etc.; Examples thereof include but are not limited to, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1 ,1-Dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1- Methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl Alkynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butane Alkynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl Alkynyl, 2-ethyl-3-butynyl, 1-ethylmethyl-2-propynyl, etc.

In the present invention, the term "C _1-6 alkoxy" refers to a "C _1-6 alkyl-O-" group, wherein "Q_ ₆ alkyl" is as defined above, including, for example, "Cw alkoxy ", "CM alkoxy", "Cw alkoxy"etc.; examples thereof include but are not limited to, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy, etc.

In the present invention, the term "3-14 membered cycloalkyl" refers to a cycloalkyl group having 3-14 carbon atoms, including, for example, "3-12 membered cycloalkyl", "3-10 membered cycloalkane Base", "3-8 membered cycloalkyl", "3-6 membered cycloalkyl", "5-10 membered cycloalkyl", "5-8 membered cycloalkyl", "5-10 membered cycloalkane ", "4-6 membered cycloalkyl group" and the like; also include "3-8 membered monocyclic cycloalkyl group" and "6-14 membered condensed ring cycloalkyl group".

The "3-8 membered monocyclic cycloalkyl group" refers to a monocyclic cycloalkyl group with 3-8 carbon atoms, including for example "3-6 membered monocyclic cycloalkyl group", "5-8 membered monocyclic group Cycloalkyl", "5-6 membered monocyclic cycloalkyl" and the like; examples include but are not limited to: cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, cycloheptyl, cyclo Octyl, etc.; said "3-8 membered monocyclic cycloalkyl", can also be further substituted by C alkyl, including but not limited to: methylcyclopropyl, dimethylcyclopropyl, methylcyclobutane Alkyl, dimethylcyclobutanyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl, etc.

The "6-14 membered fused ring cycloalkyl" refers to the condensed ring formed by two or more ring structures sharing two adjacent carbon atoms with each other, including for example "6-12 membered fused ring naphthenes ", "8-12 membered fused ring cycloalkyl", "7-10 membered fused ring cycloalkyl" etc.; Examples include but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[4.1 .0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octyl, octahydroindenyl, decalinyl, Tetrahydrophenanthrene and others.

In the present invention, the term "6-14 membered aryl" refers to an aromatic group having 6-14 carbon atoms, including, for example, "6-10 membered aryl"; also includes "6-8 membered monocyclic aryl " and "8-14 membered fused ring aryl".

The "6-8 membered monocyclic aryl group" includes, for example, phenyl.

The "8-14 membered fused ring aryl group" refers to two or more ring structures that share two adjacent carbon atoms with each other and have 8-14 carbon atoms and at least one ring is aromatic fused ring groups, including 10-14 membered fused ring aryl groups whose rings are all aromatic rings, such as naphthalene, phenanthrene, etc.

In the present invention, the term "3-14 membered heterocycloalkyl" refers to a cyclic group containing 3-14 ring atoms (including at least one heteroatom), including, for example, "3-10 membered heterocycloalkyl ", "4-12 membered heterocycloalkyl", "3-8 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "5-8 membered heterocycloalkyl", "5-6 "Heterocycloalkyl", etc., also includes "3-8 membered monocyclic heterocycloalkyl" and "6-14 membered condensed ring heterocycloalkyl". The heteroatoms mentioned include nitrogen, oxygen and sulfur, etc., ring The atom can be oxo when it is _CH2 .

The "3-8 membered monocyclic heterocycloalkyl" refers to a monocyclic heterocycloalkyl containing 3-8 ring atoms (including at least one heteroatom), including, for example, "5-8 membered monocyclic Heterocycloalkyl", "5-6 membered monocyclic heterocycloalkyl", "3-6 membered saturated monocyclic heterocycloalkyl"etc.; specific examples include but are not limited to: aziridine, aza Cyclobutanyl, Thietanyl, Tetrahydrofuranyl, Tetrahydropyrrolyl, Imidazolidinyl, Pyrazolidinyl, Tetrahydrofuryl, 1,4-dioxanyl, 1,3-Dioxo Heterocyclohexyl, 1,3-dithianyl, piperidinyl, morpholinyl, piperazinyl, etc.; further, when the ring atom is CH ₂ , it can be oxo, such as piperidine-2- Ketones etc.

The "6-14 membered fused ring heterocycloalkyl" refers to 6-14 ring atoms (including at least one heteroatom) connected by two or more ring structures sharing two adjacent atoms The condensed ring heterocycloalkyl groups formed together include, for example, "8-12 membered fused ring heterocycloalkyl", "7-10 membered fused ring heterocycloalkyl", "9-10 membered fused ring heterocycloalkane Base", "9-12 membered condensed ring heterocycloalkyl group, etc.; Specific examples thereof include, but are not limited to: cyclobutane tetrahydropyrrolyl, cyclopentane tetrahydropyrrolyl, azetidin imidazolidinyl, etc.

In the "5-14 membered heteroaryl group" described in the present invention, the ring atoms include one or more heteroatoms in addition to carbon atoms, and the "heteroatoms" include but are not limited to oxygen atoms, nitrogen atoms and <atoms . Heteroaryl can be bonded through carbon or hetero ring atoms. Including 5-8 membered monocyclic heteroaryl and 8-14 membered condensed heteroaryl.

"5-8 membered monocyclic heteroaryl" refers to an aromatic cyclic group containing heteroatoms, including for example "5-6 membered monocyclic heteroaryl", "5-7 membered monocyclic heteroaryl "etc.; Specific examples thereof include, but are not limited to, furyl, thiazolyl, pyrrolyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, ¹ , 3,4-thiadiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, oxazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazinyl, 1,2,4-tri Azinyl, tetrazolyl, oxatriazolyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 2H-1,3-oxazinyl Base, 4H-1,3-oxazinyl, 611-1,3-oxazinyl, 2H-1,4-oxazinyl, 4H-1,4-oxazinyl, isoxazinyl, 1,3, 5-triazinyl, 1,2,4,5-tetrazinyl, pyridazinyl, pyrimidinyl and pyridinyl.

The "8-14 membered fused heterocyclic aryl group" refers to a condensed heterocyclic group in which all rings are aromatic rings, including, for example, "8-12 membered condensed heterocyclic aryl group", "9-10 membered fused heterocyclic aryl", "10-14 membered condensed heterocyclic aryl", etc., such as fused heterocyclic aryl formed by benzo 5-8 membered monocyclic heteroaryl, 5-8 membered monocyclic heteroaryl and A condensed heterocyclic aryl group formed by a 5-8 membered monocyclic heteroaryl group, etc., and its specific examples include but are not limited to: benzofuryl, benzoisofuryl, benzothienyl, indolyl, benzoxa Azolyl, benzimidazolyl, indazolyl, benzotriazolyl, ^lindyl , ^isolinyl , pyridopyrazolyl, pyridopyrazolyl, pyrimidopyrazolyl ^. Chinopyrrolyl, ^acridyl , phenanthridinyl, benzoda. Qinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridyl, purinyl, isoindole, isoindolyl, indolyl, benzodiazinyl, benziso Oxazolyl, benzoxazinyl, pyrazolo[3,4-b]pyridyl, etc.

In the present invention, the term "7-12-membered bridged ring group" refers to an aliphatic hydrocarbon group containing 7-12 ring atoms formed by any two rings sharing two atoms that are not directly connected, and the ring atoms may all be carbon Atoms may contain heteroatoms, such as nitrogen, oxygen and sulfur. The "7-12 member bridged ring" includes "7-12 membered saturated bridged ring group" and "7-12 membered unsaturated bridged ring group".

The "7-12 membered saturated bridging ring group" refers to a cyclic group in which all rings in the bridging ring are saturated,

"7-10 membered saturated bridging ring group", "7-8 membered saturated bridging ring group" etc., specific examples thereof include

The "7-12 membered unsaturated bridged ring group,,, refers to a ring group in which at least one ring is unsaturated in the bridged ring group, including for example "7-10 membered unsaturated bridged ring group" , "7-8 membered unsaturated bridging ring group", etc., its specific examples include but are not limited to:

In the present invention, the term "7-12 membered spirocyclic group" refers to a type of aliphatic hydrocarbon group containing 7-12 ring atoms formed by at least two rings sharing one atom, and the ring atoms can all be carbon atoms or Contains heteroatoms, the heteroatoms are selected from nitrogen, oxygen, sulfur and the like. Including, for example, "7-11 membered spirocyclyl", "8-11 membered spirocyclyl", "9-10 membered spirocyclyl", etc., also includes "7-12 membered saturated spirocyclyl" and "7- 12-membered unsaturated spirocyclyl".

The "7-12 membered saturated spirocyclic group" means that all rings in the spirocyclic group are saturated rings, including for example "7-11 membered saturated spirocyclic group", "8-", "9- 10 yuan full"

The "7-12 membered unsaturated spirocyclic group" refers to a ring in which at least one ring in the spirocyclic group is unsaturated, including for example "7-11 membered unsaturated spirocyclic group", "8-11 Elementary unsaturated spirocyclic group", "9-10 yuan

In the present invention, heteroatoms refer to O, N, S, SO and SO:

Some compounds of the present invention:

Structural formula

HZ

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

680000/M0ZN3/X3d 98Ϊ Ϊ/ 0Ζ OAV

98ΪΪ/ 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

Intermediate 2 Raw material 3 Compound represented by formula (I)

(la) (lb)

reaction steps

(1) Mix raw material 1 and malononitrile in absolute ethanol, add glacial acetic acid, heat up, 30-100°C. C was reacted for 5-24 hours, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether→petroleum ether:ethyl acetate=1:0.5-2) obtained a yellow solid;

(2) Dissolve intermediate 1 in tetrahydrofuran, under nitrogen protection, slowly add sodium hydride, 0-30. Stir at C for 10-120 minutes, add raw material 2, 0-30. C, reacted for 5-24 hours, added water, adjusted to weak acidity with hydrochloric acid, precipitated solid, filtered, washed the filter cake with water, dried the filter cake to obtain a solid, which was directly used in the next step;

(3) Add sodium hydride to A^V-dimethylacetamide, add raw material 3, react at 0-30°C for 10-120 minutes, then add intermediate 2, then heat up to 50-150°C to react 3- After 15 hours, the reaction solution was spin-dried, and subjected to silica gel column chromatography (dichloromethane→dichloromethane:methanol=20:0.1-5) to obtain the compound shown in formula (I).

X, Y, G, U, Z, W, L, R ¹ , R ² and n in the above reaction equation are as defined above, and the compound shown in formula (I) can be its isomer such as formula (I & ) or the compound shown in (I b). If necessary, the functional group to be protected can be protected with a conventional protecting agent, and then removed by a conventional method; if necessary, some compounds can also be prepared, such as the preparation of raw material 1.

The present invention claims "pharmaceutically acceptable salts" of compounds represented by formula (I), (la) or (lb), including alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, Such as calcium salt, magnesium salt, etc.; other metal salts, such as aluminum salt, iron salt, zinc salt, copper salt, nickel salt, cobalt salt, etc.; inorganic alkali salt, such as ammonium salt; organic alkali salt, such as tert-octylamine salt , dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt , dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylamine salt, tris(hydroxymethyl)aminomethane salt; hydrohalide salt, Such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkane sulfonates, such as methanesulfonate salt, trifluoromethanesulfonate, ethanesulfonate, etc.; arylsulfonate, such as benzenesulfonate, p-benzenesulfonate, etc.; organic acid salt, such as acetate, malate, fumarate salt, succinate, citrate, tartrate, oxalate, maleate, etc.; amino acid salts, such as glycinate, trimethylglycinate, arginine, ornithine, glutamic acid Salt, aspartate, etc.

The present invention claims to protect the "stereoisomers" of the compounds represented by formula (I), (la) or (lb), when there are one or more asymmetric carbon atoms in the compound structure, enantiomers will be produced; When the compound contains alkenyl or cyclic structure, cis/trans isomers will be produced; when the compound contains ketone or oxime, tautomers will be produced and so on. All such isomers and mixtures are within the scope of the present invention.

The compound represented by formula (I), (la) or (lb) of the present invention, its pharmaceutically acceptable salt or its stereoisomer can be prepared into a pharmaceutical preparation with one or more pharmaceutically acceptable carriers. The pharmaceutical preparations refer to conventional preparations used clinically, and can be administered to patients who need such treatment by oral or parenteral administration. Such as tablets, granules, capsules, powders, injections, inhalants, sublingual preparations, syrups, gels, ointments, suppositories, lotions, nasal drops, eye drops, sprays, transdermal preparations, etc. . These preparations can be prepared by conventional methods by adding pharmaceutical carriers such as excipients, binders, wetting agents, disintegrants, thickeners and the like.

The compound represented by formula (I), (la) or (lb) of the present invention, its pharmaceutically acceptable salt or its stereoisomer can be used to treat and/or prevent ischemia-reperfusion injury, diabetes, neurodegeneration Diseases such as lesions, chronic inflammation, pulmonary fibrosis, liver fibrosis, fatty liver or cirrhosis.

Chronic inflammation includes allergy, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, allergic keratitis, dry eye, retinopathy, glaucoma.

In this document, the following abbreviations have the following meanings:

HOAc: acetic acid

THF: Tetrahydrofuran

DMA: N,N-Dimethylacetamide

TLC: thin layer chromatography

DCM: Dichloromethane

MeOH: Methanol

DMSO: dimethyl sulfoxide

Ac: Acetyl

Me: methyl

PE: petroleum ether EA: ethyl acetate

HATU: 2-(7-Azobenzotriazole)-N,N,N,,N,-tetramethyluronium hexafluorophosphate

TBS: tert-butyldimethylsilyl

TBSC1: tert-butyldimethylsilyl chloride

DIPEA: N,N-Diisopropylethylamine

Boc: tert-butoxycarbonyl

Hepes: 4-Hydroxyethylpiperazineethanesulfonic acid

Brij-35: lauryl polyethylene glycol ether

DTT: Di^Τυthreitol

FAM: carboxyfluorescein

ATP: adenosine triphosphate

ALT: alanine aminotransferase

AST: aspartate aminotransferase

The beneficial effects of the compounds of the present invention are further described below through the in vitro enzymatic activity of the compounds of the present invention. Other compounds of the present invention have the same beneficial effects as the compounds of the present invention listed in the test, but this should not be interpreted as that the compounds of the present invention only have The following beneficial effects.

Experimental example 1 In vitro pharmacological activity of compounds of the present invention

Test product: Part of the compounds of the present invention, prepared according to the methods in the examples; the reference drug AS-602801, self-made.

Experiment method: Enzyme assay ( enzyme assay )

Caliper Mobility-Shift J K2 Assay:

Accurately weigh the test substance, add DMSO to dissolve, mix thoroughly, and make 10 mM. It was diluted to 50-fold final concentration with DMSO. Transfer 100 μl of the compound to the well plate, and perform a 3-fold serial dilution, with a total of 10 concentrations. 10 μl of the compound was transferred to a new 96-well plate, and 90 ul of kinase buffer (50 mM Hepes pH 7.5, 10 mM MgCl ₂ , 0.0015% Brij-35, 2 mM DTT) was added to each well of the 96-well plate. The final concentration of the compound was a maximum of 10 μΜ. After transferring 5 ul to a 384-well plate, add 10 μl of a kinase buffer containing JNK2, and after incubating at room temperature for 30 min, add 10 μl of a peptide buffer containing FAM-labeled peptide and ATP, and after incubating at 28°C for a specific time, add 25 μl of stop solution, stop the reaction. The substrate and product were separated and detected by electrophoresis, the conversion rate was calculated by Caliper's Reviewer software, and the inhibition rate was calculated by the following formula. The inhibition rate was calculated with Prism 5.0 to calculate the IC ₅ Q value.

Inhibition rate=[transformation rate (ZPE)-transformation rate (sample)] x 100/[transformation rate (ZPE)-conversion rate (HPE)] Note: HPE: the blank control without enzyme; ZPE: the blank without compound control.

Experimental results and conclusions: Table 1 IC ₅₀ values of compounds of the present invention to JNK2

Compound JNK2 enzyme inhibitory activity IC ₅ Q ( nM )

AS-602801 320

Compound 1 177

Compound 2 309

Conclusion: It can be seen from Table 1 that the compound of the present invention has a certain degree of inhibitory activity on JNK2 enzyme. Experimental example 2 In vitro pharmacological activity of the compounds of the present invention

Test product: Some compounds of the present invention were prepared according to the methods in the examples; the reference drug AS-602801 was self-made according to the method of WO2003047570.

Experiment method: Enzyme assay

HTRF JNK2 Assay (homogeneous time-resolved fluorescence technique to measure the activity of JNK2 enzyme): In this experiment, the HTRF method (Cisbio) was used to measure the inhibitory activity of the compound on JNK2. Accurately weigh the test product, add DMSO to dissolve, mix thoroughly, and make 10 mM. It was diluted to 50-fold final concentration with DMSO. Transfer 30 μl of the compound to a 96-well plate, and perform 4-fold serial dilutions, with a total of 7 concentrations. Then transfer 2μ1 to Kinase buffer containing 38μ1 to obtain a final concentration of up to

25 μM working solution. The compound was added to a 384-well plate, 4 μl per well. Then add a concentration of

0.04n^l of JNK2 kinase 2μ1, after incubation for 10min, ATP and substrate ATF-2 (Cell

Signaling) mixed solution 4 μl. After incubation at 25°C for 30 min, a mixture of Anti-GST-XL665 monoclonal antibody (Cisbio) and anti-phospho ATF2 Antibody-Cryptate (Cisbio) was added. After incubating at 25°C for 1 h, the fluorescence values of the test samples at 615nm and 665nm were detected with a microplate reader. The data is processed as follows:

Ratio= (665nm fluorescence value/615nm fluorescence value) ΐθ ⁴

, ,, Ratio ( Positive ) -Ratio ( Sample )

% inhibition rate = ——— ^ ——— xl 00%

Ratio ( Positive ) -Ratio ( negative )

STDEV ( Positive ) +STDEV ( negative )

Z'=l-3x

AVERAGE ( Positive ) - AVERAGE ( negative )

GraphPad 5.0 software was used for curve fitting, and the fitting equation was

Y=Bottom+(Top-Bottom)/(l+10 ^A ((LogIC ₅₀ -X)*HillSlope)), get the IC ₅₀ value' Table 2 The IC ₅ o value of the compound of the present invention to JNK2

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: It can be seen from Table 2 that the compounds of the present invention have better inhibitory activity on JNK2 than the control drug AS-602801.

Experimental example 3 Pharmacokinetic characteristics of the compound of the present invention in rats

Test product: some compounds of the present invention, prepared according to the methods in the examples

Real face method: PK experiment in rats ( in vivo PK evaluation in rats )

1. Animal experiments

Normal SD rats, intravenous injection (iv) and intragastric administration (po), 3/administration route. The dosages of the test products were 2 mg/kg and 4 mg/kg respectively, the administration concentration was 1 mg/ml, and the administration volumes were 2 ml/kg and 4 ml/kg respectively. For SD rats administered iv (intravenous injection), blood was collected from the tail vein at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration; SD rats administered po (oral) For rats, blood was collected from the tail vein at 0.17h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration. The resulting whole blood was placed in heparinized tubes. Plasma was separated after low-speed centrifugation (3500 rpm) for 8 min, almost 4. C Keep away from light. After the experiment was completed, all plasma samples were placed at -70. C refrigerator preservation.

2. Sample Analysis

The sample to be tested was taken out from the water tank (-70°C), and vortexed for 3 min after natural melting at room temperature. Precisely pipet 20 μl of sample into a 1.5 ml centrifuge tube. Add 200 μl of internal standard solution (AS-602801 50ng/ml methanol solution), vortex for 3 minutes, and centrifuge for 5 minutes (12000 rpm). Precisely pipette 50 μl of the supernatant, add 150 μl of water, vortex for 3 min, and then enter the LC-MS/MS system for sample analysis. The concentration of the test substance was output using Analyst 1.6.1 of AB Company. Microsoft Excel calculates the mean, standard deviation, coefficient of variation and other parameters (the direct output of Analyst 1.6.1 does not need to be calculated), and the PK parameters are calculated using the non-compartmental model (NCA) of Pharsight Phoenix 6.2 software. 3. Experimental results

Table 3 Summary of the PK parameters of the compounds of the present invention in rats

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 ± 310

AS-602801 68±12

1.32±0.55 3277±603

1.08±0.10 5305±357

Compound 5 78±42

2.97±1.16 8228±4424

6.75±4.88 11411±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±1525

Compound 93 109±18

3.00±0.18

3.27±0.60 100340±16494

Compound 217 97±7

2.75±0.23

2.30±0.56 11893±4267

Compound 218 100±21

4.95 ± 1.65

Remarks: tl/2 is half-life, AUC is exposure, F% is bioavailability.

The half-life of Compound 5 of the present invention is equivalent to that of AS-602801 when administered iv, and the half-life is more than twice that of AS-602801 when administered po. The exposure and bioavailability of Compound 5 of the present invention are better than AS-602801, the half-life, exposure and bioavailability of compound 29 of the present invention are better than those of AS-602801, so the compound of the present invention has a stronger advantage in PK compared with AS-602801.

Experimental Example 4 In vivo pharmacological activity of compounds of the present invention

Test product: some compounds of the present invention, prepared according to the methods in the examples

Experimental method: concanavalin-induced acute hepatitis model

After the C57BL/6 mice were acclimatized in the SPF animal room for 1 week, they were randomly divided into the model group and each administration group according to their weight; Gender and test date; Model group animals were given vehicle 30min after (10ml/kg), tail vein administration of Concanavalin A, ConA, 15mg/kg; each administration group was given the same dose of ConA through tail vein after 30min administration, After ConA was administered for 7 hours, the mice were anesthetized by sodium pentobarbital (intraperitoneal injection of 45 mg/kg), blood was collected from the inner canthus sinus for 30 (^1 (SOP-DS-200024-A), and placed in 1.5 ml without In the centrifuge tube of anticoagulant, let it stand at room temperature for 1h, and the blood sample is centrifuged with an eppendorf 5424R centrifuge. The centrifugation conditions were 3500rpm, 4°C, 10min, and then the serum was extracted, of which 100 μl of serum was determined for the contents of ALT and AST by an automatic biochemical analyzer, and the rest of the serum was stored in a -80°C refrigerator.

Inhibitory effects of compounds in Table 4 on mouse serum ALT and AST in the ConA-induced acute hepatitis model

Compound ALT 7h decreased ^0/0 _AST ^7h decreased _0/0

AS-602801 59 67 Compound 119 79 74 Conclusion: The compound of the present invention can significantly reduce the levels of ALT and AST in acute hepatitis model mice, and the effect is better than AS-602801.

The above-mentioned content of the present invention will be further described in detail through specific implementation in the form of examples below. However, it should not be construed that the scope of the above-mentioned subject matter of the present invention is limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. Example 1: 2-(2-(4-(morpholinomethyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-W pyridin-2-yl)acetonitrile (compound 1) Preparation

(1) Preparation of 2-(thiazolo[5,4-]pyridin-2-yl)acetonitrile

In a dry round bottom flask, add 10 mL ethanol, 1.26 g (10 mmol) pyridine-1-thiol, 660 mg (10 mmol) malononitrile, 720 mg (12 mmol) glacial acetic acid, and heat to reflux for reaction 15 h, TLC monitors the end of the reaction. The solvent was spin-dried, and column chromatography (DCM:MeOH=500:1) gave 1.01 g of a yellow solid with a yield of 57.7%.

Preparation of -(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile

In a dry reaction flask, add 20 mL THF, 1.01 g (5.77 mmol) 2-(thiazolo[5,4-)]pyridin-2-yl)acetonitrile, 346 mg (8.66 mmol) 60% NaH, 860 mg ( 5.77 mmol ) 2,4-Dichloropyrimidine was reacted for 15 h at room temperature. Add ice water to quench, add dilute hydrochloric acid to adjust to weak acidity, precipitate a solid, filter with suction, wash the filter cake with water, methanol, and ethyl acetate, and dry to obtain 860 mg of a yellow solid, with a yield of 51.8%.

(3) 2-(2-(4-(morpholinomethyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile

Dissolve 1.24 g (6 mmol) of 4-(morpholinomethyl)benzyl alcohol in 20 mL of DMA, add 480 mg (12 mmol) of 60% NaH, stir at room temperature for 1 h, then add 860 mg (2.99 mmol) 2-(2-Chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, heated to 100°C for 15 h. The reaction solution was poured into water, and dilute hydrochloric acid was added to make it acidic, and a crude solid was precipitated, which was filtered by suction and purified by column chromatography (DCM:MeOH=20:l) to obtain 600 mg of a yellow solid, with a yield of 43.8%.

Molecular formula: C ₂₄ H ₂₂ N ₆ 0 ₂ S; 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).

Example 2: 2-(2-(4-(morpholinomethyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)

Preparation of 3-aminopyridine-4-thiol

Weigh 4-chloro-3-nitropyridine (4.74 g, 30.0 mmol) and sodium hydrosulfide (5.04 g, 90.0 mmol) and dissolve in 300 mL of absolute ethanol solution, stir and react at room temperature for 1 hour, then add sodium hydrosulfide (sodium dithionite) (15.66 g, 90.0 mmol) in 100 mL of aqueous solution, heated to 80 ° C for 12 hours, filtered, the filtrate was concentrated, and silica gel column chromatography (petroleum ether→petroleum ether:ethyl acetate=3:1) get yellow green 3.3 g of colored solid, yield 87%.

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

3-Pyridine-4-thiol (2.52 g, 20.0 mmol) and malononitrile (1.32 g, 20.0 mmol) were mixed in 150 mL of absolute ethanol, 2.0 mL of glacial acetic acid was added, and the temperature was raised to 80°C. C was reacted for 12 hours, the reaction solution was concentrated, and silica gel column chromatography (petroleum sulfide→petroleum ether: ethyl acetate = 1:1) gave 2.6 g of a yellow solid, with a yield of 74%.

Preparation of -(2-chloropyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile

Weigh 2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile (1.75 g, 10.0 mmol) and dissolve it in 15 mL of dry tetrahydrofuran, under nitrogen protection, slowly add sodium hydride (60%, 0.8 g , 20 mmol), stirred at room temperature for half an hour, then added 2,4-dichloropyrimidine (1.49 g, 10.0 mmol), reacted at room temperature for 12 hours, added water, made weakly acidic with 1N hydrochloric acid, precipitated solid, filtered, The filter cake was washed with water and dried to obtain 3.0 g of solid, which was directly used in the next step.

( 4 ) 2-(2-(4-(morpholinomethyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile

Weigh sodium hydride (60%, 0.4 g, 10 mmol) into 5 mL of N-dimethylacetamide, add 4-(morpholinomethyl) benzyl alcohol (1.04 g, 5.0 mmol), room temperature After reacting for 1 hour, 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile (0.719 g, 2.5 mmol) was added, and then the temperature was raised to 100°C. C was reacted for 8 hours, the reaction solution was spin-dried, and silica gel column chromatography (dichloromethane→dichloromethane:methanol=20:1) gave 0.6 g of the product with a yield of 52.4%.

Molecular formula: C ₂₄ H ₂₂ N ₆ 0 ₂ S; Molecular weight: 458.15; Mass spectrum (M+H): 458.9

^-NMRiDMSO-^, 400 MHz): δ 8.89 (1H, 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).

Example 3: 2-(2-(4-((2,6-dimethylmorpholino)methyl)benzpyrimidin-4-yl)-2-(thiazolo[5,4-W pyridine-2 - base) preparation of acetonitrile (compound 3)

- Preparation of methyl dimethylmorpholino)methyl)benzoate

To the dry reaction flask, 30 mL of methanol, 576 mg (5.0 mmol) of 2,6-dimethylmorpholine, 2.46 g (15 mmol) of methyl p-formylbenzoate and 1 mL of glacial acetic acid were added respectively, and the reaction was carried out at 40°C for 18 h . Add 4.24 g (20 mmol) sodium triacetoxyborohydride slowly, and continue the reaction for 10 h. The solvent was spin-dried, and column chromatography (PE:EA=10:1-5:1) yielded 1.9 g of crude product as a white solid.

Preparation of methylmorpholino)methyl)phenyl)methanol

1.9 g of the crude product obtained in the previous step was dissolved in 40 mL of tetrahydrofuran, and 760 mg (20 mmol) of lithium aluminum hydride was slowly added in portions, and reacted at room temperature for 1 h. Ammonium chloride aqueous solution was added to quench, diatomaceous earth was suction filtered, the filter cake was washed with methanol, the filtrate was spin-dried, and purified by preparative liquid chromatography (methanol:water=50:50w/w) to obtain 700 mg of a white solid, which was collected in the above two steps. The rate is 59.5%.

( 3 ) 2-(2-(4-((2,6-Dimethylmorpholino)methyl)benzyloxy)pyrimidin- ⁴ -yl)-2-(thiazolo[5,4-

Dissolve 470 mg (2 mmol) (4-((2,6-dimethylmorpholino)methyl)phenyl)methanol in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, Stir at room temperature for 1 h, add 288 mg (1 mmol) 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-?]pyridin-2-yl)acetonitrile, N ₂ protection, 100 °C for 18 h. Add water, adjust to neutral with dilute hydrochloric acid, extract with dichloromethane, wash with water, dry, spin-dry, column chromatography (DCM→DCM:MeOH=100:1), obtain 140 mg of yellow solid, dissolve it in 4mL di In methyl chloride, 8 mL of ether was slowly added, a solid was precipitated, and centrifuged to obtain 40 mg of a yellow solid, with a yield of 8.2%.

Molecular formula: C ₂₆ H ₂₆ N ₆ 0 ₂ S; Molecular weight: 486.2; Mass 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).

Example 4: 2-(2-(4-(piperidin-1-ylmethyl)benzylpyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridine-2-

(1) Preparation of methyl 4-(piperidin-1-ylmethyl)benzoate

30 mL of methanol, 852 mg (10 mmol) of piperidine, 1.64 g (10 mmol) of methyl p-formylbenzoate, and 1 mL of glacial acetic acid were added to the dry reaction flask of CQzMe, and reacted at 40°C for 18 h. Then 2.54 g (12 mmol) sodium triacetoxyborohydride was added slowly, and the reaction was continued for 10 h. Spin to dry, and column chromatography (PE:EA=5:1→100%EA) yielded 1.4 g of crude product as a white solid.

( 2 ) Preparation of (4-(piperidinylmethyl)phenyl)methanol

1.4 g of the crude product obtained in the previous step was dissolved in 40 mL of tetrahydrofuran, and 600 mg (15.8 mmol) of lithium aluminum hydride was slowly added in portions, and reacted at room temperature for 1 h. Add ammonium chloride aqueous solution to quench, diatomaceous earth suction filtration, methanol wash the filter cake, spin dry the filtrate, preparative liquid chromatography (methanol: water = 50:50w/w) to obtain a white solid 850 mg, the above two steps The rate is 41.4%.

(3) 2-(2-(4-(piperidin-1-ylmethyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)

Dissolve 410 mg (2 mmol) (4-(piperidin-1-ylmethyl)phenyl)methanol in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, stir at room temperature for 1 h, add 288 mg ( 1 mmol ) of 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, protected by N ₂ , reacted at 100°C for 18 h. Add water, adjust to neutral with dilute hydrochloric acid, filter with suction, dry the filter cake, and perform column chromatography (DCM→DCM:MeOH=10:l) to obtain 220 mg of a yellow solid, with a yield of 48.2%.

Molecular formula: C ₂₅ H ₂₄ N ₆ OS; Molecular weight: 456.2; Mass spectrum (M+H 456.9

^- MR (DMSO-i 6+D ₂ 0, 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).

Example 5: 2-(2-(4-((2-oxopyrrolidin-1-yl)methyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo

Preparation of [5,4--2-yl)acetonitrile (compound 29)

- Preparation of methyl ((2-oxopyrrolidin-1-yl)methyl)benzoate

Add pyrrolidone (1.7 g, 20 mmol) to 10 mL of DMA, add 60% NaH (800 mg, 20 mmol), stir at room temperature for 1 h, then add methyl p-bromomethylbenzoate (2.28 g , 9.95 mmol ), react at room temperature for 3 h. The system was poured into 100 mL of water, neutralized to neutral with dilute hydrochloric acid, extracted three times with ethyl acetate, washed with water, dried, spin-dried, column chromatography (PE:EA=5:1→1:2), and 1.11 g of the product was obtained , Yield: 47.8%.

Preparation of -(4-(hydroxymethyl)benzyl)pyrrolidin-2-one

Methyl 4-((2-oxopyrrolidin-1-yl)methyl)benzoate (1.11 g, 4.76 mmol) was added to 10 mL of THF, and slowly dropped into 2.5 ft at -25°C 1.9 mL of mol/L Lithium Aluminum Hydride was reacted for 3 h. 180 mg of water and 180 mg of 10% NaOH solution were added dropwise to the system, stirred thoroughly, filtered with suction, the filtrate was spin-dried, and purified by preparative liquid chromatography (methanol:water=50:50w/w) to obtain 230 mg of the product, yield: 23.5%.

(3) 2-(2-(4-((2-oxopyrrolidin-1-yl)methyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-]pyridine -2-yl) Preparation of acetonitrile

Dissolve l-(4-(hydroxymethyl)benzyl)pyrrolidin-2-one (230 mg, 1.12 mmol) in 2 mL of DMA, add 60% NaH (90 mg, 2.25 mmol), and add , stirred at room temperature for 2 h. Then 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile (161 mg, 0.56 mmol ) was added, and the temperature was raised to 100 °C under the protection of N ₂ °C for 16 h. Pour the system into water, adjust the pH to neutral with dilute hydrochloric acid, spin the system to dryness, and purify by preparative liquid chromatography (methanol:water=60:40w/w) to obtain 40 mg of the product, yield: 15.6%.

Molecular formula: C ₂₄ H ₂₀ N ₆ O ₂ S; Molecular weight: 456.14; Mass spectrum (M+H): 457.1

^] H-NMR (OMSO-d ₆ , 400 MHz): δ 8.19 (1H, 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).

Example 6 2-(2-(4-((1-pyrazol-1-yl)methyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo

Preparation of [5,4-2-yl)acetonitrile (compound 31)

-Preparation of ((1//-pyrazole small base)methyl)methyl benzoate

Methyl p-bromomethylbenzoate (3.42 g, 14.9 mmol), pyrazole (2.04 g, 30 mmol), and potassium carbonate (4.14 g, 30 mmol) were added to 30 mL of DMA respectively, and reacted at 50°C for 16 h. The system was poured into 100 mL of water, extracted three times with ethyl acetate, washed with water, dried, spin-dried, and subjected to column chromatography (PE:EA=5: 1→1:1), 2.5 g of the product was obtained, yield: 77.9%.

Preparation of -((li7-pyrazol-1-yl)methyl)phenyl)methanol

Add methyl 4-((1/-pyrazol-1-yl)methyl)benzoate (2.16 g, 9.99 mmol) to 20 mL of THF, and slowly add lithium aluminum hydride (0.76 g , 20 mmol ) at room temperature for 3 h. Add 0.76 g of water and 0.76 mL of 10% NaOH solution dropwise to the system, stir well, filter with suction, wash the filter cake twice with THF, spin the filtrate to dry, and perform column chromatography (PE:EA =5:1→100%EA ), 1.03 g of the product was obtained, yield: 54.8%.

(3) 2-(2-(4-((1-pyrazol-1-yl)methyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridine Pyridine-2-

Dissolve (4-((1/-pyrazol-1-yl)methyl)phenyl)methanol (188 mg, 1 mmol) in 2 mL of DMA, add 60% NaH (80 mg, 2 mmol) , the addition was completed, and stirred at room temperature for 2 h. Then 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-]pyridin-2-yl)acetonitrile (144 mg, 0.5 mmol) was added, and the temperature was raised to 100°C under the protection of N ₂ C was reacted for 16 h. Pour the system into water, adjust the pH to neutral with dilute hydrochloric acid, spin the system to dryness, and purify by preparative liquid chromatography (methanol:water=60:40 w/w) to obtain 20 mg of the product, yield: 9.1%.

Molecular formula: C ₂₃ H ₁₇ N ₇ OS; Molecular weight: 439.12; Mass spectrum (M+H): 440.1

^-NMR (DMSO- 400 MHz): δ 12.82 (1H, s), 8.34 (1H, 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).

Example 7: Preparation of 2-(2-(4-ethylbenzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (compound 37)

Dissolve 272 mg (2 mmol) H-ethylbenzyl alcohol in 10 ml DMA, add 160 mg (4 mmol) 60% NaH, stir at room temperature for 1 h, add 288 mg (1 mmol) 2-(2-chloropyrimidine -4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, _N2 protection, 100 ° C reaction for 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, filter with suction, The filter cake was dried, and the filter cake was further subjected to column chromatography (DCM--DCM:MeOH=500:1) to obtain 240 mg of a yellow solid with a yield of 61.9%.

Molecular formula: C ₂₁ H ₁₇ N ₅ OS; Molecular weight: 387.12; Mass spectrum (M+H): 388.1

MM R(DMSO-i ₆ , 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).

Example 8: Preparation of 2-(2-(cyclohexylmethoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-blpyridin-2-yl)acetonitrile (compound 89)

Dissolve 228 mg (2 mmol) cyclohexylmethanol in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, stir at room temperature for 1 h, add 288 mg (1 mmol) 2-(2-chloropyrimidine-4 - Base) -2-(thiazolo[5,4->]pyridin-2-yl)acetonitrile, N ₂ protection, 100 ° C reaction for 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, extract with dichloromethane, wash with water, dry, spin-dry, column chromatography (DCM→DCM:MeOH=500:1), obtain 210 mg of yellow solid, yield 57.5%.

Molecular formula: C ₁₉ H ₁₉ N ₅ OS; Molecular weight: 365.13; Mass (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).

Example 9: 2-(2-((tetrahydro-2 pyran-4-yl)methoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridine-2-acetonitrile (compound 93) preparation

Dissolve 228 mg (2 mmol) (tetrahydro-2-pyran-4-yl)methanol in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, stir at room temperature for 1 h, add 288 mg ( 1 mmol) 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, N ₂ protection, 100 ° C for 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, extract with dichloromethane, wash with water, dry the organic phase, spin dry, column chromatography (DCM→DCM:MeOH=100:l), and obtain 230 mg of yellow solid, yield 62.6% .

Molecular formula... C ₁₈ H ₁₇ N ₅ 0 ₂ S; 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).

Example 10: 2-(5-Methylthiazolo[5,4-6]pyridin-2-yl)-2-(2-(4-(morpholinomethyl)benzyl1J pyrimidin4-yl)acetonitrile (compound 119) preparation

(1) Preparation of 3-amino-6-methylpyridine-2-thiol

'NH ₂

SH

Weigh 2-chloro-6-methyl-3-nitropyridine (6.90 g, 40.0 mmol) and sodium hydrosulfide (6.61 g, 0.12 mol) and dissolve them in 500 mL of absolute ethanol solution, and stir the reaction at room temperature for 1 hour , then add 150 mL of an aqueous solution of sodium hydrosulfite (20.89 g, 0.12 mol), heat up to 80°C for 12 hours, filter, concentrate the filtrate, perform silica gel column chromatography (100% petroleum ether→petroleum ether: ethyl acetate=2 : 1) Obtain 1.95 g of yellow solid, yield 34.8%.

(2) Preparation of 2-(5-methylthiazolo[5,4-6]pyridin-2-yl)acetonitrile

.CN Mix 3-amino-6-methylpyridine-2-thiol (1.95 g, 13.9 mmol) and malononitrile (0.92 g, 13.9 mmol) in 50 mL of anhydrous methanol, add 20 mL of glacial acetic acid, Raise temperature to 90. C was reacted for 12 hours, the reaction solution was concentrated, dissolved in ethyl acetate, washed once with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried and concentrated to obtain 1.45 g of a yellow solid with a yield of 55.1%.

Preparation of -(2-chloropyrimidin-4-yl)-2-(5-methylthiazolo[5,4->]pyridin-2-yl)acetonitrile

Weigh 2-(5-methylthiazolo[5,4-6]pyridin-2-yl)acetonitrile (1.45 g, 7.66 mmol) and dissolve it in 20 mL of dry tetrahydrofuran, under nitrogen protection, slowly add sodium hydride (60 %, 0.612 g, 15.3 mmol), stirred at room temperature for half an hour, then added 2,4-dichloropyrimidine (1.141 g, 7.66 mmol), reacted at room temperature for 12 hours, added water, adjusted to weak acidity with 1N hydrochloric acid, and precipitated The solid was filtered, the filter cake was washed with water, and the filter cake was dried to obtain 2.3 g of a yellow solid, yield: 99.5%.

( 4 ) 2-(5-Methylthiazolo[5,4-6]pyridin-2-yl)-2-(2-(4-(morpholinomethyl)benzyloxy)pyrimidin-4-yl ) Preparation of acetonitrile

Weigh sodium hydride (60%, 0.2 g, 5.0 mmol) into 5 mL A^V-dimethylacetamide, add 4-(morpholinomethyl)benzyl alcohol (0.52 g, 2.51 mmol), room temperature Add 2-(2-chloropyrimidin-4-yl)-2-(5-methylthiazolo[5,4->]pyridin-2-yl)acetonitrile (0.377 g, 1.25 mmol) after reacting for 1 hour. The temperature was raised to 100°C to react for 8 hours, the reaction solution was spin-dried, and silica gel column chromatography (dichloromethane→dichloromethane:methanol=20:1) yielded 0.32 g of the product with a yield of 54.2%.

Molecular formula: C ₂₅ H ₂₄ N ₆ 0 ₂ S; Molecular weight: 472.17; Mass (M+H): 473.2

^-NMR (CDCl ₃ , 400 MHz): δ 14.41 (1H, 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).

Example 11: 2-(4-((4-(cyano(thiazolo[5,4-b]pyridin-2-yl)methyl)pyrimidin-2-yloxy)methyl-Λ^ν- Preparation of dimethylacetamide (compound 39)

- Preparation of (4-(methoxycarbonyl)phenyl)acetic acid

Methyl 4-(2-methoxy-2-oxoethyl)benzoate (4 g, 19.2 mmol ), lithium hydroxide monohydrate (847 mg, 20.17 mmol ) were dissolved in tetrahydrofuran/methanol/water Mixed solvent (60 mL, 4: 1: 1), stirred at room temperature for 24 h, concentrated under reduced pressure to remove most of the organic solvent, adjusted the pH to 3 in an ice bath, precipitated, filtered with suction, and dried the solid to obtain 3.4 g of a white solid , yield 91.2%.

(2) Preparation of methyl 4-(2-(dimethylamino)-2-oxoethyl)benzoate Dissolve 2-(4-(methoxylyl)phenyl)acetic acid (2.89 g, 14.88 mmol) in dichloromethane (40 mL), add 3 drops of AV "dimethylformamide, ice bath Oxalyl chloride (5.67 g, 44.64 mmol ) was slowly added dropwise, and after the drop was completed, it was stirred at room temperature for 2 h, concentrated under reduced pressure and dissolved in 20 mL of dichloromethane for later use.

Dimethylamine hydrochloride (4.85 g, 59.51 mmol) and triethylamine (9.04 g, 89.3 mmol) were dissolved in dichloromethane (100 mL), and slowly added dropwise to the above acid chloride in an ice bath solution, after dropping, stirred at room temperature for 2 h, and concentrated under reduced pressure to obtain a solid that was washed with water and dried to obtain 2.82 g of a yellow solid, with a yield of 85.7%.

Preparation of -(4-(hydroxymethyl)phenyl)-A^V-dimethylacetamide

Dissolve methyl 4-(2-(dimethylamino)-2-oxoethyl)benzoate (2.82 g, 12.7 mmol) in tetrahydrofuran (80 mL), add sodium borohydride (4.82 g, 127 mmol), Heated to reflux for 36 h, concentrated most of the solvent under reduced pressure, added water, extracted with ethyl acetate, dried the organic phase, concentrated, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a white solid 1.05 g, yield 42.5%.

Preparation of -(4-(chloromethyl)phenyl)-A^-dimethylacetamide

2-(4-(Hydroxymethyl)phenyl)-A^V-dimethylacetamide (0.41 g, 2.12 mmol) was dissolved in thionyl chloride (10 mL), and stirred at room temperature for 2 h. It was directly used in the next step after concentration under reduced pressure.

Preparation of -(2-hydroxypyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile

2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (863 mg, 3 mmol), sodium hydroxide (1.2 g, 30 mmol ) was added to water (20 mL), reacted at 90°C for 6 h, cooled, adjusted the pH to 6-7, a yellow solid was precipitated, filtered with suction, dried and then chromatographed on a silica gel column (dichloromethane:methanol=10:1) , to obtain 595 mg of yellow solid, with a yield of 73.6%.

( 6 ) 2-(4-((4-(cyano(thiazolo[5,4-b]pyridin-2-yl)methyl)pyrimidin-2-yloxy)methyl)phenyldimethyl Preparation of acetamide

2-(2-Hydroxypyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile (380 mg, 1.41 mmol ), 2-(4-(chloromethyl)phenyl)-N-dimethylacetamide (448 mg, 2.12 mmol ), cesium carbonate (1378 mg, 4.23 mmol ), potassium iodide (24 mg, 0.141 mmol ) Added V,N" dimethylacetamide (20 mL), reacted at 70°C for 16 h, cooled, poured into ice water, a yellow solid precipitated, suction filtered, dried, and silica gel column chromatography (dichloromethane: Methanol=10:1 ), 147 mg of a yellow solid was obtained, with a yield of 23.5%.

Molecular formula: C ₂₃ H _2Q N ₆ 0 ₂ S; 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).

Example 12: 2-(2-(4-((6-methylpyridin-3-yl)methyl)benzyl|Λ)pyrimidin-4-yl)-2-(thiazolo

Preparation of [5,4--2-yl)acetonitrile (compound 27)

(1) Preparation of (4-iodobenzyloxy)dimethyl tert-butylsilane

Dissolve p-iodobenzyl alcohol (9.9 g, 42.3 mmol ), imidazole (5.76 g, 84.6 mmol ) in 20 mL DMF, then slowly add TBSC1 (7.20 g, 47.3 mmol ), stir at room temperature for 14 h, and then 0°C CH was slowly added dropwise to 100 mL of water, the resulting solution was filtered, the filter cake was washed three times with 250 mL of water, and the filter cake was dried at 45°C to obtain 12.1 g of white solid, yield: 82%.

-Methoxy group-ΛΓ, the preparation of 6-dimethylnicotinamide

6-Methylnicotinic acid (2.00 g, 14.59 mmol), ΛζO-dimethylhydroxylamine hydrochloride (1.706 g, 17.51 mmol), DIPEA (4.05 g, 31.7 mmol), HATU (6.665 g, 17.51 mmol) were dissolved In 100 mL of dichloromethane, the solution was stirred overnight, then 100 mL of water was added, extracted with dichloromethane, the organic phase was dried, concentrated, and passed through a silica gel column (PE/EA=4: 1) to obtain 2.40 g of a light red solid. Yield: 91.4%

(3) Preparation of (4-((tert-butyldimethylsilyloxy)methyl)phenyl)(6-methylpyridin-3-yl)methanone

Take a 250 mL three-necked flask, dissolve (4-iodobenzyloxy) dimethyl tert-butylsilane (6.960 g, 20 mmol ) in 50 mL THF, replace with nitrogen three times, and then add the solution to the solution at -30°C Slowly add 2.4 N n-butyllithium hexane solution (4.2 mL, 10.08 mmol), stir at -30°C for 30 min, and cool to -78° (:. Then IV-methoxydimethylnicotinamide (1.8 g, 10 mmol) of 25 mL of anhydrous THF solution was slowly added dropwise to the above reaction solution, stirred for 120 min, TLC monitored the disappearance of the raw material, added 50 mL of ammonium chloride aqueous solution, extracted twice with 100 mL of ethyl acetate, The organic phase was dried, filtered, spin-dried, and passed through a silica gel column (PE:EA=4:1) to obtain 1.40 g of a colorless oil, yield: 41.1%

Preparation of -methylpyridin-3-yl)methyl)phenyl)methanol

Dissolve (4-((tert-butyldimethylsilyloxy)methyl)phenyl)(6-methylpyridin-3-yl)methanone (1.40 g, 4.11 mmol) in 20 mL triethyl Diol, then added 5 mL of 40% hydrazine hydrate, the solution was stirred at 110 ° C for 1 h, then added KOH (0.690 g, 12.35 mmol ), the solution was stirred at 140 ° C for 2 hours, and then cooled to room temperature , adding 100 mL of ethyl acetate and 50 mL of water for extraction, the organic phase was dried, spin-dried, and passed through a silica gel column (PE:EA=2:1) to obtain 0.54 g of a colorless oil, with a yield of 61.6%.

Preparation of -(4-(chloromethyl)benzyl)-2-picoline

Dissolve (4-((6-methylpyridin-3-yl)methyl)phenyl)methanol (0.54 g, 2.53 mmol) in 20 mL of dichloromethane, then slowly add 1 mL of dichloromethane dropwise Sulfone, the solution was stirred at room temperature for 2 hours, and spin-dried to obtain 0.58 g of a colorless oil, with a yield of 98.8%

( 6 ) 2-(2-(4-((6-methylpyridin-3-yl)methyl)benzyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridine - base) the preparation of acetonitrile

2-(2-Hydroxypyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (0.326 g, 1.212 mmol ), 5-(4-(chloromethyl ) benzyl) -2-picoline (0.42 g, 1.818 mmol ), cesium carbonate (1.184 g, 3.636 mmol ) and potassium iodide (20 mg, 0.121 mmol ) were added to A ^-dimethylacetamide (20 mL ), Reacted at 60 °C for 46 h, cooled, poured into ice water, a yellow solid was precipitated, filtered with suction, dried, and subjected to silica gel column chromatography (dichloromethane:methanol=15:1), to obtain 57 mg of a yellow solid, yield 10.1% .

Molecular formula: C ₂₆ H ₂ . N ₆ OS; 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).

Example 13: 2-(2-(cyclohexylmethylpyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile (

(1) Preparation of 2-(2-(cyclohexylmethoxy)pyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile

Weigh sodium hydride (60%, 0.320 g, 8.0 mmol) and add it to 6 mL A^V "dimethylacetamide, add cyclohexylmethanol (0.457 g, 4.0 mmol), react at room temperature for 1 hour, then add 2-( 2-chloropyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile (0.575 g, 2.0 mmol), then heated to 100°C for 4 hours, then spin-dried solution, silica gel column chromatography (dichloromethane→dichloromethane:methanol=100:1), the product 0.311 g was obtained, and the yield was 42.5%.

Molecular formula: C ₁₉ H ₁₉ N ₅ OS; Molecular weight: 365.1; Mass spectrum (M+H): 366.1

-NMR (^-DMSO, 400 MHz): δ 9.02 (1H, s), 8.32 (1H, 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).

Example 14: 2-(2-(piperidin-4-ylmethoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-W pyridin-2-yl)acetonitrile (compound 91

( 1 ) 4-((4-(cyano(thiazolo[5,4-6]pyridin-2-yl)methyl)pyrimidin-2-yloxy)methyl)piperidine·1-

Dissolve 300 mg (2 mmol) tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, stir at room temperature for 1 h, add 288 mg ( 1 mmol ) 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, protected by N ₂ , reacted at 100°C for 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, filter with suction, and purify the filter cake by high-pressure liquid phase preparative chromatography to obtain 220 mg of a yellow solid, with a yield of 47.2%.

(2) Preparation of 2-(2-(piperidin-4-ylmethoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile

220 mg (0.47 mmol) of 4-((4-(thiazolo[5,4-6]pyridin-2-yl)methyl)pyrimidin-2-yloxy)methyl)piperidine-1-carboxylic acid tert Butyl ester was dissolved in a mixed solvent of 20 mL of dichloromethane and 1 mL of methanol, and reacted for 2 h by passing dry HCl gas under an ice bath, and the reaction was completed by TLC monitoring. Suction filtration and drying of the filter cake gave 160 mg of a yellow solid with a yield of 93.6%.

Molecular formula: C ₁₈ H ₁₈ N ₆ OS; 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).

Example 15: 2-(4-(cyclohexylmethylpyrimidin-2-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (

The preparation method refers to Example 8, and it is obtained by separation by high-pressure liquid chromatography after column chromatography.

Molecular formula: C ₁₉ H ₁₉ N ₅ OS; Molecular weight: 365.1; Mass (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).

Example 16: 2-(2-((6-methylpyridin-3-yl)methoxy)pyrimidin 4-yl)-2-(thiazolo[5,4-b]pyridin--yl)acetonitrile ( Compound 216 ) Preparation

(1) Preparation of (6-methylpyridin-3-yl)methanol

1.51 g (10 mmol) of methyl 6-methylnicotinate was dissolved in 50 ml of THF, and 570 mg (15 mmol) of lithium aluminum tetrahydride was slowly added under ice-cooling, and reacted at room temperature for 1 h, and the reaction was completed by TLC monitoring. Add crystalline sodium sulfate decahydrate, filter with suction, spin the filtrate to dryness, and perform column chromatography (PE:EA=3:1→1:1) to obtain 1.1 g of a light green liquid with a yield of 89.4%.

- Preparation of (chloromethyl) -2-picoline

246 mg (2 mmol) (6-methylpyridin-3-yl)methanol was added to 5 mL of thionyl chloride, stirred at room temperature for 5 h, and the solvent was directly spin-dried for the next reaction.

( 3 ) 2-(2-((6-methylpyridin-3-yl)methoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)

Dissolve 260 mg (0.97 mmol) 2-(2-hydroxypyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile in 10 mL DMA, add 1.3 g ( 4 mmol) of cesium carbonate and 5-(chloromethyl)-2-picoline (about 2 mmol), and finally 20 mg (0.12 mmol) of potassium iodide was added, and the reaction was carried out at 70°C for 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, extract with dichloromethane, wash with water, dry, concentrate, and column chromatography (DCM:MeOH=500:l→ 100:1) to obtain 105 mg of yellow solid, yield 28.9%

Molecular formula: C ₁₉ H ₁₄ N ₆ OS; 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).

Example 17: 2-(2-(cyclohexyloxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (compound

Dissolve 200 mg (2 mmol) cyclohexanol in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, stir at room temperature for 1 h, add 288 mg (1 mmol) 2-(2-chloropyrimidine-4 -yl)-2-(thiazolo[5,4-]pyridin-2-yl)acetonitrile, N ₂ protection, 100°C for 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, filter with suction, and separate the filter cake by high-pressure liquid chromatography to obtain 160 mg of a yellow solid, with a yield of 45.5%. Molecular formula: C ₁₈ H ₁₇ N ₅ OS; Molecular weight: 351.1; Mass spectrum (M+ H): 352.1

-aldehyde R (DMSO-, 400 MHz): δ 12.67 (1H, 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 ).

Example 18: 2-(2-(2-cyclohexylethoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile

Dissolve 256 mg (2 mmol) cyclohexyl ethanol in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, stir at room temperature for 1 h, add 288 mg (1 mmol) 2-(2-chloropyrimidine-4 - Base) -2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, N ₂ protection, 100°C for 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, filter with suction, and separate the filter cake by preparative high-pressure liquid chromatography to obtain 180 mg of yellow solid, yield 47.4%

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

^-NMRCDMSO-^, 400 MHz): δ 12.72 (1H, 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).

Example 19: 2-(2-(2-cyclohexylpyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile

( 1 ) Preparation of 2-(2-(2-cyclohexylethoxy)pyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile

Weigh sodium hydride (60%, 0.211 g, 5.28 mmol) into 5 mL TV^N-dimethylacetamide, add 2-cyclohexyl ethanol (0.338 g, 2.64 mmol), react at room temperature for 1 hour, then add 2 -(2-chloropyrimidin-4-yl)-2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile (0.38 g, 1.32 mmol), then heated to 100. C was reacted for 8 hours, the reaction solution was spin-dried, and silica gel column chromatography (dichloromethane→dichloromethane:methanol=100:1) yielded 0.254 g of the product with a yield of 50.7%.

Molecular formula: C ₂ . H ₂₁ N ₅ OS; Molecular Weight: 379.1 ; Mass Spectrum (M+H): 380.2 ^-NMR (d ₆ -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).

Example 20: 2-(2-((1-methyl-1H-pyrazol-3-yl)methoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-W pyridine-2- Base) B

- Preparation of methylpyrazole-3-carboxylic acid methyl ester

Add 1.26 g (10 mmol) of 1-methylpyrazole-3-carboxylic acid into 30 mL of anhydrous methanol, add 2.38 g (20 mmol) of thionyl chloride under ice-cooling, move to room temperature for 18 h, spin The solvent was dried to obtain a white solid which was directly used in the next reaction.

- Preparation of methylpyrazol-3-yl)methanol

The product from the previous step (about 10 mmol) was added to 40 mL of tetrahydrofuran, and 570 mg (15 mmol) of lithium aluminum hydride was slowly added under ice-cooling. After the addition was completed, it was moved to room temperature for 3 h, and crystalline sodium sulfate decahydrate was added, and suction filtered. The filtrate was spin-dried and subjected to column chromatography (PE:EA=3:1→1:1) to obtain 800 mg of a colorless oil, and the yield of the above two steps was 71.4%.

( 3 ) 2-(2-((1-methyl-177-pyrazol-3-yl)methoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridine-2- base) the preparation of acetonitrile

Dissolve 224 mg ( ² mmol) (1-methyl-li/-pyrazol-3-yl)methanol in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, stir at room temperature for 1 h, Add 288 mg (1 mmol) 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, protect with N ₂ , react at 100°C for 18 h . Add water, adjust to weak acidity with dilute hydrochloric acid, filter with suction, the filter cake is separated by high-pressure liquid chromatography to obtain an impure product, recrystallized from DMSO to obtain 20 mg of a yellow solid, yield 5.5% Molecular formula: C ₁₇ H ₁₃ N ₇ OS; 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).

Example 21: ^2- ( ^2- ( ^2_ (2_oxopyrrolidin- ¹ -yl)ethoxy)pyrimidin_4-yl)-2-(thiazolo

[5,4--2-yl) the preparation of acetonitrile (compound 221)

Dissolve 258 mg (2 mmol) 1-(2-hydroxyethyl)pyrrolidin-2-one in 10 mL DMA, add 160 mg (4 mmol) 60% NaH, stir at room temperature for 1 h, add 288 mg ( 1 mmol) 2-(2-chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, protected by N ₂ , reacted at 100°C for 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, filter with suction, and separate the filter cake by preparative high-pressure liquid chromatography to obtain 160 mg of yellow solid, yield 42.1%

Molecular formula: C ₁₈ H ₁₆ N ₆ 0 ₂ S; 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).

Example 22: 2-(2-((4,4-difluorocyclohexyl)methoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-b]pyridin-2-yl)acetonitrile (

(1) Preparation of (4,4-difluorocyclohexyl)methanol

Add 1.92 g (10 mmol) of ethyl 4,4-difluorocyclohexylcarboxylate into 40 mL of tetrahydrofuran, slowly add 570 mg (15 mmol) of lithium aluminum tetrahydride under ice cooling, and move to room temperature for 3 h. Add crystalline sodium sulfate decahydrate, filter with suction, and spin the filtrate to dryness. Added water, extracted with ethyl acetate, dried, and spin-dried to obtain 1.1 g of light yellow oil with a yield of 73.3%.

(2) 2-(2-((4,4-difluorocyclohexyl)methoxy)pyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile preparation

Dissolve 3000¾(201)(4,4-difluorocyclohexyl)methanol in 10mLDMA, add 160 mg (4 mmol) 60% NaH, stir at room temperature for 1 h, add 288 mg (1 mmol) 2-( 2-Chloropyrimidin-4-yl)-2-(thiazolo[5,4-6]pyridin-2-yl)acetonitrile, N ₂ protection, 100°C for 18 h. Add water, adjust to weak acidity with dilute hydrochloric acid, filter with suction, dry the filter cake and dissolve it with DMSO, add a small amount of methanol, and precipitate a yellow solid 140 mg, yield 34.9%

Molecular formula: Ci ₉ H ₁₇ F ₂ N ₅ OS; Molecular weight: 401.1; Mass spectrum (M+H): 402.1

^-NMRCDMSO-^, 400 MHz): δ 12.79 (1H, 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)

Claims 1. The compound represented by general formula (I), (la) or (lb), its pharmaceutically acceptable salt or (I) (la) (!b) in, X and Y are independently N or CR ¹ , wherein at least one of X and Y is N; Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N; R ¹ and R ² are independently hydrogen, sulfonyl, halogen, alkyl, halo- ₆ alkyl, d.6 alkoxy, amino, cyano, hydroxyl, C _2-6 alkenyl, C ₂ _ ₆ -alkynyl, 6-14-membered aryl, 5-14-membered heteroaryl, 3-14-membered cycloalkyl, 3-14-membered heterocycloalkyl; n is selected from 0, 1, 2 or 3; ! ^ for. ^ alkyl, alkoxy, -N(R ^a R ^b ), unsubstituted or substituted by at least one R ³ 6-14 membered aryl group, 5-14 membered heteroaryl group, 3-14 membered cycloalkyl group, 3-14 membered heterocycloalkyl group, 7-12 membered spirocyclic group, 7-12 membered bridged ring group, wherein all The cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be fused with another 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; where m is selected from 0, 1, 2 or 3, R ⁴ is sulfonyl, halogen, C^ ₆ alkyl, halogenated C _1-6 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), ^ ₆ alkoxy , amino, cyano, hydroxyl, C^ ₆ alkenyl, C^ ₆ alkynyl, unsubstituted or at least one R ⁵ substituted 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered Cycloalkyl, 3-14 membered heterocycloalkyl, 7-12 membered spirocyclic group, 7-12 membered bridged ring group, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be combined with another 1-2 cycloalkyl, heterocycloalkyl, Aryl or heteroaryl fused, any CH ₂ of 3-14 membered heterocycloalkyl can be replaced by C(O); R ⁵ is sulfonyl, halogen, C _1-6 alkyl, halogenated C!— ₆ alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C( 0)-C _1-6 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(C ¾ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, amino, hydroxyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-14 membered cycloalkyl, 6-14 membered aryl or 3-14 membered heterocyclic group; R ^a and R ^b are independently hydrogen, C _1-6 alkyl, -(C ) _p -OC _1-6 alkyl or 6-14 membered aryl C _1-6 alkyl, p is selected from 1, 2, 3 or 4. 2. The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer: wherein, X and Y are independently N or CR ¹ , wherein at least one of X and Y is N; Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N; R ¹ and R ² are independently hydrogen, sulfonyl, halogen, (^ ₆ alkyl, d. ₆ alkoxy, amino, fj ^. hydroxyl, C _2-6 alkenyl, C _2-6 alkynyl, 6-14 membered aryl; n is selected from 0, 1 , 2 or 3; L is C _1-6 alkyl group, d_6 alkoxy group, -N(R ^a R ^b ), unsubstituted or at least one R ³ substituted 6-14 membered aryl group, 5-14 membered heteroaryl group, 3 -14-membered cycloalkyl, 3-14-membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be combined with another 1-2 cycloalkyl, heterocycloalkyl, Aryl or heteroaryl fused; 0 R ³ is or ^e , R ⁴ , where m is selected from 0, 1, 2 or 3, R ⁴ is sulfonyl, halogen, alkyl, halogenated _d.6 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), C _1-6 alkoxy, amino , cyano, hydroxyl, 6-14 membered aryl, ^5-14 membered heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 7 -12-membered spirocyclic group, 7-12-membered bridged ring group, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be combined with another 1-2 cycloalkyl, heterocycloalkyl, aryl Group or heteroaryl fused, any CH ₂ of 3-14 membered heterocycloalkyl can be replaced by C(O); R ⁵ is sulfonyl, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C( 0)-C _1-6 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, , , hydroxyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-14 membered cycloalkyl , 6-14 membered aryl or 3-14 membered heterocyclic group; R ^a , R ^b are independently hydrogen, C _1-6 alkyl, -(CH ₂ ) _p -OC _1-6 alkyl, phenyl C _1-6 alkyl, p is selected from 1, 2, 3 or 4. 3. The compound according to claim 2, its pharmaceutically acceptable salt or its stereoisomer: wherein, X and Y are independently N or CR ¹ , wherein at least one of X and Y is N; Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N; R ¹ , R ² are independently hydrogen, sulfonyl, halogen, _{d_6 alkyl, C 1-6 alkoxy} , amino, cyano, optional n is selected from 0, 1, 2 or 3; ! ^ is ^^ alkyl, alkoxy, -N(R ^a R ^b ), unsubstituted or phenyl substituted by at least one R ³ , quinolinyl, 5-6-membered heteroaryl, 3-8-membered Cycloalkyl or 3-8 membered heterocycloalkyl; 0 _R 3 is/^ _R4 or/e, _R4 , wherein m is selected from 0, 1, 2 or 3, R ⁴ is sulfonyl, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), alkoxy, Amino, cyano, hydroxyl, 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl that are unsubstituted or substituted by at least one R ⁵ , Wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be combined with another 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, 3-14 membered heterocycloalkane Any _CH of the group can be replaced by C(O); R ⁵ is sulfonyl, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C( 0)-C _1-6 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, , , hydroxyl, C ₂ _ ₆ alkenyl, C _2-6 alkynyl, 3-14 membered cycloalkyl , 6-14 membered aryl or 3-14 membered heterocyclic group; R ^a and R ^b are independently hydrogen, C _1-6 alkyl, -(C ¾ ) _p -OC _1-6 alkyl, benzyl or phenylethyl, and p is selected from 1, 2, 3 or 4. 4. The compound as claimed in claim 3, its pharmaceutically acceptable salt or its stereoisomer: wherein, X and Y are independently N or CR ¹ , wherein at least one of X and Y is N; Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N; R ¹ and R ² are independently hydrogen and _{d_6} alkyl; n is selected from 0, 1, 2 or 3; L is ^ ₆ alkyl, (^ ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or at least one R ³ substituted phenyl, quinolinyl, 5-6 membered heteroaryl, 3 -8-membered cycloalkyl or 3-8-membered heterocycloalkyl; 0 _R 3 is /^ or /^:, _r4 , wherein m is selected from 0, 1, 2 or 3, R ⁴ is sulfonyl, halogen, C _1-6 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), ₆ alkoxy, amino, cyano, hydroxyl, un Phenyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, substituted or at least one R ⁵ substituted, wherein the cycloalkyl, heterocycloalkyl, Phenyl or heteroaryl can be fused with another cycloalkyl, heterocycloalkyl, phenyl or heteroaryl, and any CH ₂ of 3-8 membered heterocycloalkyl can be replaced by C(O); R ⁵ is C _1-6 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C(0)-C _1-6 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-6 alkyl, -(CH ₂ ) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, amino, cyano, hydroxyl, 3-8 membered cycloalkyl, phenyl, 3-8 membered heterocyclic group; R ^a , R ^b are independently hydrogen, C _1-6 alkyl, -(CH ₂ ) _p -OC _1-6 alkyl, benzyl or phenylethyl; p is selected from 1, 2, 3 or 4 . 5. The compound as claimed in claim 4, its pharmaceutically acceptable salt or its stereoisomer: wherein, X and Y are independently N or CR ¹ , wherein at least one of X and Y is N; Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N; R ¹ and R ² are independently hydrogen and C alkyl; n is selected from 0, 1, 2 or 3; ! ^ is ^— ₆ alkyl, d.6 alkoxy, -N(R ^a R ^b ), unsubstituted or at least one R ³ substituted phenyl, quinolinyl, 6-membered heteroaryl, 3- 8-membered cycloalkyl or 3-8-membered heterocycloalkyl; 0 R ³ is ^^ or / ^e , R ⁴ , wherein m is selected from 0, 1, 2 or 3, R ⁴ is sulfonyl, halogen, ₃ alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), C _1-6 alkoxy, amino, cyano, hydroxyl, un Phenyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl or piperidophenyl substituted or at least one R ⁵ substituted, wherein 3-8 membered hetero Any _CH of cycloalkyl can be replaced by C(O); R ⁵ is d. ₆ alkyl, C _1-6 alkoxy, -cc -oc ^ alkyl, -C ^-C ^ alkyl, -(CH ₂ ) _p -C(0)-0-C _{1 -6} alkyl, -(C¾) _p -0-C _1-6 alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(C¾) _p -OH, amino, cyanide radical or hydroxyl; R ^A and R ^B are independently hydrogen, _{d_6} alkyl, -(CH^-OC alkyl or benzyl, and p is selected from 1, 2 or 3. 6. The compound as claimed in claim 5, its pharmaceutically acceptable salt or its stereoisomer: wherein, X and Y are independently N or CR ¹ , wherein at least one of X and Y is N; Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N; R ¹ and R ² are independently hydrogen and alkyl; n is selected from 0, 1, 2 or 3; is ^ alkyl, ^ ₆ alkoxy, -N(R ^a R ^b ), unsubstituted or at least one R ³ substituted phenyl, quinolinyl, 6-membered heteroaryl, 3-8-membered cycloalkane Base or 3-8 membered heterocycloalkyl; 0 R ³ is or, R ⁴ , where m is selected from 0, 1 , 2 or 3 , R ⁴ is sulfonyl, halogen, C _1-3 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), C _1-6 alkoxy, amino, cyano, Hydroxy, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or piperidophenyl that is unsubstituted or substituted by at least one R ⁵ , wherein any CH ₂ of the 3-8 membered heterocycloalkyl can be replaced by C(O); R ⁵ is _{d_3} alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C(0)-Cw alkyl, -(CH ₂ ) _p -C( 0)-0-C _1-3 alkyl, -(CH pO-Cw alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH, , or hydroxyl; R ^a and R ^b are independently hydrogen, C _1-6 alkyl, -(CH ₂ ) _p -OCw alkyl or benzyl, and p is selected from 1, 2 or 3. 7. The compound as claimed in claim 6, its pharmaceutically acceptable salt or its stereoisomer: wherein, X and Y are independently N or CR ¹ , wherein at least one of X and Y is N; Z, W, U, and G are independently N or CR ¹ , wherein at least one of Z, W, U, and G is N; R ¹ and R ² are independently hydrogen, methyl or ethyl; n is selected from 0, 1 , 2 or 3; L is _{d_6} alkyl, -N(R ^a R ^b ), unsubstituted or at least one R ³ substituted phenyl, quinolinyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl, tetra Hydropyranyl, piperazinyl or morpholinyl; 0 _R 3 is/( R ₄ or ^e , _R 4 , where m is selected from 0 or 1, R ⁴ is sulfonyl, halogen, C _1-3 alkyl, -C(0)N(R ^a R ^b ), -N(R ^a R ^b ), unsubstituted or at least one pyryl ¹¹ substituted by R ⁵ Base, pyrazolyl, imidazolyl, pyrimidine ⁵¹ base, piperidophenyl, morpholinyl, piperidine ¹¹ base, piperidine. Qin group, tetrahydropyrrole 2-one group; R ⁵ is Ci _-3 alkyl, C _1-6 alkoxy, -C(0)-0-C _1-6 alkyl, -C(0)-C _1-3 alkyl, -(CH ₂ ) _p -C(0)-0-C _1-3 alkyl, -(CH pO-Cw alkyl, -(CH ₂ ) _p -C(0)N(R ^a R ^b ), -(CH ₂ ) _p -OH; R ^a and R ^b are independently hydrogen, ₆ alkyl, -(CH p-OCw alkyl or benzyl, p is selected from 1 , 2 or 3. 8. The compound according to any one of claims 1-7, its pharmaceutically acceptable salt or its stereoisomer, where one of X and Y is N and the other is CR 9. The compound according to any one of claims 1-8, its pharmaceutically acceptable salt or its stereoisomer, Where Z stands for CH, W stands for CH; U stands for N and G stands for N. 10. A compound selected from the following, a pharmaceutically acceptable salt thereof or a stereoisomer thereof: 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 11. A compound selected from the group consisting of: 12. A pharmaceutical composition comprising the compound of any one of claims 1-11, its pharmaceutically acceptable salt or its stereoisomer and one or more pharmaceutically acceptable carriers. 13. The compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt or its stereoisomer or the pharmaceutical composition of claim 12 is used in the preparation of treatment and/or prevention of ischemia-reperfusion injury, diabetes, Neurodegeneration, chronic inflammation (eg, allergy, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, allergic keratitis, dry eye, retinopathy, glaucoma), pulmonary fibrosis Drug use in liver fibrosis, fatty liver or cirrhosis. 14. A treatment and/or prevention of ischemia-reperfusion injury, diabetes, neurodegeneration, chronic inflammation (such as allergy, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, A method for allergic keratitis, dry eye, retinopathy, glaucoma), pulmonary fibrosis, liver fibrosis, fatty liver or cirrhosis, comprising administering a therapeutically effective amount of any one of claims 1 to 12 to a patient in need thereof The above-mentioned compound, its pharmaceutically acceptable salt or its stereoisomer or the pharmaceutical composition of claim 13. 15. For the treatment and/or prevention of ischemia-reperfusion injury, diabetes, neurodegeneration, chronic inflammation (such as allergy, asthma, rheumatoid arthritis, osteoarthritis, atherosclerosis, allergic conjunctivitis, Allergic keratitis, dry eye, retinopathy, glaucoma), pulmonary fibrosis, liver fibrosis, fatty liver or cirrhosis of the compound described in any one of claims 1 to 12, its pharmaceutically acceptable salt or Its stereoisomer or the pharmaceutical composition of claim 13.