TWI836822B - P38 mapk/mk2 pathway regulator, and composition, preparation method, and use thereof - Google Patents

Abstract

The present disclosure disclosed a compound as shown in formula I, and racemate, stereoisomer, tautomer, isotope marker, solvate, pharmaceutically acceptable salt or prodrug thereof, and composition, preparation method, and use thereof. The compound has a good regulatory effect on p38 MAPK/MK2 pathway, and has good selectivity, pharmacokinetics and other properties. Furthermore, it can be used to treat diseases related to p38 kinase inhibitors and to prepare drugs for such diseases or conditions.

Description

p38 MAPK/MK2 pathway regulators and compositions thereof, preparation methods and uses thereof

This invention claims priority to a prior application filed with the National Intellectual Property Administration of China on December 29, 2021, with patent application number 202111642855.0, entitled "A p38 MAPK/MK2 pathway regulator and its composition, preparation method and use". The entire text of the prior application is incorporated into this invention by reference.

The invention belongs to the field of medicine, and specifically relates to a p38 MAPK/MK2 pathway regulator and its composition, preparation method and use.

Biological signal transduction involves specific protein-protein interactions and post-translational modifications, regulating genetic and epigenetic processes to respond to the effects of internal and external environments. Mitogen-activated protein kinase (MAPK) is a group of serine-threonine protein kinases that can be activated by different internal and external stresses in cells. It is an important transmitter of signals from the cell surface to the cell nucleus. Stress factors include cytokines, neurotransmitters, hormones, cell stress and cell adhesion.

As a subfamily of the MAPK family, p38 MAPK is phosphorylated and activated when cells respond to external signals and inflammatory cytokines. A variety of downstream protein kinases and transcription factors, thereby playing complex biological roles. p38 MAPK includes four members, namely p38α, p38β, p38γ and p38δ. Among them, p38α is considered to play an important role in the signaling pathway of the inflammatory process, while the biological functions of other isomers have not yet been fully discovered, but they have pleiotropic effects. Studies have shown that p38β plays an important role in cell protection mechanisms, and mitogen-activated protein kinase MKK3 (MAP Kinase Kinase 3) mediates p38δ to have an effect on the proliferation and survival of advanced colorectal cancer (CRC) cells. As an attractive target in the field of drug development, multiple inhibitor drugs of p38 MAPK have entered clinical research, but so far no drug has been approved for marketing. According to the invention information, some candidate compounds failed in the clinical research stage. The main reasons for clinical failure include dose limitation to avoid toxicity, leading to insufficient exposure of drug molecules at the target, downregulation of anti-inflammatory pathways, redundancy of signaling networks, or involvement of other Key proteins in the feedback regulation of the MAPK pathway are inhibited, etc., and inhibiting the feedback mechanism may upregulate other pro-inflammatory pathways, leading to increased inflammation. Therefore, developing a safe and effective p38 MAPK inhibitor is a major challenge currently facing drug development in this field.

p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013(152),924]. Therefore, selectively inhibiting the activation of p38 MAPK downstream effectors is the main strategy to avoid side effects/lack of efficacy caused by overall inhibition of p38 MAPK. MAPK-activated protein kinase 2 (MK2) is a direct downstream substrate of p38 MAPK and can be activated by p38α and p38β. As the first discovered p38 MAPK substrate, MK2 can regulate the expression of inflammatory factors at the transcriptional and post-transcriptional levels, thereby playing an important role in the regulation of multiple inflammatory diseases. Studies have shown that MK2 can increase the expression of inflammatory factors such as TNF-α, IL-6, IL-8 and COX-2 by stabilizing the AU-rich elements of mRNA. In the postoperative intestinal obstruction model of mice [The Journal of surgical research 2013(185),102], MK2 inhibitors can reduce the expression of inflammatory factors such as MIP-1α, TNF-α, IL-6 and IL-1β, and at the same time, reduce the infiltration of polymorphonuclear leukocytes, mast cells, and monocytes and macrophages and improve the contractile performance of intestinal smooth muscle. In the mouse collagen-induced arthritis (CIA) model [Journal of immunology 2006 (177), 1913], knocking out the MK2 gene can reduce the occurrence of collagen-induced arthritis. Compared with wild-type mice, the incidence and severity of collagen-induced arthritis in MK2-/- and MK2+/- mice were reduced, and the expression of inflammatory factors TNF-α and IL-6 was also reduced to varying degrees. In the MK2 knockout hypercholesterolemia mouse model [Circ Res 2007 (101), 1104], lipid deposition and macrophages in the large arteries of mice were reduced, and the expression of inflammatory factors such as VCAM-1 and MCP-1 was reduced. In addition, studies have shown that inhibiting MK2 can be used in the development of anti-tumor drugs [Cancer cell 2007(11),175].

Many diseases are associated with the p38 MAPK/MK2 pathway, including (but not limited to) autoimmune and inflammatory diseases (such as rheumatoid arthritis, hidradenitis abscessus, psoriasis, inflammatory bowel disease, atopic dermatitis, systemic lupus erythematosus, etc.), bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases. Selective inhibition of the p38 MAPK/MK2 pathway reduces the impact on other downstream pathways of p38 MAPK, thereby reducing potential toxic side effects and insufficient efficacy in drug development; meeting the unmet clinical needs in the field of diseases related to the p38 MAPK/MK2 pathway.

In order to improve the problems existing in the prior art, the present invention provides a compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or Its prodrugs:

連接的N原子以外，還任選地含有1個、2個或更多個選自O、N或S的雜原子；R¹選自H、鹵素、CN和C_1-6烷基；R²選自-OR⁸¹、-NH-C(O)R⁸²、-NHR⁸³和-C(O)NHR⁸⁴；R³選自H、C₁-₁₀烷基和C_3-20環烷基；R⁴選自H、鹵素和C₁-₁₀烷基；R⁵分別獨立地選自H、鹵素、-OH、-C_1-6烷基、-C_1-6烷氧基、側氧基(=O)、-C(O)C_1-6烷基、羥基取代的C₁-₁₀烷基、-C(O)OH、-C(O)NR^91aR^91b、-S(O)₂R⁹²和-S(O)₂NR^93aR^93b；R⁶選自H、鹵素和甲基；R⁷分別獨立地選自H、鹵素、未取代或被Ra取代的C_1-10烷基和C_3-20 環烷基；Ra選自鹵素和C_3-20環烷基；R⁸¹、R⁸²、R⁸³、R⁸⁴相同或不同，彼此獨立地選自無取代或任選被1、2、3、4或5個Rb取代的C_6-14芳基-C₁-₁₀烷基、5-14員雜芳基-C₁-₁₀烷基、C_6-14芳基和5-14員雜芳基；每個Rb相同或不同，彼此獨立地選自鹵素、鹵代C₁-₁₀烷基、C₁-₁₀烷基和C_1-10烷氧基；R^91a、R^91b、R⁹²、R^93a、R^93b相同或不同，彼此獨立地選自H、C_1-6烷基和C_3-20環烷基。 Wherein, W is CH or N; m is an integer of 0-5; n is an integer of 0-3; Ring A is a 3-20-membered nitrogen-containing heterocyclic group, except for the parent nucleus

In addition to the connected N atom, it optionally contains 1, 2 or more heteroatoms selected from O, N or S; R ¹ is selected from H, halogen, CN and C _1-6 alkyl; R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ; R ³ is selected from H, C _{1-10 alkyl} and C _3-20 cycloalkyl; R ⁴ is selected from H, halogen _and C _1-10 alkyl; R ⁵ is independently selected from H, halogen, -OH, -C _1-6 alkyl, -C _1-6 alkoxy, pendoxy (=O), -C(O)C _1-6 alkyl, hydroxy substituted C _1-10 alkyl, -C(O)OH, -C(O)NR ^91a R ^91b , -S( _O ) ₂ R R ⁹² and -S(O) ₂ NR ^93a R ^93b ; R ⁶ is selected from H, halogen and methyl; R ⁷ is independently selected from H, halogen, C _1-10 alkyl and C _3-20 cycloalkyl which are unsubstituted or substituted by Ra; Ra is selected from halogen and C _3-20 cycloalkyl; R ⁸¹ , R ⁸² , R ⁸³ and R ⁸⁴ are the same or different and are independently selected from C _6-14 aryl-C ₁ - ₁₀ alkyl, 5-14 membered heteroaryl-C ₁ - ₁₀ alkyl, C _6-14 aryl and 5-14 membered heteroaryl which are unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 R b; each R b is the same or different and is independently selected from halogen, halogenated C ₁ - ₁₀ alkyl, C ₁ - _R ^91a , R ^91b , R ⁹² , R ^93a , R ^93b are the same _or different and are independently selected from H, C _1-6 alkyl and C _3-20 cycloalkyl.

According to an embodiment of the present invention, W is CH or N; m is an integer of 0-5; n is an integer of 0-3; Ring A is a 3-20-membered nitrogen-containing heterocyclic group, which, in addition to the N atom connected to the parent core, optionally contains 1, 2 or more heteroatoms selected from O, N or S; R ¹ is selected from H, halogen, CN and C _1-6 alkyl; R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ; R ³ is selected from H, C _1-10 alkyl and C _3-20 cycloalkyl; R ⁴ is selected from H, halogen and C _1-10 alkyl; R ⁵ _is independently selected from H, halogen, -OH, C _1-6 alkyl, C 3-20 cycloalkyl _; wherein R is selected from H, halogen and methyl; _{R is} independently selected from H, halogen, _{C 1-10} alkyl and C _3-20 ^{cycloalkyl ; R 81, R 82, R 83 and R 84 are the same} or ^different and _{are independently selected from C 6-14 aryl -} C _1-10 alkyl _{, 5-14 membered heteroaryl-C 1-10 alkyl, C 6-14} ^{aryl and} _{5-14 membered} heteroaryl; wherein C _{The 6-14} membered aryl or 5-14 membered heteroaryl is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from halogen, halogenated C _1-10 alkyl, C _1-10 alkyl and C _1-6 alkoxy groups; R ^91a , R ^91b , R ⁹² , R ^93a , R ^93b are the same or different and independently selected from H, C _1-6 alkyl and C _3-20 cycloalkyl.

According to an embodiment of the present invention, W is CH or N; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3; Ring A is a 3-12 membered nitrogen-containing heterocyclic group, optionally containing 1, 2 or more heteroatoms selected from O, N or S in addition to the N atom connected to the _parent core; R ¹ is selected from H, halogen, CN and C _1-6 alkyl; R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ; R ³ is selected from H, C _1-6 alkyl and C _3-12 cycloalkyl; R ⁴ is selected from H, halogen and C _1-6 alkyl; R ⁵ is independently selected from H, halogen, -OH, C _1-6 alkyl, C _3-12 cycloalkyl wherein the at least one aryl group is selected from _the group consisting of: a C _1-6 alkoxy group, a pendooxy group (=O), a -C(O)C _1-6 alkyl group, a hydroxy-substituted C _1-6 alkyl group, -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ; R ⁶ is selected from the group consisting of H, halogen and methyl; R ⁷ is independently selected from the group consisting of H, halogen, C _1-6 alkyl group and C _3-12 cycloalkyl group; R ⁸¹ , R ⁸² , R ⁸³ and R ⁸⁴ are the same or different and are independently selected from the group consisting of C _6-14 aryl-C _1-6 alkyl group, 5-14 membered heteroaryl-C _1-6 alkyl group, C _6-14 membered aryl and 5-14 membered heteroaryl; wherein the aryl or heteroaryl is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from halogen, halogenated C _1-6 alkyl, C _1-6 alkyl and C _1-3 alkoxy; R ^91a , R ^91b , R ⁹² , R ^93a , R ^93b are the same or different and are independently selected from H, C _1-6 alkyl and C _3-10 cycloalkyl.

According to an embodiment of the present invention, W is CH or N; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3; Ring A is a 3-9-membered nitrogen-containing heterocyclyl group , in addition to the N atoms connected to the mother core, optionally also contains 1, 2 or more heteroatoms selected from O, N or S; R ¹ is selected from halogen; R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ; R ³ is selected from C ₁ - ₃ alkyl and C _3-6 cycloalkyl; R ⁴ is C ₁ - ₃ Alkyl or halogen; R ⁵ is independently selected from halogen, -OH, -C _1-3 alkyl, -C _1-3 alkoxy, side oxy (=O), -C(O)C _{1- 3Alkyl} , hydroxy-substituted C ₁ - ₃ alkyl, -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ; R ⁶ is selected from H, halogen and methyl; R ⁷ is independently selected from H, halogen and C _1-3 alkyl; R ⁸¹ , R ⁸² , R ⁸³ and R ⁸⁴ are the same or different and are independently selected from each other. C _6-8 aryl-C _1-3 alkyl, 5-6 membered heteroaryl-C _1-3 alkyl, C _6-8 aryl, 5-6 membered heteroaryl; where aryl or heteroaryl The groups are each unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C _1-3 alkyl, C _1-3 alkyl and C _1-3 alkoxy; R ^91a , R ^91b , R ⁹² , R ^93a , and R ^93b are the same or different, and are independently selected from H, C _1-3 alkyl and C _3-7 cycloalkyl.

According to an embodiment of the present invention, W is CH or N; m is 0, 1, 2 or 3; n is 0 or 1; Ring A is selected from the following structures:

R ¹ is Cl or Br; R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ; R ³ is methyl or cyclopropyl; R ⁴ is methyl; R ⁵ is selected from F, -OH, methyl, methoxy, ethoxy, oxo (=O), -C(O)C _1-3 alkyl, 2-hydroxyisopropyl, -C(O)OH, -C(O)NH ₂ , -C(O)NHCH ₃ , -S(O) ₂ CH ₃ , S(O) ₂ CH ₂ CH ₃ and -S(O) ₂ -cyclopropane; R ⁶ is selected from H, F and Cl; R ⁷ is H; R ⁸¹ , R ⁸² , R ⁸³ , R ⁸⁴ are the same or different and are independently selected from phenylmethyl, pyridylmethyl, pyridylethyl, phenyl and pyridyl which are unsubstituted or optionally substituted with 1, 2 or 3 Rb; each Rb is the same or different and is independently selected from F, Cl and _CF3 .

According to an embodiment of the present invention, the structure formed by R ⁵ and ring A can be selected from:

其中，R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、A、W、m和n具有上文所述的定義，加粗的化學鍵表示化合物中存在軸掌性。 In a preferred embodiment, the compound of formula I has a structure shown in formula Ia or Ib:

Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A, W, m and n have the meanings as described above, and the bold chemical bonds indicate the presence of chiral properties in the compound.

In a preferred embodiment, the compound of formula I has the structure shown in formula II:

wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n, W and ring A are independently defined as above; R ¹⁰ is selected from the following groups which are H, halogen, unsubstituted or optionally substituted with 1, 2 or more halogens, OH, NH ₂ : C _1-10 alkyl, C _1-10 alkoxy, halogenated C _1-10 alkyl, halogenated C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkenyloxy, C _2-10 alkynyl and C _2-10 alkynyloxy; each R ¹¹ is the same or different and is independently selected from H, halogen, C _1-6 alkyl and halogenated C _1-10 alkyl; p is an integer from 0 to 4.

According to an embodiment of the invention, R ¹⁰ is selected from the following groups: H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH ₂ : C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkyl, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkenyloxy, C _2-6 alkynyl and C _2-6 alkynyloxy; each R ¹¹ is the same or different, independently selected from H, halogen, C _1-6 alkyl and halogenated C _1-6 alkyl; p is 0, 1, 2, 3 or 4.

According to an embodiment of the present invention, R ¹⁰ is selected from H, halogen, C _1-3 alkyl and halogenated C _1-3 alkyl; p is 0, 1 or 2; each R ¹¹ is the same or different and is independently selected from H, halogen, C _1-3 alkyl and halogenated C _1-3 alkyl.

According to an embodiment of the present invention, R ¹⁰ is H or methyl; p is 0, 1 or 2; each R ¹¹ is the same or different and is independently selected from F, Cl and CF ₃ .

其中，R¹、R³、R⁴、R⁵、R⁶、R⁷、R¹⁰、R¹¹、A、W、m、n和p具有上文所述的定義，加粗的化學鍵表示存在軸掌性。 In a more preferred embodiment, the compound of formula II has a structure shown in formula IIa or formula IIb:

Wherein, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , A, W, m, n and p have the meanings as described above, and the bold chemical bonds indicate the presence of chirality.

In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein W is N.

In some embodiments, the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its precursor Drug, wherein R ² is -OR ⁸¹ or -NHR ⁸³ ; R ⁸¹ and R ⁸³ are the same or different, and are independently C _6-8 aryl- _{C 1-3 alkyl} -or 5-6 membered heteroaryl- C ₁ - ₃ alkyl-; wherein C _6-8 aryl and 5-6 membered heteroaryl are unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C _{1 -3} alkyl, C ₁ - ₃ alkyl and C _1-3 alkoxy substituted, the C ₁ - ₃ alkyl part is connected to O or NH.

In some embodiments, the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its precursor medicine, wherein R ² is -OR ⁸¹ ; R ⁸¹ is C _6-8 aryl-C ₁ - ₃ alkyl or 5-6 membered heteroaryl-C ₁ - ₃ alkyl; wherein C _6-8 aryl and The 5-6 membered heteroaryl group is unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C ₁ - ₃ alkyl, C ₁ - ₃ alkyl and C _1-3 Alkoxy substitution; C ₁ - ₃ alkyl moiety is attached to O. In some embodiments, the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its precursor Drug, wherein R ² is -OR ⁸¹ ; R ⁸¹ is -CH ₂ -pyridyl; wherein, pyridyl is unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C Substituted _{with 1-3 alkyl, C 1-3 alkyl and C 1-3} alkoxy.

In some embodiments, the compounds represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, their racemates, stereoisomers, tautomers, isotopically labeled substances, solvates, pharmaceutically acceptable salts or prodrugs thereof, wherein R ⁵ is independently selected from H, -OH, -C _1-6 alkyl, -C _1-6 alkoxy, -C(O)C _1-6 alkyl, hydroxy-substituted C _1-10 alkyl, -C( _O )OH, -C(O)NR ^91a R ^91b and -S(O) ₂ R ⁹² ; R ^91a , R ^91b and R ⁹² are the same or different and are independently selected from H, C _1-6 alkyl and C _3-10 cycloalkyl.

In some embodiments, compounds represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, their racemates, stereoisomers, tautomers, isotopic labels, solvates, A pharmaceutically acceptable salt or prodrug thereof, wherein ^R1 is halogen.

In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein R ³ is C _{1-3 alkyl} .

In some embodiments, compounds represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, their racemates, stereoisomers, tautomers, isotopic labels, solvates, Pharmaceutically acceptable salts or prodrugs thereof, wherein R ⁴ is halogen or C ₁ - ₃ alkyl.

In some embodiments, compounds represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, their racemates, stereoisomers, tautomers, isotopic labels, solvates, A pharmaceutically acceptable salt or prodrug thereof, wherein ^R6 is H or halogen.

According to embodiments of the present invention, compounds of formula I include, but are not limited to, the following structures:

According to the embodiments of the present invention, the compound shown in Formula I includes but is not limited to the following structure:

The present invention also provides a method for preparing a compound of formula I, comprising:

Scheme 1: Compound a1 and compound a2 undergo coupling reaction to obtain a compound of formula I.

The reaction formula is as follows:

Wherein, Y is Cl or Br; W, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n and ring A independently have the above definitions;

Scheme 2: When W is N and R ₇ is H, compound b1 reacts with compound b2 to obtain the compound of formula II; the reaction formula is as follows:

wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , m, n, p and ring A independently have the definitions described above; according to an embodiment of the present invention, the reaction is carried out in the presence of an inorganic base; the inorganic base is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide.

According to the embodiment of the present invention, when R ⁵ is OH, the OH in compound b2 may be protected by a silicon protecting group, and the silicon protecting group may be tert-butyldiphenylsilyl; the silicon protecting group will be removed in the reaction to obtain deprotected OH.

The present invention also provides at least one of the compounds represented by formula I, their racemates, stereoisomers, tautomers, isotope markers, solvates, pharmaceutically acceptable salts or their prodrug compounds in the preparation of Uses in medicines.

According to the embodiment of the present invention, the drug can be a drug for treating and/or preventing diseases associated with p38 kinase inhibitors, for example, it can be a MK2 inhibitor or a p38 MAPK/MK2 pathway regulator.

The present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound represented by Formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, and pharmaceutically acceptable salt or at least one of its prodrug compounds.

According to the embodiment of the present invention, the drug composition also includes at least one pharmaceutically acceptable carrier.

According to the embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

The carrier includes disintegrants such as methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium cross-linked carboxymethylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, starch, etc.; lubricants include calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, etc.; binders include gelatin, polyethylene glycol, sugar, gum, starch, hydroxypropyl cellulose, etc.; diluents include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol and starch; surfactants include polysorbate 80, sodium lauryl sulfate, talc and silicon dioxide. The compositions of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.

The present invention also provides the use of the compound shown in Formula I, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, pharmaceutically acceptable salt or prodrug compound in the treatment and/or prevention of diseases mediated by p38 kinase inhibitors.

The present invention also provides a method for treating and/or preventing diseases mediated by p38 kinase inhibitors, comprising administering to a patient a therapeutically or preventively effective amount of a compound of formula I, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, pharmaceutically acceptable salt or prodrug compound thereof.

According to the implementation scheme of the present invention, the disease can be a disease related to the p38 MAPK/MK2 pathway, for example, autoimmune diseases and inflammatory diseases (such as rheumatoid arthritis, hidradenitis psoriasis, psoriasis, inflammatory bowel disease, atopic dermatitis, systemic lupus erythematosus, etc.), bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases.

The compounds of the present invention have good regulatory effects on the p38 MAPK/MK2 pathway and good selectivity. In addition, the compounds of the present invention have good drug metabolic kinetics and other properties. In addition, the compounds of the present invention can be used to treat diseases mediated by p38 kinase inhibitors and to prepare drugs for such conditions or diseases.

Definition and explanation of terms

Unless otherwise stated, the definitions of groups and terms recorded in the present invention specification and the scope of the patent application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in the embodiments, etc., can be arbitrarily combined and combined with each other. The group definitions and compound structures after such combination and combination should be understood to be within the scope recorded in the present invention specification and/or the scope of the patent application.

Unless otherwise stated, the numerical ranges described in this specification and the patent application are equivalent to at least recording each specific integer value therein. For example, the numerical range "1-20" is equivalent to recording each integer value in the numerical range "1-20", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ,13,14,15,16,17,18,19,20. In addition, when certain numerical ranges are defined as "numbers," it should be understood that the two endpoints of the range, every integer within the range, and every decimal within the range are recited. For example, "numbers from 0 to 10" should be understood as not only recording every integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also recording at least one of the integers respectively. The sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.

It should be understood that when describing one, two or more, "more" shall refer to an integer greater than 2, such as greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10 .

It should be understood that the term "optionally containing 1, 2 or more impurity atoms selected from O, N or S" means a case where there is no impurity atom, or a case where there is 1, 2 or more impurity atoms selected from O, N or S.

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

The term "C _1-10 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1 to 10 carbon atoms. For example, "C _1-6 alkyl" means straight and branched chain alkyl groups with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. , straight and branched chain alkyl groups of 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl , 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methyl Pentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl , 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferably, the alkoxy group contains 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (C _1-12 alkoxy), and more preferably, the alkoxy group contains 1 to 6 carbon atoms (C _1-6 alkoxy). Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted.

The term " _C2-10 alkenyl" is understood to preferably mean a linear or branched monovalent alkyl group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably " _C2-8 alkenyl". " _C2-10 alkenyl" is understood to preferably mean a linear or branched monovalent alkyl group containing one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., _C2-6 alkenyl), having 2 or 3 carbon atoms (i.e., _C2-3 alkenyl). It should be understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)- pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

The term " _C2-10 alkynyl" is to be understood as preferably meaning a linear or branched monovalent hydrocarbon radical comprising one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., " _C2-8 alkynyl"), having 2, 3, 4, 5 or 6 carbon atoms (i.e., " _C2-6 alkynyl"), having 2 or 3 carbon atoms (" _C2-3 alkynyl"). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 4-methylbut-2-ynyl, 5-methylbut-3-ynyl, 6-methylbut-1-ynyl, 7-methylbut-2-ynyl, 8-methylbut-1-ynyl, 9-methylbut-2-ynyl, 10-methylbut-1-ynyl, 11-methylbut-2-ynyl, 12-methylbut-1-ynyl, 13-methylbut-2-ynyl, 14-methylbut-1-ynyl, 15-methylbut-1-ynyl, 16-methylbut-2-ynyl, 17-methylbut-1-ynyl, 18-methylbut-1-ynyl, 19-methylbut-1-ynyl, 19-methylbut-1-ynyl, 12-methylbut-1-ynyl, 13-methylbut-1-ynyl, 14-methylbut-1-ynyl, 15-methylbut-2 In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl.

The term "C _3-20 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as bicyclic, spirocyclic, bridged) alkyl or tricyclic alkane having 3 to 20 carbon atoms, preferably "C _3-12 cycloalkyl", more preferably "C _3-8 cycloalkyl". The term "C _3-12 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged, spirocyclic) alkyl or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The C The _3-12- cycloalkyl group may be a monocyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic alkyl group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2 .2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonanyl, 2,6-diazaspiro[3,4]octanyl, or a tricyclic alkyl group such as adamantyl.

The term "3-20 membered nitrogen-containing heterocyclyl" refers to a saturated or unsaturated nitrogen-containing non-aromatic ring or ring system, for example, which is 4-, 5-, 6- or 7-membered Monocyclic, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered bicyclic (such as paracyclic, spirocyclic, bridged) or tricyclic ring systems, and contain at least An N may also not contain or contain, for example, 1, 2, 3, 4, 5 or more heteroatoms selected from O and S, wherein N and S may also be optionally oxidized to various oxidation states to The state of nitrogen oxide, -S(O)- or -S(O) ₂ - is formed. Preferably, the heterocyclic group can be selected from "3-12-membered nitrogen-containing heterocyclic group". The term "3-12 membered nitrogen-containing heterocyclyl" means a saturated or unsaturated nitrogen-containing non-aromatic ring or ring system and containing at least one N atom, free of or containing selected from O and S and of heteroatoms. The heterocyclyl group is attached to the parent core through an N atom and may be attached to the rest of the molecule through any one of the carbon atoms or other nitrogen atoms, if present. The heterocyclyl group may include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl group may include, but is not limited to: 4-membered ring, such as azetidinyl; 5-membered ring, such as pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring. A membered ring, such as piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclyl group may be benzo-fused. The heterocyclyl group may be bicyclic, such as but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring. Heterocyclyl may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl , 1,2,3,5-tetrahydroxazolyl or 4H-[1,4]thiazinyl, or it can be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3-12-membered nitrogen-containing heterocyclic group is connected to other groups to form the compound of the present invention, the N atom on the 3-12-membered nitrogen-containing heterocyclic group can be connected to the mother core, and the carbon atom is connected to other groups. The group is connected. For example, when the 3-12-membered nitrogen-containing heterocyclic group is selected from the piperazinyl group, the nitrogen atom on the piperazinyl group can be connected to the parent core. Or when the 3-12-membered nitrogen-containing heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring can be connected to the parent core.

The term "spiro" refers to a ring system in which two rings share one ring-forming atom.

The term "parallel ring" refers to a ring system in which two rings share two ring-forming atoms.

The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

The term "C _6-14 aryl- _{C 1-10 alkyl" refers to a C 1-10 alkyl group} substituted with a C _6-14 aryl group, _with the attachment point being _{the C 1-10 alkyl} group.

The term "5-14-membered heteroaryl-C _1-10 alkyl" refers to _{a C 1-10 alkyl} group substituted by a _5-14 -membered heteroaryl group, _{and the attachment point is at the C 1-10 alkyl} group.

和

。芳基可以是取代的或未取代的。 The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably 6 to 10 members such as phenyl and naphthyl. The aryl ring includes an aryl ring fused to a heteroaryl, heterocyclyl or cycloalkyl ring as described herein, where the ring attached to the parent structure is an aryl ring, which is not limited to Examples include:

and

. Aryl groups may be substituted or unsubstituted.

和

。雜芳基可以是取代的或未取代的。 The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 (eg, 1, 2, 3, and 4) heteroatoms, and from 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members (such as 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described herein, where the ring attached to the parent structure is a heteroaryl ring, which is not limited to Sexual examples include:

and

. Heteroaryl groups may be substituted or unsubstituted.

The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" as used herein may be substituted or unsubstituted; when substituted When , it can be substituted at any available point of attachment, and the substituents are preferably independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano One or more substituents that are the same or different from the group consisting of amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

Pharmaceutically acceptable salts of the compounds described in the present invention can be inorganic salts or organic salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form a base. Addition salts; these compounds can also form internal salts if they contain both acidic centers (e.g. carboxyl groups) and basic centers (e.g. amine groups).

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers , (L)-isomers, racemic mixtures and other mixtures, as well as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

」表示未指定構型，「

」或「

」表示絕對構型，即如果化學結構中存在掌性異構物，鍵「

」可以為「

」或「

」，或者同時包含「

」和「

」兩種構型，「

」表示存在軸掌性。 In the chemical structure of the compound of the present invention, the bond "

” means that the configuration is not specified, “

"or"

"Indicates the absolute configuration, that is, if there is a chiral isomer in the chemical structure, the bond"

” can be “

"or"

", or both "

"and"

"Two configurations,"

” indicates the existence of axial chirality.

」表示未指定構型，包括順式(E)或反式(Z)構型。 Key

" indicates unspecified configuration, including cis (E) or trans (Z) configuration.

In addition, the compounds and intermediates of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. "Tautomers" refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactam Isomerization of imines. All tautomeric forms of all compounds of the invention are within the scope of the invention. The name of a compound named in a single way does not exclude any tautomers.

The invention also includes compounds of the invention that have the same structure as described herein but are isotopically labeled with one or more atoms replaced by atoms of atomic weights or mass numbers different from those typically found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ respectively N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl, etc. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

Unless otherwise stated, when a position is specifically designated as deuterium (D), that position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10 % deuterium incorporation). Examples of compounds having a natural abundance greater than deuterium may be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. A person of ordinary skill in the art can synthesize the deuterated form of the compound with reference to the relevant literature. In preparing deuterated forms of compounds commercially available deuterated Starting materials, or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated ethyl iodide, and deuterated ethane. Methyl iodide, etc.

The "therapeutically effective amount" of the present invention refers to the amount of active compounds or drugs that researchers, veterinarians, physicians or other clinicians are looking for to cause biological or medical responses in tissues, systems, animals, individuals or humans, and it includes One or more of the following: (1) Prevention of disease: e.g., prevention of a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who has not yet experienced or developed the pathology or symptoms of the disease. (2) Inhibition of disease: e.g., inhibition of a disease, disorder, or condition (i.e., preventing further progression of pathology and/or symptoms) in an individual who is experiencing or developing pathology or symptoms of the disease, disorder, or condition. (3) Disease amelioration: e.g., alleviation of a disease, disorder, or condition (i.e., reversal of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. For a drug or pharmacologically active agent, the "therapeutically effective dose" refers to a non-toxic amount of the drug or agent that is sufficient to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in an individual case can be determined by a person with ordinary knowledge in the art based on routine experiments.

The term "pharmaceutically acceptable" in the present invention means that these compounds, materials, compositions and/or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reaction or other problems or complications within the scope of reasonable medical judgment, have a reasonable benefit/risk ratio, and are effective for the intended use.

The "patient" of the present invention refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or spirits. Long animals, preferably humans.

The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following examples are only illustrative and explain the present invention, and should not be construed as limiting the scope of the present invention. All technologies implemented based on the above contents of the present invention are covered by the scope of protection intended by the present invention.

Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR was measured using a Bruker ASCEND ^TM -400 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl styrene (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). The internal standard was Tetramethylsilane (TMS).

MS was determined using A gilent 6110, A gilent 1100, A gilent 6120, and A gilent G6125B liquid chromatography-mass spectrometry instruments.

HPLC determination was performed using Shimadzu HPLC-2010C high performance liquid column chromatograph (XBRID GE 2.1*50mm; 3.5μm column).

Chiral HPLC analysis was performed using THARSFC X5.

The thin layer chromatography silica plate uses the Yantai Qingdao GF254 silica plate. The silica plate used in thin layer column chromatography (TLC) uses a specification of 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

Column chromatography generally uses Qingdao Marine Silica Gel with a mesh size of 200-300 as the carrier.

High-performance liquid phase preparation uses Waters 2767, Waters 2545, and Chuangxinheng Pass LC3000 preparative column chromatograph.

For chiral preparation column analysis, Shimadzu LC-20AP, THARSFC PREP 80.

CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The pressurized hydrogenation reaction uses Beijing Jiawei Kechuang Technology GCD-500 G type hydrogen generator.

Microwave reaction uses Biotag initiator+ type microwave reactor.

Unless otherwise specified in the experimental examples, the reactions were carried out under an argon atmosphere or a nitrogen atmosphere.

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

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.

Unless otherwise specified in the experimental examples, the reaction temperature is room temperature, and the temperature range is 20℃-30℃.

Synthesis of intermediate compound A-5

Step 1: Synthesis of compound A-5b

Trisene chloride (22.43g, 188.5mmol) was slowly added dropwise to a solution of compound A-5a (20.00g, 125mol) in ethanol (60mL), and the reaction mixture was heated at 60°C for 3 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure to remove the solvent to obtain the compound. A-5b (20.00g) crude product, this crude product was directly used in the next step of reaction.

MS m/z (ESI): 187.9 [M+1] ⁺ .

Step 2: Synthesis of Compound A-5c

Compound A-5b (16.00 g, 85.6 mmol) was dissolved in ethanol (60 mL), and sodium borohydride (6.48 g, 171.2 mmol) was slowly added to the solution in batches at 0°C. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed by reducing pressure and concentration, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:5) to obtain compound A-5c (16.00 g; yield: 73.5%).

MS m/z (ESI): 146.1 [M+1] ⁺ .

Step 3: Synthesis of Compound A-5

At room temperature, sulfonyl chloride (1.77 g, 0.015 mol) was slowly added to a solution of compound A-5c (1.80 g, 0.012 mol) and N,N-dimethylformamide (5 drops) in dichloromethane (50 mL), and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, ammonium chloride solution (100 mL, 4 M) was added to the reaction solution to adjust the pH value to neutral, then water (20 mL) was added and extracted with dichloromethane (10 mL × 3). The combined organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:0~5:1) to obtain compound A-5 (1.80 g; yield: 84.68%).

¹ H NMR(400MHz, CDCl ₃ )δ 8.35(d,J=2.4Hz,1H),7.26(ddd,J=9.1,8.0,2.6Hz,1H),4.72(d,J=2.1Hz,2H).

Synthesis of compound A

Step 1: Synthesis of compound A-2

At -78°C, a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (141 mL, 141 mmol) was slowly added to a solution of compound A-1 (20 g, 141 mmol) in tetrahydrofuran (500 mL). The reaction solution was stirred at -78°C for 1 hour, and then acetyl chloride (6.6 g, 844 mmol) was slowly added dropwise. The resulting mixture was stirred at -78°C for 1 hour. After the reaction was completed, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (500 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:0~2:1) to obtain compound A-2 (6.6 g; yield: 30%).

MS m/z(ESI): 185.1[M+1] ⁺ .

Step 2: Synthesis of Compound A-4

A solution of compound A-2 (8.98g, 48.7mmol) and compound A-3 (4.63g, 32.5mmol) in 1,4-dioxane (150mL) was heated to 90°C and stirred for 3.5 hours. After the reaction solution was naturally cooled to room temperature, methanesulfonic acid (3.12g, 32.5mmol) was added, and then the reaction was heated to 50°C and stirred for 3 hours. After the reaction is completed, the reaction mixture is naturally cooled to room temperature. The mixture was filtered, and the filter cake was collected and dried to obtain compound A-4 (5.60 g, yield: 69%).

MS m/z(ESI): 251.0[M+1] ⁺ .

Step 3: Synthesis of compound A-6

Compound A-5 (4.01g, 24.6mmol) was added to compound A-4 (5.60g, 22.3mmol), potassium carbonate (7.69g, 55.7mmol) and 18-crown-6 (1.18g, 4.4mmol) N , N-dimethylformamide (80 mL) mixture, the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into water (100 mL), and extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with brine (20 mL .

MS m/z(ESI): 378.0[M+1] ⁺ .

Step 4: Synthesis of compound A-8

Bistriphenylphosphine palladium dichloride (1.56g, 2.22mmol) was added to compound A-6 (8.4g, 22.2mmol) and tributyl(1-ethoxyethylene)tin (compound A-7) ( 10.21g, 24.2mmol) in a solution of 1,4-dioxane (100mL), the reaction solution was heated to 130°C and stirred for 4 hours. The reaction solution was then filtered, and the filtrate was directly concentrated under reduced pressure. Tetrahydrofuran (100 mL) was added to the residue to dissolve, and then 5 mL of concentrated hydrochloric acid was added dropwise and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate) to obtain compound A-8 (5 g; yield: 60%).

MS m/z(ESI): 386.0[M+1] ⁺ .

Step 5: Synthesis of compound A-9

Acetic acid (2 mL) was added dropwise to a solution of compound A-8 (5 g, 13 mmol) and N-chlorosuccinimide (1.90 g, 14.3 mmol) in isopropanol (100 mL), and the reaction was stirred at 60 ° C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate) to obtain compound A-9 (3.60 g; yield: 70%).

MS m/z (ESI): 420.0 [M+1] ⁺ .

Step Six: Synthesis of Compound A

N,N-dimethylformamide dimethyl acetal (0.85g, 7.2mmol) was added to a solution of compound A-9 (1.30g, 3.1mmol) in N,N-dimethylformamide (15mL), and the reaction mixture was stirred at 100°C for 3 hours. After the reaction was completed, the reaction mixture was poured into water (50mL) and extracted with ethyl acetate (30mL×3). The combined organic phase was washed with saturated brine (30mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 1:0~50:1) to obtain compound A (900mg; yield: 78%).

MS m/z (ESI): 474.9 [M+H] ⁺ .

Synthesis of intermediate compound B:

Step One: Synthesis of Compound B-2

Add diphenyl phosphate (23.5g, 0.085mol) to a mixed solution of compound B-1 (10g, 0.057mol) and triethylamine (17.3g, 0.17mol) in tert-butyl alcohol/toluene (50mL/50mL), and the reaction mixture is carried out at 110°C for 16 hours. After the reaction is completed, the reaction solution is poured into water and extracted with dichloromethane (200mL×3). The combined organic phase is washed with water (30mL), dried over anhydrous sodium sulfate and filtered, the filtrate is concentrated under reduced pressure to remove the solvent, and the resulting residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0~10:1) to obtain compound B-2 (3.6g, yield: 25%).

MS m/z(ESI): 247.0[M+1] ⁺ .

Step 2: Synthesis of compound B-3

Compound B-2 (3.6 g, 14.5 mol) was added to a mixed solution of trifluoroacetic acid/dichloromethane (15 mL/30 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was decompressed and concentrated to remove the solvent, and the resulting residue was purified by column chromatography (dichloromethane: methanol = 1:0~20:1) to obtain a crude compound B-3 (3.1 g).

MS m/z (ESI): 147.0 [M+1] ⁺ .

Step 3: Synthesis of compound B-4

Silver sulfate (6.61 g, 0.02 mol) and iodine (5.38 g, 0.02 mol) were added to a solution of compound B-3 (3.1 g, 0.02 mol) in ethanol (50 mL), and the reaction mixture was stirred at 50 ° C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 1: 0~10: 1) to obtain compound B-4 (4.9 g; yield: 65%). MS m/z (ESI): 272.7 [M+1] ⁺ .

Step 4: Synthesis of compound B-6

Under nitrogen protection, methylboric acid (530 mg, 8.8 mmol), cesium carbonate (8.96 g, 27.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (450 mg, 0.55 mmol) were added sequentially to a solution of compound B-4 (1.5 g, 5.5 mmol) in 1,4-dioxane (30 mL), and the reaction mixture was reacted at 100 ° C for 1.5 hours. After the reaction was completed, sodium bicarbonate aqueous solution was added to the reaction solution for dilution, and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:3) to obtain compound B-6 (0.43 g; yield: 48%).

MS m/z (ESI): 161.0 [M+1] ⁺ .

Step 5: Synthesis of Compound B-7

Compound B-6 (1.20 g, 6.88 mmol) was added to a solution of compound A-2 (850 mg, 5.29 mmol) in anhydrous 1,4-dioxane (8 mL), and the reaction was heated to 110 ° C and stirred at this temperature for 1 hour. After the reaction solution was cooled to 50 ° C naturally, methanesulfonic acid (285 mg, 2.96 mmol) was added, and then the reaction was continued at 50 ° C for 1 hour. After the reaction was completed, water (50 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain compound B-7 (530 mg; yield: 66%).

MS m/z (ESI): 269.0 [M+1] ⁺ .

Step 6: Synthesis of compound B-8

Potassium carbonate (1.14g, 8.28mmol), 18-crown-6 (175mg, 0.66mmol) were added to compound A-5 (702mg, 4.30mmol) and compound B-7 (890mg, 3.31 mmol) in N,N-dimethylformamide (15 mL), the reaction was heated to 40°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, added with water (50 mL) for dilution, and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound B-8 (1.5 g; purity: 84%; yield: 96%), which was directly used in the next reaction.

MS m/z(ESI): 395.8[M+1] ⁺ .

Step Seven: Synthesis of Compound B-9

Compound A-7 (2.01 g, 5.55 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (257 mg, 0.37 mmol) were added to a solution of compound B-8 (1.45 g, 3.70 mmol) in 1,4-dioxane (20 mL), and the mixture was stirred at 130 °C for 1.5 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a crude compound B-9 (3.90 g), which was directly used in the next step.

MS m/z (ESI): 431.9 [M+1] ⁺ .

Step 8: Synthesis of compound B-10

Compound B-9 (1.45 g, 3.40 mmol) was added to tetrahydrofuran (15 mL) and concentrated hydrochloric acid (0.50 mL) solution, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was reduced pressure and concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain B-10 (910 mg; yield: 66%).

MS m/z(ESI): 403.9[M+1] ⁺ .

Step 9: Synthesis of compound B-11

Combine N-chlorosuccinimide (330 mg, 2.48 mmol) and glacial acetic acid (0.20 mL) was sequentially added to a solution of compound B-10 (910 mg, 2.25 mmol) in isopropanol (12 mL), and the reaction was stirred at 60°C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound B-11 (1.13 g).

MS m/z (ESI): 437.8 [M+1] ⁺ .

Step 10: Synthesis of Compound B

N,N-dimethylformamide dimethyl acetal (600 mg, 5.0 mmol) was added to a solution of compound B-11 (1.08 g, 2.5 mmol) in N, N-dimethylformamide (15 mL) , the reaction was stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was naturally cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain the compound. B (900 mg; yield: 72%).

MS m/z (ESI): 492.7 [M+1] ⁺ .

Example 1 Synthesis of Compounds 2, 2-P1 and 2-P2

Step 1: Synthesis of compound 2-3

Compound 2-1 (300 mg, 2.42 mmol), compound 2-2 (753 mg, 2.42 mmol) and N,N-diisopropylethylamine (627 mg, 4.85 mmol) were dissolved in acetonitrile (15 mL) and stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0~4:1) to obtain compound 2-3 (620 mg; yield: 77.3%).

MS m/z (ESI): 330.0 [M+1] ⁺ .

Step 2: Synthesis of Compound 2-4

At room temperature, a solution of hydrogen chloride in 1,4-dioxane (1.9 mL, 4 M) was slowly added to a solution of compound 2-3 (500 mg, 1.52 mmol) in dichloromethane (10 mL) and reacted at room temperature for 12 hours. After the reaction was completed, the solvent was removed by reducing pressure and concentration to obtain compound 2-4 (200 mg; crude product). The crude product was directly subjected to the next step. MS m/z (ESI): 130.1 [M+1] ⁺ .

Step 3: Synthesis of Compound 2

Compound A (100 mg, 0.21 mmol), compound 2-4 (70 mg, 0.42 mmol) and potassium carbonate (87 mg, 0.63 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction mixture was heated to Stir at 90°C for 16 hours. After the reaction was completed, add water (30 mL) to dilute, and extract with ethyl acetate (20 mL × 3). Combine the organic phases, wash with saturated brine (20 mL ,150×21.2mm, 5μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-70%; column temperature: 25°C; flow rate: 14mL/min; wavelength: 214nm; column pressure: 80bar) purified Compound 2 (40 mg; yield 35.0%).

MS m/z (ESI): 540.8 [M+1] ⁺ ; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.48 (dd, J=12.2, 4.1 Hz, 2H), 8.41 (s, 1H), 7.83-7.72 (m, 2H), 6.79 (s, 1H), 5.51 (d, J=1.8 Hz, 2H), 4.20-4.11 (m, 4H), 2.17 (d, J=3.7 Hz, 3H), 1.99 (s, 3H), 1.55 (s, 3H).

Compound A (300 mg, 0.63 mmol), compound 2-4 (314 mg, 1.89 mmol) and potassium carbonate (175 mg, 1.26 mmol) were dissolved in N, N-dimethylformamide (10 mL) solution, and the reaction mixture was heated Stir to 90°C for 16 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL ) was purified to obtain crude compound 2, which was subjected to supercritical fluid chiral column chromatography ((Equipment: SFC Thar prep 80; Column: CHIRALPAK WHELK-01 250mm*21.1mm, 5μm, mobile phase: 40% MeOH/CO ₂ (NH ₄ OH 0.2%), total flow rate: 40g/min) to obtain compound 2-P1 (29.1 mg, yield 8.5%) and compound 2-P2 (40.2 mg, yield 11.7%).

Compound 2-P1:

ESI-MS[M+H] ⁺ : 541.2. SFC: retention time = 4.84min; ¹ H NMR (400MHz, CD ₃ OD) δ 8.69 (s, 1H), 8.42 (d, J = 5.2Hz, 1H), 8.39 (d, J = 2.4Hz, 1H), 8.30(s,1H),7.61(d,J=5.2Hz,1H),7.32(ddd,J=9.0,8.0,2.4Hz,1H),6.33(s,1H),5.38(t,J=2.2Hz ,2H),4.15-4.03(m,4H),2.12(s,3H),1.83(s,3H),1.54(s,3H).

Compound 2-P2:

ESI-MS [M+H] ⁺ : 541.0. SFC: retention time = 6.79 min; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.71 (s, 1H), 8.42 (d, J = 5.3 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.24 (s, 1H), 7.62 (d, J = 5.3 Hz, 1H), 7.32 (ddd, J = 9.0, 8.0, 2.4 Hz, 1H), 6.35 (s, 1H), 5.39 (s, 2H), 4.12 (dt, J = 15.3, 6.2 Hz, 4H), 2.14 (s, 3H), 1.87 (s, 3H), 1.55 (s, 3H).

Example 2 Synthesis of Compound 6

Step One: Synthesis of Compound 6-2

S-methylisothiourea sulfate (799 mg, 4.25 mol) was added to an aqueous solution (5 mL) of compound 6-1 (500 mg, 5.74 mol), and the reaction mixture was stirred at 90°C for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was washed with ethanol to obtain compound 6-2 (900 mg; yield: 92.80%).

MS m/z(ESI): 130.2[M+1] ⁺ .

Step 2: Synthesis of Compound 6

Compound 6-2 (383 mg, 1.68 mmol) and potassium carbonate (233 mg, 1.68 mmol) were added to a solution of compound A (200 mg, 0.42 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was heated at 60 Stir for 16 hours at ℃. After the reaction was completed, add water (50 mL) to dilute, and extract with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high-performance liquid phase preparative column chromatography (column chromatography column: Gemini-C18, 150× 21.2mm, 5μm; flow Phase: acetonitrile-water (0.1% formic acid); gradient: 25-50%; column temperature: 25°C; flow rate: 14mL/min; wavelength: 214nm; column pressure: 80bar) and purified to obtain compound 6 (60mg, yield: 26.3 %).

MS m/z (ESI): 541.2 [M+1] ⁺ ; ¹ H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.52 (d, J=5.0 Hz, 1H), 8.28 (s, 1H), 8.14-8.06 (m, 1H), 7.51 (d, J=5.0 Hz, 1H), 6.83 (s, 1H), 5.49 (d, J=1.2 Hz, 2H), 5.05-4.82 (m, 1H), 4.50-4.25 (m, 1H), 3.82-3.45 (m, 4H), 2.10-1.85 (m, 8H).

Example 3 Synthesis of Compound 10

Potassium carbonate (87.32 mg, 0.63 mmol) and compound 10-2 (54.4 mg, 0.42 mmol) were added to a solution of compound A (100 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 90° C. for 12 hours. After the reaction was completed, water (50 mL) was added for dilution, ethyl acetate was used for extraction (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by HPLC preparative column chromatography (column chromatography column: Xbrid ge-C18; 150 × 21.2 mm, 5 μm; column temperature: 25 ° C; flow rate: 20 mL/min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-60%) to obtain compound 10 (30.5 mg; yield: 25.4%).

MS m/z (ESI): 540.8[M+1] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD): δ 8.74 (s, 1H), 8.48 (d, J = 5.1Hz, 1H), 8.44 (d ,J=2.3Hz, 1H),8.25(s,1H),7.75-7.68(m,1H),7.58(d,J=5.1Hz,1H),6.80(s,1H),5.48(d,J= 1.5Hz,2H),3.85-3.78(m,4H),3.76-3.68(m,4H),2.13(s,3H),2.03(s,3H).

Example 4 Synthesis of Compound 11

Step One: Synthesis of Compound 11-2

Compound 11-1 (1g, 9.90mmol) and S-methylisothiourea sulfate (0.93g, 4.95mmol) were dissolved in water (15mL), and the reaction mixture was stirred at 90°C for 1 hour. Ethanol (20mL) was added and stirred for 30 minutes, filtered, and the filter cake was dried to obtain compound 11-2 (0.88g, yield: 74.1%).

MS m/z (ESI): 144.1 [M+H] ⁺ .

Step 2: Synthesis of compound 11

Compound A (119 mg, 0.25 mmol), compound 11-2 (200 mg, 1.40 mmol), potassium carbonate (116 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (5 mL) solution, stirred at 90 ° C for 12 hours. After the reaction was completed, water (10 mL) was added, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and then purified by The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 1:0~10:1), and the crude product was purified by HPLC preparative column chromatography (column chromatography column: Gemini-C18; 150×21.2mm, 5μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-70%; column temperature: 25℃; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar) to obtain compound 11 (37mg; yield: 26.7%).

MS m/z (ESI): 555.2 [M+1] ⁺ ; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.78 (s, 1H), 8.49-8.46 (m, 2H), 8.29 (s, 1H), 7.78-7.72 (m, 1H), 7.56 (d, J=5.1 Hz, 1H), 6.84 (s, 1H), 5.53 (d, J=1.9 Hz, 2H), 4.54 (d, J=13.7 Hz, 2H), 3.93-3.84 (m, 1H), 3.36 (s, 1H), 3.31 (s, 1H), 2.17 (s, 3H), 2.07 (s, 3H), 1.98-1.90 (m, 2H), 1.50 (d, J=10.7 Hz, 2H).

Example 5 Synthesis of Compounds 12, 12-P1 and 12-P2

Step 1: Synthesis of compound 12-2

S-methylisothiourea sulfate (351 mg, 1.86 mmol) was added to an aqueous solution (5.0 mL) of compound 12-1 (430 mg, 3.73 mmol) at room temperature. The reaction mixture was stirred at 90°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 12-2 (600 mg; crude product). The product was directly used in the next reaction without purification.

MS m/z (ESI): 158.1 [M+1] ⁺ .

Step 2: Synthesis of compounds 12-P1 and 12-P2

A solution of compound 12-2 (559 mg, 2.19 mmol), compound A (260 mg, 0.55 mmol) and potassium carbonate (302 mg, 2.19 mmol) in N,N-dimethylformamide (15 mL) was heated to 60°C and reacted for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 1:0~10:1) to obtain a crude product with a content of 80%. The crude product was purified by HPLC preparation column chromatography (column chromatography column: Gemini-C18; 150×21.2mm, 5μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%; column temperature: 25℃ flow rate: 14mL/min; wavelength: 214nm; column pressure: 80bar) to obtain compound 12 (45mg; yield: 14.3%).

MS m/z (ESI): 569.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.28 (s, 1H), 8.14-8.08 (m, 1H), 7.49 (d, J=5.0 Hz, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 4.39 (s, 1H), 4.28 (d, J=12.3 Hz, 2H), 3.50-3.42 (m, 2H), 2.06 (s, 3H), 1.95 (s, 3H), 1.52-1.43 (m, 4H), 1.15 (s, 3H).

Compound 12 was separated by supercritical fluid preparation column chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H, 250mm×20mm, 5μm; mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia water); flow rate: 12.5g/min) to obtain compound 12-P1 (15.4mg) and compound 12-P2 (15.8mg).

Compound 12-P1:

MS m/z (ESI): 568.8[M+1] ⁺ ; SFC: retention time = 3.50min; ¹ H NMR (400MHz, CD ₃ OD) δ 8.73 (s, 1H), 8.43 (t, J = 4.1Hz ,2H),8.24(s,1H),7.75-7.67(m,1H),7.50(d,J=5.1Hz,1H),6.79(s,1H),5.48(d,J=1.8Hz,2H) ,4.33-4.24(m,2H),3.54(ddd,J=13.5,10.1,3.8Hz,2H),2.13(s,3H),2.02(s,3H),1.63-1.54(m,4H),1.22 (s,3H).

Compound 12-P2:

MS m/z (ESI): 568.8 [M+1] ⁺ ; SFC: retention time = 5.76 min; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.66 (s, 1H), 8.36 (dd, J = 5.2, 3.7 Hz, 2H), 8.17 (s, 1H), 7.67-7.59 (m, 1H), 7.43 (d, J = 5.1 Hz, 1H), 6.72 (s, 1H), 5.40 (d, J = 1.8 Hz, 2H), 4.21 (dd, J = 13.5, 4.5 Hz, 2H), 3.53-3.43 (m, 2H), 2.05 (s, 3H), 1.95 (s, 3H), 1.56-1.47 (m, 4H), 1.15 (s, 3H).

Example 6 Synthesis of Compound 13

Step One: Synthesis of Compound 13-2

Heat an aqueous solution (50 mL) of 13-1 (1 g, 7.8 mmol) and S-methylisothiourea sulfate (730 mg, 3.90 mmol) to 90 °C and stir for 1 hour. The reaction solution was concentrated under reduced pressure, and 20 mL of ethanol was added to the residue, stirred for 30 minutes, filtered, and the filter cake was dried to obtain compound 13-2 (0.5 g; yield: 36%).

¹ H NMR (400MHz, CD ₃ OD) δ 3.76-3.68 (m, 4H), 3.67-3.52 (m, 4H), 2.15 (d, J = 7.8Hz, 3H).

Step 2: Synthesis of compound 13

A solution of compound A (100 mg, 0.21 mmol), compound 13-2 (72 mg, 0.42 mmol) and potassium carbonate (58 mg, 0.42 mmol) in N,N-dimethylformamide (10 mL) was heated to 90°C and stirred for 12 hours. The reaction mixture was diluted with water (50 mL), and extracted with dichloromethane (30 mL × 3). Combine the organic phases, wash with saturated brine (20 mL , 150×21.2mm, 5μm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 30-50%, column temperature: 25℃; flow rate: 14mL/min; wavelength: 214nm; column pressure: 80bar) Purification gave compound 13 (14.9 mg; yield: 12.2%). MS m/z (ESI): 582.1[M+H] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ 8.80 (s, 1H), 8.54 (d, J = 5.2Hz, 1H), 8.49 (d, J=2.4Hz,1H),8.36(s,1H),7.76(ddd,J=9.6,8.6,2.4Hz,1H),7.67(d,J=5.2Hz,1H),6.84(s,1H), 5.53(d,J=1.9Hz,2H),4.03-3.96(m,2H),3.96-3.89(m,2H),3.73-3.62(m,4H),2.19(s,3H),2.17(s, 3H),2.07(s,3H).

Example 7 Synthesis of compounds 33, 33-P1 and 33-P2

Step One: Synthesis of Compound 33-2

Compound 33-1 (3.60g, 23.75mmol), compound 2-2 (7.37g, 23.75mmol,) and N,N-diisopropylethylamine (6.14g, 47.50mmol) were added to acetonitrile (50mL) , stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0~5:1) to obtain compound 33-2 (7.5g; yield: 84.8 %).

MS m/z (ESI): 358.2 [M+1] ⁺ .

Step 2: Synthesis of compound 33-3

At room temperature, slowly add a solution of hydrogen chloride in dioxane (26 mL, 4 M) to a solution of compound 33-2 (7.5 g, 21 mmol) in dichloromethane (100 mL), and stir at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure to obtain compound 33-3 (6 g; crude product). The product is directly used for the next step without purification.

MS m/z (ESI): 158.1 [M+1] ⁺ .

Step 3: Synthesis of compound 33-4

Compound A (500 mg, 1.05 mmol), compound 33-3 (4.07 g; Crude product) and a solution of potassium carbonate (1.45g, 10.53mmol) in N,N-dimethylformamide (10mL) was heated to 90°C and stirred for 16 hours. The reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (20 mL × 3). Combine the organic phases, wash with saturated brine (20mL 1) Purify to obtain compound 33-4 (150 mg; yield: 22.54%).

MS m/z (ESI): 568.8 [M+1] ⁺ .

Step 4: Synthesis of Compound 33

Compound 33-4 (150 mg, 0.27 mmol) and lithium hydroxide hydrate (37 mg, 0.81 mmol) were dissolved in 10 mL of a mixed solvent of tetrahydrofuran and water (V:V=1:1), and stirred at room temperature for 12 hours. After the reaction was completed, 1 M hydrochloric acid was added dropwise to the reaction solution until pH=7. Filter and dry the filter cake to obtain a crude product. The crude product was purified by HPLC preparative column chromatography (column chromatography column: Gemini-C18; 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-50%; column temperature: 25°C; flow rate: 20 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 33 (23.2 mg, yield: 15.5%).

MS m/z (ESI): 554.6 [M+1] ⁺ ; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.85 (s, 1H), 8.49 (t, J=4.2 Hz, 2H), 8.41 (s, 1H), 7.84 (d, J=5.8 Hz, 1H), 7.80-7.71 (m, 1H), 6.81 (s, 1H), 5.52 (d, J=1.7 Hz, 2H), 4.50 (td, J=9.1, 3.3 Hz, 2H), 4.42 (td, J=8.9, 6.0 Hz, 2H), 3.70-3.63 (m, 1H), 2.19 (s, 3H), 2.03 (s, 3H).

The scaled-up batch of compound 33 (30 mg) was separated by supercritical fluid palmitic column chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH/CO ₂ (NH ₄ OH 0.2%), total flow rate: 40 g/min) to obtain compound 33-P1 (12.6 mg) and compound 33-P2 (10.4 mg).

Compound 33-P1:

MS m/z (ESI): 554.8 [M+1] ⁺ . SFC: retention time = 3.03min; UV = 254nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (s, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.23 (s, 1H), 8.14-8.07 (m, 1H), 7.61 (d, J = 5.1 Hz, 1H), 6.82 (s, 1H), 5.48 (d, J = 1.1 Hz, 2H), 4.31-4.08 (m, 4H), 3.51 (s, 1H), 2.07(s, 3H), 1.93(s, 3H).

Compound 33-P2:

MS m/z(ESI): 554.8[M+1] ⁺ . SFC: retention time=3.57min; UV=254nm. ¹ H NMR(400MHz, DMSO-d ₆ )δ 8.81(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=5.1Hz,1H),8.23(s,1H), 8.10(td,J=9.9,2.3Hz,1H),7.61(d,J=5.1Hz,1H),6.82(s,1H),5.48(s,2H),4.29-4.15(m,4H),3.50 (s,1H),2.07(s,3H),1.95(s,3H).

Example 8 Synthesis of Compounds 35, 35-P1 and 35-P2

Route 1:

Compound 33 (150 mg, 0.27 mmol), methylamine hydrochloride (109 mg, 1.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (155 mg, 0.81 mmol), 1-hydroxybenzotriazole (110 mg, 0.81 mmol) and triethylamine (82 mg, 0.81 mmol) were dissolved in dichloromethane (20 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, water (10 mL) was added for dilution, and dichloromethane was extracted (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 1: 0 ~ 20: 1) to obtain a crude product, which was purified by HPLC preparative column chromatography (column: Gemini-C18 150 x 21.2 mm, 5 μm mobile phase: ACN--H ₂ O (0.1% FA), gradient: 20-60, temperature: 45 ° C; pressure: 80 bar; wavelength: 214/254 nm; flow rate: 20 mL/min) to obtain compound 35 (2.7 mg; yield: 1.74%).

MS m/z (ESI): 567.7 [M+1] ⁺ ; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.79 (s, 1H), 8.50-8.45 (m, 2H), 8.26 (s, 1H), 7.75 (s, 1H), 7.68 (d, J=5.2 Hz, 1H), 6.83 (s, 1H), 5.52 (d, J=1.9 Hz, 2H), 4.34-4.25 (m, 4H), 3.96 (s, 1H), 2.78 (s, 3H), 2.17 (s, 3H), 2.06 (s, 3H).

Route 2:

Step 1: Synthesis of compound 35-2

Compound 35-1 (1.7 g, 7.9 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (10 mL, 4 M), and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 35-2 (1.5 g, crude product). MS m/z(ESI): 115.1[M+1] ⁺ .

Step 2: Synthesis of compound 35-3

Compound 35-2 (1.5g, 9.96mmol) was added to a solution of compound 2-2 (3.4g, 10.96mmol) and N,N-diisopropylethylamine (2.57g, 19.92mmol) in acetonitrile (30mL). , the reaction mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0~3:1) to obtain compound 35-3 (3g, yield: 84.5%). MS m/z(ESI): 357.0.[M+1] ⁺ .

Step 3: Synthesis of compound 35-4

Compound 35-3 (500 mg, 1.40 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (10 mL, 4 M), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 35-4 (300 mg, crude product). MS m/z (ESI): 157.1 [M+1] ⁺ .

Step 4: Synthesis of compound 35

Compound 35-4 (300 mg, 1.92 mmol) was added to a solution of compound A (182.43 mg, 0.38 mmol) and potassium carbonate (530.94 mg, 3.84 mmol) in N,N-dimethylformamide (10 mL), and the reaction was carried out The mixture was stirred at 90°C for 12 hours. After the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Compound 35 was purified by silica gel column chromatography (dichloromethane: methanol = 1:0~10:1). Compound 35 was passed through supercritical fluid chiral column chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD -H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO ₂ (NH ₄ OH 0.2%), total flow rate: 40g/min) to obtain compound 35-P1 (48.6mg, yield 4.5%) and compound 35-P2 (59.8 mg, yield 5.5%).

Compound 35-P1:

MS m/z(ESI): 568.2[M+1] ⁺ . SFC: retention time=2.76min, UV=254nm. ¹ H NMR(400MHz, DMSO-d ₆ )δ 8.81(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=5.0Hz,1H),8.21(s,1H), 8.16-8.06(m,1H),7.98(d,J=4.7Hz,1H),7.59(d,J=5.1Hz,1H),6.82(s,1H),5.48(s,2H),4.21(t ,J=8.6Hz,2H),4.12(dd,J=14.9,8.7Hz,2H),3.41(td,J=8.5,4.2Hz,1H),2.61(d,J=4.6Hz,3H),2.08 (s,3H),1.95(s,3H).

Compound 35-P2:

MS m/z(ESI): 568.2[M+1] ⁺ . SFC: retention time=3.2min, UV=254nm. ¹ H NMR(400MHz, DMSO-d ₆ )δ 8.81(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=5.1Hz,1H),8.21(s,1H), 8.15-8.08(m,1H),7.98(d,J=4.6Hz,1H),7.59(d,J=5.1Hz,1H),6.82(s,1H),5.49(d,J=1.1Hz,2H ),4.21(t,J=8.5Hz,2H),4.12(dd,J=14.8,8.7Hz,2H),3.49-3.36(m,1H),2.61(d,J=4.6Hz,3H),2.08 (s,3H),1.95(s,3H).

Example 9 Synthesis of Compound 38

Step 1: Synthesis of compound 38-2

Compound 38-1 (500mg, 2.17mmol), methylamine hydrochloride (161mg, 2.39mmol), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N', N'-tetramethylurea hexafluorophosphate) (1.65g, 4.34mmol), N,N-diisopropylethylamine (840mg, 6.51mmol) was dissolved in N,N-dimethylformamide (10mL ), stir at room temperature for 16 hours under nitrogen protection. After the reaction was completed, add water (10 mL) to dilute, and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 1:0~20:1) to obtain compound 38. -2 (550 mg; purity 75%; yield: 78.1%).

MS m/z(ESI): 265.0[M+23] ⁺ .

Step 2: Synthesis of compound 38-3

Add a solution of 1,4-dioxane in hydrogen chloride (3mL, 4M) to a solution of compound 38-2 (600mg, 2.48mmol) in dichloromethane (10mL) and stir at room temperature for 2 hours. After the reaction is completed, reduce the pressure and concentrate to obtain compound 38-3 (600mg; crude product). The product is directly used for the next reaction without purification.

MS m/z (ESI): 143.1 [M+1] ⁺ .

Step 3: Synthesis of compound 38-4

Compound 38-3 (300 mg, 1.68 mmol), compound 2-2 (520 mg, 1.68 mmol), and N,N-diisopropylethylamine (434 mg, 3.35 mmol) were dissolved in acetonitrile (5 mL), and the reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 1:0~20:1) to obtain compound 38-4 (650 mg; yield: 80.7%).

MS m/z(ESI): 385.0[M+1] ⁺ .

Step 4: Synthesis of compound 38-5

A solution of hydrogen chloride in 1,4-dioxane (3 mL, 4 M) was added to a solution of compound 38-4 (550 mg, 1.43 mmol) in dichloromethane (5 mL), and the reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound 38-5 (500 mg; crude product). The product was directly subjected to the next step without purification.

MS m/z(ESI): 185.2[M+1] ⁺ .

Step 5: Synthesis of compound 38

Compound 38-5 (264 mg, 1.20 mmol), compound A (171 mg, 0.36 mmol) and potassium carbonate (247 mg, 1.79 mmol) were dissolved in N-N dimethylformamide (10 mL) and stirred at 65°C for 16 hours. . After the reaction was completed, dilute with water (100 mL) and extract with ethyl acetate (50 mL × 3). Combine the organic phases, dry and filter over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0~2:1) to obtain a crude product, which is purified by high-performance liquid Phase preparation column chromatography (column chromatography column: Gemini-C18, 150×21.2mm, 5μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-50%; column temperature: 25°C; flow rate :20mL/min; wavelength: 214nm; column pressure: 80bar) purification Compound 38 (40 mg; yield: 18.6%) was obtained.

MS m/z (ESI): 596.2[M+1] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ 8.79 (s, 1H), 8.49 (d, J = 3.1Hz, 1H), 8.48 (s, 1H),8.31(s,1H),7.79-7.71(m,1H),7.60(d,J=5.2Hz,1H),6.84(s,1H),5.52(d,J=1.9Hz,2H), 2.99(t,J=12.3Hz,3H),2.73(s,3H),2.55-2.45(m,1H),2.18(s,3H),2.07(s,3H),1.86(d,J=10.8Hz ,2H),1.68(dd,J=25.0,12.4Hz,3H).

Example 10 Synthesis of compounds 41, 41-P1 and 41-P2

Step 1: Synthesis of compound 41-2

Compound 41-1 (400 mg, 2.33 mmol), compound 2-2 (723 mg, 2.33 mmol,) and N,N-diisopropylethylamine (602 mg, 4.66 mmol) were dissolved in acetonitrile (20 mL), and the reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the pressure was reduced and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0~4:1) to obtain compound 41-2 (600 mg; yield: 64.8%).

MS m/z (ESI): 377.9 [M+1] ⁺ .

Step 2: Synthesis of compound 41-3

A solution of hydrogen chloride in 1,4-dioxane (1.7 mL, 4 M) was slowly added to a solution of compound 41-2 (500 mg, 1.32 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 41-3 (220 mg; crude product). The product was directly subjected to the next step without purification.

MS m/z(ESI): 178.0[M+1] ⁺ .

Step 3: Synthesis of Compound 41

A solution of compound A (150 mg, 0.31 mmol), compound 41-3 (135 mg; crude product) and potassium carbonate (128 mg, 0.93 mmol) in N,N-dimethylformamide (15 mL) was heated to 90°C and stirred for 16 hours. After the reaction was completed, water (30 mL) was added to dilute it, and then extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by HPLC preparative column chromatography (column chromatography column: Gemini-C18, 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-50%, column temperature: 25 ° C, flow rate: 14 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 41 (41.6 mg; yield 21.9%).

MS m/z (ESI): 588.8 [M+1] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (s, 1H), 8.58 (d, J=2.4 Hz, 1H), 8.55 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 8.07 (ddd, J=10.0, 9.0, 2.4 Hz, 1H), 7.64 (d, J=5.1 Hz, 1H), 6.80 (s, 1H), 5.45 (d, J=1.5 Hz, 2H), 4.45-4.21 (m, 5H), 3.02 (s, 3H), 2.04 (s, 3H), 1.92 (s, 3H).

The scaled-up batch of compound 41 was separated by supercritical fluid palmitic column chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO ₂ (NH ₄ OH 0.2%), total flow rate: 40g/min) to obtain compound 41-P1 (33.3mg, yield 10.5%) and compound 41-P2 (29.8mg, yield 9.3%).

Compound 41-P1:

MS m/z (ESI): 588.7 [M+1] ⁺ . SFC: retention time = 6.92 min, UV = 254 nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.68 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.20 (s, 1H), 7.68-7.58 (m, 2H), 6.71 (s, 1H), 5.40 (d, J = 1.9 Hz, 2H), 4.42-4.29 (m, 4H), 4.29-4.22 (m, 1H), 2.90 (s, 3H), 2.06 (s, 3H), 1.93 (s, 3H).

Compound 41-P2:

MS m/z (ESI): 588.7 [M+1] ⁺ . SFC: retention time = 8.76 min, UV = 254 nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.68 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.20 (s, 1H), 7.69-7.59 (m, 2H), 6.71 (s, 1H), 5.40 (d, J = 1.8 Hz, 2H), 4.43-4.30 (m, 4H), 4.26 (d, J = 8.2 Hz, 1H), 2.89 (d, J = 5.7 Hz, 3H), 2.06 (s, 3H), 1.93 (s, 3H).

Example 11 Synthesis of Compound 45

Step 1: Synthesis of compound 45-2

Compound 45-1 (500 mg, 3.86 mmol), compound 2-2 (1.2 g, 3.86 mmol) and N, N-diisopropylethylamine (998 mg, 7.72 mmol) were dissolved in acetonitrile (15 mL) at room temperature. Stir for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0~4:1) to obtain compound 45-2 (1.2g; yield: 88% )

MS m/z (ESI): 335.9 [M+1] ⁺ .

Step 2: Synthesis of compound 45-3

Add a solution of 1,4-dioxane in hydrogen chloride (1.8 mL, 4 M) to a solution of compound 45-2 (800 mg, 2.38 mmol) in dichloromethane (15 mL) and stir at room temperature for 12 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain compound 45-3 (200 mg; crude product). The product is directly used for the next step without purification.

MS m/z (ESI): 136.1 [M+1] ⁺ .

Step 3: Synthesis of compound 45

A solution of compound A (100 mg, 0.21 mmol), compound 45-3 (72 mg, 0.42 mmol) and potassium carbonate (87 mg, 0.63 mmol) in N,N-dimethylformamide (8 mL) was heated to 90 °C and stirred for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by HPLC preparative column chromatography (column chromatography column: Gemini-C18; 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%; column temperature: 25 ° C; flow rate: 14 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 45 (20.2 mg; yield 16.6%).

MS m/z (ESI): 546.8 [M+1] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 8.62 (dd, J=8.6, 3.7 Hz, 2H), 8.26 (s, 1H), 8.11 (td, J=10.0, 2.3 Hz, 1H), 7.74 (d, J=5.1 Hz, 1H), 6.84 (s, 1H), 5.50 (s, 2H), 4.56 (t, J=12.5 Hz, 4H), 2.09 (s, 3H), 1.96 (s, 3H).

Example 12 Synthesis of Compounds 34, 34-P1 and 34-P2

Step One: Synthesis of Compound 34-2

Isobutyl chloroformate (2.7 g, 19.78 mmol) was added to a tetrahydrofuran (50 mL) solution of compound 34-1 (2.0 g, 9.88 mmol) and N-methylmorpholine (1.5 g, 14.83 mmol), and the reaction mixture was stirred at -10 ° C for 1 hour, and then ammonia methanol solution (20 mL) was added and stirred for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0~1:1) to obtain compound 34-2 (2.1 g, yield: 84.41%). MS m/z (ESI): 145.1 [M+1] ⁺ .

Step 2: Synthesis of compound 34-3

A solution of hydrogen chloride in 1,4-dioxane (15 mL, 4 M) was added to a solution of compound 34-2 (2.1 g, 10.43 mmol) in dichloromethane (15 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 34-3 (1.5 g; yield: 86.14%). MS m/z(ESI): 101.1[M+1] ⁺ .

Step 3: Synthesis of compound 34-4

Compound 2-2 (3.1g, 9.99mmol) was added to a solution of compound 34-3 (1.0g, 9.99mmol) and N,N-diisopropylethylamine (2.58g, 19.98mmol) in acetonitrile (15mL). , the reaction mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0~1:1) to obtain compound 34-4 (1.0g, yield: 26.32%) . MS m/z(ESI): 342.9.[M+1] ⁺ .

Step 4: Synthesis of compound 34-5

A solution of hydrogen chloride in 1,4-dioxane (3 mL, 4 M) was added to a solution of compound 34-4 (1.0 g, 2.92 mmol) in dichloromethane (3 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 34-5 (450 mg; yield: 97.55%). MS m/z (ESI): 143.0.[M+1] ⁺ .

Step 5: Synthesis of Compound 34

Compound 34-5 (449 mg, 3.16 mmol) was added to a solution of compound A (300 mg, 0.63 mmol) and potassium carbonate (523.84 mg, 3.79 mmol) in N,N-dimethylformamide (5 mL), and the reaction was carried out The mixture was stirred at 90°C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 1:0~10:1) to obtain compound 34. Compound 34 was subjected to supercritical fluid chiral column chromatography ((Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO ₂ (NH ₄ OH 0.2%), total flow rate: 40g/min), the compound 34-P1 (40.5 mg, yield 11.3%) and compound 34-P2 (47.1 mg, yield 13.1%).

Compound 34-P1:

MS m/z(ESI): [M+1] ⁺ 553.8. SFC: retention time=3.81min, UV=214nm. ¹ H NMR(400MHz, CD ₃ OD)δ 8.74(s,1H),8.43(dd,J=3.8,1.3Hz,2H),8.24(s,1H),7.75-7.68(m,1H),7.63( d,J=5.2Hz,1H),6.77(s,1H),5.47(d,J=1.8Hz,2H),4.35-4.17(m,4H),3.59-3.46(m,1H),2.12(s ,3H),2.00(s,3H).

Compound 34-P2:

ESI-MS[M+H] ⁺ : 553.8. SFC: retention time=4.6min, UV=214nm. 1H NMR(400MHz, CD ₃ OD)δ 8.74(s,1H),8.43(dd,J=3.9,1.1Hz,2H),8.24(s,1H),7.75-7.67(m,1H),7.63(d ,J=5.2Hz,1H),6.77(s,1H),5.47(d,J=1.6Hz,2H),4.35-4.18(m,4H),3.59-3.46(m,1H),2.13(s, 3H),2.00(s,3H).

Example 13 Synthesis of Compounds 29, 29-P1 and 29-P2

Compound 2-4 (303 mg, 1.83 mmol) was added to a solution of compound B (300 mg, 0.61 mmol) and potassium carbonate (168 mg, 1.22 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated Stir to 90°C for 16 hours. After the reaction was completed, the reaction solution was poured into water (30 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL ) was purified to obtain crude compound 29, which was subjected to supercritical fluid chiral column chromatography ((Equipment: SFC Thar prep 80, column: CHIRALPAK IC 250mm*4.6mm, 5μm, mobile phase: 40% MeOH/CO ₂ ( NH ₄ OH 0.2%), total flow rate: 40g/min) was separated to obtain compound 29-P1 (19.5 mg, yield 5.7%) and compound 29-P2 (22.6 mg, yield 6.6%).

Compound 29-P1:

ESI-MS [M+H] ⁺ : 559.1. SFC: retention time = 5.44 min, UV = 214 nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.63 (s, 1H), 8.44 (dd, J = 3.8, 1.3 Hz, 2H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 7.27 (d, J = 5.1 Hz, 1H), 6.85 (d, J = 0.5 Hz, 1H), 5.49 (d, J = 1.9 Hz, 2H), 4.09-3.91 (m, 4H), 2.19 (s, 3H), 2.10 (s, 3H), 1.51 (s, 3H).

Compound 29-P2:

ESI-MS [M+H] ⁺ : 559.1. SFC: retention time = 15.16 min, UV = 214 nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.63 (s, 1H), 8.44 (dd, J = 3.8, 1.3 Hz, 2H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 7.32-7.21 (m, 1H), 6.85 (s, 1H), 5.49 (d, J = 1.9 Hz, 2H), 4.10-3.93 (m, 4H), 2.19 (s, 3H), 2.10 (s, 3H), 1.51 (s, 3H).

According to the above examples, the following compounds were prepared:

biological evaluation

1. Determination of p38 MAPK/MK2 activity in vitro

The inhibitory effect of the compounds on p38 MAPK/MK2 was detected using Z-LYTE kinase assay kit (Thermo, PV3177). The test compounds were dissolved in DMSO to a 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound was 10 μM, 1% DMSO, 5-fold dilution, 8 concentrations, duplicate wells; 50 mM HEPES pH 7.5, 10 mM MgCl ₂ , 0.01% Brij-35, 1 mM EGTA were used as reaction buffer to prepare 2x active p38a/inactive MK2/Ser/Thr 4 mixture. The final 10 μL reaction system was carried out in a 384-well plate (Corning, 4514), containing 500 ng/mL inactive MK2 (abcam, 79910), 8 ng/mL active p38a (Carna, 04-152), 2 μm Ser/Thr 4; after reacting at 20°C for 1 hour, Development Rea gent diluted 2048 times was added to each well. A, after incubation at room temperature for 1 hour, 5 μL of stop buffer solution was added to terminate the reaction, and the enzyme marker was used for detection (Ex. 400nm, Em. 445nm; Ex. 400nm, Em. 520nm). The concentration-effect curve was fitted using GraphPad Prism 8 software, and the compound concentration with 50% inhibition effect, i.e. IC ₅₀ , was calculated. The results are shown in Table 1.

As can be seen from Table 1, the compounds of the present invention have good inhibitory activity against p38 MAPK/MK2.

2. In vitro activity assay of p38 MAPK/MK5

The inhibitory effect of compounds on p38 MAPK/MK5 was detected using Z-LYTE kinase detection kit (Thermo, PV3177). Dissolve the test compound in DMSO to 10mM stock solution and store at -20°C until use. The starting concentration of the compound is 10μM, 1% DMSO, 5-fold dilution, 8 concentrations, double wells; 50mM HEPES pH 7.5, 10mM MgCl ₂ , 0.01% Brij-35, 1mM EGTA are used as reaction buffer to prepare 2x active p38a/inactive MK5/Ser/Thr 4 mixture, the final 10 μL reaction system was carried out in a 384-well plate (Corning, 4514), containing 10 μg/mL inactive MK5 (abcam, 217826), 1ng/mL active p38a (Carna, 04-152), 2μm Ser/Thr 4; after 4 hours of reaction at 20°C, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, add 5μL of stop buffer solution to terminate the reaction, and detect with a microplate reader ( Ex.400nm, Em.445nm; Ex.400nm, Em.520nm). Use GraphPad Prism 8 software to fit the concentration-effect curve and calculate the compound concentration with 50% inhibitory effect, that is, IC ₅₀ . The results are shown in Table 2.

As can be seen from Table 2, the inhibitory activities of the compounds of the present invention on p38 MAPK/MK5 are all greater than 2 μm. This further demonstrates that the compounds of the present invention have good selectivity for p38 MAPK/MK2.

3. Determination of p38 MAPK/ATF2 activity in vitro

The inhibitory effect of the compound on p38a-catalyzed ATF2 was detected by HTRF method. The test compound was dissolved in DMSO to a 10 mM stock solution and stored at -20°C until use. The starting concentration of the compound was 10 μM, 0.25% DMSO, 5-fold dilution, 8 concentrations, duplicate wells; 40 mM Tris pH 7.5, 20 mM MgCl ₂ , 0.1 mg/mL BSA, 50 μm DTT was used as reaction buffer to prepare 3.5 x p38a (MAPK14, Carna Biosciences, 04-152) protein working solution, 3.5 x Human ATF2 Protein (Sino Biological, 11599-H20B) working solution and 3.5 x ATP working solution, 10 mM EDTA was used to terminate the reaction, and the final 14 μL reaction system was carried out in a 96-well plate (cisbio, 66PL96025), containing 0.29 ng/μL p38a, 0.29 μM Human ATF2 Protein; 25 μM ATP. After reacting at 20℃ for 35min, pre-prepared antibody solution (cibio, 63ADK015PEG, Phospho-ATF2 Eu Cryptate antibody, Phospho-ATF2 d2 antibody, diluted 40 times with Detection buffer) was added to each well and incubated at room temperature overnight. The reaction was detected by ELISA (HTRF compatible reader). The concentration-effect curve was fitted using GraphPad Prism 8 software, and the compound concentration with 50% inhibition effect, i.e. IC ₅₀ , was calculated. The results are shown in Table 3.

As can be seen from Table 3, the inhibitory activity of the compounds of the present invention on p38 MAPK/ATF2 is greater than 3.7μm. This further shows that the compounds of the present invention have good selectivity for p38 MAPK/MK2.

4. Determination of in vitro activity of TNF-α in human PBMC cell supernatant

The experimental protocol for the inhibitory effect of compounds on TNF-α in human PBMC cell supernatants was tested using Elisa detection kit (Beyotime, PI518). Dissolve the test compound in DMSO to 10mM stock solution and store it at -20°C until use. The starting concentration of the compound is 2 μM, 5-fold dilution, 6 concentrations, cells are plated in double wells, Elisa detection is single well, the final concentration of DMSO is 0.4%, the starting concentration of the compound can also be changed according to the actual situation of compound screening. , dilution ratio, number of gradient concentrations and number of duplicate wells.

Fresh human peripheral blood mononuclear cells (PBMC) (Sel Bio) were plated in a 96-well plate (Corning, 3599) at a number of 2*10^5, and each well contained 100 μL of RPMI-1640 (Gibco#A1049101)+10 % FBS (Gibco, 10099141C), cultured overnight at 37°C, 5% _CO2 ; the compound to be tested was added to the 96-well culture plate at a volume of 25 μL/well. After 1 hour, 5 μL of LPS was added to make the final concentration 100ng/mL. , no LPS and compounds were added to the negative control wells, and no compounds were added to the positive control wells. After continuing to culture for 24 hours at 37°C and 5% CO ₂ , centrifuge at 500 rcf for 8 minutes to collect the cell culture supernatant. Follow the operation manual in the Elisaa kit. Detect the concentration of TNF-α. Use GraphPad Prism 8 software to fit the concentration-effect curve and calculate the compound concentration with 50% inhibitory effect, that is, IC ₅₀ . The results are shown in Table 4.

As can be seen from Table 4, the compounds of the present invention have good inhibitory effects on TNF-α in human PBMC cells.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiment. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (18)

A compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label or its pharmaceutically acceptable salt:

Among them, W is CH or N; m is an integer from 0 to 5; n is an integer from 0 to 3; ring A is a 3-20-membered nitrogen-containing heterocyclic group, except for the parent nucleus

In addition to the connected N atoms, it optionally contains 1, 2 or more heteroatoms selected from O, N or S; R ¹ is selected from H, halogen, CN and C _1-6 alkyl; R ² Selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ; R ³ is selected from H, C ₁ - ₁₀ alkyl and C _3-20 cycloalkyl; R ⁴ is selected from H, halogen and C _1-10 alkyl; R ⁵ _is independently selected from H, halogen, -OH, -C _1-6 alkyl, -C _1-6 alkoxy, side oxy (= O), -C(O)C _1-6 alkyl, hydroxy-substituted C ₁ - ₁₀ alkyl, -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ; R ⁶ is selected from H, halogen and methyl; R ⁷ is independently selected from H, halogen, unsubstituted or Ra-substituted C _1-10 alkyl, C _{3 -20} cycloalkyl; Ra is selected from halogen and C _3-20 cycloalkyl; R ⁸¹ , R ⁸² , R ⁸³ , R ⁸⁴ are the same or different, and are independently selected from unsubstituted or optionally substituted by 1, 2, 3 , 4 or 5 Rb substituted C _6-14 aryl-C ₁ - ₁₀ alkyl, 5-14 membered heteroaryl-C ₁ - ₁₀ alkyl, C _6-14 aryl and 5-14 membered heteroaryl group; each Rb is the same or different, independently selected from halogen, halogenated C ₁ - ₁₀ alkyl, C ₁ - ₁₀ alkyl and C _1-10 alkoxy; R ^91a , R ^91b , R ⁹² , R ^93a and R ^93b are the same or different, and are independently selected from H, C _1-6 alkyl and C _3-20 cycloalkyl. The compound as described in claim 1, its racemate, stereoisomer, tautomer, isotope-labeled substance or a pharmaceutically acceptable salt thereof, wherein W is CH or N; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3; Ring A is a 3-12 membered nitrogen-containing heterocyclic group, optionally containing 1, 2 or more heteroatoms selected from O, N or S in addition to the N atom connected to the parent nucleus; R ¹ is selected from H, halogen, CN and C _1-6 alkyl; R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ; R ³ is selected from H, C _1-6 alkyl and C _3-12 cycloalkyl; R ⁴ is selected from H, _{halogen and C 1-6 alkyl ;} R ^{R 5} _is independently selected from H, halogen, -OH, C _1-6 alkyl, C _1-6 alkoxy, pendooxy (=O), -C(O)C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ; R ⁶ is selected from H, halogen and methyl; R ⁷ is independently selected from H, halogen, C _1-6 alkyl and C _3-12 cycloalkyl; R ⁸¹ , R ⁸² , R ⁸³ and R ⁸⁴ are the same or different and are independently selected from C _6-14 aryl-C _1-6 alkyl, 5-14 membered heteroaryl-C _1-6 alkyl, C wherein the aryl or heteroaryl is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from halogen, halogenated C _1-6 alkyl, C _1-6 alkyl and C _1-3 alkoxy; R ^91a , R _91b , R ⁹² , R ^93a , R ^93b are the same or different and are independently selected ^from H, C _1-6 alkyl and C _3-10 cycloalkyl. The compound described in claim 1, its racemate, stereoisomer, tautomer, isotope label or its pharmaceutically acceptable salt, W is CH or N; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3; Ring A is a 3-9 membered nitrogen-containing heterocyclic group, in addition to the N atom connected to the mother core, it also optionally contains 1, 2 or more heteroatoms selected from O, N or S; R ¹ is selected from halogen; R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O) NHR ⁸⁴ ; R ³ is selected from C ₁ - ₃ alkyl and C _3-6 cycloalkyl; R ⁴ is C ₁ - ₃ alkyl or halogen; R ⁵ is independently selected from halogen, -OH, -C _{1- 3} alkyl, -C _1-3 alkoxy, side oxygen group (=O), -C(O)C _1-3 alkyl, hydroxy-substituted C _{1-3 alkyl} , -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ; R ⁶ is selected from H, halogen and methyl; R ⁷ is independently selected from H, Halogen and C _1-3 alkyl; R ⁸¹ , R ⁸² , R ⁸³ , R ⁸⁴ are the same or different, and are independently selected from C _6-8 aryl-C _1-3 alkyl, 5-6 membered heteroaryl -C _1-3 alkyl, C _6-8 aryl, 5-6 membered heteroaryl; wherein the aryl or heteroaryl is each unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently of each other Selected from halogen, halogenated C _1-3 alkyl, C _1-3 alkyl and C _1-3 alkoxy substitution; R ^91a , R ^91b , R ⁹² , R ^93a , R ^93b are the same or different, independently of each other Selected from H, C _1-3 alkyl and C _3-7 cycloalkyl. The compound described in any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotope label or pharmaceutically acceptable salt thereof, characterized in that, W is CH or N; m is 0, 1, 2 or 3; n is 0 or 1; the ring A is selected from the following structures:

R ¹ is Cl or Br; R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ; R ³ is methyl or cyclopropyl; R ⁴ is Methyl; R ⁵ is selected from F, -OH, methyl, methoxy, ethoxy, side oxy (=O), -C(O)C _1-3 alkyl, 2-hydroxyisopropyl, -C(O)OH, -C(O)NH ₂ , -C(O)NHCH ₃ , -S(O) ₂ CH ₃ , S(O) ₂ CH ₂ CH ₃ and -S(O) ₂ -rings Propane; R ⁶ is selected from H, F and Cl; R ⁷ is H; R ⁸¹ , R ⁸² , R ⁸³ , R ⁸⁴ are the same or different, and are independently selected from unsubstituted or optionally 1, 2 or 3 Rb Substituted phenylmethyl, pyridylmethyl, pyridylethyl, phenyl and pyridyl; each Rb is the same or different and independently selected from F, Cl and _CF3 . The compound as described in any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotope-labeled substance or a pharmaceutically acceptable salt thereof, wherein the structure formed by R ⁵ and ring A can be selected from:

The compound as described in any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotope label or its pharmaceutically acceptable salt, wherein the compound of formula I has formula Ia Or the structure shown in Ib:

Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A, W, m and n have the definitions described in claim 1. The compound described in any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotope label or pharmaceutically acceptable salt thereof, wherein the compound of formula I has formula II Structure shown:

wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n, W and ring A independently have the definitions described in claim 1; R ¹⁰ is selected from H, halogen, unsubstituted or The following groups optionally substituted by 1, 2 or more halogens, OH, NH ₂ : C _1-10 alkyl, C _1-10 alkoxy, halo C _1-10 alkyl, halo C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkenyloxy, C _2-10 alkynyl and C _2-10 alkynyloxy; each R ¹¹ is the same or different, independent of each other Ground is selected from H, halogen, C _1-6 alkyl and halogenated C _1-10 alkyl; p is an integer from 0 to 4. The compound as claimed in claim 7, its racemate, stereoisomer, tautomer, isotope-labeled substance or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is H or methyl; p is 0, 1 or 2; each R ¹¹ is the same or different and is independently selected from F, Cl and CF ₃ . The compound described in claim 7, its racemate, stereoisomer, tautomer, isotope label or pharmaceutically acceptable salt thereof, wherein the compound of formula II has formula IIa or formula IIb:

Wherein, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , A, W, m, n and p have the definitions described in claim 7. The compound according to any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotope label or pharmaceutically acceptable salt thereof, wherein the compound has the following structure :

. A compound as described in any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotope label or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula I has The following structure:

. A method for preparing the compound as claimed in any one of claims 1 to 11, its racemate, stereoisomer, tautomer, isotope-labeled substance or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps: Scheme 1: Compound a1 and compound a2 undergo a coupling reaction to obtain a compound of formula I; the reaction formula is as follows:

Wherein, Y is Cl or Br; W, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , m, n and ring A are independently defined as in any one of claims 1 to 11; Scheme 2: When W is N and _R7 is H, compound b1 reacts with compound b2 to obtain a compound of formula II; the reaction formula is as follows:

wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , m, n, p and ring A independently have the definitions described in any one of claims 1 to 11; when R ⁵ is OH, the OH in compound b2 may be protected by a silicon protecting group, and the silicon protecting group may be tert-butyldiphenylsilyl; the silicon protecting group will be removed in the reaction to obtain deprotected OH. A pharmaceutical composition comprising a therapeutically effective amount of a compound described in any one of claims 1 to 11, at least one of its racemates, stereoisomers, tautomers, isotope-labeled substances or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers. A compound as described in any one of claims 1 to 11, at least one of its racemate, stereoisomer, tautomer, isotope label or pharmaceutically acceptable salt thereof, or as claimed Use of the pharmaceutical composition described in item 13 in the preparation of medicines. The use as described in claim 14, wherein the drug is a drug for treating and/or preventing diseases associated with p38 kinase inhibitors. The use as described in claim 14, wherein the drug is an MK2 inhibitor or a p38 MAPK/MK2 pathway regulator. The use as described in claim 15, wherein the disease is autoimmune disease and inflammatory disease, bone disease, metabolic disease, neurological and neurodegenerative disease, cancer, cardiovascular disease, allergy and asthma, Alzheimer's disease and hormone-related diseases. The use as described in claim 17, wherein the inflammatory disease is rheumatoid arthritis, hidradenitis abscessus, psoriasis, inflammatory bowel disease, atopic dermatitis, systemic lupus erythematosus; and the neurological and neurodegenerative diseases are neurodegenerative diseases.