CN117683042A - Fused tetracyclic compound, preparation method thereof and application thereof in medicines - Google Patents

Abstract

The present disclosure relates to fused tetracyclic compounds, their preparation methods and their applications in medicine. Specifically, the present disclosure relates to a fused tetracyclic compound represented by general formula (I), its preparation method, pharmaceutical compositions containing such compounds, and its use as a therapeutic agent, especially as an MK2 inhibitor. Uses and uses for the treatment and/or prevention of autoimmune disorders, chronic or acute inflammatory disorders and autoinflammatory disorders.

Description

Condensed tetracyclic compound, preparation method thereof and application thereof in medicine

Technical Field

The present disclosure belongs to the field of medicine, and relates to a fused tetracyclic compound, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a fused tetracyclic 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

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.

p38 MAPK was identified as a key regulator of inflammatory cytokine biosynthesis in 1994, and numerous research and development 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.

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 binds to cytokine mRNAs with the same adenylate-uridylate-rich element (ARE) in the 30 untranslated regions, destabilizing these mRNAs 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 its replacement 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.

The patent applications for MK2 inhibitors that have been disclosed include WO2016044463A2, WO2018170204A1, WO2018170201A1, WO2018170200A1 and WO2014149164A1.

Summary of the invention

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

in:

Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring B is a 5-membered heteroaryl group or a 5-membered heterocyclic group;

W is selected from C, CR ⁰ and N;

R ⁰ is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;

T is selected from a bond, an alkylene group, -O-, -NR ^A -, -C(O)-, -S-, -S(O)-, -SO ₂ -, -C(S)-, and -P(O) ₂ -, wherein the alkylene group is optionally substituted with one or more substituents selected from an oxo group, a deuterium atom, a halogen, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, and a hydroxyl group;

^RA is selected from the ^group consisting of a hydrogen atom, an alkyl group, a ^haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, -( ^{CRaRb )} _mNRcRd , a cycloalkyl group, a cycloalkylalkyl group, and a heterocyclylalkyl group;

R ^1a , R ² and R ^2a are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a hydroxyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group and -OSO ₃ H; or R ² and R ^2a together form =0;

R ¹ is selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, -(CR ^x R ^y ) _w OR ⁹ , -S(O) _s R ⁹ , -(CR ^x R ^y ) _w NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ⁹ , -C(O)OR ⁹ , -NR ¹² C(O)R ⁹ , -S(O) _s NR ¹⁰ R ¹¹ , -NR ¹² S(O) ₂ R ⁹ , a cyano group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more R ^B ;

^R3 is selected from the ^group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a ^hydroxyalkyl group, an alkoxyalkyl group, -( ^{CRaRb )} _mNRcRd , a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a cycloalkyl group, and a heterocyclyl group;

or ^R1 and ^R3 together with the atoms to which they are attached form a heterocyclic group; or ^R1 and ^R2 together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclic group; or ^R2 and ^R3 together with the atoms to which they are attached form a heterocyclic group; the cycloalkyl or heterocyclic group is each independently optionally substituted by one or more R ^B ;

R ⁵ is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, a hydroxyalkyl group, a cyano group, -OR ⁹ , -S(O) _s R ⁹ , -OSO ₃ H, -OSO ₂ R ⁹ , -OC(O)R ⁹ and -OP(O) ₂ OR ⁹ ; or, R ⁵ is a warhead group;

each ^R4 and each ^R6 are the same or different and are each independently selected from an oxo group, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group ^, an alkoxy group, a haloalkoxy group, an alkoxyalkoxy group, an alkenyl group, an _alkynyl group, -OSO3H, -( ^CRxRy ) _wOR9 ^, -( ^{CRxRy )} wNR10R11, ^-C (O)NR10R11, -OC(O) ^R9 , -C ^{( O} ) ^R9 , ^-C ( _O )OR9 ^{, -NR12C(O)R9 , -NR12C (} O ^{) OR9} , _-NR12C (O) ^NR10R11 , ^-S (O) _sR9 ^{, -NR12S} (O) ^2R9 , cyano, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R ^B ;

R ^B is the same or different at each occurrence and is independently selected from oxo, a deuterium atom, a halogen, an alkyl, an alkenyl, an alkynyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, an alkoxy, a haloalkoxy, a deuterated alkoxy, a hydroxyl, a cyano, a nitro, an alkoxyalkyl, -(CR ^h R ⁱ ) _v NR ^j R ^k , -S(O) ₂ alkyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a cycloalkylalkyl, a heterocyclylalkyl, an arylalkyl, a heteroarylalkyl, a cycloalkyloxy, a heterocyclyloxy, an aryloxy, and a heteroaryloxy;

R ⁷ and R ⁸ 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, a hydroxyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkoxyalkyl group, a cyano group, an amino group, a -NH alkyl group and a -N(alkyl) ₂ ;

^Ra , ^Rb , ^Rh , ^Ri , ^Rx and ^Ry are the same or different at each occurrence and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a hydroxyl group, a haloalkyl group, a deuterated alkyl group and a hydroxyalkyl group;

^R9 , ^R10 , R11, ^R12 , ^Rc , ^Rd , ^Rj and ^Rk are the same or different at each occurrence and are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl ^, heterocyclylalkyl, aryl and heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R ^C ;

or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a heterocyclic group; the heterocyclic group is optionally substituted by one or more R ^C ;

R ^C is the same or different at each occurrence and is independently selected from oxo, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, hydroxy, cyano, nitro, alkoxyalkyl, amino, -NHalkyl, -N(alkyl) ₂ , cycloalkyl, heterocyclyl, aryl and heteroaryl;

w and v are each independently 0, 1, 2, 3 or 4;

m is 1, 2, 3 or 4;

n is 0, 1, 2 or 3;

s is 0, 1, or 2; and

t is 0, 1, 2, or 3.

In some embodiments of the present disclosure, in the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, R ^1a is a hydrogen atom or a deuterium atom; preferably, R ^1a is a hydrogen atom.

In some embodiments of the present disclosure, in the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, R ^2a is a hydrogen atom or a deuterium atom; preferably, R ^2a is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² is selected from a hydrogen atom, a deuterium atom, a halogen and a C _1-6 alkyl group; preferably, R ² is a hydrogen atom.

In some embodiments of the present disclosure, in the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, R ^1a is a hydrogen atom; and/or R ^2a is a hydrogen atom; and/or R ² is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ^R1 and ^R2 together with the carbon atoms to which they are connected form a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocyclic group, and the 4- to 7-membered cycloalkyl or the 4- to 7-membered heterocyclic group is optionally substituted with one or more substituents selected from halogen, _C1-6 alkyl, _C1-6 haloalkyl and hydroxyl; preferably, ^R1 and ^R2 together with the carbon atoms to which they are connected form a 4- to 7-membered cycloalkyl or a 4- to 7-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 ^R2 and ^R3 together with the atoms to which they are connected form a 4- to 7-membered heterocyclic group, and the 4- to 7-membered heterocyclic group is optionally substituted with one or more substituents selected from halogen, _C1-6 alkyl, _C1-6 haloalkyl and hydroxyl; preferably, ^R2 and ^R3 together with the atoms to which they are connected form a 4- to 7-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 ^R7 is selected from a hydrogen atom, a deuterium atom, a halogen and a _C1-6 alkyl; preferably, ^R7 is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is selected from a hydrogen atom, a deuterium atom, a halogen and a C _1-6 alkyl; preferably, R ⁸ is a hydrogen atom.

In some embodiments of the present disclosure, in the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, R ⁷ is a hydrogen atom; and/or R ⁸ is a hydrogen atom.

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-membered heteroaryl group; preferably, ring A is selected from pyrimidinyl, pyridinyl, pyridazinyl and 1,3,5-triazinyl; more preferably, ring A is pyrimidinyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from Preferably R ^6a is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, -OSO ₃ H, -(CR ^x R ^y ) _w OR ⁹ , -(CR ^x R ^y ) _w NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -OC(O)R ⁹ , -C(O)R ⁹ , -C(O)OR ⁹ , -NR ¹² C(O)R ⁹ , -NR ¹² C(O)OR ⁹ , -NR ¹² C(O)NR ¹⁰ R ¹¹ , -S(O) _s R ⁹ , -NR ¹² S(O) ₂ R ⁹ , cyano, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted with one or more ^RB ; and ^Rx , ^Ry , ^RB , R5, ^R9 , ^R10 , ^R11 , ^R12 , w and s are as defined in Formula (I); in some embodiments ^, for In some embodiments, for

In some embodiments of the present disclosure, in the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, W is C.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2, preferably, n is 0 or 1. In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroaryl group; preferably, ring B is selected from pyrazolyl, pyrrolyl, imidazolyl and 1,2,4-triazolyl; more preferably, ring B is pyrazolyl or 1,2,4-triazolyl; most preferably, ring B is pyrazolyl; in some embodiments, ring B is 1,2,4-triazolyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from Preferably More preferably wherein the * bond is connected to T; R ^4a and R ^4b 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 hydroxyalkyl group, an alkoxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, -OSO ₃ H, -(CR ^x R ^y ) _w OR ⁹ , -(CR ^x R ^y ) _w NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -OC(O)R ⁹ , -C(O)R ⁹ , -C(O)OR ⁹ , -NR ¹² C(O)R ⁹ , -NR ¹² C(O)OR ⁹ , -NR ¹² C(O)NR ¹⁰ R ¹¹ , -S(O) _s R ⁹ , -NR ¹² S(O) ₂ R ⁹ , cyano, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted with one or more ^RB ; and ^Rx , ^Ry , ^RB , ^R9 , ^R10 , ^R11 , ^R12 , w and s are as defined in the general formula (I).

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:

in:

X is N or CR ^4a ;

Y is N or CR ^4b ;

R ¹ is selected from the group consisting of a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, -(CR ^x R ^y ) _w OR ⁹ , -S(O) _s R ⁹ , -(CR ^x R ^y ) _w NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ⁹ , -C(O)OR ⁹ , -NR ¹² C(O)R ⁹ , -S(O) _s NR ¹⁰ R ¹¹ , -NR ¹² S(O) ₂ R ⁹ , a cyano group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more R ^B ;

R ^4a , R ^4b and R ^6a 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 hydroxyalkyl group, an alkoxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, -OSO ₃ H, -(CR ^x R ^y ) _w OR ⁹ , -(CR ^x R ^y ) _w NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -OC(O)R ⁹ , -C(O)R ⁹ , -C(O)OR ⁹ , -NR ¹² C(O)R ⁹ , -NR ¹² C(O)OR ⁹ , -NR ¹² C(O)NR ¹⁰ R ¹¹ , -S(O) _s R ⁹ , -NR ¹² S(O) ₂ R ⁹ , cyano, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R ^B ; and

^T , ^RB , ^R3 , ^R5 , R9, ^R10 , ^R11 , ^R12 , ^Rx , ^Ry , s and w are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein ^RA is a hydrogen atom or a _C1-6 alkyl group; preferably, ^RA is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein T is selected from -O-, -S- and -NR ^A -; ^RA is as defined in the general formula (I); preferably, T is -O- or -NH-; more preferably, T is -O-.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from halogen, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl and _C1-6 deuterated alkyl; preferably, ^R1 is selected from _C1-6 alkyl, _C1-6 haloalkyl and _C1-6 deuterated alkyl; further preferably, ^R1 is _C1-6 alkyl; more preferably, ^R1 is methyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom or a C _1-6 alkyl group; preferably, R ³ is a hydrogen atom.

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, wherein R ¹ is a C _1-6 alkyl group; and/or R ³ is a hydrogen atom. In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C _1-6 alkyl group, and R ³ is a hydrogen atom; or, R ¹ and R ³ together with the atoms to which they are connected form a 5- to 8-membered heterocyclic group, and the 5- to 8-membered heterocyclic group is optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl and hydroxyl; preferably, R ¹ is a C _1-6 alkyl group, and R ³ is a hydrogen atom, or R ¹ and R ³ together with the atoms to which they are connected form a 5- to 8-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 each R ⁴ is the same or different and is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R ⁴ is the same or different and is independently selected from halogen, C _1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R ⁴ is the same or different and is independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; preferably, R ⁴ is C _1-6 alkyl; more preferably, R ⁴ is methyl; in some embodiments, each R ⁴ is the same or different and is independently selected from F, Cl, methyl and cyclopropyl.

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^4a is selected from a hydrogen atom, a halogen, a C _1-6 alkyl, a C _1-6 haloalkyl and a 3 to 6-membered cycloalkyl; in some embodiments, R ^4a is selected from a hydrogen atom, a halogen, a C _1-6 alkyl and a 3 to 6-membered cycloalkyl; in some embodiments, R ^4a is selected from a hydrogen atom, a halogen, a C _1-6 alkyl and a C _1-6 haloalkyl; preferably, R ^4a is a hydrogen atom or a C _1-6 alkyl; more preferably, R ^4a is a hydrogen atom or a methyl; in some embodiments, R ^4a is selected from a hydrogen atom, F, Cl, a methyl and a cyclopropyl.

In some embodiments of the present disclosure, in the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, R ^4b is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group and a C _1-6 haloalkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein X is N or CR ^4a ; R ^4a is selected from a hydrogen atom, a halogen, a C _1-6 alkyl, a C _1-6 haloalkyl and a 3-6 membered cycloalkyl; in some embodiments, X is N or CR ^4a ; R ^4a is selected from a hydrogen atom, a halogen, a C _1-6 alkyl and a 3-6 membered cycloalkyl; in some embodiments, X is N or CR ^4a ; R ^4a is selected from a hydrogen atom, a halogen, a C _1-6 alkyl and a C _1-6 haloalkyl; in some embodiments, X is CR ^4a ; R ^4a is as defined in the general formula (II); in some embodiments, X is selected from N, CH, C-CH ₃ , CF, C-Cl and C-cyclopropyl; preferably, X is selected from N, CH and C-CH ₃ .

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein Y is N. In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein X is N or CR ^4a ; R ^4a is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and 3 to 6-membered cycloalkyl; and/or Y is N; in some embodiments, X is N or CR ^4a ; R ^4a is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; and/or Y is N; in some embodiments, X is N or CR ^4a ; R ^4a is selected from hydrogen atom, halogen, C _1-6 alkyl and 3 to 6-membered cycloalkyl; and/or Y is N.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is -S(O) _s R ⁹ or halogen; s and R ⁹ are as defined in the general formula (I); preferably, R ⁵ is halogen; more preferably, R ⁵ is Cl or F; most preferably, R ⁵ is Cl.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein s is 0 or 2.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R ⁹ is a hydrogen atom or a C _1-6 alkyl group; preferably, R ⁹ is a hydrogen atom or a methyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is -S(O) ₂ R ⁹ or -SR ⁹ , R ⁹ is as defined in the general formula (I); preferably, R ⁵ is -S(O) ₂ CH ₃ or -SCH ₃ .

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, wherein R ⁵ is a warhead group; preferably, R ⁵ is selected from More preferably, R ⁵ is

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1, preferably 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein ^RB is selected from a deuterium atom, a halogen, a _C1-6 alkyl group, a _C1-6 haloalkyl _group , a hydroxyl group, a _C1-6 alkoxy group and a _C1-6 haloalkoxy group; wherein the _C1-6 alkoxy group is preferably _-OCH2CH3 or -OtBu.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ^R6 is selected from cyano, nitro, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 hydroxyalkyl _{, C1-6} alkoxyC1-6 alkyl and _{C1-6 alkoxyC1-6} alkoxy _; preferably _, ^R6 is _{C1-6 alkoxyC1-6} alkyl; more preferably, ^R6 is _-CH2OCH2CH3 or _-CH2OtBu .

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^6a is selected from a hydrogen atom, a cyano group, a nitro group, a halogen group, a C _{1-6 alkyl group, a C 1-6 alkoxy} group, a C _1-6 hydroxyalkyl group, a C _1-6 alkoxy C _1-6 alkyl group and a C _1-6 alkoxy C _1-6 alkoxy group; preferably, R ^6a is a C _1-6 alkoxy C _1-6 alkyl group; more preferably, R ^6a is -CH ₂ OCH ₂ CH ₃ or -CH ₂ OtBu; in some embodiments, R ^6a is -CH ₂ OCH ₂ CH ₃ . In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ^R1 is a _C1-6 alkyl group, ^R2 is a hydrogen atom, and ^R3 is a hydrogen atom; or ^R1 is a _C1-6 alkyl group, and ^R2 and ^R3 together with the atoms to which they are connected form a 4- to 7-membered heterocyclic group; or ^R2 is a hydrogen atom, and ^R1 and ^R3 together with the carbon atoms to which they are connected form a 5- to 8-membered heterocyclic group; or ^R3 is a hydrogen atom, and ^R1 and ^R2 together with the carbon atoms to which they are connected form a 4- to 7-membered cycloalkyl group or a 4- to 7-membered heterocyclic group; preferably, ^R1 is a _C1-6 alkyl group, ^R2 is a hydrogen atom, and ^R3 is a hydrogen atom; more preferably, ^R1 is a methyl group, ^R2 is a hydrogen atom, and ^R3 is a hydrogen atom.

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 pyrimidinyl group; for wherein the * bond is connected to T; T is -O-; R ^4a is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and 3 to 6 membered cycloalkyl; R ^1a is hydrogen atom; R ^2a is hydrogen atom; R ¹ is C _1-6 alkyl; R ² is hydrogen atom; R ³ is hydrogen atom; R ⁵ is halogen; R ⁶ is C _1-6 alkoxy C _1-6 alkyl; R ⁷ is hydrogen atom; R ⁸ is hydrogen atom; and t is 1.

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-membered heteroaryl group; Selected from wherein the * bond is connected to T; T is -O- or -NH-; R ^4a is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group and a C _1-6 haloalkyl group; R ^4b is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group and a C _1-6 haloalkyl group; R ^1a is a hydrogen atom; R ^2a is a hydrogen atom; R ¹ is a C _1-6 alkyl group, R ² is a hydrogen atom, and R ³ is a hydrogen atom; or R ¹ is a C _1-6 alkyl group, R ² and R ³ together with the atoms to which they are connected form a 4- to 7-membered heterocyclic group; or R ² is a hydrogen atom, R ¹ and R ³ together with the carbon atoms to which they are connected form a 5- to 8-membered heterocyclic group; or R ³ is a hydrogen atom, R ¹ and R ² together with the carbon atoms to which they are connected form a 4- to 7-membered cycloalkyl group or a 4- to 7-membered heterocyclic group; R ⁵ is a halogen; R ⁶ is a C _1-6 alkoxy C _1-6 alkyl group; R ^R7 is a hydrogen atom; ^R8 is a hydrogen atom; and t is 1.

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein T is -O- or -NH-; X is N or CR ^4a ; R ^4a is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group and a C _1-6 haloalkyl group; Y is N; R ¹ is a C _1-6 alkyl group; R ³ is a hydrogen atom; R ⁵ is a halogen; and R ^6a is a C _1-6 alkoxy C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein T is -O-; X is N or CR ^4a ; R ^4a is selected from a hydrogen atom, a halogen, a C _1-6 alkyl, a C _1-6 haloalkyl and a 3- to 6-membered cycloalkyl; Y is N; R ¹ is a C _1-6 alkyl; R ³ is a hydrogen atom; R ⁵ is a halogen; and R ^6a is a C _1-6 alkoxy C _1-6 alkyl.

Table A Typical compounds of the present disclosure include, but are not limited to:

The present disclosure provides a compound represented by general formula (IA) or a salt thereof:

in:

T is O or NR ^A ;

Ring B, R ¹ , R ^1a , R ² , R ^2a , R ³ , R ⁴ , R ⁷ , R ⁸ , ^RA , W and n are as defined in the general formula (I).

The present disclosure provides a compound represented by general formula (IIA) or a salt thereof:

in:

T is O or NR ^A ;

X, Y, R ¹ , R ³ and ^RA are as defined in the general formula (II).

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

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:

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

in:

^XL is a leaving group, preferably a halogen, more preferably Cl;

T is O or NR ^A ;

Ring A, Ring B, R ¹ , R ^1a , R ² , R ^2a , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , ^RA , W, n and t are as defined in the general formula (I).

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:

The compound represented by the general formula (IIA) or its salt undergoes a nucleophilic substitution 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;

in:

^XL is a leaving group, preferably a halogen, more preferably Cl;

T is O or NR ^A ;

X, Y, R ¹ , R ³ , R ⁵ , R ^6a and ^RA are as defined in the general formula (II).

Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound of the present disclosure of general formula (I) or general formula (II) and shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to the use of the compound represented by the general formula (I) or the general formula (II) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of an MK2 inhibitor.

The present disclosure further relates to the use of compounds of formula (I) or (II) and shown in 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.

The present disclosure further relates to the use of the compounds of general formula (I) or general formula (II) and shown in Table A or their pharmaceutically acceptable salts or pharmaceutical compositions comprising the same in the preparation of medicaments 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 present disclosure further relates to a method for inhibiting MK2, which comprises administering to a patient in need thereof a compound of formula (I) or formula (II) and shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method for treating and/or preventing diseases or conditions mediated by MK2, comprising administering to a patient in need thereof an effective inhibitory amount of a compound of formula (I) or (II) and shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method for treating and/or preventing autoimmune disorders, chronic or acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasia, and cardiovascular or cerebrovascular disorders, comprising administering to a patient in need thereof a compound of formula (I) or formula (II) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a compound represented by general formula (I) or general formula (II) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a medicament.

The present disclosure further relates to a compound represented by general formula (I) or general formula (II) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as an MK2 inhibitor.

The present disclosure further relates to a compound of formula (I) or formula (II) and shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and/or preventing diseases or conditions mediated by MK2.

The present disclosure further relates to a compound of formula (I) or formula (II) and shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug 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 present disclosure further relates to a compound of formula (I) or formula (II) and shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and/or preventing autoimmune diseases, chronic or acute inflammatory diseases, autoinflammatory diseases, fibrotic diseases, metabolic diseases, neoplasia and cardiovascular or cerebrovascular diseases.

Preferably, the MK2-mediated disease or disorder of the present disclosure is selected from the group consisting of autoimmune disorders, chronic or acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasia, and cardiovascular or cerebrovascular disorders.

Preferably, the MK2-mediated disease or disorder of the present disclosure is selected from the group consisting of an autoimmune disorder, a chronic or acute inflammatory disorder, and an autoinflammatory disorder.

Preferably, the disease or disorder mediated by MK2 according to the present disclosure is a fibrotic disorder.

Preferably, the disease or disorder mediated by MK2 described in the present disclosure is a metabolic disorder.

Preferably, the disease or disorder mediated by MK2 according to the present disclosure is neoplasia.

Preferably, the disease or disorder mediated by MK2 described in the present disclosure is a cardiovascular or cerebrovascular disorder.

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, 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, systemic 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 Syndrome, 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, endotoxic 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, muscle fiber 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 and bronchitis; more preferably selected from inflammatory bowel disease, ulcerative colitis, psoriasis, Crohn's disease (CD), multiple sclerosis, psoriasis, arthritis, ankylosing spondylitis (also known as ankylosing spondylitis spondylitis), asthma, chronic obstructive pulmonary disease (COPD), cryptopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold-induced 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.

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

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.

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

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, sarcoma), melanoma, teratoma, rhabdomyosarcoma, metastatic and skeletal conditions, cancers of the bone, mouth/throat, esophagus, larynx, stomach, intestine, colon, rectum, lung, liver, pancreas, nerves, brain, head and neck, throat, ovary, uterus, prostate, testicles, bladder, kidney, breast, gallbladder, cervix, thyroid, prostate, and skin, non-small cell lung cancer, small cell lung cancer, glioma, and glioblastoma multiforme.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding 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.

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.

Terminology

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

The term "alkyl" refers to a saturated straight 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., _C1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., _C1-12 alkyl), and more preferably an alkyl group having 1 to 6 carbon atoms (i.e., _C1-6 alkyl). Non-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 substituents are 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.

The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group is as defined above, and has 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., _C1-20 alkylene). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., _C1-12 alkylene), and more preferably an alkylene group having 1 to 6 carbon atoms (i.e., _C1-6 alkylene). Non-limiting examples include: _-CH2- , -CH( _CH3 )-, _-C ( _CH3 ) _2- , _-CH2CH2- , -CH( _CH2CH3 )-, -CH2CH _{( CH3} )- _{, -CH2C(CH3 )} 2-, -CH2CH2CH2- _{, -CH2CH2CH2- ,} -CH2CH2CH2CH2-, _etc. The alkylene group _may be substituted or unsubstituted, _and 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, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, _hydroxyalkyl , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 _alkenyl ). The alkenyl group preferably has an alkenyl group of 2 to 6 carbon atoms (i.e., _C2-6 alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. The alkenyl group 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.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., _C2-12 alkynyl). The alkynyl group preferably has an alkynyl group of 2 to 6 carbon atoms (i.e., _C2-6 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.

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.

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).

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

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

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 -O-O-, -O-S- or -S-S-), 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:

Its connection point can be at any position;

wait.

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: , whose connection points can be at any position; wait.

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), and more preferably has a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 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 bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include: Its connection point can be at any position.

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.

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 oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S- or -S-S-), 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); most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).

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

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

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 does not include -O-O-, -O-S- or -S-S-), 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), and more preferably has 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:

wait.

The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms 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 -O-O-, -O-S- or -S-S-), 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 bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, 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 heterocyclic groups. Non-limiting examples include:

wait.

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 -O-O-, -O-S-, or -S-S-), 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:

wait.

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.

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:

wait.

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.

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 -O-O-, -O-S-, or -S-S-), 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).

The monocyclic heteroaryl group includes, but is not limited to, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

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:

wait.

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.

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.

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.

The term "warhead group" refers to a functional group present on the disclosed compounds that can covalently bind to an amino acid residue (such as cysteine, lysine, histidine or other residues that can be covalently modified) present in the binding pocket of a target protein, thereby inhibiting the protein. Non-limiting examples of warhead groups include:

The disclosed compounds comprise a warhead group, denoted as ^R5, as described herein. Without wishing to be bound by any particular theory, it is believed that such ^R5 groups (i.e., warhead groups) are particularly suitable for covalently binding to key cysteine residues in the binding domain of MK2 kinase. One of ordinary skill in the art will appreciate that MK2 kinase and its mutants have cysteine residues in the binding domain. Without wishing to be bound by any particular theory, it is believed that the proximity of the warhead group to the relevant cysteine promotes covalent modification of the cysteine by the warhead group.

In some embodiments, the compounds of the present invention include a warhead group, characterized in that provided compounds covalently modify Cys140 of MK2.

In certain embodiments, the compounds of the invention include a warhead group, characterized in that the compound covalently modifies the target of Cys140 of MK2, thereby inhibiting the kinase.

The term "target protein" refers to proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In some embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integral functions of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, white matter involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. The proteins include proteins from eukaryotic and prokaryotic organisms, including microorganisms, viruses, fungi and parasites, as well as numerous others, including humans, microorganisms, viruses, fungi and parasites as targets for drug therapy, other animals including domestic animals), microorganisms used as targets for the determination of antibiotics and other antimicrobials and plants and even viruses, as well as numerous others.

"Leaving group", or leaving group, is an atom or functional group that detaches from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called a substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called a leaving group. Groups that are easy to accept electrons and have strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to detach from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to combine with other atoms, and the tendency to exist in the form of anions (or electrically neutral leaving groups) is enhanced. Common leaving groups include but are not limited to halogens, -OTs or -OH.

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: _-CH2OCH3 , _{-CH2OCH2CH3 ,} and _-CH2OtBu .

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 .

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

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

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

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

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

The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein cycloalkyl is as defined above.

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

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

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

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

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

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

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

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

The term "hydroxy" refers to -OH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" or "oxo" refers to "=0".

The term "carbonyl" refers to C=O.

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

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.

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

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.

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.

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 diastereomers is usually completed by chromatography.

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.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included in 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, that is, 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:

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

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

Compounds of the present disclosure include all suitable isotopic derivatives of their compounds. 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 different atomic masses. Examples of isotopes that can be introduced into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 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.

Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. 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.

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).

"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.

"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 without undue effort (by experiment or theory). 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).

"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.

"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.

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 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.

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

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.

Synthesis method of the disclosed compound

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

Solution 1

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:

The compound represented by the general formula (IA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (IB) or its salt under alkaline conditions to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

in:

^XL is a leaving group, preferably a halogen, more preferably Cl;

T is O or NR ^A ;

Ring A, Ring B, R ¹ , R ^1a , R ² , R ^2a , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , ^RA , W, n and t are as defined in the general formula (I).

Solution 2

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:

The compound represented by the general formula (IIA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (IIB) or its salt under alkaline conditions to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt;

in:

^XL is a leaving group, preferably a halogen, more preferably Cl;

T is O or NR ^A ;

X, Y, R ¹ , R ³ , R ⁵ , R ^6a and ^RA are as defined in the general formula (II).

The reagents providing alkaline conditions include organic bases and inorganic bases, and 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 potassium carbonate, more preferably anhydrous potassium carbonate.

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

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.

Example

The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

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

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

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

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

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

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

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

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

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.

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

The average kinase inhibition rate and _IC50 value were determined using NovoStar microplate reader (BMG, Germany).

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, Darui Chemicals and other companies.

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

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

Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

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

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

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

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

Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the system of eluent for column chromatography used for purifying the compound and the developing solvent system for 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.

Example 1

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 1

first step

3-Bromothieno[3,2-c]pyridine-2-carboxylic acid methyl ester 1b

3-Aminothieno[3,2-c]pyridine-2-carboxylic acid methyl ester 1a (3 g, 14.41 mmol, Leyan) was dissolved in acetonitrile (75 mL), cooled to 0°C under nitrogen protection and stirring, 2.6 mL of tert-butyl nitrite (2.23 g, 21.61 mmol, Shaoyuan) was slowly added dropwise, and stirring was continued at 0°C for 2 hours. Copper bromide (3.86 g, 17.29 mmol, Shaoyuan) was added and stirred at room temperature for 3 hours. The reaction solution was added to 200 mL of water and extracted with 2% methanol in dichloromethane solution (200 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 1b (440 mg, yield: 11.22%).

MS m/z(ESI):271.9[M+1],273.9[M+1]

Step 2

3-Bromo-2-(methoxycarbonyl)thieno[3,2-c]pyridine-5-oxide 1c

Compound 1b (440 mg, 1.62 mmol) was dissolved in dichloromethane (13 mL), cooled to 0°C under nitrogen protection with stirring, and m-chloroperbenzoic acid (419 mg, 2.42 mmol, Adamas) was added in batches, and the temperature was naturally raised to 30°C and stirred for 3 hours. 20 mL of ice water was added, and the pH value was adjusted to 8 with saturated sodium carbonate solution, and extracted with dichloromethane (20 mL×2), and the organic phases were combined, washed with 20 mL of saturated brine, 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 1c (393 mg, yield: 84.36%).

MS m/z(ESI):287.9[M+1],289.9[M+1]

Step 3

3-Bromo-4-(2-methoxy-2-oxoethyl)thieno[3,2-c]pyridine-2-carboxylic acid methyl ester 1d

In a dry flask filled with nitrogen, compound 1c (393 mg, 1.36 mmol) and tert-butyl-(1-methoxyvinyloxy)-dimethylsilane (514 mg, 2.73 mmol, Leyan) were dissolved in anhydrous tetrahydrofuran (10 mL), and N,N-diisopropylethylamine (529 mg, 4.09 mmol, Adamas) and tripyrrolidinophosphonium bromide hexafluorophosphate (699 mg, 1.50 mmol, Adamas) were added under stirring at room temperature, and stirred at room temperature for 2 hours. 15 mL of ice water and 15 mL of dichloromethane were added, stirred and separated, and the organic phase was taken, 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 1d (280 mg, yield: 59.64%).

MS m/z(ESI):344.1[M+1],346.1[M+1]

Step 4

9-Bromo-2-hydroxypyrazolo[1,5-a]thieno[3,2-c]pyridine-8-carboxylic acid methyl ester 1e

Compound 1d (280 mg, 813.5 μmol) was dissolved in N,N-dimethylformamide (5 mL), O-(2,4-dinitrophenyl)hydroxylamine (162 mg, 813.5 μmol, Bid) was added under stirring, and the temperature was raised to 60°C and stirred for 48 hours. The mixture was concentrated, 10 mL of ethyl acetate and 10 mL of petroleum ether were added for slurrying, filtered, and the filter cake was vacuum dried to obtain the title compound 1e (266 mg, yield: 99.9%).

MS m/z(ESI):327.1[M+1],329.1[M+1]

Step 5

2-(Benzyloxy)-9-bromopyrazolo[1,5-a]thieno[3,2-c]pyridine-8-carboxylic acid methyl ester 1f

Compound 1e (266 mg, 813.1 μmol), anhydrous potassium carbonate (337 mg, 2.4 mmol, Sinopharm) and sodium iodide (122 mg, 813.1 μmol, Shaoyuan) were added to N,N-dimethylformamide (5 mL), and benzyl bromide (139 mg, 813.1 μmol, Adamas) was slowly added dropwise under stirring, and the temperature was raised to 90°C and stirred for 16 hours. After cooling to room temperature, 15 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (15 mL×2), 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 1f (180 mg, yield: 53.05%).

MS m/z(ESI):416.9[M+1],418.9[M+1]

Step 6

(R)-2-(Benzyloxy)-9-((2-((tert-butyloxycarbonyl)amino)propyl)amino)pyrazolo[1,5-a]thieno[3,2-c]pyridine-8-carboxylic acid methyl ester 1 g

Compound 1f (180 mg, 431.4 μmol) and tert-butyl N-[(1R)-2-amino-1-methylethyl]carbamate (113 mg, 647.05 μmol, Bidler) were dissolved in toluene (6 mL), anhydrous cesium carbonate (281 mg, 862.7 μmol, Adamas) was added, the gas in the system was replaced with nitrogen three times, tris(dibenzylideneacetone)dipalladium (40 mg, 43.1 μmol, Bidler) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (27 mg, 43.1 μmol, Shaoyuan) were added, the gas in the system was replaced with nitrogen three times again, and the reaction solution was heated to 110°C and stirred for 16 hours. Cool, filter and wash the filter cake with ethyl acetate, concentrate the filtrate, and purify the residue by column chromatography with eluent system C to obtain the title compound 1g (150 mg, yield: 68.1%).

MS m/z(ESI):511[M+1]

Step 7

(R)-9-((2-aminopropyl)amino)-2-(benzyloxy)pyrazolo[1,5-a]thieno[3,2-c]pyridine-8-carboxylic acid methyl ester 1h trifluoroacetate

Compound 1g (150 mg, 293.8 μmol) was dissolved in dichloromethane (4.5 mL), cooled to 0°C under nitrogen protection and stirring, 0.6 mL of trifluoroacetic acid (921 mg, 8.1 mmol, Adamas) was slowly added dropwise, and the temperature was naturally raised to 25°C and stirred for 2 hours. Concentrate, add dichloromethane to dissolve and concentrate under reduced pressure, and vacuum dry to obtain the trifluoroacetate salt of the title compound 1h (154 mg, yield: 99.9%).

MS m/z(ESI):411.1[M+1]

Step 8

(R)-2-(Benzyloxy)-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thiophene

[3,2-e][1,4]diazepine-8-one 1i

In a dry flask, the trifluoroacetate of compound 1h (154 mg, 293.6 μmol) was dissolved in methanol (5 mL), sodium methoxide (79.3 mg, 1.5 mmol, Adamas) was added under stirring at room temperature, and the temperature was raised to 90°C and stirred for 12 hours. Concentrate, add 15 mL of water to dilute and stir, extract with ethyl acetate (15 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography with eluent system C to obtain the title compound 1i (111 mg, yield: 99.9%).

MS m/z(ESI):379.1[M+1]

Step 9

(R)-2-Hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thiophene[3,2-e][1,4]diazepin-8-one 1j

Compound 1i (111 mg, 293.3 μmol) was dissolved in anhydrous methanol (6 mL), 10% palladium/carbon (31 mg, 29.3 μmol, Shaoyuan) was added under nitrogen protection, the gas in the system was replaced with hydrogen 3 times, the temperature was raised to 75°C and stirred for 5 hours under hydrogen. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 1j (85 mg, yield: 99.9%).

MS m/z(ESI):289.1[M+1]

Step 10

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 1

Compound 1j (85 mg, 293.1 μmol) was dissolved in dimethyl sulfoxide (3 mL), anhydrous potassium carbonate (81 mg, 586.1 μmol, Chinese medicine) was added, stirred for 10 minutes, 2,4-dichloro-5-(ethoxymethyl)pyrimidine (91 mg, 439.6 μmol, synthesized by referring to the synthesis method of compound INT-60 on page 87 of patent US20160075720A1), and stirred at room temperature for 16 hours. Filter, and the filtrate was purified by high performance liquid chromatography (chromatographic column: welch prep C18, 5 μm 30*150 mm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 25%-45%) to obtain the title compound 1 (46 mg, yield: 34.2%).

MS m/z(ESI):459[M+1]

¹ H NMR (500MHz, DMSO-d ₆ ): δ8.74(s,1H),8.55(d,1H),7.97(d,1H),7.39(d,1H),7.20(s,1H),6.76 -6.74(m,1H),4.65(d,2H),3.64-3.58(m,3H),3.42-3.41(m,2H),1.25-1.16(m,6H).

Example 2

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1,10-dimethyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 2

first step

3-Bromo-4-(1-methoxy-1-oxopropan-2-yl)thieno[3,2-c]pyridine-2-carboxylic acid methyl ester 2a

In a dry flask filled with nitrogen, compound 1c (2.5 g, 8.68 mmol) and 1-methoxy-1-trimethylsilyloxypropylene (2.22 g, 13.88 mmol, TCI) were dissolved in anhydrous tetrahydrofuran (75 mL), and N,N-diisopropylethylamine (3.36 g, 26.00 mmol, Adamas) and tripyrrolidinophosphonium bromide hexafluorophosphate (4.45 g, 9.54 mmol, Adamas) were added under stirring at room temperature, and stirred at room temperature for 2 hours. 50 mL of ice water and 50 mL of dichloromethane were added and stirred, and the layers were separated. The organic phase was taken, 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 2a (3.0 g, yield: 96.52%).

MS m/z(ESI):358.1[M+1],359.9[M+1]

Step 2

9-Bromo-2-hydroxy-1-methylpyrazolo[1,5-a]thieno[3,2-c]pyridine-8-carboxylic acid methyl ester 2b

Compound 2a (3.0 g, 8.37 mmol) was dissolved in N,N-dimethylformamide (50 mL), O-(2,4-dinitrophenyl)hydroxylamine (1.67 g, 8.37 mmol, Bid) was added under stirring, and the temperature was raised to 60°C and stirred for 48 hours. The mixture was concentrated, 50 mL of ethyl acetate and 50 mL of petroleum ether were added for slurrying, filtered, and the filter cake was dried under vacuum to obtain the title compound 2b (345 mg, yield: 12.07%).

MS m/z(ESI):340.9[M+1],343.1[M+1]

Step 3

2-(Benzyloxy)-9-bromo-1-methylpyrazolo[1,5-a]thieno[3,2-c]pyridine-8-carboxylic acid methyl ester 2c

Compound 2b (345 mg, 1.01 mmol), anhydrous potassium carbonate (419 mg, 3.03 mmol, Sinopharm) and sodium iodide (151 mg, 1.01 mmol, Shaoyuan) were added to N,N-dimethylformamide (7 mL), and benzyl bromide (173 mg, 1.01 mmol, Adamas) was slowly added dropwise under stirring, and the temperature was raised to 90°C and stirred for 16 hours. The mixture was cooled to room temperature, diluted with 15 mL of water, extracted with ethyl acetate (15 mL×2), 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 2c (100 mg, yield: 22.92%).

MS m/z(ESI):431.2[M+1],433.1[M+1]

Step 4

(R)-2-(Benzyloxy)-9-((2-((tert-butyloxycarbonyl)amino)propyl)amino)-1-methylpyrazolo[1,5-a]thieno[3,2-c]pyridine-8-carboxylic acid methyl ester 2d

Compound 2c (100 mg, 231.8 μmol) and tert-butyl N-[(1R)-2-amino-1-methylethyl]carbamate (60 mg, 347.8 μmol, Bid) were dissolved in toluene (3 mL), anhydrous cesium carbonate (151 mg, 463.7 μmol, Adamas) was added, the gas in the system was replaced with nitrogen three times, tris(dibenzylideneacetone)dipalladium (21 mg, 23.1 μmol, Adamas) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (14 mg, 23.1 μmol, Shaoyuan) were added, the gas in the system was replaced with nitrogen three times again, the reaction solution was heated to 110°C and stirred for 16 hours. After cooling, filtering and washing the filter cake with ethyl acetate, the filtrate was concentrated, and the residue was purified by column chromatography with eluent system C to obtain the title compound 2d (95 mg, yield: 78.1%).

MS m/z(ESI):525.4[M+1]

Step 5

(R)-9-((2-aminopropyl)amino)-2-(benzyloxy)-1-methylpyrazolo[1,5-a]thieno[3,2-c]pyridine-8-carboxylic acid methyl ester 2e trifluoroacetate

Compound 2d (95 mg, 181.1 μmol) was dissolved in dichloromethane (3 mL), cooled to 0°C under nitrogen protection and stirring, 0.4 mL of trifluoroacetic acid (921 mg, 8.1 mmol, Adamas) was slowly added dropwise, and the temperature was naturally raised to 25°C and stirred for 2 hours. Concentrated, dichloromethane was added to dissolve and concentrated under reduced pressure, and vacuum dried to obtain the trifluoroacetate salt of the title compound 2e (97 mg, yield: 99.5%).

MS m/z(ESI):425.7[M+1]

Step 6

(R)-2-(Benzyloxy)-1,10-dimethyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 2f

In a dry flask, the trifluoroacetate of compound 2e (97 mg, 180.1 μmol) was dissolved in methanol (3 mL), sodium methoxide (48.7 mg, 901.4 μmol, Shaoyuan) was added under stirring at room temperature, and the temperature was raised to 90°C and stirred for 12 hours. Concentrate, add 15 mL of water to dilute and stir, extract with ethyl acetate (15 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography with eluent system C to obtain the title compound 2f (45 mg, yield: 63.6%).

MS m/z(ESI):393.2[M+1]

Step 7

(R)-2-Hydroxy-1,10-dimethyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 2g

Compound 2f (45 mg, 114.6 μmol) was dissolved in anhydrous methanol (4 mL), 10% palladium/carbon (12 mg, 11.4 μmol, Shaoyuan) was added under nitrogen protection, the gas in the system was replaced with hydrogen three times, the temperature was raised to 75°C and stirred for 5 hours under hydrogen atmosphere. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 2g (34 mg, yield: 98.1%).

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

Step 8

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1,10-dimethyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 2

Compound 2g (34 mg, 112.4 μmol) was dissolved in dimethyl sulfoxide (3 mL), anhydrous potassium carbonate (31 mg, 225.0 μmol, Chinese medicine) was added, stirred for 10 minutes, 2,4-dichloro-5-(ethoxymethyl)pyrimidine (35 mg, 168.5 μmol) was added, and stirred at room temperature for 16 hours. Filtered, the filtrate was purified by high performance liquid chromatography (chromatographic column: Sharpsil-TPrep C18, 5 μm 30*150 mm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 35%-55%) to obtain the title compound 2 (8.5 mg, yield: 16.0%).

MS m/z(ESI):473.3[M+1]

¹ H NMR(500MHz,DMSO)δ8.71(s,1H),8.46(d,1H),8.00(d,1H),7.31(d,1H),6.27(t,1H),4.68(s,2H ),3.63(q,2H),3.60-3.55(m,1H),3.44-3.39(m,2H),2.04-1.98(m,3H),1.23-1.17(m,6H).

Example 3

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1’,2’]pyrido[3’,4’:4,5]thieno[3,2-e][1,4]diazepin-8-one 3

Example 4

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,2,4]triazolo[1",5":1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 4

first step

4-Amino-3-bromothieno[3,2-c]pyridine-2-carboxylic acid methyl ester 4a

Compound 1c (2.1 g, 7.29 mmol) and tert-butylamine (2.66 g, 36.37 mmol, Sinopharm) were dissolved in trifluorotoluene (36 mL), 4-toluenesulfonic anhydride (4.76 g, 14.58 mmol, Adamas) was added at 0°C, and stirred at 0°C for 10 minutes. Subsequently, 5 mL of trifluoroacetic acid was added, and the reaction solution was heated to 70°C and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 50 mL of dichloromethane was added to dissolve, and washed with saturated sodium carbonate solution (50 mL). The organic phase was taken, 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 4a (700 mg, yield: 33.45%).

MS m/z(ESI):286.8[M+1],289.0[M+1]

Step 2

4,5-Diamino-3-bromo-2-(methoxycarbonyl)thieno[3,2-c]pyridin-5-ium 2,4-dinitrophenolate 4b

In a dry sealed tube, compound 4a (700 mg, 2.44 mmol) was dissolved in acetonitrile (25 mL), O-(2,4-dinitrophenyl)hydroxylamine (485 mg, 2.44 mmol, Bid) was added under stirring, and the temperature was raised to 60°C and stirred for 48 hours. The crude product compound 4b was obtained by concentration and used directly in the next step without purification.

MS m/z(ESI):302.1[M+1],304.0[M+1]

Step 3

9-Bromo-2-hydroxythieno[3,2-c][1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester 4c

The crude product compound 4b (737 mg, 2.43 mmol) of the previous step and N,N'-carbonyldiimidazole (1.97 g, 12.15 mmol, Shaoyuan) were dissolved in tetrahydrofuran (35 mL), followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (960 mg, 6.31 mmol, Shaoyuan), and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to obtain the title compound 4c (490 mg, yield: 61.42%).

MS m/z(ESI):328.0[M+1],330.0[M+1]

Step 4

2-(Benzyloxy)-9-bromothieno[3,2-c][1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester 4d

Compound 4c (480 mg, 1.46 mmol), anhydrous potassium carbonate (610 mg, 4.41 mmol, Sinopharm) and sodium iodide (220 mg, 1.46 mmol, Shaoyuan) were added to N,N-dimethylformamide (10 mL), and benzyl bromide (275 mg, 1.61 mmol, Adamas) was slowly added dropwise under stirring, and the temperature was raised to 90°C and stirred for 16 hours. The mixture was cooled to room temperature, diluted with 30 mL of water, extracted with ethyl acetate (30 mL×2), 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 4d (500 mg, yield: 81.72%).

MS m/z(ESI):418.2[M+1],419.9[M+1]

Step 5

(R)-2-(Benzyloxy)-9-((2-((tert-butyloxycarbonyl)amino)propyl)amino)thieno[3,2-c][1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester 4e

Compound 4d (500 mg, 1.19 mmol) and tert-butyl N-[(1R)-2-amino-1-methylethyl]carbamate (315 mg, 1.81 mmol, Bid) were dissolved in toluene (10 mL), anhydrous cesium carbonate (780 mg, 2.39 mmol, Adamas) was added, the gas in the system was replaced with nitrogen three times, tris(dibenzylideneacetone)dipalladium (110 mg, 120.1 μmol, Adamas) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (150 mg, 240.9 μmol, Shaoyuan) were added, the gas in the system was replaced with nitrogen three times again, the reaction solution was heated to 110°C and stirred for 16 hours. After cooling, filtering and washing the filter cake with ethyl acetate, the filtrate was concentrated, and the residue was purified by column chromatography with eluent system C to obtain the title compound 4e (450 mg, yield: 73.6%).

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

Step 6

(R)-9-((2-aminopropyl)amino)-2-(benzyloxy)thieno[3,2-c][1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester 4f trifluoroacetate

Compound 4e (450 mg, 879.6 μmol) was dissolved in dichloromethane (10 mL), cooled to 0°C under nitrogen protection and stirring, 0.6 mL of trifluoroacetic acid (1 g, 8.7 mmol, Adamas) was slowly added dropwise, and the temperature was naturally raised to 25°C and stirred for 2 hours. Concentrate, add dichloromethane to dissolve and concentrate under reduced pressure, and vacuum dry to obtain the trifluoroacetate salt of the title compound 4f (361 mg, yield: 99.7%).

MS m/z(ESI):412.4[M+1]

Step 7

(R)-2-(Benzyloxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,2,4]triazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 4g

In a dry flask, the trifluoroacetate of compound 4f (361 mg, 879.7 μmol) was dissolved in methanol (15 mL), sodium methoxide (790 mg, 4.38 mmol, Shaoyuan) was added under stirring at room temperature, and the temperature was raised to 90°C and stirred for 12 hours. Concentrate, add 30 mL of water to dilute and stir, extract with ethyl acetate (30 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography with eluent system C to obtain the title compound 4g (310 mg, yield: 92.8%).

MS m/z(ESI):380.2[M+1]

Step 8

(R)-2-Hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,2,4]triazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 4h

Compound 4g (100 mg, 263.5 μmol) was dissolved in anhydrous methanol (5 mL), 10% palladium/carbon (56 mg, 52.6 μmol, Shaoyuan) was added under nitrogen protection, the gas in the system was replaced with hydrogen three times, the temperature was raised to 75°C and stirred for 24 hours under hydrogen. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 4h (70 mg, yield: 91.8%).

MS m/z(ESI):290.1[M+1]

Step 9

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,2,4]triazolo[1",5":1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 4

Compound 4h (70 mg, 241.9 μmol) was dissolved in dimethyl sulfoxide (5 mL), anhydrous potassium carbonate (67 mg, 483.9 μmol, Chinese medicine) was added, stirred for 10 minutes, 2,4-dichloro-5-(ethoxymethyl)pyrimidine (50 mg, 241.9 μmol) was added, and stirred at room temperature for 16 hours. Filtered, the filtrate was purified by high performance liquid chromatography (chromatographic column: Sharpsil-TPrep C18, 5 μm 30*150 mm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 30%-50%) to obtain the title compound 4 (5 mg, yield: 4.5%).

MS m/z(ESI):460.3[M+1]

¹ H NMR(500MHz,DMSO)δ8.84(d,1H),8.80(s,1H),8.01(d,1H),7.79(d,1H),4.66(s,2H),3.62(q,2H ),3.50(s,1H),2.02-1.98(m,2H),1.24-1.11(m,6H).

Example 5

(R)-2-((5-(tert-butoxymethyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1’,2’]pyrido[3’,4’:4,5]thieno[3,2-e][1,4]diazepin-8-one 5

Example 6

(R)-1-chloro-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 6

first step

(R)-1-Chloro-2-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 6a

Compound 1j (35 mg, 121.4 μmol) was dissolved in N,N-dimethylformamide (2 mL), and N-chlorosuccinimide (16 mg, 119.8 μmol, Adamas) was added and stirred at room temperature for 3 minutes. The reaction solution was concentrated under reduced pressure, 10 mL of ethyl acetate and 10 mL of petroleum ether were added for slurrying, filtered, and the filter cake was vacuum dried to obtain the title compound 6a (35 mg, yield: 89.3%).

MS m/z(ESI):323.1[M+1]

Step 2

(R)-1-chloro-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 6

Compound 6a (35 mg, 108.4 μmol) was dissolved in dimethyl sulfoxide (2 mL), anhydrous potassium carbonate (30 mg, 217.1 μmol, Chinese medicine) was added, stirred for 10 minutes, 2,4-dichloro-5-(ethoxymethyl)pyrimidine (35 mg, 169.0 μmol) was added, and stirred at room temperature for 16 hours. Filtered, the filtrate was purified by high performance liquid chromatography (chromatographic column: Sharpsil-TPrep C18, 5 μm 30*150 mm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 35%-55%) to obtain the title compound 6 (8 mg, yield: 14.9%).

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

¹ H NMR(500MHz,DMSO)δ8.78(s,1H),8.58(d,1H),8.05(d,1H),7.51(d,1H),6.82(t,1H),4.68(s,2H ),3.62(q,3H),3.51(dd,1H),3.42(dt,1H),1.20(q,6H).

Example 7

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1’,2’]pyrido[3’,4’:4,5]thieno[3,2-e][1,4]diazepin-8-one 7

first step

(R)-1-Fluoro-2-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 7a

Compound 1j (310 mg, 1.07 mmol) was dissolved in N,N-dimethylformamide (15 mL), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (380 mg, 1.07 mmol, Shaoyuan) was added, and stirred at room temperature for 3 minutes. The reaction solution was concentrated under reduced pressure, 10 mL of ethyl acetate and 10 mL of petroleum ether were added for slurrying, filtered, and the filter cake was vacuum dried to obtain the title compound 7a (320 mg, yield: 97.1%).

MS m/z(ESI):307.0[M+1]

Step 2

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1-fluoro-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1’,2’]pyrido[3’,4’:4,5]thieno[3,2-e][1,4]diazepin-8-one 7

Compound 7a (320 mg, 1.04 mmol) was dissolved in dimethyl sulfoxide (5 mL), anhydrous potassium carbonate (288 mg, 2.08 mmol, Chinese medicine) was added, stirred for 10 minutes, 2,4-dichloro-5-(ethoxymethyl)pyrimidine (216 mg, 1.04 mmol) was added, and stirred at room temperature for 2 hours. Filtered, the filtrate was purified by high performance liquid chromatography (chromatographic column: Sharpsil-TPrep C18, 5 μm 30*150 mm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 40%-60%) to obtain the title compound 7 (12 mg, yield: 2.4%).

MS m/z(ESI):477.0[M+1]

¹ H NMR(500MHz,DMSO)δ8.78(s,1H),8.47(d,1H),8.02(d,1H),7.42(d,1H),4.68(s,2H),3.62(q,2H ),3.60-3.57(m,1H),3.48-3.36(m,2H),1.22-1.16(m,6H).

Example 8

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1-cyclopropyl-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 8

first step

(R)-2-(Benzyloxy)-1-bromo-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1",5":1',2']pyrido[3',4':4,5]

Thieno[3,2-e][1,4]diazepin-8-one 8a

Compound 1i (100 mg, 264.2 μmol) was dissolved in N,N-dimethylformamide (2.2 mL), and N-bromosuccinimide (47 mg, 264.1 μmol, Adamas) was added, and stirred at room temperature for 2 hours. 10 mL of saturated sodium bicarbonate solution was added to quench, and extracted with ethyl acetate (15 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 8a (117 mg, yield: 96.8%).

MS m/z(ESI):457.1[M+1],458.9[M+1]

Step 2

(R)-2-(Benzyloxy)-1-cyclopropyl-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 8b

Compound 8a (160 mg, 349.8 μmol) and cyclopropylboronic acid pinacol ester (147 mg, 874.8 μmol, Bid) were dissolved in 1,4-dioxane (2.4 mL) and water (0.8 mL), anhydrous potassium carbonate (145 mg, 1.05 mmol, Sinopharm) and tetrakis(triphenylphosphine)palladium (41 mg, 35.0 μmol, Shaoyuan) were added, the gas in the system was replaced with nitrogen three times, and the reaction solution was stirred at 120°C for 2 hours. Cool, filter and wash the filter cake with ethyl acetate, concentrate the filtrate, and purify the residue by column chromatography with eluent system C to obtain the title compound 8b (110 mg, yield: 75.1%).

MS m/z(ESI):419.1[M+1]

Step 3

(R)-1-Cyclopropyl-2-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 8c

Compound 8b (110 mg, 262.8 μmol) was dissolved in anhydrous methanol (5 mL), 10% palladium/carbon (28 mg, 26.3 μmol, Shaoyuan) was added under nitrogen protection, the gas in the system was replaced with hydrogen three times, the temperature was raised to 75°C and stirred for 5 hours under hydrogen. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 8c (86 mg, yield: 99.6%).

MS m/z(ESI):329.1[M+1]

Step 4

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-1-cyclopropyl-10-methyl-9,10,11,12-tetrahydro-8H-pyrazolo[1”,5”:1',2']pyrido[3',4':4,5]thieno[3,2-e][1,4]diazepin-8-one 8

Compound 8c (86 mg, 261.9 μmol) was dissolved in dimethyl sulfoxide (1.8 mL), anhydrous potassium carbonate (72 mg, 523.8 μmol, Chinese medicine) was added, stirred for 10 minutes, 2,4-dichloro-5-(ethoxymethyl)pyrimidine (81 mg, 392.6 μmol) was added, and stirred at room temperature for 16 hours. Filtered, the filtrate was purified by high performance liquid chromatography (chromatographic column: Sharpsil-TPrep C18, 5 μm 30*150 mm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 40%-70%) to obtain the title compound 8 (2.5 mg, yield: 1.9%).

MS m/z(ESI):499.4[M+1]

¹ H NMR (500MHz, DMSO) δ8.74(s,1H),8.48(d,1H),8.02(d,1H),7.38(t,1H),7.36(d,1H),4.68(s,2H ),3.63(q,3H),3.55-3.50(m,1H),3.47-3.44(m,1H),2.03-1.97(m,1H),1.94-1.90(m,1H),1.47-1.43(m ,1H),1.23-1.16(m,6H),0.89-0.84(m,1H),0.82-0.78(m,1H).

Embodiment 9

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-9-methyl-8,9,10,11-tetrahydro-7H-imidazo[1",2":1',6']pyrido[2',3':4,5]thieno[3,2-e][1,4]diazepin-7-one 9

first step

3-Amino-5-chlorothieno[3,2-b]pyridine-2-carboxylic acid methyl ester 9b

3,6-Dichloropyridinecarbonitrile 9a (15 g, 86.71 mmol, Bid) was dissolved in N,N-dimethylformamide (200 mL), and methyl thioglycolate (13 g, 122.47 mmol, Adamas) was added under stirring. The reaction solution was heated to 65°C and anhydrous potassium carbonate (24 g, 173.65 mmol, Sinopharm) was added. The reaction was stirred at 65°C for 3 hours. After cooling to room temperature, 200 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (200 mL×2). 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 9b (1.75 g, yield: 8.3%).

MS m/z(ESI):243.0[M+1]

Step 2

(R)-3-((2-((tert-Butyloxycarbonyl)amino)propyl)amino)-5-chlorothieno[3,2-b]pyridine-2-carboxylic acid methyl ester 9c

Compound 9b (1.75 g, 7.21 mmol) was dissolved in N,N-dimethylformamide (25 mL), sodium hydride (420 mg, 10.96 mmol, Sinopharm) was added at 0°C, and the reaction solution was stirred for 30 minutes. Subsequently, (R)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (1.89 g, 7.96 mmol, Shaoyuan) was added, and the reaction was stirred for 30 minutes at 0°C. 5 mL of saturated ammonium chloride solution was added to quench the reaction, and the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 9c (2.8 g, yield: 97.1%).

MS m/z(ESI):400.1[M+1]

Step 3

(R)-3-((2-aminopropyl)amino)-5-chlorothieno[3,2-b]pyridine-2-carboxylic acid methyl ester 9d trifluoroacetate

Compound 9c (2.8 g, 7.0 mmol) was dissolved in dichloromethane (30 mL), cooled to 0°C under nitrogen protection with stirring, trifluoroacetic acid (8 g, 70 mmol, Adamas) was slowly added dropwise, and the temperature was naturally raised to 25°C with stirring for 2 hours. Concentrated, dichloromethane was added to dissolve and concentrated under reduced pressure, and vacuum dried to obtain the trifluoroacetate salt of the title compound 9d (2.09 g, yield: 99.5%).

MS m/z(ESI):300.0[M+1]

Step 4

(R)-9-Chloro-3-methyl-1,2,3,4-tetrahydro-5H-pyrido[2',3':4,5]thieno[3,2-e][1,4]diazepin-5-one 9e

In a dry flask, the trifluoroacetate of compound 9d (2.09 g, 6.97 mmol) was dissolved in methanol (30 mL), sodium methoxide (2.0 g, 37.02 mmol, Shaoyuan) was added under stirring at room temperature, and the temperature was raised to 70°C and stirred for 2 hours. After concentration, 30 mL of water was added to dilute and stir, and then extracted with ethyl acetate (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 9e (1.6 g, yield: 85.7%).

MS m/z(ESI):268.0[M+1]

Step 5

(R)-9-Chloro-3-methyl-5-oxo-2,3-dihydro-1H-pyrido[2',3':4,5]thieno[3,2-e][1,4]diazepine-1,4(5H)-dicarboxylic acid di-tert-butyl ester 9f

Compound 9e (1.3 g, 4.85 mmol) was dissolved in dichloromethane (35 mL), and 4-dimethylaminopyridine (120 mg, 0.98 mmol, Shaoyuan), triethylamine (1.3 g, 12.85 mmol, Guoyao) and di-tert-butyl dicarbonate (4.2 g, 19.24 mmol, Shaoyuan) were added under stirring, and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system C to obtain the title compound 9f (1.3 g, yield: 57.2%).

MS m/z(ESI):468.0[M+1]

Step 6

(R)-9-((Benzhydryl)amino)-3-methyl-5-oxo-2,3-dihydro-1H-pyrido[2',3':4,5]thieno[3,2-e][1,4]diazepine-1,4(5H)-dicarboxylic acid di-tert-butyl ester 9g

Compound 9f (600 mg, 1.28 mmol) and benzophenone imine (348 mg, 1.92 mmol, Shaoyuan) were dissolved in 1,4-dioxane (10 mL), anhydrous cesium carbonate (835 mg, 2.56 mmol, Adamas) and methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2'-amino-1,1'-biphenyl] palladium (II) dichloromethane complex (121 mg, 127.6 μmol, Bid), the gas in the system was replaced with nitrogen three times, the reaction solution was heated to 110°C and stirred for 16 hours. After cooling, filtering and washing the filter cake with ethyl acetate, the filtrate was concentrated, and the residue was purified by column chromatography with eluent system C to obtain the title compound 9g (560 mg, yield: 71.3%).

MS m/z(ESI):613.0[M+1]

Step 7

(R)-9-Amino-3-methyl-5-oxo-2,3-dihydro-1H-pyrido[2',3':4,5]thieno[3,2-e][1,4]diazepine-1,4(5H)-dicarboxylic acid di-tert-butyl ester 9h

Compound 9g (560 mg, 913.9 μmol) was dissolved in tetrahydrofuran (3 mL), and 3M aqueous hydrochloric acid solution (3 mL) was added under stirring. The reaction solution was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added to adjust pH=7-8, and extracted with ethyl acetate (15 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 9h (230 mg, yield: 56.1%).

MS m/z(ESI):449.0[M+1]

Step 8

(R)-9-(2-Chloroacetylamino)-3-methyl-5-oxo-2,3-dihydro-1H-pyrido[2',3':4,5]thieno[3,2-e][1,4]diazepine-1,4(5H)-dicarboxylic acid di-tert-butyl ester 9i

Compound 9h (230 mg, 512.8 μmol) and triethylamine (155 mg, 1.53 mmol, Sinopharm) were dissolved in dichloromethane (3 mL), and chloroacetyl chloride (115 mg, 1.02 mmol, Adamas) was added under stirring, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system C to obtain the title compound 9i (120 mg, yield: 44.6%).

MS m/z(ESI):525.2[M+1]

Step 9

(R)-2-Hydroxy-9-methyl-7-oxo-9,10-dihydro-7H-imidazo[1",2":1',6']pyrido[2',3':4,5]thieno[3,2-e][1,4]diazepine-8,11-dicarboxylic acid di-tert-butyl ester 9j

Compound 9i (120 mg, 228.5 μmol) was dissolved in tetrahydrofuran (3 mL), sodium hydride (18 mg, 469.8 μmol, Chinese medicine) was added at 0°C, and the reaction was stirred at 0°C for 1 hour. 10 mL of saturated ammonium chloride solution was added to quench, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 9j (110 mg, yield: 98.5%). The product was used directly in the next step without purification.

MS m/z(ESI):489.2[M+1]

Step 10

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-9-methyl-7-oxo-9,10-dihydro-7H-imidazo[1”,2”:1',6']pyrido[2',3':4,5]thieno[3,2-e][1,4]diazepine-8,11-dicarboxylic acid di-tert-butyl ester 9k

Compound 9j (110 mg, 225.1 μmol) was dissolved in dimethyl sulfoxide (3 mL), anhydrous potassium carbonate (63 mg, 455.8 μmol, Chinese medicine) was added, stirred for 10 minutes, 2,4-dichloro-5-(ethoxymethyl)pyrimidine (47 mg, 227.0 μmol) was added, and stirred at room temperature for 16 hours. 15 mL of water was added to dilute and stir, and extracted with ethyl acetate (15 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 9k (148 mg, yield: 99.7%). The product was used directly in the next step without purification.

MS m/z(ESI):659.0[M+1]

Step 11

(R)-2-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-9-methyl-8,9,10,11-tetrahydro-7H-imidazo[1",2":1',6']pyrido[2',3':4,5]thieno[3,2-e][1,4]diazepin-7-one 9

Compound 9k (148 mg, 224.5 μmol) was dissolved in dichloromethane (3 mL), zinc bromide (252 mg, 1.12 mmol, Adamas) was added, and the reaction solution was stirred at room temperature for 16 hours. Filtered, the filtrate was purified by high performance liquid chromatography (chromatographic column: Sharpsil-T Prep C18, 5 μm 30*150 mm; mobile phase: water phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: water phase 25%-50%) to obtain the title compound 9 (11 mg, yield: 10.7%).

MS m/z(ESI):459.0[M+1]

¹ H NMR (500MHz, DMSO) δ8.70(d,1H),8.19(d,1H),7.82(d,1H),7.61(d,1H),6.95(t,1H),4.65(s,2H ),3.62(q,2H),3.59-3.40(m,3H),1.23-1.15(m,6H).

Biological evaluation

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.

Test Example 1: An endpoint enzymatic experiment based on HTRF technology was used to evaluate the inhibitory activity of the disclosed compounds on MK2 kinase.

1. Experimental Materials and Instruments

1. MAPKAPK2 protein (Thermo, PR5320A)

2. HTRF KinEASE-STK S1 kit, (Cisbio, 62ST1PEC)

3. HEPES buffer (Sigma, H3375)

4. Magnesium chloride (Sigma, 63069)

5. ATP, adenosine triphosphate (Promega, V915B)

6. BSA, bovine serum albumin (Sanggong, A500023-0100)

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

2. Experimental steps

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, 0.004nM MK2, 0.2μM biotin-labeled kinase substrate S1 (Km value), 4μM ATP (Km value) and different concentrations of compounds were incubated at room temperature for 1 hour. The reaction buffer was 20mM HEPES (pH 7.5), 10mM MgCl ₂ , 0.01% TritonX-100, 0.01% BSA, 1mM DTT. The enzymatic reaction was carried out in a Coring384 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 were added to terminate the enzyme reaction at a final concentration of 12.5nM. After incubation for 1 hour at room temperature, the fluorescence signals at 620 nm and 665 nm were detected using a PHERAstar FS microplate reader under 337 nm wavelength excitation light. The calibrated fluorescence signal was obtained by calculating the ratio of the fluorescence signals at 665 nm to 620 nm. 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 value was calculated to reflect the inhibitory activity of different compounds on MK2.

Table 1 Inhibitory activity of the disclosed compounds on MK2

Conclusion: The disclosed compounds have a good inhibitory effect on MK2.

Test Example 2: Inhibitory activity of the disclosed compounds on TNFa secretion in U937 cells.

1. Experimental Materials and Instruments

1. U937 cells (ATCC)

2.RIPM1640 (Dalian Meilun Biotechnology, PWL015)

3. FBS (Gibco, 10099-141)

4.DPBS (Gibco, 14190250)

5.PMA (InvivoGen, tlrl-pma)

6. LPS (Biyuntian, S1732-5mg)

7.100mm dish(Costar,430167)

8. Human TNF-αELISAkit (Xinbo Sheng, EHC103a.96.10)

9.T175 cell culture flask (Corning, 431080)

10. Cell scraper (Corning, CON-3010)

11. 96-well flat-bottom cell culture plate (Corning, 3599)

12. 96-well round-bottomed dispensing plate (Corning, 3788)

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

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

15. Biological safety cabinet (ESCO, ClassⅡBSC)

16. Centrifuge (ThermoFisher Scientific, ST40R)

17. Bravo (Agilent)

18. PHERAstar FS microplate reader (BMG Labtech)

2. Experimental process

U937 cells were cultured with 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 37°C cell culture incubator. On the fourth day, U937 cells were plated into 96-well plates at 5×10 ⁴ per well and cultured overnight in a 37°C cell culture incubator. On the fifth day, 8 serial dilutions containing 10× compound medium were added to 96-well plates and cultured with U937 cells at 37°C for 60 minutes. After that, LPS with a final concentration of 100 ng/ml was added to stimulate the cells. After 6 hours, the supernatant was collected to test 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 according to 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 were fitted with Graphpad Prism curve and the _IC50 value was calculated.

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

Compound No. TNFa_U937 IC ₅₀ (nM) 6 14.0

Conclusion: The compounds disclosed in the present invention have an inhibitory effect on the secretion of TNFa in U937 cells.

Test Example 3: Solubility of the compounds disclosed herein

1. Experimental Materials

Reagents: dimethyl sulfoxide (chromatographic grade, Sigma-Aldrich, catalog number 472301-4X4L), ethanol (chromatographic grade, CNW, catalog number 4.016362.4000), acetonitrile (chromatographic grade, Merck, catalog number 1.00030.4008), NaH ₂ PO ₄ ·2H ₂ O (analytical grade, Sinopharm Chemical Reagent Co., Ltd., catalog number 20040717), ammonium acetate (chromatographic grade, Fluka Honeywell, catalog number 17836-250G), sodium taurocholate (98%, J&K Technology, catalog number 551055-25G), lecithin (≥99%, Sigma P3556-1G), sodium hydroxide (analytical grade, Sinopharm Chemical Reagent Co., Ltd., catalog number 10019718), sodium chloride (analytical grade, Sinopharm Chemical Reagent Co., Ltd., catalog number 10019318), hydrochloric acid (analytical grade, Sinopharm Chemical Reagent Co., Ltd., catalog number 10011018), glacial acetic acid (analytical grade, Sinopharm Chemical Reagent Co., Ltd., catalog number 10000218) and ultrapure water (made by ELGA CHORUS laboratory ultrapure water machine).

Instrument: Agilent 1200DAD liquid chromatograph (Agilent, USA)

2. Material preparation

2.1 Preparation of FassIF solution

Solution (A): Add 4.441 g NaH ₂ PO ₄ ·2H ₂ O, 0.348 g NaOH pellets and 6.186 g NaCl to 900 mL ultrapure water, mix well, add 1 M NaOH to adjust the pH of the solution to 6.5 ± 0.05, make up to 1000 mL with water, and refrigerate at 4°C for later use.

FaSSIF solution (B): Dissolve 0.161 g sodium taurocholate (NaTC) and 59 mg lecithin in 20 mL of solution (A), stir vigorously overnight to form a clear micellar solution, add solution (A) to the volume of 100 mL, and refrigerate at 4°C for use (no more than 2 weeks).

2.2 Preparation of FessIF solution

Solution (A): Accurately weigh 20.2 g NaOH pellets, 43.25 g glacial acetic acid and 59.37 g sodium chloride, dissolve them in appropriate amount of ultrapure water and make up to 5 L, adjust the pH to 5.0 with 1 M NaOH or 1 M HCl, and refrigerate at 4°C for later use.

FeSSIF solution (B): Dissolve 0.80652 g of sodium taurocholate (NaTC) and 295.5 mg of lecithin in 25 mL of solution (A). Stir vigorously overnight to form a clear micellar solution. Add solution (A) to make the volume 100 mL and refrigerate at 4°C for use (no more than 2 weeks).

3. Experimental steps

Dissolution tests in FassIF solution and FessIF solution.

3.1 Weigh an appropriate amount of the compound to be tested and use DMSO as solvent to prepare a 10mM stock solution. Accurately measure 10μL of the stock solution (concentration 10mM, dissolved in DMSO) and 990μL of an organic mixed solvent (usually DMSO: acetonitrile: ethanol = 1:1:1) in a 2mL sample bottle and mix well to obtain a clear 100μM sample solution as a reference solution.

3.2 Dissolve 1 mg of the sample to be tested in 900 μL FassIF solution (or FessIF solution), mix vigorously, and prepare two solutions in parallel; after shaking in a 37°C water bath for 24 hours, centrifuge at 12000 rpm for 30 minutes, and transfer the supernatant as the sample solution to liquid chromatography analysis.

4. Experimental results

Solubility (μM) = peak area of sample/peak area of reference × concentration of reference solution (μM) × dilution factor of sample solution.

The average of the two measured values was taken as the final solubility in FassIF solution and FessIF solution.

Table 3. Solubility of compounds of the present disclosure.

Compound No. FassIF solution (μM) FessIF solution (μM) Compound 1 54.56 141.86

Conclusion: The disclosed compounds have good solubility in both FassIF and FessIF solutions.

Claims (18)

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring B is a 5-membered heteroaryl group or a 5-membered heterocyclyl group; W is selected from C, CR ⁰ and N; R ⁰ is selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group and a hydroxyalkyl group; T is selected from bond, alkylene, -O-, -NR ^A -, -C(O)-, -S-, -S(O)-, -SO ₂ -, -C(S)-, and -P (O) ₂ -, wherein the alkylene group is optionally selected from one or more substituents selected from oxo group, deuterium atom, halogen, alkoxy group, haloalkoxy group, deuterated alkoxy group and hydroxyl group replaced; R ^A is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, -(CR ^a R ^b ) _m NR ^c R ^d , a cycloalkyl group, a cycloalkylalkyl group, and a heterocyclyl alkyl group. base; R ^1a , R ² and R ^2a are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a hydroxyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group and -OSO ₃ H; or R ² and R ^2a together form =O; R ¹ is selected from hydrogen atom, deuterium atom, halogen, alkyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkenyl group, alkynyl group, -(CR ^x R ^y ) _w OR ⁹ , -S(O) _s R ⁹ , -(CR ^x R ^y ) _w NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ⁹ , -C(O)OR ⁹ , -NR ¹² C(O)R ⁹ , -S(O) _s NR ¹⁰ R ¹¹ , -NR ¹² S(O) ₂ R ⁹ , cyano, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl Base, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R ^B ; R ³ is selected from hydrogen atom, alkyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkoxyalkyl group, -(CR ^a R ^b ) _m NR ^c R ^d , cycloalkylalkyl group, heterocyclyl group Alkyl, arylalkyl, heteroarylalkyl, cycloalkyl and heterocyclyl; Or R ¹ and R ³ together with the atoms to which they are attached form a heterocyclyl group; or R ¹ and R ² together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl group; or R ² and R ³ to the atoms to which they are attached Together, they form a heterocyclyl group; each of the cycloalkyl or heterocyclyl groups is independently optionally substituted with one or more R ^B ; R ⁵ is selected from hydrogen atom, deuterium atom, halogen, alkyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, cyano group, -OR ⁹ , -S(O) _s R ⁹ , -OSO ₃ H, -OSO ₂ R ⁹ , -OC(O)R ⁹ and -OP(O) ₂ OR ⁹ ; or, R ⁵ is a warhead group; Each R ⁴ and each R ⁶ are the same or different, and are each independently selected from an oxo group, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxy group, a haloalkoxy group, Alkoxyalkoxy, alkenyl, alkynyl, -OSO ₃ H, -(CR ^x R ^y ) _w OR ⁹ , -(CR ^x R ^y ) _w NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -OC(O)R ⁹ , -C(O)R ⁹ , -C(O)OR ⁹ , -NR ¹² C(O)R ⁹ , -NR ¹² C(O)OR ⁹ , -NR ¹² C (O)NR ¹⁰ R ¹¹ , -S(O) _s R ⁹ , -NR ¹² S(O) ₂ R ⁹ , cyano, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycle alkylalkyl, aryl and heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl Independently optionally substituted by one or more R ^B ; R ^B is the same or different on each occurrence and is each independently selected from oxo, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy , haloalkoxy, deuterated alkoxy, hydroxyl, cyano, nitro, alkoxyalkyl, -(CR ^h R ⁱ ) _v NR ^j R ^k , -S(O) _2alkyl , cycloalkyl , heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, aryloxy base and heteroaryloxy; R ⁷ and R ⁸ are the same or different, and are each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, hydroxyl, alkoxy, haloalkoxy, deuterated Alkoxy, alkoxyalkyl, cyano, amino, -NHalkyl and -N(alkyl) ₂ ; R ^a , R ^b , Rh , R ⁱ , R ^x and R ^y are the same or ^different on each occurrence, and are each independently selected from hydrogen atoms, deuterium atoms, halogens, alkyl groups, hydroxyl groups, haloalkyl groups, deuterated Alkyl and hydroxyalkyl; R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^c , R ^d , R ^j and R ^k are the same or different each time they appear, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, Cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl Base, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R ^C ; Or R ¹⁰ and R ¹¹ together with the attached nitrogen atom form a heterocyclyl group; the heterocyclyl group is optionally substituted by one or more R ^C ; R ^C is the same or different on each occurrence, and is each independently selected from oxo, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, Haloalkoxy, deuterated alkoxy, hydroxyl, cyano, nitro, alkoxyalkyl, amino, -NH alkyl, -N(alkyl) ₂ , cycloalkyl, heterocyclyl, aryl and heteroaryl; w and v are each independently 0, 1, 2, 3 or 4; m is 1, 2, 3 or 4; n is 0, 1, 2 or 3; s is 0, 1 or 2; and t is 0, 1, 2 or 3. 2. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^1a is a hydrogen atom; and/or R ^2a is a hydrogen atom; and/or R ² is a hydrogen atom. . 3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ^R7 is a hydrogen atom; and/or ^R8 is a hydrogen atom. 4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein ring A is a 6-membered heteroaryl group; preferably, ring A is a pyrimidinyl group . 5. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein ring B is a 5-membered heteroaryl, preferably pyrazolyl or 1, 2,4-triazolyl. 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: X is N or CR ^4a ; Y is N or CR ^4b ; R ¹ is selected from deuterium atom, halogen, alkyl group, haloalkyl group, deuterated alkyl group, hydroxyalkyl group, alkenyl group, alkynyl group, -(CR ^x R ^y ) _w OR ⁹ , -S(O) _s R ⁹ , -(CR ^x R ^y ) _w NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -C(O)R ⁹ , -C(O)OR ⁹ , -NR ¹² C(O)R ⁹ , - S(O) _s NR ¹⁰ R ¹¹ , -NR ¹² S(O) ₂ R ⁹ , cyano, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl Base, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R ^B ; R ^4a , R ^4b and R ^6a 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 hydroxyalkyl group, an alkoxyalkyl group, an alkoxy group, a haloalkoxy group, Alkoxyalkoxy, alkenyl, alkynyl, -OSO ₃ H, -(CR ^x R ^y ) _w OR ⁹ , -(CR ^x R ^y ) _w NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -OC(O)R ⁹ , -C(O)R ⁹ , -C(O)OR ⁹ , -NR ¹² C(O)R ⁹ , -NR ¹² C(O)OR ⁹ , -NR ¹² C (O)NR ¹⁰ R ¹¹ , -S(O) _s R ⁹ , -NR ¹² S(O) ₂ R ⁹ , cyano, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycle alkylalkyl, aryl and heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl independently optionally substituted by one or more R ^B ; and T, R ^B , R ³ , R ⁵ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^x , Ry ^, s and w are 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 T is -O- or -NH-; preferably, T is -O -. 8. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ¹ is C _1-6 alkyl; and/or R ³ is hydrogen atom. 9. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 8, wherein X is N or CR ^4a ; R ^4a is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and 3 to 6-membered cycloalkyl; and/or Y is N. 10. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ⁵ is halogen; preferably, R ⁵ is Cl. 11. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 10, wherein R ^6a is C _1-6 alkoxy C _1-6 alkyl, Preferred is -CH ₂ OCH ₂ CH ₃ or -CH ₂ OtBu. 12. A compound or a pharmaceutically acceptable salt thereof, which is selected from any of the following compounds: 13. A compound represented by general formula (IA) or a salt thereof: in: T is O or NR ^A ; Rings B, R ¹ , R ^1a , R ² , R ^2a , R ³ , R ⁴ , R ⁷ , R ⁸ , RA , ^W and n are as defined in claim 1 . 14. A compound or a salt thereof, which is selected from any of the following compounds: 15. A method for preparing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, the method comprising: A nucleophilic substitution reaction occurs between a compound represented by general formula (IA) or a salt thereof and a compound represented by general formula (IB) or a salt thereof, to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof; in: X ^L is a leaving group, preferably halogen, more preferably Cl; T is O or NR ^A ; Ring A, Ring B, R ¹ , R ^{1a , R 2 , R 2a , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , RA , W , n and t} are as claimed in claim 1 definition. 16. A pharmaceutical composition containing a compound represented by general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more Pharmaceutically acceptable carrier, diluent or excipient. 17. Use of the compound represented by general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 16 in the preparation of MK2 inhibitors . 18. The compound represented by the general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 16 when prepared for treatment and/or Use in medicines to prevent autoimmune disorders, chronic or acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplasia and cardiovascular or cerebrovascular disorders; said autoimmune disorders, chronic or acute inflammation Sexual 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, 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 testicularitis, autoimmune thrombocytopenia, systemic lupus erythematosus, vasculitis syndrome, hypophysitis, idiopathic platelet purpura, pemphigus, autoimmune deafness , meningitis, myocarditis, gingivitis, enterocolitis, sinusitis, uveitis, ophthalmitis, optic neuritis, gastric ulcer, esophagitis, peritonitis, radicular periostitis, dermatomyositis, gastritis, myositis and bronchitis ; The arthritis is preferably selected from the group consisting of rheumatoid arthritis (RA), osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis and spondyloarthritis.