TWI866007B - 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 202111640112.X, 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 present 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 responds to external signals and inflammatory cytokines in cells. After being activated, p38 MAPK is phosphorylated and activates multiple downstream protein kinases and transcription factors, thereby playing a complex biological role. p38 MAPK includes four members, namely p38α, p38β, p38γ and p38δ. Among them, p38α is believed 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 the cell protection mechanism, while mitogen-activated protein kinase MKK3 (MAP Kinase Kinase 3) mediates p38δ to play a role in the proliferation and survival of advanced colorectal cancer (CRC) cells. As an attractive target in drug development, p38 MAPK has multiple inhibitor drugs entering clinical research, but no drug has been approved for marketing so far. According to public information, some candidate compounds failed in the clinical research stage. The main reasons for clinical failure include limited dosage to avoid toxicity, resulting in insufficient exposure of drug molecules at the target site, downregulation of anti-inflammatory pathways, redundant signaling networks, or inhibition of key proteins involved in feedback regulation of other MAPK pathways, etc. Inhibition of feedback mechanisms may upregulate other pro-inflammatory pathways, leading to increased inflammation. Therefore, the development of a safe and effective p38 MAPK inhibitor is the main 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 substrate downstream 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.

The present invention provides a compound as shown in Formula I, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, pharmaceutically acceptable salt or prodrug thereof:

wherein W is CH or N; m is an integer of 0-5; n is an integer of 0-3; ring A is a C _3-20 cycloalkyl group or a 3-20 membered heterocyclic group, the carbon atoms in ring A are connected to the parent nucleus, and the 3-20 membered heterocyclic group contains 1, 2 or more O, N or S atoms; 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 _{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 halogen or 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 _1-20 alkyl which are unsubstituted or ^optionally substituted by 1, ₂ , 3, 4 or ₅ R ^b . _{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 C _3-20 cycloalkyl group or a 3-20 membered heterocyclic group, the carbon atoms in Ring A are connected to the parent nucleus, and the 3-20 membered heterocyclic group contains 1, 2 or more O, N or S atoms; 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 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; 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 or 3; Ring A is a C _3-12 cycloalkyl group or a 3-12 membered heterocyclic group, the carbon atoms in Ring A are connected to the parent nucleus, and the 3-12 membered heterocyclic group contains 1, 2 or more O, N or S atoms; 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 halogen, -OH, -C _{wherein 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 _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 1-6 alkyl ,} C _1-6 alkyl and C _1-3 alkoxy groups; R ^91a , R ^91b , R ⁹² , R ^93a , R ^93b are the same or different and independently selected from H, C _1-3 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 or 3; Ring A is a C _3-9 cycloalkyl group, a 3-9 membered heterocyclic group, the carbon atom in Ring A is connected to the parent nucleus, and the 3-9 membered heterocyclic group contains 1, 2 or more O, N or S atoms; R ¹ is a halogen; R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ; R ³ is a C _{1-3 alkyl} group and a C _{3-6 cycloalkyl} group; R ⁴ is a C _1-3 alkyl group; R ⁵ is independently selected from a halogen, -OH, -C _1-3 alkyl group, -C _1-3 alkoxy group, a pendoxy group (=O), -C(O)C 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 C _{6-8 aryl} -C _1-3 alkyl, 5-6 membered heteroaryl- _{C 1-3} alkyl, C _{6-14 aryl and 5-14 membered heteroaryl; wherein the C 6-14 aryl} ^{and 5-14} membered heteroaryl are unsubstituted or optionally substituted with ₁ , 2, ³ , 4 or ₅ members independently selected from halogen, halogenated C _1-3 alkyl, C _6-14 aryl and 5-14 membered heteroaryl. _R ^91a , R _91b , R ⁹² _, R ^93a , R ^93b are the _same or different and are independently selected ^from H, C _1-3 alkyl and C _3-6 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 piperidinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, oxacyclobutanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, azacyclobutanyl, tetrahydropyrrolyl, thiacyclobutanyl, tetrahydro-2H-thiopyranyl; R ¹ is Cl or Br; R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR R ⁸⁴ ; R ³ is methyl or cyclopropyl; R ⁴ is methyl; R ⁵ is independently selected from F, -OH, methyl, methoxy, oxo (=O), -C(O)C _1-3 alkyl, -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 and 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 R b; each R b is the same or different and is independently selected from F, Cl and CF ₃ .

According to the embodiment of the present invention, Ring A can be selected from:

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、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:

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

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

wherein R ¹ , R ³ , R ^{4 , R 5 ,} R ⁶ , R ⁷ , W, m, n 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} , C _2-10 alkynyloxy; each R ¹¹ is the same or different and is independently selected from H, halogen, C _1-6 alkyl, halogenated C _1-10 alkyl; p is an integer from 0 to 4.

According to an embodiment of the present invention, R ¹⁰ is selected from H, halogen, the following groups which are unsubstituted or optionally substituted with 1, 2 or more halogens, OH, NH ₂ : C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-6 alkenyl, C _{2-6 alkenyloxy, C 2-6 alkynyl, C 2-6 alkynyloxy; each R 11 is the same or different and is independently selected from H, halogen, C 1-6 alkyl ,} ^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, 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, halogenated C _1-3 alkyl.

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

其中，R¹、R³、R⁴、R⁵、R⁶、R⁷、R¹⁰、R¹¹、A、W、m、n、p具有上文所述的定義，加粗的化學鍵表示化合物存在軸掌性。 In a more preferred embodiment, 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 same meanings as described above, and bold chemical bonds indicate that the compound has chiral properties.

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-labeled substance, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein R ² is -OR ⁸¹ or -NHR ⁸³ ; R ⁸¹ and R ⁸³ 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 and 5-6 membered heteroaryl; wherein the C _6-8 aryl and 5-6 membered heteroaryl are unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from halogen, halogenated C ₁ - ₃ alkyl, C ₁ - ₃ alkyl and C _{1 - 3} alkoxy; the C ₁ - ₃ alkyl portion 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-labeled substance, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein R ² is -OR ⁸¹ ; R ⁸¹ is C ₆ aryl-C ₁ - ₃ alkyl or 6-membered heteroaryl-C ₁ - ₃ alkyl; wherein the C ₆ aryl or 6-membered heteroaryl is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from halogen, halogenated C ₁ - ₃ alkyl, C ₁ - ₃ alkyl and C _{1 -} 3 alkoxy; and the C ₁ - ₃ alkyl portion is connected to O.

為

，R⁵選自鹵素、-OH、-C_1-3烷基、-C_1-3烷氧基、側氧基(=O)、-C(O)C_1-3烷基、-C(O)OH、-C(O)NR^91aR^91b、-S(O)₂R⁹²和-S(O)₂NR^93aR^93b，R^91a、R^91b、R⁹²、R^93a、R^93b相同或不同，彼此獨立地選自H、C_1-3烷基和C_3-6環烷基。 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

for

, R ⁵ is selected from halogen, -OH, -C _1-3 alkyl, -C _1-3 alkoxy, oxo (=O), -C(O)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 ^91a , R ^91b , R ⁹² , R ^93a , R ^93b are the same or different and are independently selected from H, C _1-3 alkyl and C _3-6 cycloalkyl.

為

，R⁵選自F、-OH、甲基、甲氧基、-C(O)C_1-3烷基、-C(O)OH、-C(O)NH₂、-C(O)NHCH₃、-S(O)₂CH₃、-S(O)₂CH₂CH₃和-S(O)₂-環丙烷。 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

for

, R ⁵ is selected from F, -OH, methyl, methoxy, -C(O)C _1-3 alkyl, -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.

、

和

。 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 does not include

,

and

.

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 ¹ is a 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, 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 ⁴ is a halogen or a C _1-3 alkyl group.

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 ⁶ is H or halogen.

According to an embodiment of the present invention, the compound of formula I has the following structure:

The * in the structural formula of compounds 10 and 63 indicates the presence of a cis-trans structure, and the * is either cis or trans.

According to the implementation scheme of the present invention, the compound shown in formula I has the following structure:

The * in the structural formula of compounds 10-P1 or 10-P2 and 63-P1 or 63-P2 indicates the presence of a cis-trans structure, and the * is either cis or trans.

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 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 _R7 is H, compound b1 reacts with compound b2 to obtain a compound of formula I; the reaction formula is as follows:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n and ring A independently have the above definitions; 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 the use of at least one of the compounds shown in Formula I, their racemates, stereoisomers, tautomers, isotope-labeled substances, solvates, pharmaceutically acceptable salts or prodrug compounds thereof in the preparation of drugs.

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 drug composition comprising a therapeutically effective amount of at least one of the compounds of Formula I, its racemates, stereoisomers, tautomers, isotope-labeled substances, solvates, pharmaceutically acceptable salts or prodrug compounds thereof.

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, cross-linked sodium carboxymethylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, starch, etc.; lubricants, including calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, etc.; binders, including gelatin, polyethylene glycol, sugar, gum, starch, hydroxypropyl cellulose, etc.; diluents, including mannitol, xylitol, lactose, dextrose, sucrose, sorbitol and starch; surfactants, including 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 embodiments of the present invention, the disease may be a disease related to the p38 MAPK/MK2 pathway, such as 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 pharmacokinetic 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 patent application are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-20" is equivalent to describing each integer value in the numerical range "1-20", namely 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, each integer in the range, and each decimal in the range are described. For example, "numbers from 0 to 10" should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also recording at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 respectively.

It should be understood that in the description of one, two or more herein, "more" should refer to an integer greater than 2, such as an integer greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

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

The term "C _1-10 alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1 to 10 carbon atoms. For example, it means a straight or branched alkyl radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and "C _1-6 alkyl" means a straight or branched alkyl radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 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 or the like or isomers thereof.

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-methyl but-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, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4 In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl, prop-2-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-ethylprop-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl. 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 heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered bicyclic (such as a cyclic, spirocyclic, bridged) or tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) ₂ -. Preferably, the heterocyclic group may be selected from "3-12 membered heterocyclic groups". The term "3-12 membered heterocyclic group" means a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclic group may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom (if present). The heterocyclic group may include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclic group may include, but is not limited to: a 3-membered ring, such as oxirane; a 4-membered ring, such as azacyclobutane, oxacyclobutane; a 5-membered ring, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazacycloheptanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example 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 hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e. it may contain one or more double bonds, for example but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example but not limited to dihydroisoquinolinyl. When the 3-12 membered heterocyclic group is connected with other groups to form the compound of the present invention, the carbon atom on the 3-12 membered heterocyclic group may be connected with the other groups, or the heterocyclic atom on the 3-12 membered heterocyclic group may be connected with the other groups. For example, when the 3-12 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl may be connected with the other groups. Or when the 3-12 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at the para position thereof may be connected with the other groups.

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

The term "annular" refers to a ring system in which two rings share two ring 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 with a 5-14 membered heteroaryl group, with the attachment point being _{the C 1-10 alkyl} group.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described herein fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

Aryl groups can be substituted or unsubstituted.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5 to 10 members (e.g., 5, 6, 7, 8, 9, or 10 members), more preferably 5 or 6 members, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, oxazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl as described herein fused to an aryl, heterocyclo or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups can be substituted or unsubstituted.

The pharmaceutically acceptable salts of the compounds described in the present invention may be inorganic salts or organic salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form a base addition salt; if these compounds contain both an acidic center (such as a carboxyl group) and a basic center (such as an amine group), they may also form an internal salt.

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, diastereoisomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures, as well as enantiomers or diastereoisomers enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may exist in substituents such as alkyl groups. All of these isomers and their mixtures are included in 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 "

" indicates that the configuration is not specified, "

"or"

" indicates the absolute configuration, that is, if there are chiral isomers in the chemical structure, the bond "

" can be "

"or"

", or both

"and"

"Two configurations,"

" indicates the presence of palmarity.

」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 in the scope of the present invention. "Tautomers" refer to structural isomers of different energies that can interconvert via low energy bases. For example, proton tautomers (also called proton transfer tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactam isomerization. All tautomeric forms of all compounds in the present invention are within the scope of the present invention. The name of a compound named in a single manner does not exclude any tautomers.

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

Unless otherwise indicated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times greater abundance of deuterium (i.e., at least 10% deuterium incorporation) than the natural abundance of deuterium, which is 0.015%. Examples of compounds having greater than the natural abundance of deuterium may be at least 1000 times greater abundance of deuterium, at least 2000 times greater abundance of deuterium, at least 3000 times greater abundance of deuterium, at least 4000 times greater abundance of deuterium, at least 5000 times greater abundance of deuterium, at least 6000 times greater abundance of deuterium, or more. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person with ordinary knowledge in the art can synthesize deuterated compounds by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare deuterated compounds, or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

The "therapeutically effective amount" of the present invention refers to the amount of active compound or drug that causes a biological or medical response in a tissue, system, animal, individual or human that is sought by researchers, veterinarians, doctors or other clinicians, and includes one or more of the following: (1) Prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed the disease pathology or symptoms. (2) Inhibition of disease: for example, inhibition of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., preventing the further development of the pathology and/or symptoms). (3) Relief of disease: for example, relief of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and/or symptoms). For drugs or pharmacologically active agents, "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person with ordinary knowledge in the relevant technical field 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 primates, and most preferably humans.

The following will further explain the technical solution of the present invention in combination with specific embodiments. It should be understood that the following embodiments are only for illustrative purposes to illustrate and explain the present invention, and should not be interpreted as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within 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 structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using a Bruker ASCEND ^TM -400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

MS was determined using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent 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 200~300 mesh as the carrier.

High performance liquid phase preparation uses Waters 2767, Waters 2545, and Chuangxin Hengtong LC3000 preparative column chromatographs.

Chiral preparative column chromatography uses Shimadzu LC-20AP and THARSFC PREP 80.

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

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

Microwave reaction uses Biotage initiator+ type microwave reactor.

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

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.

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℃.

和

，*處為順式或反式中的一種。 The asterisk (*) in the chemical structure in the reaction scheme indicates that a specific ring structure position has cis-trans isomerism (a person with ordinary knowledge in the art will understand that cis-trans isomerism exists in the structure of substituted cycloalkane). Exemplary cis-trans isomerism is as follows:

and

, * is either cis or trans.

Those with common knowledge in the relevant technical field should understand that the separated chiral compounds can be distinguished by the order of retention time in the chiral column chromatography column. Therefore, the chiral compounds separated in order of retention time are distinguished by the corresponding number suffixes P1 and P2. That is, the suffix P1 corresponds to the chiral structure separated first, and the suffix P2 corresponds to the chiral structure separated later. If the absolute configuration of the compound is listed in the reaction formula, it does not mean that it corresponds one-to-one with the compounds with the suffixes P1 and P2, but only indicates two forms of existence of the absolute configuration. The absolute configuration of the compounds with the suffixes P1 and P2 shall be based on the absolute configuration objectively corresponding to the specific retention time.

Synthesis of intermediate compound A-5

Step 1: Synthesis of compound A-5b

Sulfur dioxide chloride (22.43 g, 188.5 mmol) was slowly added dropwise to a solution of compound A-5a (20 g, 125 mol) in ethanol (60 mL), and the reaction mixture was reacted at 60°C for 3 hours. After the reaction was completed, the reaction solution was directly reduced in pressure and concentrated to remove the solvent to obtain a crude compound A-5b (20 g), which was directly used in the next reaction. MS m/z (ESI): 187.9 [M+1] ⁺ .

Step 2: Synthesis of compound A-5c

Compound A-5b (16 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 g, yield: 73.5%). MS m/z (ESI): 146.1 [M+1] ⁺ .

Step 3: Synthesis of compound A-5

Sulfuryl chloride (1.77 g, 0.015 mol) was slowly added to a solution of compound A-5c (1.8 g, 0.0124 mol) and N,N-dimethylformamide (5 drops) in dichloromethane (50 mL) at room temperature, and the reaction mixture was reacted 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 over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/0~5/1) to obtain compound A-5 (1.8 g, yield: 84.68%). ¹ H NMR (400MHz, CDCl ₃ )δ 8.35 (d, J = 2.4 Hz, 1H), 7.26 (ddd, J = 9.1, 8.0, 2.6 Hz, 1H), 4.72 (d, J = 2.1 Hz, 2H).

Synthesis of intermediate 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 saline (300 mL x 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 = 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 (8.98 g, 48.7 mmol) and compound A-3 (4.63 g, 32.5 mmol) in 1,4-dioxane (150 mL) was heated to 90°C and stirred for 3.5 hours. After the reaction solution was cooled to room temperature naturally, methanesulfonic acid (3.12 g, 32.5 mmol) was added, and then the reaction was heated to 50°C and stirred for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature naturally and filtered. The filter cake was collected and dried to obtain compound A-4 (5.6 g, yield: 69%). MS m/z (ESI): 251.0 [M+1] ⁺ .

Step 3: Synthesis of compound A-6

Compound A-5 (4.01 g, 24.6 mmol) was added to a mixture of compound A-4 (5.6 g, 22.3 mmol), potassium carbonate (7.69 g, 55.7 mmol) and 18-crown-6 (1.18 g, 4.4 mmol) in N,N-dimethylformamide (80 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction, 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 × 3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound A-6 (8.4 g, yield 80%), which was directly used in the next step. MS m/z(ESI): 378.0[M+1] ⁺ .

Step 4: Synthesis of compound A-8

Add bistriphenylphosphine palladium dichloride (1.56 g, 2.22 mmol) to a solution of compound A-6 (8.4 g, 22.2 mmol) and tributyl (1-ethoxyethylene) tin (compound A-7) (10.21 g, 24.2 mmol) in 1,4-dioxane (100 mL), heat the reaction solution to 130 ° C and stir for 4 hours. Then filter the reaction solution, directly reduce the pressure and concentrate the filtrate, add tetrahydrofuran (100 mL) to the residue to dissolve, and then drop 5 mL of concentrated hydrochloric acid and stir for 1 hour. 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-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 (1.9 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 (3.6 g, yield: 70%). MS m/z (ESI): 420.0 [M+1] ⁺ .

Step 6: Synthesis of compound A

N, N-dimethylformamide dimethyl acetal (0.85 g, 7.2 mmol) was added to a solution of compound A-9 (1.3 g, 3.1 mmol) in N, N-dimethylformamide (15 mL), and the reaction mixture was stirred at 100 ° C for 3 hours. After the reaction was completed, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 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 = 50/1) to obtain compound A (900 mg, yield: 78%). MS m/z(ESI): 474.9[M+H] ⁺ .

Synthesis of intermediate compound B:

Step 1: Synthesis of compound B-2

Add diphenyl azidophosphate (23.5 g, 0.085 mol) to a mixed solution of compound B-1 (10 g, 0.057 mol) and triethylamine (17.3 g, 0.17 mol) in tert-butyl alcohol/toluene (50 mL/50 mL), 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 (200 mL×3). The combined organic phase is washed with water (30 mL), 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 = 10/1) to obtain compound B-2 (3.6 g, 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 concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (dichloromethane/methanol = 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 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 = 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), anhydrous 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 heated 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 (1.2 g, 6.88 mmol) was added to a solution of compound A-5 (850 mg, 5.29 mmol) in anhydrous 1,4-dioxane (8 mL), and the reaction mixture 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, and the 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 (1.14 g, 8.28 mmol) and 18-crown-6 (175 mg, 0.66 mmol) were added to a solution of compound A-5 (702 mg, 4.30 mmol) and compound B-7 (890 mg, 3.31 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture 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, water (50 mL) was added for dilution, and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a 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 7: 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 reaction mixture was stirred at 130°C for 1.5 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude compound B-9 (3.9 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 (0.5 mL) solution, and the reaction mixture was stirred at room temperature for 1 hour. 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 (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

N-chlorosuccinimide (330 mg, 2.48 mmol) and glacial acetic acid (0.2 mL) were added to a solution of compound B-10 (910 mg, 2.25 mmol) in isopropanol (12 mL) in sequence, and the reaction mixture 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 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), and the reaction mixture 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 phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain compound B (900 mg, yield: 72%). MS m/z(ESI): 492.7[M+1] ⁺ .

Example 1 Synthesis of Compound 1

Step 1: Synthesis of compound 1-2

Compound A (200 mg, 0.42 mmol) was added to a solution of compound 1-1 (191.5 mg, 0.84 mmol) and potassium carbonate (232.9 mg, 1.684 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was heated to 60 ° C and stirred at this temperature for 18 hours. After the reaction was completed, the reaction solution was naturally cooled to room temperature, ethyl acetate (40 mL) was added to dilute, and then washed with saturated brine (20 mL×5). The organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (methanol/dichloromethane = 1/10) to obtain compound 1-2 (200 mg, yield: 71%). MS m/z(ESI): 661.0[M+23] ⁺ .

Step 2: Synthesis of compounds 1-3

Compound 1-2 (280 mg) was added to a trifluoroacetic acid/dichloromethane (3 mL/6 mL) mixed solution, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (methanol/dichloromethane = 1:10) to obtain compound 1-3 (220 mg, yield: 84%). MS m/z (ESI): 538.7 [M+1] ⁺ .

Step 3: Synthesis of compound 1

Paraformaldehyde (55 mg) and glacial acetic acid (0.1 mL) were added to a solution of compound 1-3 (110 mg) in methanol (5 mL), and the reaction was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (39 mg) was added and the reaction was continued at room temperature 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 HPLC preparative column chromatography (column chromatography column: Xbridge-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: 15-40%) to obtain compound 1 (25.5 mg, yield: 22%). MS m/z (ESI): 553.0 [M+1] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.90(d,J=5.2Hz,1H),8.85(s,1H),8.49(d,J=2.3Hz,1H),8.38(s,1H), 8.31(d,J=5.2Hz,1H),7.80-7.72(m,1H),6.86(s,1H),5.54(d,J=1.6Hz, 2H),3.42-3.33(m,2H),3.22-3.10(m,1H),2.84(t,J=11.2Hz,2H),2.70 (s,3H),2.32-2.22(m,3H),2.20(s,3H),2.19-2.12(m,1H),2.08(s,3H).

Example 2 Synthesis of compounds 2, 2-P1 and 2-P2

Acetic anhydride (51.15 mg, 0.50 mmol) was added to a solution of compound 1-3 (90 mg, 0.16 mmol) and triethylamine (67.59, 0.67 mmol) in dichloromethane (8 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phase was 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 column chromatography (dichloromethane/methanol = 10/1) and preparative HPLC (column chromatography column: Xbridge-Gemini-C18, 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid) gradient: 30-60%) to obtain compound 2 (43.8 mg, yield: 43.77%). MS m/z (ESI): 580.8 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.88(d,J=5.3Hz,1H),8.83(s,1H),8.49(d,J=2.3Hz,1H),8.42(s,1H),8 .29(dd,J=5.3,2.3Hz,1H),7.81-7.72(m,1H),6.84(s,1H),5.53(d,J=1. 8Hz,2H),4.69-4.57(m,1H),4.06(d,J=11.8Hz,1H),3.31-3.16(m,2H),2 .84(t,J=12.7Hz,1H),2.19(s,3H),2.17-2.05(m,8H),2.04-1.83(m,2H).

Compound 2 was separated by supercritical fluid preparation column chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H, 250mm x 20mm, 5μm; mobile phase: 40% methanol (methanol/carbon dioxide, 0.2% ammonia water); total flow rate: 12.5g/min) to obtain compound 2-P1 (19.4mg) and compound 2-P2 (18.6mg).

Compound 2-P1:

MS m/z (ESI): 581.1 [M+H] ⁺ ; SFC: retention time = 4.08 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.83 (d, J = 5.2 Hz, 1H), 8.79 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.25 (dd, J = 5.3, 2.3 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.80 (s, 1H),5.49(d,J=1.9Hz,2H),4.64-4.50(m,1H),4.06-3.97(m,1H),3.21(ddd,J=15.4,11.1,7.8H z,2H),2.80(t,J=12.8Hz,1H),2.15(s,3H),2.11-2.05(m,5H),2.04(s,3H),2.01-1.86(m,2H).

Compound 2-P2:

MS m/z (ESI): 581.1 [M+H] ⁺ ; SFC: retention time = 5.51 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.83 (dd, J = 5.3, 0.6 Hz, 1H), 8.79 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.36 (s, 1H), 8.25 (dd, J = 5.3, 2.2 Hz, 1H), 7.76-7.66 (m, 1H), 6.81 (s, 1H), 5.49 (d, J = 2.0 Hz, 2H), 4 .58(ddd,J=13.0,5.4,3.2Hz,1H),4.00(dd,J=18.6,12.5Hz,1H),3.26-3.15(m,2 H),2.87-2.74(m,1H),2.15(s,3H),2.10(m,5H),2.04(m,3H),1.99-1.84(m,2H).

Example 3 Synthesis of Compound 3 and 3-P1 and 3-P2

Compound 3-1 (134 mg, 1.05 mmol) and potassium carbonate (218 mg, 1.57 mmol) were added to a solution of compound A (250 mg, 0.52 mmol) in N,N-dimethylformamide (5 mL). The reaction solution was heated to 60°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated by reduced pressure to remove the solvent, and the residue was purified by HPLC preparative column chromatography (column chromatography column: Xbridge-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: 30-60%) to obtain compound 3 (121.2 mg, yield: 47%). MS m/z (ESI): 540.2[M+1] ⁺ ; ¹ H NMR (400MHz, DMSO-d6): δ 8.90(d,J=5.2Hz,1H),8.83(s,1H),8.58(d,J=2.4Hz,1H),8.34(s,1H),8.17(d,J=5.2Hz,1H),8.11-8.04(m,1H),6.79(s,1H),5.45 (d,J=1.5Hz,2H),3.96-3.87(m,2H),3.43(td,J=11.6,2.4Hz,2H),3.15-3.04(m,1H),2.05(s,3H),1.93(s,3H),1.91-1.79(m,4H).

Compound 3 was separated by supercritical fluid preparation column chromatography (equipment: SFC Thar prep 80; column chromatography column: chiralpak-AD; mobile phase: 40% isopropanol (isopropanol/carbon dioxide, 0.2% ammonia water), flow rate: 12.5 g/min) to obtain compound 3-P1 (62.1 mg, yield 21%) and compound 3-P2 (59.1 mg, yield 20%).

Compound 3-P1:

MS m/z (ESI): 540.2 [M+1] ⁺ ; SFC: retention time = 3.42 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.88(d,J=5.2Hz,1H),8.84(s,1H),8.49(d,J=2.2Hz,1H),8.41(s,1H),8.29(d,J=5.3Hz,1H),7.80-7.71(m,1H),6.86(s,1H), 5.54(d,J=1.4Hz,2H),4.08(d,J=11.1Hz,2H),3.62(dd,J=17.9,6.7Hz,2H),3.28-3.17(m,1H),2.20(s,3H),2.13-1.91(m,7H).

Compound 3-P2:

MS m/z (ESI): 540.2 [M+1] ⁺ ; SFC: retention time = 4.64 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.88 (d, J = 5.3 Hz, 1H), 8.84 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.41 (s, 1H), 8.29 (d, J = 5.3 Hz,1H),7.80-7.71(m,1H),6.85(s,1H),5.54(d,J=1.8Hz,2H),4.12-4.03(m,2H) ,3.62(dt,J=13.0,6.7Hz,2H),3.27-3.17(m,1H),2.20(s,3H),2.12-1.95(m,7H).

Example 4 Synthesis of Compound 4

Potassium carbonate (87.32 mg, 0.63 mmol) and compound 4-1 (63.44 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 80° C. for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (50 mL × 3). The combined organic phase was 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 preparation column (column: Xbridge-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: 35-60%) to obtain compound 4 (36.6 mg, yield: 31.7%). MS m / z (ESI): 525.8 [M + 1] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.83(dd,J=5.2,0.9Hz,1H),8.80(s,1H),8.44(d,J=2.4Hz,1H),8.37(d,J=1.5Hz,1H ),8.26(dd,J=5.2,0.9Hz,1H),7.71(ddd,J=9.6,8.6,2.4Hz,1H),6.81(d,J=0.5Hz,1H ),5.49(d,J=1.9Hz,2H),4.23-4.14(m,1H),4.133.99(m,2H),3.94-3.86(m,1H),3.85 -3.76(m,1H),2.39(ddd,J=13.5,6.7,1.4Hz,2H),2.15(s,3H),2.04(d,J=0.7Hz,3H).

Example 5 Synthesis of Compound 6

Potassium carbonate (116 mg, 0.84 mmol) and compound 6-1 (62 mg, 0.42 mmol) were added to a solution of compound A (100 mg, 0.21 mmol) in N,N-dimethylformamide (3 mL), and the reaction mixture was heated to 60° C. and stirred at the temperature for 16 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated by reduced pressure to remove the solvent. The residue was purified by high performance liquid chromatography (column chromatography column: Xbridge-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: 50-70%) to obtain compound 6 (35.3 mg, yield: 32%). MS m / z (ESI): 524.0 [M + 1] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.90(d,J=5.2Hz,1H),8.86(s,1H),8.61(d,J=2.4Hz,1H),8.31(s,1H),8.17(d,J=5.2Hz,1H),8.14-8.07(m,1H),6.83(s,1H),5.4 9(s,2H),3.40-3.33(m,1H),2.10(s,3H),2.08-2.00(m,2H),1.96(s,3H),1.94-1.86(m,2H),1.83-1.72(m,2H),1.71-1.59(m,2H).

Example 6 Synthesis of Compound 7

Potassium carbonate (186.25 mg, 1.35 mmol) and compound 7-1 (81.2 mg, 0.67 mmol) were added to a solution of compound A (160 mg, 0.34 mmol) in N,N-dimethylformamide (2 mL), and the reaction mixture was heated to 60° C. and stirred at the temperature for 18 hours. After the reaction was completed, ethyl acetate (30 mL) was added to the reaction solution for dilution, and the solution was washed with saturated salt water (30 mL × 5), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by HPLC preparative column chromatography (Gemini-C18, 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid) = 45-60%, UV: 214 nm) to obtain compound 7 (43 mg, yield: 25.2%). MS m/z (ESI): 496.0 [M+1] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ 8.85(s,1H),8.80(d,J=5.2Hz,1H),8.61(d,J=2.4Hz,1H),8.32(s,1H),8.14-8.08(m,2H),6.83(s,1 H),5.50(s,2H),2.33-2.24(m,1H),2.09(s,3H),1.96(s,3H),1.18-1.15(m,1H),1.12-1.06(m,3H).

Example 7 Synthesis of Compound 8

Potassium carbonate (87.32 mg, 0.63 mmol) and compound 8-1 (56.7 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 solution was heated to 80° C. and stirred at this temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by HPLC preparative column chromatography (column chromatography column: Xbridge-C18, 150×21.2 mm, 5 um; 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: 35-60%) to obtain compound 8 (52.9 mg, yield: 47.8%). MS m/z (ESI): 509.8 [M+1] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ 8.83-8.78(m,2H),8.44(d,J=2.4Hz,1H),8.38(s,1H),8.22(d,J=5.3Hz,1H),7.71(ddd,J=9.6,8.6,2.4Hz,1H),6.80(d,J=0.5Hz,1H),5.49(d ,J=2.0Hz,2H),3.91-3.79(m,1H),2.57-2.44(m,2H),2.41-2.31(m,2H) ,2.15(s,3H),2.13-2.06(m,1H),2.06-2.03(m,3H),1.99-1.89(m,1H).

Example 8 Synthesis of Compound 9

Step 1: Synthesis of compound 9-2

Under ice bath, sodium borohydride (200 mg, 5 mmol) was slowly added to a methanol (15 mL) solution of compound 9-1 (1 g, 10 mmol). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to give compound 9-2 (560 mg, yield: 57%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.28-4.18 (m, 1H), 2.79-2.69 (m, 2H), 2.62-2.51 (m, 1H), 2.37-2.26 (m, 2H).

Step 2: Synthesis of compound 9-4

Compound 9-3 (1.56 g, 5.68 mmol) was added to a solution of compound 9-2 (460 mg, 4.74 mmol) and imidazole (644 mg, 9.47 mmol) in dichloromethane (15 mL), and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into water (30 mL) for dilution, extracted with dichloromethane (20 mL×3), and the combined organic phase was washed with water (20 mL), 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 = 10/1) to obtain compound 9-4 (1.2 g, yield: 80%). MS m/z (ESI): 358.0 [M+23] ⁺ .

Step 3: Synthesis of compound 9-5

A hydrochloric acid ether solution (2.0M, 5mL) was added dropwise to a methanol (27mg, 0.89mmol) solution of compound 9-4 (100mg, 0.29mmol). The reaction mixture was stirred at room temperature for 16 hours, and then the reaction solution was concentrated under reduced pressure. Amine methanol solution (7.0M, 5mL) was added, and the reaction was continued at room temperature for 3 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude compound 9-5 (41mg, yield 39%), which was directly used in the next step. MS m/z (ESI): 353.0 [M+1] ⁺ .

Step 4: Synthesis of compound 9

Potassium carbonate (30 mg, 0.221 mmol) and compound 9-5 (39 mg, 0.110 mmol) were added to a solution of compound A (35 mg, 0.073 mmol) in N,N-dimethylformamide (5 mL), and the reaction was heated to 100°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phase was 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 thin plate chromatography (dichloromethane/methanol = 10/1) to obtain compound 9 (8.7 mg, yield: 15%). MS m/z (ESI): 525.7[M+1] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD): δ 8.82-8.77(m,2H),8.46-8.41(m,2H),8.24(d,J=5.2Hz,1H),7.74-7.67(m,1H),6.82(s,1H),5.49(d,J=1.9H z,2H),4.25-4.21(m,1H),3.26-3.24(m,1H),2.75-2.62(m,2H),2.51-2.31(m,2H),2.16(s,3H),2.05(s,3H).

Example 9 Synthesis of Compounds 10, 10-P1 & 10-P2

Step 1: Synthesis of compound 10-2

At -5°C, titanium tetrachloride (6.3mL, 6.3mmol) and methyl lithium lithium chloride complex (2.0M, 3.2mL, 6.3mmol) were slowly added dropwise to a toluene (15mL) solution of compound 10-1 (500mg, 5.2mmol), and the reaction system was naturally heated to room temperature and stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was poured into a saturated aqueous ammonium chloride solution (30mL) for quenching and extracted with ethyl acetate (20mL×3). The combined organic phase was washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 10-2 (230mg), which was directly used in the next reaction.

Step 2: Synthesis of compound 10-3

A hydroxylamine aqueous solution (50%, 2 mL) was added to a solution of compound 10-2 (160 mg, 1.44 mmol) in ethanol (5 mL), and the reaction was heated to 75°C and stirred at this temperature for 12 hours. After the reaction was completed, the reaction solution was directly reduced in pressure and concentrated to obtain a crude compound 10-3 (300 mg), which was directly used in the next reaction. MS m/z (ESI): 145.1 [M+H] ⁺ .

Step 3: Synthesis of compound 10-4

At room temperature and under nitrogen protection, add Raney nickel (400 mg) to a methanol (8 mL) solution of compound 10-3 (200 mg, 1.39 mmol). The reaction was carried out at room temperature under a hydrogen atmosphere and normal pressure for 12 hours. After the reaction, the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 10-4 (160 mg), which was directly used in the next reaction. MS m/z (ESI): 129.1 [M+H] ⁺ .

Step 4: Synthesis of compounds 10-P1 and 10-P2

Compound 10-4 (160 mg, 1.11 mmol) and potassium carbonate (262 mg, 1.89 mmol) were added to a solution of compound A (300 mg, 0.63 mmol) in N,N-dimethylformamide (15 mL), and the reaction was heated to 90° C. and stirred at this temperature for 12 hours. After the reaction was completed, the reaction mixture was poured into water (30 mL), extracted with dichloromethane (20 mL × 3), the combined organic phase was washed with water (20 mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid phase preparation column chromatography (column chromatography column: Gemini-C18, 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-55%, column temperature: 25 ° C; flow rate: 14 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 10 (70 mg).

The compound 10 was subjected to chiral separation 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 compounds 10-P1 (15.7mg, yield: 4.6%) and 10-P2 (17.2mg, yield: 5.1%).

Compound 10-P1:

MS m/z (ESI): 539.8 [M+1] ⁺ ; SFC: retention time = 2.66 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.79 (d, J = 5.1 Hz, 2H), 8.48-8.42 (m, 2H), 8.23 (d, J = 5.3 Hz, 1H), 7.75-7.67 (m, 1H), 6.81 (s, 1H), 5.49 (d, J = 1.9 Hz, 2H), 3.41-3.30 (m, 1H), 2.63-2.50 (m, 2H), 2.39-2.44 (m, 2H), 2.15 (s, 3H), 2.05 (s, 3H), 1.44 (s, 3H).

Compound 10-P2:

MS m/z (ESI): 539.8 [M+1] ⁺ ; SFC: retention time = 3.22 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.79 (d, J = 5.2 Hz, 2H), 8.49-8.42 (m, 2H), 8.23 (d, J = 5.3 Hz, 1H), 7.68-7.72 (m, 1H), 6.82 (d, J = 0.6 Hz, 1H), 5.49 (d, J = 1.9 Hz, 2H), 3.38-3.31 (m, 1H), 2.55 (dd, J = 10.7, 9.7 Hz, 2H), 2.47-2.36 (m, 2H), 2.15 (s, 3H), 2.05 (s, 3H), 1.44 (s, 3H).

Example 10 Synthesis of compounds 14, 14-G1 and 14-G2

Step 1: Synthesis of compound 14-2

At -5°C, titanium tetrachloride (19.4 mL, 19.40 mmol, 1 M) and methyl lithium (9.7 mL, 19.40 mmol, 2 M) were slowly added dropwise to a toluene (50 mL) solution of compound 14-1 (2.0 g, 16.20 mmol). After the addition, the reaction mixture was naturally heated to room temperature and stirred at room temperature for 3 hours. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether = 1/2) to obtain compound 14-2 (1.0 g, yield: 40%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.87-2.33 (m, 1 H), 2.05-1.80 (m, 2H), 1.79-1.53 (m, 3H), 1.39 (m, 3H), 1.28-1.19 (m, 3H).

Step 2: Synthesis of compound 14-3

A hydroxylamine aqueous solution (50%, 0.5 mL) was added to a solution of compound 14-2 (200 mg, 1.4 mmol) in ethanol (5 mL), and the reaction was heated to 75°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude compound 14-3 (300 mg), which was directly used in the next reaction. MS m/z (ESI): 173.1 [M+H] ⁺ .

Step 3: Synthesis of compound 14-4

Under nitrogen protection, Raney nickel (40 mg) was added to a methanol (10 mL) solution of compound 14-3 (300 mg, 1.70 mmol), and the reaction was carried out at room temperature and normal pressure hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure to obtain a crude compound 14-4 (300 mg), which was directly used in the next step. MS m/z (ESI): 157.1 [M+H] ⁺ .

Step 4: Synthesis of compounds 14-G1 and 14-G2

Compound 14-4 (200 mg, 1.2 mmol) and potassium carbonate (34 mg, 2.50 mmol) were added to a solution of compound A (304 mg, 0.64 mmol) in N,N-dimethylformamide (10 mL), and the reaction was heated to 90° C. and stirred at this temperature for 12 hours. After the reaction was completed, the reaction mixture was poured into water (50 mL), extracted with dichloromethane (30 mL x 3), the combined organic phase was washed with water (20 mL x 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid phase preparation column chromatography (column chromatography column: Gemini-C18, 150×21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 35-45%, column temperature: 25°C; flow rate: 14 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain two groups of compounds 14-G1 (10 mg, yield: 1.20%) and compound 14-G2 (20 mg, yield: 2.34%).

Compound 14-G1:

MS m/z (ESI): 568.7 [M+H] ⁺ ; HPLC: retention time = 5.00 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.92-8.81 (m, 2H), 8.49 (d, J = 2.3 Hz, 1H), 8.41 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 7.81-7.70 (m, 1H), 6.85 (s, 1H), 5.53 (d, J = 1.8 Hz, 2H), 3.02-2.93 (m,1H),2.20(s,3H),2.11-2.01(m,5H),1.94-1.78(m,4H),1.67(dd,J=12.6,3.9Hz,2H),1.31(s,3H).

Compound 14-G2:

MS m/z (ESI): 568.1 [M+H] ⁺ ; HPLC: retention time = 5.31 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.91-8.82 (m, 2H), 8.52-8.44 (m, 2H), 8.33 (d, J = 5.4 Hz, 1H), 7.81-7.70 (m, 1H), 6.86 (s, 1H), 5.54 (d, J = 1.8 Hz, 2H), 2.92 (ddd, J = 12.6, 7.8, 3.3 Hz, 1H), 2.23-2.04 (m, 8H), 1.83 (t, J = 13.6 Hz, 4H), 1.63-1.52 (m, 2H), 1.26 (s, 3H).

Example 11 Synthesis of compounds 16, 16-P1 and 16-P2

Step 1: Synthesis of compound 16-2

In an ice bath, trimethylsilyl cyanide (11.89 g, 119.8 mmol) and zinc iodide (0.82 g, 2.56 mmol) were slowly added to a tetrahydrofuran (100 mL) solution of compound 16-1 (6 g, 85.6 mmol). The reaction was naturally heated to room temperature and stirred at room temperature for 40 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound 16-2 (5.2 g, yield: 59.5%). ¹ H NMR (400MHz, CDCl ₃ ) δ 3.55 (s, 1H), 2.71-2.57 (m, 2H), 2.42-2.28 (m, 2H), 2.05-1.88 (m, 2H).

Step 2: Synthesis of compound 16-3

Compound 16-2 (5.2 g, 53.5 mmol) was added to a hydrochloric acid ethanol solution (4 M, 25 mL) and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was slurried with ether (20 mL), filtered, and the filter cake was collected and dried to obtain compound 16-3 (2.8 g, yield: 32.9%). MS m/z (ESI): 144.0 [M+1] ⁺¹ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.13(d,J=111.0Hz,2H), 4.54(q,J=7.0Hz,2H), 2.43-2.20(m,2H), 1.98-1.65(m,2H), 1.49-1.31(m,3H).

Step 3: Synthesis of compound 16-4

Compound 16-3 (2.8 g, 19.6 mmol) was added to an ethanol solution of ammonia (2 M, 30 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was slurried with ether (15 mL), filtered, and the filter cake was collected and dried to obtain compound 16-4 (1.4 g, yield: 56.1%). MS m/z (ESI): 115.1 [M+1] ⁺ .

Step 4: Synthesis of compound 16

Compound 16-4 (144.21 mg, 1.26 mmol) and potassium carbonate (261.92 mg, 1.895 mmol) were added to a solution of compound A (300 mg, 0.63 mmol) in N,N-dimethylformamide (5 mL), and the reaction was stirred under microwave (90° C.) conditions for 2 hours. After the reaction was completed, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate and filtered, the filtrate was reduced and concentrated, and the residue was purified by column chromatography (dichloromethane/methanol = 10/1) and HPLC column chromatography (column chromatography column: gemini-C18, 150 × 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid), gradient: 40-60%) to obtain compound 16 (60 mg).

MS m/z(ESI): 525.8[M+1] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ 8.92(d,J=5.2Hz,1H),8.80(s,1H),8.51(s,1H),8.44(d,J=2.3Hz,1H),8.28(d,J=5.2Hz,1H), 7.76-7.67(m,1H),6.81(s,1H), 5.49(d,J=1.9Hz,2H),2.77-2.66(m,2H),2.37(dd,J=10.5,9.1Hz,2H),2.16(s,3H),2.04(d,J=5.9Hz ,3H),2.02-1.94(m,2H).

Compound 16 was purified by supercritical fluid chiral preparative column chromatography (equipment: SFC Thar prep 80; Column: CHIRALPAK AD-H 250mm*20mm, 5 μm ; mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia water); flow rate: 12.5 g/min) to obtain compounds 16-P1 (21.8 mg) and 16-P2 (22 mg).

Compound 16-P1:

MS m/z (ESI): 525.8 [M+1] ⁺¹ . Chiral HPLC: retention time = 6.36 min, UV = 214 nm. ¹ H NMR (400MHz, CD ₃ OD) δ 8.92(d,J=5.2Hz,1H),8.80(s,1H),8.51(s,1H),8.44(d,J=2.4Hz,1H),8.28(d,J=5.2Hz,1H),7.71(ddd,J=9.7,8.6,2.4Hz,1H),6.81(d,J =0.6Hz,1H),5.49(d,J=2.0Hz,2H),2.77-2.67(m,2H),2.38(dt,J=11.8,8.8Hz,2H),2.16(s,3H),2.05(d,J=0.5Hz,3H),2.03-1.94(m,2H).

Compound 16-P2:

MS m/z (ESI): 525.8 [M+1] ⁺¹ . Chiral HPLC: retention time = 16.05 min, UV = 214 nm. ¹ H NMR (400MHz, CD ₃ OD) δ 8.92(d,J=5.2Hz,1H),8.80(s,1H),8.51(s,1H),8.44(d,J=2.4Hz,1H),8 .28(d,J=5.2Hz,1H),7.71(ddd,J=9.6,8.6,2.4Hz,1H),6.81(d,J=0.5Hz ,1H),5.49(d,J=2.0Hz,2H),2.71(ddd,J=9.8,7.2,5.1Hz,2H),2.38(dd, J=9.3,3.4Hz,2H),2.16(s,3H),2.05(d,J=0.5Hz,3H),2.03-1.94(m,2H).

Example 12 Synthesis of Compound 33, 33-P1 or 33-P2

Step 1: Synthesis of compound 33-2

Under ice bath, trimethyl silane (3.31 g, 33.3 mmol) and zinc iodide (0.23 g, 0.71 mmol) were added to a tetrahydrofuran (25 mL) solution of compound 33-1 (2.0 g, 23.8 mmol) in sequence. The reaction was naturally heated to room temperature and stirred at room temperature for 24 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 = 10/1) to obtain compound 33-2 (1.5 g, yield: 32.7%). ¹ H NMR (400MHz, CDCl ₃ ): δ 2.11-2.05(m,2H), 2.04-1.96(m,2H), 1.89-1.73(m,4H), 0.25-0.22(m,9H).

Step 2: Synthesis of compound 33-3

Compound 33-2 (1.5 g, 8.2 mmol) was added to a hydrochloric acid ethanol solution (4 M, 15 mL) and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was slurried with ether (15 mL), filtered, and the filter cake was collected and dried to obtain compound 33-3 (0.8 g, yield: 58.5%). MS m/z (ESI): 158.1 [M+H] ⁺ .

Step 3: Synthesis of compound 33-4

Compound 33-3 (0.5 g, 3.2 mmol) was added to an ethanol solution of ammonia (2 M, 15 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was slurried with ether (15 mL), filtered, and the filter cake was collected and dried to obtain compound 33-4 (0.23 g, yield: 50.8%). MS m/z (ESI): 129.1 [M+H] ⁺ .

Step 4: Synthesis of Compound 33-P1 and Compound 33-P2

Compound 33-4 (162 mg, 1.26 mmol) and potassium carbonate (262 mg, 1.9 mmol) were added to a solution of compound A (300 mg, 0.63 mmol) in N,N-dimethylformamide (15 mL), and the reaction was heated to 90° C. and stirred at this temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 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 = 10/1) and HPLC preparative column chromatography (column chromatography column: Gemini-C18 150×21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-60%) to obtain compound 33.

Compound 33 was separated by supercritical fluid preparation column chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H, 250mm×20mm, 5μm; mobile phase: 40% isopropanol (isopropanol/carbon dioxide, 0.2% ammonia water); flow rate: 15g/min) to obtain compound 33-P1 (11.3mg) and compound 33-P2 (14.2mg).

Compound 33-P1:

MS m/z (ESI): 539.8 [M+H] ⁺ ; SFC: retention time = 6.67 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.92 (d, J = 5.2 Hz, 1H), 8.84 (s, 1H), 8.56 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 5.2 Hz, 1H), 7.81-7.71 (m, 1H), 6.86 (s, 1H), 5.53 (d, J = 1.9 Hz, 2H), 2.42-2.26 (m, 2H), 2.20 (s, 3H), 2.10 (s, 3H), 2.06-1.83 (m, 6H).

Compound 33-P2:

MS m/z (ESI): 539.8 [M+H] ⁺ ; SFC: retention time = 11.99 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.80 (d, J = 5.2 Hz, 1 H), 8.72 (s, 1 H), 8.44 (s, 1 H), 8.36 (d, J = 2.3 Hz, 1 H), 8.17 (d, J = 5.2 Hz, 1 H), 7.64-7.61 (m, 1 H), 6.74 (s, 1 H), 5.41 (d, J = 1.9 Hz, 2 H), 2.42-2.23 (m, 2 H), 2.08 (s, 3 H), 1.98 (s, 3 H), 1.93-1.72 (m, 6 H).

Example 13 Synthesis of Compounds 41, 41-P1 and 41-P2

Step 1: Synthesis of compound 41-2

A hydroxylamine aqueous solution (50%, 5 mL) was added to a solution of 41-1 (5.0 g, 1.4 mmol) in ethanol (5 mL), and the reaction was heated to 75°C and stirred at this temperature for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude compound 41-2 (5.8 g), which was directly used in the next reaction. MS m/z (ESI): 160.1 [M+H] ⁺ .

Step 2: Synthesis of compound 41-3

Under nitrogen protection, Raney nickel (3.0 g) was added to a methanol (50 mL) solution of compound 41-2 (5.8 g, 27.9 mmol), and the reaction was carried out at room temperature and normal pressure in a hydrogen atmosphere for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure to obtain a crude compound 41-3 (5.2 g), which was directly used in the next reaction. MS m/z (ESI): 200.1 [M+H] ⁺ .

Step 3: Synthesis of compound 41-4

Compound 41-3 (193 mg, 0.96 mmol) and potassium carbonate (201 mg, 1.45 mmol) were added to a solution of compound A (230 mg, 0.48 mmol) in N,N-dimethylformamide (10 mL), and the reaction was heated to 90°C and stirred at this temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane/methanol = 10/1) to obtain compound 41-4 (90 mg, yield: 28%). MS m/z(ESI): 510.8[M-Boc] ⁺ .

Step 4: Synthesis of compound 41-5

Trifluoroacetic acid (84 mg, 0.74 mmol) was slowly added to a dichloromethane solution (10 mL) of compound 41-4 (90 mg, 0.15 mmol), and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude compound 41-5 (70 mg), which was directly used in the next reaction. MS m/z (ESI): 510.8 [M+H] ⁺ .

Step 5: Synthesis of compound 41, compound 41-P1 and compound 41-P2

Acetic anhydride (60 mg, 0.59 mmol) was slowly added to a solution of compound 41-5 (100 mg, 0.19 mmol) and triethylamine (59 mg, 0.59 mmol) in dichloromethane (8 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, then poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was chromatographed on a high performance liquid phase preparation column (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 41 (50 mg).

Compound 41 was purified by supercritical fluid preparation column chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H 250mm×20mm, 5μm; mobile phase: 40% methanol (methanol/carbon dioxide, 0.2% ammonia water); flow rate: 12.5g/min) to obtain compound 41-P1 (19mg yield: 17.6%) and compound 41-P2 (17mg yield: 15.7%).

Compound 41-P1

MS m/z (ESI): 552.8 [M+H] ⁺ ; SFC: retention time = 6.33 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.90(dd,J=5.2,4.3Hz,1H),8.81(s,1H),8.44(d,J=2.4Hz,1H),8.39(d,J=2.3 Hz,1H),8.30(dd,J=5.3,1.1Hz,1H),7.71(ddd,J=9.6,8.6,2.4Hz,1H),6.80(s ,1H),5.48(d,J=1.9Hz,2H),4.57(ddd,J=14.7,8.7,4.3Hz,2H),4.40-4.30(m, 2H),4.16(ddd,J=8.8,5.9,2.8Hz,1H),2.15(s,3H),2.03(s,3H),1.87(s,3H).

Compound 41-P2

MS m/z (ESI): 552.8 [M+H] ⁺ ; SFC: retention time = 13.32 min, UV = 214 nm; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.90(dd,J=5.2,4.4Hz,1H),8.81(s,1H),8.44(d,J=2.4Hz,1H),8.38(s,1H) ,8.31(dd,J=5.2,1.2Hz,1H),7.71(ddd,J=9.6,8.6,2.4Hz,1H),6.81(s,1H) ,5.49(d,J=1.9Hz,2H),4.57(ddd,J=14.7,8.8,4.1Hz,2H),4.40-4.30(m,2H ),4.17(ddd,J=8.9,5.9,2.9Hz,1H),2.15(s,3H),2.04(s,3H),1.87(s,3H).

Example 14: Synthesis of Compound 63, 63-P1 or 63-P2

Step 1: Synthesis of compound 63

Compound 10-4 (104 mg, 0.81 mmol) and potassium carbonate (168 mg, 1.2 mmol) were added to a solution of compound B (200 mg, 0.41 mmol) in N,N-dimethylformamide (15 mL), and the reaction was heated to 90°C and stirred at this temperature for 12 hours. After the reaction was completed, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 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 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-65%, column temperature: 25°C; flow rate: 14 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 63 (65 mg).

Compound 63 was purified 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), total flow rate: 40g/min) to obtain compound 63-P1 (25.3mg, yield: 11.2%) and compound 63-P2 (26.7mg, yield: 11.8%).

Compound 63-P1:

MS m/z (ESI): 557.8 [M+1] ⁺ ; SFC: retention time = 2.90 min, UV = 220 nm; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.89(d,J=5.3Hz,1H),8.73(d,J=0.5Hz,1H),8.48(d,J=2.3Hz,1H),7.98(d,J=4.8Hz,1H),7.75(ddd,J=9.6,8.6,2.4Hz,1H),6.91(s,1H),5 .55(d,J=1.9Hz,2H),3.42(dd,J=17.0,8.6Hz,1H),2.59(dd,J=15.0,5.7Hz,2H),2.53-2.44(m,2H),2.25(s,3H),2.16(s,3H),1.48(s,3H).

Compound 63-P2:

MS m/z (ESI): 557.8 [M+1] ⁺ ; SFC: retention time = 5.56 min, UV = 220 nm; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.77(d,J=5.3Hz,1H),8.61(d,J=0.6Hz,1H),8.36(d,J=2.4Hz,1H),7.86(d,J=4.8Hz,1H),7.63(ddd,J=9.6,8.6,2.4Hz,1H),6.78(d,J =0.6Hz,1H),5.42(d,J=1.9Hz,2H),3.31(t,J=8.3Hz,1H),2.53-2.42(m,2H),2.41-2.32(m,2H),2.13(s,3H),2.04(s,3H),1.36(s,3H).

Example 15 Synthesis of Compound 58

Step 1: Synthesis of compound 58-1

Trifluoromethanesulfonic anhydride (2.37 g, 8.4 mmol) was slowly added to a dichloromethane (20 mL) solution of compound A-4 (1.2 g, 4.2 mmol) and triethylamine (1.27 g, 12.6 mmol). The reaction was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed by reducing pressure and concentration, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/5) to obtain compound 58-1 (0.35 g, yield: 64%). MS m/z (ESI): 416.9 [M+1] ⁺ .

Step 2: Synthesis of compound 58-4

Compound 58-2 (205 mg, 1.45 mmol) was added to a solution of compound 58-1 (500 mg, 1.2 mmol) in 1,4-dioxane (10 mL), and the reaction was heated to 90°C and stirred at this temperature for 12 hours. After the reaction was completed, the solvent was removed by reducing pressure and concentration, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 2/3) to obtain compound 58-3 (1.3 g, yield: 71.4%). MS m/z (ESI): 409.9 [M+1] ⁺ .

Step 3: Synthesis of compound 58-4

Bistriphenylphosphine palladium dichloride (68 mg, 0.1 mmol) was added to a solution of compound 58-3 (200 mg, 0.48 mmol) and compound A-7 (704 mg, 1.95 mmol) in 1,4-dioxane/water (10 mL/1 mL), and the reaction was heated to 110°C and stirred at this temperature for 3 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (dichloromethane/methanol = 5/1) to obtain compound 58-4 (0.11 g, yield: 48%). MS m/z (ESI): 446.1 [M+1] ⁺ .

Step 4: Synthesis of compound 58-5

Compound 58-4 (120 mg, 0.67 mmol) was dissolved in tetrahydrofuran/hydrochloric acid (5 mL/1 mL) solution and stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed by reducing pressure and concentration, and the residue was purified by column chromatography (dichloromethane/methanol = 10/1) to obtain compound 58-5 (0.1 g, yield: 80.4%). MS m/z (ESI): 418.1 [M+1] ⁺ .

Step 5: Synthesis of compound 58-6

Compound 58-5 (100 mg, 0.24 mmol) was added to a solution of N,N-dimethylformamide dimethyl acetal (42 mg, 0.36 mmol) in N,N-dimethylformamide (10 mL), and the reaction was heated to 100°C and stirred at this temperature for 2 hours. After the reaction was completed, the solvent was removed by reducing pressure and concentration, and the residue was purified by column chromatography (dichloromethane/methanol = 10/1) to obtain compound 58-6 (0.1 g, yield: 80%). MS m/z (ESI): 472.8 [M+1] ⁺ .

Step 6: Synthesis of compound 71

Compound 58-7 (108 mg, 0.84 mmol) and potassium carbonate (58 mg, 0.42 mmol) were added to a solution of compound 58-6 (100 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL), and the reaction was heated to 90°C and stirred at this temperature for 16 hours. After the reaction was completed, the solvent was removed by reduced pressure and concentration, and the residue was purified by high performance liquid preparative column chromatography (column chromatography column: Gemini-C18, 150×21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-70%) to obtain compound 71 (9.1 mg, yield: 7.9%). MS m/z (ESI): 538.1[M+1] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD): δ 8.86(d,J=5.3Hz,1H),8.80(s,1H),8.34(s,1H),8.27(d,J=5.3Hz,1H),7.48-7.39(m,1H),7.07-6.98(m,2H),6.23(s,1 H),4.67(s,2H),4.11-4.04(m,2H),3.66-3.57(m,2H),3.25-3.14(m,1H),2.19(s,3H),2.10-1.96(m,4H),1.94(s,3H).

Example 16 Synthesis of Compound 12

Step 1: Synthesis of compound 12-2

A hydroxylamine aqueous solution (1 mL) was added to a solution of compound 12-1 (234 mg, 2.0 mmol) in ethanol (5 mL), and the reaction mixture was heated to 75°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 12-2 (260 mg, crude product). MS m/z (ESI): 151.0 [M+1] ⁺ .

Step 2: Synthesis of compound 12-3

Raney nickel (508 mg) was added to a methanol (10 mL) solution of compound 12-2 (260 mg, 1.73 mmol), and the reaction mixture was stirred at normal pressure for 12 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12-3 (180 mg, crude product). MS m/z (ESI): 135.1 [M+H] ⁺ .

Step 3: Synthesis of compound 12

Potassium carbonate (104 mg, 0.75 mmol) was added to a solution of compound A (120 mg, 0.25 mmol) and compound 12-3 (68 mg, 0.50 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was heated to 90°C and stirred for 12 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 phase was 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: 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 12 (17.1 mg, yield 12.4%). MS m/z (ESI): 545.8 [M+1] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ 8.86(d,J=5.3Hz,1H),8.80(s,1H),8.44(d,J=2.4Hz,1H),8.38(s,1H),8.27(d,J=5.3Hz,1H),7.71(ddd,J=9.6,8.6,2.4Hz, 1H),6.80(d,J=0.5Hz,1H),5.49(d,J=2.0Hz,2H),3.70-3.59(m,1H),3.08-2.91(m,4H),2.15(s,3H),2.04(d,J=0.5Hz,3H).

Example 17 Synthesis of Compound 37

Potassium carbonate (252 mg, 1.82 mmol) was added to a solution of intermediate B (300 mg, 0.61 mmol) and intermediate 16-4 (139 mg, 1.2 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was heated to 90 ° C and stirred for 2 hours under microwave conditions. After the reaction was completed, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phases were 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, which 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 37 (17.7 mg, yield: 5.1%). MS m/z(ESI): 543.7[M+1] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ 8.96(d,J=5.2Hz,1H),8.70(s,1H),8.44(d,J=2.4Hz,1H),8.06(d,J=5.2Hz,1H),7.71(ddd,J=9.6,8.6,2.4Hz,1H),6 .87(s,1H),5.50(d,J=1.9Hz,2H),2.75-2.66(m,2H),2.46-2.35(m,2H),2.21(s,3H),2.12(s,3H),2.03-1.90(m,2H).

Example 18 Synthesis of Compound 38

Potassium carbonate (405 mg, 3 mmol) was added to a solution of compound B (200 mg, 0.4 mmol) and compound 33-4 (400 mg 3 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was heated to 90°C and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phases were 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, which 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: 40-60%; column temperature: 25 ° C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 38 (22 mg, yield 15%). MS m/z(ESI): 558.1[M+1] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ 8.98(d,J=5.3Hz,1H),8.75(s,1H),8.49(d,J=2.4Hz,1H),8.13(d,J=5.3Hz,1H),7.76(ddd,J=9.6,8. 6,2.4Hz,1H),6.91(s,1H),5.55(d,J=1.9Hz,2H),2.41-2.30(m,2H),2.26(s,3H),2.16(s,3H),2.04- 1.89(m,6H).

Example 19 Synthesis of Compound 42

At 0°C, propionyl chloride (13 mg, 0.14 mmol) was added dropwise to a dichloromethane (5 mL) solution of compound 41-5 (35 mg, 0.068 mmol) and triethylamine (21 mg, 0.21 mmol), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, the residue was diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phase was 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 HPLC preparative column chromatography (column chromatography column: Gemini-C18; 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-36%; column temperature: 25 ° C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 42 (16.7 mg, yield: 42%). MS m / z (ESI): 556.8 [M + H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 9.01-8.89(m,1H),8.85(s,1H),8.49(d,J=2.4Hz,1H),8.43(d,J=1.7Hz,1H) ,8.35(dd,J=5.2,1.4Hz,1H),7.80-7.72(m,1H),6.84(d,J=1.9Hz,1H),5.53( d,J=1.8Hz,2H),4.60(dt,J=14.4,8.7Hz,2H),4.46-4.32(m,2H),4.26-4.14( m,1H),2.26-2.12(m,5H),2.07(d,J=1.7Hz,3H),1.10(dt,J=9.2,7.6Hz,3H).

Example 20 Synthesis of Compound 43

At 0°C, isobutyl chloride (25 mg, 0.23 mmol) was added dropwise to a solution of compound 41-5 (60 mg, 0.12 mmol) and triethylamine (36 mg, 0.35 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phase was 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 HPLC preparative column chromatography (column: Gemini-C18; 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-70%; column temperature: 25 ° C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 43 (16.7 mg, yield: 12.5%). MS m / z (ESI): 580.8 [M + H] ⁺ . ¹ H NMR (400 MHz, CD3OD) δ 8.94(dd,J=6.7,5.3Hz,1H),8.85(s,1H),8.49(d,J=2.2Hz,1H),8.41(d,J=4.1Hz,1H),8.35(d,J=5. 2Hz,1H),7.81-7.72(m,1H),6.85(d,J=2.6Hz,1H),5.53(s,2H),4.68(t,J=8.6Hz,1H),4.60(dd,J=8 .6,5.8Hz,1H),4.41(t,J=9.5Hz,1H),4.36-4.27(m,1H),4.25-4.13(m,1H),2.60(dd,J=13.6,6.8Hz ,1H),2.20(d,J=1.8Hz,3H),2.07(d,J=2.0Hz,3H),1.11(dd,J=6.8,3.2Hz,3H),1.05(dd,J=14.0,6.8 3.2Hz,3H).

Example 21 Synthesis of Compound 44

Step 1: Synthesis of compound 44-2

Hydroxylamine aqueous solution (0.5 mL) was added to the ethanol solution of compound 44-1 (200 mg, 1.0 mmol), and the reaction mixture was heated to 80°C and stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 44-2 (300 mg, crude product). MS m/z (ESI): 230.1 [M+H] ⁺ .

Step 2: Synthesis of compound 44-3

Raney nickel (30 mg) was added to a methanol (10 mL) solution of compound 44-2 (300 mg, 1.3 mmol), and the reaction mixture was stirred at normal pressure for 12 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 44-3 (300 mg, crude product). MS m/z (ESI): 214.1 [M+H] ⁺ .

Step 3: Synthesis of compound 44-4

Potassium carbonate (260 mg, 1.9 mmol) was added to a solution of compound 44-3 (200 mg, 0.93 mmol) and compound A (356 mg, 0.75 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated to 90 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was 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 compound 44-4 (90 mg, yield: 13%). MS m/z(ESI): 525.0[M-100] ⁺ .

Step 4: Synthesis of compound 44-5

At room temperature, a solution of 1,4-dioxane in hydrogen chloride (4M, 2 mL) was added to a solution of compound 44-4 (70 mg, 0.11 mmol) in dichloromethane (10 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 44-5 (100 mg, crude product). MS m/z (ESI): 525.2 [M+H] ⁺ .

Step 5: Synthesis of compound 44

At room temperature, acetic anhydride (20 mg, 0.19 mmol) was added to a dichloromethane (5 mL) solution of compound 44-5 (70 mg, 0.13 mmol) and triethylamine (27 mg, 0.26 mmol), 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, the residue was diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phase was 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 chromatographed on a HPLC preparative column (column: Gemini-C18; 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 15-50%; column temperature: 25 ° C; flow rate: 20 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 44 (10 mg, yield: 12.6%). MS m/z (ESI): [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ 8.91(d,J=5.2Hz,1H),8.85(s,1H),8.49(dd,J=2.2,1.1Hz,1H),8.43-8.30(m,2H),7.80-7.71(m,1H),6. 85(s,1H),5.54(s,2H),4.14-3.63(m,5H),2.56-2.30(m,2H),2.20(s,3H),2.08(dd,J=11.2,5.0Hz,6H).

Example 22 Synthesis of compounds 66, 66-P1, 66-P2, 66-P3 and 66-P4

Step 1: Synthesis of compound 66-2

Compound 66-1 (3 g, 23 mmol) was added to an ethanol solution of ammonia (150 mL), and the reaction mixture was stirred at 90° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 66-2 (3 g, yield: 90%). MS m/z (ESI): 130.3 [M+1] ⁺ .

Step 2: Synthesis of compound 66-3

p-Toluenesulfonyl chloride (5.3 g, 27.8 mmol) was added to a dichloromethane (20 mL) solution of compound 66-2 (3 g, 23.2 mmol) and triethylamine (4.7 g, 46 mmol), and the reaction mixture was stirred at room temperature for 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 (dichloromethane: methanol = 1: 0~10: 1) to obtain compound 66-3 (5.2 g, yield: 71%). MS m/z (ESI): 284.0 [M+1] ⁺ .

Step 3: Synthesis of compound 66-4

A solution of compound 66-3 (5.78 g, 20.4 mmol) and sodium cyanide (2 g, 40.8 mmol) in dimethylsulfoxide (40 mL) was heated to 110°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was quenched by adding water (150 mL), extracted with ethyl acetate (100 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: methanol = 1:0~10:1) to obtain compound 66-4 (400 mg, yield: 13%). ¹ H NMR (400MHz, CD ₃ OD) δ3.30-3.21(m,2H), 2.68(s,3H), 2.64-2.51(m,2H), 2.50-2.42(m,2H).

Step 4: Synthesis of compound 66-5

A hydroxylamine aqueous solution (1 mL) was added to a solution of compound 66-4 (400 mg, 2.89 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 75° C. for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 66-5 (350 mg, yield: 56%). MS m/z (ESI): 172.1 [M+1] ⁺ .

Step 5: Synthesis of compound 66-6

Raney nickel (1.2 g, 20 mmol) was added to a methanol (15 mL) solution of compound 66-5 (350 mg, 2 mmol) and acetic acid (122 mg, 2 mmol), and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 66-6 (300 mg, yield: 89%). MS m/z (ESI): 156.2 [M+1] ⁺ .

Step 6: Synthesis of compound 66

Potassium carbonate (232 mg, 1.68 mmol) was added to a solution of compound 66-6 (196 mg, 1.26 mmol) and compound A (200 mg, 0.42 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 90°C for 16 hours. After the reaction was completed, the reaction solution was 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 compound, which was purified 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: 40g/min) to obtain compound 66-P1 (16.3mg, yield 6.8%), compound 66-P2 (7.4mg, yield 3.1%), compound 66-P3 (14.7mg, yield 6.1%) and compound 66-P4 (8.2mg, yield 3.4%).

Compound 66-P1:

MS m/z (ESI): 566.8 [M+1] ⁺ . Supercritical fluid column chromatography SFC: retention time = 7.2 min, UV = 214 nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.73 (d, J = 5.3 Hz, 2H), 8.40-8.34 (m, 2H), 8.17 (d, J = 5.3 Hz, 1H), 7.68-7.59 (m, 1H), 6.74 (s, 1H), 5.42 (d, J = 1.8 Hz, 2H), 3.69-3.59 (m, 1H), 3.01 (ddd, J = 17.8, 9.6, 8.3 Hz, 1H), 2.67-2.54 (m, 7H), 2.08 (s, 3H), 1.98 (s, 3H).

Compound 66-P2:

MS m/z(ESI): 566.8[M+1] ⁺ . Supercritical fluid chromatography (SFC): retention time = 7.9 min, UV = 214 nm. ¹ H NMR (400MHz, CD ₃ OD) δ 8.88(d,J=5.3Hz,1H),8.85(s,1H),8.49(d,J=2.3Hz,1H),8.43(s,1H),8.29(d,J=5.3Hz,1H),7.81-7.72(m,1H),6.85(s, 1H),5.53(d,J=1.8Hz,2H),3.91(dt,J=14.8,7.2Hz,1H),3.31-3.24(m,1H),2.75-2.58(m,7H),2.20(s,3H),2.09(s,3H).

Compound 66-P3:

MS m/z (ESI): 566.8 [M+1] ⁺ . Supercritical fluid column chromatography SFC: retention time = 8.56 min, UV = 214 nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.85 (d, J = 5.3 Hz, 2H), 8.49 (d, J = 2.4 Hz, 1H), 8.47 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 7.78-7.72 (m, 1H), 6.86 (s, 1H), 5.54 (d, J = 1.9 Hz, 2H), 3.82-3.72 (m, 1H), 3.18-3.09 (m, 1H), 2.73-2.58 (m, 7H), 2.20 (s, 3H), 2.10 (s, 3H).

Compound 66-P4:

MS m/z(ESI): 566.8[M+1] ⁺ . Supercritical fluid chromatography (SFC): retention time = 9.8 min, UV = 214 nm. 1H NMR(400MHz,CD ₃ OD)δ 8.76(d,J=5.2Hz,1H),8.73(s,1H),8.37(d,J=2.4Hz,1H),8.31(s,1H),8.17(d,J=5.3Hz,1H),7.68-7.60(m,1H),6. 73(s,1H),5.41(d,J=1.8Hz,2H),3.86-3.73(m,1H),3.18-3.10(m,1H),2.65-2.55(m,7H),2.08(s,3H),1.97(s,3H).

Example 23 Synthesis of Compound 69

Step 1: Synthesis of compound 69-2

A hydroxylamine aqueous solution (1 mL) was added to a solution of compound 69-1 (500 mg, 3.93 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 75° C. for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 69-2 (610 mg, yield: 82.3%). MS m/z (ESI): 161.1 [M+1] ⁺ .

Step 2: Synthesis of compound 69-3

Raney nickel (670 mg, 11.42 mmol) was added to a mixed solution of compound 69-2 (610 mg, 3.81 mmol) in methanol and acetic acid (15 mL/1 mL), 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 69-3 (500 mg, crude product). MS m/z (ESI): 145.1.[M+1] ⁺ .

Step 3: Synthesis of compound 69-4

Potassium carbonate (174 mg, 1.26 mmol) was added to a solution of compound 69-3 (182 mg, 1.26 mmol) and compound A (150 mg, 0.32 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at 75°C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol = 1/0~10/1) to obtain compound 69-4 (100 mg, yield: 54%). MS m/z (ESI): 555.7.[M+1] ⁺ .

Step 4: Synthesis of compound 69

Potassium hydrogen persulfate (331.6 mg, 0.54 mmol) was added to a methanol (5 mL) solution of compound 69-4 (100 mg, 0.18 mmol), 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, the residue was diluted with water (20 mL), extracted with ether (20 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0~1/2) to obtain crude compound 69, which was subjected to high performance liquid preparative column chromatography. (Column chromatography: Gemini-C18; 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-60%; column temperature: 25°C; flow rate: 20 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 69 (40 mg, yield: 35.9%). MS m/z (ESI): 587.7 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ )δ 8.92(d,J=5.2Hz,1H),8.83(s,1H),8.57(d,J=2.4Hz,1H),8.29(s,1H),8.19( d,J=5.2Hz,1H),8.07(ddd,J=10.0,9.0,2.4Hz,1H),6.79(s,1H),5.46(d,J=1. 7Hz,2H),3.35-3.32(m,1H),3.27(ddd,J=9.5,3.8,1.7Hz,2H),3.09(dt,J=6. 9,6.2Hz,2H),2.45-2.34(m,2H),2.32-2.20(m,2H),2.06(s,3H),1.93(s,3H).

Example 24 Synthesis of compounds 70, 70-P1, 70-P2, 70-P3 and 70-P4

Step 1: Synthesis of compound 70-2

Sodium borohydride (1.53 g, 40.4 mmol) was added to a methanol (150 mL) solution of compound 70-1 (3.5 g, 36.8 mmol), and the reaction mixture was stirred at 0°C for 1 hour. After the reaction was completed, the reaction solution was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 70-2 (3.4 g, yield: 76%).

Step 2: Synthesis of compound 70-3

At 0°C, p-toluenesulfonyl chloride (7.34 g, 38.5 mmol) was added dropwise to a dichloromethane (50 mL) solution of compound 70-2 (3.4 g, 35 mmol), 4-dimethylaminopyridine (0.86 g, 7 mmol) and triethylamine (4.25 g, 42 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with hydrochloric acid (1 M), extracted with dichloromethane (30 mL × 3), and 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 (petroleum ether/ethyl acetate = 1/0~10/1) to obtain compound 70-3 (5 g, yield: 54%). ¹ H NMR (400MHz, CDCl ₃ ) δ 7.77(d,J=8.3Hz,2H), 7.37(d,J=8.0Hz,2H), 4.81-4.69(m,1H), 2.74-2.59(m,3H), 2.59-2.48(m,2H), 2.46(s,3H).

Step 3: Synthesis of compound 70-4

Potassium thioacetate (3.64 g, 31.8 mmol) was added to a solution of compound 70-3 (4 g, 15.91 mmol) in N,N-dimethylformamide (40 mL), and the reaction mixture was stirred at 80°C for 2 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 to 3/1) to obtain compound 70-4 (2 g, yield: 72%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.31-4.18 (m, 1H), 3.29-3.25 (m, 1H), 2.93-2.86 (m, 2H), 2.50-2.42 (m, 2H), 2.31 (s, 3H).

Step 4: Synthesis of compound 70-5

Potassium carbonate (890 mg, 6.44 mmol) was added to a methanol (10 mL) solution of compound 70-4 (500 mg, 3.22 mmol), and the reaction mixture was stirred at 50°C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), adjusted to pH = 4 with 1N hydrochloric acid, extracted with ethyl acetate (15 mL × 3), and 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 (petroleum ether/ethyl acetate = 1/0~3/1) to obtain compound 70-5 (600 mg, yield: 74%). ¹ H NMR (400MHz, CDCl ₃ ) δ 3.81-3.73(m,2H), 3.31-3.11(m,2H), 2.83-2.62(m,4H), 2.55-2.35(m,4H).

Step 5: Synthesis of compound 70-6

Hydrochloric acid (31.2 mL, 2M) was added to a tetrahydrofuran (15 mL) solution of compound 70-5 (700 mg, 3.12 mmol), and zinc powder (2.04 g, 3.12 mmol) was added under stirring. The reaction mixture was stirred at 45°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (10 mL), extracted with ethyl acetate (15 mL×3), the combined organic phases were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 70-6 (320 mg, yield: 81%). ¹ H NMR (400MHz, CDCl ₃ ) δ3.80-3.74(m,1H), 3.22-3.30(m,1H), 2.95-2.79(m,2H), 2.45-2.30(m,2H), 1.90(d,J=7.2Hz,1H).

Step 6: Synthesis of compound 70-7

Iodomethane (1.2 g, 8.5 mmol) was added to a solution of compound 70-7 (320 mg, 2.83 mmol) and potassium carbonate (781 mg, 5.6 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (15 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate 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 70-7 (350 mg, yield: 87%). ¹ H NMR (400MHz, CDCl ₃ ) δ 3.67-3.56 (m, 1H), 3.36-3.24 (m, 1H), 2.81-2.69 (m, 2H), 2.40-2.29 (m, 2H), 2.07 (s, 3H).

Step 7: Synthesis of compound 70-8

Hydroxylamine (649 mg, 19.65 mmol) was added to a solution of compound 70-7 (500 mg, 3.93 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 70° C. for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 70-8 (600 mg, yield: 66%). MS m/z (ESI): 161.2 [M+1] ⁺ .

Step 8: Synthesis of compound 70-9

Aluminum nickel alloy (2.650 g, 31.2 mmol) was added to a methanol (10 mL) solution of compound 70-8 (500 mg, 3.12 mmol) and acetic acid (2 mL), and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 70-9 (500 mg, yield: 77%). MS m/z (ESI): 145.2 [M+1] ⁺ .

Step 9: Synthesis of compound 70-10

Compound 70-9 (455 mg, 3.15 mmol) was added to a solution of compound A (500 mg, 1.05 mmol) and potassium carbonate (436 mg, 3.15 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was stirred at 90°C for 12 hours. After the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 5/4) to obtain compound 70-10 (350 mg, yield: 50%). MS m/z (ESI): 555.8 [M+1] ⁺ .

Step 10: Synthesis of compound 70

Potassium hydrogen persulfate (1127 mg, 1.83 mmol) was added to a methanol (20 mL) solution of compound 70-10 (340 mg, 0.61 mmol), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 1/0 to 10/1) to obtain compound 70. Compound 70 was purified by supercritical fluid palmial 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: 40g/min) to obtain compound 70-P1 (16.5mg, yield 4.6%), compound 70-P2 (6.3mg, yield 1.7%), compound 70-P3 (23.0mg, yield 6.4%) and compound 70-P4 (6.9mg, yield 1.9%).

Compound 70-P1:

MS m/z(ESI): 587.7[M+1] ⁺ . Supercritical fluid chromatography (SFC): retention time = 7.59 min, UV = 214 nm. ¹ H NMR (400MHz, CD ₃ OD) δ 8.87-8.79(m,2H),8.44(s,2H),8.25(d,J=5.3Hz,1H),7.73-7.67(m,1H),6.81(s,1H),5.49(s,2H),4.09-3.98(m,1H),3 .90-3.79(m,1H),2.99(dt,J=12.6,9.4Hz,1H),2.92-2.81(m,4H),2.78-2.66(m,2H),2.15(s,3H),2.06(d,J=0.4Hz,3H).

Compound 70-P2:

MS m/z (ESI): 587.7 [M+1] ⁺ . Supercritical fluid column chromatography SFC: retention time = 7.96 min, UV = 214 nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.90-8.78 (m, 2H), 8.47-8.39 (m, 2H), 8.27 (d, J = 5.3 Hz, 1H), 7.73-7.67 (m, 1H), 6.80 (s, 1H), 5.49 (d, J = 1.9 Hz, 2H), 4.13-3.91 (m, 2H), 2.96-2.88 (m, 5H), 2.88-2.78 (m, 2H), 2.15 (s, 3H), 2.05 (s, 3H).

Compound 70-P3:

MS m/z(ESI): 587.7[M+1] ⁺ . Supercritical fluid chromatography (SFC): retention time = 9.71 min, UV = 214 nm. ¹ H NMR (400MHz, CD ₃ OD) δ 8.87-8.77(m,2H),8.44(d,J=2.7Hz,2H),8.25(d,J=5.3Hz,1H),7.73-7.67(m,1H),6.80(d,J=0.7Hz,1H),5.49(d,J=1.9Hz,2H),4 .07-3.95(m,1H),3.89-3.80(m,1H),3.03-2.96(m,1H),2.92-2.82(m,4H),2.77-2.66(m,2H),2.15(s,3H),2.05(d,J=0.5Hz,3H).

Compound 70-P4:

MS m/z (ESI): 587.7 [M+1] ⁺ . Supercritical fluid column chromatography SFC: retention time = 10.98 min, UV = 214 nm. 1H NMR (400 MHz, CD ₃ OD) δ 8.86 (d, J = 5.3 Hz, 1H), 8.80 (s, 1H), 8.48-8.38 (m, 2H), 8.27 (d, J = 5.3 Hz, 1H), 7.73-7.67 (m, 1H), 6.80 (s, 1H), 5.49 (d, J = 1.8 Hz, 2H), 4.12-3.90 (m, 2H), 2.99-2.78 (m, 7H), 2.15 (s, 3H), 2.04 (s, 3H).

Example 25 Synthesis of Compound 76

Step 1: Synthesis of compound 76-2

Sulfur dioxide chloride (813 g, 6.8 mmol) was added to a solution of compound 76-1 (800 mg, 4.6 mmol) in ethanol (20 mL), and the reaction mixture was stirred at 60°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched by adding saturated sodium bicarbonate solution (10 mL), and the ethanol was removed by reducing the pressure and concentrating. The residue was added with water (20 mL), extracted with ethyl acetate (20 mL×2), and the combined organic phase was concentrated by reducing the pressure to obtain compound 76-2 (900 mg, crude product). MS m/z (ESI): 204.1 [M+H] ⁺ .

Step 2: Synthesis of compound 76-3

Sodium borohydride (334 mg, 8.8 mmol) was added to a solution of compound 76-2 (900 mg, 4.4 mmol) in ethanol (20 mL), and the reaction mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was quenched by adding a saturated ammonium chloride solution (5 mL), and the ethanol was removed by concentration under reduced pressure. The residue was diluted with (20 mL) water, extracted with ethyl acetate (30 mL×3), and the combined organic phase was concentrated under reduced pressure to obtain compound 76-3 (600 mg, crude product). MS m/z (ESI): 162.1 [M+H] ⁺ .

Step 3: Synthesis of compound 76-4

After adding 2 drops of N,N-dimethylformamide to a solution of compound 76-3 (100 mg, 0.62 mmol) in dichloromethane (10 mL), 0.1 mL of sulfoxide chloride solution was added, 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 76-4 (100 mg, crude product).

Step 4: Synthesis of compound 76-5

Compound A-4 (143 mg, 0.55 mmol) was added to a solution of compound 76-4 (100 mg, 0.55 mmol) and potassium carbonate (154 mg, 1.11 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 65 ° C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was 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 = 1/0~2/1) to obtain compound 76-5 (100 mg, yield: 45%). MS m/z(ESI): 402.0[M+H] ⁺ .

Step 5: Synthesis of compound 76-6

N-Chlorosuccinimide (50 mg, 0.37 mmol) was added to a solution of compound 76-5 (100 mg, 0.25 mmol) in isopropanol (10 mL), and the reaction solution 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 silica gel column chromatography (dichloromethane/methanol = 1/0 to 5/1) to obtain compound 76-6 (100 mg, yield: 92%). MS m/z (ESI): 435.9 [M+H] ⁺ .

Step 6: Synthesis of compound 76-7

N,N-dimethylformamide dimethyl acetal (55 mg, 0.46 mmol) was added to a solution of compound 76-6 (100 mg, 0.23 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 100°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 1/0~5/1) to obtain compound 76-7 (80 mg, yield: 71%). MS m/z (ESI): 491.0 [M+H] ⁺ .

Step 7: Synthesis of compound 76

Tetrahydropyran-4-carboximidamide (42 mg, 0.33 mmol) was added to a solution of compound 76-7 (80 mg, 0.16 mmol) and potassium carbonate (68 mg, 0.49 mmol) in N, N-dimethylformamide (10 mL), and the reaction mixture was stirred at 90 ° C for 16 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (30 mL × 3). The combined organic phase was 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 high pressure liquid phase preparative column chromatography (column chromatography column: Gemini-C18, 150 × 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-70%, column temperature: 25 ° C; flow rate: 14 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 76 (13.4 mg, yield: 14.7%). MS m/z (ESI): 556.1 558.1 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ )δ 8.82(d,J=3.9Hz,1H),8.74(s,1H),8.48(d,J=1.5Hz,1H),8.31(s,1H),8.21(d,J=3.5Hz,1H),7.59(dd,J=8.8,1.8Hz,1H),6.42(s,1H),5. 43(s,2H),4.11(dd,J=12.5,6.0Hz,2H),3.58(t,J=10.8Hz,2H),3.19(t,J=10.6Hz,1H),2.20(s,3H),2.13-2.07(m,2H),2.01-1.96(m,5H).

Example 26 Synthesis of Compound 77

Step 1: Synthesis of compound 77-2

Sulfonitrile dichloride (813 mg, 6.83 mmol) was slowly added dropwise to a solution of compound 77-1 (800 mg, 4.56 mmol) in ethanol (15 mL), and the reaction mixture was stirred at 60° C. for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 77-2 (910 mg, crude product). MS m/z (ESI): 203.9 [M+H] ⁺ .

Step 2: Synthesis of compound 77-3

Sodium borohydride (353.07 mg, 9.3 mmol) was added in batches to a solution of compound 77-2 (910 mg, 4.6 mmol) in ethanol (15 mL), 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, the residue was diluted with water (50 mL), and extracted with ethyl acetate (80 mL×3). The combined organic phases were washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 77-3 (700 mg, crude product). MS m/z (ESI): 162.0 [M+H] ⁺ .

Step 3: Synthesis of compound 77-4

After 2 drops of N,N-dimethylformamide were added to a solution of compound 77-3 (120 mg, 0.74 mmol) in dichloromethane (5 mL), 0.5 mL of sulfoxide chloride solution was added, 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 77-4 (60 mg, crude product). MS m/z (ESI): 180.7 [M+H] ⁺ .

Step 4: Synthesis of compound 77-5

Compound A-4 (110 mg, 0.42 mmol) was added to a solution of compound 77-4 (76 mg, 0.42 mmol) and potassium carbonate (117 mg, 0.85 mmol) in N,N-dimethylformamide (20 mL), and the reaction mixture was stirred at 60°C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (80 mL×3). The combined organic phases were washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 77-5 (80 mg, yield 42%). MS m/z (ESI): 401.9 [M+H] ⁺ .

Step 5: Synthesis of compound 77-6

N-Chlorosuccinimide (26 mg, 0.19 mmol) was added to a solution of compound 77-5 (80 mg, 0.91 mmol) in isopropanol (15 mL), and the reaction mixture was stirred at 60°C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0/1 to 1/0) to obtain compound 77-6 (80 mg, yield: 73%). MS m/z (ESI): 437.0 [M+H] ⁺ .

Step 6: Synthesis of compound 77-7

N,N-dimethylformamide dimethyl acetal (87 mg, 0.73 mmol) was added to a solution of compound 77-6 (80 mg, 0.18 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated brine (30 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 = 1/0~50/1) to obtain compound 77-7 (35 mg, yield: 34%). MS m/z(ESI): 491.0[M+H] ⁺ .

Step 7: Synthesis of compound 77

Tetrahydropyran-4-carboximidamide (18 mg, 0.14 mmol) was added to a solution of compound 77-7 (35 mg, 0.07 mmol) and potassium carbonate (29 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, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (30 mL×3). The combined organic phase was 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: Gemini-C18, 150 × 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-70%, column temperature: 25 ° C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 77 (6.6 mg, yield: 14.2%). MS m / z (ESI): 556.0 558.0 [M + H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ 8.88(d,J=5.3Hz,1H),8.84(s,1H),8.55(d,J=2.5Hz,1H),8.41(s,1H),8.29(d,J=5.3Hz,1H),7.97(dd,J=8.2,2.5Hz,1H),6 .81(s,1H),5.58(s,2H),4.12-4.03(m,2H),3.62(dd,J=17.8,6.6Hz,2H),3.27-3.14(m,1H),2.20(s,3H),2.09-1.96(m,7H).

Example 27 Synthesis of compounds 78, 78-P1 and 78-P2

Step 1: Synthesis of compound 78-1

Compound 69-3 (878 mg, 6.09 mmol) was added to a solution of compound B (500 mg, 1.01 mmol) and potassium carbonate (981 mg, 7.10 mmol) in acetonitrile (10 mL), and the reaction mixture was stirred at 75°C for 12 hours. After the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 1/0 to 20/1) to obtain compound 78-1 (100 mg, yield: 16%). MS m/z (ESI): 574.0 [M+1] ⁺ .

Step 2: Synthesis of compound 78

Potassium hydrogen persulfate (546 mg, 0.89 mmol) was added to a methanol (10 mL) solution of compound 78-1 (170 mg, 0.30 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was 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 78. Compound 78 was purified by supercritical fluid palmial 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 give compound 78-P1 (15.6 mg, yield 8.26%) and compound 78-P2 (19.0 mg, yield 10%).

Compound 78-P1:

MS m/z (ESI): 606.0 [M+1] ⁺ . Supercritical fluid column chromatography SFC: retention time = 4.58 min, UV = 214 nm. ¹ H NMR (400MHz, CD ₃ OD) δ 8.89-8.84(m,1H),8.66-8.59(m,1H),8.41(d,J=2.4Hz,1H),7.95(d,J=5.2Hz,1H),7.54-7.52(m,1H),6.58(d,J=0.6Hz,1H), 5.41(d,J=2.0Hz,2H),3.30-3.19(m,1H),3.15-3.04(m,4H),2.41(dd,J=12.0,5.9Hz,4H),2.15(d,J=0.4Hz,3H),1.99(s,3H).

Compound 78-P2:

MS m/z (ESI): 606.0 [M+1] ⁺ . Supercritical fluid chromatography (SFC): retention time = 6.39 min, UV = 214 nm. ¹ H NMR (400MHz, CD ₃ OD) δ 8.86(d,J=5.2Hz,1H),8.62(s,1H),8.41(d,J=2.4Hz,1H),7.95(d,J=5.2Hz,1H),7.54-7.52(m,1H),6.58(d,J=0.5Hz,1 H),5.41(d,J=2.0Hz,2H),3.30-3.20(m,1H),3.16-3.04(m,4H),2.41(dd,J=12.0,5.9Hz,4H),2.15(s,3H),1.99(s,3H).

Example 28 Synthesis of compounds 82, 82-P1 and 82-P2

Step 1: Synthesis of compound 82-2

Methylamine (2.38 g, 35.2 mmol) was added to a solution of compound 82-1 (3 g, 17.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.75 g, 35.2 mmol), 1-hydroxybenzotriazole (4.76 g, 35.2 mmol) and triethylamine (5.34 g, 52.8 mmol) in dichloromethane (50 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was diluted with water (150 mL), extracted with dichloromethane (100 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 (petroleum ether/ethyl acetate = 1/0~5/2) to obtain compound 82-2 (1.1 g, yield: 30%). MS m/z (ESI): 184.1 [M+1] ⁺ .

Step 2: Synthesis of compound 82-3

Compound 82-2 (1.1 g, 6 mmol) was added to an ethanol solution of ammonia (8.6 mL, 60 mmol), and the reaction mixture was placed in a sealed tube, heated to 90°C and stirred at this temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 82-3 (1 g, yield: 90%). MS m/z (ESI): 168.9 [M+1] ⁺ .

Step 3: Synthesis of compound 82-4

Trifluoroacetic anhydride (1.86 g, 8.8 mmol) was added to a dichloromethane (20 mL) solution of compound 82-3 (1 g, 5.9 mmol) and triethylamine (3 g, 29.5 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mL × 3), and the combined organic phase was 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 82-4 (280 mg, yield: 28%). MS m/z (ESI): 150.9 [M+1] ⁺ .

Step 4: Synthesis of compound 82-5

An aqueous solution of hydroxylamine (2 mL, 3.73 mmol) was added to a solution of compound 82-4 (280 mg, 1.86 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 75°C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 82-5 (300 mg, yield: 79%). MS m/z (ESI): 184.0 [M+1] ⁺ .

Step 5: Synthesis of compound 82-6

Raney nickel (14 mg, 0.24 mmol) was added to a solution of compound 82-5 (300 mg, 1.6 mmol) and acetic acid (1 mL) in methanol (10 mL), and the reaction mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 82-6 (300 mg, yield: 98%). MS m/z (ESI): 168.2 [M+1] ⁺ .

Step 6: Synthesis of compound 82

Compound 82-6 (300 mg, 0.6 mmol) was added to a solution of compound A (211 mg, 1.2 mmol) and potassium carbonate (175 mg, 1.2 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 90°C for 12 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 1/0 to 10/1) to obtain compound 82. Compound 82 was further purified by supercritical fluid palmial 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 give compound 82-P1 (35.2 mg, yield 9.61%) and compound 82-P2 (36.6 mg, yield 10.61%).

Compound 82-P1:

MS m/z (ESI): 578.8 [M+1] ⁺ . Supercritical fluid column chromatography SFC: retention time = 2.37 min, UV = 254 nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.89-8.83 (m, 2H), 8.49 (d, J = 2.3 Hz, 1H), 8.39-8.31 (m, 2H), 7.79-7.71 (m, 1H), 6.85 (s, 1H), 5.54 (d, J = 1.8 Hz, 2H), 2.77 (s, 3H), 2.43 (d, J = 12.0 Hz, 6H), 2.19 (s, 3H), 2.08 (s, 3H).

Compound 82-P2:

MS m/z (ESI): 578.8 [M+1] ⁺ . Supercritical fluid column chromatography SFC: retention time = 7.9 min, UV = 254 nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.88-8.84 (m, 2H), 8.49 (d, J = 2.3 Hz, 1H), 8.38-8.32 (m, 2H), 7.79-7.71 (m, 1H), 6.85 (s, 1H), 5.53 (d, J = 1.8 Hz, 2H), 2.77 (s, 3H), 2.45 (s, 6H), 2.19 (s, 3H), 2.08 (s, 3H).

According to the method of above-mentioned embodiment 1-28, prepare the following compound:

，參照WO2021195475A1實施例1的方法製備得到。 Compound C:

, prepared according to the method of Example 1 of WO2021195475A1.

Biological evaluation

Test example 1. Determination of p38 MAPK/MK2 in vitro activity

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 Reagent 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.

Test example 2. p38 MAPK/MK5 in vitro activity assay

The inhibitory effect of the compounds on p38 MAPK/MK5 was detected using the 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 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), 1 ng/mL active p38a (Carna, 04-152), 2 μm Ser/Thr 4; after 4 hours of reaction at 20°C, Development Reagent A diluted 2048 times was added to each well. After incubation at room temperature for 1 hour, 5 μL of stop buffer solution was added to terminate the reaction and detected by enzyme marker (Ex.400nm, Em.445nm; Ex.400nm, Em.520nm). GraphPad Prism 8 software was used to fit the concentration-effect curve and calculate the compound concentration with 50% inhibition effect, i.e. IC ₅₀ . The results are shown in Table 2.

As can be seen from Table 2, the inhibitory activity of the compounds of the present invention on p38 MAPK/MK5 is greater than 0.6μm. This further shows that the compounds of the present invention have good selectivity for p38 MAPK/MK2.

Test Example 3. Determination of p38 MAPK/ATF2 in vitro activity

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 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 enzyme marker was used for detection (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 0.8μm. This further shows that the compounds of the present invention have good selectivity for p38 MAPK/MK2.

Test Example 4. In vitro activity determination of TNF-α in human PBMC cell supernatant

The experimental scheme for the inhibitory effect of compounds on TNF-α in human PBMC cell supernatant was tested using an Elisa test kit (Biyuntian, PI518). The test compound was dissolved in DMSO to a 10mM stock solution and stored at -20°C for later use. The starting concentration of the compound was 2μM, 5-fold dilution, 6 concentrations, duplicate wells for cell plating, single well for Elisa detection, and the final DMSO concentration was 0.4%. The starting concentration of the compound, dilution multiple, number of gradient concentrations, and number of duplicate wells can also be changed according to the actual situation of compound screening.

Fresh human peripheral blood mononuclear cells (PBMC) (Sai Li Biotechnology) were plated in a 96-well plate (Corning, 3599) at a number of 2*10^5, each well containing 100μL RPMI-1640 (Gibco#A1049101) + 10% FBS (Gibco, 10099141C), and cultured overnight at 37°C, 5% CO ₂ ; the test compound was added to the 96-well culture plate at a volume of 25μL/well, and 1 hour later, 5μL of LPS was added to make the final concentration of 100ng/mL, and LPS and compounds were not added to the negative control wells, and compounds were not added to the positive control wells, and the culture was continued at 37°C, 5% CO 2. ₂ After 24 hours of continuous culture, the cell culture supernatant was collected by centrifugation at 500 rcf for 8 minutes, and the concentration of TNF-α was detected according to the operation manual in the Elisaa reagent box. The concentration-effect curve was fitted using GraphPad Prism 8 software, and the compound concentration with 50% inhibitory effect, i.e., IC ₅₀ , was calculated. The results are shown in Table 4.

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

Test Example 5. In vitro CYP enzyme inhibition evaluation

This experiment used the cocktail method to study the inhibitory activity of the test compound on the 1A2, 2B6, 2C8, 2C19, 2C9, 2D6 and 3A4 subtypes of CYP enzymes, and measured the IC50 values of the test compound on the activity of several CYP enzyme subtypes. The control compounds were Fluvoxamine (1A2), Ketoconazole (2B6), Montelukast (2C8), Tranylcypromine (2C19), Sulfaphenazole (2C9), Quinindium (2D6) and Ketoconazole (3A4/5); the CYP enzyme probe substrates used were Phenacetin (1A2), Bupropion (2B6), Amodiaquine (2C8), Mephenytoin (2C19), Diclofenac (2C9), Dextromethorphan (2D6) and Testosterone (3A4/5). PBS Buffer is 50mM K2HPO4 buffer. The concentrations of the test compounds are 50μM, 12.5μM, 3.125μM, 0.781μM, 0.195μM, and 0.0488μM. The corresponding probe substrate and microsomes were added to PBS and mixed evenly. Then, the control compound/test compound/DMSO solution were added to the corresponding reaction system, pre-incubated in a 37℃ water bath for 5min, 10mM NADPH solution was added, and the reaction was reacted in a 37℃ water bath for 10min. The internal standard acetonitrile solution was added to terminate the reaction. Centrifuge at 4000rpm, take the supernatant solution and add an equal volume of pure water to mix evenly, LC-MS/MS (AB Triple Quard 5500) analyzes the amount of each probe substrate reaction product, and uses GraphPad Prism 5 to calculate IC50 based on the measured product production. The results are shown in Table 5:

As can be seen from Table 5, the compounds 10-P1 and 63-P1 of the present invention have no inhibitory effect on in vitro CYP enzymes.

Test Example 6. In vitro time-dependent CYP3A4 enzyme inhibition evaluation

In this experiment, the test compound was pre-reacted with the microsome reaction system and the experimental conditions without pre-reaction, and the changes in the IC50 values of the test compound on the CYP3A4/5 subtype enzyme activity were compared under the above two conditions, and the corresponding IC50 shift values were calculated. The control compound is: Verapamil (CYP3A4/5), and the probe substrate is: Testosterone (CYP3A4/5). PBS Buffer is a 50mM K2HPO4 buffer. The concentrations of the test compounds are 50μm, 10μm, 2μm, 0.4μm, 0.08μm, and 0.016μm. The probe substrate and PBS solution are pre-prepared into a substrate solution (1990μL PBS + 10μL substrate). The microsomes were added to PBS. After the samples without pre-reaction were pre-incubated in a 37°C water bath for 30 min, the control compound/test compound/DMSO solution, 10 mM NADPH solution and probe substrate solution were added to the corresponding reaction system, placed in a 37°C water bath for 10 min, and the internal standard acetonitrile solution was added to terminate the reaction; the control compound/test compound/DMSO solution and 10 mM NADPH solution were added to the corresponding system of the pre-reaction group samples, mixed evenly, placed in a 37°C water bath for 30 min, then the probe substrate solution was added, placed in a 37°C water bath for 10 min, and the internal standard acetonitrile solution was added to terminate the reaction. After centrifugation at 4000 rpm, the supernatant solution was added with an equal volume of pure water and mixed evenly. LC-MS/MS (AB Triple Quard 5500) was used to analyze the amount of each probe substrate reaction product, and the IC50 was calculated using GraphPad Prism 5 using the measured product production amount. The results are shown in Table 6: Table 6

As can be seen from Table 6, the compounds 10-P1 and 63-P1 of the present invention have no time-dependent CYP3A4 enzyme inhibition effect.

Test Example 7. Evaluation of in vitro liver microsome stability

The control compound used in this experiment is Ketanserin, and the final concentration of microsomes in the experimental system is 0.5 mg/mL. PBS Buffer is a 50 mM K2HPO4 buffer. The concentration of the test compound is 1 μm. Add the microsomes to PBS, add the control compound/test compound to the corresponding reaction system, mix well, place in a 37°C water bath for pre-incubation for 5 minutes, add 20 mM NADPH solution, and start the reaction in a 37°C water bath (for No NADPH samples, replace the 20 mM NADPH solution with an equal volume of PBS solution). At the reaction time points of 0 min, 10 min, 30 min, 60 min and 90 min, take out 30 μL of reaction samples from each reaction system (for No NADPH samples, take samples at the reaction time points of 0 min and 90 min respectively), and immediately add 300 μL of internal standard acetonitrile solution to terminate the reaction. After centrifugation at 4000 rpm, add the supernatant solution to an equal volume of pure water and mix evenly. LC-MS/MS (AB Triple Quard 5500) detects the amount of compounds in the sample at each time point and calculates T _1/2 . The results are shown in Table 7:

As can be seen from Table 7, the compound 10-P1 of the present invention has good in vitro liver microsome stability (human/mouse/rat).

Test Example 8. Pharmacokinetic evaluation in mice

The compound was weighed and dissolved in a mixed solvent of DMAC:Solutol:PBS=1:1:8. After intravenous/gavage administration to mice, 30 μL of whole blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 7 and 24 hours. After anticoagulation with EDTA-K2, the blood was immediately centrifuged at 4000 rpm for 5 min at 4°C. The supernatant was taken and the sample was frozen in a -80°C refrigerator. Treatment of plasma samples: After precipitation with CH3CN precipitant containing internal standard, centrifugation was performed at 12700 rpm for 10 min. The supernatant was taken and analyzed by LC-MS/MS (AB Triple Quard 5500) to obtain blood drug concentration, and parameters were calculated by Winnolin 8.1 version of the non-compartmental model. The results are shown in Table 8:

As can be seen from Table 8, within the range of drug concentration, dosage and detection time, both Compound 10-P1 and Compound 63-P1 of the present invention have good exposure, in vivo clearance and bioavailability. In intravenous injection, the in vivo clearance rate CL of compound 10-P1 is 1241.95mL/hr/kg, which is significantly better than the in vivo clearance rate CL of compound C (2313.22mL/hr/kg); in oral administration, the blood drug exposure of compound 10-P1 is 2120.68hr*ng/mL, which is doubled compared with the blood drug exposure of compound C; the in vivo clearance rate CL of compound 63-P1 is 1492.93mL/hr/kg, which is significantly better than the in vivo clearance rate CL of compound C (2313.22mL/hr/kg); in oral administration, the blood drug exposure of compound 63-P1 is 2596.40hr*ng/mL, which is doubled compared with the blood drug exposure of compound C. Therefore, this shows that the compound of the present invention has good in vivo pharmacokinetic properties and is significantly better than the control compound C.

The above is an explanation of the implementation of the present invention. However, the present invention is not limited to the above implementation. Any modification, equal replacement, improvement, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims (18)

A compound of formula I, its racemate, stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

wherein W is CH or N; m is an integer of 0-5; n is an integer of 0-3; ring A is a C _3-20 cycloalkyl group or a 3-20 membered heterocyclic group, the carbon atoms in ring A are connected to the parent nucleus, and the 3-20 membered heterocyclic group contains 1, 2 or more O, N or S atoms; 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 _{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 _1-20 alkyl which are unsubstituted or optionally substituted by ₁ , ² , 3, 4 or _{5 R} ^b . _{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} ; provided that when R ₅ is selected from OH, the ring _A is _not

; and the compound represented by the formula I is not the following structure:

The compound as claimed in claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein W is CH or N; m is an integer of 0-5; n is an integer of 0-3; ring A is a C _3-20 cycloalkyl group or a 3-20 membered heterocyclic group, the carbon atoms in ring A are connected to the parent nucleus, and the 3-20 membered heterocyclic group contains 1, 2 or more O, N or S atoms; 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 _1-6 R ⁵ is independently selected from H, _halogen , OH, C _1-6 alkyl, C _1-6 alkoxy, oxo (=O), -C(O)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 _1-10 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 wherein the C _6-14 aryl and the 5-14 membered heteroaryl are 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. The compound as claimed in claim 1, its racemate, stereoisomer, tautomer or 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 C _3-9 cycloalkyl, 3-9 membered heterocyclic group, the carbon atom in ring A is connected to the parent nucleus, and the 3-9 membered heterocyclic group contains 1, 2 or more O, N or S atoms; R ¹ is halogen; R ² is selected from -OR ⁸¹ , -NH-C(O) _R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ; R ³ is C _{1-3 alkyl} or C _3-6 cycloalkyl; R ⁴ is C _1-3 alkyl; R ⁵ is independently selected from halogen, -OH, -C wherein 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 C _6-8 ^aryl _- C _{1-3 alkyl} , _5-6 membered heteroaryl- _{C 1-3} 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 1-3 alkyl, C _1-3 alkyl and C _1-3 alkoxy groups; R ^91a , R ^91b , R ⁹² , R ^93a , R ^93b are the same or different and independently selected from H, C _1-3 alkyl and C _3-6 cycloalkyl. The compound of claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein W is CH or N; m is 0, 1, 2 or 3; n is 0 or 1; Ring A is selected from piperidinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, oxacyclobutanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxaspiro[3.3]heptyl, 2-oxaspiro[3.5]nonanyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, azacyclobutanyl, tetrahydropyrrolyl, thiacyclobutanyl, tetrahydro-2H-thiopyranyl; R ¹ is selected from Cl, Br; R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ , -C(O)NHR ⁸⁴ ; R ³ is selected from methyl and cyclopropyl; R ⁴ is selected from methyl; R ⁵ is independently selected from F, -OH, methyl, methoxy, oxo (=O), -C(O)C _1-3 alkyl, -C(O)OH, -C(O)NH ₂ , -C(O)NHCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₂ CH ₂ CH ₃ , -S(O) ₂ -cyclopropane; R ⁶ is selected from H, F, Cl; R ⁷ is selected from H; R ⁸¹ , R ⁸² , R ⁸³ , R ⁸⁴ are the same or different and are independently selected from unsubstituted or arbitrarily substituted with 1, 2 or 3 R ^b -substituted phenylmethyl, pyridylmethyl, pyridylethyl, phenyl, pyridyl; each R ^b is the same or different and is independently selected from F, Cl, CF ₃ . The compound as claimed in claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the ring A is selected from the following structures:

The compound as claimed in claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the structure formed by R ₅ and ring A is selected from:

The compound as described in any one of claims 1 to 6, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound represented by formula I has a structure represented by 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 defined in any one of claims 1 to 6. The compound as described in any one of claims 1 to 6, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Formula I has the structure shown in Formula II:

wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , W, m, n and ring A are independently defined in any one of claims 1 to 6; 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, C _2-10 alkynyloxy; each R ¹¹ is the same or different and is independently selected from H, halogen, C _1-6 alkyl, halogenated C _1-10 alkyl; _p is an integer from 0 to 4. The compound as claimed in claim 8, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ¹⁰ is selected from H, methyl; p is 0, 1 or 2; each R ¹¹ is the same or different and is independently selected from F, Cl, CF ₃ . The compound as described in claim 8, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound represented by formula II has the structure represented by formula IIa or 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 same meanings as defined above or in claim 8. The compound as described in any one of claims 1 to 6, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

The * in the structural formula of compounds 10 and 63 indicates the presence of a cis-trans structure at that location, and the * is either cis or trans. The compound as described in any one of claims 1 to 6, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound represented by formula I has the following structure:

The * in the structural formula of compounds 10-P1 or 10-P2 and 63-P1 or 63-P2 indicates the presence of a cis-trans structure at that location, and the * is either a cis or a trans structure. A method for preparing a compound as described in any one of claims 1 to 12, its racemate, stereoisomer, tautomer 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 in any one of claims 1 to 12; Scheme 2: When W is N and _R7 is H, compound b1 reacts with compound b2 to obtain a compound of formula I as follows:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n, p and ring A independently have the definitions described in any one of claims 1 to 12; when R ⁵ is OH, the OH in compound b2 is protected by a silicon protecting group, and the silicon protecting group is tert-butyldiphenylsilyl; the silicon protecting group is removed in the reaction to obtain deprotected OH. A pharmaceutical composition comprising a therapeutically effective amount of a compound as described in any one of claims 1 to 12, at least one of its racemates, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers. Use of a compound as described in any one of claims 1 to 12, at least one of its racemates, stereoisomers, tautomers or pharmaceutically acceptable salts, or a drug composition as described in claim 14 in the preparation of a drug for treating a disease associated with an MK2 inhibitor or a p38 MAPK/MK2 inhibitor. The use as described in claim 15, 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.