TW202332439A - 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 modulators and compositions, preparation methods and uses thereof

The present invention claims to enjoy the patent application number 202111640112. First to file priority. The entirety of this prior application is incorporated herein by reference.

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

Biological signal transduction involves specific protein-protein interactions and post-translational modifications, regulating genetic and epigenetic processes in response to the effects of internal and external environments. Mitogen-activated protein kinase MAPK (mitogen-activated protein kinase) is a group of serine-threonine protein kinases that can be activated by different intracellular and external stresses. It is an important transmission of signals from the cell surface to the interior of the nucleus. By. 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 p38 MAPK is initiated, it phosphorylates and activates multiple downstream protein kinases and transcription factors, thereby playing complex biological roles. . p38 MAPK includes four members, namely p38α, p38β, p38γ and p38δ. Among them, p38α is considered to play an important role in the signaling pathway of the inflammatory process, while the biological functions of other isomers have not yet been fully discovered, but they have pleiotropic effects. Studies have shown that p38β plays an important role in cell protection mechanisms, and mitogen-activated protein kinase MKK3 (MAP Kinase Kinase 3) mediates p38δ to have an effect on the proliferation and survival of advanced colorectal cancer (CRC) cells. As an attractive target in the field of drug development, multiple inhibitor drugs of p38 MAPK have entered clinical research, but so far no drug has been approved for marketing. According to public information, some candidate compounds failed in the clinical research stage. The main reasons for clinical failure include dose limitation to avoid toxicity, leading to insufficient exposure of drug molecules at the target, downregulation of anti-inflammatory pathways, redundancy of signaling networks, or involvement of other Key proteins in the feedback regulation of the MAPK pathway are inhibited, etc., and inhibiting the feedback mechanism may upregulate other pro-inflammatory pathways, leading to increased inflammation. Therefore, developing a safe and effective p38 MAPK inhibitor is a major challenge currently facing drug development in this field.

p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013(152),924], so selectively inhibiting the initiation of p38 MAPK downstream effectors is to avoid the overall inhibition of p38 MAPK. Primary strategy for side effects/insufficient efficacy. MAPK-activated protein kinase 2 (MK2) is a direct receptor downstream of p38 MAPK and can be activated by p38α and p38β. As the first discovered substrate of p38 MAPK, 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 element of mRNA. In a mouse postoperative intestinal obstruction model [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, At the same time, it was found that the infiltration of polymorphonuclear leukocytes, mast cells, and mononuclear macrophages was reduced and the contractile properties of intestinal smooth muscle were improved. In the mouse model of collagen-induced arthritis (CIA) [Journal of immunology 2006(177), 1913], knocking out the MK2 gene can reduce the occurrence of collagen-induced arthritis. Compared with wild-type mice, MK2-/ The incidence and severity of collagen-induced arthritis in - 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 mouse model of hypercholesterolemia [Circ Res 2007(101), 1104], the lipid deposition and macrophages in the mouse aorta were reduced, and the expression of inflammatory factors such as VCAM-1 and MCP-1 was reduced. . In addition, some studies have shown that inhibiting MK2 can be used for 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 diseases and inflammatory diseases (e.g., rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic 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, etc. Selectively inhibiting the p38 MAPK/MK2 pathway reduces the impact on other downstream pathways of p38 MAPK, thereby reducing potential toxic side effects and insufficient drug efficacy in drug development; meeting the existing needs in the field of diseases related to the p38 MAPK/MK2 pathway Unmet clinical needs.

The invention provides a compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug: Wherein, W is CH or N; m is an integer from 0 to 5; n is an integer from 0 to 3; Ring A is C _3-20 cycloalkyl, 3-20 membered heterocyclyl, and the carbon atoms in ring A are Connected to the mother core, 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 _1-6 alkoxy, pendant oxy ( =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, unsubstituted or substituted C _1-10 alkyl and C _3-20 cycloalkyl by Ra; Ra is halogen Or C _3-20 cycloalkyl; R ⁸¹ , R ⁸² , R ⁸³ , R ⁸⁴ are the same or different, and are independently selected from C ₆ that is unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 Rb _-14 aryl-C ₁ - ₁₀ alkyl, 5-14 membered heteroaryl -C ₁ - ₁₀ alkyl, C _6-14 aryl and 5-14 membered heteroaryl; each Rb is the same or different from each other Independently selected from halogen, halogenated C _1-10 alkyl, C _1-10 alkyl and C _1-10 alkoxy _; R ^91a , R ^91b , R ⁹² , ^{R 93a} _, R ^93b are the same or different, independent of each other is 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 from 0 to 5; n is an integer from 0 to 3; Ring A is C _3-20 cycloalkyl, 3-20 membered heterocyclyl, ring The carbon atom in A is connected to the mother core, 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 _1-6 alkoxy, pendant oxygen group (=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 , R ⁸⁴ is the same or different, 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 _6-14 aryl and 5-14-membered heteroaryl are unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C ₁ - ₁₀ alkyl, C _1-10 alkyl and C _1-6 alkoxy substituted; _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 group and C _3-20 cycloalkyl group.

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 C _3-12 cycloalkyl, 3- 12-membered heterocyclyl group, the carbon atom in ring A is connected to the mother core, the 3-12-membered heterocyclyl 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 _1-6 alkyl, - C _1-6 alkoxy group, side oxy group (=O), -C(O)C _1-6 alkyl group, -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ; R ⁶ is selected from H, halogen and methyl; R ⁷ is independently selected from H, halogen, C _1-6 alkyl and C _3-12 cycloalkyl group; R ⁸¹ , R ⁸² , R ⁸³ , 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 _6-14 aryl and 5-14 membered heteroaryl are unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently of each other. is selected from halogen, halogenated C _1-6 alkyl, C _1-6 alkyl and C _1-3 alkoxy substituted; R ^91a , R ^91b , R ₉₂ ^, R _93a , ^{R 93b are} the same or different, independent of each other is 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 C _3-9 cycloalkyl, 3- 9-membered heterocyclyl group, the carbon atom in ring A is connected to the mother core, the 3-9-membered heterocyclyl 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 and C _3-6 cycloalkyl; R ⁴ is C _1-3 alkyl; R ⁵ is independently selected from halogen, -OH, -C _1-3 alkyl, -C _1-3 alkoxy, side oxy (=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 ⁶ is selected from H, Halogen and methyl; R ⁷ are independently selected from H, halogen and C _1-3 alkyl; R ⁸¹ , R ⁸² , R ⁸³ , R ⁸⁴ are the same or different, and are independently selected from C _6-8 aryl- C ₁ - ₃ alkyl, 5-6 membered heteroaryl - C ₁ - ₃ alkyl, C _6-14 aryl and 5-14 membered heteroaryl; among which, C _6-14 aryl, 5-14 membered Heteroaryl is unsubstituted or optionally substituted by 1, 2, 3, 4 or _{5 independently selected from halogen, halogenated C 1-3 alkyl ,} C _1-3 alkyl and C _1-3 alkoxy ; 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, oxygen Hetetanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxaspiro[3.3]heptyl, 2-oxaspiro[3.5]nonyl, 2-azaspiro [3.3]Heptyl, 2-azaspiro[3.5]nonyl, azetidinyl, tetrahydropyrrolyl, thietanyl, 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 ⁸⁴ ; R ³ is methyl or cyclopropyl; R ⁴ is methyl; R ⁵ is independently selected from F, -OH, methyl, methoxy, side oxy (=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 , R ⁸⁴ are the same or different, and are independently selected from phenylmethyl and pyridylmethyl that are unsubstituted or optionally substituted by 1, 2 or 3 Rb base, pyridylethyl, phenyl and pyridyl; each Rb is the same or different and independently selected from F, Cl and CF ₃ . According to embodiments of the invention, Ring A may be selected from: .

According to embodiments of the present invention, the structure formed by R ₅ and ring A may be selected from: In a preferred embodiment, the compound of formula I has the structure shown in formula Ia or Ib: ; Among them, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A, W, m, n have the definitions mentioned above, and the bold chemical bonds indicate the presence of axial chiral properties in the compound. .

In a preferred embodiment, the compound of formula I has the structure shown in formula II: wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , W, m, n and ring A independently have the definitions described above; R ¹⁰ is selected from H, halogen, unsubstituted or any Select the following groups substituted by 1, 2 or more halogens, OH, _NH2 : C _1-10 alkyl, C _1-10 alkoxy, halo C _1-10 alkyl, halo C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkenyloxy, C _2-10 alkynyl, C _2-10 alkynyloxy; each R ¹¹ is the same or different, independently of each other 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 invention, R ¹⁰ is selected from the following groups: H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH ₂ : C _1-6 alkyl, C _1-6 alkoxy, 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, 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, independently of each other 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 .

In a more preferred embodiment, the compound of Formula II has Formula IIa or Formula IIb: ; Among them, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , A, W, m, n, p have the definitions mentioned above, and the chemical bonds in bold represent compounds There is axial polarity.

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

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

In some embodiments, the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its precursor medicine, wherein R ² is -OR ⁸¹ ; R ⁸¹ is C ₆ aryl-C ₁ - ₃ alkyl or 6-membered heteroaryl-C ₁ - ₃ alkyl; wherein C ₆ aryl or 6-membered heteroaryl has no Substituted or _{optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C 1-3 alkyl, C 1-3 alkyl and} C _1-3 alkoxy; C ₁ - _3The alkyl moiety is attached to O.

In some embodiments, compounds represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, their racemates, stereoisomers, tautomers, isotopic labels, solvates, Pharmaceutically acceptable salts or prodrugs thereof, wherein for , R ⁵ is selected from halogen, -OH, -C _1-3 alkyl, -C _1-3 alkoxy, side oxy (=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, independently selected from H, C _1-3 alkyl and C _3-6 cycloalkyl.

In some embodiments, compounds represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, their racemates, stereoisomers, tautomers, isotopic labels, solvates, Pharmaceutically acceptable salts or prodrugs 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.

In some embodiments, compounds represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, their racemates, stereoisomers, tautomers, isotopic labels, solvates, Pharmaceutically acceptable salts or prodrugs thereof do not include , , , , and .

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

In some embodiments, compounds represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, their racemates, stereoisomers, tautomers, isotopic labels, solvates, Pharmaceutically acceptable salts or prodrugs thereof, wherein R ³ is C _1-3 alkyl.

In some embodiments, compounds represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, their racemates, stereoisomers, tautomers, isotopic labels, solvates, Pharmaceutically acceptable salts or prodrugs thereof, wherein R ⁴ is halogen or C _1-3 alkyl.

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

According to an embodiment of the invention, the compound of formula I has the following structure: No. Structural formula No. Structural formula 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 twenty one twenty two twenty three twenty four 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82

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

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

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

The invention also provides a method for preparing the compound of formula I, which includes:

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

The reaction formula is as follows:

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

Option 2: When W is N and R ₇ is H, compound b1 reacts with compound b2 to obtain the 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 definitions set forth above;

According to an embodiment of the present invention, the reaction is carried out in the presence of an inorganic base; the inorganic base is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide.

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

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

According to embodiments of the present invention, the drug may be a drug for treating and/or preventing diseases related to p38 kinase inhibitors, for example, it may be a MK2 inhibitor or a p38 MAPK/MK2 pathway modulator.

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

According to an embodiment of the present invention, the pharmaceutical composition further includes at least one pharmaceutically acceptable carrier.

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

The carrier includes disintegrating agents, such as methylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium, polyvinylpyrrolidone, carboxypropylcellulose, 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 dihydrogen Silicon oxide. The compositions of the present invention may be formulated to provide immediate, sustained or delayed release of the active ingredient after administration to the patient using methods known in the art.

The present invention also provides the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound, in the treatment and/or Use in the prevention of diseases mediated by p38 kinase inhibitors.

The present invention also provides methods for treating and/or preventing diseases related to p38 kinase inhibitors, which include administering to patients a therapeutically or preventively effective amount of the compound represented by Formula I, its racemate, stereoisomer, and tautomer. At least one of a structure, an isotope label, a solvate, a pharmaceutically acceptable salt or a prodrug compound thereof.

According to embodiments of the present invention, the disease may be a disease related to the p38 MAPK/MK2 pathway, for example, it may be an autoimmune disease and an inflammatory disease (such as rheumatoid arthritis, hidradenitis purulenta, psoriasis , inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular disease, allergies and asthma, Alzheimer's disease and hormones related diseases.

The compound of the present invention has a good regulatory effect on the p38 MAPK/MK2 pathway and has good selectivity. In addition, the compound of the present invention has good pharmacokinetic and other properties. Furthermore, the compounds of the present invention are useful in the treatment of diseases associated with p38 kinase inhibitor mediation, and in the preparation of medicaments for such conditions or diseases.

Definitions and explanations of terms

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

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

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

The term "halogen" means fluorine, chlorine, bromine and iodine.

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

The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined herein. Preferably, an alkoxy group (C _1-12 alkoxy group) containing 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, More preferred is an alkoxy group containing 1 to 6 carbon atoms (C _1-6 alkoxy group). Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be substituted or unsubstituted.

The term "C _2-10 alkenyl" should be understood to preferably mean a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 Or 10 carbon atoms, preferably "C _2-8 alkenyl". "C _2-10 alkenyl" is understood to preferably mean a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms , for example, has 2, 3, 4, 5 or 6 carbon atoms (ie, C _2-6 alkenyl), has 2 or 3 carbon atoms (ie, C _2-3 alkenyl). It will be understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated. 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 base, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (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-methyl Butylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2- Alkenyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E) )-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methyl But-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

The term "C _2-10 alkynyl" should be understood to preferably represent a linear or branched monovalent hydrocarbon radical containing 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., "C _2-8 alkynyl"), having 2, 3, 4, 5 or 6 carbon atoms atom (i.e., "C _2-6 alkynyl"), having 2 or 3 carbon atoms ("C _2-3 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-ynyl, 1-methylpentyl -4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut- 2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbutyl -3-alkynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term "C _3-20 cycloalkyl" should be understood to mean a saturated monovalent monocyclic, bicyclic (such as paracyclic, spirocyclic, bridged cyclic) hydrocarbon ring or tricycloalkane, which has 3 to 20 carbon atoms, "C _3-12 cycloalkyl" is preferred, and "C _3-8 cycloalkyl" is more preferred. The term "C _3-12 cycloalkyl" should be understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged ring, spirocyclic) hydrocarbon ring or tricycloalkane, which has 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12 carbon atoms. The C _3-12 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecanyl, or bicyclic Hydrocarbon groups such as bornyl, 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 base, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or tricyclic hydrocarbon group such as adamantyl.

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

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

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

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

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

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

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably 6 to 10 members such as phenyl and naphthyl. The aryl ring includes an aryl ring fused to a heteroaryl, heterocyclyl or cycloalkyl ring as described herein, where the ring attached to the parent structure is an aryl ring, which is not limited to Examples include: and . Aryl groups may be substituted or unsubstituted.

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

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

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

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

In the chemical structure of the compound of the present invention, the bond " ” means that the configuration is not specified, “ "or" "Indicates the absolute configuration, that is, if there is a chiral isomer in the chemical structure, the bond" ” can be “ "or" ", or both " "and" "Two configurations," ” indicates the existence of axial chirality.

key ” means unspecified configuration, including cis (E) or trans (Z) configuration.

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

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

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

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

"Pharmaceutically acceptable" as used herein means those compounds, materials, compositions and/or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with patient tissue without undue toxicity, irritation, allergic reactions or other problems or complications, have a reasonable benefit/risk ratio, and be 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 A good person.

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

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

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

MS was measured using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent G6125B liquid chromatography mass spectrometer.

The HPLC measurement used Shimadzu HPLC-2010C high-performance liquid phase column chromatography (XBRID GE 2.1*50 mm, 3.5 μm column chromatography column).

Chiral HPLC analysis was performed using THARSFC X5.

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

Column chromatography generally uses Qingdao Marine Silica Gel 200~300 mesh silica gel as the carrier.

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

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

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

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

Microwave reaction uses Biotage initiator+ type microwave reactor.

Unless otherwise stated in the experimental examples, the reactions were carried out in an argon atmosphere or 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.

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

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

The asterisk (*) in the chemical structural formula in the reaction route indicates the existence of cis-trans isomerism at a specific ring structure position (a person with ordinary knowledge in the technical field can understand that cis-trans isomerism exists in the substituted cycloalkane structure), an exemplary cis-trans isomerism The heterogeneous phenomena are as follows:

and , the * is one of cis or trans.

Those with ordinary knowledge in the art should understand that the resolved chiral compounds can be distinguished by the order of retention times in the chiral column chromatography column. Therefore, the chiral compounds separated successively with respect to the retention times are distinguished by The number suffixes P1 and P2 correspond to the distinction. That is, the tail code P1 corresponds to the palmar structure separated first, and the tail code P2 corresponds to the palmar structure separated later. If the absolute configuration of a compound is listed in the reaction formula, it does not mean that it corresponds to the compounds with numbers ending in P1 and P2, but only indicates the two existence forms of the absolute configuration. The absolute configuration of the compounds with numbers ending in P1 and P2 shall be based on the absolute configuration objectively corresponding to the specific retention time.

Synthesis of intermediate compound A-5

Step One: Synthesis of Compound A-5b

Trisene 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 heated at 60 ^° C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain crude compound A-5b (20 g), which was directly used in the next step of the 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 concentrated under reduced pressure, 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

Strylene chloride (1.77 g, 0.015 mol) was slowly added to compound A-5c (1.8 g, 0.0124 mol) and N,N-dimethylformamide (5 drops) in dichloromethane at room temperature. (50 mL) solution and the reaction mixture was allowed to proceed at room temperature for 1 h. After the reaction, add ammonium chloride solution (100 mL, 4M) to the reaction solution to adjust the pH value to neutral, then add water (20 mL) and extract with dichloromethane (10 mL × 3), and the combined organic phases are Dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the resulting 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 (400 MHz, 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 One: Synthesis of Compound A-2

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) at -78 °C. , the reaction solution was stirred at -78 °C for 1 hour, and then acetyl chloride (6.6 g, 844 mmol) was slowly added dropwise, and the resulting mixture was continued to stir at -78 °C for 1 hour. After the reaction, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (500 mL), and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting 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 naturally cooled to room temperature, 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, the reaction mixture was naturally cooled to room temperature 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 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) mixture, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with brine (20 mL reaction. MS m/z (ESI): 378.0 [M+1] ⁺ .

Step 4: Synthesis of Compound A-8

Bistriphenylphosphine palladium dichloride (1.56 g, 2.22 mmol) was added to 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), the reaction solution was heated to 130 °C and stirred for 4 hours. The reaction solution was then filtered, and the filtrate was directly concentrated under reduced pressure. Tetrahydrofuran (100 mL) was added to the residue to dissolve, and then 5 mL of concentrated hydrochloric acid was added dropwise and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate) to obtain compound A-8 (5 g, yield: 60%). MS m/z (ESI): 386.0 [M+1] ⁺ .

Step 5: Synthesis of Compound A-9

Acetic acid (2 mL) was added dropwise to a solution of compound A-8 (5 g, 13 mmol) and N-chlorosuccinimide (1.9 g, 14.3 mmol) in isopropyl alcohol (100 mL), and the reaction was Stir at 60°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate) to obtain compound A-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 compound A-9 (1.3 g, 3.1 mmol) in N,N-dimethylformamide (15 mL ) solution, 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 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 column chromatography (dichloromethane/methanol = 50/1) to obtain the compound. A (900 mg, yield: 78%). MS m/z (ESI): 474.9 [M+H] ⁺ .

Synthesis of intermediate compound B:

Step One: Synthesis of Compound B-2

Diphenylphosphoryl azide (23.5 g, 0.085 mol) was added to compound B-1 (10 g, 0.057 mol) and triethylamine (17.3 g, 0.17 mol) in tert-butanol/toluene (50 mL/50 mL), the reaction mixture was heated at 110°C for 16 hours. After the reaction was completed, the reaction solution was poured into water and extracted with dichloromethane (200 mL × 3). The combined organic phases were washed with water (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 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 the 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 resulting residue was purified by column chromatography (dichloromethane/methanol = 20/1) to obtain 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 obtained 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, methylboronic acid (530 mg, 8.8 mmol), cesium carbonate (8.96 g, 27.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( 450 mg, 0.55 mmol) was 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, add sodium bicarbonate aqueous solution to the reaction solution to dilute it, extract with ethyl acetate (50 mL × 3), wash the combined organic phases once with saturated brine, dry over anhydrous sodium sulfate and filter, and the filtrate is concentrated under reduced pressure. The solvent was removed, and the resulting 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 heated at Stir at this temperature for 1 hour. After the reaction solution was naturally cooled to 50°C, methylsulfonic acid (285 mg, 2.96 mmol) was added, and 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 the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain compound B-7 (530 mg, Yield: 66%). MS m/z (ESI): 269.0 [M+1] ⁺ .

Step Six: Synthesis of Compound B-8

Potassium carbonate (1.14 g, 8.28 mmol), 18-crown-6 (175 mg, 0.66 mmol) was added to the N of compound A-5 (702 mg, 4.30 mmol) and compound B-7 (890 mg, 3.31 mmol). , N-dimethylformamide (15 mL) solution, the reaction mixture was heated to 40 °C and stirred at this temperature for 16 hours. After the reaction, the reaction solution was cooled to room temperature, added with water (50 mL) for dilution, and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. and filtered, and the filtrate was concentrated under reduced pressure to obtain compound B-8 (1.5 g, purity: 84%, yield: 96%) crude product, which was directly used in the next reaction. MS m/z(ESI): 395.8 [M+1] ⁺ .

Step Seven: Synthesis of Compound B-9

Compound A-7 (2.01 g, 5.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (257 mg, 0.37 mmol) was added to compound B-8 (1.45 g, 3.70 mmol) in 1,4-dioxane (20 mL), the reaction mixture was stirred at 130 °C for 1.5 h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain 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 a solution of tetrahydrofuran (15 mL) and concentrated hydrochloric acid (0.5 mL), 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 resulting 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 sequentially to a solution of compound B-10 (910 mg, 2.25 mmol) in isopropyl alcohol (12 mL), and the reaction was The 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 resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound B-11 (1.13 g). MS m/z (ESI): 437.8 [M+1] ⁺ .

Step 10: Synthesis of Compound B

N,N-dimethylformamide dimethyl acetal (600 mg, 5.0 mmol) was added to compound B-11 (1.08 g, 2.5 mmol) in N,N-dimethylformamide (15 mL ) solution, 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 phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain compound B. (900 mg, yield: 72%). MS m/z (ESI): 492.7 [M+1] ⁺ .

Example 1 Synthesis of Compound 1

Step One: 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, diluted with ethyl acetate (40 mL), 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. The 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 the 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 resulting 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). The reaction was stirred at room temperature for 0.5 hours, and sodium cyanoborohydride ( 39 mg) and continue the reaction at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was subjected to high-performance liquid phase 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 purify compound 1 (25.5 mg, yield: 22% ). MS m/z (ESI): 553.0 [M+1] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.90 (d, J = 5.2 Hz, 1H), 8.85 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.38 (s, 1H) , 8.31 (d, J = 5.2 Hz, 1H), 7.80-7.72 (m, 1H), 6.86 (s, 1H), 5.54 (d, J = 1.6 Hz, 2H), 3.42-3.33 (m, 2H), 3.22-3.10 (m, 1H), 2.84 (t, J = 11.2 Hz, 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 phases were washed with saturated brine (20 mL × 3), and dried over anhydrous sodium sulfate. And filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to 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%) and purified to obtain compound 2 (43.8 mg, yield: 43.77%). MS m/z (ESI): 580.8 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.88 (d, J = 5.3 Hz, 1H), 8.83 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.42 (s, 1H) , 8.29 (dd, J = 5.3, 2.3 Hz, 1H), 7.81-7.72 (m, 1H), 6.84 (s, 1H), 5.53 (d, J = 1.8 Hz, 2H), 4.69-4.57 (m, 1H ), 4.06 (d, J = 11.8 Hz, 1H), 3.31-3.16 (m, 2H), 2.84 (t, J = 12.7 Hz, 1H), 2.19 (s, 3H), 2.17-2.05 (m, 8H) , 2.04-1.83 (m, 2H).

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

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 = 1.9 Hz, 2H), 4.64-4.50 (m, 1H), 4.06-3.97 (m, 1H) , 3.21 (ddd, J = 15.4, 11.1, 7.8 Hz, 2H), 2.80 (t, J = 12.8 Hz, 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, 3.2 Hz, 1H), 4.00 (dd, J = 18.6, 12.5 Hz, 1H), 3.26-3.15 (m, 2H), 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 (50mL C18, 150×21.2 mm, 5 μm; column temperature: 25 ^o 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 (400 MHz, DMSO-d6): δ 8.90 (d, J = 5.2 Hz, 1H), 8.83 (s, 1H), 8.58 ( d, J = 2.4 Hz, 1H), 8.34 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 8.11-8.04 (m, 1H), 6.79 (s, 1H), 5.45 (d, J = 1.5 Hz, 2H), 3.96-3.87 (m, 2H), 3.43 (td, J = 11.6, 2.4 Hz, 2H), 3.15-3.04 (m, 1H), 2.05 (s, 3H), 1.93 (s, 3H), 1.91-1.79 (m, 4H).

Compound 3 was passed through 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), Flow rate: 12.5 g/min), compound 3-P1 (62.1 mg, yield 21%) and compound 3-P2 (59.1 mg, yield 20%) were obtained.

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 = 5.2 Hz , 1H), 8.84 (s, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.41 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 7.80-7.71 (m, 1H) , 6.86 (s, 1H), 5.54 (d, J = 1.4 Hz, 2H), 4.08 (d, J = 11.1 Hz, 2H), 3.62 (dd, J = 17.9, 6.7 Hz, 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 = 1.8 Hz, 2H), 4.12-4.03 (m, 2H), 3.62 (dt, J = 13.0, 6.7 Hz, 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) , the reaction mixture was stirred at 80 °C for 12 h. After the reaction, the reaction solution was poured into water, extracted with ethyl acetate (50 mL×3), the combined organic phases were washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue Purified by high performance liquid phase preparative column chromatography (column chromatography column: Xbridge-C18, 150×21.2 mm, 5 μm; column temperature: 25 ^o 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 (400 MHz, CD ₃ OD): δ 8.83 (dd, J = 5.2, 0.9 Hz, 1H), 8.80 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.26 (dd, J = 5.2, 0.9 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.81 (d, J = 0.5 Hz, 1H), 5.49 (d, J = 1.9 Hz, 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, 1.4 Hz, 2H), 2.15 (s, 3H), 2.04 (d, J = 0.7 Hz, 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) , the reaction mixture was heated to 60°C and stirred at this temperature for 16 hours. After the reaction, pour the reaction solution into water, extract with ethyl acetate (50 mL×3), wash the combined organic phases with saturated brine (50 mL×3), dry over anhydrous sodium sulfate and filter, and the filtrate is filtered through The solvent was concentrated to remove, and the residue was subjected to high performance liquid phase preparative column chromatography (column chromatography column: Xbridge-C18, 150×21.2 mm, 5 μm; column temperature: 25 ^o 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 (400 MHz, DMSO-d ₆ ): δ 8.90 (d, J = 5.2 Hz, 1H), 8.86 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H ), 8.17 (d, J = 5.2 Hz, 1H), 8.14-8.07 (m, 1H), 6.83 (s, 1H), 5.49 (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) , the reaction mixture was heated to 60°C and stirred at this temperature for 18 hours. After the reaction, ethyl acetate (30 mL) was added to the reaction solution to dilute it, washed with saturated brine (30 mL × 5), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was passed through a high-performance liquid phase preparation tube Column chromatography (Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid) = 45-60%, UV: 214 nm) purified compound 7 (43 mg, yield: 25.2 %). MS m/z (ESI): 496.0 [M+1] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.85 (s, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.32 (s, 1H), 8.14-8.08 (m, 2H), 6.83 (s, 1H), 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) , the reaction solution was heated to 80°C and stirred at this temperature for 12 hours. After the reaction, the reaction solution was poured into water, 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, and the filtrate was concentrated under reduced pressure. The solvent was removed, and the residue was subjected to high performance liquid phase preparative column chromatography (column chromatography column: Xbridge-C18, 150×21.2 mm, 5 um; column temperature: 25 ^o 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 (400 MHz, CD ₃ OD) δ 8.83-8.78 (m, 2H), 8.44 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.22 (d, J = 5.3 Hz, 1H ), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.80 (d, J = 0.5 Hz, 1H), 5.49 (d, J = 2.0 Hz, 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 One: Synthesis of Compound 9-2

Sodium borohydride (200 mg, 5 mmol) was slowly added to a solution of compound 9-1 (1 g, 10 mmol) in methanol (15 mL) under ice bath. 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 resulting residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain 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 at room temperature. Stir for 16 hours. After the reaction, the reaction solution was poured into water (30 mL) and diluted, extracted with dichloromethane (20 mL × 3), the combined organic phases were washed with water (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was decompressed. After concentration, the obtained 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

Ethyl hydrochloride solution (2.0 M, 5 mL) was added dropwise to a solution of compound 9-4 (100 mg, 0.29 mmol) in methanol (27 mg, 0.89 mmol), and the reaction mixture was stirred at room temperature for 16 hours. Concentrate under reduced pressure, add amine methanol solution (7.0 M, 5 mL), and continue the reaction at room temperature for 3 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to obtain crude compound 9-5 (41 mg, 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) , the reaction was heated to 100°C and stirred at this temperature for 16 hours. After the reaction, the reaction mixture was poured into water (20 mL), 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 solution was concentrated under reduced pressure, and the resulting 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 (400 MHz, CD ₃ OD): δ 8.82-8.77 (m, 2H), 8.46-8.41 (m, 2H), 8.24 (d , J = 5.2 Hz, 1H), 7.74-7.67 (m, 1H), 6.82 (s, 1H), 5.49 (d, J = 1.9 Hz, 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 Compound 10, 10-P1 & Compound 10-P2

Step One: Synthesis of Compound 10-2

Titanium tetrachloride (6.3 mL, 6.3 mmol) and methyllithium chloride complex (2.0 M, 3.2 mL, 6.3 mmol) were slowly added dropwise to compound 10-1 (500 mg) at -5 ^° C. , 5.2 mmol) in toluene (15 mL), the reaction system was naturally warmed to room temperature and stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was poured into saturated aqueous ammonium chloride solution (30 mL) to quench, 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 to obtain crude compound 10-2 (230 mg), which was directly used in the next reaction.

Step 2: Synthesis of compound 10-3

Hydroxylamine aqueous solution (50%, 2 mL) was added to a solution of compound 10-2 (160 mg, 1.44 mmol) in ethanol (5 mL). 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 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

Raney nickel (400 mg) was added to a solution of compound 10-3 (200 mg, 1.39 mmol) in methanol (8 mL) at room temperature under nitrogen protection. The reaction was carried out under normal pressure in a hydrogen atmosphere at room temperature for 12 hours. After the reaction, the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain 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) , 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 phases were washed with water (20 mL × 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was decompressed. Concentrate, and the residue obtained is subjected to high performance liquid phase preparative 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 ^o 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 supercritical fluid preparation column chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H 250mm*20 mm, 5 μm; mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia) ; flow rate: 12.5 g/min) for chiral separation to obtain compounds 10-P1 (15.7 mg, yield: 4.6%) and 10-P2 (17.2 mg, 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 One: Synthesis of Compound 14-2

Titanium tetrachloride (19.4 mL, 19.40 mmol, 1 M) and methyllithium (9.7 mL, 19.40 mmol, 2 M) were slowly added dropwise to the solution of compound 14-1 (2.0 g, 16.20 mmol) at -5 °C. Toluene (50 mL) solution, after the dropwise addition, the reaction was naturally warmed to room temperature and stirred at room temperature for 3 hours. After the reaction, add saturated ammonium chloride solution (20 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (50 mL x3), and wash the combined organic phases with saturated brine (50 mL), anhydrous sulfuric acid The mixture was dried over sodium and filtered, and the filtrate was concentrated under reduced pressure. The resulting 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

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). 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 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 solution of compound 14-3 (300 mg, 1.70 mmol) in methanol (10 mL), and the reaction was carried out at room temperature and normal pressure in a 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 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), The reaction was heated to 90°C and stirred at this temperature for 12 hours. After the reaction, the reaction mixture was poured into water (50 mL), extracted with dichloromethane (30 mL x3), the combined organic phases were washed with water (20 mL x2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. , the obtained residue was subjected to high performance liquid phase preparative 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 ^o C; flow rate: 14 mL/min; wavelength: 214 nm; column pressure: 80 bar) and purified to obtain two groups of compound 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 , 3.9 Hz, 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 One: Synthesis of Compound 16-2

Under ice bath, trimethylsilyl cyanide (11.89 g, 119.8 mmol) and zinc iodide (0.82 g, 2.56 mmol) were slowly added to compound 16-1 (6 g, 85.6 mmol) in tetrahydrofuran (100 mL). in solution. The reaction was allowed to warm to room temperature naturally and stirred at room temperature for 40 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the resulting 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 (400 MHz, 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 ethanol hydrochloric acid solution (4M, 25 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure, and the resulting residue was slurried with diethyl ether (20 mL) and filtered. 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 (400 MHz, DMSO-d ₆ ): δ 11.13 (d, J = 111.0 Hz, 2H), 4.54 (q, J = 7.0 Hz, 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 a solution of ammonia in ethanol (2M, 30 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was slurried with diethyl 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) , the reaction was stirred under microwave (90°C) conditions for 2 hours. After the reaction, the reaction solution was poured into water (20 mL), 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 liquid was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane/methanol=10/1) and high-performance liquid phase column chromatography (column chromatography column: gemini-C18, 150×21.2 mm, 5um; Mobile phase: acetonitrile-water (0.1% formic acid), gradient: 40-60%) was further purified to obtain compound 16 (60 mg).

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

Compound 16 was prepared by supercritical fluid chiral prep column chromatography (Equipment: SFC Thar prep 80; Column: CHIRALPAK AD-H 250mm*20 mm, 5 μm; Mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia water) ); flow rate: 12.5 g/min) and purified 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 (400 MHz, CD ₃ OD) δ 8.92 (d, J = 5.2 Hz, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 5.2 Hz, 1H), 7.71 (ddd, J = 9.7, 8.6, 2.4 Hz, 1H), 6.81 (d, J = 0.6 Hz, 1H), 5.49 (d, J = 2.0 Hz, 2H ), 2.77 – 2.67 (m, 2H), 2.38 (dt, J = 11.8, 8.8 Hz, 2H), 2.16 (s, 3H), 2.05 (d, J = 0.5 Hz, 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 (400 MHz, CD ₃ OD) δ 8.92 (d, J = 5.2 Hz, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 5.2 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.81 (d, J = 0.5 Hz, 1H), 5.49 (d, J = 2.0 Hz, 2H ), 2.71 (ddd, J = 9.8, 7.2, 5.1 Hz, 2H), 2.38 (dd, J = 9.3, 3.4 Hz, 2H), 2.16 (s, 3H), 2.05 (d, J = 0.5 Hz, 3H) , 2.03 – 1.94 (m, 2H).

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

Step One: Synthesis of Compound 33-2

Under ice bath, trimethylsilyl nitrile (3.31 g, 33.3 mmol) and zinc iodide (0.23 g, 0.71 mmol) were added successively to the solution of compound 33-1 (2.0 g, 23.8 mmol) in tetrahydrofuran (25 mL). . The reaction was allowed to warm to room temperature naturally and stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 33-2 (1.5 g, yield: 32.7%). ¹ H NMR (400 MHz, 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 ethanolic hydrochloric acid solution (4M, 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 resulting residue was slurried with diethyl 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 a solution of ammonia in ethanol (2M, 15 mL) and the reaction was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was slurried with diethyl 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) , the reaction was heated to 90°C and stirred at this temperature for 12 hours. After the reaction, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL x3), the combined organic phases were washed with saturated brine (20 mL x3), dried over anhydrous sodium sulfate and filtered, the filtrate was reduced to Concentrate under pressure, and the resulting residue is purified by column chromatography (dichloromethane/methanol=10/1) and high-performance liquid phase preparative column chromatography (column chromatography column: Gemini-C18 150×21.2 mm, 5um; Mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-60%) to obtain compound 33.

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

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, 1H), 8.72 (s, 1H), 8.44 (s, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.64–7.61 (m, 1H), 6.74 (s, 1H), 5.41 (d, J = 1.9 Hz, 2H), 2.42–2.23 (m, 2H), 2.08 (s, 3H), 1.98 (s, 3H), 1.93–1.72 (m, 6H) .

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

Step One: Synthesis of Compound 41-2

Hydroxylamine aqueous solution (50%, 5 mL) was added to a solution of 41-1 (5.0 g, 1.4 mmol) in ethanol (5 mL). The reaction was heated to 75 °C and stirred at this temperature for 12 hours. After the reaction was completed, the reaction The liquid was directly concentrated under reduced pressure to obtain 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 solution of compound 41-2 (5.8 g, 27.9 mmol) in methanol (50 mL), 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 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) , the reaction was heated to 90°C and stirred at this temperature for 12 hours. After the reaction, pour the reaction solution into water (50 mL), extract with ethyl acetate (50 mL x3), wash the combined organic phases with saturated brine (20 mL x3), dry over anhydrous sodium sulfate and filter, and filter the filtrate. The mixture 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 solution of compound 41-4 (90 mg, 0.15 mmol) in dichloromethane (10 mL), and the reaction was carried out at room temperature for 12 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to obtain 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 carried out at room temperature. Stir 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 x3), the combined organic phases were washed with saturated brine (20 mL x3), dried over anhydrous sodium sulfate, and Filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to high-performance liquid phase 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 ^o C; flow rate: 14 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 41 (50 mg).

Compound 41 was prepared by supercritical fluid column chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H 250 mm×20 mm, 5 μm; mobile phase: 40% methanol (methanol/carbon dioxide, 0.2% ammonia); Flow rate: 12.5 g/min) was purified to obtain compound 41-P1 (19 mg yield: 17.6%) and compound 41-P2 (17 mg 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, 4.3 Hz, 1H), 8.81 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.30 (dd, J = 5.3, 1.1 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.80 (s, 1H), 5.48 (d, J = 1.9 Hz, 2H), 4.57 (ddd, J = 14.7, 8.7, 4.3 Hz, 2H) , 4.40 – 4.30 (m, 2H), 4.16 (ddd, J = 8.8, 5.9, 2.8 Hz, 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, 4.4 Hz, 1H), 8.81 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.31 (dd, J = 5.2, 1.2 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.81 (s, 1H), 5.49 (d, J = 1.9 Hz, 2H), 4.57 (ddd, J = 14.7, 8.8, 4.1 Hz, 2H), 4.40 – 4.30 ( m, 2H), 4.17 (ddd, J = 8.9, 5.9, 2.9 Hz, 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 One: 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) , 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 x3). The combined organic phases were washed with saturated brine (20 mL 150×21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-65%, column temperature: 25 ^o C; flow rate: 14 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 63 (65 mg).

Compound 63 was prepared by supercritical fluid column chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm×20 mm, 5 μm; mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia), total Flow rate: 40 g/min) was purified to obtain compound 63-P1 (25.3 mg, yield: 11.2%) and compound 63-P2 (26.7 mg, 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 = 5.3 Hz, 1H), 8.73 (d, J = 0.5 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.75 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.91 (s, 1H), 5.55 (d, J = 1.9 Hz, 2H), 3.42 (dd, J = 17.0, 8.6 Hz, 1H), 2.59 (dd, J = 15.0, 5.7 Hz, 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 = 5.3 Hz, 1H), 8.61 (d, J = 0.6 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 4.8 Hz, 1H), 7.63 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.78 (d, J = 0.6 Hz, 1H), 5.42 (d, J = 1.9 Hz, 2H), 3.31 (t, J = 8.3 Hz, 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 One: Synthesis of Compound 58-1

Triflate (2.37 g, 8.4 mmol) was slowly added to a solution of compound A-4 (1.2 g, 4.2 mmol) and triethylamine (1.27 g, 12.6 mmol) in dichloromethane (20 mL). The reaction was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the resulting 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 at this temperature Stir for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the resulting 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 1,4-dioxane of compound 58-3 (200 mg, 0.48 mmol) and compound A-7 (704 mg, 1.95 mmol). The reaction was heated to 110°C and stirred at this temperature for 3 hours in a solution of ring/water (10 mL/1 mL). After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting 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 the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the resulting 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 N,N-dimethylformamide dimethyl acetal (42 mg, 0.36 mmol) in N,N-dimethylformamide (10 mL) In solution, the reaction was heated to 100°C and stirred at this temperature for 2 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the resulting 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 compound 58-6 (100 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL) In solution, the reaction was heated to 90°C and stirred at this temperature for 16 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the resulting residue was subjected to high performance liquid phase preparative column chromatography (column chromatography column: Gemini-C18, 150×21.2 mm, 5um; mobile phase: acetonitrile-water (0.1% formic acid ); gradient: 35-70%) was purified to obtain compound 71 (9.1 mg, yield: 7.9%). MS m/z (ESI): 538.1 [M+1] ⁺ ; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.86 (d, J = 5.3 Hz, 1H), 8.80 (s, 1H), 8.34 ( s, 1H), 8.27 (d, J = 5.3 Hz, 1H), 7.48-7.39 (m, 1H), 7.07-6.98 (m, 2H), 6.23 (s, 1H), 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 One: Synthesis of Compound 12-2

Hydroxylamine aqueous solution (1 mL) was added to a solution of compound 12-1 (234 mg, 2.0 mmol) in ethanol (5 mL). The reaction mixture was heated to 75°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution Concentrate 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 solution of compound 12-2 (260 mg, 1.73 mmol) in methanol (10 mL), and the reaction mixture was stirred under normal pressure under hydrogen atmosphere for 12 hours. After the reaction, 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) , 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 phases were washed with saturated brine (20 mL C18; 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-50%; column temperature: 25 ^o 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 (400 MHz, CD ₃ OD) δ 8.86 (d, J = 5.3 Hz, 1H), 8.80 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.27 (d, J = 5.3 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.80 (d, J = 0.5 Hz, 1H), 5.49 (d, J = 2.0 Hz, 2H ), 3.70 – 3.59 (m, 1H), 3.08 – 2.91 (m, 4H), 2.15 (s, 3H), 2.04 (d, J = 0.5 Hz, 3H).

Example 17 Synthesis of Compound 37

Potassium carbonate (252 mg, 1.82 mmol) was added to Intermediate B (300 mg, 0.61 mmol) and Intermediate 16-4 (139 mg, 1.2 mmol) in N,N-dimethylformamide (15 mL) In the solution, the reaction mixture was heated to 90°C under microwave conditions and stirred for 2 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 ) was purified to obtain a crude product, which was subjected to high performance liquid phase 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 ^o 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 (400 MHz, CD ₃ OD) δ 8.96 (d, J = 5.2 Hz, 1H), 8.70 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 5.2 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.87 (s, 1H), 5.50 (d, J = 1.9 Hz, 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). 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 ) was purified to obtain a crude product, which was subjected to 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 ^o 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 (400 MHz, CD ₃ OD) δ 8.98 (d, J = 5.3 Hz, 1H), 8.75 (s, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.76 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.91 (s, 1H), 5.55 (d, J = 1.9 Hz, 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

Propionyl chloride (13 mg, 0.14 mmol) was added dropwise to a solution of compound 41-5 (35 mg, 0.068 mmol) and triethylamine (21 mg, 0.21 mmol) in dichloromethane (5 mL) at 0°C. , the reaction mixture was stirred at room temperature for 12 hours. After the reaction, 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 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 subjected to high-performance liquid phase 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 ^o 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 = 2.4 Hz, 1H), 8.43 (d, J = 1.7 Hz, 1H ), 8.35 (dd, J = 5.2, 1.4 Hz, 1H), 7.80 – 7.72 (m, 1H), 6.84 (d, J = 1.9 Hz, 1H), 5.53 (d, J = 1.8 Hz, 2H), 4.60 (dt, J = 14.4, 8.7 Hz, 2H), 4.46 – 4.32 (m, 2H), 4.26 – 4.14 (m, 1H), 2.26 – 2.12 (m, 5H), 2.07 (d, J = 1.7 Hz, 3H ), 1.10 (dt, J = 9.2, 7.6 Hz, 3H).

Example 20 Synthesis of Compound 43

Isobutyryl 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) at 0°C. medium, 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 phases were washed with saturated brine (20 mL ;150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-70%; column temperature: 25 ^o 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, 5.3 Hz, 1H), 8.85 (s, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.41 (d, J = 4.1 Hz, 1H), 8.35 (d, J = 5.2 Hz, 1H), 7.81 – 7.72 (m, 1H), 6.85 (d, J = 2.6 Hz, 1H), 5.53 (s, 2H), 4.68 (t, J = 8.6 Hz, 1H), 4.60 (dd, J = 8.6, 5.8 Hz, 1H), 4.41 (t, J = 9.5 Hz, 1H), 4.36 – 4.27 (m, 1H), 4.25 – 4.13 (m, 1H) , 2.60 (dd, J = 13.6, 6.8 Hz, 1H), 2.20 (d, J = 1.8 Hz, 3H), 2.07 (d, J = 2.0 Hz, 3H), 1.11 (dd, J = 6.8, 3.2 Hz, 3H), 1.05 (dd, J = 14.0, 6.8 3.2 Hz, 3H).

Example 21 Synthesis of Compound 44

Step One: 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 solution of compound 44-2 (300 mg, 1.3 mmol) in methanol (10 mL), and the reaction mixture was stirred under normal pressure under hydrogen atmosphere for 12 hours. 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) , 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 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 resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=1:0~10: 1) Purify 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 hydrogen chloride in 1,4-dioxane (4 M, 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 at room temperature. Stir 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 solution of compound 44-5 (70 mg, 0.13 mmol) and triethylamine (27 mg, 0.26 mmol) in dichloromethane (5 mL), and the reaction mixture Stir 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 phases were washed with saturated brine (20 mL C18; 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 15-50%; column temperature: 25 ^o 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 (400 MHz, CD ₃ OD) δ 8.91 (d, J = 5.2 Hz, 1H), 8.85 (s, 1H), 8.49 (dd, J = 2.2, 1.1 Hz, 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, 5.0 Hz, 6H).

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

Step One: Synthesis of Compound 66-2

Compound 66-1 (3 g, 23 mmol) was added to a solution of ammonia in ethanol (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

Toluene sulfonate chloride (5.3 g, 27.8 mmol) was added to a solution of compound 66-2 (3 g, 23.2 mmol) and triethylamine (4.7 g, 46 mmol) in dichloromethane (20 mL), and the reaction mixture Stir 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 dimethylstyrene (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 with water (150 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography ( Dichloromethane: methanol = 1:0~10:1) was purified to obtain compound 66-4 (400 mg, yield: 13%). ¹ H NMR (400 MHz, 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

Aqueous hydroxylamine 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 h. 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 solution of compound 66-5 (350 mg, 2 mmol) and acetic acid (122 mg, 2 mmol) in methanol (15 mL), and the reaction mixture was maintained at room temperature under hydrogen atmosphere. Stir for 16 hours. After the reaction was completed, the reaction liquid 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) , the reaction mixture was stirred at 90°C for 16 hours. After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane:methanol=1:0~10:1) to obtain a crude compound, which is passed through a supercritical fluid chiral 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) Compound 66-P1 (16.3 mg, yield 6.8%), compound 66-P2 (7.4 mg, yield 3.1%), compound 66-P3 (14.7 mg, yield 6.1%) and compound 66-P4 ( 8.2 mg, 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 = 214nm. 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 column chromatography SFC: retention time = 7.9 min, UV = 214nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.88 (d, J = 5.3 Hz, 1H), 8.85 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.43 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 7.81 – 7.72 (m, 1H), 6.85 (s, 1H), 5.53 (d, J = 1.8 Hz, 2H), 3.91 (dt, J = 14.8, 7.2 Hz , 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 = 214nm. 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 column chromatography SFC: retention time = 9.8 min, UV = 214nm. 1H NMR (400 MHz, CD ₃ OD) δ 8.76 (d, J = 5.2 Hz, 1H), 8.73 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H), 8.17 (d, J = 5.3 Hz, 1H), 7.68 – 7.60 (m, 1H), 6.73 (s, 1H), 5.41 (d, J = 1.8 Hz, 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 One: Synthesis of Compound 69-2

Aqueous hydroxylamine 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 h. 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, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. (Dichloromethane/methanol=1/0~10/1) was purified 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 solution of compound 69-4 (100 mg, 0.18 mmol) in methanol (5 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with ether (20 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 Silica gel column chromatography (petroleum ether/ethyl acetate = 1/0~1/2) purified crude compound 69, which was subjected to high-performance liquid phase 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: 20 mL/min; wavelength: 214 nm; column pressure: 80 bar) purification Compound 69 (40 mg, yield: 35.9%) was obtained. MS m/z (ESI): 587.7 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (d, J = 5.2 Hz, 1H), 8.83 (s, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.29 (s, 1H) , 8.19 (d, J = 5.2 Hz, 1H), 8.07 (ddd, J = 10.0, 9.0, 2.4 Hz, 1H), 6.79 (s, 1H), 5.46 (d, J = 1.7 Hz, 2H), 3.35 – 3.32 (m, 1H), 3.27 (ddd, J = 9.5, 3.8, 1.7 Hz, 2H), 3.09 (dt, J = 6.9, 6.2 Hz, 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 One: Synthesis of Compound 70-2

Sodium borohydride (1.53 g, 40.4 mmol) was added to a solution of compound 70-1 (3.5 g, 36.8 mmol) in methanol (150 mL), 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) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were 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 compound 70-2 (3.4 g, 35 mmol), 4-dimethylaminopyridine (0.86 g, 7 mmol) and triethylamine. (4.25 g, 42 mmol) in dichloromethane (50 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction, the reaction solution was quenched with hydrochloric acid (1M) and extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. (Petroleum ether/ethyl acetate=1/0~10/1) was purified to obtain compound 70-3 (5 g, yield: 54%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.0 Hz, 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 the solution of compound 70-3 (4 g, 15.91 mmol) 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 = 1/0~3/1) 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 solution of compound 70-4 (500 mg, 3.22 mmol) in methanol (10 mL), and the reaction mixture was stirred at 50°C for 3 hours. After the reaction, the reaction solution was diluted with water (10 mL), adjusted to pH=4 with 1 N hydrochloric acid, and 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. , 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 (400 MHz, 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, 2 M) was added to a solution of compound 70-5 (700 mg, 3.12 mmol) in tetrahydrofuran (15 mL), zinc powder (2.04 g, 3.12 mmol) was added with stirring, and the reaction mixture was heated at 45°C. Stir for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the compound. 70-6 (320 mg, yield: 81%). ¹ H NMR (400 MHz, 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 = 7.2 Hz, 1H).

Step 6: Synthesis of compound 70-7

Methyl iodide (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) , the reaction mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution 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, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Petroleum ether/ethyl acetate = 1/0~4/1) was purified to obtain compound 70-7 (350 mg, yield: 87%). ¹ H NMR (400 MHz, 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 Seven: 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 h. 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 solution of compound 70-8 (500 mg, 3.12 mmol) and acetic acid (2 mL) in methanol (10 mL), and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. . After the reaction, 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) , the reaction mixture was stirred at 90 °C for 12 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0~5/4) 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 solution of compound 70-10 (340 mg, 0.61 mmol) in methanol (20 mL). 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=1/0~10/1) to obtain compound 70. Compound 70 was subjected to supercritical fluid chiral column chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH/CO ₂ (NH ₄ OH 0.2%), total flow rate: 40 g/min) to obtain compound 70-P1 (16.5 mg, yield 4.6%), compound 70-P2 (6.3 mg, yield 1.7%), compound 70-P3 (23.0 mg, yield 6.4%) and compound 70-P4 (6.9 mg, yield 1.9% ).

Compound 70-P1:

MS m/z (ESI): 587.7 [M+1] ⁺ . Supercritical fluid column chromatography SFC: retention time = 7.59 min, UV = 214nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.87 – 8.79 (m, 2H), 8.44 (s, 2H), 8.25 (d, J = 5.3 Hz, 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, 9.4 Hz, 1H), 2.92 – 2.81 (m , 4H), 2.78 – 2.66 (m, 2H), 2.15 (s, 3H), 2.06 (d, J = 0.4 Hz, 3H).

Compound 70-P2:

MS m/z (ESI): 587.7 [M+1] ⁺ . Supercritical fluid column chromatography SFC: retention time = 7.96 min, UV = 214nm. 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 column chromatography SFC: retention time = 9.71 min, UV = 214nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.87 – 8.77 (m, 2H), 8.44 (d, J = 2.7 Hz, 2H), 8.25 (d, J = 5.3 Hz, 1H), 7.73 – 7.67 (m , 1H), 6.80 (d, J = 0.7 Hz, 1H), 5.49 (d, J = 1.9 Hz, 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 = 0.5 Hz, 3H).

Compound 70-P4:

MS m/z (ESI): 587.7 [M+1] ⁺ . Supercritical fluid column chromatography SFC: retention time = 10.98 min, UV = 214nm. 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 One: Synthesis of Compound 76-2

Trisene 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, the reaction solution was cooled to room temperature, quenched by adding saturated sodium bicarbonate solution (10 mL), concentrated under reduced pressure to remove ethanol, water (20 mL) was added to the residue, and extracted with ethyl acetate (20 mL × 2). The combined organic phases were concentrated under reduced 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, the reaction solution was quenched by adding saturated ammonium chloride solution (5 mL), concentrated under reduced pressure to remove ethanol, the residue was diluted with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were subtracted. Concentrate under 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

To a solution of compound 76-3 (100 mg, 0.62 mmol) in dichloromethane (10 mL), 2 drops of N,N-dimethylformamide were added, and then 0.1 mL of trisene chloride solution was added. 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 compound 76-4 (100 mg, 0.55 mmol) and potassium carbonate (154 mg, 1.11 mmol) in N,N-dimethylformamide (5 mL) In solution, 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 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 subjected to silica gel column chromatography (dichloromethane/methanol=1/0~2/1 ) was purified 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 isopropyl alcohol (10 mL), and the reaction solution was stirred at 60°C for 16 hours. . After the reaction, 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 76-6 (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 compound 76-6 (100 mg, 0.23 mmol) in N,N-dimethylformamide (10 mL ) solution, 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 Seven: Synthesis of Compound 76

Tetrahydropyran-4-carboxamidine (42 mg, 0.33 mmol) was added to compound 76-7 (80 mg, 0.16 mmol) and potassium carbonate (68 mg, 0.49 mmol) in N,N-dimethylformamide. A solution of amine (10 mL) was added and the reaction mixture was stirred at 90 °C for 16 h. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (30 mL × 3). The combined organic phases were 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 subjected to high-pressure liquid phase preparative column chromatography (column chromatography column: Gemini-C18 , 150×21.2 mm, 5 um; flow term: 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 (400 MHz, CDCl ₃ ) δ 8.82 (d, J = 3.9 Hz, 1H), 8.74 (s, 1H), 8.48 (d, J = 1.5 Hz, 1H), 8.31 (s, 1H), 8.21 (d, J = 3.5 Hz, 1H), 7.59 (dd, J = 8.8, 1.8 Hz, 1H), 6.42 (s, 1H), 5.43 (s, 2H), 4.11 (dd, J = 12.5, 6.0 Hz, 2H), 3.58 (t, J = 10.8 Hz, 2H), 3.19 (t, J = 10.6 Hz, 1H), 2.20 (s, 3H), 2.13 - 2.07 (m, 2H), 2.01-1.96 (m, 5H ).

Example 26 Synthesis of Compound 77

Step One: Synthesis of Compound 77-2

Trianine dichloride (813 mg, 6.83 mmol) was slowly dropped into 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 portionwise 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. 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

Add 2 drops of N,N-dimethylformamide to a solution of compound 77-3 (120 mg, 0.74 mmol) in dichloromethane (5 mL), then add 0.5 mL of trisene chloride solution, and react. The 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 compound 77-4 (76 mg, 0.42 mmol) and potassium carbonate (117 mg, 0.85 mmol) in N,N-dimethylformamide (20 mL) In solution, 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. 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 isopropyl alcohol (15 mL), and the reaction mixture was stirred at 60°C for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0/1~1/0) 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 compound 77-6 (80 mg, 0.18 mmol) in N,N-dimethylformamide (10 mL ) solution, 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 subjected to silica gel column chromatography (dichloromethane/methanol=1/0~50/1 ) was purified to obtain compound 77-7 (35 mg, yield: 34%). MS m/z (ESI): 491.0 [M+H] ⁺ .

Step Seven: Synthesis of Compound 77

Tetrahydropyran-4-carboxamidine (18 mg, 0.14 mmol) was added to compound 77-7 (35 mg, 0.07 mmol) and potassium carbonate (29 mg, 0.21 mmol) in N,N-dimethylformamide. A solution of amine (10 mL) was added and the reaction mixture was stirred at 90 °C for 12 h. After the reaction was completed, the reaction solution was diluted with water (50 mL), and extracted with dichloromethane (30 mL × 3). The combined organic phases were 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 subjected to high-performance liquid phase preparative column chromatography (column chromatography column: Gemini-C18 , 150×21.2 mm, 5 um; flow term: 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 (400 MHz, CD ₃ OD) δ 8.88 (d, J = 5.3 Hz, 1H), 8.84 (s, 1H), 8.55 (d, J = 2.5 Hz, 1H), 8.41 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 7.97 (dd, J = 8.2, 2.5 Hz, 1H), 6.81 (s, 1H), 5.58 (s, 2H), 4.12 – 4.03 (m, 2H), 3.62 (dd, J = 17.8, 6.6 Hz, 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 One: 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 was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) 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 solution of compound 78-1 (170 mg, 0.30 mmol) in methanol (10 mL), 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 subjected to supercritical fluid chiral column chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH/CO ₂ (NH ₄ OH 0.2%), total flow rate: 40 g/min) to obtain compound 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 = 214nm. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.89 – 8.84 (m, 1H), 8.66 – 8.59 (m, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 5.2 Hz , 1H), 7.54– 7.52 (m, 1H), 6.58 (d, J = 0.6 Hz, 1H), 5.41 (d, J = 2.0 Hz, 2H), 3.30 – 3.19 (m, 1H), 3.15 – 3.04 ( m, 4H), 2.41 (dd, J = 12.0, 5.9 Hz, 4H), 2.15 (d, J = 0.4 Hz, 3H), 1.99 (s, 3H).

Compound 78-P2:

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

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

Step One: Synthesis of Compound 82-2

Methylamine (2.38 g, 35.2 mmol) was added to 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), the reaction mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was diluted with water (150 mL) and 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 subjected to silica gel column chromatography. (Petroleum ether/ethyl acetate=1/0~5/2) was purified 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). 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 solution of compound 82-3 (1 g, 5.9 mmol) and triethylamine (3 g, 29.5 mmol) in dichloromethane (20 mL), and the reaction mixture chamber Stir warm for 2 hours. After the reaction, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (50 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 subjected to silica gel column chromatography. (Dichloromethane/methanol=1/0~10/1) was purified 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 h. 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 under a hydrogen atmosphere for 12 hours. . After the reaction was completed, the reaction liquid 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 Six: 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, the reaction liquid 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 the compound 82, compound 82 was then subjected to supercritical fluid chiral 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), compound 82-P1 (35.2 mg, yield 9.61%) and compound 82-P2 (36.6 mg, yield 10.61%) were obtained.

Compound 82-P1:

MS m/z (ESI): 578.8 [M+1] ⁺ . Supercritical fluid column chromatography SFC: retention time = 2.37 min, UV = 254nm. 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 = 254nm. 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 the above embodiments 1-28, the following compounds were prepared: MS m/z (ESI): 512 [M+1] ⁺ MS m/z (ESI): 540 [M+1] ⁺ MS m/z (ESI): 546 [M+1] ⁺ MS m/z (ESI): 554 [M+1] ⁺ MS m/z (ESI): 634 [M+1] ⁺ MS m/z (ESI): 634 [M+1] ⁺ MS m/z (ESI): 602 [M+1] ⁺ MS m/z (ESI): 602 [M+1] ⁺ MS m/z (ESI): 662 [M+1] ⁺ MS m/z (ESI): 662 [M+1] ⁺ MS m/z (ESI): 630[M+1] ⁺ MS m/z (ESI): 630[M+1] ⁺ MS m/z (ESI): 585[M+1] ⁺ MS m/z (ESI): 587[M+1] ⁺ MS m/z (ESI): 552[M+1] ⁺ MS m/z (ESI): 580[M+1] ⁺ MS m/z (ESI): 565[M+1] ⁺ MS m/z (ESI): 593[M+1] ⁺ MS m/z (ESI): 588[M+1] ⁺ MS m/z (ESI): 558[M+1] ⁺ MS m/z (ESI): 554[M+1] ⁺ MS m/z (ESI): 574[M+1] ⁺ MS m/z (ESI): 567[M+1] ⁺ MS m/z (ESI): 581[M+1] ⁺ MS m/z (ESI): 567[M+1] ⁺ MS m/z (ESI): 581[M+1] ⁺ MS m/z (ESI): 595[M+1] ⁺ MS m/z (ESI): 539[M+1] ⁺ MS m/z (ESI): 567[M+1] ⁺ MS m/z (ESI): 539[M+1] ⁺ MS m/z (ESI): 525[M+1] ⁺ MS m/z (ESI): 552[M+1] ⁺ MS m/z (ESI): 580[M+1] ⁺ MS m/z (ESI): 552[M+1] ⁺ MS m/z (ESI): 552[M+1] ⁺ MS m/z (ESI): 525[M+1] ⁺ MS m/z (ESI): 554[M+1] ⁺ MS m/z (ESI): 539[M+1] ⁺ MS m/z (ESI): 538[M+1] ⁺ MS m/z (ESI): 540[M+1] ⁺ MS m/z (ESI): 538[M+1] ⁺ MS m/z (ESI): 566[M+1] ⁺ MS m/z (ESI): 566[M+1] ⁺ MS m/z (ESI): 554[M+1] ⁺ MS m/z (ESI): 553[M+1] ⁺ MS m/z (ESI): 567[M+1] ⁺ MS m/z (ESI): 560[M+1] ⁺ MS m/z (ESI): 595[M+1] ⁺ MS m/z (ESI): 588[M+1] ⁺ MS m/z (ESI): 512 [M+1] ⁺ MS m/z (ESI): 588[M+1] ⁺ MS m/z (ESI): 556[M+1] ⁺ MS m/z (ESI): 530[M+1] ⁺ MS m/z (ESI): 544[M+1] ⁺ MS m/z (ESI): 558[M+1] ⁺ MS m/z (ESI): 572[M+1] ⁺ MS m/z (ESI): 602[M+1] ⁺ MS m/z (ESI): 614[M+1] ⁺ MS m/z (ESI): 616[M+1] ⁺ MS m/z (ESI): 630[M+1] ⁺ MS m/z (ESI): 642[M+1] ⁺

Compound C: , prepared by referring to the method of Example 1 of WO2021195475A1.

biological evaluation

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

The inhibitory effect of compounds on p38 MAPK/MK2 was detected using Z-LYTE kinase assay kit (Thermo, PV3177). Dissolve test compounds in DMSO to 10 mM stock solution and store at -20°C until use. The starting concentration of the compound is 10 μM, 1% DMSO, 5-fold dilution, 8 concentrations, double wells; 50 mM HEPES pH 7.5, 10 mM mgCl ₂ , 0.01% Brij-35, 1mM EGTA is used as reaction buffer To prepare 2x active p38a/inactive MK2/Ser/Thr 4 mixture, the final 10 μL reaction system was run 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, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, then add 5 μL stop buffer solution Stop the reaction and detect with a microplate reader (Ex. 400 nm, Em. 445 nm; Ex. 400 nm, Em. 520 nm). Use GraphPad Prism 8 software to fit the concentration-effect curve and calculate the compound concentration with 50% inhibitory effect, that is, IC ₅₀ . The results are shown in Table 1.

Table 1 compound p38 MAPK/MK2 IC ₅₀ (nM) Compound 2 6.14 Compound 2-P1 0.6 Compound 3 2.34 Compound 3-P1 2.92 Compound 4 3.56 Compound 6 7.55 Compound 7 35.53 Compound 8 1.86 Compound 9 4.52 Compound 10 6.67 Compound 10-P1 1.59 Compound 14-G1 12.92 Compound 14-G2 10.5 Compound 16 1.46 Compound 16-P1 0.12 Compound 33-P1 1.82 Compound 37 1.11 Compound 38 0.18 Compound 41 11.03 Compound 41-P1 15.15 Compound 42 46.0 Compound 44 13.57 Compound 58 4.81 Compound 63-P1 0.45 Compound 12 3.29 Compound 43 135.2 Compound 66-P2 1.88 Compound 69 28.22 Compound 70-P2 0.32 Compound 76 8.93 Compound 78-P1 0.35 Compound 82-P2 0.65

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

Table 2 compound p38 MAPK /MK5 IC ₅₀ (nM) Compound 3 9353 Compound 3-P1 3155 Compound 4 5729 Compound 6 3933 Compound 7 9321 Compound 8 4621 Compound 9 864 Compound 10 2894 Compound 10-P1 1980 Compound 14-G1 773.2 Compound 14-G2 2674 Compound 16-P1 8940 Compound 33-P1 679.5 Compound 42 2091 Compound 58 873.7 Compound 63-P1 5449

As can be seen from Table 2, the inhibitory activities of the compounds of the present invention on p38 MAPK/MK5 are all greater than 0.6 μm. This further demonstrates 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 compounds on p38a-catalyzed ATF2 was detected using the HTRF method. Dissolve test compounds in DMSO to 10 mM stock solution and store at -20°C until use. The starting concentration of the compound is 10 μM, 0.25% DMSO, 5-fold dilution, 8 concentrations, double wells; 40 mM Tris pH 7.5, 20 mM MgCl ₂ , 0.1 mg/mL BSA, 50 μM DTT as reaction buffer Used 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 is used to terminate the reaction. , 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 ^° C for 35 minutes, add the pre-configured antibody solution (cibio, 63ADK015PEG, Phospho-ATF2 Eu Cryptate antibody, Phospho-ATF2 d2 antibody, diluted 40 times with Detection buffer) to each well and incubate at room temperature overnight, and use a microplate reader Detection (HTRF compatible reader). Use GraphPad Prism 8 software to fit the concentration-effect curve and calculate the compound concentration with 50% inhibitory effect, that is, IC ₅₀ . The results are shown in Table 3.

table 3 compound p38 MAPK/ATF2 IC ₅₀ (nM) Compound 2-P1 902.7 Compound 3-P1 4715 Compound 4 28021 Compound 6 854.7 Compound 7 5389 Compound 8 1450 Compound 9 6976 Compound 10 4657 Compound 10-P1 1173 Compound 14-G1 15915 Compound 14-G2 8262 Compound 16-P1 8634 Compound 33-P1 ＞20000 Compound 41 ＞20000 Compound 63-P1 1250

As can be seen from Table 3, the inhibitory activities of the compounds of the present invention on p38 MAPK/ATF2 are all greater than 0.8 μm. This further demonstrates that the compounds of the present invention have good selectivity for p38 MAPK/MK2.

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

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

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

Table 4 compound TNF-α IC50 (nM) Compound 2 45.38 Compound 2-P1 10.39 Compound 3 41.40 Compound 3-P1 6.39 Compound 6 14.96 Compound 7 41.48 Compound 9 37.91 Compound 10 17.68 Compound 10-P1 7.58 Compound 14-G1 7.96 Compound 14-G2 4.84 Compound 16 29.15 Compound 16-P1 9.27 Compound 33-P1 22.79 Compound 37 0.61 Compound 38 0.21 Compound 41 98.84 Compound 63-P1 1.73 Compound 66-P2 24.62 Compound 70-P2 9.92 Compound 82-P2 17.27

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

Test Example 5. In vitro CYP enzyme inhibition evaluation

This experiment uses the cocktail method to study the inhibition of the enzyme activity of the 1A2, 2B6, 2C8, 2C19, 2C9, 2D6 and 3A4 subtypes of CYP enzymes by the test compound, and determines the IC50 value of the activity of the test compound against several CYP enzyme subtypes. The control compounds are: Fluvoxamine (1A2), Ketoconazole (2B6), Montelukast sodium (2C8), Tranylcypromine (2C19), Sulfaphenazole (2C9), Quin Quinindium (2D6) and Ketoconazole (3A4/5); the CYP enzyme probe substrates used are: 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 compounds to be tested were 50 μm, 12.5 μm, 3.125 μm, 0.781 μm, 0.195 μm, and 0.0488 μm. Add the corresponding probe substrate and microsomes to PBS, mix evenly, then add the control compound/test compound/DMSO solution to the corresponding reaction system respectively, pre-incubate in a 37°C water bath for 5 min, add 10 mM NADPH solution, and place The reaction was carried out in a water bath at 37°C for 10 min, and the internal standard acetonitrile solution was added to terminate the reaction. Centrifuge at 4000 rpm, add an equal volume of pure water to the supernatant solution and mix evenly. Analyze the amount of each probe substrate reaction product using LC-MS/MS (AB Triple Quard 5500), and use the measured product amount to analyze with GraphPad. Prism 5 performs IC50 calculations. The results are shown in Table 5:

table 5 Example IC50 (μm) 1A2 2C9 2C19 2D6 3A4/5 2B6 2C8 Compound 10-P1 >50 >50 >50 >50 >50 >50 >50 Compound 63-P1 >50 >50 >50 >50 >50 >50 >50

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

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

This experiment compares the IC50 value changes of the compound to be tested on the inhibition of CYP3A4/5 subtype enzyme activity under the experimental conditions of pre-reaction with the microsomal reaction system and no pre-reaction under the above two conditions, and calculates Get the corresponding IC50 shift value. The control compound is: Verapamil (CYP3A4/5), and the probe substrate is: Testosterone (CYP3A4/5). PBS Buffer is 50mM K2HPO4 buffer. The concentrations of the compounds to be tested were 50 μm, 10 μm, 2 μm, 0.4 μm, 0.08 μm, and 0.016 μm. The probe substrate and PBS solution are pre-prepared to form a substrate solution (1990 μL of PBS + 10 μL of substrate). Add the microsomes to PBS, and pre-incubate the samples in the non-pre-reaction group in a water bath at 37°C for 30 minutes. Then add the control compound/test compound/DMSO solution, 10 mM NADPH solution and probe substrate solution to the corresponding reaction system, and place React in a 37°C water bath for 10 minutes, add internal standard acetonitrile solution to terminate the reaction; add control compound/test compound/DMSO solution and 10 mM NADPH solution to the corresponding system of the pre-reaction group samples, mix evenly, place in a 37°C water bath for 30 minutes, then add The probe substrate solution was 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, add an equal volume of pure water to the supernatant solution and mix evenly. Analyze the amount of each probe substrate reaction product using LC-MS/MS (AB Triple Quard 5500), and use the measured product amount to GraphPad Prism 5 performed IC50 calculations. The results are shown in Table 6:

Table 6 Example preincubation CYP3A4 IC50(μm) Shift Compound 10-P1 preincubation >50 / Not preincubated >50 Compound 63-P1 preincubation >50 / Not preincubated >50

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

Test Example 7. In vitro liver microsome stability evaluation

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 50mM K2HPO4 buffer. The concentration of the compound to be tested is 1 μM. Add the microsomes to PBS, add the control compound/test compound to the corresponding reaction system respectively, mix evenly, place it in a 37°C water bath for pre-incubation for 5 minutes, add 20mM NADPH solution, and start the reaction under 37°C water bath conditions (For No NADPH samples, replace the 20mM 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. The solution terminates 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:

Table 7 Example mouse liver microsomes rat liver microsomes human liver microsomes Half-life T _1/2 (min) Half-life T _1/2 (min) Half-life T _1/2 (min) Compound 10-P1 ＞279.57 ＞279.57 ＞279.57

As can be seen from Table 7, 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/gastric administration of mice, whole blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 7 and 24 hours for 30 seconds. μL, after anticoagulation with EDTA-K2, immediately centrifuge at 4°C and 4000rpm for 5 min, take the supernatant, and freeze the sample in a -80°C refrigerator. Processing of plasma samples: After precipitation with CH3CN precipitant containing internal standard, centrifuge at 12700 rpm for 10 min, take the supernatant and send it to LC-MS/MS (AB Triple Quard 5500) for analysis to obtain the blood drug concentration, and pass it through Winnolin version 8.1 Non-compartmental models perform parameter calculations. The results are shown in Table 8:

Table 8 compound Dosing method Peak concentration C _max (ng/mL) Half-life T _1/2 (hr) Curve area AUC _0-24h (hr*ng/mL) Distribution solvent Vd (L/kg) Clearance CL (mL/hr/kg) Bioavailability F% Compound 10-P1 Intravenous injection group 1 mg/kg / 0.83 810.27 0.80 1241.95 / Oral administration group: 5 mg/kg 1361.73 / 2120.68 / / 56.46 Compound 63-P1 Intravenous injection group 1 mg/kg / 2.25 668.70 0.84 1492.93 / Oral administration group: 5 mg/kg 1394.97 / 2596.40 / / 90.85 Compound C Intravenous injection group 1 mg/kg / 0.57 433.91 1.88 2313.22 / Oral administration group: 5 mg/kg 654.80 / 1163.26 / / 54.05

As can be seen from Table 8, within the administered concentration dose and detection time range, both compound 10-P1 and compound 63-P1 of the present invention have good exposure, in vivo clearance and bioavailability. In intravenous administration, the in vivo clearance CL of compound 10-P1 was 1241.95 mL/hr/kg, which was significantly better than the in vivo clearance CL of compound C (2313.22 mL/hr/kg); in intragastric administration, The plasma exposure of Compound 10-P1 is 2120.68 hr*ng/mL, which is twice as high as that of Compound C; the in vivo clearance CL of Compound 63-P1 is 1492.93 mL/hr/kg, which is significantly better than that of Compound C. Compared with the body clearance rate CL of compound C (2313.22 mL/hr/kg); during intragastric administration, the plasma exposure of compound 63-P1 was 2596.40 hr*ng/mL, which was higher than the plasma exposure of compound C. doubled. Therefore, this shows that the compound of the present invention has good pharmacokinetic properties in vivo and is significantly better than the control compound C.

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

without

Claims (11)

A compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug: Wherein, W is CH or N; m is an integer from 0 to 5; n is an integer from 0 to 3; Ring A is C _3-20 cycloalkyl, 3-20 membered heterocyclyl, and the carbon atoms in ring A are Connected to the mother core, 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 _1-6 alkoxy, pendant oxy ( =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, unsubstituted or substituted C _1-10 alkyl and C _3-20 cycloalkyl; Ra is selected from Halogen, C _3-20 cycloalkyl; R ⁸¹ , R ⁸² , R ⁸³ , R ⁸⁴ are the same or different, each independently selected from C that is unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 Rb _6-14 aryl-C ₁ - ₁₀ alkyl, 5-14 membered heteroaryl-C ₁ - ₁₀ alkyl, C _6-14 aryl and 5-14 membered heteroaryl; each Rb is the same or different, are independently selected from halogen, halogenated C _1-10 alkyl, C _1-10 alkyl and C _1-10 alkoxy _; R ^91a , R ^91b , R ⁹² , R ^93a , R ^93b _are the same or different from each other. Independently selected from H, C _1-6 alkyl and C _3-20 cycloalkyl. The compound described in claim 1, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein W is CH or N; m is an integer from 0 to 5; n is an integer from 0 to 3; Ring A is a C _3-20 cycloalkyl group, a 3-20 membered heterocyclic group, and the carbon atom in Ring A is connected to the mother core, 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 are independently selected from H, halogen, OH, C _1-6 alkyl, C _1-6 alkoxy, side oxy (=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 are independently selected from H, halogen, C _1-10 alkyl and C _3-20 cycloalkyl; R ⁸¹ , R ⁸² , R ⁸³ , 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 _6-14 aryl The base, 5-14 membered heteroaryl group is unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C ₁ - ₁₀ alkyl, C ₁ - ₁₀ alkyl and C _{1 -6} alkoxy substitution; 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. The compound described in claim 1 or 2, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug 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 heterocyclyl, and in ring A The carbon atom is connected to the mother core, 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 respectively Independently selected from halogen, -OH, -C _1-3 alkyl, -C _1-3 alkoxy, pendant oxy (=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 ⁶ is selected from H, halogen and methyl; R ⁷ is independently selected From H, halogen and C _1-3 alkyl; R ⁸¹ , R ⁸² , R ⁸³ , R ⁸⁴ are the same or different, independently selected from C _6-8 aryl-C ₁ - ₃ alkyl, 5-6 member Heteroaryl-C _1-3 alkyl, C _6-14 aryl and 5-14 membered heteroaryl; _wherein , C _6-14 aryl and 5-14 membered heteroaryl are unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 are independently selected from halogen, halogenated C ₁ - ₃ alkyl, C ₁ - ₃ alkyl and C _1-3 alkoxy substituted; R ^91a , R ^91b , R ⁹² , R ^93a and R ^93b are the same or different, and are independently selected from H, C _1-3 alkyl and C _3-6 cycloalkyl. The compound described in any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug 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, oxetanyl, ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxaspiro[3.3]heptyl, 2-oxaspiro[3.5]nonyl, 2-azaspiro[3.3]heptyl, 2-Azaspiro[3.5]nonyl, azetidinyl, tetrahydropyrrolyl, thietidinyl, tetrahydro-2H-thiopyranyl; R ¹ is selected from Cl, Br; R ² Selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ , -C(O)NHR ⁸⁴ ; R ³ is selected from methyl, cyclopropyl; R ⁴ is selected from methyl; R ⁵ is independently Ground is selected from F, -OH, methyl, methoxy, side oxy (=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 Selected from H; R ⁸¹ , R ⁸² , R ⁸³ , R ⁸⁴ are the same or different, and are independently selected from phenylmethyl, pyridylmethyl, which are unsubstituted or optionally substituted by 1, 2 or 3 R ^b . Pyridylethyl, phenyl, pyridyl; each R ^b is the same or different, independently selected from F, Cl, CF ₃ . The compound described in any one of claims 1 to 4, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein, The ring A is selected from the following structures: ; Preferably, the structure formed by R ₅ and ring A is selected from: ; Preferably, the compound represented by formula I has the structure represented by formula Ia or Ib: Among them, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A, W, m, and n have the definitions described in any one of claims 1 to 4. The compound described in any one of claims 1 to 5, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug 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 independently have the definitions described in any one of claims 1 to 5; R ¹⁰ is selected from H, Halogen, unsubstituted or the following groups optionally substituted by 1, 2 or more halogens, OH, NH ₂ : C _1-10 alkyl, C _1-10 alkoxy, 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, independently selected from H, halogen, C _1-6 alkyl, halogenated C _1-10 alkyl; p is an integer from 0 to 4; preferably, 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 ; Preferably, 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, p have the above or any one of claims 1 to 5. definition. The compound described in claim 1 or 6, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein, for , R ⁵ is selected from halogen, -OH, -C _1-3 alkyl, -C _1-3 alkoxy, side oxy (=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, independently selected from H, C _1-3 alkyl and C _3-6 cycloalkyl; preferably, 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. The compound described in any one of claims 1 to 7, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein, The compound has the following structure: No. Structural formula No. Structural formula 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 twenty one twenty two twenty three twenty four 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 Among them, the * in the structural formulas of compounds 10 and 63 indicates that there is a cis-trans structure, and the * is one of cis or trans; Preferably, the compound represented by formula I has the following structure: Among them, the * in the structural formulas of compounds 10-P1 or 10-P2 and 63-P1 or 63-P2 indicates that there is a cis-trans structure there, and the * is one of cis or trans. A method for preparing the compound as described in any one of claims 1 to 8, characterized by comprising 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, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n and ring A independently have the above definitions; Option 2: When W is N and R ₇ is H, compound b1 reacts with compound b2 to obtain the 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, p and ring A independently have the definitions described in any one of claims 1 to 7; preferably , 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; Preferably, when R ⁵ is OH, the compound The OH in b2 can be protected by a silicon protecting group, and the silicon protecting group can be a tert-butyldiphenylsilyl group; the silicon protecting group will be removed during the reaction to obtain deprotected OH. A pharmaceutical composition, which contains a therapeutically effective amount of the compound described in any one of claims 1 to 7, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutical at least one of the acceptable salts or prodrug compounds thereof, and one or more pharmaceutically acceptable carriers. A compound as described in any one of claims 1 to 8, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound The use of at least one of the pharmaceutical compositions or the pharmaceutical composition as described in claim 10 in the preparation of medicaments; Preferably, the drug is a drug for treating and/or preventing diseases related to p38 kinase inhibitors, such as MK2 inhibitors or p38 MAPK/MK2 pathway modulators; Preferably, the disease is a disease related to the p38 MAPK/MK2 pathway, for example, it can be an autoimmune disease and an inflammatory disease, such as rheumatoid arthritis, hidradenitis purulenta, psoriasis, inflammatory bowel disease. diseases, idiopathic 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.