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

Abstract

The present disclosure relates to fused tetracyclic compounds, methods of preparing the same, and their use in medicine. In particular, the present disclosure relates to fused tetracyclic compounds of general formula (I), methods for their preparation, pharmaceutical compositions containing them and their use as therapeutic agents, in particular as MK2 inhibitors and for the treatment and/or prophylaxis of autoimmune disorders, chronic or acute inflammatory disorders and autoinflammatory disorders.

Description

Fused tetracyclic compound, preparation method thereof and application thereof in medicines

Technical Field

The present disclosure belongs to the field of medicine, and relates to a fused tetracyclic compound, a preparation method thereof and application thereof in medicine. In particular, the present disclosure relates to fused tetracyclic compounds of general formula (I), methods for their preparation, pharmaceutical compositions containing them, their use as MK2 inhibitors and for the treatment and/or prophylaxis of autoimmune disorders, chronic or acute inflammatory disorders and autoinflammatory disorders.

Background

Inflammatory cytokines play an important role in the pathogenesis of autoimmune diseases. Antibodies neutralizing key inflammatory cytokines such as anti-tnfα have proven useful in the treatment of inflammatory diseases such as psoriasis, crohn's Disease (CD), rheumatoid Arthritis (RA), and spinal arthritis. Biological agents are currently administered parenterally and there is a risk of reduced efficacy over extended periods of time, and therefore, there is a need to develop new oral therapies for the treatment of inflammatory diseases.

p38 MAPK was identified in 1994 as a key regulator of inflammatory cytokine biosynthesis and numerous research and development institutions have carried out work on small molecule kinase inhibitors against p 38. Most p38 kinase inhibitors show efficacy in animal disease models but have been further developed clinically due to insufficient safety window. 3 p38 compounds entering clinical stage two, clinical trials were performed in patients with RA or CD, with a decrease in disease scores or biomarkers of inflammation observed at the initial stages of the trial, and then continued administration resulted in a rapid drug resistance response. This phenomenon was analyzed primarily because inhibition of p38, in addition to inhibiting inflammation, also activates the feedback mechanism of p 38. Given the important role of the p38 signaling pathway in cytokine biosynthesis, targeting p38 upstream or downstream pathway molecules may circumvent regulatory feedback and provide the long-lasting therapeutic benefits required to continuously inhibit inflammatory cytokines.

MAPK activated protein kinase 2 (MK 2) is a direct downstream substrate of p38, mediating the inflammatory process by increasing translation and stability of pro-inflammatory cytokine mRNA, including IL-6 and TNFa. Tristetraprolin (TTP) is a zinc finger protein that binds cytokine mRNAs with identical adenylate-uridylate rich elements (AREs) in 30 untranslated regions, destabilizing them to inhibit protein translation of these cytokines, whereas the human antigen R (HuR) acts in the opposite direction and stimulates translation. Activated MK2 phosphorylates TTP, resulting in substitution of TTP by HuR, thereby regulating cytokine production. In the MK2 knock-out mouse model, mice grew normally, against LPS-induced endotoxin shock, manifested by a decrease in TNF alpha, IL-6 and interferon gamma levels; in addition, knock-out MK2 in many models of inflammatory diseases, including collagen-induced arthritis models, may alleviate the occurrence or inflammatory levels of these diseases. MK2 is therefore a powerful target for the potential treatment of inflammation. Although there is no evidence that MK2 is in a complex feedback pathway, such as p38, its activation does activate signal feedback, limiting inflammation at TTP-regulated translation or mRNA stability levels.

Patent applications for MK2 inhibitors that have been published today are WO2016044463A2, WO2018170204A1, WO2018170201A1, WO2018170200A1, WO2014149164A1, etc.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by general formula (I):

wherein:

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring B is a 5 membered heteroaryl or a 5 membered heterocyclyl;

w is selected from C, CR ⁰ And N;

R ⁰ selected from the group consisting of 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 said alkylene group is optionally substituted with one or more substituents selected from oxo, deuterium atom, halogen, alkoxy, haloalkoxy, deuteroalkoxy and hydroxy;

R ^A selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, - (CR) ^a R ^b ) _m NR ^c R ^d Cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl;

R ^1a 、R ² and R is ^2a Identical or different and are each independently selected from the group consisting of 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 an-OSO ₃ H is formed; or R is ² And R is ^2a Together form = O;

R ¹ selected from hydrogen atoms, deuteriumAtom, halogen, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkenyl, alkynyl, - (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 said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R ^B Substitution;

R ³ selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, - (CR) ^a R ^b ) _m NR ^c R ^d Cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl and heterocyclyl;

or R is ¹ And R is ³ Together with the atoms to which each is attached, form a heterocyclic group; or R is ¹ And R is ² Forms a cycloalkyl or heterocyclyl group together with the carbon atom to which each is attached; or R is ² And R is ³ Together with the atoms to which each is attached, form a heterocyclic group; the cycloalkyl or heterocyclyl groups are each independently optionally substituted with one or more R ^B Substitution;

R ⁵ selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, a cyano, -OR ⁹ 、-S(O) _s R ⁹ 、-OSO ₃ H、-OSO ₂ R ⁹ 、-OC(O)R ⁹ and-OP (O) ₂ OR ⁹ The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, R ⁵ Is a warhead group;

each R is ⁴ And each R ⁶ Identical or different and are each independently selected from oxo, deuterium atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, 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, 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 Substitution;

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

R ⁷ and R is ⁸ The same or different and are each independently selected from the group consisting of 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, -NH alkyl group, and-N (alkyl group) ₂ ；

R ^a 、R ^b 、R ^h 、R ⁱ 、R ^x And R is ^y Is the same or different at each occurrence and is each independently selected from the group consisting of 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;

R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ^c 、R ^d 、R ^j And R is ^k At each occurrence of time phaseAnd are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, and heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl groups are each independently optionally substituted with one or more R ^C Substitution;

or R is ¹⁰ And R is ¹¹ Together with the nitrogen atom to which they are attached form a heterocyclic group; the heterocyclic groups optionally being substituted by one or more R ^C Substitution;

R ^C and are each independently selected from oxo, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuteroalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteroalkoxy, hydroxy, cyano, nitro, alkoxyalkyl, amino, -NH alkyl, -N (alkyl) at each occurrence 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 is also provided with

t is 0, 1, 2 or 3.

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

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

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein 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 of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ And R is ² Together with the carbon atoms to which each is attached, form a 4-to 7-membered cycloalkyl or 4-to 7-membered heterocyclyl, said 4-to 7-membered cycloalkyl or 4-to 7-membered heterocyclyl optionally being selected from halogen, C _1-6 Alkyl, C _1-6 One or more substituents in haloalkyl and hydroxy; preferably, R ¹ And R is ² Together with the carbon atoms to which each is attached, form a 4 to 7 membered cycloalkyl or 4 to 7 membered heterocyclyl.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² And R is ³ Together with the atoms to which each is attached, form a 4-to 7-membered heterocyclic group, said 4-to 7-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, C _1-6 One or more substituents in haloalkyl and hydroxy; preferably, R ² And R is ³ Together with the atoms to which each is attached, form a 4 to 7 membered heterocyclic group.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁷ Selected from the group consisting of hydrogen atom, deuterium atom, halogen and C _1-6 An alkyl group; preferably, R ⁷ Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁸ Selected from the group consisting of hydrogen atom, deuterium atom, halogen and C _1-6 An alkyl group; preferably, R ⁸ Is a hydrogen atom.

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

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring a is 6 membered heteroaryl; 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 of formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from->Preferably isR ^6a 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 R ^B Substitution; and R is ^x 、R ^y 、R ^B 、R ⁵ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² W and s are as defined in formula (I); in some embodiments, the->Is->In some embodiments, the->Is->

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

In some embodiments of the present disclosure, the compound of 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 of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 5 membered heteroaryl; 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 of formula (I) or a pharmaceutically acceptable salt thereof, whereinSelected from->Preferably +.> More preferably +.>Wherein the bond is attached to T; r is R ^4a And R is ^4b Identical or different and are each independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, 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, 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 Substitution; and R is ^x 、R ^y 、R ^B 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² W and s are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II):

wherein:

x is N or CR ^4a ；

Y is N or CR ^4b ；

R ¹ Selected from deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, - (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 said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups Each independently optionally substituted with one or more R ^B Substitution;

R ^4a 、R ^4b and R is ^6a Identical or different and are each independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, 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, 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 Substitution; and is also provided with

T、R ^B 、R ³ 、R ⁵ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ^x 、R ^y S and w are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^A Is a hydrogen atom or C _1-6 An alkyl group; preferably, R ^A Is a hydrogen atom.

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

In some embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl and C _1-6 Deuterated alkyl; preferably, R ¹ Selected from C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Deuterated alkyl; further preferably, R ¹ Is C _1-6 An alkyl group; more preferably, R ¹ Is methyl.

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

In some embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R ¹ Is C _1-6 An alkyl group; and/or R ³ Is a hydrogen atom. In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ Is C _1-6 Alkyl, R ³ Is a hydrogen atom; alternatively, R ¹ And R is ³ Together with the atoms to which each is attached, form a 5-to 8-membered heterocyclic group, said 5-to 8-membered heterocyclic group optionally being selected from halogen, C _1-6 Alkyl, C _1-6 One or more substituents in haloalkyl and hydroxy; preferably, R ¹ Is C _1-6 Alkyl, R ³ Is a hydrogen atom, or R ¹ And R is ³ Together with the atoms to which each is attached, form a 5-to 8-membered heterocyclic group.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R ⁴ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R ⁴ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R ⁴ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ⁴ Is C _1-6 An alkyl group; more preferably, R ⁴ Is methyl; in some embodiments, each R ⁴ The same or different and are each independently selected from F, cl, methyl and cyclopropyl.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^4a Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, R ^4a Selected from hydrogen atoms, halogen, C _1-6 Alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R ^4a Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ^4a Is a hydrogen atom or C _1-6 An alkyl group; more preferably, R ^4a Is a hydrogen atom or a methyl group; in some embodiments, R ^4a Selected from the group consisting of hydrogen atoms, F, cl, methyl and cyclopropyl.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^4b Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein X is N or CR ^4a ；R ^4a Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, X is N or CR ^4a ；R ^4a Selected from hydrogen atoms, halogen, C _1-6 Alkyl and 3 to 6 membered cycloalkyl; in some embodiments, X is N or CR ^4a ；R ^4a Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; in some embodiments, X is CR ^4a ；R ^4a As defined in formula (II); in some embodiments, X is selected from N, CH, C-CH ₃ C-F, 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 of formula (II) or a pharmaceutically acceptable salt thereof, wherein Y is N. In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, whereinX is N or CR ^4a ；R ^4a Selected from hydrogen atoms, 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 Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; and/or Y is N; in some embodiments, X is N or CR ^4a ；R ^4a Selected from hydrogen atoms, 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 of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is-S (O) _s R ⁹ Or halogen; s and R ⁹ As defined in 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 of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein s is 0 or 2.

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

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

In some embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is a warhead group; preferably, R ⁵ Selected from the group consisting of More preferably, R ⁵ Is->

In some embodiments of the present disclosure, the compound of 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 of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^B Selected from deuterium atoms, halogens, C _1-6 Alkyl, C _1-6 Haloalkyl, hydroxy, C _1-6 Alkoxy and C _1-6 Haloalkoxy groups; wherein said C _1-6 Alkoxy is preferably-OCH ₂ CH ₃ or-OtBu.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁶ Selected from cyano, nitro, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy C _1-6 Alkyl and C _1-6 Alkoxy C _1-6 An alkoxy group; preferably, R ⁶ Is C _1-6 Alkoxy C _1-6 An alkyl group; more preferably, R ⁶ is-CH ₂ OCH ₂ CH ₃ or-CH ₂ OtBu。

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^6a Selected from hydrogen atom, cyano group, nitro group, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy C _1-6 Alkyl and C _1-6 Alkoxy C _1-6 An alkoxy group; preferably, R ^6a Is C _1-6 Alkoxy C _1-6 An 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 of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ Is C _1-6 Alkyl, R ² Is a hydrogen atom, R ³ Is a hydrogen atom; or R is ¹ Is C _1-6 Alkyl, R ² And R is ³ Together with the atoms to which each is attached, form a 4 to 7 membered heterocyclyl; or R is ² Is a hydrogen atom, R ¹ And R is ³ Together with the carbon atoms to which each is attached, form a 5-to 8-membered heterocyclic group; or R is ³ Is a hydrogen atom, R ¹ And R is ² Together with the carbon atoms to which each is attached, form a 4 to 7 membered cycloalkyl or 4 to 7 membered heterocyclyl; preferably, R ¹ Is C _1-6 Alkyl, R ² Is a hydrogen atom, R ³ Is a hydrogen atom; more preferably, R ¹ Is methyl, R ² Is a hydrogen atom, R ³ Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring a is pyrimidinyl;is->Wherein the bond is attached to T; t is-O-; r is R ^4a Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl; r is R ^1a Is a hydrogen atom; r is R ^2a Is a hydrogen atom; r is R ¹ Is C _1-6 An alkyl group; r is R ² Is a hydrogen atom; r is R ³ Is a hydrogen atom; r is R ⁵ Is halogen; r is R ⁶ Is C _1-6 Alkoxy C _1-6 An alkyl group; r is R ⁷ Is a hydrogen atom; r is R ⁸ Is a hydrogen atom; t is 1.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring a is 6 membered heteroaryl;selected from->Wherein the bond is attached to T; t is-O-or-NH-; r is R ^4a Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; r is R ^4b Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; r is R ^1a Is a hydrogen atom; r is R ^2a Is a hydrogen atom; r is R ¹ Is C _1-6 Alkyl, R ² Is a hydrogen atom, R ³ Is a hydrogen atom; or R is ¹ Is C _1-6 Alkyl, R ² And R is ³ Together with the atoms to which each is attached, form a 4 to 7 membered heterocyclyl; or R is ² Is a hydrogen atom, R ¹ And R is ³ Together with the carbon atoms to which each is attached, form a 5-to 8-membered heterocyclic group; or R is ³ Is a hydrogen atom, R ¹ And R is ² Together with the carbon atoms to which each is attached, form a 4 to 7 membered cycloalkyl or 4 to 7 membered heterocyclyl; r is R ⁵ Is halogen; r is R ⁶ Is C _1-6 Alkoxy C _1-6 An alkyl group; r is R ⁷ Is a hydrogen atom; r is R ⁸ Is a hydrogen atom; t is 1.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein T is-O-or-NH-; x is N or CR ^4a ；R ^4a Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; y is N; r is R ¹ Is C _1-6 An alkyl group; r is R ³ Is a hydrogen atom; r is R ⁵ Is halogen; r is R ^6a Is C _1-6 Alkoxy C _1-6 An alkyl group.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein T is-O-; x is N or CR ^4a ；R ^4a Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl; y is N; r is R ¹ Is C _1-6 An alkyl group; r is R ³ Is a hydrogen atom; r is R ⁵ Is halogen; r is R ^6a Is C _1-6 Alkoxy C _1-6 An alkyl group.

Table a typical compounds of the present disclosure include, but are not limited to:

the present disclosure provides a compound represented by the general formula (IA):

wherein:

t is O or NR ^A ；

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

The present disclosure provides a compound represented by the general formula (IIA):

wherein:

t is O or NR ^A ；

X、Y、R ¹ 、R ³ And R is ^A As defined in the general formula (II)。

Table B typical intermediate compounds of the present disclosure 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:

nucleophilic substitution reaction is carried out between the compound shown in the general formula (IA) or salt thereof and the compound shown in the general formula (IB) or salt thereof to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof;

wherein:

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 、R ^A W, n and t are as defined in 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:

carrying out nucleophilic substitution reaction on a compound shown in a general formula (IIA) or salt thereof and a compound shown in a general formula (IIB) or salt thereof to obtain a compound shown in a general formula (II) or pharmaceutically acceptable salt thereof;

Wherein:

X ^L is a leaving group, preferably halogen, more preferably Cl;

t is O or NR ^A ；

X、Y、R ¹ 、R ³ 、R ⁵ 、R ^6a And R is ^A As defined in formula (II).

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

The disclosure further relates to the use of a compound of formula (I) or formula (II) and a compound shown in 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 a compound of formula (I) or formula (II) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder mediated by MK 2.

The present disclosure further relates to the use of a compound of formula (I) or formula (II) and table a or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the manufacture of a medicament for the treatment and/or prevention of autoimmune disorders, chronic or acute inflammatory disorders, auto-inflammatory disorders, fibrotic disorders, metabolic disorders, neoplasias and cardiovascular or cerebrovascular disorders.

The present disclosure further relates to a method of inhibiting MK2 comprising administering to a patient in need thereof a compound of formula (I) or formula (II) as well as a compound 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 of treating and/or preventing a disease or disorder mediated by MK2, comprising administering to a patient in need thereof an inhibitory effective amount of a compound of formula (I) or formula (II) as well as a compound 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 of treating and/or preventing autoimmune disorders, chronic or acute inflammatory disorders, auto-inflammatory 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 a compound of formula (a) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a compound of formula (I) or formula (II) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to a compound of formula (I) or formula (II) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an MK2 inhibitor.

The present disclosure further relates to a compound of formula (I) or formula (II) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of a disease or disorder mediated by MK 2.

The present disclosure further relates to a compound of formula (I) or formula (II) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of autoimmune disorders, chronic or acute inflammatory disorders, autoimmune inflammatory disorders, fibrotic disorders, metabolic disorders, neoplasia and cardiovascular or cerebrovascular disorders.

The present disclosure further relates to a compound of formula (I) or formula (II) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of autoimmune disorders, chronic or acute inflammatory disorders, autoimmune inflammatory disorders, fibrotic disorders, metabolic disorders, neoplasia and cardiovascular or cerebrovascular disorders.

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

Preferably, the MK2 mediated disease or disorder described in the present disclosure is selected from the group consisting of autoimmune disorders, chronic or acute inflammatory disorders, and auto-inflammatory disorders.

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

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

The autoimmune disorders, chronic or acute inflammatory disorders and autoimmune inflammatory disorders described in the present disclosure are preferably selected from the group consisting of 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), cryptomelane-related periodic syndrome, mu Keer-Wells syndrome (Muckel-Wells syndrome), familial cold-induced autoimmune inflammatory syndrome, neonatal multiple system inflammatory disease, TNF receptor-related periodic syndrome, acute and chronic pancreatitis, atherosclerosis, gout, fibrotic disorders, liver fibrosis, idiopathic pulmonary disease, kidney disease, sarcoidosis, scleroderma, systemic anaphylaxis diabetes mellitus (type 1 diabetes mellitus, type 2 diabetes mellitus), diabetic retinopathy, still's disease, sarcoidosis, pulmonary 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 testing, autoimmune thrombocytopenia, silicone implant-related autoimmune disease, sjogren's syndrome, familial mediterranean fever, systemic lupus erythematosus, temporal arteritis, takayasu's arteritis and giant cell arteritis, behcet's disease, wegener's granulomatosis, sjogren's disease, white spot disease, secondary blood expression to autoimmune disease, anemia, drug-induced autoimmunity, hashimoto's thyroiditis (Hashimoto's thyroiditis), vasculitis Syndrome, pituitary inflammation, idiopathic thrombocytopenic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune deafness, meniere's disease, goodpasture's Syndrome, graves 'disease, HW-related autoimmune Syndrome, grignard-Barre disease (Gullain-Barre disease), addison's disease, antiphospholipid Syndrome, atopic dermatitis, celiac disease, cushing's Syndrome, dermatomyositis, idiopathic adrenal atrophy idiopathic thrombocytopenia, kawasaki Syndrome (Kawasaki Syndrome), lanbert-Eaton Syndrome (Lambert-Eaton Syndrome), pernicious anemia, pollinosis, polyarteritis nodosa, primary biliary cirrhosis, primary sclerosing cholangitis, lei Laode's disease, lyter's Syndrome, recurrent polychondritis, schmidt's Syndrome, thyrotoxicosis, sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, gram-negative sepsis (gram negative sepsis), toxic shock Syndrome, silk spheroid nephritis, peritonitis, interstitial cystitis, oxygen-hyperstimulation-induced inflammation, graft-versus-host reaction, graft-versus-host disease, allograft rejection, acute allograft rejection, chronic allograft rejection, early stage graft rejection, acute allograft rejection, reperfusion injury, pain (preferably acute pain, chronic pain, neuralgia, fibromyalgia), chronic infection, meningitis, encephalitis, myocarditis, gingivitis, post-operative trauma, tissue injury, traumatic brain injury, enterocolitis, sinusitis, uveitis, ophthalmitis, optic neuritis, gastric ulcers, esophagitis, peritonitis, tooth 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), asthma, chronic Obstructive Pulmonary Disease (COPD), cryptopyretic protein-related periodic syndrome, mu Keer-Wecke-Wells syndrome, familial cold-induced autoimmune inflammatory syndrome, neonatal onset multisystemic inflammatory disease, TNF receptor-related 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 testicular inflammation, autoimmune thrombocytopenia, systemic lupus erythematosus, vasculitis syndrome, pituitary inflammation, idiopathic thrombocytopenic purpura, pemphigus, autoimmune immunositis, meningitis, gingivitis, myocarditis, myositis, gastritis, esophagitis, gastroenteritis, peritonitis, gastritis, and other diseases.

The arthritis is preferably selected from the group consisting of Rheumatoid Arthritis (RA), osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis and spondyloarthritis.

The fibrotic condition described in the present disclosure is preferably selected from systemic sclerosis/scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, 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 kidney disease, digestive or gastrointestinal fibrosis, kidney fibrosis, liver or gall fibrosis, liver fibrosis, non-alcoholic steatohepatitis, hepatitis C, hepatocellular carcinoma, liver cirrhosis, primary biliary cirrhosis liver cirrhosis caused by fatty liver disease, liver cirrhosis caused by alcoholic fatty liver disease, liver cirrhosis caused by non-alcoholic steatosis/non-alcoholic fatty liver disease, radiation induced fibrosis, head and neck fibrosis, gastrointestinal fibrosis, pulmonary fibrosis, primary sclerosing cholangitis, restenosis, heart fibrosis, endocardial myocardial fibrosis, atrial fibrosis, ophthalmic scarring, fibrosis, fibrotic cancer, fibroids, fibromas, fibroadenomas, fibrosarcomas, graft arterial disease, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive mass fibrosis and nephrogenic systemic fibrosis.

The metabolic disorders described in the present disclosure are preferably selected from obesity, steroid resistance, glucose intolerance and metabolic syndrome.

The neoplasia described in the present disclosure is preferably selected from angiogenic disorders, multiple myeloma, leukemia, acute lymphoblastic leukemia, acute and chronic myelogenous leukemia, chronic lymphoblastic leukemia, acute lymphoblastic leukemia, promyelocytic leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, burkitt's lymphoma, mast cell tumor, hodgkin's disease, non-Hodgkin's disease, myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, neuroglioma, T-cell lymphoma, hodgkin's lymphoma schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer, kaposi's sarcoma, melanoma, teratoma, rhabdomyosarcoma, metastatic and skeletal disorders, bone, oral/throat, esophagus, larynx, stomach, intestine, colon, rectum, lung, liver, pancreas, nerves, brain, head and neck, throat, ovary, uterus, prostate, testicular, bladder, kidney, breast, gall bladder, cervix, thyroid, prostate and skin cancers, non-small cell lung cancer, glioma and glioblastoma multiforme.

Described in the present disclosure are cardiovascular or cerebrovascular disorders preferably selected from atherosclerosis, restenosis of atherosclerotic coronary arteries, acute coronary syndrome, myocardial infarction, myocardial allograft vascular lesions, 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 compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure may 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 guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.

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

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations 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 oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant 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 preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure 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 may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health 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 optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, 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., C _1-20 Alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C _1-12 Alkyl groups), more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-butylPentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. The alkyl 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 atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a divalent alkyl group, where alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C _1-20 An alkylene group). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C _1-12 Alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C _1-6 An alkylene group). Non-limiting examples include: -CH ₂ -、-CH(CH ₃ )-、-C(CH ₃ ) ₂ -、-CH ₂ CH ₂ -、-CH(CH ₂ CH ₃ )-、-CH ₂ CH(CH ₃ )-、-CH ₂ C(CH ₃ ) ₂ -、-CH ₂ CH ₂ CH ₂ -、-CH ₂ CH ₂ CH ₂ CH ₂ -and the like. 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 atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C _2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C _2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where alkyl is as defined above having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C _2-12 Alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C _2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy 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 atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, full-carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic (i.e., polycyclic cycloalkyl) system 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 group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8 membered cycloalkyl group), most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6 membered cycloalkyl group) or a cycloalkyl group having 4 to 7 ring atoms (i.e., a 4 to 7 membered cycloalkyl group).

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

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

The term "spirocycloalkyl" refers to a polycyclic ring system having one or more carbon atoms (referred to as spiro atoms) shared between the rings, which may contain one or more double bonds within the ring, or which may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., to form a nitroxide; the sulfur may optionally be oxo, i.e., to form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-S-), provided that at least one full carbocyclic ring is contained and the point of attachment is on the full carbocyclic ring, 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., 5 to 20 membered spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spirocycloalkyl group), more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered spirocycloalkyl group). The spirocycloalkyl group includes a mono-spirocycloalkyl group and a multi-spirocycloalkyl group (e.g., a double spirocycloalkyl group, etc.), preferably a mono-spirocycloalkyl group or a double spirocycloalkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered single spirocycloalkyl group. Non-limiting examples include:

The connection point can be at any position;

etc.

The term "fused ring alkyl" refers to a polycyclic ring system having two adjacent carbon atoms shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl fused to one or more of a heterocyclyl, aryl, or heteroaryl group, wherein the point of attachment is on the monocyclic cycloalkyl group, which may contain one or more double bonds within the ring, and 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., 5 to 20 membered fused ring alkyl groups). The condensed ring alkyl group is preferably a condensed ring alkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered condensed ring alkyl group), more preferably a condensed ring alkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered condensed ring alkyl group). The condensed ring alkyl group includes a bicyclic condensed ring alkyl group and a polycyclic condensed ring alkyl group (e.g., a tricyclic condensed ring alkyl group, a tetracyclic condensed ring alkyl group, etc.), preferably a bicyclic condensed ring alkyl group or a tricyclic condensed ring alkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, or 7-membered/6-membered bicyclic condensed ring alkyl group. Non-limiting examples include: The connection point can be at any position; Etc.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system having two carbon atoms in common between the rings that are not directly attached, which may contain one or more double bonds within the ring, and which has from 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., a 5 to 20 membered bridged cycloalkyl). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10 membered bridged cycloalkyl group). The bridged cycloalkyl group includes a bicyclic bridged cycloalkyl group and a polycyclic bridged cycloalkyl group (e.g., a tricyclic bridged cycloalkyl group, a tetracyclic bridged cycloalkyl group, etc.), preferably a bicyclic bridged cycloalkyl group or a tricyclic bridged cycloalkyl group. Non-limiting examples include:the connection point can be at any position.

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they 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, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1,2,3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., forming a nitroxide; the sulfur may optionally be oxo, i.e., forming a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-), and having from 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 heterocyclyl) within the ring. The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12 membered heterocyclic group); further preferred are heterocyclyl groups having 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl groups); 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 preferred are heterocyclyl groups having 5 or 6 ring atoms (i.e., 5 or 6 membered heterocyclyl groups).

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

The polycyclic heterocyclic group includes spiro heterocyclic group, condensed heterocyclic group and bridged heterocyclic group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system having one or more double bonds shared between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-) with the proviso that at least one monocyclic heterocyclic ring is contained and the point of attachment is on the monocyclic heterocyclic ring, 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., 5 to 20 membered spiroheterocyclic groups). The spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spiroheterocyclyl group), more preferably a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered spiroheterocyclyl group). The spiroheterocyclyl group includes a mono-spiroheterocyclyl group and a multi-spiroheterocyclyl group (e.g., a double-spiroheterocyclyl group, etc.), preferably a mono-or double-spiroheterocyclyl group, more preferably a 3/4-, 3/5-, 3/6-, 4/4-, 4/5-, 4/6-, 5/3-, 5/4-, 5/5-, 5/6-, 5/7-, 6/3-, 6/4-, 6/5-, 6/6-, 6/7-, 7/5-or 7-membered mono-spiroheterocyclyl group. Non-limiting examples include:

Etc.

The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system having two adjacent atoms shared between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur within the ring (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-), which is a monocyclic heterocyclic group fused to one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused to one or more of cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on a monocyclic heterocyclic group 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 heterocyclic groups). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes a bicyclic and polycyclic fused heterocyclic group (e.g., a tricyclic fused heterocyclic group, a tetracyclic fused heterocyclic group, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered bicyclic fused heterocyclic group. Non-limiting examples include:

Etc.

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system having two atoms not directly connected between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-or-S-), 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., 5 to 20 membered bridged heterocyclyl). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10 membered bridged heterocyclic group). The number of constituent rings may be classified into a bicyclic bridged heterocyclic group and a polycyclic bridged heterocyclic group (e.g., a tricyclic bridged heterocyclic group, a tetracyclic bridged heterocyclic group, etc.), with a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group being preferred. Non-limiting examples include:

etc.

The heterocyclic 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 atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having from 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14 membered aryl) having a conjugated pi electron system. The aryl group is preferably an aryl group having 6 to 10 ring atoms (i.e., a 6 to 10 membered aryl group). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of such polycyclic aryl groups include: naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes a phenyl group fused to one or more of a heterocyclic group or a cycloalkyl group, or a naphthyl group fused to one or more of a heterocyclic group or a cycloalkyl group, wherein the point of attachment is on the phenyl or naphthyl group, and in such cases the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

etc.

Aryl groups may be substituted or unsubstituted, and when substituted, they 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, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a monocyclic heteroaryl ring having a conjugated pi electron system (i.e., a monocyclic heteroaryl group) or a polycyclic heteroaryl ring system (i.e., a polycyclic heteroaryl group) containing at least one (e.g., 1, 2, 3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-) within the ring having 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 group). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10 membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6 membered heteroaryl group).

Non-limiting examples of such monocyclic heteroaryl groups include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridones (e.g.)Etc.), pyrazinyl, pyridazinyl, etc.

Non-limiting examples of such polycyclic heteroaryl groups include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more of a cycloalkyl or heterocyclic group, where the point of attachment is on the monocyclic heteroaryl ring, and in such a case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

Etc.

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they 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, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "amino protecting group" refers to an easily removable group introduced on an amino group in order to keep the amino group unchanged when the reaction is performed at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyloxycarbonyl (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, and the like.

The term "hydroxy protecting group" refers to an easily removable group introduced on a hydroxy group for blocking or protecting the hydroxy group to react on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

The term "warhead group" refers to a functional group present on a compound of the present disclosure that is capable of covalently binding to an amino acid residue (e.g., cysteine, lysine, histidine, or other residue that can be covalently modified) present in a binding pocket of a target protein, thereby inhibiting the protein. Non-limiting examples of warhead groups include:

the compounds of the present disclosure comprise a compound represented by R as described herein ⁵ Is a warhead group of (a). Without wishing to be bound by any particular theory, it is believed that such R ⁵ The group (i.e., the warhead group) is particularly suitable for covalent binding to a critical cysteine residue in the binding domain of MK2 kinase. One of ordinary skill in the art will appreciate that MK2 kinases and mutants thereof 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 facilitates covalent modification of the cysteine by the warhead group.

In some embodiments, a compound of the invention includes a warhead group, wherein the compound provided covalently modifies Cys140 of MK 2.

In certain embodiments, a compound of the invention comprises a warhead group, wherein the compound covalently modifies a target of Cys140 of MK2, thereby inhibiting a kinase.

The term "target protein" refers to proteins and peptides having any biological function or activity, including structure, regulation, hormone, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In some embodiments, the target protein comprises a structural protein, a receptor, an enzyme, a cell surface protein, a protein associated with an integrated function 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 transduction factor activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulatory reactions, behavioral proteins, cell adhesion proteins, proteins 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, pathogenic agents, concomitant protein regulator activity, nucleic acid binding activity, transcriptional regulator activity, extracellular architecture and biological origin activity, translation regulator activity. The proteins include proteins from eukaryotes and prokaryotes including microorganisms, viruses, fungi and parasites and numerous others including humans, microorganisms, viruses, fungi and parasites targeted for pharmacotherapy, other animals including domestic animals), microorganisms and other antimicrobial agents of the subject gram and plants and even viruses for the determination of antibiotics and numerous others.

The term "leaving group", or "leaving group", is used in the term nucleophilic substitution reaction and elimination reaction as an atom or functional group that is released from a larger molecule in a chemical reaction. In nucleophilic substitution reactions, the reactant that is attacked by a nucleophile is referred to as a substrate (substrate), and the atom or group of atoms that breaks away from a pair of electrons in the substrate molecule is referred to as a leaving group. Groups that accept electrons easily and bear a strong negative charge are good leaving groups. The smaller the pKa of the leaving group conjugate acid, the easier the leaving group will be to disengage from the other molecule. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to be bound to other atoms, and the tendency to exist in anionic (or charge neutral leaving group) form is enhanced. Common leaving groups include, but are not limited to, halogen, -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: -CH ₂ OCH ₃ 、-CH ₂ OCH ₂ CH ₃ and-CH ₂ OtBu。

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, where alkyl and cycloalkyl are as defined above.

The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, where 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 aryl-O-, wherein 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 the alkoxy group 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 "deuteroalkoxy" 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 hydroxyl 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-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

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

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 pharmaceutical composition is in a unit dose of 0.001mg to 1000mg.

In certain embodiments, the pharmaceutical composition comprises 0.01 to 99.99% of the foregoing compound, or a pharmaceutically acceptable salt or isotopic substitution thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical compositions comprise 0.1-99.9% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substitutions thereof. In certain embodiments, the pharmaceutical compositions comprise 0.5% to 99.5% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substituents thereof. In certain embodiments, the pharmaceutical compositions comprise 1% to 99% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substituents thereof. In certain embodiments, the pharmaceutical compositions comprise 2% to 98% of the foregoing compounds, or pharmaceutically acceptable salts or isotopic substitutions thereof.

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

The compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to an isomer that is identical in structure but differs in the arrangement 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, conformational isomers and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may present additional asymmetric atoms. All such stereoisomers, and mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is performed by conventional methods well known in the art to give the pure isomer. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structure of the compounds of the present disclosure, the bondIndicating the unspecified configuration, i.e.the bond +.>Can be +.>Or->Or at the same time contain->And->Two configurations. For all carbon-carbon double bonds, Z and E are included even if only one configuration is named.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any proportions. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. Examples of the lactam-lactam balance are shown below:

as reference to pyrazolyl, it is understood to include mixtures of either or both tautomers of either of the following structures:

all tautomeric forms are within the scope of the disclosure, and the naming of the compounds does not exclude any tautomers.

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

Compared with non-deuterated medicines, deuterated medicines have the advantages of reducing toxic and side effects, increasing medicine stability, enhancing curative effect, prolonging biological half-life of medicines and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein replacement of deuterium may be partial or complete, with partial replacement of deuterium meaning that at least one hydrogen is replaced by at least one deuterium.

When a position of a compound of the present disclosure is specifically designated as "deuterium" or "D", that position is understood to mean that the abundance of deuterium is at least 1000-fold 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 per 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 per 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 per 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 per 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 per 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 per 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 per designated deuterium atom is at least 4500-fold greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per 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 per 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 per 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 per 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 per 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 per 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 per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation).

"optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that it includes instances where the event or circumstance occurs or does not. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"substituted" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated bonds (e.g., alkenes).

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. May be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate groups with an appropriate 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 and organic acids.

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

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

scheme one

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises the steps of:

a nucleophilic substitution reaction is carried out between a compound shown in a general formula (IA) or a salt thereof and a compound shown in a general formula (IB) or a salt thereof under an alkaline condition, so as to obtain a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

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 、R ^A W, n and t are as defined in formula (I).

Scheme II

A process for the preparation of a compound of formula (II) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises the steps of:

a nucleophilic substitution reaction is carried out between a compound shown in a general formula (IIA) or a salt thereof and a compound shown in a general formula (IIB) or a salt thereof under an alkaline condition, so as to obtain a compound shown in a general formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

X ^L is a leaving group, preferably halogen, more preferably Cl;

t is O or NR ^A ；

X、Y、R ¹ 、R ³ 、R ⁵ 、R ^6a And R is ^A As defined in formula (II).

The reagent for providing alkaline conditions includes organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the inorganic base includes, but is 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 agent that provides alkaline conditions is potassium carbonate, more preferably anhydrous potassium carbonate.

The above reaction is preferably carried out in a solvent, including but 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-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

MS was determined using an Agilent 1200/1290DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS).

waters ACQuity UPLC-QD/SQD (manufacturers: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

Thermo Ultimate 3000-Q actual (manufacturer: thermo, MS model: THERMO Q Exactive)

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatography.

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

The high performance liquid phase was prepared by using a Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

The known starting materials of the present invention may be synthesized using or following methods known in the art, or may be purchased from the companies ABCR GmbH & Co.KG, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemical, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: the volume ratio of the petroleum ether to the ethyl acetate is adjusted according to the polarity of the compound, and small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like can 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

Methyl 3-aminothiophene [3,2-c ] pyridine-2-carboxylate 1a (3 g,14.41mmol, le-ground) was dissolved in acetonitrile (75 mL), cooled to 0℃under nitrogen protection with stirring, 2.6mL of t-butyl nitrite (2.23 g,21.61mmol, shao-d) was slowly added dropwise, stirring was continued at 0℃for 2 hours, copper bromide (3.86 g,17.29mmol, shao-d) was added, and stirring was continued at room temperature for 3 hours. The reaction solution was added to 200mL of water, extracted with a 2% methanol solution in methylene chloride (200 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system C to give the title compound 1b (440 mg, yield: 11.22%).

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

Second step

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 0deg.C under nitrogen, and m-chloroperoxybenzoic acid (319 mg,2.42mmol, hadamard) was added in portions and stirred for 3 hours at 30℃with natural temperature increase. 20mL of ice water was added, pH was adjusted to 8 with saturated sodium carbonate solution, extracted with methylene chloride (20 mL. Times.2), the organic phases were combined, washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system A to give the title compound 1c (393 mg, yield: 84.36%).

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

Third step

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

In a dry nitrogen-filled flask, compound 1c (393 mg,1.36 mmol) and tert-butyl- (1-methoxyethyleneoxy) -dimethylsilane (514 mg,2.73mmol, lem) were dissolved in anhydrous tetrahydrofuran (10 mL), N-diisopropylethylamine (529 mg,4.09mmol, aldamas) and tripyrrolidinylphosphonium bromide hexafluorophosphate (699 mg,1.50mmol, aldamas) were added with stirring at room temperature and stirred for 2 hours at room temperature. 15mL of ice water and 15mL of methylene chloride were added and stirred for delamination, the organic phase was taken, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system C to give the title compound 1d (280 mg, yield: 59.64%).

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

Fourth step

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

Compound 1d (280 mg, 813.5. Mu. Mol) was dissolved in N, N-dimethylformamide (5 mL), O- (2, 4-dinitrophenyl) hydroxylamine (162 mg, 813.5. Mu. Mol, obtained) was added with stirring, and the mixture was heated to 60℃and stirred for 48 hours. Concentrated, slurried with 10mL ethyl acetate and 10mL petroleum ether, filtered, and the filter cake dried in vacuo to give the title compound 1e (266 mg, yield: 99.9%).

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

Fifth step

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

Compound 1e (266 mg, 813.1. Mu. Mol), anhydrous potassium carbonate (337 mg,2.4mmol, national drug) and sodium iodide (122 mg, 813.1. Mu. Mol, shao) were added to N, N-dimethylformamide (5 mL), benzyl bromide (139 mg, 813.1. Mu. Mol, adamas) was slowly added dropwise with stirring, and the mixture was heated to 90℃and stirred for 16 hours. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system C to give the title compound 1f (180 mg, yield: 53.05%).

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

Sixth step

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

Compound 1f (180 mg, 431.4. Mu. Mol) and tert-butyl N- [ (1R) -2-amino-1-methylethyl ] carbamate (113 mg, 647.05. Mu. Mol, bi) were dissolved in toluene (6 mL), anhydrous cesium carbonate (281mg, 862.7. Mu. Mol, aldamas) was added, the gas in the system was replaced with nitrogen three times, tris (dibenzylideneacetone) dipalladium (40 mg, 43.1. Mu. Mol, bi) and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (27 mg, 43.1. Mu. Mol, O. Sha) were added, the gas in the system was replaced with nitrogen three times again, and the reaction solution was heated to 110℃and stirred for 16 hours. The residue obtained was purified by column chromatography with eluent system C to give the title compound 1g (150 mg, yield: 68.1%).

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

Seventh step

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

1g (150 mg, 293.8. Mu. Mol) of the compound was dissolved in methylene chloride (4.5 mL), cooled to 0℃under nitrogen, and 0.6mL of trifluoroacetic acid (921 mg,8.1mmol, aldamax) was slowly added dropwise thereto, and the mixture was stirred for 2 hours at 25℃with natural temperature rise. Concentration, dissolution in methylene chloride and concentration under reduced pressure gave the title compound as trifluoroacetate salt (154 mg, yield: 99.9%) for 1h, which was dried under vacuum.

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

Eighth step

(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] diazepin-8-one 1i

In a dry flask, compound 1h of trifluoroacetate (154 mg, 293.6. Mu. Mol) was dissolved in methanol (5 mL), sodium methoxide (79.3 mg,1.5mmol, hadamard) was added with stirring at room temperature, and the mixture was heated to 90℃and stirred for 12 hours. Concentrated, diluted with 15mL of water, stirred, extracted with ethyl acetate (15 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound 1i (111 mg, yield: 99.9%) as the residue was purified by column chromatography using eluent system C.

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

Ninth step

(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. Mu. Mol) was dissolved in anhydrous methanol (6 mL), 10% palladium on carbon (31 mg, 29.3. Mu. Mol, distal from shao) was added under nitrogen, the gas in the system was replaced with hydrogen 3 times, and the temperature was raised to 75℃under hydrogen and stirred for 5 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1j (85 mg, yield: 99.9%).

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

Tenth step

(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. Mu. Mol) was dissolved in dimethyl sulfoxide (3 mL), anhydrous potassium carbonate (81 mg, 586.1. Mu. Mol, national drug) was added, stirred for 10 minutes, 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (91 mg, 439.6. Mu. Mol, synthesized by the method of Synthesis of Compound INT-60 on page 87 of U.S. Pat. No. 3,62A 1) was added, and the mixture was stirred at room temperature for 16 hours. The filtrate was filtered and purified by high performance liquid chromatography (column: welch prep C18,5 μm 30 x 150mM; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 25% -45%) to give 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 nitrogen-filled flask, compound 1c (2.5 g,8.68 mmol) and 1-methoxy-1-trimethylsiloxypropene (2.22 g,13.88mmol, TCI) were dissolved in anhydrous tetrahydrofuran (75 mL), N-diisopropylethylamine (3.36 g,26.00mmol, hadamard) and tripyrrolidinylphosphonium bromide hexafluorophosphate (4.45 g,9.54mmol, hadamard) were added with stirring at room temperature and stirred for 2 hours. 50mL of ice water and 50mL of methylene chloride were added, 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, and the resulting residue was purified by column chromatography with eluent system C to give the title compound 2a (3.0 g, yield: 96.52%).

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

Second step

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,8.37mmol, obtained) was added with stirring, and the mixture was heated to 60℃and stirred for 48 hours. Concentrated, slurried with 50mL of ethyl acetate and 50mL of petroleum ether, filtered, and the cake dried in vacuo to give the title compound 2b (345 mg, yield: 12.07%).

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

Third step

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 (319 mg,3.03mmol, national drug) and sodium iodide (151 mg,1.01mmol, shaotong) were added to N, N-dimethylformamide (7 mL), benzyl bromide (173 mg,1.01mmol, aldamasc) was slowly added dropwise with stirring, and the mixture was heated to 90℃and stirred for 16 hours. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system C to give the title compound 2C (100 mg, yield: 22.92%).

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

Fourth step

(R) -2- (benzyloxy) -9- ((2- ((tert-Butoxycarbonyl) 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. Mu. Mol) and tert-butyl N- [ (1R) -2-amino-1-methylethyl ] carbamate (60 mg, 347.8. Mu. Mol, bi) were dissolved in toluene (3 mL), anhydrous cesium carbonate (151 mg, 463.7. Mu. Mol, hadamard) was added, the gas in the system was replaced with nitrogen three times, tris (dibenzylideneacetone) dipalladium (21 mg, 23.1. Mu. Mol, hadamard) and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (14 mg, 23.1. Mu. Mol, shao far) were added, the gas in the system was replaced with nitrogen three times again, and the reaction solution was warmed to 110℃and stirred for 16 hours. The residue obtained was purified by column chromatography with eluent system C to give the title compound 2d (95 mg, yield: 78.1%).

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

Fifth step

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

Compound 2d (95 mg, 181.1. Mu. Mol) was dissolved in methylene chloride (3 mL), cooled to 0℃under stirring under nitrogen, and 0.4mL of trifluoroacetic acid (921 mg,8.1mmol, hadamard) was slowly added dropwise thereto, and the mixture was stirred for 2 hours at 25℃with natural heating. Concentration, dissolution in methylene chloride and concentration under reduced pressure gave the trifluoroacetate salt of the title compound 2e (97 mg, yield: 99.5%) which was dried under vacuum.

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

Sixth step

(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 salt of compound 2e (97 mg, 180.1. Mu. Mol) was dissolved in methanol (3 mL), sodium methoxide (48.7 mg, 901.4. Mu. Mol, shao Yuan) was added with stirring at room temperature, and the mixture was heated to 90℃and stirred for 12 hours. Concentrated, diluted with 15mL of water, stirred, extracted with ethyl acetate (15 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title compound 2f (45 mg, yield: 63.6%) as the residue was purified by column chromatography using eluent system C.

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

Seventh step

(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. Mu. Mol) was dissolved in anhydrous methanol (4 mL), 10% palladium on carbon (12 mg, 11.4. Mu. Mol, distal to shao) was added under nitrogen, the gas in the system was replaced with hydrogen 3 times, and the mixture was stirred under hydrogen atmosphere at 75℃for 5 hours. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give 2g (34 mg, yield: 98.1%) of the title compound.

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

Eighth step

(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

2g (34 mg, 112.4. Mu. Mol) of the compound was dissolved in dimethyl sulfoxide (3 mL), anhydrous potassium carbonate (31 mg, 225.0. Mu. Mol, national drug) was added, and the mixture was stirred for 10 minutes, and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (35 mg, 168.5. Mu. Mol) was added, followed by stirring at room temperature for 16 hours. The filtrate was filtered and purified by high performance liquid chromatography (column: sharpsil-TPrep C18,5 μm 30. Times.150 mM; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 35% -55%) to give 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,36.37mmol, country drug) were dissolved in benzotrifluoride (36 mL), 4-toluenesulfonic anhydride (4.76 g,14.58mmol, aldamax) was added at 0deg.C and stirred for 10 min at 0deg.C. Then, 5mL of trifluoroacetic acid was added thereto, and the reaction solution was stirred for 16 hours at a temperature of 70 ℃. The reaction solution was cooled to room temperature, concentrated under reduced pressure, dissolved in 50mL of methylene chloride, washed with saturated sodium carbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system C to give the title compound 4a (700 mg, yield: 33.45%).

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

Second step

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

In a dry tube sealer, compound 4a (700 mg,2.44 mmol) was dissolved in acetonitrile (25 mL), O- (2, 4-dinitrophenyl) hydroxylamine (480 mg,2.44mmol, obtained) was added with stirring, and the mixture was heated to 60℃and stirred for 48 hours. Concentration gave crude compound 4b which was used directly in the next reaction without purification.

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

Third step

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

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

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

Fourth step

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,4.41mmol, country) and sodium iodide (220 mg,1.46mmol, shaoyuan) were added to N, N-dimethylformamide (10 mL), benzyl bromide (275 mg,1.61mmol, aldamasc) was slowly added dropwise with stirring, and the mixture was heated to 90℃and stirred for 16 hours. Cooled to room temperature, diluted with 30mL of water, extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system C to give the title compound 4d (500 mg, yield: 81.72%).

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

Fifth step

(R) -2- (benzyloxy) -9- ((2- ((tert-Butoxycarbonyl) 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,1.81mmol, bi) were dissolved in toluene (10 mL), anhydrous cesium carbonate (780 mg,2.39mmol, hadamard) was added, the gas in the system was replaced with nitrogen three times, tris (dibenzylideneacetone) dipalladium (110 mg, 120.1. Mu. Mol, hadamard) and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (150 mg, 240.9. Mu. Mol, shao Yuan) were added, the gas in the system was replaced with nitrogen three times again, and the reaction solution was warmed to 110℃and stirred for 16 hours. The residue obtained was purified by column chromatography with eluent system C to give the title compound 4e (450 mg, yield: 73.6%).

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

Sixth step

(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 salt

Compound 4e (450 mg, 879.6. Mu. Mol) was dissolved in methylene chloride (10 mL), cooled to 0℃under stirring under nitrogen, and 0.6mL of trifluoroacetic acid (1 g,8.7mmol, hadamard) was slowly added dropwise thereto, and the mixture was stirred for 2 hours at 25℃with natural heating. Concentration, dissolution in methylene chloride and concentration under reduced pressure gave the trifluoroacetate salt of the title compound 4f (361 mg, yield: 99.7%) by vacuum drying.

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

Seventh step

(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 salt of compound 4f (361 mg, 879.7. Mu. Mol) was dissolved in methanol (15 mL), sodium methoxide (790 mg,4.38mmol, shao Yuan) was added with stirring at room temperature, and the mixture was stirred at 90℃for 12 hours. Concentrated, diluted with 30mL of water, stirred, extracted with ethyl acetate (30 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 4g (310 mg, yield: 92.8%) of the title compound as the residue was purified by column chromatography with eluent system C.

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

Eighth step

(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

4g (100 mg, 263.5. Mu. Mol) of the compound was dissolved in anhydrous methanol (5 mL), 10% palladium on carbon (56 mg, 52.6. Mu. Mol, distal to shao) was added under nitrogen, the gas in the system was replaced with hydrogen 3 times, and the mixture was stirred at 75℃for 24 hours under hydrogen. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (70 mg, yield: 91.8%) for 4 h.

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

Ninth step

(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. Mu. Mol) was dissolved in dimethyl sulfoxide (5 mL), anhydrous potassium carbonate (67 mg, 483.9. Mu. Mol, national drug) was added, stirred for 10 minutes, and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (50 mg, 241.9. Mu. Mol) was added, followed by stirring at room temperature for 16 hours. The filtrate was filtered and purified by high performance liquid chromatography (column: sharpsil-TPrep C18,5 μm 30. Times.150 mM; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 30% -50%) to give 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. Mu. Mol) was dissolved in N, N-dimethylformamide (2 mL), and N-chlorosuccinimide (16 mg, 119.8. Mu. Mol, hadamard) was added thereto, followed by stirring at room temperature for 3 minutes. The reaction solution was concentrated under reduced pressure, 10mL of ethyl acetate and 10mL of petroleum ether were added to the mixture, the mixture was slurried, filtered, and the cake was dried in vacuo to give the title compound 6a (35 mg, yield: 89.3%).

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

Second step

(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. Mu. Mol) was dissolved in dimethyl sulfoxide (2 mL), anhydrous potassium carbonate (30 mg, 217.1. Mu. Mol, national drug) was added, and the mixture was stirred for 10 minutes, and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (35 mg, 169.0. Mu. Mol) was added, followed by stirring at room temperature for 16 hours. The filtrate was filtered and purified by high performance liquid chromatography (column: sharpsil-TPrep C18,5 μm 30. Times.150 mM; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 35% -55%) to give 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), and 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (380 mg,1.07mmol, shao) was added thereto, followed by stirring at room temperature for 3 minutes. The reaction solution was concentrated under reduced pressure, 10mL of ethyl acetate and 10mL of petroleum ether were added to the mixture, the mixture was slurried, filtered, and the cake was dried in vacuo to give the title compound 7a (320 mg, yield: 97.1%).

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

Second step

(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,2.08mmol, national drug) was added, stirred for 10 min, and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (216 mg,1.04 mmol) was added and stirred at room temperature for 2 h. The filtrate was filtered and purified by high performance liquid chromatography (column: sharpsil-TPrep C18,5 μm 30. Times.150 mM; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 40% -60%) to give 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. Mu. Mol) was dissolved in N, N-dimethylformamide (2.2 mL), and N-bromosuccinimide (47 mg, 264.1. Mu. Mol, adamas) was added thereto and stirred at room temperature for 2 hours. 10mL of saturated sodium bicarbonate solution was added, the mixture was extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system C to give the title compound 8a (117 mg, yield: 96.8%).

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

Second step

(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. Mu. Mol) and pinacol cyclopropylborate (147 mg, 874.8. Mu. Mol, bi) were dissolved in 1, 4-dioxane (2.4 mL) and water (0.8 mL), anhydrous potassium carbonate (145 mg,1.05mmol, national drug) and tetrakis (triphenylphosphine) palladium (41 mg, 35.0. Mu. Mol, shaogue) were added, the gas in the system was replaced with nitrogen three times, and the reaction solution was stirred for 2 hours at 120℃with microwaves. The residue obtained was purified by column chromatography with eluent system C to give the title compound 8b (110 mg, yield: 75.1%).

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

Third step

(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. Mu. Mol) was dissolved in anhydrous methanol (5 mL), 10% palladium on carbon (28 mg, 26.3. Mu. Mol, distal to shao) was added under nitrogen, the gas in the system was replaced with hydrogen 3 times, and the mixture was stirred for 5 hours at 75℃under hydrogen. Cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 8c (86 mg, yield: 99.6%).

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

Fourth step

(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. Mu. Mol) was dissolved in dimethyl sulfoxide (1.8 mL), anhydrous potassium carbonate (72 mg, 523.8. Mu. Mol, national drug) was added, and the mixture was stirred for 10 minutes, and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (81 mg, 392.6. Mu. Mol) was added, followed by stirring at room temperature for 16 hours. The filtrate was filtered and purified by high performance liquid chromatography (column: sharpsil-TPrep C18,5 μm 30. Times.150 mM; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 40% -70%) to give 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)。

Example 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-dichloropyridine carbonitrile 9a (15 g,86.71mmol, obtained) was dissolved in N, N-dimethylformamide (200 mL), methyl thioglycolate (13 g,122.47mmol, aldammars) was added with stirring, and after heating the reaction solution to 65℃anhydrous potassium carbonate (24 g,173.65mmol, guogui) was added and the reaction was continued stirring at 65℃for 3 hours. Cooled to room temperature, diluted with 200mL of water, extracted with ethyl acetate (200 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system C to give the title compound 9b (1.75 g, yield: 8.3%).

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

Second step

(R) -3- ((2- ((tert-Butoxycarbonyl) 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), and sodium hydride (420 mg,10.96mmol, national drug) was added at 0deg.C, and the reaction stirred for 30 minutes. (R) -4-methyl-2, 2-dioxo- [1,2,3] oxathiazolidine-3-carboxylic acid tert-butyl ester (1.89 g,7.96mmol, shao Yuan) was then added and the reaction was stirred at 0deg.C for a further 30 minutes. The reaction was quenched by the addition of 5mL of saturated ammonium chloride solution, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using eluent system C to give the title compound 9C (2.8 g, yield: 97.1%).

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

Third step

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

Compound 9c (2.8 g,7.0 mmol) was dissolved in dichloromethane (30 mL), cooled to 0deg.C under nitrogen, and trifluoroacetic acid (8 g,70mmol, aldamax) was slowly added dropwise, and the mixture was stirred for 2 hours at 25℃with natural temperature rise. Concentration, dissolution in methylene chloride and concentration under reduced pressure gave the trifluoroacetate salt of the title compound 9d (2.09 g, yield: 99.5%) by vacuum drying.

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

Fourth step

(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 salt of compound 9d (2.09 g,6.97 mmol) was dissolved in methanol (30 mL), sodium methoxide (2.0 g,37.02mmol, shao Yuan) was added with stirring at room temperature, and the temperature was raised to 70℃and stirred for 2 hours. Concentrated, diluted with 30mL of water, stirred, extracted with ethyl acetate (30 mL. Times.3), the combined organic phases dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system C to give the title compound 9e (1.6 g, yield: 85.7%).

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

Fifth step

(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), 4-dimethylaminopyridine (120 mg,0.98mmol, shao), triethylamine (1.3 g,12.85mmol, guo Yao) and di-tert-butyl dicarbonate (4.2 g,19.24mmol, shao) were added with stirring, and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography using an eluent system C to give the title compound 9f (1.3 g, yield: 57.2%).

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

Sixth step

(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,1.92mmol, shao) were dissolved in 1, 4-dioxane (10 mL), anhydrous cesium carbonate (835 mg,2.56mmol, hadamard) and methane sulfonic acid [9, 9-dimethyl-4, 5-bis (diphenylphosphine) xanthene ] [2 '-amino-1, 1' -biphenyl ] palladium (II) dichloromethane complex (121 mg, 127.6. Mu. Mol, bi.) were added, the gas in the system was replaced with nitrogen three times, and the reaction solution was warmed to 110℃and stirred for 16 hours. The residue obtained was purified by column chromatography with eluent system C to give 9g (560 mg, yield: 71.3%) of the title compound.

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

Seventh step

(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

9g (560 mg, 913.9. Mu. Mol) of the compound was dissolved in tetrahydrofuran (3 mL), and a 3M aqueous hydrochloric acid solution (3 mL) was added with stirring, and the reaction solution was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added to adjust ph=7 to 8, extraction was performed with ethyl acetate (15 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system C to give the title compound 9h (230 mg, yield: 56.1%).

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

Eighth step

(R) -9- (2-Chloroacetamido) -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. Mu. Mol) and triethylamine (155 mg,1.53mmol, country) were dissolved in dichloromethane (3 mL), chloroacetyl chloride (115 mg,1.02mmol, aldamasc) was added with stirring, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography using an eluent system C to give the title compound 9i (120 mg, yield: 44.6%).

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

Ninth step

(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. Mu. Mol) was dissolved in tetrahydrofuran (3 mL), sodium hydride (18 mg, 469.8. Mu. Mol, national drug) was added at 0℃and the reaction was stirred at 0℃for 1 hour. 10mL of saturated ammonium chloride solution was added to quench, extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 9j (110 mg, yield: 98.5%). The product was used directly in the next reaction without purification.

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

Tenth step

(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. Mu. Mol) was dissolved in dimethyl sulfoxide (3 mL), anhydrous potassium carbonate (63 mg, 455.8. Mu. Mol, national drug) was added, stirred for 10 minutes, and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (47 mg, 227.0. Mu. Mol) was added, followed by stirring at room temperature for 16 hours. 15mL of water was added thereto, diluted and stirred, extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 9k (148 mg, yield: 99.7%). The product was used directly in the next reaction without purification.

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

Eleventh step

(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. Mu. Mol) was dissolved in methylene chloride (3 mL), and zinc bromide (252 mg,1.12mmol, hadamard) was added thereto, and the reaction solution was stirred at room temperature for 16 hours. The filtrate was filtered and purified by high performance liquid chromatography (column: sharpsil-T Prep C18,5 μm 30. Times.150 mM; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 25% -50%) to give 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 explained in further detail below in connection with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1 an endpoint method enzymatic assay based on HTRF technology was used to evaluate the inhibitory activity of compounds of the present disclosure on MK2 kinase.

1. Experimental material and instrument

1. MAPKAPK2 protein (Thermo, PR 5320A)

2. HTRF KinEASE-STK S1 kit (Cisbio, 62ST1 PEC)

3. HEPES buffer (Sigma, H3375)

4. Magnesium chloride (Sigma, 63069)

5. ATP, adenosine triphosphate (Promega, V915B)

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

7. Enzyme label instrument (BMG LABECH GmbH, PHERAstar FS)

2. Experimental procedure

HTRF KinEASE-STK S1 is a general method developed by Cisbio for detecting serine/threonine kinase activity based on HTRF technology. In optimized experimental conditions, 0.004nM MK2, 0.2. Mu.M biotin-labeled kinase substrate S1 (Km value), 4. Mu.M ATP (Km value) was incubated with various concentrations of compound for 1 hour at room temperature. The reaction buffer was 20mM HEPES (pH 7.5), 10mM MgCl ₂ 0.01% TritonX-100,0.01%BSA,1mM DTT. Enzymatic reactions were performed in Coring 384 surface low adhesion microwell plates with a total reaction volume of 10. Mu.L. At the end of the enzymatic reaction, 10. Mu.L of streptavidin labeled XL665 and Eu labeled STK antibody were added to terminate the enzymatic reaction at a final concentration of 12.5 nM. After incubation for 1 hour at room temperature, fluorescence signals at 620nm and 665nm were detected using a PHERAstar FS microplate reader under excitation light at 337 nm. The calibrated fluorescence signal was obtained by calculating the ratio of 665nm to 620nm fluorescence signals. A concentration-effect curve of compound concentration and enzyme activity inhibition rate was obtained by using a GraphPad PRISM software (Version 9.00;GraphPad San Diego,CA) four-parameter nonlinear fit, and the relative IC was calculated ₅₀ Values, to reflect the inhibitory activity of different compounds on MK 2.

TABLE 1 inhibitory Activity of the presently disclosed compounds against MK2

Conclusion: the compound disclosed by the invention has a better inhibition effect on MK 2.

Test example 2, the compounds of the present disclosure, were tested for their inhibitory activity on TNFa secretion in U937 cells.

1. Experimental material and instrument

U937 cells (ATCC)

RIPM1640 (Dalian Mei Lun organism, PWL 015)

3.FBS(Gibco,10099-141)

4.DPBS(Gibco,14190250)

5.PMA(InvivoGen,tlrl-pma)

LPS (Biyundian, S1732-5 mg)

7.100mm dish(Costar,430167)

8.Human TNF-alpha ELISAkit (Xinbo Sheng, EHC103 a.96.10)

T175 cell culture flask (Corning 431080)

10. Cell scraper (Corning, CON-3010)

11.96 well flat bottom cell culture plate (Corning, 3599)

12.96 Kong Yuande dispensing plate (Corning, 3788)

13. Cell counter (Shanghai Rui Yu biotechnology Co., ltd., count star IC 1000)

14. Cell incubator (ThermoFisher Scientific, forma steri-cycle i 160)

15. Biological safety cabinet (ESCO, class II BSC)

16. Centrifuge (ThermoFisher Scientific ST 40R)

17.Bravo(Agilent)

PHERAstar FS enzyme label instrument (BMG Labtech)

2. Experimental procedure

U937 cells were cultured with complete 1640 medium containing final concentration of 10ng/ml PMA, after 48 hours cells were washed twice with DPBS, and further cultured in a 37℃cell incubator with addition of complete 1640 medium. On day four, U937 cells were plated at 5X 10 ⁴ Each well was plated into 96-well plates and incubated overnight at 37 ℃. Fifth day8 serial dilutions of 10 XCompound-containing medium were added to 96-well plates and incubated with U937 cells for 60 min at 37℃after which cells were stimulated with LPS at a final concentration of 100ng/ml for 6 hours and supernatants were harvested for testing for TNF-alpha factor (ELISA). TNF-alpha ELISA test was performed according to the manufacturer's instructions and data were read using a PHERAstar FS microplate reader. And (3) data processing: and calculating the TNF-alpha value of the test hole according to a standard curve, wherein the inhibition ratio calculation formula is as follows: % inhibition= [ AVG (maximum) -test well value]/[ AVG (maximum) -AVG (minimum)]*100%. Finally, the data is fitted with a graphpad prism to calculate an IC ₅₀ Values.

TABLE 2 inhibitory Activity of the compounds of the present disclosure on TNFa secretion in U937 cells

Numbering of compounds	TNFa_U937 IC 50 (nM)
		6	14.0

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

Test example 3 solubility of the compounds of the present disclosure

1. Experimental materials

Reagent: dimethyl sulfoxide (chromatographic purity, sigma-Aldrich, cat# 472301-4X 4L), ethanol (chromatographic purity, CNW, cat# 4.016362.4000), acetonitrile (chromatographic purity, merck, cat# 1.00030.4008), naH ₂ PO ₄ ·2H ₂ O (analytical purity, chemicals, inc. of national medicine group, cat# 20040717), ammonium acetate (chromatographic purity, fluka Honeywell, cat# 17836-250G), sodium taurate (98%, carboline technologies, cat# 551055-25G), lecithin (. Gtoreq.99%, sigma ald) rich, cat No. P3556-1G), sodium hydroxide (analytically pure, chinese medicine group chemicals limited, cat No. 10019718), sodium chloride (analytically pure, chinese medicine group chemicals limited, cat No. 10019318), hydrochloric acid (analytically pure, chinese medicine group chemicals limited, cat No. 10011018), glacial acetic acid (analytically pure, chinese medicine group chemicals limited, cat No. 10000218) and ultrapure water (manufactured by ELGA CHORUS laboratory ultrapure water machine).

Instrument: agilent 1200DAD liquid chromatograph (Agilent company of America)

2. Material preparation

2.1 preparation of FassIF solution

Solution (a): 4.441g of NaH was added to 900mL of ultrapure water ₂ PO ₄ ·2H ₂ O, 0.348g of NaOH particles and 6.186g of NaCl are uniformly mixed, 1M of NaOH is added to adjust the pH of the solution to 6.5+/-0.05, water is used for constant volume to 1000mL, and the solution is refrigerated at 4 ℃ for standby.

FaSSIF solution (B): 20mL of solution (A) was dissolved with 0.161g sodium taurate (NaTC) and 59mg lecithin, stirred vigorously overnight to form a clear micellar solution, and the solution (A) was added to a volume of 100mL and refrigerated at 4℃for use (no more than 2 weeks).

2.2 preparation of FessIF solution

Solution (a): 20.2g of NaOH particles, 43.25g of glacial acetic acid and 59.37g of sodium chloride are accurately weighed, dissolved with a proper amount of ultrapure water and fixed to a volume of 5L, and the pH is adjusted to 5.0,4 ℃ by using 1M NaOH or 1M HCl for refrigeration for later use.

FeSSIF solution (B): 25mL of solution (A) was dissolved in 0.80652g of sodium taurate (NaTC) and 295.5mg of lecithin, stirred vigorously overnight to form a clear micellar solution, and the solution (A) was added to a volume of 100mL and refrigerated at 4℃for use (no more than 2 weeks).

3. Experimental procedure

Dissolution test in FassIF solution and FessIF solution.

3.1 weighing a proper amount of a compound to be tested, and preparing a 10mM stock solution by using DMSO as a solvent. Precisely 10. Mu.L of stock solution (concentration 10mM, dissolved in DMSO) was measured and mixed with 990. Mu.L of an organic mixed solvent (usually DMSO: acetonitrile: ethanol=1:1:1) in a 2mL sample bottle to give a clear 100. Mu.M sample solution as a reference solution.

3.2 dissolving 1mg of sample to be tested to 900. Mu.L of FassIF solution (or FessIF solution), mixing vigorously, and preparing two solutions in parallel; after shaking in a water bath at 37℃for 24 hours, the mixture was centrifuged at 12000rpm for 30 minutes, and the supernatant was transferred as a sample solution to liquid chromatography.

4. Experimental results

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

The two measurements were averaged to obtain the final solubility in FassIF and FessIF solutions.

Table 3, solubility of compounds of the present disclosure.

Numbering of compounds	FassIF solution (mu M)	FessIF solution (mu M)
			Compound 1	54.56	141.86

Conclusion: the compounds of the present disclosure have good solubility in both FassIF and FessIF solutions.

Claims (18)

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring B is a 5 membered heteroaryl or a 5 membered heterocyclyl;

w is selected from C, CR ⁰ And N;

R ⁰ selected from the group consisting of 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 said alkylene group is optionally substituted with one or more substituents selected from oxo, deuterium atom, halogen, alkoxy, haloalkoxy, deuteroalkoxy and hydroxy;

R ^A selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, - (CR) ^a R ^b ) _m NR ^c R ^d Cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl;

R ^1a 、R ² and R is ^2a Identical or different and are each independently selected from the group consisting of 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 an-OSO ₃ H is formed; or R is ² And R is ^2a Together form = O;

R ¹ selected from the group consisting of 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 Cyano, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R ^B Substitution;

R ³ selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, - (CR) ^a R ^b ) _m NR ^c R ^d Cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl and heterocyclyl;

or R is ¹ And R is ³ Together with the atoms to which each is attached, form a heterocyclic group; or R is ¹ And R is ² Forms a cycloalkyl or heterocyclyl group together with the carbon atom to which each is attached; or R is ² And R is ³ Together with the atoms to which each is attached, form a heterocyclic group; the cycloalkyl or heterocyclyl groups are each independently optionally substituted with one or more R ^B Substitution;

R ⁵ selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, an alkyl, a haloalkyl, a deuterated alkyl, a hydroxyalkyl, a cyano, -OR ⁹ 、-S(O) _s R ⁹ 、-OSO ₃ H、-OSO ₂ R ⁹ 、-OC(O)R ⁹ and-OP (O) ₂ OR ⁹ The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, R ⁵ Is a warhead group;

each R is ⁴ And each R ⁶ Identical or different and are each independently selected from oxo, deuterium atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, 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, 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 Substitution;

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

R ⁷ and R is ⁸ The same or different and are each independently selected from the group consisting of 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, -NH alkyl group, and-N (alkyl group) ₂ ；

R ^a 、R ^b 、R ^h 、R ⁱ 、R ^x And R is ^y Is the same or different at each occurrence and is each independently selected from the group consisting of 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;

R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ^c 、R ^d 、R ^j And R is ^k Is the same or different at each occurrence and is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, and heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl groups are each independently optionally substituted with one or more R ^C Substitution;

or R is ¹⁰ And R is ¹¹ Together with the nitrogen atom to which they are attached form a heterocyclic group; the heterocyclic groups optionally being substituted by one or more R ^C Substitution;

R ^C is the same or different at each occurrence and is each independently selected from oxo, deuterium, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuteroalkyl, hydroxyalkyl, alkoxy, haloAlkoxy, deuteroalkoxy, hydroxy, 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 is also provided with

t is 0, 1, 2 or 3.

2. The compound of 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. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ⁷ Is a hydrogen atom; and/or R ⁸ Is a hydrogen atom.

4. A compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring a is 6 membered heteroaryl; preferably, ring a is pyrimidinyl.

5. A compound of 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. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound of general formula (II):

wherein:

x is N or CR ^4a ；

Y is N or CR ^4b ；

R ¹ Selected from deuterium atoms, halogens, alkyl groups, haloalkyl groups, deuterated alkyl groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, - (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 said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R ^B Substitution;

R ^4a 、R ^4b and R is ^6a Identical or different and are each independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, 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, 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 Substitution; and is also provided with

T、R ^B 、R ³ 、R ⁵ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ^x 、R ^y S and w are as defined in claim 1.

7. A compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein T is-O-or-NH-; preferably, T is-O-.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ¹ Is C _1-6 An alkyl group; and/or R ³ Is a hydrogen atom.

9. A compound of 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 Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and 3 to 6 membered cycloalkyl; and/or Y is N.

10. A compound of 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. A compound of 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, preferably-CH ₂ OCH ₂ CH ₃ or-CH ₂ OtBu。

12. A compound or a pharmaceutically acceptable salt thereof selected from any one of the following:

13. a compound of the general formula (IA):

wherein:

t is O or NR ^A ；

Ring B, R ¹ 、R ^1a 、R ² 、R ^2a 、R ³ 、R ⁴ 、R ⁷ 、R ⁸ 、R ^A W and n are as defined in claim 1.

14. A compound or salt thereof selected from any one of the following compounds:

15. a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which comprises:

nucleophilic substitution reaction is carried out between the compound shown in the general formula (IA) or the salt thereof and the compound shown in the general formula (IB) or the salt thereof to obtain the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof;

wherein:

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 、R ^A W, n and t are as defined in claim 1.

16. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of a compound of general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 for the preparation of an MK2 inhibitor.

18. Use of a compound of general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 for the manufacture of a medicament for the treatment and/or prophylaxis of autoimmune disorders, chronic or acute inflammatory disorders, autoimmune inflammatory disorders, fibrotic disorders, metabolic disorders, neoplasias and cardiovascular or cerebrovascular disorders; the autoimmune disorder, chronic or acute inflammatory disorder and autoimmune inflammatory disorder is 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), cryptopyrene-related periodic syndrome, mu Keer-wels syndrome (mucke-Wells syndrome), familial cold-induced autoimmune inflammatory syndrome, neonatal onset multisystemic inflammatory disease, TNF receptor-related 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 testes, autoimmune thrombocytopenia, systemic lupus erythematosus, vasculitis syndrome, pituitary inflammation, idiopathic thrombocytopenic purpura, pemphigus, autoimmune dermatitis, myocarditis, myositis, myelitis, peritonitis, gastroenteritis, peritonitis, and peritonitis; the arthritis is preferably selected from the group consisting of Rheumatoid Arthritis (RA), osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis and spondyloarthritis.