Heterocyclic compound as well as preparation method and medical application thereof

Abstract

The invention relates to a heterocyclic compound, a preparation method thereof and application of the heterocyclic compound in medicine. Specifically, the invention relates to a heterocyclic compound shown in a general formula (I), a preparation method of the heterocyclic compound, a pharmaceutical composition containing the heterocyclic compound and application of the heterocyclic compound as a therapeutic agent, in particular application of the heterocyclic compound as an MK2 inhibitor and application of the heterocyclic compound to treatment and / or prevention of autoimmune diseases, chronic or acute inflammatory diseases and autoinflammatory diseases. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine, and relates to a heterocyclic compound, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a heterocyclic compound represented by general formula (I), a preparation method thereof, and a pharmaceutical composition containing the compound, as well as its use as an MK2 inhibitor and its use for treating and / or preventing autoimmune diseases, chronic or acute inflammatory diseases, and autoinflammatory diseases. Background Art

[0002] Inflammatory cytokines play an important role in the pathogenesis of autoimmune diseases. Biologics that neutralize key inflammatory cytokines, such as anti-TNFα antibodies, have been shown to be useful in treating inflammatory diseases such as psoriasis, Crohn's disease (CD), rheumatoid arthritis (RA), and spondyloarthritis. Biologics are currently administered parenterally, and as the duration of medication increases, there is a risk of reduced efficacy. Therefore, new oral therapies for the treatment of inflammatory diseases need to be developed.

[0003] p38 MAPK was identified as a key regulator of inflammatory cytokine biosynthesis in 1994, and numerous R&D institutions have conducted work on small molecule kinase inhibitors targeting p38. Most p38 kinase inhibitors have shown efficacy in animal disease models, but have not been further developed clinically due to insufficient safety windows. Three p38 compounds that have entered Phase II clinical trials were conducted in patients with RA or CD. In the initial stages of the experiments, a decrease in disease scores or biomarkers of inflammation was observed, and then continued administration led to rapid drug resistance. Analysis showed that this phenomenon was mainly due to the inhibition of p38, which, in addition to inhibiting inflammation, also activates the feedback mechanism of p38. Given the important role of the p38 signaling pathway in cytokine biosynthesis, targeting molecules in the upstream or downstream pathways of p38 may circumvent regulatory feedback and provide the lasting therapeutic benefits required for sustained inhibition of inflammatory cytokines.

[0004] MAPK-activated protein kinase 2 (MK2) is a direct downstream substrate of p38 and mediates the inflammatory process by increasing the translation and stability of proinflammatory cytokine mRNAs, including IL-6 and TNFa. Tristetraprolin (TTP) is a zinc finger protein that can bind to cytokine mRNAs with the same adenylate-uridylate-rich element (ARE) in the 30 untranslated regions, making these mRNAs unstable and inhibiting the protein translation of these cytokines, while human antigen R (HuR) plays the opposite role and stimulates translation. Activated MK2 phosphorylates TTP, resulting in TTP being replaced by HuR, thereby regulating cytokine production. In the MK2 knockout mouse model, mice grow normally, resist LPS-induced endotoxin shock, and show reduced levels of TNFα, IL-6, and interferon γ; in addition, knocking out MK2 in many inflammatory disease models, including the collagen-induced arthritis model, can alleviate the occurrence of these diseases or the level of inflammation. Therefore, MK2 is a potential target for the treatment of inflammation. Although there is no evidence that MK2 is in a complex feedback pathway like p38, its activation does activate signaling feedback that limits inflammation at the level of TTP-regulated translation or mRNA stability.

[0005] The patent applications for MK2 inhibitors that have been disclosed include WO2023283338A1, WO2022212489A1, WO2014197846A1, WO2013086208A1, WO2012078684A1 and WO 2012078674A1, etc. Summary of the invention

[0006] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] Ring A is an aryl group or a heteroaryl group;

[0010] Ring B is aryl or heteroaryl;

[0011] X is N or CR X ;

[0012] R X is selected from the group consisting of a hydrogen atom, an alkyl group, a halogen group, a hydroxyl group, and a hydroxyalkyl group;

[0013] R 1 and R 2are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, and a heterocyclylalkyl group; or R 1 and R 2 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace;

[0014] Each R 3 and R 5 and are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxyalkyl, an aminoalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, an alkenyl, an alkynyl, a cyano group, a nitro group, a hydroxyl group, an amino group, an oxo group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CH 2 ) t OR 7 、-(CH 2 ) t NR 8 R 9 、-C(O)R 7 、-C(O)OR 7 、-OC(O)R 7 、-OC(O)OR 7 、-C(O)NR 8 R 9 、-OC(O)NR 8 R 9 、-S(O) v R 7 、-S(O) v NR 8 R 9 、-NR 10 C(O)NR 8 R 9 、-NR 10 C(O)R 7 、-NR 10 C(O)OR 7 、-NR 10 S(O) v NR 8 R 9 and-NR 10 S(O) v R 7 wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0015] R 4a , R 4b and R 4c are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH 2 ) t OR 7 、-(CH 2 ) t NR 8 R 9 、-C(O)R 7 、-C(O)OR 7 、-OC(O)R 7 、-OC(O)OR 7 、-C(O)NR 8 R 9 、-OC(O)NR 8 R 9 、-S(O) v R 7 、-S(O) v NR 8 R 9 、-NR 10 C(O)NR 8 R 9 、-NR 10 C(O)R 7 、-NR 10 C(O)OR 7 、-NR 10 S(O) v NR 8 R 9 and-NR 10 S(O) v R 7 wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0016] Each R 6 are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a hydroxyl group, an amino group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH 2 ) t OR 7 、-(CH 2) t NR 8 R 9 、-C(O)R 7 、-C(O)OR 7 、-OC(O)R 7 、-OC(O)OR 7 、-C(O)NR 8 R 9 、-OC(O)NR 8 R 9 、-S(O) v R 7 、-S(O) v NR 8 R 9 、-NR 10 C(O)NR 8 R 9 、-NR 10 C(O)R 7 、-NR 10 C(O)OR 7 、-NR 10 S(O) v NR 8 R 9 and-NR 10 S(O) v R 7 wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0017] Or two R 6 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace;

[0018] R a , R b and R c are the same or different and are each independently selected from hydrogen, hydroxy, cyano, amino, nitro, halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; or, R b and R c Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 Replace; or, R a , R b and R cTogether with the carbon atom to which it is attached, it forms a bridged ring group, which is optionally substituted by one or more R 0 replace;

[0019] R 0 are the same or different at each occurrence and are each independently selected from the group consisting of a deuterium atom, a halogen, an alkyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxyalkyl, an aminoalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, an alkenyl, an alkynyl, a cyano group, a nitro group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, an oxo group, a -(CH 2 ) t OR 11 、-(CH 2 ) t NR 12 R 13 、-C(O)R 11 、-C(O)OR 11 and -C(O)NR 12 R 13 ;

[0020] R 7 and R 11 are the same or different at each occurrence and are each independently selected from hydrogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replace;

[0021] R 8 , R 9 , R 10 , R 12 and R 13 are the same or different at each occurrence and are each independently selected from hydrogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replace;

[0022] or R 8 and R 9 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, which is optionally substituted by one or more R 01 Replace; or R 12 and R 13Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, which is optionally substituted by one or more R 01 replace;

[0023] R 01 are the same or different at each occurrence and are each independently selected from a deuterium atom, a halogen, an alkyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxyalkyl, an aminoalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, an alkenyl, an alkynyl, a cyano group, a nitro group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, an oxo group, a -NHCH 3 、-N(CH 3 ) 2 , -C(O)alkyl and -C(O)NH 2 ;

[0024] m is 0, 1, 2, 3, 4 or 5;

[0025] p is 0, 1, 2, 3, 4 or 5;

[0026] q is 0, 1, 2, 3, or 4;

[0027] t is 0, 1, 2, 3, or 4; and

[0028] v is 0, 1, or 2.

[0029] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are the same or different and are each independently selected from hydrogen atoms, deuterium atoms, halogens and C 1-6 alkyl; in some embodiments, R 1 and R 2 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 1 and R 2 are the same or different and are each independently a hydrogen atom or a deuterium atom; in some embodiments, R 1 and R 2 is a hydrogen atom; in some embodiments, R 1 and R 2 A deuterium atom.

[0030] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; in some embodiments, ring A is a phenyl group or a 5- or 6-membered heteroaryl group; in some embodiments, ring A is a 5- or 6-membered heteroaryl group; in some embodiments, ring A is a 6-membered heteroaryl group; in some embodiments, ring A is a pyridyl group; in some embodiments, ring A is a phenyl group; in some embodiments, ring A is a pyridyl group or a phenyl group.

[0031] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; in some embodiments, each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 3 is halogen; in some embodiments, each R 3 are the same or different and are each independently selected from F, Cl, methyl and trifluoromethyl; in some embodiments, R 3 For F.

[0032] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 2.

[0033] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; and / or m is 2; in some embodiments, R 3 is halogen; and / or m is 2.

[0034] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 6 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; or, two R 6 Together with the attached carbon atom, it forms a 5- or 6-membered heterocyclic group; in some embodiments, each R 6are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 6 C 1-6 Alkyl; or, two R 6 Together with the attached carbon atom, it forms a 5- or 6-membered heterocyclic group; in some embodiments, R 6 C 1-6 alkyl; in some embodiments, R 6 It is methyl.

[0035] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein two R 6 Together with the attached carbon atom, they form a 5- or 6-membered heterocyclic group; in some embodiments, the two R 6 Together with the carbon atom to which it is attached, it forms a 5-membered heterocyclic group. In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, 2 or 3; in some embodiments, q is 1 or 2; in some embodiments, q is 2.

[0036] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 6 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; and / or q is 2; in some embodiments, R 6 C 1-6 alkyl; and / or q is 2.

[0037] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

[0038]

[0039] in:

[0040] G 0 N or CR 3e ;

[0041] R 3a , R 3b , R 3c , R 3d and R 3e are the same or different and are each independently a hydrogen atom or R 3 ;

[0042] R 6a and R 6bare the same or different and are each independently a hydrogen atom or R 6 ;

[0043] Ring B, X, R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R a , R b , R c and p are as defined in the general formula (I).

[0044] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

[0045]

[0046] in:

[0047] R 6a and R 6b are the same or different and are each independently R 6 ;

[0048] Ring B, X, G 0 , R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c , R 5 , R 6 , R a , R b , R c and p are as defined in the general formula (II).

[0049] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R X A hydrogen atom.

[0050] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein X is N or CH; in some embodiments, X is N; in some embodiments, X is CH.

[0051] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- or 6-membered heteroaryl group; in some embodiments, ring B is a 6-membered heteroaryl group; in some embodiments, ring B is selected from pyrimidinyl, pyridone and pyrazolyl; in some embodiments, ring B is pyrimidinyl or pyridone; in some embodiments, ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Ring B is In some embodiments, Ring B is pyrimidinyl; in some embodiments, Ring B is The end is connected to pyridine.

[0052] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein Selected from p is 0 or 1; R 5 , R a , R b and R c As defined in formula (I); in some embodiments, for p is 0 or 1; R 5 , R a , R b and R c As defined in formula (I); in some embodiments, Selected from a , R b and R c As defined in formula (I); in some embodiments, for R a , R b and R c As defined in general formula (I).

[0053] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy and C1-6 haloalkoxy; in some embodiments, each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R 3 are the same or different and are each independently halogen; in some embodiments, each R 3 are the same or different and are each independently selected from F, Cl, methyl and trifluoromethyl; in some embodiments, R 3 For F.

[0054] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 3a , R 3b , R 3c and R 3d are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; in some embodiments, R 3a , R 3b , R 3c and R 3d are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 3a , R 3b , R 3c and R 3d are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 3a , R 3b , R 3c and R 3d are the same or different and are each independently selected from hydrogen, F, Cl, methyl and trifluoromethyl; in some embodiments, R 3a , R 3b , R 3c and R 3d are the same or different and are each independently a hydrogen atom or F; in some embodiments, R 3a and R 3c are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3band R 3d is a hydrogen atom; in some embodiments, R 3a and R 3c are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3b and R 3d is a hydrogen atom; in some embodiments, R 3a and R 3c are the same or different and are each independently selected from F, Cl, methyl and trifluoromethyl; R 3b and R 3d is a hydrogen atom; in some embodiments, R 3a and R 3c are the same or different and are each independently halogen; R 3b and R 3d is a hydrogen atom; in some embodiments, R 3a and R 3c F; R 3b and R 3d A hydrogen atom.

[0055] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 3e is a hydrogen atom or a halogen; in some embodiments, R 3e A hydrogen atom.

[0056] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein G 0 is N or CH; in some embodiments, G 0 is N; in some embodiments, G 0 For CH.

[0057] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof, wherein G 0 is N or CH; and / or R 3a and R 3c are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; and / or R 3b and R 3d is a hydrogen atom; in some embodiments, G 0 N; and / or R 3a and R 3c is halogen; and / or R 3b and R 3d A hydrogen atom.

[0058] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 4a , R 4b and R 4c are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; in some embodiments, R 4a , R 4b and R 4c are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; in some embodiments, R 4a , R 4b and R 4c are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; in some embodiments, R 4a is a hydrogen atom or a halogen; R 4b Selected from halogen, C 1-6 Alkyl and C 1-6 Alkoxy; R 4c is a hydrogen atom; in some embodiments, R 4a is a hydrogen atom or a halogen; R 4b C 1-6 Alkyl; R 4c is a hydrogen atom; in some embodiments, R 4a is a hydrogen atom or F; R 4b is methyl; R 4c A hydrogen atom.

[0059] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 4a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; in some embodiments, R 4a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; in some embodiments, R 4a is a hydrogen atom or a halogen; in some embodiments, R 4a Selected from hydrogen atoms, F and Cl.

[0060] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 4b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; in some embodiments, R 4b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; in some embodiments, R 4b Selected from halogen, C 1-6 Alkyl and C 1-6 Alkoxy; R 4b C 1-6 alkyl; in some embodiments, R 4b is selected from methyl, F and methoxy; in some embodiments, R 4b It is methyl.

[0061] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 4c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; in some embodiments, R 4c Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; in some embodiments, R 4c A hydrogen atom.

[0062] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein each R 5 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0063] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1; in some embodiments, p is 0.

[0064] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 6 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 6 C 1-6 alkyl; in some embodiments, R 6 It is methyl.

[0065] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 6a and R 6b are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 6a and R 6b are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 6a and R 6b are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, R 6a and R 6b The same or different, and each independently is C 1-6 alkyl; in some embodiments, R 6a A hydrogen atom or C 1-6 Alkyl; R 6b C 1-6 alkyl; in some embodiments, R 6a is a hydrogen atom or a methyl group; R 6b is methyl; in some embodiments, R 6a and R 6b It is methyl.

[0066] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R a , R b and R c are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy and 3 to 6-membered cycloalkyl; or, R b and R cTogether with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl; in some embodiments, R a , R b and R c The same or different, and each independently selected from C 1-6 Alkyl, hydroxyl, C 1-6 Haloalkyl, C 1-6 hydroxyalkyl and 3 to 6 membered cycloalkyl; in some embodiments, R a , R b and R c The same or different, and each independently selected from C 1-6 alkyl, hydroxyl and 3 to 6-membered cycloalkyl; or, R b and R c Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, R a , R b and R c The same or different, and each independently selected from C 1-6 alkyl, hydroxyl and 3 to 6 membered cycloalkyl; in some embodiments, R a , R b and R c are the same or different and are each independently selected from hydroxy, methyl and cyclopropyl; or, R b and R c Together with the attached carbon atom, it forms a cyclopropyl group; in some embodiments, R a , R b and R c are the same or different and are each independently selected from hydroxy, methyl and cyclopropyl; in some embodiments, R a is hydroxyl group; R b and R c The same or different, and each independently is C 1-6 alkyl or 3 to 6-membered cycloalkyl; or, R b and R c Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, R a is hydroxyl group; R b and R c The same or different, and each independently is C 1-6 alkyl or 3 to 6 membered cycloalkyl; in some embodiments, R a is hydroxyl group; R b and R c are the same or different and are each independently methyl or cyclopropyl; or, R b and R c Together with the attached carbon atom, it forms a cyclopropyl group; in some embodiments, R a is hydroxyl group; R b and Rc are the same or different and are each independently methyl or cyclopropyl.

[0067] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R a , R b and R c Together with the carbon atoms to which they are attached, they form a 5- to 10-membered bridged cycloalkyl group, wherein the 5- to 10-membered bridged cycloalkyl group is optionally substituted by one or more R 0 Replacement; R 0 As defined in Formula (I); in some embodiments, R a , R b and R c Together with the carbon atom to which it is attached, Said Optionally one or more R 0 Replacement; R 0 As defined in general formula (I).

[0068] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R b and R c Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl or the 3- to 6-membered heterocyclic group is optionally substituted by one or more R 0 Replacement; R 0 As defined in Formula (I); in some embodiments, R b and R c Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl, tetrahydropyranyl or oxetanyl group, wherein the cyclopropyl, cyclobutyl, tetrahydropyranyl or oxetanyl group is optionally substituted by one or more R 0 Replacement; R 0 As defined in Formula (I); in some embodiments, R b and R c Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, R b and R c Together with the carbon atom to which it is attached it forms a cyclopropyl group.

[0069] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein in some embodiments, Selected from Selected from In some embodiments, for

[0070] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 11 is the same or different at each occurrence and is independently a hydrogen atom or a C 1-6 alkyl.

[0071] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 8 , R 9 , R 10 , R 12 and R 13 is the same or different at each occurrence and is independently a hydrogen atom or a C 1-6 alkyl.

[0072] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 0 are the same or different at each occurrence and are independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0073] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 01 are the same or different at each occurrence and are independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0074] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein X is N; Ring A is pyridyl; Ring B is pyrimidyl or pyridone; R 1 and R 2 is a hydrogen atom; R 3 is halogen; m is 2; R 4a is a hydrogen atom or a halogen; R 4b C 1-6 Alkyl; R 4c is a hydrogen atom; p is 0; R 6 C 1-6 Alkyl; q is 2; R a is hydroxyl group; R b and R c The same or different, and each independently is C 1-6 Alkyl or 3- to 6-membered cycloalkyl.

[0075] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein X is N; G 0 N; R 3a and R 3c is halogen; R 3b and R 3d is a hydrogen atom; Ring B is R 4a is a hydrogen atom or a halogen; R 4b C 1-6 Alkyl; R 4c is a hydrogen atom; p is 0; R 6a and R 6b The same or different, and each independently is C 1-6 Alkyl; R a is hydroxyl group; R b and R c The same or different, and each independently is C 1-6 Alkyl or 3- to 6-membered cycloalkyl.

[0076] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is pyridyl or phenyl; each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; m is 2; R 1 and R 2 are the same or different and are each independently a hydrogen atom or a deuterium atom; X is N; R 6 C 1-6 Alkyl; or, two R 6 Together with the carbon atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; q is 0, 1, 2 or 3; R 4a is a hydrogen atom or a halogen; R 4b Selected from halogen, C 1-6 Alkyl and C 1-6 Alkoxy; R 4c is a hydrogen atom; p is 0; Ring B is selected from pyrimidinyl, pyridone and pyrazolyl; R a , R b and R c The same or different, and each independently selected from C 1-6 alkyl, hydroxyl and 3 to 6-membered cycloalkyl; or, R b and R c Together with the carbon atom to which it is connected, it forms a 3- to 6-membered cycloalkyl group. In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G 0 N or CH; R3a and R 3c are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3b and R 3d is a hydrogen atom; X is N; R 6a and R 6b are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; R 4a is a hydrogen atom or a halogen; R 4b Selected from halogen, C 1-6 Alkyl and C 1-6 Alkoxy; R 4c is a hydrogen atom; Ring B is selected from The end is connected to pyridine; p is 0; R a , R b and R c The same or different, and each independently selected from C 1-6 alkyl, hydroxyl and 3 to 6-membered cycloalkyl; or, R b and R c Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group.

[0077] In some embodiments of the present disclosure, the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein G 0 N or CH; R 3a and R 3c are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3b and R 3d is a hydrogen atom; X is N; R 6a and R 6b The same or different, and each independently is C 1-6 Alkyl; R 4a is a hydrogen atom or a halogen; R 4b Selected from halogen, C 1-6 Alkyl and C 1-6 Alkoxy; R 4c is a hydrogen atom; Ring B is selected from The end is connected to pyridine; p is 0; R a , R b and R c The same or different, and each independently selected from C 1-6 alkyl, hydroxyl and 3 to 6-membered cycloalkyl; or, R b and R cTogether with the attached carbon atom, it forms a 3 to 6-membered cycloalkyl group. Table A Typical compounds disclosed herein include, but are not limited to:

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094] Table B Typical intermediate compounds disclosed herein include but are not limited to:

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0102]

[0103] The compound represented by the general formula (IA) or its salt undergoes a condensation reaction with the compound represented by the general formula (IB) or its salt to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

[0104] in:

[0105] Ring A, Ring B, X, R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R a , R b , R c , m, p and q are as defined in the general formula (I).

[0106] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0107]

[0108] The compound represented by the general formula (IA) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIB) or its salt to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt;

[0109] in:

[0110] Ring B, X, G 0 , R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c , R 5 , R 6a , R 6b , R a , R b , R c and p are as defined in the general formula (II).

[0111] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0112]

[0113] The compound represented by the general formula (IA) or its salt undergoes a condensation reaction with the compound represented by the general formula (II-1B) or its salt to obtain the compound represented by the general formula (II-1) or its pharmaceutically acceptable salt;

[0114] in:

[0115] Ring B, X, G 0 , R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c , R 5 , R 6a , R 6b , R a , R b , R c and p are as defined in the general formula (II-1).

[0116] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound of the present disclosure represented by general formula (I), general formula (II), general formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0117] The present disclosure further relates to the use of compounds represented by formula (I), formula (II), formula (II-1) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, in the preparation of MK2 inhibitors.

[0118] The present disclosure further relates to the use of compounds shown in general formula (I), general formula (II), general formula (II-1) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, in the preparation of drugs for treating and / or preventing diseases or conditions mediated by MK2.

[0119] The present disclosure further relates to the use of the compounds shown in general formula (I), general formula (II), general formula (II-1) and Table A or their pharmaceutically acceptable salts or pharmaceutical compositions comprising the same in the preparation of drugs for treating and / or preventing autoimmune diseases, chronic or acute inflammatory diseases, autoinflammatory diseases, fibrotic diseases, metabolic diseases, neoplasia and cardiovascular or cerebrovascular diseases; the autoimmune diseases, chronic or acute inflammatory diseases and autoinflammatory diseases are preferably selected from inflammatory bowel diseases, ulcerative colitis, psoriasis, Crohn's disease (CD), multiple sclerosis, psoriasis, arthritis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease (COPD), cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (Muckle-Wells syndrome), and the like. syndrome), familial cold autoinflammatory syndrome, neonatal onset multisystem inflammatory disease, TNF receptor-associated periodic syndrome, acute and chronic pancreatitis, atherosclerosis, gout, acute respiratory distress syndrome, autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, systemic lupus erythematosus, vasculitis syndrome, Hypophysitis, idiopathic thrombocytic purpura, pemphigus, autoimmune deafness, meningitis, myocarditis, gingivitis, enterocolitis, sinusitis, uveitis, ophthalmitis, optic neuritis, gastric ulcer, esophagitis, peritonitis, root periostitis, dermatomyositis, gastritis, myositis, bronchitis and suppurative hidradenitis; the arthritis is preferably selected from rheumatoid arthritis (RA), osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis, psoriatic arthritis and spondyloarthritis.

[0120] In some embodiments, the MK2-mediated disease or disorder described in the present disclosure is selected from an autoimmune disorder, a chronic or acute inflammatory disorder, an autoinflammatory disorder, a fibrotic disorder, a metabolic disorder, a neoplasia, and a cardiovascular or cerebrovascular disorder.

[0121] In some embodiments, the MK2-mediated disease or disorder described in the present disclosure is selected from an autoimmune disorder, a chronic or acute inflammatory disorder, and an autoinflammatory disorder.

[0122] In some embodiments, the disease or disorder mediated by MK2 described herein is a fibrotic disorder.

[0123] In some embodiments, the disease or disorder mediated by MK2 described in the present disclosure is a metabolic disorder.

[0124] In some embodiments, the disease or condition mediated by MK2 described in the present disclosure is neoplasia.Preferably, the disease or condition mediated by MK2 described in the present disclosure is a cardiovascular or cerebrovascular disorder.

[0125] The autoimmune disorders, chronic or acute inflammatory disorders and autoinflammatory disorders of the present disclosure are preferably selected from inflammatory bowel disease, ulcerative colitis, psoriasis, Crohn's disease (CD), multiple sclerosis, psoriasis, arthritis, ankylosing spondylitis (also known as ankylosing spondylitis), asthma, chronic obstructive pulmonary disease (COPD), cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (Muckle-Wells syndrome), and the like. syndrome), familial cold autoinflammatory syndrome, neonatal onset multisystem inflammatory disease, TNF receptor-associated periodic syndrome, acute and chronic pancreatitis, atherosclerosis, gout, fibrotic disorders, liver fibrosis, idiopathic pulmonary fibrosis, kidney disease, sarcoidosis, scleroderma, anaphylaxis, diabetes (type 1 diabetes, type 2 diabetes), diabetic retinopathy, Still's disease, sarcoidosis, lung inflammation, acute respiratory distress syndrome, wet and dry age-related macular degeneration, autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silicone implant-related autoimmune diseases, Sjogren's syndrome syndrome), familial Mediterranean fever, systemic lupus erythematosus, temporal arteritis, Takayasu's arteritis and giant cell arteritis, Behcet's disease, Wegener's granulomatosis, vitiligo, secondary blood expression of autoimmune diseases, anemia, drug-induced autoimmunity, Hashimoto's thyroiditis, vasculitis syndrome, hypophysitis, idiopathic thrombocytic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune deafness, Meniere's disease, Goodpasture's syndrome, Graves' disease, HW-related autoimmune syndrome, Gullain-Barre disease, Addison's disease disease), antiphospholipid syndrome, atopic dermatitis, celiac disease, Cushing's syndrome, dermatomyositis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, Kawasaki syndrome, Lambert-Eaton syndromeSyndrome, pernicious anemia, hay fever, polyarteritis nodosa, primary biliary cirrhosis, primary sclerosing cholangitis, Raynaud's, Reiter's Syndrome, relapsing polychondritis, Schmidt's syndrome, thyrotoxicosis, sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, gram negative sepsis sepsis), toxic shock syndrome, glomerulonephritis, peritonitis, interstitial cystitis, hyperoxia-induced inflammation, graft-versus-host reaction, graft-versus-host disease, allograft rejection, acute allograft rejection, chronic allograft rejection, early transplant rejection, acute allograft rejection, reperfusion injury, pain (preferably acute pain, chronic pain, neuralgia, muscular pain), chronic infection, meningitis, encephalitis, myocarditis, gingivitis, postoperative trauma, tissue damage, traumatic brain injury , enterocolitis, sinusitis, uveitis, ophthalmitis, optic neuritis, gastric ulcer, esophagitis, peritonitis, root periostitis, dermatomyositis, gastritis, myositis, polymyalgia, pneumonia, bronchitis and suppurative hidradenitis; more preferably selected from inflammatory bowel disease, ulcerative colitis, psoriasis, Crohn's disease (CD), multiple sclerosis, psoriasis, arthritis, ankylosing spondylitis (also called ankylosing spondylitis), asthma, chronic obstructive pulmonary disease (COPD), cryptopyrin-associated periodic syndrome, Muckle-Wells syndrome (Muckle-Wells syndrome), familial cold autoinflammatory syndrome, neonatal onset multisystem inflammatory disease, TNF receptor-associated periodic syndrome, acute and chronic pancreatitis, atherosclerosis, gout, acute respiratory distress syndrome, autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, systemic lupus erythematosus, vasculitis syndrome, hypophysitis, idiopathic thrombocytic purpura, pemphigus, autoimmune deafness, meningitis, myocarditis, gingivitis, enterocolitis, sinusitis, uveitis, ophthalmitis, optic neuritis, gastric ulcer, esophagitis, peritonitis, periostitis, dermatomyositis, gastritis, myositis, and bronchitis.

[0126] The above-mentioned arthritis is preferably selected from rheumatoid arthritis (RA), osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis, psoriatic arthritis and spondyloarthritis.

[0127] The fibrotic disorder of the present disclosure is preferably selected from systemic sclerosis / scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scars, spinal cord injury, CNS scars, acute lung injury, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease, diabetic nephropathy, hypertension-induced nephropathy, digestive or gastrointestinal tract fibrosis, renal fibrosis, liver or gallbladder fibrosis, liver fibrosis, nonalcoholic steatohepatitis, hepatitis C, hepatocellular carcinoma, cirrhosis, primary biliary tract, Cirrhosis, cirrhosis due to fatty liver disease, cirrhosis due to alcoholic fatty liver disease, cirrhosis due to nonalcoholic steatosis / nonalcoholic fatty liver disease, radiation-induced fibrosis, fibrosis of the head and neck, gastrointestinal fibrosis, pulmonary fibrosis, primary sclerosing cholangitis, restenosis, cardiac fibrosis, endomyocardial fibrosis, atrial fibrosis, ophthalmic scarring, fibrosclerosis, fibrotic cancer, fibroids, fibromas, fibroadenomas, fibrosarcomas, transplant arteriopathy, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, and nephrogenic systemic fibrosis.

[0128] The metabolic disorder of the present disclosure is preferably selected from obesity, steroid resistance, glucose intolerance and metabolic syndrome.

[0129] The neoplasia of the present disclosure is preferably selected from the group consisting of angiogenic disorders, multiple myeloma, leukemia, acute lymphocytic leukemia, acute and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, promyelocytic leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors, Hodgkin's disease, non-Hodgkin's disease, myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer, Kaposi's sarcoma, In some embodiments, the neoplasia is a cancer of the bone, oral cavity / throat, esophagus, larynx, stomach, intestine, colon, rectum, lung, liver, pancreas, nerve, brain, head and neck, throat, ovary, uterus, prostate, testicle, bladder, kidney, breast, gallbladder, cervix, thyroid, prostate and skin, non-small cell lung cancer, small cell lung cancer, glioma and glioblastoma multiforme; in some embodiments, the neoplasia is a cancer; in some embodiments, the neoplasia is a breast cancer; in some embodiments, the neoplasia is a hormone receptor positive HER-2 negative metastatic breast cancer.

[0130] The present disclosure relates to cardiovascular or cerebrovascular disorders preferably selected from atherosclerosis, restenosis of atherosclerotic coronary arteries, acute coronary syndrome, myocardial infarction, myocardial allograft vasculopathy, stroke, central nervous system disorders with inflammatory or apoptotic components, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia and peripheral neuropathy.

[0131] The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0132] As a general guide, the active compound is preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the disclosed compound or composition can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

[0133] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0134] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0135] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution.

[0136] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.

[0137] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0138] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0139] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0140] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0141] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0142] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0143] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0144] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0145] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0146] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0147] Terminology

[0148] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0149] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0150] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 Alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples include: -CH 2 -、-CH(CH 3 )-、-C(CH 3 ) 2 -、-CH 2 CH 2 -、-CH(CH 2 CH 3 )-、-CH 2 CH(CH 3 )-、-CH2 C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 -、-CH 2 CH 2 CH 2 CH 2 -, etc. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available attachment point, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0151] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0152] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0153] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0154] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20-membered cycloalkyl). The cycloalkyl is preferably a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), more preferably a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), and most preferably a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl) or a cycloalkyl having 4 to 7 ring atoms (i.e., 4 to 7-membered cycloalkyl).

[0155] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0156] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0157] The term "spirocycloalkyl" refers to a polycyclic system in which one carbon atom (called spiro atom) is shared between the rings, and the rings may contain one or more double bonds, or the rings may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but not including -OO-, -OS- or -SS-), provided that at least one all-carbon ring is contained and the connection point is on the all-carbon ring, and it has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). The spirocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan monospirocycloalkyl. Non-limiting examples include:

[0158] Its connection point can be at any position;

[0159] wait.

[0160] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). The fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused cycloalkyl. Non-limiting examples include:

[0161] , whose connection points can be at any position;

[0162]

[0163] wait.

[0164] The term "bridged cycloalkyl" refers to a full carbon polycyclic system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl) or a bridged cycloalkyl of 5 to 10 carbon atoms (i.e., 5 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0165] Its connection point can be at any position.

[0166] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0167] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl), which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-) in the ring, and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group) or a heterocyclic group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclic group) or a heterocyclic group having 5 to 8 ring atoms (i.e., a 5- to 8-membered heterocyclic group) or a heterocyclic group having 4 to 8 ring atoms (i.e., a 4- to 8-membered heterocyclic group); most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).

[0168] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0169] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0170] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered spiro heterocyclic radical), more preferably a spiro heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered spiro heterocyclic radical). The spiro heterocyclic radical includes a monospiro heterocyclic radical and a polyspiro heterocyclic radical (such as a bispiro heterocyclic radical, etc.), preferably a monospiro heterocyclic radical or a bispiro heterocyclic radical, more preferably a 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan monospiro heterocyclic radical. Non-limiting examples include:

[0171] wait.

[0172] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more of cycloalkyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic group preferably has a fused heterocyclic group of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and more preferably has a fused heterocyclic group of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, more preferably a 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan bicyclic fused heterocyclic group. Non-limiting examples include:

[0173]

[0174] wait.

[0175] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS-, or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0176] wait.

[0177] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

[0178] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 6- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group). The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthryl, etc. The polycyclic aromatic group also includes a phenyl group fused with one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused with one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group or the naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, and non-limiting examples include:

[0179] wait.

[0180] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0181] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS-, or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), and more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl).

[0182] The monocyclic heteroaryl group includes, but is not limited to, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, N-alkylpyrrolyl, pyridinyl, pyridone (e.g. ), N-alkyl pyridone (such as etc.), pyrimidine groups (e.g. ), pyrimidinone (such as ), pyrazinyl, pyrazinone (such as ), pyridazinyl, pyridazinone (such as ), imidazole, imidazolide (such as )wait.

[0183] The polycyclic heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0184]

[0185] wait.

[0186] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0187] The term "amino protecting group" refers to a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule are reacted. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.

[0188] The term "hydroxy protecting group" refers to a group that is easily removed and introduced on a hydroxyl group, and is used to block or protect the hydroxyl group while reacting on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0189] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above. Non-limiting examples include: -CH 2 OCH 3 、-CH 2 OCH 2 CH 3 and -CH 2 OtBu.

[0190] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, wherein alkyl is as defined above. Non-limiting examples include: -CH 2 NH 2 .

[0191] The term "alkoxyalkoxy" refers to an alkoxy group substituted with one or more alkoxy groups, wherein alkoxy is as defined above. Non-limiting examples include: -OCH 2 CH 2 OCH 3 and -OCH 2 OCH 3 .

[0192] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein alkyl and cycloalkyl are as defined above.

[0193] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein alkyl and heterocyclyl are as defined above.

[0194] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein alkyl and aryl are as defined above.

[0195] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein alkyl and heteroaryl are as defined above.

[0196] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0197] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0198] The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

[0199] The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

[0200] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0201] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0202] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0203] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.

[0204] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0205] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0206] The term "hydroxy" refers to -OH.

[0207] The term "amino" refers to -NH 2 .

[0208] The term "cyano" refers to -CN.

[0209] The term "nitro" refers to -NO 2 .

[0210] The term "oxo" or "oxo" refers to "=0".

[0211] The term "carbonyl" refers to C=O.

[0212] The term "carboxy" refers to -C(O)OH.

[0213] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

[0214] The term "bridged cyclyl" refers to a "bridged cycloalkyl" or a "bridged heterocyclyl"; wherein the bridged cycloalkyl and bridged heterocyclyl are as defined above.

[0215] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereoisomers is usually completed by chromatography.

[0216] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or or include both and For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0217] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e., in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of a lactam-lactim equilibrium is shown below:

[0218]

[0219] For example, when referring to pyrazolyl, it is understood to include either or a mixture of two tautomers of the following two structures:

[0220]

[0221] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0222] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, respectively. 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p. 33 p. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0223] Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0224] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D", the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0225] "Optionally" or "optionally" means that the event or environment described later can but does not necessarily occur, and includes two situations in which the event or environment occurs or does not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes the situation in which alkyl is substituted with halogen or cyano and the situation in which alkyl is not substituted with halogen and cyano.

[0226] "Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in a group are replaced independently by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0227] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

[0228] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. They may be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0229] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0230] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0231] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0232] Synthesis method of the disclosed compound

[0233] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0234] Solution 1

[0235] The present invention discloses a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0236]

[0237] The compound represented by the general formula (IA) or its salt and the compound represented by the general formula (IB) or its salt undergo condensation reaction under alkaline conditions in the presence of a condensing agent to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

[0238] in:

[0239] Ring A, Ring B, X, R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R a , R b , R c , m, p and q are as defined in the general formula (I).

[0240] Solution 2

[0241] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0242]

[0243] The compound represented by the general formula (IA) or its salt and the compound represented by the general formula (IIB) or its salt undergo condensation reaction under alkaline conditions in the presence of a condensing agent to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt;

[0244] in:

[0245] Ring B, X, G 0 , R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c , R 5 , R 6a , R 6b , R a , R b , R c and p are as defined in the general formula (II).

[0246] Option 3

[0247] The present invention discloses a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0248]

[0249] The compound represented by the general formula (IA) or its salt and the compound represented by the general formula (II-1B) or its salt undergo condensation reaction under alkaline conditions in the presence of a condensing agent to obtain the compound represented by the general formula (II-1) or its pharmaceutically acceptable salt;

[0250] in:

[0251] Ring B, X, G 0 , R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c , R 5 , R 6a , R 6b , R a , R b , R c and p are as defined in the general formula (II-1).

[0252] The reagents providing alkaline conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably, the reagent providing alkaline conditions is N,N-diisopropylethylamine.

[0253] In the above synthesis scheme, the condensing agent includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazole-1-yl)-N,N,N',N ′-tetramethyluronium hexafluorophosphate (HATU), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate or 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; preferably, the condensing agent is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0254] The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: N-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof. DETAILED DESCRIPTION

[0255] The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0256] Example

[0257] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer, and the solvent used was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0258] MS was measured using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0259] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0260] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO QExactive)

[0261] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0262] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0263] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0264] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0265] The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0266] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0267] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0268] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0269] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Bid Pharmaceuticals, Darui Chemicals and other companies.

[0270] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0271] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0272] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0273] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0274] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0275] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0276] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0277] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0278] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0279] Example 1

[0280] ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 1

[0281]

[0282] Step 1 2-(Chloromethyl)-3,5-difluoropyridine 1b

[0283] Dissolve (3,5-difluoropyridin-2-yl)methanol 1a (18 g, 124.05 mmol, Bidex Pharmaceuticals) in dichloromethane (150 mL, Sinopharm), add 3 drops of N,N-dimethylformamide, add thionyl chloride (14.8 g, 124.40 mmol, Sinopharm) under stirring at 0°C, and react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to dryness to obtain the title compound 1b (17.3 g, yield: 85.3%).

[0284] MS m / z(ESI):164.3[M+1]

[0285] Step 2

[0286] (2R,5S)-tert-butyl 4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate 1c

[0287] Compound 1b (787 mg, 3.67 mmol) was dissolved in N,N-dimethylformamide (10 mL, Chinese medicine), and (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (500 mg, 3.06 mmol) and potassium carbonate (845 mg, 6.11 mmol, Chinese medicine) were added, and the mixture was reacted at room temperature for 16 hours. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×3), and the organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography with eluent system C to obtain the title compound 1c (620 mg, yield: 59.4%).

[0288] MS m / z(ESI):342.5[M+1]

[0289] Step 3

[0290] (2S,5R)-1-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazine 1d

[0291] Compound 1c (100 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL, Sinopharm), trifluoroacetic acid (770 mg, 6.75 mmol, Adamas) was added, and the mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1d (70 mg, yield: 99.1%).

[0292] MS m / z(ESI):242.4[M+1]

[0293] Step 4

[0294] 2-Chloro-3-fluoro-5-methylisonicotinic acid 1f

[0295] Dissolve 2-chloro-3-fluoro-5-methylpyridine 1e (3 g, 20.61 mmol, Bidex Pharmaceuticals) in tetrahydrofuran (30 mL, Adamas), add lithium diisopropylamide (2 M, 20.67 mL), and react at -78°C for 1 hour. Add dry ice and react at -78°C for 1 hour. Add 10 mL of saturated ammonium chloride solution to quench, adjust the pH to 4-5 with 1 M hydrochloric acid, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with 30 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 1f (1 g, yield: 25.6%).

[0296] MS m / z(ESI):189.9[M+1]

[0297] Step 5

[0298] 2-Chloro-3-fluoro-5-methylisonicotinic acid methyl ester 1g

[0299] Compound 1f (900 mg, 4.75 mmol) was dissolved in tetrahydrofuran (5 mL, Chinese medicine) and methanol (1 mL, Chinese medicine), and (trimethylsilyl)diazomethane (2 M, 4.75 mL) was added at room temperature, and reacted at room temperature for 2 hours. After concentration, the residue was purified by column chromatography with eluent system C to obtain the title compound 1g (855 mg, yield: 88.5%).

[0300] MS m / z(ESI):204.2[M+1]

[0301] Step 6

[0302] 2-Acetyl-3-fluoro-5-methylisonicotinic acid methyl ester 1h

[0303] Compound 1g (1.05g, 5.16mmol) was dissolved in 1,4-dioxane (30mL, Chinese medicine), tributyl (1-ethoxyethylene) tin (2.8mg, 7.75mmol), [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (437mg, 0.52mmol, Bidex Pharmaceuticals), cuprous iodide (98.3mg, 0.52mmol, Bidex Pharmaceuticals), and reacted at 105°C for 16 hours under nitrogen protection. The residue was concentrated and purified by column chromatography with eluent system C to obtain the title compound 1h (880mg, yield: 80.8%).

[0304] MS m / z(ESI):212.1[M+1]

[0305] Step 7

[0306] (E) 2-(3-(dimethylamino)acryloyl)-3-fluoro-5-methylisonicotinate 1i

[0307] Dissolve compound 1h (880 mg, 4.17 mmol) in N,N-dimethylformamide (5 mL, Chinese medicine), add 1,1-dimethoxy-N,N-dimethylmethylamine (3.98 g, 33.4 mmol), and react at 70°C for 24 hours. Add 20 mL of water, extract with dichloromethane (20 mL × 3), combine the organic phases, wash with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound 1i (1.1 g, yield: 99.14%). MS m / z (ESI): 267.0 [M+1]

[0308] Step 8

[0309] 3-Fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylisonicotinate 1j

[0310] Compound 1i (605 mg, 2.27 mmol) was dissolved in N,N-dimethylformamide (10 mL, Chinese medicine), 2-hydroxy-2-methylpropionamidine hydrochloride (945 mg, 6.82 mmol) and potassium carbonate (817 mg, 5.91 mmol, Chinese medicine) were added, and the mixture was reacted at 65°C for 24 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography with eluent system C to obtain the title compound 1j (1.1 g, yield: 99.1%).

[0311] MS m / z(ESI):306.1[M+1]

[0312] Step 9

[0313] 3-Fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5-methylisonicotinic acid 1k

[0314] Compound 1j (605 mg, 2.27 mmol) was dissolved in tetrahydrofuran (10 mL, Chinese medicine) and water (2 mL), and lithium hydroxide (191 mg, 4.55 mmol) was added, and the mixture was reacted at room temperature for 2 hours. 5 mL of water was added, and the pH was adjusted to 4-5 with citric acid, and the mixture was extracted with ethyl acetate (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the title compound 1k (200 mg, yield: 30.3%).

[0315] MS m / z(ESI):292.4[M+1]

[0316] Step 10 ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(2-hydroxypropane

[0317] -2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 1

[0318] Compound 1d (30 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL, Chinese medicine), and compound 1k (40 mg, 0.13 mmol), N,N-diisopropylethylamine (65 mg, 0.50 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (71 mg, 0.50 mmol) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography with eluent system A to obtain the title compound 1 (33 mg, yield: 51.6%).

[0319] MS m / z(ESI):515.1[M+1]

[0320] 1H NMR (500MHz, DMSO-d 6 ): δ9.01-8.98(m,1H),8.60-8.55(m,1H),8.44-8.43(m1H),7.96-7.90(m,2H),5.34-5.33(m,1H),4.67(s,1H),4.24-4.22 (m,1H),3.65-3.63(m,1H),3.60-3.54(m,3H),2.80-2.77(m,2H),2.40-2.31(m,3H),1.56-1.53(m,6H),1.24-1.17(m,6H).

[0321] Example 2

[0322] 3-(1-cyclopropyl-1-hydroxyethyl)-4'-((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazine-1-

[0323] Carbonyl)-5'-methyl-2H-[1,2'-bipyridyl]-2-one

[0324]

[0325] first step

[0326] 2-Bromo-5-methylisonicotinic acid methyl ester 2b

[0327] 2-Chloro-5-methylisonicotinic acid methyl ester 2a (610 mg, 3.29 mmol, Bidex Pharmaceuticals) was dissolved in acetonitrile (15 mL, Sinopharm), and trimethylsilyl bromide (3.53 g, 20.06 mmol, Adamas) was added under nitrogen protection, and the reaction was carried out at 80°C for 16 hours. 30 mL of saturated sodium bicarbonate was added to the reaction solution, extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography with eluent system C to obtain the title compound 2b (730 mg, yield: 96.6%).

[0328] MS m / z(ESI):232.1[M+1]

[0329] Step 2

[0330] 3-(2-Cyclopropylpropan-2-yl)-5'-methyl-2-oxo-2H-[1,2'-bipyridine]-4'-carboxylic acid methyl ester 2c

[0331] Compound 2b (380 mg, 1.65 mmol) was dissolved in 1,4-dioxane (10 mL, Chinese medicine), and cuprous iodide (32 mg, 0.17 mmol, Bid Pharmaceuticals) was added, 3-(2-cyclopropylpropan-2-yl)pyridin-2(1H)-one (358 mg, 1.99 mmol, prepared by the method disclosed in compound 14A on page 79 of the specification of patent application WO2023283338A1), potassium carbonate (456 mg, 3.30 mmol, Chinese medicine), N,N-dimethylethylenediamine (15 mg, 0.17 mmol, Chinese medicine), nitrogen protection, microwave 110 ° C for 2 hours. The reaction solution was concentrated and purified by column chromatography with eluent system A to obtain the title compound 2c (440 mg, yield: 81.13%). MS m / z (ESI): 329.4 [M+1]

[0332] Step 3

[0333] 3-(2-Cyclopropylpropane-2-yl)-5'-methyl-2-oxo-2H-[1,2'-bipyridine]-4'-carboxylic acid 2d

[0334] Compound 2c (100 mg, 0.30 mmol) was dissolved in tetrahydrofuran (2 mL, Chinese medicine) and water (0.5 mL), lithium hydroxide (39 mg, 0.93 mmol) was added, and the mixture was reacted at room temperature for 2 hours. 1 mL of water was added, pH was adjusted to 4-5 with citric acid, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 2d (95 mg, yield: 99.24%).

[0335] MS m / z(ESI):315.4[M+1]

[0336] Step 4

[0337] 3-(1-cyclopropyl-1-hydroxyethyl)-4'-((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazine-1-

[0338] Carbonyl)-5'-methyl-2H-[1,2'-bipyridyl]-2-one

[0339] Compound 1d (30 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL, Chinese medicine), and compound 2d (45 mg, 0.14 mmol), N,N-diisopropylethylamine (65 mg, 0.50 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (71 mg, 0.50 mmol) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography with eluent system A to obtain the title compound 2 (33 mg, yield: 49.4%).

[0340] MS m / z(ESI):538.6[M+1]

[0341] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.53-8.50(m,1H),8.44(s,1H),7.94-7.90(m,1H),7.78-7.76(m,1H),7.65-7.64(m, 1H),7.56-7.45(m,1H),6.42-6.39(m,1H),5.03-5.00(m,1H),4.67(s,1H),4.18-4.16(m ,1H),3.77-3.76(m,1H),3.61-3.59(m,1H),3.47-3.44(m,1H),3.15-3.06(m,1H),2.89- 2.82(m,2H),2.35-2.19(m,3H),1.53-1.52(m,3H),1.24-1.13(m,7H),0.48-0.13(m,4H).

[0342] Example 3

[0343] ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(2-(2-(-2-hydroxypropane-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 3

[0344]

[0345] first step

[0346] 2-Acetyl-5-methylisonicotinic acid methyl ester 3b

[0347] 2-Chloro-5-methylisonicotinic acid methyl ester 3a (1 g, 5.39 mmol) was dissolved in 1,4-dioxane (20 mL, Sinopharm), tributyl(1-ethoxyethylene)tin (3 g, 8.31 mmol, Shaoyuan), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (228 mg, 0.27 mmol, Bidex Pharmaceuticals), cuprous iodide (51.4 mg, 0.27 mmol, Bidex Pharmaceuticals), and reacted at 105°C for 16 hours under nitrogen protection. The residue was concentrated and purified by column chromatography with eluent system C to obtain the title compound 3b (952 mg, yield: 91.4%).

[0348] MS m / z(ESI):194.0[M+1]

[0349] Step 2

[0350] (E)-2-(3-(Dimethylamino)acryloyl)-5-methylisonicotinic acid methyl ester 3c

[0351] Compound 3b (952 mg, 4.93 mmol) was dissolved in N,N-dimethylformamide (8 mL, Sinopharm), 1,1-dimethoxy-N,N-dimethylmethylamine (4.7 g, 39.44 mmol, Shaoyuan) was added, and the mixture was reacted at 70°C for 24 hours. 20 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 3c (1.2 g, yield: 98.1%). MS m / z (ESI): 249.1 [M+1]

[0352] Step 3

[0353] 2-(2-(2-Hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylisonicotinic acid methyl ester 3d

[0354] Compound 3c (1.2 g, 4.83 mmol) was dissolved in N,N-dimethylformamide (60 mL, Sinopharm), 2-hydroxy-2-methylpropionamidine hydrochloride (2.1 g, 15.15 mmol, Shaoyuan) and potassium carbonate (1.7 g, 12.30 mmol, Sinopharm) were added, and the mixture was reacted at 65°C for 24 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system C to obtain the title compound 3d (913 mg, yield: 65.7%). MS m / z (ESI): 288.1 [M+1]

[0355] Step 4

[0356] 2-(2-(2-Hydroxypropane-2-yl)pyrimidin-4-yl)-5-methylisonicotinic acid 3e

[0357] Compound 3d (900 mg, 3.13 mmol) was dissolved in tetrahydrofuran (15 mL, Sinopharm) and water (3 mL), and lithium hydroxide (263 mg, 6.27 mmol, Adamas) was added, and the mixture was reacted at room temperature for 2 hours. 5 mL of water was added, and the pH was adjusted to 4-5 with citric acid, and the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3e (759 mg, yield: 88.7%), which was directly used for the next step without purification.

[0358] MS m / z(ESI):274.4[M+1]

[0359] Step 5 ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(2-(2-(-2-hydroxypropane-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 3

[0360] Compound 3e (240 mg, 0.88 mmol) was dissolved in N,N-dimethylformamide (4 mL, Sinopharm), and compound 1d (40 mg, 0.13 mmol), N,N-diisopropylethylamine (450 mg, 3.48 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (497 mg, 1.31 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 3 (275 mg, yield: 63.6%).

[0361] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.95-8.94(m,1H),8.71-8.67(m,1H),8.51-8.44(m,2H),8.20-8.19(m,1H),7.94-7.90(m,1H),5.34-5.33(m,1H),4.67(s,1H),4 .24-4.22(m,1H),3.65-3.63(m,1H),3.60-3.54(m,3H),2.80-2.77(m,2H),2.40-2.31(m,3H),1.56-1.53(m,6H),1.24-1.17(m,6H).

[0362] MS m / z(ESI):497.2[M+1]

[0363] Example 4

[0364] 4'-((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazine-1-carbonyl)-3-(2-hydroxypropane-2-

[0365] 4-(2-(4-(2-pyridyl)-5'-methyl-2H-[1,2'-bipyridyl]-2-one)

[0366]

[0367] first step

[0368] 3-(2-Hydroxypropan-2-yl)pyridin-2(1H)-one 4b

[0369] 2-Oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester 4a (1.5 g, 9.80 mmol, Bidex Pharmaceuticals) was dissolved in tetrahydrofuran (40 mL, Sinopharm), and methylmagnesium bromide (1 M, 49.00 mL, 49.00 mmol, Adamas) was added dropwise at room temperature, and the reaction was allowed to proceed for 1 hour at room temperature. 30 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 4b (1 g, yield: 66.6%).

[0370] MS m / z(ESI):154.1[M+1]

[0371] Step 2

[0372] 3-(2-Hydroxypropan-2-yl)-5'-methyl-2-oxo-2H-[1,2'-bipyridine]-4'-carboxylic acid methyl ester 4c

[0373] Compound 4b (400 mg, 2.61 mmol) was dissolved in 1,4-dioxane (10 mL, Chinese medicine), and cuprous iodide (42 mg, 0.22 mmol, Bidex Pharmaceuticals), compound 2b (500 mg, 2.17 mmol), potassium carbonate (601 mg, 4.35 mmol, Chinese medicine), N,N-dimethylethylenediamine (19 mg, 0.22 mmol, Chinese medicine) were added, and the mixture was reacted at 110°C for 2 hours under nitrogen protection microwave. The reaction solution was concentrated, and the residue was purified by column chromatography with eluent system A to obtain the title compound 4c (360 mg, yield: 54.8%).

[0374] MS m / z(ESI):303.4[M+1]

[0375] Step 3

[0376] 3-(2-Hydroxypropan-2-yl)-5'-methyl-2-oxo-2H-[1,2'-bipyridine]-4'-carboxylic acid 4d

[0377] Compound 4c (100 mg, 0.33 mmol) was dissolved in tetrahydrofuran (2 mL, Sinopharm), water (0.5 mL) was added with lithium hydroxide (42 mg, 1.00 mmol, Adamas), and reacted at room temperature for 2 hours. 1 mL of water was added, pH was adjusted to 4-5 with citric acid, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude title compound 4d (95 mg, yield: 99.6%), and the product was directly used for the next step without purification.

[0378] MS m / z(ESI):289.3[M+1]

[0379] Step 4

[0380] 4'-((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazine-1-carbonyl)-3-(2-hydroxypropane-2-

[0381] 4-(2-(4-(2-pyridyl)-5'-methyl-2H-[1,2'-bipyridyl]-2-one)

[0382] Compound 1d (30 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL, Sinopharm), and compound 4d (45 mg, 0.14 mmol), N,N-diisopropylethylamine (65 mg, 0.50 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (71 mg, 0.20 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 4 (18 mg, yield: 35.2%).

[0383] MS m / z(ESI):512.1[M+1]

[0384] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.53-8.50(m,1H),8.44(s,1H),7.94-7.90(m,1H),7.78-7.76(m,1H),7.65-7. 64(m,1H),7.56-7.45(m,1H),6.42-6.39(m,1H),5.25(s,1H),4.67(s,1H),4.18-4 .16(m,1H),3.77-3.76(m,1H),3.61-3.59(m,1H),3.47-3.44(m,1H),3.15-3.06(m ,1H),2.89-2.82(m,2H),2.35-2.19(m,4H),1.47-1.46(m,6H),1.24-1.00(m,5H).

[0385] Example 5

[0386] ((2R,5S)-4-(2,4-difluorobenzyl)-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidine-4-

[0387] 5-Methylpyridin-4-yl)methanone

[0388]

[0389] first step

[0390] (2R,5S)-tert-butyl 4-(2,4-difluorobenzyl)-2,5-dimethylpiperazine-1-carboxylate 5b

[0391] 1-(Bromomethyl)-2,4-difluorobenzene 5a (500 mg, 2.42 mmol) was dissolved in N,N-dimethylformamide (8 mL, Sinopharm), and (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (570 mg, 2.65 mmol, Bidex) and potassium carbonate (668 mg, 4.83 mmol, Sinopharm) were added, and the mixture was reacted at room temperature for 16 hours. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×3), and the organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography with eluent system C to obtain the title compound 5b (800 mg, yield: 97.3%).

[0392] MS m / z(ESI):341.4[M+1]

[0393] Step 2

[0394] (2S,5R)-1-(2,4-difluorobenzyl)-2,5-dimethylpiperazine 5c

[0395] Compound 5b (100 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL, Sinopharm), trifluoroacetic acid (770 mg, 6.75 mmol, Adamas) was added, and the mixture was reacted at room temperature for 2 hours. The mixture was concentrated, 5 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5c (70 mg, yield: 99.2%).

[0396] MS m / z(ESI):241.4[M+1]

[0397] Step 3 ((2R,5S)-4-(2,4-difluorobenzyl)-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidine-4-

[0398] 5-Methylpyridin-4-yl)methanone

[0399] Compound 5c (35 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1 mL, Chinese medicine), and compound 1k (51 mg, 0.18 mmol), N,N-diisopropylethylamine (95 mg, 0.74 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 5 (36 mg, yield: 70.1%).

[0400] MS m / z(ESI):514.5[M+1]

[0401] 1 H NMR (500 MHz, DMSO-d 6 ): δ9.01-8.98(m,1H),8.60-8.55(m,1H),7.96-7.93(m,1H),7.53-7.51(m, 1H),7.22-7.17(m,1H),7.10-7.06(m,1H),5.10-5.06(m,1H),4.25(s,1H),3 .65-3.63(m,1H),3.60-3.54(m,3H),3.31-3.27(m,1H),2.95-2.70(m,3H), 2.41-2.20(m,4H),1.56-1.53(m,4H),1.29-1.18(m,3H),1.05-0.89(m,3H).

[0402] Example 6

[0403] 4'-((2R,5S)-4-(2,4-difluorobenzyl)-2,5-dimethylpiperazine-1-carbonyl)-3-(2-hydroxypropan-2-yl)-5'-methyl

[0404] -2H-[1,2'-bipyridyl]-2-one 6

[0405]

[0406] first step

[0407] 4'-((2R,5S)-4-(2,4-difluorobenzyl)-2,5-dimethylpiperazine-1-carbonyl)-3-(2-hydroxypropan-2-yl)-5'-methyl

[0408] -2H-[1,2'-bipyridyl]-2-one 6

[0409] Compound 5c (35 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1 mL, Sinopharm), and compound 4d (51 mg, 0.18 mmol), N,N-diisopropylethylamine (96 mg, 0.74 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 6 (42 mg, yield: 56.5%).

[0410] MS m / z(ESI):511.5[M+1]

[0411] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.53-8.50(m,1H),7.77-7.67(m,2H),7.58-7.46(m,2H),7.21-7.18(m,1H) ,7.10-7.06(m,1H),6.42-6.39(m,1H),5.25(s,1H),4.67(s,1H),4.18-4.16(m ,1H),3.64-3.44(m,3H),3.23-3.21(m,1H),3.09-3.07(m,1H),3.02-3.01(m,1 H),2.89-2.82(m,1H),2.35-2.19(m,4H),1.47-1.46(m,4H),1.24-0.85(m,6H).

[0412] Example 7

[0413] (2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)methanone 7

[0414]

[0415] first step

[0416] 2-Chloro-3-fluoro-5-methylisonicotinic acid 7b

[0417] 2-Chloro-3-fluoro-5-methylpyridine 7a (10 g, 68.70 mmol, Shaoyuan) was dissolved in tetrahydrofuran (150 mL, Sinopharm), and lithium diisopropylamide (2 M, 68.61 mL, 137.22 mmol, Adamas) was added at -78°C under nitrogen protection, and reacted at -78°C for 1 hour. Dry ice was added, and the reaction was continued at -78°C for 1 hour. 30 mL of water was added dropwise to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude title compound 7b (10 g, yield: 76.8%), which was directly used for the next step without purification.

[0418] MS m / z(ESI):190.1[M+1]

[0419] Step 2

[0420] 2-Chloro-3-fluoro-5-methylisonicotinic acid methyl ester 7c

[0421] Compound 7b (10 g, 52.75 mmol) was dissolved in tetrahydrofuran (60 mL, Sinopharm) and methanol (10 mL, Sinopharm), and (trimethylsilyl)diazomethane (12.1 g, 137.22 mmol, Adamas) was added at room temperature under nitrogen protection, and reacted at room temperature for 12 hours. The mixture was concentrated and purified by column chromatography with eluent system C to obtain the title compound 7c (6.4 g, yield: 59.6%).

[0422] MS m / z(ESI):204.1[M+1]

[0423] Step 3

[0424] 2-Acetyl-3-fluoro-5-methylisonicotinic acid methyl ester 7d

[0425] Compound 7c (500 mg, 2.46 mmol) was dissolved in 1,4-dioxane (15 mL, Sinopharm), tributyl(1-ethoxyethylene)tin (1.33 g, 3.68 mmol, Shaoyuan), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (208 mg, 0.25 mmol, Bidex Pharmaceuticals), and cuprous iodide (47 mg, 0.25 mmol, Bidex Pharmaceuticals) were added, and the mixture was reacted at 105°C for 16 hours under nitrogen protection. After concentration, the residue was purified by column chromatography with eluent system C to obtain the title compound 7d (480 mg, yield: 92.5%).

[0426] MS m / z(ESI):212.1[M+1]

[0427] Step 4

[0428] (E)-2-(3-(Dimethylamino)acryloyl)-3-fluoro-5-methylisonicotinate 7e

[0429] Compound 7d (480 mg, 2.27 mmol) was dissolved in N,N-dimethylformamide (3 mL, Sinopharm), 1,1-dimethoxy-N,N-dimethylmethylamine (2.17 g, 18.21 mmol, Shaoyuan) was added, and the mixture was reacted at 70°C for 24 hours. 20 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the title compound 7e (605 mg, yield: 100.0%).

[0430] MS m / z(ESI):267.1[M+1]

[0431] Step 5

[0432] 2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylisonicotinic acid methyl ester 7f

[0433] Compound 7e (150 mg, 0.56 mmol) was dissolved in N,N-dimethylformamide (2 mL, Sinopharm), 2-cyclopropyl-2-hydroxy-propionamidine hydrochloride (279 mg, 1.69 mmol, Shaoyuan) and potassium carbonate (312 mg, 2.25 mmol, Sinopharm) were added, and the mixture was reacted at 80°C for 4 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with eluent system C to obtain the title compound 7f (186 mg, yield: 99.6%). MS m / z (ESI): 332.1 [M+1]

[0434] Step 6

[0435] 2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylisonicotinic acid 7g

[0436] Compound 7f (186 mg, 0.56 mmol) was dissolved in tetrahydrofuran (3 mL, Sinopharm), water (0.6 mL) was added with lithium hydroxide (71 mg, 1.69 mmol, Adamas), and reacted at room temperature for 2 hours. 5 mL of water was added, pH was adjusted to 4-5 with citric acid, extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7g (60 mg, yield: 33.7%), and the product was directly used for the next step without purification.

[0437] MS m / z(ESI):318.4[M+1]

[0438] Step 7

[0439] (2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)methanone 7

[0440] Compound 7g (60 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (1 mL, Sinopharm), and compound 1d (42 mg, 0.17 mmol), N,N-diisopropylethylamine (90 mg, 0.70 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (100 mg, 0.26 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography with eluent system A to obtain the title compound 7 (25 mg, yield: 26.6%).

[0441] MS m / z(ESI):541.7[M+1]

[0442] 1 H NMR (500 MHz, DMSO-d 6 ): δ9.04-9.00(m,1H),8.61-8.56(m,1H),8.44-8.43(m,1H),8.01-7.97 (m,1H),7.94-7.90(m,1H),4.77-4.67(m,2H),4.24-4.22(m,1H),3.65-3 .63(m,1H),3.60-3.54(m,3H),3.22-3.10(m,2H),2.80-2.77(m,2H),2.4 0-2.31(m,4H),1.56-1.53(m,3H),1.24-1.17(m,4H),0.45-0.12(m,4H).

[0443] Example 7-1, Example 7-2

[0444] (2-(2-((R)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)methanone 7-1

[0445] (2-(2-((S)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)methanone 7-2

[0446]

[0447] Compound 7 (100 mg, 0.18 mmol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAKIG, 5 μm, 20 mm*250 mm (Phenomenex); mobile phase: n-hexane / ethanol / 7 M ammonia methanol solution = 75 / 25 / 0.5 (V / V / V), flow rate: 20 mL / min), and the corresponding components were collected and concentrated under reduced pressure to give the title compound (28 mg, 28 mg).

[0448] Single configuration compound (short retention time: 28 mg):

[0449] MS m / z(ESI):541.7[M+1].

[0450] Chiral HPLC analysis: retention time 5.125 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG, 5 μm, 20 mm*250 mm (Phenomenex); mobile phase: n-hexane / ethanol / 7 M ammonia methanol solution = 75 / 25 / 0.5 (V / V / V), flow rate: 20 mL / min).

[0451] 1 H NMR (500 MHz, DMSO-d 6 ): δ9.04-9.00(m,1H),8.61-8.56(m,1H),8.44-8.43(m,1H),8.01-7.97 (m,1H),7.94-7.90(m,1H),4.77-4.67(m,2H),4.24-4.22(m,1H),3.65-3 .63(m,1H),3.60-3.54(m,3H),3.22-3.10(m,2H),2.80-2.77(m,2H),2.4 0-2.31(m,4H),1.56-1.53(m,3H),1.24-1.17(m,4H),0.45-0.12(m,4H).

[0452] Single configuration compound (longer retention time: 28 mg):

[0453] MS m / z(ESI):541.7[M+1].

[0454] Chiral HPLC analysis: retention time 7.349 minutes, chiral purity: 100% (chromatographic column: CHIRALPAKIG, 5 μm, 20 mm*250 mm (Phenomenex); mobile phase: n-hexane / ethanol / 7 M ammonia methanol solution = 75 / 25 / 0.5 (V / V / V), flow rate: 20 mL / min).

[0455] 1 H NMR (500 MHz, DMSO-d 6 ): δ9.04-9.00(m,1H),8.61-8.56(m,1H),8.44-8.43(m,1H),8.01-7.97 (m,1H),7.94-7.90(m,1H),4.77-4.67(m,2H),4.24-4.22(m,1H),3.65-3 .63(m,1H),3.60-3.54(m,3H),3.22-3.10(m,2H),2.80-2.77(m,2H),2.4 0-2.31(m,4H),1.56-1.53(m,3H),1.24-1.17(m,4H),0.45-0.12(m,4H).

[0456] Example 8

[0457] (2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-5-methylpyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridine-2-

[0458] 2,5-dimethylpiperazin-1-yl)methanone 8

[0459]

[0460] first step

[0461] 2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-5-methylisonicotinate 8a

[0462] Compound 3c (100 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (1 mL, Sinopharm), 2-cyclopropyl-2-hydroxy-propionamidine hydrochloride (400 mg, 2.43 mmol, Shaoyuan) and potassium carbonate (446 mg, 3.23 mmol, Sinopharm) were added, and the mixture was reacted at 80°C for 16 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with eluent system C to obtain the title compound 8a (126 mg, yield: 99.8%).

[0463] MS m / z(ESI):314.1[M+1]

[0464] Step 2

[0465] 2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-5-methylisonicotinic acid 8b

[0466] Compound 8a (126 mg, 0.40 mmol) was dissolved in tetrahydrofuran (2 mL, Sinopharm), water (0.6 mL) was added with lithium hydroxide (51 mg, 1.22 mmol, Adamas), and reacted at room temperature for 2 hours. 5 mL of water was added, pH was adjusted to 4-5 with citric acid, extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude title compound 8b (80 mg, yield: 66.5%), which was directly used for the next step without purification.

[0467] MS m / z(ESI):300.4[M+1]

[0468] Step 3 (2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-5-methylpyridin-4-yl) ((2R,5S)-4-((3,5-difluoropyridine-2-

[0469] 2,5-dimethylpiperazin-1-yl)methanone 8

[0470] Compound 8b (30 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1 mL, Sinopharm), and compound 1d (28 mg, 0.12 mmol), N,N-diisopropylethylamine (52 mg, 0.40 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (58 mg, 0.15 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 8 (5 mg, yield: 9.6%).

[0471] MS m / z(ESI):523.5[M+1]

[0472] 1 H NMR (500 MHz, DMSO-d 6): δ8.97-8.96(m,1H),8.71-8.61(m,2H),8.55-8.54(m,1H),8.22-8.21 (m,1H),7.94-7.90(m,1H),4.77-4.67(m,2H),4.24-4.22(m,1H),3.65-3 .63(m,1H),3.60-3.54(m,3H),3.22-3.10(m,2H),2.80-2.77(m,2H),2.4 0-2.31(m,4H),1.56-1.53(m,3H),1.24-1.17(m,4H),0.45-0.12(m,4H).

[0473] Example 8-1, Example 8-2

[0474] (2-(2-((R)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-5-methylpyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)methanone 8-1

[0475] (2-(2-((S)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-5-methylpyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)methanone 8-2

[0476]

[0477] Compound 8 (109 mg, 0.21 mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALPAKIG, 5 μm, 20 mm*250 mm (Phenomenex); mobile phase: n-hexane / ethanol / 7 M ammonia methanol solution = 10 / 90 / 0.5 (V / V / V), flow rate: 10 mL / min), and the corresponding components were collected and concentrated under reduced pressure to give the title compound (45 mg, 39 mg).

[0478] Single configuration compound (short retention time: 45 mg):

[0479] MS m / z(ESI):523.5[M+1].

[0480] Chiral HPLC analysis: retention time 6.294 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG, 5 μm, 20 mm*250 mm (Phenomenex); mobile phase: n-hexane / ethanol / 7 M ammonia methanol solution = 10 / 90 / 0.5 (V / V / V), flow rate: 10 mL / min).

[0481] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.97-8.96(m,1H),8.71-8.61(m,2H),8.55-8.54(m,1H),8.22-8.21 (m,1H),7.94-7.90(m,1H),4.77-4.67(m,2H),4.24-4.22(m,1H),3.65-3 .63(m,1H),3.60-3.54(m,3H),3.22-3.10(m,2H),2.80-2.77(m,2H),2.4 0-2.31(m,4H),1.56-1.53(m,3H),1.24-1.17(m,4H),0.45-0.12(m,4H).

[0482] Single configuration compound (longer retention time: 39 mg):

[0483] MS m / z(ESI):523.5[M+1].

[0484] Chiral HPLC analysis: retention time 21.476 minutes, chiral purity: 100% (chromatographic column: CHIRALPAKIG, 5 μm, 20 mm*250 mm (Phenomenex); mobile phase: n-hexane / ethanol / 7 M ammonia methanol solution = 10 / 90 / 0.5 (V / V / V), flow rate: 10 mL / min).

[0485] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.97-8.96(m,1H),8.71-8.61(m,2H),8.55-8.54(m,1H),8.22-8.21 (m,1H),7.94-7.90(m,1H),4.77-4.67(m,2H),4.24-4.22(m,1H),3.65-3 .63(m,1H),3.60-3.54(m,3H),3.22-3.10(m,2H),2.80-2.77(m,2H),2.4 0-2.31(m,4H),1.56-1.53(m,3H),1.24-1.17(m,4H),0.45-0.12(m,4H).

[0486] Example 9

[0487] ((2R,5S)-4-((5-chloro-3-fluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(2-hydroxypropane-2-

[0488] 4-(2-Methylpyridin-4-yl)-5-(2-methylpyridin-4-yl)methanone

[0489]

[0490] The synthetic route of Example 1 was adopted, and the raw material compound 1a was replaced with (4-chloro-2-fluorophenyl)methanol to prepare the title compound 9 (13 mg, yield: 35.6%).

[0491] MS m / z(ESI):531.2[M+1]

[0492] 1 H NMR (500 MHz, DMSO-d 6 ): δ9.01-8.98(m,1H),8.60-8.55(m,1H),8.44-8.43(m,1H),7.96-7.90(m,2H),5.34-5.33(m,1H),4.67(s,1H),4.24-4.22 (m,1H),3.65-3.63(m,1H),3.60-3.54(m,3H),2.80-2.77(m,2H),2.40-2.31(m,3H),1.56-1.53(m,6H),1.24-1.17(m,6H).

[0493] Example 10

[0494] ((2R,5S)-4-((5-chloro-3-fluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(2-(2-(-2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 10

[0495]

[0496]

[0497] first step

[0498] (2R,5S)-tert-butyl 4-((5-chloro-3-fluoropyridin-2-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate 10b

[0499] 5-Chloro-2-(chloromethyl)-3-fluoropyridine 10a (300 mg, 1.67 mmol, Leyan) was dissolved in N,N-dimethylformamide (10 mL, Sinopharm), and (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (429 mg, 2.00 mmol, Bidex) and potassium carbonate (461 mg, 3.34 mmol, Sinopharm) were added, and the mixture was reacted at room temperature for 16 hours. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×3), and the organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography with eluent system C to obtain the title compound 10b (150 mg, yield: 25.2%).

[0500] MS m / z(ESI):358.5[M+1]

[0501] Step 2

[0502] (2S,5R)-1-((5-chloro-3-fluoropyridin-2-yl)methyl)-2,5-dimethylpiperazine 10c

[0503] Compound 10b (50 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL, Sinopharm), trifluoroacetic acid (770 mg, 6.75 mmol, Adamas) was added, and the mixture was reacted at room temperature for 2 hours. 5 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 10c (36 mg, yield: 99.9%). MS m / z (ESI): 258.4 [M+1]

[0504] Step 3 ((2R,5S)-4-((5-chloro-3-fluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(2-(2-(-2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 10

[0505] Compound 10c (35 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (1 mL, Sinopharm), and compound 3e (45 mg, 0.16 mmol), N,N-diisopropylethylamine (71 mg, 0.55 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (78 mg, 0.21 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 10 (32 mg, yield: 45.9%).

[0506] MS m / z(ESI):513.2[M+1]

[0507] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.95-8.94(m,1H),8.71-8.67(m,1H),8.51-8.44(m,2H),8.20-8.19(m,1H),7.94-7.90(m,1H),5.34-5.33(m,1H),4.67(s,1H),4 .24-4.22(m,1H),3.65-3.63(m,1H),3.60-3.54(m,3H),2.80-2.77(m,2H),2.40-2.31(m,3H),1.56-1.53(m,6H),1.24-1.17(m,6H).

[0508] Embodiment 11

[0509] ((2R,5S)-4-((3-chloro-5-fluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(2-hydroxypropane-2-

[0510] 4-(2-(2-methylpyridin-4-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 11

[0511]

[0512] The synthetic route of Example 1 was adopted, and the raw material compound 1a was replaced with (3-chloro-5-fluorophenyl)methanol to prepare the title compound 11 (19 mg, yield: 34.7%).

[0513] MS m / z(ESI):531.2[M+1]

[0514] 1 H NMR (500 MHz, DMSO-d 6 ): δ9.01-8.98(m,1H),8.60-8.55(m,1H),8.44-8.43(m,1H),7.96-7.90(m,2H),5.34-5.33(m,1H),4.67(s,1H),4.24-4.22 (m,1H),3.65-3.63(m,1H),3.60-3.54(m,3H),2.80-2.77(m,2H),2.40-2.31(m,3H),1.56-1.53(m,6H),1.24-1.17(m,6H).

[0515] Example 12

[0516] ((2R,5S)-4-((3-chloro-5-fluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(2-(2-(-2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 12

[0517]

[0518] The synthetic route of Example 10 was adopted to replace the raw material compound 10a with 3-chloro-2-(chloromethyl)-5-fluoropyridine to prepare the title compound 12 (50 mg, yield: 71.8%).

[0519] MS m / z(ESI):513.1[M+1]

[0520] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.95-8.94(m,1H),8.71-8.67(m,1H),8.51-8.44(m,2H),8.20-8.19(m,1H),7.94-7.90(m,1H),5.34-5.33(m,1H),4.67(s,1H),4 .24-4.22(m,1H),3.65-3.63(m,1H),3.60-3.54(m,3H),2.80-2.77(m,2H),2.40-2.31(m,3H),1.56-1.53(m,6H),1.24-1.17(m,6H).

[0521] Example 13

[0522] ((2R,5S)-4-((3-fluoro-5-methylpyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(2-hydroxypropyl)

[0523] -2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 13

[0524]

[0525] The synthetic route of Example 1 was adopted to replace the raw material compound 1b with 2-(chloromethyl)-3-fluoro-5-methylpyridine to prepare the title compound 13 (33 mg, yield: 54.8%).

[0526] MS m / z(ESI):511.2[M+1]

[0527] 1 H NMR (500 MHz, DMSO-d6 ): δ9.01-8.98(m,1H),8.60-8.55(m,1H),8.44-8.43(m,1H),7.96-7.90(m,2H),5.34-5.33(m,1H),4.67(s,1H),4.24-4.22 (m,1H),3.65-3.63(m,1H),3.60-3.54(m,3H),2.80-2.77(m,2H),2.40-2.31(m,6H),1.56-1.53(m,6H),1.24-1.17(m,6H).

[0528] Embodiment 14

[0529] ((2R,5S)-4-((3-fluoro-5-methylpyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 14

[0530]

[0531] The synthetic route of Example 10 was adopted to replace the raw material compound 10a with the compound 2-(chloromethyl)-3-fluoro-5-methylpyridine to prepare the title compound 14 (40 mg, yield: 55.1%).

[0532] MS m / z(ESI):493.2[M+1]

[0533] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.95-8.94(m,1H),8.71-8.67(m,1H),8.51-8.44(m,2H),8.20-8.19(m,1H),7.94-7.90(m,1H),5.34-5.33(m,1H),4.67(s,1H),4 .24-4.22(m,1H),3.65-3.63(m,1H),3.60-3.54(m,3H),2.80-2.77(m,2H),2.40-2.31(m,6H),1.56-1.53(m,6H),1.24-1.17(m,6H).

[0534] Embodiment 15

[0535] 4'-((2R,5S)-4-((3-fluoro-5-methylpyridin-2-yl)methyl)-2,5-dimethylpiperazine-1-carbonyl)-3-(2-hydroxypropane-2-

[0536] 15-(2-(2-pyridyl)-5'-methyl-2H-[1,2'-bipyridyl]-2-one

[0537]

[0538]

[0539] first step

[0540] (2R,5S)-tert-butyl 4-((3-fluoro-5-methylpyridin-2-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate 15b

[0541] 2-(Chloromethyl)-3-fluoro-5-methylpyridine 15a (290 mg, 1.82 mmol) was dissolved in N,N-dimethylformamide (8 mL, Sinopharm), and (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (429 mg, 2.00 mmol, Bidex) and potassium carbonate (461 mg, 3.34 mmol, Sinopharm) were added, and the mixture was reacted at room temperature for 16 hours. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×3), and the organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system C to obtain the title compound 15b (390 mg, yield: 63.6%).

[0542] MS m / z(ESI):338.5[M+1]

[0543] Step 2

[0544] (2S,5R)-1-((3-fluoro-5-methylpyridin-2-yl)methyl)-2,5-dimethylpiperazine 15c

[0545] Compound 15b (40 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL, Sinopharm), trifluoroacetic acid (770 mg, 6.75 mmol, Adamas) was added, and the mixture was reacted at room temperature for 2 hours. 5 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 15c (28 mg, yield: 99.5%). MS m / z (ESI): 238.4 [M+1]

[0546] Step 3

[0547] 4'-((2R,5S)-4-((3-fluoro-5-methylpyridin-2-yl)methyl)-2,5-dimethylpiperazine-1-carbonyl)-3-(2-hydroxypropane-2-

[0548] 15-(2-(2-pyridyl)-5'-methyl-2H-[1,2'-bipyridyl]-2-one

[0549] Compound 15c (25 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (1 mL, Sinopharm), and compound 4d (37 mg, 0.13 mmol), N,N-diisopropylethylamine (55 mg, 0.43 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (60 mg, 0.16 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 15 (33 mg, yield: 61.7%).

[0550] MS m / z(ESI):508.2[M+1]

[0551] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.53-8.50(m,1H),7.77-7.67(m,2H),7.58-7.46(m,2H),7.21-7.18(m,1H) ,7.10-7.06(m,1H),6.42-6.39(m,1H),5.25(s,1H),4.67(s,1H),4.18-4.16(m ,1H),3.64-3.44(m,3H),3.23-3.21(m,1H),3.09-3.07(m,1H),3.02-3.01(m,1 H), 2.89-2.82(m,1H),2.35-2.19(m,6H),1.47-1.46(m,4H),1.24-0.85(m,6H).

[0552] Example 16

[0553] ((2R,5S)-4-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(2-

[0554] (hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 16

[0555]

[0556] The synthetic route of Example 1 was adopted to replace the raw material compound 1a with (3-fluoro-5-(trifluoromethyl)pyridin-2-yl)methanol to prepare the title compound 16 (23 mg, yield: 63.8%).

[0557] MS m / z(ESI):565.6[M+1]

[0558] 1 H NMR (500 MHz, DMSO-d 6 ): δ9.01-8.98(m,1H),8.60-8.55(m,1H),8.44-8.43(m,1H),7.96-7.90(m,2H),5.34-5.33(m,1H),4.67(s,1H),4.24-4.22 (m,1H),3.65-3.63(m,1H),3.60-3.54(m,3H),2.80-2.77(m,2H),2.40-2.31(m,3H),1.56-1.53(m,6H),1.24-1.17(m,6H).

[0559] Embodiment 17

[0560] ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl-d 2 )-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(2-hydroxypropyl)

[0561] -2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 17

[0562]

[0563] first step

[0564] (3,5-Difluoropyridin-2-yl)methane-d 2 -alcohol 17b

[0565] Ethyl 3,5-difluoropicolinate 17a (1 g, 5.34 mmol, Bidex Pharmaceuticals) was dissolved in tetrahydrofuran (2 mL, Sinopharm) and deuterated methanol (1 mL, Sinopharm), and sodium deuterated borohydride (224 mg, 5.35 mmol, Adamas) was added at 0°C under nitrogen protection, and reacted at room temperature for 2 hours. Deuterated water was added at 0°C to quench, 30 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with eluent system C to obtain the title compound 17b (660 mg, yield: 84.0%).

[0566] MS m / z(ESI):148.2[M+1]

[0567] Step 2

[0568] 2-(Chloromethyl-d 2)-3,5-difluoropyridine 17c

[0569] Compound 17b (660 mg, 4.47 mmol) was dissolved in dichloromethane (3 mL, Chinese medicine), N,N-dimethylformamide (33 mg, 0.45 mmol, Chinese medicine) was added, and thionyl chloride (1.34 g, 11.26 mmol, Chinese medicine) was added under stirring at 0°C, and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to dryness to obtain the title compound 17c (742 mg, yield: 99.9%).

[0570] MS m / z(ESI):166.3[M+1]

[0571] Step 3

[0572] (2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl 2 )-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester 17d

[0573] Compound 17c (742 mg, 4.48 mmol) was dissolved in N,N-dimethylformamide (14 mL, Sinopharm), and (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (700 mg, 3.37 mmol, Bidex) and potassium carbonate (903 mg, 6.53 mmol, Sinopharm) were added, and the mixture was reacted at room temperature for 16 hours. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system C to obtain the title compound 17d (670 mg, yield: 59.7%).

[0574] MS m / z(ESI):344.5[M+1]

[0575] Step 4

[0576] e

[0577] (2S,5R)-1-((3,5-difluoropyridin-2-yl)methyl-d 2 )-2,5-Dimethylpiperazine 17e

[0578] Compound 17d (150 mg, 0.44 mmol) was dissolved in dichloromethane (2 mL, Sinopharm), trifluoroacetic acid (770 mg, 6.75 mmol, Adamas) was added, and the mixture was reacted at room temperature for 2 hours. After concentration, 5 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (5 mL×3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 17e (106 mg, yield: 99.7%).

[0579] MS m / z(ESI):244.4[M+1]

[0580] Step 5 ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl-d 2 )-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(2-hydroxypropyl)

[0581] -2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 17

[0582] Compound 17e (106 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (2 mL, Sinopharm), and compound 1k (127 mg, 0.44 mmol), N,N-diisopropylethylamine (226 mg, 1.75 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (249 mg, 0.65 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 17 (34 mg, yield: 17.1%).

[0583] MS m / z(ESI):517.5[M+1]

[0584] 1 H NMR (500 MHz, DMSO-d 6 ): δ9.01-8.98(m,1H),8.60-8.55(m,1H),8.44-8.43(m,1H),7.96-7.90(m,2H),5.34-5.33(m,1H),4.67(s,1H),4.24-4.22 (m,1H),3.65-3.63(m,1H),3.60-3.54(m,1H),2.80-2.77(m,2H),2.40-2.31(m,3H),1.56-1.53(m,6H),1.24-1.17(m,6H).

[0585] Embodiment 18

[0586] (3-chloro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridine

[0587] -2-yl)methyl)-2,5-dimethylpiperazin-1-yl)methanone 18

[0588]

[0589] first step

[0590] 2,3-Dichloro-5-methylisonicotinic acid 18b

[0591] 2,3-Dichloro-5-methylpyridine 18a (500 mg, 3.09 mmol, Bidex Pharmaceuticals) was dissolved in tetrahydrofuran (5 mL, Adamas), and lithium diisopropylamide (2 M, 3.09 mL, 6.18 mmol, Adamas) was added, and the mixture was reacted at -78 °C for 1 hour. Dry ice was added, and the mixture was reacted at -78 °C for 1 hour. 10 mL of saturated ammonium chloride solution was added to quench the mixture, and the pH was adjusted to 4-5 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 18b (450 mg, yield: 70.8%).

[0592] MS m / z(ESI):206.1[M+1]

[0593] Step 2

[0594] 2,3-Dichloro-5-methylisonicotinic acid methyl ester 18c

[0595] Compound 18b (450 mg, 2.18 mmol) was dissolved in tetrahydrofuran (3 mL, Sinopharm) and methanol (0.6 mL, Sinopharm), and (trimethylsilyl)diazomethane (2 M, 2.19 mL, 4.38 mmol, Adamas) was added at room temperature, and reacted at room temperature for 2 hours. The residue was concentrated and purified by column chromatography with eluent system C to obtain the title compound 18c (270 mg, yield: 56.2%).

[0596] MS m / z(ESI):220.1[M+1]

[0597] Step 3

[0598] 2-Acetyl-3-chloro-5-methylisonicotinic acid methyl ester 18d

[0599] Compound 18c (270 mg, 1.23 mmol) was dissolved in 1,4-dioxane (6 mL, Sinopharm), tributyl(1-ethoxyethylene)tin (887 mg, 2.46 mmol, Shaoyuan), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (104 mg, 0.12 mmol, Bidex Pharmaceuticals), and cuprous iodide (24 mg, 0.12 mmol, Bidex Pharmaceuticals) were added, and the mixture was reacted at 105°C for 16 hours under nitrogen protection. After concentration, the residue was purified by column chromatography with eluent system C to obtain the title compound 18d (250 mg, yield: 89.5%).

[0600] MS m / z(ESI):228.3[M+1]

[0601] Step 4

[0602] (E)-(3-chloro-2-(3-(dimethylamino)acryloyl)-5-methylisonicotinic acid methyl ester 18e

[0603] Compound 18d (250 mg, 1.10 mmol) was dissolved in N,N-dimethylformamide (1.5 mL, Sinopharm), 1,1-dimethoxy-N,N-dimethylmethylamine (1.05 g, 8.81 mmol, Shaoyuan) was added, and the mixture was reacted at 70°C for 24 hours. 20 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the title compound 18e (310 mg, yield: 99.8%).

[0604] MS m / z(ESI):283.0[M+1]

[0605] Step 5

[0606] 3-Chloro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylisonicotinate 18f

[0607] Compound 18e (310 mg, 1.10 mmol) was dissolved in N,N-dimethylformamide (5 mL, Sinopharm), 2-hydroxy-2-methylpropionamidine hydrochloride (456 mg, 3.29 mmol, Shaoyuan) and potassium carbonate (395 mg, 2.86 mmol, Sinopharm) were added, and the mixture was reacted at 65°C for 24 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system C to obtain the title compound 18f (352 mg, yield: 99.8%).

[0608] MS m / z(ESI):322.0[M+1]

[0609] Step 6

[0610] 3-Chloro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylisonicotinic acid 18g

[0611] Compound 18f (352 mg, 1.09 mmol) was dissolved in tetrahydrofuran (5 mL, Sinopharm), sodium hydroxide (138 mg, 3.45 mmol, Adamas) was added, and the mixture was reacted at 60°C for 6 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3), and the pH was adjusted to 2 with hydrochloric acid, and the mixture was concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 18g (80 mg, yield: 23.8%).

[0612] MS m / z(ESI):308.3[M+1]

[0613] Step 7 (3-chloro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridine-2-yl)

[0614] 1-(2,5-dimethylpiperazin-1-yl)methanone

[0615] Compound 18g (40 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (1 mL, Sinopharm), and compound 1d (28 mg, 0.12 mmol), N,N-diisopropylethylamine (60 mg, 0.46 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (67 mg, 0.18 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography with eluent system A to obtain the title compound 18 (3 mg, yield: 4.9%).

[0616] MS m / z(ESI):531.5[M+1]

[0617] 1 H NMR (500 MHz, DMSO-d 6): δ9.01-8.98(m,1H),8.60-8.55(m,1H),8.44-8.43(m,1H),7.96-7.90(m,2H),5.34-5.33(m,1H),4.67(s,1H),4.24-4.22 (m,1H),3.65-3.63(m,1H),3.60-3.54(m,3H),2.80-2.77(m,2H),2.40-2.31(m,3H),1.56-1.53(m,6H),1.24-1.17(m,6H).

[0618] Embodiment 19

[0619] (3,5-difluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)pyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridine-2-

[0620] 1-(2,5-dimethylpiperazin-1-yl)methanone

[0621]

[0622]

[0623] first step

[0624] 3,5-Difluoroisonicotinic acid methyl ester 19b

[0625] In a dry flask, 3,5-difluoropyridine-4-carboxylic acid 19a (2 g, 12.57 mmol, Bid) was dissolved in tetrahydrofuran (10 mL, Sinopharm), methanol (2 mL, Sinopharm), (trimethylsilyl)diazomethane (2M, 18.87 mL, Adamas) was added dropwise at room temperature, and reacted at room temperature for 2 hours. 30 mL of water was added, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography with the residue system C to obtain the title compound 19b (1.9 g, yield: 87.3%).

[0626] Step 2

[0627] 3,5-Difluoro-4-(methoxycarbonyl)pyridine 1-oxide 19c

[0628] In a dry sealed tube, compound 19b (1.9 g, 10.97 mmol) was dissolved in 1,2-dichloroethane (30 mL, Sinopharm), and m-chloroperbenzoic acid (3.79 g, 21.96 mmol, Adamas) was added, and the mixture was reacted at 80°C for 16 hours. Saturated sodium bicarbonate solution (20 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 19c (1.7 g, yield: 81.9%).

[0629] MS m / z(ESI):190.2[M+1]

[0630] Step 3

[0631] 2-Chloro-3,5-difluoroisonicotinic acid methyl ester 19d

[0632] In a dry flask, compound 19c (1.2 g, 6.35 mmol) was dissolved in phosphorus oxychloride (4.9 g, 31.96 mmol, Chinese medicine) and reacted at 110°C for 2 hours. Ice bath, crushed ice was added to quench, saturated sodium carbonate solution was added dropwise until the pH of the reaction solution was 7-8, and ethyl acetate (30 mL×3) was used for extraction. The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 19d (1.2 g, yield: 91.1%).

[0633] Step 4

[0634] 2-Acetyl-3,5-difluoroisonicotinic acid methyl ester 19e

[0635] In a dry flask, compound 19d (1.2 g, 5.78 mmol) was dissolved in 1,4-dioxane (30 mL, Sinopharm), tributyl(1-ethoxyethylene)tin (3.1 g, 8.58 mmol, Alpha), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (489.6 mg, 0.58 mmol, Hanhong), cuprous iodide (110.1 mg, 0.58 mmol, Adamas) were added, nitrogen was replaced three times, and the mixture was reacted at 100°C for 16 hours. After cooling to room temperature, hydrochloric acid (30 mL, Sinopharm) was added and the mixture was reacted for 1 hour. Saturated sodium bicarbonate solution was added dropwise until the pH of the reaction solution was 7-8, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to give the title compound 19e (1 g, yield: 80.4%).

[0636] MS m / z(ESI):216.1[M+1]

[0637] Step 5

[0638] (E)-2-(3-(Dimethylamino)acryloyl)-3,5-difluoroisonicotinic acid methyl ester 19f

[0639] In a dry flask, compound 19e (2.5 g, 11.62 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethylamine (2.1 g, 17.62 mmol, Adamas), and reacted at 100°C for 1 hour. 20 mL of water was added, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system A to obtain the title compound 19f (1.4 g, yield: 44.6%).

[0640] MS m / z(ESI):271.0[M+1]

[0641] Step 6

[0642] 3,5-Difluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)isonicotinic acid methyl ester 19g

[0643] Compound 19f (1.4 g, 5.18 mmol) was dissolved in tert-butyl alcohol (26 mL, Chinese medicine), 2-hydroxy-2-methylpropionamidine hydrochloride (1.6 g, 15.67 mmol, Aikang), potassium carbonate (1.9 g, 13.75 mmol, Chinese medicine) were added, and the mixture was reacted at 80°C for 7 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 19g (180 mg, yield: 11.2%). MS m / z (ESI): 310.0 [M+1]

[0644] Step 7

[0645] 3,5-Difluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)isonicotinic acid 19h

[0646] Compound 19g (170 mg, 0.55 mmol) was dissolved in tetrahydrofuran (2 mL, Chinese medicine) and water (0.5 mL), and lithium hydroxide (69 mg, 1.65 mmol, Adamas) was added, and the reaction was carried out at room temperature for 2 hours. 1 mL of water was added, and citric acid was added dropwise until the pH of the reaction solution was 4-5, and the mixture was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the title compound 19h (90 mg, yield: 55.5%). MS m / z (ESI): 296.0 [M+1]

[0647] Step 8 (3,5-difluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)pyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)methanone 19

[0648] Compound 1d (103 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (5 mL, Sinopharm), and compound 19h (90 mg, 0.31 mmol), N,N-diisopropylethylamine (158 mg, 1.22 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (174 mg, 0.46 mmol, Adamas) were added, and reacted at room temperature for 3 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system A to obtain the title compound 19 (150 mg, yield: 94.9%).

[0649] MS m / z(ESI):519.2[M+1]

[0650] 1 H NMR (500MHz, CD 3 OD)δ9.03-8.95(m,1H),8.78-8.72(m,1H),8.57-8.49(m,1H),8.06-8.02(m,1H),7.85-7.77(m,1H),4 .65-4.54(m,2H),4.27-4.18(m,1H),4.08-3.94(m,2H),3.85-3.57(m,4H),1.65(s,6H),1.33(d,6H).

[0651] Embodiment 20

[0652] ((2R,5S)-4-(2,4-difluorobenzyl)-2,5-dimethylpiperazin-1-yl)(3,5-difluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidine

[0653] -4-yl)pyridin-4-yl)methanone 20

[0654]

[0655] Compound 5c (21 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (1 mL, Sinopharm), and compound 19h (14 mg, 0.05 mmol), N,N-diisopropylethylamine (25 mg, 0.19 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (28 mg, 0.07 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system A to obtain the title compound 20 (17 mg, yield: 69.7%).

[0656] MS m / z(ESI):518.5[M+1]

[0657] 1 H NMR (500 MHz, DMSO-d 6 ): δ9.01-8.98(m,1H),8.60-8.55(m,1H),7.96-7.93(m,1H),7.53-7.51(m, 1H),7.22-7.17(m,1H),7.10-7.06(m,1H),5.10-5.06(m,1H),4.25(s,1H),3 .65-3.63(m,1H),3.60-3.54(m,3H),3.31-3.27(m,1H),2.95-2.70(m,3H), 2.41-2.20(m,1H),1.56-1.53(m,4H),1.29-1.18(m,3H),1.05-0.89(m,3H).

[0658] Embodiment 21

[0659] ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(5-fluoro-2-(2-(2-hydroxypropane-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)

[0660] 4-yl)pyrimidin-4-yl)pyridin-4-yl)methanone 21

[0661]

[0662] first step

[0663] 2-Acetyl-5-fluoroisonicotinic acid methyl ester 21b

[0664] 2-Bromo-5-fluoroisonicotinic acid methyl ester 21a (1g, 8.55mmol, Bidex) was dissolved in 1,4-dioxane (40mL, Sinopharm), tributyl(1-ethoxyethylene)tin (4.63mg, 12.82mmol, Shaoyuan), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (3.62g, 4.28mmol, Bidex), cuprous iodide (814mg, 4.28mmol, Bidex), and reacted at 105°C for 16 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography with eluent system C to obtain the title compound 21b (1.2g, yield: 71.2%). MS m / z (ESI): 198.2 [M+1]

[0665] Step 2

[0666] (E)-2-(3-(Dimethylamino)acryloyl)-5-fluoroisonicotinic acid methyl ester 21c

[0667] Compound 21b (1.2 g, 6.09 mmol) was dissolved in N,N-dimethylformamide (8 mL, Sinopharm), 1,1-dimethoxy-N,N-dimethylmethylamine (5.91 g, 49.60 mmol, Shaoyuan) was added, and the mixture was reacted at 70°C for 24 hours. 20 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the title compound 21c (1 g, yield: 65.1%).

[0668] MS m / z(ESI):253.4[M+1]

[0669] Step 3

[0670] 5-Fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)isonicotinic acid methyl ester 21d

[0671] Compound 21c (1 g, 3.96 mmol) was dissolved in N,N-dimethylformamide (20 mL, Sinopharm), 2-hydroxy-2-methylpropionamidine hydrochloride (1.65 g, 11.91 mmol, Adamas), potassium carbonate (1.43 g, 10.35 mmol, Sinopharm) were added, and the mixture was reacted at 65°C for 24 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system C to obtain the title compound 21d (300 mg, yield: 26.1%).

[0672] MS m / z(ESI):292.3[M+1]

[0673] Step 4

[0674] 5-Fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)isonicotinic acid 21e

[0675] Compound 21d (60 mg, 0.21 mmol) was dissolved in tetrahydrofuran (2 mL, Sinopharm) and water (1 mL), and lithium hydroxide (27 mg, 0.64 mmol, Adamas) was added, and the mixture was reacted at room temperature for 2 hours. 5 mL of water was added, and the pH was adjusted to 4-5 with citric acid, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the title compound 21e (30 mg, yield: 52.5%).

[0676] MS m / z(ESI):278.3[M+1]

[0677] Step 5 ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(5-fluoro-2-(2-(2-hydroxypropane-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)

[0678] 4-yl)pyrimidin-4-yl)pyridin-4-yl)methanone 21

[0679] Compound 1d (11 mg, 0.046 mmol) was dissolved in N,N-dimethylformamide (2 mL, Sinopharm), and compound 21e (10 mg, 0.036 mmol), N,N-diisopropylethylamine (19 mg, 0.15 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (21 mg, 0.055 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with a developing solvent system A to obtain the title compound 21 (8 mg, yield: 44.3%).

[0680] MS m / z(ESI):501.5[M+1]

[0681] 1 H NMR (500 MHz, DMSO-d 6): δ8.98-8.97(m,1H),8.88-8.86(m,1H),8.77-8.70(m,1H),8.44(s,1H) ,8.17-8.16(m,1H),7.94-7.90(m,1H),5.30(s,1H),3.82-3.77(m,1H),3 .63-3.60(m,2H),3.51-3.48(m,1H),3.04-3.01(m,1H),2.88-2.79(m,2H ),2.39-2.23(m,1H),1.51(s,6H),1.21-1.14(m,3H),1.06-0.96(m,3H).

[0682] Embodiment 22

[0683] ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methoxypyridin-4-yl)methanone 22

[0684]

[0685] The synthetic route of Example 21 was adopted, and the raw material compound 21a was replaced with 2-bromo-5-methoxyisonicotinic acid methyl ester (prepared using the method disclosed in intermediate 71-1 on page 106 of the specification of patent application WO2023077070A1) to obtain the title compound 22 (5 mg, yield: 28.2%).

[0686] MS m / z(ESI):513.5[M+1]

[0687] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.90-8.88(m,1H),8.61-8.51(m,2H),8.30-8.24(m,2H),7.60-7.55(m,1H),5.30(s,1H),4.60-4.54(m,1H),4.30-4.26(m,1H),4.16-4 .04(m,3H),3.81-3.76(m,1H),3.75-3.56(m,2H),3.25-3.24(m,1H), 3.02-2.96(m,2H),1.64(s,6H),1.42-1.26(m,3H),1.25-1.20(m,3H).

[0688] Embodiment 23

[0689] (5-chloro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)pyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)methanone 23

[0690]

[0691]

[0692] first step

[0693] 2-Acetyl-5-chloroisonicotinic acid methyl ester 23b

[0694] 2-Bromo-5-chloroisonicotinic acid methyl ester 23a (500 mg, 2.00 mmol, Anaiji) was dissolved in 1,4-dioxane (15 mL, Sinopharm), tributyl (1-ethoxyethylene) tin (1.1 g, 3.05 mmol, Shaoyuan), [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (169 mg, 0.20 mmol, Bid Pharmaceuticals), cuprous iodide (38 mg, 0.20 mmol, Bid Pharmaceuticals), and reacted at 105 ° C for 16 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography with eluent system C to obtain the title compound 23b (290 mg, yield: 68.0%).

[0695] MS m / z(ESI):214.1[M+1]

[0696] Step 2

[0697] (E)-5-chloro-2-(3-(dimethylamino)acryloyl)isonicotinic acid methyl ester 23c

[0698] Compound 23b (260 mg, 1.22 mmol) was dissolved in N,N-dimethylformamide (5 mL, Chinese medicine), 1,1-dimethoxy-N,N-dimethylmethylamine (1.16 g, 9.73 mmol) was added, and the mixture was reacted at 70°C for 24 hours. 20 mL of water was added, and the mixture was extracted with dichloromethane (20 mL×3), and the organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude title compound 23c (327 mg).

[0699] MS m / z(ESI):269.1[M+1]

[0700] Step 3

[0701] 5-Chloro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)isonicotinic acid methyl ester 23d

[0702] Compound 23c (327 mg, 1.22 mmol) was dissolved in N,N-dimethylformamide (10 mL, Sinopharm), 2-hydroxy-2-methylpropionamidine hydrochloride (1.00 g, 7.22 mmol, Aikang), potassium carbonate (1.18 g, 8.54 mmol, Sinopharm) were added, and the mixture was reacted at 65°C for 24 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 23d (150 mg, yield: 40.1%).

[0703] MS m / z(ESI):308.1[M+1]

[0704] Step 4

[0705] 5-Chloro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)isonicotinic acid 23e

[0706] Compound 23d (30 mg, 97 μmol) was dissolved in tetrahydrofuran (1.5 mL, Sinopharm) and water (0.5 mL), and lithium hydroxide (7 mg, 0.29 mmol, Adamas) was added, and the mixture was reacted at room temperature for 2 hours. 5 mL of water was added, and the pH was adjusted to 4-5 with citric acid, and the mixture was extracted with ethyl acetate (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the crude title compound 23e (28 mg).

[0707] MS m / z(ESI):294.1[M+1]

[0708] Step 5

[0709] (5-chloro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)pyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)methanone 23

[0710] Compound 23e (28 mg, 95 μmol) was dissolved in N,N-dimethylformamide (2 mL, Sinopharm), and compound 1d (23 mg, 95 μmol), N,N-diisopropylethylamine (50 μL, 0.29 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (71 mg, 0.50 mmol, Bidler) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system A to obtain the title compound 23 (15 mg, yield: 30.4%).

[0711] MS m / z(ESI):517.1[M+1]

[0712] 1 H NMR (500 MHz, DMSO-d 6 ): δ9.02-8.97(m,1H),8.92-8.88(m,1H),8.78-8.71(m,1H),8.44(s,1H),8 .20-8.17(m,1H),7.94-7.90(m,1H),5.33-5.28(m,1H),4.21-4.18(m,1H),3 .82-3.76(m,1H),3.63-3.60(m,1H),3.50-3.41(m,1H),3.33-3.08(m,1H), 2.96-2.78(m,2H),2.43-2.37(m,1H),1.59-1.42(m,6H),1.25-0.97(m,6H).

[0713] Embodiment 24

[0714] ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(1-hydroxycyclopropyl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 24

[0715]

[0716] first step

[0717] 1-(Benzyloxy)cyclopropane-1-carboxylic acid methyl ester 24b

[0718] 1-Hydroxycyclopropane-1-carboxylic acid methyl ester 24a (5.0 g, 43 mmol, Leyan) was dissolved in N,N-dimethylformamide (50 mL, Sinopharm), sodium hydride (2.6 g, purity 60%, 64 mmol, Sinopharm) was added under stirring at 0°C, stirred at 0°C for 0.5 hours, benzyl bromide (15 g, 86 mmol, Adamas) was added, the temperature was raised to room temperature, and stirred for 2 hours. 50 mL of saturated ammonium chloride solution was added, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 24b (4.1 g, yield: 46.2%).

[0719] Step 2

[0720] 1-(Benzyloxy)cyclopropane-1-carboximidamide 24c

[0721] Ammonium chloride (10.6 g, 198 mmol, Chinese medicine) was dissolved in toluene (100 mL, Chinese medicine), trimethylaluminum (12.2 g, 169 mmol, Adamas) was added under stirring at 0°C, stirred at 0°C for 0.5 hours, a toluene (20 mL, Chinese medicine) solution of compound 24b (4.1 g, 20 mmol) was added dropwise, the temperature was raised to 80°C, and stirred for 12 hours. 20 mL of methanol was added to quench, the filter residue was washed with ethanol (50 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain the crude title compound 24c (3.0 g).

[0722] Step 3

[0723] 2-(2-(1-(Benzyloxy)cyclopropyl)pyrimidin-4-yl)-3-fluoro-5-methylisonicotinate 24d

[0724] Compound 1i (500 mg, 1.88 mmol) was dissolved in N,N-dimethylformamide (5 mL, Chinese medicine), compound 24c (2.55 g, 11.2 mmol), potassium carbonate (2.08 g, 15.1 mmol, Chinese medicine) were added, and the mixture was reacted at 100°C for 7 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 24d (250 mg, yield: 33.8%).

[0725] MS m / z(ESI):394.1[M+1]

[0726] Step 4

[0727] 2-(2-(1-(Benzyloxy)cyclopropyl)pyrimidin-4-yl)-3-fluoro-5-methylisonicotinic acid 24e

[0728] Compound 24d (250 mg, 0.64 mmol) was dissolved in tetrahydrofuran (3 mL, Sinopharm) and water (1 mL), and lithium hydroxide (46 mg, 1.92 mmol, Adamas) was added, and the mixture was reacted at room temperature for 2 hours. 5 mL of water was added, and the pH was adjusted to 4-5 with citric acid, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude title compound 24e (240 mg).

[0729] MS m / z(ESI):380.1[M+1]

[0730] Step 5 (2-(2-(1-(benzyloxy)cyclopropyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)methanone 24f

[0731] Compound 24e (200 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (5 mL, Sinopharm), and compound 1d (127 mg, 0.53 mmol), N,N-diisopropylethylamine (204 mg, 1.58 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (300 mg, 0.79 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system A to obtain the title compound 24f (160 mg, yield: 50.4%).

[0732] MS m / z(ESI):603.3[M+1]

[0733] Step 6 ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(3-fluoro-2-(2-(1-hydroxycyclopropyl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 24

[0734] Compound 24f (160 mg, 0.27 mmol) was dissolved in toluene (10 mL, Sinopharm), aluminum chloride (212 mg, 1.60 mmol, Sinopharm) was added, and the mixture was reacted at room temperature for 6 hours. The mixture was filtered and concentrated, and the residue was purified by column chromatography with eluent system A to give the title compound 24 (20 mg, yield: 14.7%).

[0735] MS m / z(ESI):513.2[M+1]

[0736] 1 H NMR (500 MHz, DMSO-d 6): δ8.92-8.90(m,1H),8.57-8.51(m,1H),8.45-8.43(m,1H),7.93-7.89(m, 1H),7.81-7.77(m,1H),6.03-5.99(m,1H),4.72(s,1H),4.26-4.20(m,1H),3 .78-3.75(m,1H),3.64-3.48(m,2H),3.25-3.08(m,1H),2.90-2.75(m,2H), 2.52-2.22(m,3H),1.39-1.29(m,2H),1.27-1.14(m,6H),1.07-0.93(m,2H).

[0737] Embodiment 25

[0738] ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(2-(2-(1-hydroxycyclopropyl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone 25

[0739]

[0740] The synthetic route of Example 24 was adopted to replace the raw material compound 1i with compound 3c to prepare the title compound 25 (4.0 mg, yield: 59.1%).

[0741] MS m / z(ESI):495.2[M+1]

[0742] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.85(s,1H),8.72-8.68(m,1H),8.44(s,1H),8.10-8.07(m,1H),7.93 -7.89(m,1H),6.12-6.07(m,1H),4.73(s,1H),4.22-4.19(m,1H),3.79-3 .75(m,1H),3.63-3.60(m,1H),3.20-3.09(m,2H),2.89-2.73(m,2H),2.3 7-2.22(m,4H),1.40-1.34(m,2H),1.28-1.17(m,6H),1.12-0.98(m,2H).

[0743] Embodiment 26

[0744] ((2R,5S)-4-((3,5-difluoropyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)(2-(3-(2-hydroxypropane-2-

[0745] 1H-pyrazol-1-yl)-5-methylpyridin-4-yl)methanone 26

[0746]

[0747] The second to fourth steps of the synthetic route of Example 4 were adopted, and the raw material compound 4b was replaced by 2-(1H-pyrazol-3-yl)propan-2-ol to prepare the title compound 26 (6 mg, yield: 16.2%).

[0748] MS m / z(ESI):485.6[M+1]

[0749] 1 H NMR (500 MHz, DMSO-d 6 ): δ8.53-8.50(m,1H),8.44(s,1H),7.78-7.76(m,1H),7.65-7.64(m,1H),7.5 6-7.45(m,1H),6.42-6.39(m,1H),5.25(s,1H),4.67(s,1H),4.18-4.16(m,1H ),3.77-3.76(m,1H),3.61-3.59(m,1H),3.47-3.44(m,1H),3.15-3.06(m,1H) ,2.89-2.82(m,2H),2.35-2.19(m,4H),1.47-1.46(m,6H),1.24-1.00(m,7H).

[0750] Embodiment 27

[0751] (R)-(4-((3,5-difluoropyridin-2-yl)methyl)-2-methylpiperazin-1-yl)(3-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidine

[0752] -4-yl)-5-methylpyridin-4-yl)methanone 27

[0753]

[0754]

[0755] first step

[0756] (R)-tert-Butyl 4-((3,5-difluoropyridin-2-yl)methyl)-2-methylpiperazine-1-carboxylate 27b

[0757] (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 27a (1g, 4.19mmol, Shaoyuan) was dissolved in N,N-dimethylformamide (20mL), potassium carbonate (1.16g, 8.39mmol, Guoyao) and compound 1b (685mg, 4.19mmol) were added, and the mixture was reacted at room temperature for 3 hours. 50mL of water was added, and the mixture was extracted with ethyl acetate (50mL×3). The organic phases were combined, washed with 30mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system B to obtain the title compound 27b (1.05g, yield: 76.6%). MS m / z (ESI): 328.1 [M+1]

[0758] Step 2

[0759] (R)-1-((3,5-difluoropyridin-2-yl)methyl)-3-methylpiperazine 27c

[0760] Compound 27b (1.05 g, 3.21 mmol) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (5 mL), and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude title compound 27c (725 mg, yield: 99.5%), which was directly used for the next step without purification.

[0761] MS m / z(ESI):228.1[M+1]

[0762] Step 3 (R)-(4-((3,5-difluoropyridin-2-yl)methyl)-2-methylpiperazin-1-yl)(3-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidine

[0763] -4-yl)-5-methylpyridin-4-yl)methanone 27

[0764] Compound 27c (38 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (3 mL), and compound 1k (40 mg, 0.13 mmol), N,N-diisopropylethylamine (71 mg, 0.55 mmol, Adamas) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (78 mg, 0.20 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system A to obtain the title compound 27 (22 mg, yield: 32.0%).

[0765] MS m / z(ESI):501.2[M+1]

[0766] 1 H NMR (500 MHz, DMSO-d 6 )δ9.01(t,1H),8.66-8.56(m,2H),8.09(s,1H),7.97(dd,1H),4.92-3.47(m,9H),2.41-2.24(m,3H),1.58-1.49(m,6H),1.36-1.22(m,3H).

[0767] Embodiment 28

[0768] Compound 28: rel-((1R,2S,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]

[0769] rel-((1R,2R,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)(3-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone or rel-((1R,2R,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)

[0770] 2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone

[0771]

[0772]

[0773] first step

[0774] 8-Benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester 28b

[0775] 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester 28a (5 g, 23.55 mmol, WuXi AppTec) was dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (6.5 g, 47.03 mmol, Sinopharm) and benzyl bromide (5.45 g, 31.86 mmol, Adamas) were added, and the mixture was reacted at room temperature for 16 hours. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography with eluent system B to obtain the title compound 28b (6.86 g, yield: 96.3%).

[0776] MS m / z(ESI):303.3[M+1]

[0777] Second step compound 28c: rel-(1R,2S,5S)-8-benzyl-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester or

[0778] rel-(1R,2R,5S)-8-Benzyl-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

[0779] Compound 28b (6.4 g, 21.16 mmol) and tetramethylethylenediamine (4.9 g, 42.17 mmol, Adamas) were dissolved in tetrahydrofuran (100 mL), sec-butyl lithium (2.7 g, 42.15 mmol, Adamas) was added at -78°C, and the mixture was reacted at -78°C for 1 hour; iodomethane (6 g, 42.27 mmol, Adamas) was added, and the mixture was reacted at room temperature for 2 hours. 10 mL of saturated ammonium chloride solution was added to quench the reaction, and the tetrahydrofuran was removed by concentration under reduced pressure. 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to obtain the title compound 28c (3.5 g, yield: 52.2%).

[0780] MS m / z(ESI):317.3[M+1]

[0781] Step 3

[0782] Compound 28d: rel-(1R,2S,5S)-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester or

[0783] rel-(1R,2R,5S)-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

[0784] Compound 28c (500 mg, 1.58 mmol) was dissolved in methanol (10 mL), and formic acid (73 mg, 1.58 mmol, Adamas) and palladium-carbon (34 mg, 0.32 mmol, 10%, Adamas) were added, and the hydrogen was replaced three times, and the reaction was carried out at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude title compound 28d (355 mg, yield: 99.3%), and the product was directly used for the next step without purification.

[0785] MS m / z(ESI):227.1[M+1]

[0786] Step 4

[0787] Compound 28e: rel-(1R,2S,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]

[0788] Octane-3-carboxylic acid tert-butyl ester or

[0789] rel-(1R,2R,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

[0790] Compound 28d (166 mg, 0.73 mmol) was dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (169 mg, 1.22 mmol, Chinese medicine) and compound 1b (100 mg, 0.61 mmol) were added, and the mixture was reacted at room temperature for 16 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography with eluent system B to obtain the title compound 28e (200 mg, yield: 92.5%).

[0791] MS m / z(ESI):354.3[M+1]

[0792] Step 5

[0793] Compound 28f: rel-(1R,2S,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octane or rel-(1R,2R,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octane

[0794] Compound 28e (200 mg, 0.57 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL), and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude title compound 28f (140 mg, yield: 97.6%), which was directly used for the next step without purification.

[0795] MS m / z(ESI):254.1[M+1]

[0796] Step 6

[0797] Compound 28: rel-((1R,2S,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]

[0798] rel-((1R,2R,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)(3-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone or rel-((1R,2R,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)

[0799] 2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone

[0800] Compound 28f (36 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (3 mL), and compound 1k (35 mg, 0.12 mmol), N,N-diisopropylethylamine (62 mg, 0.48 mmol, Adamas) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (68 mg, 0.18 mmol, Adamas) were added, and the mixture was reacted at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system A to obtain the title compound 28 (28 mg, yield: 44.2%).

[0801] MS m / z(ESI):527.3[M+1]

[0802] 1 H NMR (500 MHz, DMSO-d 6 )δ8.99(t,1H),8.54(d,1H),8.44(dd,1H),7.97-7.88(m,2H),5.07(d,1H),3.86(ddd,1H),3.69(pd,2H),2.97- 2.91(m,1H),3.26-3.12(m,3H),2.35-2.26(m,3H),2.00(dq,1H),1.87(d,2H),1.54-1.53(m,7H),1.45(dd,3H).

[0803] Example 28-1

[0804] Compound 28-1: ((1R,2S,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]

[0805] Octane-3-yl)(3-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone or

[0806] ((1S,2R,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octane-3-

[0807] ((1R,2R,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)(3-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone or ((1S,2S,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)(3-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)(3-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)methanone

[0808]

[0809] Compound 28 (140 mg, 0.36 mmol) was chirally prepared (separation conditions: CHIRALPAK IC chiral preparative column, 5 um, 20 mm×250 mm; mobile phase: n-hexane / ethanol / 7 M methylamine methanol solution = 50 / 50 / 0.5 (V / V / V), flow rate: 20 mL / min), and the components with shorter retention times were collected and concentrated under reduced pressure to obtain the single-configuration title compound 28-1 (60 mg).

[0810] MS m / z(ESI):527.2[M+1].

[0811] Chiral HPLC analysis: retention time 7.402 minutes, chiral purity: 100% (chromatographic column: CHIRALCEL IC, 4.6 mm×250 mm, 5 um; mobile phase: n-hexane / ethanol / DEA=50 / 50 / 0.1 (V / V / V).

[0812] 1 H NMR (500 MHz, DMSO-d 6)δ8.99(dd,1H),8.54(d,1H),8.44(dd,1H),7.96-7.88(m,2H),5.07(d,1H),3.94-3.80(m,1H),3.75-3.64(m,2H),3 .26-3.12(m,3H),2.98-2.90(m,1H),2.35-2.26(m,3H),2.00(dt,1H),1.88(q,2H),1.54-1.52(m,7H),1.45(dd,3H).

[0813] Example 29-1, Example 29-2

[0814] Compound 29-1: (2-(2-((R)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1R,2S,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)

[0815] Ketone

[0816] or (2-(2-((R)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1S,2R,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone or (2-(2-((R)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1R,2R,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone or (2-(2-((R)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1S,2S,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone and

[0817] Compound 29-2: (2-(2-((S)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1R,2S,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)

[0818] Ketone

[0819] or (2-(2-((S)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1S,2R,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone or (2-(2-((S)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1R,2R,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone

[0820] or (2-(2-((S)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1S,2S,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone

[0821]

[0822]

[0823] first step

[0824] Compound 29a: (1R,2S,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]

[0825] Octane

[0826] or

[0827] (1S,2R,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octane or

[0828] (1R,2R,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octane or

[0829] (1S,2S,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octane

[0830] Compound 28f (1.7 g, 3.95 mmol) was subjected to chiral preparation (separation conditions: CHIRALPAK IG chiral preparation column, 20 mm*250 mm; mobile phase: n-hexane / ethanol=80 / 20 (V / V), flow rate: 20 mL / min), and the components with longer retention times were collected and concentrated under reduced pressure to give the title compound 29a (0.6 g).

[0831] Single configuration compound (longer retention time: 0.6g):

[0832] MS m / z(ESI):254.1[M+1]

[0833] Chiral HPLC analysis: retention time 4.864 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK AD-H, 4.6mm*250mm, 5um; mobile phase: n-hexane / ethanol = 70 / 30 (V / V))

[0834] Step 2

[0835] Compound 29: (2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridine-4-

[0836] 2-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)

[0837] Ketone

[0838] or (2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1S,2R,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone or (2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1R,2R,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone or

[0839] (2-(2-(1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1S,2S,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone

[0840] In a dry flask, compound 7g (50 mg, 0.16 mmol) was dissolved in N,N-dimethylmethylamine (2 mL, Adamas), compound 29a (59.9 mg, 0.24 mmol), N,N-diisopropylethylamine (81.5 mg, 0.63 mmol, Adamas), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (90 mg, 0.24 mmol, Adamas) were added, and the mixture was reacted at room temperature for 3 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to obtain the title compound 29 (30 mg, yield: 34.5%).

[0841] MS m / z(ESI):553.2[M+1]

[0842] Step 3

[0843] Compound 29-1: (2-(2-((R)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1R,2S,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)

[0844] Ketone

[0845] or (2-(2-((R)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1S,2R,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone or (2-(2-((R)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1R,2R,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone or (2-(2-((R)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1S,2S,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone and

[0846] Compound 29-2: (2-(2-((S)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1R,2S,5S)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)

[0847] Ketone

[0848] or (2-(2-((S)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1S,2R,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone or (2-(2-((S)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1R,2R,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone (2-(2-((S)-1-cyclopropyl-1-hydroxyethyl)pyrimidin-4-yl)-3-fluoro-5-methylpyridin-4-yl)((1S,2S,5R)-8-((3,5-difluoropyridin-2-yl)methyl)-2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone

[0849] Compound 29 (30 mg, 0.05 mmol) was subjected to chiral preparation (separation conditions: EnantioPak Y5 chiral preparation column, 20 mm*250 mm; mobile phase: n-hexane / ethanol=55 / 45 (V / V), flow rate: 20 mL / min), and the corresponding fractions were collected and concentrated under reduced pressure to give the title compounds 29-1 and 29-2 (10 mg, 11 mg).

[0850] Single configuration compound (short retention time: 10 mg):

[0851] MS m / z(ESI):553.2[M+1]

[0852] Chiral HPLC analysis: retention time 3.730 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK OX-H, 4.6 mm*150 mm, 5 um; mobile phase: n-hexane / ethanol=60 / 40 (V / V)).

[0853] 1 H NMR (500MHz, CD 3OD)δ8.99-8.93(m,1H),8.57-8.50(m,1H),8.39-8.34(m,1H),8.03-7. 97(m,1H),7.65-7.56(m,1H),4.11-4.00(m,2H),3.86-3.74(m,2H),3.1 9-3.01(m,2H),2.49-2.35(m,3H),2.26-2.15(m,2H),2.11-1.97(m,2H) ,1.70-1.62(m,2H),1.64-1.54(m,2H),1.33(d,6H),0.48-0.37(m,2H).

[0854] Single configuration compound (longer retention time: 11 mg):

[0855] MS m / z(ESI):553.2[M+1]

[0856] Chiral HPLC analysis: retention time 5.159 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK OX-H, 4.6 mm*150 mm, 5 um; mobile phase: n-hexane / ethanol=60 / 40 (V / V)).

[0857] 1 H NMR (500MHz, CD 3 OD)δ8.96(t,1H),8.53(d,1H),8.39-8.33(m,1H),8.00(t,1H),7.65-7.56(m,1H),4.12-3.99(m,2H),3.84-3.75(m,2H),3.14-3.01(m ,2H),2.48-2.35(m,3H),2.25-2.14(m,2H),2.10-1.98(m,2H),1.69-1.65(m,2H),1.61-1.54(m,2H),1.33(d,6H),0.48-0.39(m,2H).

[0858] Biological evaluation

[0859] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not meant to limit the scope of the present disclosure.

[0860] Test Example 1: An endpoint enzymatic experiment based on HTRF technology was used to evaluate the inhibitory activity of the disclosed compounds on the p38alpha-iMK2 kinase cascade reaction.

[0861] 1. Experimental Materials and Instruments

[0862] 1. MAPKAPK2, Inactive protein (Thermo, PV3316)

[0863] 2. MAPK14 (p38 alpha) protein (Thermo, PR5049C)

[0864] 3. HTRF KinEASE-STK S1 kit (Cisbio, 62ST1PEC)

[0865] 4. TritonX-100, polyethylene glycol tert-octylphenyl ether (Sigma, T8787)

[0866] 5. Magnesium chloride (Sigma, 63069)

[0867] 6. ATP, adenosine triphosphate (Promega, V915B)

[0868] 8. DTT, DL-dithiothreitol (Sigma, 43816)

[0869] 7. Microplate reader (BMG LABTECH GmbH, PHERAstar FS)

[0870] 2. Experimental steps

[0871] HTRF KinEASE-STK S1 is a universal method developed by Cisbio based on HTRF technology to detect serine / threonine kinase activity. In the optimized experimental conditions, 0.05nM iMK2, 0.0015nM activated p38 alpha, biotin-labeled kinase substrate S1 (1μM), ATP (100μM) and different concentrations of compounds were incubated at room temperature for 1 hour. The reaction buffer is the HTRF Enzymatic Buffer Kinase in the HTRF KinEASE-STK S1 kit with 10mM MgCl 2, 0.01% TritonX-100, 1mM DTT. The enzymatic reaction was carried out in a Coring 384 surface low-adhesion microplate with a total reaction volume of 10μL. At the end of the enzymatic reaction, 10μL of streptavidin-labeled XL665 and Eu-labeled STK antibody with a final concentration of 62.5nM was added to terminate the enzyme reaction. After incubation for 1 hour at room temperature, the fluorescence signals at 620nm and 665nm were detected using a PHERAstar FS microplate reader under 337nm wavelength excitation light. The calibrated fluorescence signal was obtained by calculating the ratio of the fluorescence signals at 665nm and 620nm. The concentration-effect curve of the compound concentration and the enzyme activity inhibition rate was obtained by four-parameter nonlinear fitting using GraphPad PRISM software (Version 9.00; GraphPad San Diego, CA), and the relative IC 50 The values ​​were used to reflect the inhibitory activity of different compounds on the p38alpha-iMK2 cascade reaction.

[0872] Table 1 Inhibitory activity of the disclosed compounds on MK2

[0873]

[0874] Conclusion: The disclosed compounds have a good inhibitory effect on the p38alpha-iMK2 cascade reaction. Test Example 2: Inhibitory activity of the disclosed compounds on TNFa secretion in U937 cells.

[0875] 1. Experimental Materials and Instruments

[0876] 1. U937 cells (ATCC)

[0877] 2.RIPM1640 (Dalian Meilun Biotechnology, PWL015)

[0878] 3. FBS (Gibco, 10099-141)

[0879] 4.DPBS (Gibco, 14190250)

[0880] 5.PMA (InvivoGen, tlrl-pma)

[0881] 6.LPS (Biyuntian, S1732-5mg)

[0882] 7.100mm dish(Costar,430167)

[0883] 8. Human TNF-α ELISA kit (Xinbosheng, EHC103a.96.10)

[0884] 9.T175 cell culture flask (Corning, 431080)

[0885] 10. Cell scraper (Corning, CON-3010)

[0886] 11.96-well flat-bottom cell culture plate (Corning, 3599)

[0887] 12.96-well round bottom dispensing plate (Corning, 3788)

[0888] 13. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., Count star IC1000)

[0889] 14. Cell culture incubator (ThermoFisher Scientific, Forma steri-cycle i160)

[0890] 15. Biological safety cabinet (ESCO, ClassⅡBSC)

[0891] 16. Centrifuge (ThermoFisher Scientific, ST40R)

[0892] 17. Bravo (Agilent)

[0893] 18. PHERAstar FS microplate reader (BMG Labtech)

[0894] 2. Experimental process

[0895] U937 cells were cultured in complete 1640 medium containing PMA at a final concentration of 10 ng / ml. After 48 hours, the cells were washed twice with DPBS and then added with 1640 complete medium and continued to be cultured in a cell culture incubator at 37°C. On the fourth day, U937 cells were plated at 5×10 4 Each well was plated in a 96-well plate and cultured overnight in a cell culture incubator at 37°C. On the fifth day, 8 serial dilutions of culture medium containing 10× compound were added to the 96-well plate and cultured with U937 cells at 37°C for 60 minutes. Then, LPS with a final concentration of 100 ng / ml was added to stimulate the cells. After 6 hours, the supernatant was collected to test the TNF-α factor (ELISA). The TNF-α ELISA test method was carried out according to the manufacturer's instructions, and the data was finally read using a PHERAstar FS microplate reader. Data processing: The TNF-α value of the test well was calculated based on the standard curve, and the inhibition rate was calculated as follows: %inhibition = [AVG (maximum value) - test well value] / [AVG (maximum value) - AVG (minimum value)] * 100%. Finally, the data was fitted with a curve using graphpad prism to calculate the IC50 value.

[0896] Table 2 Inhibitory activity of the disclosed compounds on TNFa secretion in U937 cells

[0897]

[0898]

[0899] Conclusion: The disclosed compounds have an inhibitory effect on the secretion of TNFa in U937 cells.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is an aryl group or a heteroaryl group; Ring B is aryl or heteroaryl; X is N or CR X ; R X is selected from the group consisting of a hydrogen atom, an alkyl group, a halogen group, a hydroxyl group, and a hydroxyalkyl group; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, and a heterocyclylalkyl group; or R 1 and R 2 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace; Each R 3 and R 5 and are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxyalkyl, an aminoalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, an alkenyl, an alkynyl, a cyano group, a nitro group, a hydroxyl group, an amino group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) t OR 7 、-(CH2) t NR 8 R 9 、-C(O)R 7 、-C(O)OR 7 、-OC(O)R 7 、-OC(O)OR 7 、-C(O)NR 8 R 9 、-OC(O)NR 8 R 9 、-S(O) v R 7 、-S(O) v NR 8 R 9 、-NR 10 C(O)NR 8 R 9 、-NR 10 C(O)R 7 、-NR 10 C(O)OR 7 、-NR 10 S(O) v NR 8 R 9 and-NR 10 S(O) v R 7 wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace; R 4a , R 4b and R 4c are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) t OR 7 、-(CH2) t NR 8 R 9 、-C(O)R 7 、-C(O)OR 7 、-OC(O)R 7 、-OC(O)OR 7 、-C(O)NR 8 R 9 、-OC(O)NR 8 R 9 、-S(O) v R 7 、-S(O) v NR 8 R 9 、-NR 10 C(O)NR 8 R 9 、-NR 10 C(O)R 7 、-NR 10 C(O)OR 7 、-NR 10 S(O) v NR 8 R 9 and-NR 10 S(O) v R 7 wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace; Each R 6 are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a hydroxyl group, an amino group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) t OR 7 、-(CH2) t NR 8 R 9 、-C(O)R 7 、-C(O)OR 7 、-OC(O)R 7 、-OC(O)OR 7 、-C(O)NR 8 R 9 、-OC(O)NR 8 R 9 、-S(O) v R 7 、-S(O) v NR 8 R 9 、-NR 10 C(O)NR 8 R 9 、-NR 10 C(O)R 7 、-NR 10 C(O)OR 7 、-NR 10 S(O) v NR 8 R 9 and-NR 10 S(O) v R 7 wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace; Or two R 6 Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace; R a , R b and R c are the same or different and are each independently selected from hydrogen, hydroxy, cyano, amino, nitro, halogen, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; or, R b and R c Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 Replace; or, R a , R b and R c Together with the carbon atom to which it is attached, it forms a bridged ring group, which is optionally substituted by one or more R 0 replace; R 0 are the same or different at each occurrence and are each independently selected from a deuterium atom, a halogen, an alkyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxyalkyl, an aminoalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, an alkenyl, an alkynyl, a cyano group, a nitro group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, an oxo group, a -(CH2) t OR 11 、-(CH2) t NR 12 R 13 、-C(O)R 11 、-C(O)OR 11 and -C(O)NR 12 R 13 ; R 7 and R 11 are the same or different at each occurrence and are each independently selected from hydrogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replace; R 8 , R 9 , R 10 , R 12 and R 13 are the same or different at each occurrence and are each independently selected from hydrogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replace; or R 8 and R 9 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, which is optionally substituted by one or more R 01 Replace; or R 12 and R 13 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, which is optionally substituted by one or more R 01 replace; R 01 are the same or different at each occurrence and are each independently selected from the group consisting of a deuterium atom, a halogen, an alkyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxyalkyl, an aminoalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, an alkenyl, an alkynyl, a cyano group, a nitro group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, an oxo group, -NHCH3, -N(CH3)2, -C(O)alkyl, and -C(O)NH2; m is 0, 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, or 4; t is 0, 1, 2, 3 or 4; and v is 0, 1, or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are the same or different and are each independently a hydrogen atom or a deuterium atom; preferably, R 1 and R 2 A hydrogen atom.

3. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring A is phenyl or a 5- or 6-membered heteroaryl; preferably, ring A is pyridyl or phenyl.

4. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; and / or m is 2; preferably, R 3 is halogen; and / or m is 2.

5. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein each R 6 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; or, two R 6 Together with the carbon atom to which it is attached, it forms a 5- or 6-membered heterocyclic group.

6. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, in: G 0 N or CR 3e ; R 3a , R 3b , R 3c , R 3d and R 3e are the same or different and are each independently a hydrogen atom or R 3 ; R 6a and R 6b are the same or different and are each independently a hydrogen atom or R 6 ; Ring B, X, R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R a , R b , R c and p is as defined in claim 1.

7. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein X is N.

8. The compound represented by general formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- or 6-membered heteroaryl group, preferably selected from pyrimidinyl, pyridone and pyrazolyl, more preferably selected from The end is connected to pyridine.

9. The compound of any one of claims 6 to 8 or a pharmaceutically acceptable salt thereof, wherein G 0 is N or CH; and / or R 3a and R 3c are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; and / or R 3b and R 3d A hydrogen atom.

10. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 4a , R 4b and R 4c are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; preferably, R 4a is a hydrogen atom or a halogen; R 4b Selected from halogen, C 1-6 Alkyl and C 1-6 Alkoxy; R 4c A hydrogen atom.

11. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 10, wherein R 6a and R 6b are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; preferably, R 6a is a hydrogen atom or a methyl group; R 6b It is methyl.

12. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R a , R b and R c The same or different, and each independently selected from C 1-6 alkyl, hydroxyl and 3 to 6-membered cycloalkyl; or, R b and R c Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; preferably, R a is hydroxyl group; R b and R c The same or different, and each independently is C 1-6 Alkyl or 3- to 6-membered cycloalkyl.

13. A compound represented by general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, which is selected from any one of the following compounds:

14. A method for preparing the compound represented by general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by the general formula (IA) or its salt undergoes a condensation reaction with the compound represented by the general formula (IB) or its salt to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt; in: Ring A, Ring B, X, R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R a , R b , R c , m, p and q are as defined in claim 1.

15. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. Use of the compound represented by general formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 15 in the preparation of an MK2 inhibitor.

17. Use of a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 in the preparation of a medicament for treating and / or preventing autoimmune disorders, chronic or acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasia and cardiovascular or cerebrovascular disorders; the autoimmune disorders, chronic or acute inflammatory disorders and autoinflammatory disorders are preferably selected from inflammatory bowel disease, ulcerative colitis, psoriasis, Crohn's disease (CD), multiple sclerosis, psoriasis, arthritis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease (COPD), cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (Muckle-Wells syndrome), and the like. syndrome), familial cold autoinflammatory syndrome, neonatal onset multisystem inflammatory disease, TNF receptor-associated periodic syndrome, acute and chronic pancreatitis, atherosclerosis, gout, acute respiratory distress syndrome, autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, systemic lupus erythematosus, vasculitis syndrome, Hypophysitis, idiopathic thrombocytic purpura, pemphigus, autoimmune deafness, meningitis, myocarditis, gingivitis, enterocolitis, sinusitis, uveitis, ophthalmitis, optic neuritis, gastric ulcer, esophagitis, peritonitis, root periostitis, dermatomyositis, gastritis, myositis, bronchitis and suppurative hidradenitis; the arthritis is preferably selected from rheumatoid arthritis (RA), osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis, psoriatic arthritis and spondyloarthritis.

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