WO2023165551A1 - Six-membered aromatic ring-pyrrolidone derivative, and pharmaceutical composition thereof and use thereof - Google Patents

Abstract

The present application relates to a six-membered aromatic ring-pyrrolidone derivative, and a pharmaceutical composition thereof and the use thereof. The six-membered aromatic ring-pyrrolidone derivative has the structure as shown in formula (I).

Description

Six-membered aromatic ring pyrrolone derivative, its pharmaceutical composition and application

related application

This application requires a Chinese patent application filed on September 20, 2022, with application number 202211144337.0, entitled "Six-membered aromatic ring dipyrrolone derivatives, pharmaceutical compositions and applications thereof", and an application filed on March 2, 2022 , with the application number 202210202749.9, and the priority of a Chinese patent application entitled "Pyridopyrrolone Derivatives, Pharmaceutical Compositions and Applications thereof", which is hereby incorporated by reference in its entirety.

technical field

The present application relates to the technical field of medicine, in particular to a six-membered aromatic ring pyrrolidone derivative, its pharmaceutical composition and application.

Background technique

Phosphoinositide 3-kinase (PI3K) is a kind of phosphatidyl kinase with phosphorylation function of phosphoinositide ring, which is divided into three types: type I, type II and type III, among which type I PI3K is the most widely studied. This type is further divided into two subgroups (IA and IB). Class IA PI3Ks include three closely related kinases, PI3Kα, PI3Kβ, and PI3Kδ, which are heterodimeric, respectively, composed of the corresponding catalytic subunit ((p110α, p110β, or p110δ)) and one of several regulatory subunits body. PI3Kα and PI3Kβ are widely expressed and play a role in cell growth, division and survival (Thomas M, et al., Curr. Opin. Pharmacol., 2008; 8: 267-274). These two kinases have roles in many biological functions, such as the higher embryonic lethality observed in mice lacking PI3Kα or PI3Kβ. Due to their role in homeostasis, clinical evaluation of PI3Kα and PI3Kβ is used in the field of oncology, and some related compounds are also in various stages of clinical development. PI3Kγ is a single class IB isoform that responds primarily to G-protein coupled receptors (GPCRs) and consists of the p110γ catalytic subunit and one of two different regulatory subunits. PI3Kγ isoforms are expressed in immune cells and have limited expression in normal or malignant epithelial and connective tissue cells. The results of PI3Kγ knockout mice showed that PI3Kγ is important for cell activation and migration of some chemokines (Sasaki T., et al., Science, 2000; 287:1040-1046; Hirsch E., et al. , Science, 2000; 287: 1049-1053). PI3Kγ signaling is particularly important for myeloid cell function, and Camps et al. describe that treatment with the selective PI3Kγ inhibitor AS-60485023 inhibits the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis (Camps et al. M et al., Nat. Med. 2005, 11, 936-943). Based on studies of cellular levels and efficacy observed in various disease models, PI3Kγ inhibitors can potentially be used to treat various diseases, such as inflammation, metabolism, cancer (Cushing, T.D. et al., J.Med.Chem. 2012 , 55, 8559-8581; Ruckle, T. et al., Nat. Rev. Drug Discovery 2006, 5, 903-918; Stark, A.K. et al., Curr. Opin. Pharmacol. 2015, 23, 82-91).

Although selective PI3Kγ inhibitors have been reported in many literatures, such as WO2017153527 and WO2020210379, the selectivity and pharmacokinetic parameters of these PI3Kγ inhibitors need to be further improved. In addition, the currently developed compounds have poor solubility. And problems such as the inability to form salts, so the technical field also needs to develop PI3Kγ inhibitors with more excellent selectivity and pharmacokinetic properties, which are suitable for later development, so as to be better used in clinical needs.

Contents of the invention

The first aspect of the present application provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

in,

Ring A is a 5 or 6 membered heteroaryl ring;

(R ₀ ) _n means that the hydrogen on the ring A is replaced by n R ₀ , n is 0, 1, 2, 3 or 4; each R ₀ is the same or different, each independently deuterium, halogen, cyano, hydroxyl , carboxyl, C _1-3 alkyl, C _1-3 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, halogenated C _1-3 alkyl, halogenated C _1-3 alkoxy , NR _a1 R _b1 , -N(R _a3 )-C(O)C _1-3 alkyl, -N(R _a3 )-C(O)-deuterated C _1-3 alkyl, -N(R _a3 )-C(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -SO ₂ C _3-6 cycloalkyl, -C(O)NR _a1 R _b1 , -C(O)OC _1-3 alkyl, -OC(O)C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkyl, phenyl or 5 to 6-membered heteroaryl; wherein the 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are each independently unsubstituted or 1, 2 or 3 each independently selected from substituents Substituents of group Q are substituted;

Z is N or CR _z ; R _z is hydrogen, halogen, or C _1-8 alkyl (in some embodiments C _1-6 alkyl, in other embodiments C _1-3 alkyl);

U is N or CH;

W is cyano, ethynyl, -NHSO ₂ N(CH ₃ ) ₂ , 5 or 6 membered heteroaryl, or the structure shown in formula (Ia), formula (Ib), formula (Ic) or formula (Id) :

R _a , R _b are each independently halogen, C _1-8 alkyl (in some embodiments C _1-6 alkyl, in other embodiments C _1-3 alkyl), hydroxy-substituted C _1-8 alkyl (in some embodiments C _1-6 alkyl, in other embodiments C _1-3 alkyl) or C _3-6 cycloalkyl;

R _c is hydroxyl, halogen, C _1-3 alkyl, deuterated C _1-3 alkyl, C _3-6 cycloalkyl, halogenated C _1-3 alkyl or NR _a1 R _b1 ;

Y is C or N;

is a 5- or 6-membered heteroaryl ring, or a benzene ring;

p, q are each independently 0, 1, 2 or 3;

R _w1 , R _w2 , R _w3 , and R _w4 are each independently hydrogen, cyano, halogen, C _1-3 alkyl, halogenated C _1-3 alkyl, -N(R _a3 )-C(O)C _1-3 alkyl, -SO ₂ C _1-3 alkyl, -C(O)NR _a1 R _b1 or NR _a1 R _b1 ;

p1, p2, q1, q2 are each independently 1, 2 or 3;

_R is halo (in some embodiments, fluoro);

L ₂₁ and L ₂₂ are each independently -(CR _e2 R _f2 ) _m2 -; m ₂ is 1, 2 or 3;

_Y2 is NR _g2 or O;

R _e2 and R _f2 are each independently hydrogen, hydroxyl, oxo, C _1-3 alkyl or -C(O)C _1-3 alkyl;

R _g2 is hydrogen, C _1-3 alkyl or -C (O) C _1-3 alkyl;

R ₁ and R ₂ are each independently C _1-8 alkyl (in some embodiments, C _1-6 alkyl, in other embodiments C _1-3 alkyl), halogenated C _1-8 Alkyl (in some embodiments is halogenated C _1-6 alkyl, in other embodiments is halogenated C _1-3 alkane group) or C _3-6 cycloalkyl; said C _3-6 cycloalkyl is unsubstituted or substituted by 1 or 2 substituents independently selected from halogen and C _1-3 alkyl;

Substituent group Q is halogen, cyano, hydroxyl, carboxyl, C _1-3 alkyl, C _1-3 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, halogenated C _1-3 alkane group, halogenated C _1-3 alkoxy group, NR _a1 R _b1 , -SO ₂ C _1-3 alkyl group, -S(O)C _1-3 alkyl group, -C(O)NR _a1 R _b1 , - C(O)OC _1-3 alkyl, -OC(O)C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkyl, Phenyl or 5 to 6 membered heteroaryl;

R _a1 and R _b1 are each independently hydrogen, C _1-3 alkyl or acetyl, or R _a1 and R _b1 together with the connected nitrogen atom form a 4 to 6-membered saturated monoheterocycle; the 4 to 6-membered saturated The single heterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C _1-3 alkyl, C _1-3 alkane Oxygen, C _2-4 alkenyl, C _2-4 alkynyl, halogenated C _1-3 alkyl, halogenated C _1-3 alkoxy, -SO ₂ C _1-3 alkyl, -S(O )C _1-3 alkyl, -C(O)NH ₂ , -C(O)NH(C _1-3 alkyl), -C(O)N(C _1-3 alkyl) ₂ , -C( O) OC _1-3 alkyl, -OC (O) C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;

R _a3 is hydrogen or C _1-8 alkyl (in some embodiments C _1-6 alkyl, in other embodiments C _1-3 alkyl).

In some embodiments, W is cyano, ethynyl, or -NHSO ₂ N(CH ₃ ) ₂ .

In some embodiments, W is a 5- or 6-membered heteroaryl group selected from the group consisting of thienyl, furyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, 1,2 ,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, 1,2, 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazine group, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl.

In some embodiments, the 5- or 6-membered heteroaryl group in W is selected from one of the following structures:

In some embodiments, the 5- or 6-membered heteroaryl group in W is selected from one of the following structures:

In some embodiments, W is the structure shown in formula (I-a).

In some embodiments, formula (Ia) is selected from one of the following structures:

In some embodiments, formula (Ia) is selected from one of the following structures:

In some embodiments, W is the structure shown in formula (I-b) or (I-c).

Optionally, is a benzene ring or a 5- or 6-membered heteroaryl ring selected from the group consisting of thiophene ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, 1,2, 3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, 1,2,3 -Oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring , pyrimidine ring, pyrazine ring, triazine ring and tetrazine ring.

In some embodiments, formula (Ib) is selected from one of the following structures:

In some embodiments, the structure shown in formula (Ic) is selected from the following structures:

In some embodiments, W is the structure shown in formula (I-d).

In some embodiments, the structure shown in (Id) is selected from the following structures:

In some embodiments, Ring A is a 5- or 6-membered heteroaryl ring selected from the group consisting of thiophene ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, 1 ,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, 1, 2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, Pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring and tetrazine ring.

In some embodiments, Ring A is a thiazole ring.

In some embodiments, n is 2.

In some embodiments, each _R is the same or different, each independently C _1-3 alkyl, -NH-C(O)C _1-3 alkyl, -NH-C(O)-deuterated C _1-3 alkyl or -NH-C(O)OC _1-3 alkyl.

In some embodiments, in formula (I), For the structure shown in formula (a):

R ₀₁ and R ₀₂ are defined as R ₀ , each independently deuterium, halogen, cyano, hydroxyl, carboxyl, C _1-3 alkyl, C _1-3 alkoxy, C _2-4 alkenyl, C _{2 -4} alkynyl, halogenated C _1-3 alkyl, halogenated C _1-3 alkoxy, NR _a1 R _b1 , -N(R _a3 )-C(O)C _1-3 alkyl, -N( R _a3 )-C(O)-deuterated C _1-3 alkyl, -N(R _a3 )-C(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -SO ₂ C _3-6 cycloalkyl, -C(O)NR _a1 R _b1 , -C(O)OC _1-3 alkyl, -OC(O)C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkyl, phenyl or 5 to 6 membered heteroaryl; wherein said 3 to 6 membered heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl Each group is independently unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from Substituent Group Q.

In some embodiments, R ₀₁ is halogen, cyano, hydroxy, carboxy, C _1-3 alkyl, C _1-3 alkoxy, haloC _1-3 alkyl or haloC _1-3 alkoxy R ₀₂ is -NH-C(O)C _1-3 alkyl, -NH-C(O)-deuterated C _1-3 alkyl or -NH-C(O)OC _1-3 alkyl.

In some embodiments, R ₀₁ is methyl, ethyl, n-propyl or isopropyl. In other embodiments, R ₀₁ is methyl.

In some embodiments, R ₀₂ is -NH-C(O)C _1-3 alkyl, -NH-C(O)-deuterated C _1-3 alkyl or -NH-C(O)OC _{1- 3} alkyl. In other embodiments, R ₀₂ is -NH-C(O)CH ₃ , -NH-C(O)-CD ₃ or -NH-C(O)OCH ₃ .

In some embodiments, in formula (I), for

In some embodiments, R is _{monochloromethyl} , dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoro Methyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, monofluorosubstituted cyclopropyl Or a fluorine-substituted cyclobutyl; R ₂ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a fluoro-substituted cyclopropyl or a Fluorine-substituted cyclobutyl.

In some embodiments, R ₁ is cyclopropyl, cyclobutyl or trifluoromethyl.

In some embodiments, R ₂ is methyl, ethyl, cyclopropyl or cyclobutyl.

In some embodiments, in formula (I), Choose from one of the following structures:

In some embodiments, in formula (I), Choose from one of the following structures:

In some embodiments, Z is N or CH.

In some embodiments, the 5- or 6-membered heteroaryl (rings) described in each of the above structural formulas and groups are each independently selected from: thienyl, furyl, thiazolyl, isothiazolyl, imidazolyl, Oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4 -Triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl.

In some embodiments, each of the 5 or 6 membered heteroaryl (rings) is independently selected from the following structures:

In some embodiments, the 3-6 membered heterocycloalkyl groups described in the above structural formulas and groups are 4-6 membered heterocycloalkyl groups, each independently selected from: azetidinyl, oxygen Heterobutanyl, Tetrahydrofuranyl, Tetrahydrothiophenyl, Tetrahydropyrrolyl, Oxazolidinyl, Dioxolanyl, Piperidinyl, Piperazinyl, Morpholinyl, Dioxanyl, Thio Morpholinyl, thiomorpholin-1,1-dioxide, tetrahydropyranyl, pyrrolidin-2-onyl, dihydrofuran-2(3H)-onyl, morpholin-3-onyl , piperazin-2-one group and piperidin-2-one group.

In some embodiments, the compound of formula (I) is selected from any one of the following structures:

The second aspect of the present application provides a pharmaceutical composition, which comprises the compound described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

The third aspect of the application provides the compound described in the first aspect of the application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and the pharmaceutical composition described in the third aspect of the application in the preparation of treatment or prevention and Use in medicine for diseases associated with or mediated by PI3Kγ activity.

In some embodiments, the disease associated with or mediated by PI3Kγ activity is inflammation, metabolic disease or cancer.

The fourth aspect of the application provides the compound described in the first aspect of the application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof for the treatment or prevention of diseases related to or mediated by PI3Kγ activity body, or the pharmaceutical composition described in the second aspect of the application.

The fifth aspect of the present application provides a method for treating or preventing diseases related to PI3Kγ activity or mediated by PI3Kγ activity, comprising administering to a subject a therapeutically effective amount of the compound described in the first aspect of the application, or its A pharmaceutically acceptable salt, or a stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition described in the second aspect of the application.

It should be understood that within the scope of the present application, the above-mentioned technical features of the present application and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or optional technical solutions. Due to space limitations, we will not repeat them here.

Detailed ways

After extensive and in-depth research, the applicant unexpectedly discovered this class of six-membered aromatic ring pyrrolidone derivatives, which have excellent selective inhibitory activity against PI3Kγ kinase, enhanced pharmacokinetic activity in vivo, and solubility under acidic conditions. Therefore, the series of compounds are expected to be developed into selective inhibitors of PI3Kγ and used for treating and/or preventing diseases related to PI3Kγ activity. On this basis, the applicant has completed this application.

Definition of Terms

In order to understand the technical content of the present application more clearly, the terms of the present application will be further explained below.

"Alkyl" refers to straight and branched chain saturated aliphatic hydrocarbon groups. "C _1-8 alkyl" refers to an alkyl group having 1 to 8 carbon atoms, such as a C _1-6 alkyl group, and in some embodiments a C _1-3 alkyl group; non-limiting examples of alkyl groups Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2 -Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl Propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-di Methylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylpentyl Dimethylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl , 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5 -Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl , 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl , 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.

"Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon double bonds (C=C), and "C _2-8 alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms. _C2-6 alkenyl, in some embodiments _C2-4 alkenyl, similarly defined; non-limiting examples of alkenyl include ethenyl, propenyl, isopropenyl, n-butenyl , Isobutenyl, Pentenyl, Hexenyl, etc.

"Alkynyl" refers to straight-chain and branched unsaturated aliphatic hydrocarbon groups with one or more carbon-carbon triple bonds, and "C _2-8 alkynyl" refers to alkynyl groups with 2 to 8 carbon atoms, such as C _2-6 alkynyl, in some embodiments _C2-4 alkynyl, is similarly defined; non-limiting examples of alkynyl include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl base, hexynyl, etc.

The terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably and both refer to a saturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon group which may be fused with an aryl or heteroaryl group. Cycloalkyl rings can be optionally substituted. In certain embodiments, cycloalkyl rings contain one or more carbonyl groups, such as oxo groups. "C _3-8 cycloalkyl" refers to a monocyclic cycloalkyl group with 3 to 8 carbon atoms, non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. Examples are C _3-6 cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "C _8-10 cycloalkyl" refers to a fused bicyclic cyclic hydrocarbon group having 8 to 10 ring atoms, non-limiting examples of C _8-10 cycloalkyl include

The terms "spirocyclyl" and "spiro ring" are used interchangeably, and both refer to polycyclic cyclic hydrocarbon groups that share one carbon atom (called a spiro atom) between monocyclic rings. "7 to 11 membered spirocyclyl" refers to a spiro ring having 7 to 11 ring atoms. According to the number of rings, spiro rings are classified as double spiro rings or multi-spiro rings, for example, double spiro rings. In some embodiments, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered double spiro ring. For example:

The terms "cycloalkenyl" and "cycloalkenyl ring" are used interchangeably, and both refer to a monocyclic, bicyclic or polycyclic cyclic hydrocarbon group containing one or more carbon-carbon double bonds in the ring, which can be combined with an aryl Or heteroaryl fusion. Cycloalkenyl rings can be optionally substituted. In certain embodiments, cycloalkenyl rings contain one or more carbonyl groups, such as oxo groups. "C _3-8 cycloalkenyl" refers to a monocyclic cycloalkenyl group having 3 to 8 carbon atoms. For example, C _3-6 cycloalkenyl. Non-limiting examples of cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, cyclopentyl-2-en-1-one, cyclo Hexyl-2,5-dien-1-one, cyclohexyl-2-en-1-one, cyclohex-2-en-1,4-dione, etc.

The terms "heterocycloalkyl" and "heterocycloalkyl ring" are used interchangeably to refer to a Atoms of a cycloalkyl group that may be fused with an aryl or heteroaryl group. Heterocycloalkyl rings can be optionally substituted. In certain embodiments, heterocycloalkyl rings contain one or more carbonyl or thiocarbonyl groups, eg, groups comprising oxo and thioxo. "3 to 8 membered heterocycloalkyl" refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, for example, 4 to 8-membered heterocycloalkyl, and in some embodiments 3 to 6-membered heterocycloalkyl, having 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur , in other embodiments is a 4 to 6 membered heterocycloalkyl having 4 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples include aziridinyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuryl, tetrahydrothiophenyl, tetrahydropyrrolyl, oxazolidinyl, di Oxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, thiomorpholinyl-1,1-dioxide, tetrahydropyranyl, aza Cyclobutane-2-onyl, oxetan-2-onyl, dihydrofuran-2(3H)-onyl, pyrrolidin-2-onyl, pyrrolidin-2,5-dionyl , Dihydrofuran-2,5-dione, piperidin-2-one, tetrahydro-2H-pyran-2-one, piperazine-2-one, morpholin-3-one, etc. . The terms "6- to 12-membered heterocycloalkyl" and "6- to 12-membered fused heterocycloalkyl" are used interchangeably and refer to those having 6 to 12 ring atoms, of which 1, 2 or 3 ring atoms are optionally Fused bicyclic cyclic hydrocarbon radicals of heteroatoms from nitrogen, oxygen and sulfur. The terms "8 to 10 membered heterocycloalkyl" and "8 to 10 membered fused heterocycloalkyl" are used interchangeably and refer to having 8 to 10 ring atoms, of which 1, 2 or 3 ring atoms are optionally Fused bicyclic cyclic hydrocarbon radicals of heteroatoms from nitrogen, oxygen and sulfur. Non-limiting examples include hexahydro-1H-furo[3,4-c]pyrrole, octahydro-1H-cyclopenta[c]pyridine, hexahydro-1H-pyrrolo[2,1-c][1, 4] Oxazine, octahydropyrrolo[1,2-a]pyrazine, hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one, octahydrocyclopenta[c]pyrrole, etc. In fused bicyclic heterocycloalkyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as valence permits. Bicyclic heterocycloalkyl systems may include one or more heteroatoms in one or both rings.

The terms "heterospirocyclyl" and "heterospirocycle" are used interchangeably and refer to a monovalent, non-aromatic ring system having two monocyclic rings sharing one carbon atom, consisting of carbon atoms and atoms selected from the group consisting of nitrogen, oxygen, Consists of heteroatoms of sulfur and phosphorus, contains no unsaturation, and is attached to the parent nucleus by a single bond. Heterospirocycles can be optionally substituted. In certain embodiments, heterospirocycles contain one or more carbonyl or thiocarbonyl groups, eg, groups comprising oxo and thioxo. "7- to 11-membered heterospirocyclyl" refers to a heterospirocyclyl having 7 to 11 ring atoms, of which 1, 2 or 3 ring atoms are heteroatoms. Non-limiting examples of heterospirocyclyl include 2,6-diazaspiro[3.4]octan-5-onyl, 2-oxo-6-azaspiro[3.3]heptanyl, 6- Oxaspiro[3.3]heptane-2-yl, 7-methyl-7-azaspiro[3.5]nonan-2-yl, 7-methyl-2,7-diazaspiro[3.5]nonan Alk-2-yl, 9-methyl-9-phosphaspiro[5.5]undec-3-yl, etc. For "R _a , R _b and the connected nitrogen atoms form a 7-11 membered heterospiro ring together, wherein the 7-11 membered heterospiro ring shares one spiro atom and contains 1 or 2 members selected from nitrogen and oxygen The heteroatom _" nitrogen" in the "heterospiro ring of heteroatoms" includes a nitrogen atom attached to Ra, _Rb .

The terms "heterocycloalkenyl" and "heterocycloalkenyl ring" are used interchangeably to refer to a heterocycloalkyl group containing one or more carbon-carbon double bonds or carbon-nitrogen double bonds within the ring, but are not intended to include A heteroaryl moiety as defined herein. This group can be fused with an aryl or heteroaryl. Heterocycloalkenyl rings can be optionally substituted. In certain embodiments, the heterocycloalkenyl ring contains one or more carbonyl or thiocarbonyl groups, eg, groups comprising oxo and thioxo. "5 to 8 membered heterocyclenyl ring" means a heterocyclenyl ring having 5 to 8 ring atoms, of which 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, such as 5 to 6 membered heterocycloalkenyl ring. Non-limiting examples of heterocycloalkenyl rings include 4,5-dihydro-1H-imidazole ring, 1,4,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H- 1,4,6-oxadiazosin ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diazepine Cyclo, 2,5,6,7-tetrahydro-1,3,5-oxadiazepine ring, pyrimidin-2(1H)-one, pyrazin-2(1H)-one, pyridin-2(1H)-one.

The terms "aryl" and "aromatic ring" are used interchangeably to refer to an all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system that A group may be fused to a cycloalkyl ring, heterocycloalkyl ring, cycloalkenyl ring, heterocycloalkenyl ring, or heteroaryl. "C _6-10 aryl" refers to a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, and non-limiting examples of the aryl group include phenyl, naphthyl, and the like.

The terms "heteroaryl" and "heteroaryl ring" are used interchangeably to refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system having ring carbon atoms and ring heteroatoms (e.g., having A group of 6 or 10 π electrons shared by a like arrangement), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In this application, heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. Heteroaryl rings can be optionally substituted. "5 to 10 membered heteroaryl" means having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms A monocyclic or bicyclic heteroaryl in which the atoms are heteroatoms. "5 to 6 membered heteroaryl" means a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples include thienyl, furan base, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 ,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadi Azolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazine base. "8 to 10 membered heteroaryl" means a bicyclic heteroaryl group having 8 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples include indolyl, iso Indolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzisofuryl, benzimidazole, benzoxazolyl, benziso Oxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyrido [2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphthyridinyl, 1,7-naphthyridinyl, 1,6-naphthyridinyl, 1,5-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. "Heteroatom" means nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

"Fused" refers to a structure in which two or more rings share one or more bonds.

"Phenylheterocycloalkyl" means a group in which a benzene ring is fused with a heterocycloalkyl ring to form a bicyclic, tricyclic or polycyclic ring system, wherein the heterocycloalkyl ring is as defined above. "7 to 11 membered phenylheterocycloalkyl" means a bicyclic cyclic group having 7 to 11 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur , such as 8 to 10 membered phenylheterocycloalkyl having 8 to 10 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples include indoline, benzo[d][1,3]dioxazole, 1,2,3,4-tetrahydroisoquinoline, 3,4-dihydro-2H-benzo[ b][1,4]oxazine etc.

"Heteroarylheterocycloalkyl" means a group in which a heteroaryl ring is fused with a heterocycloalkyl ring to form a bicyclic, tricyclic or polycyclic ring system, wherein the heterocycloalkyl ring is as defined above. "7 to 11 membered heteroarylheterocycloalkyl" means a bicyclic ring group having 7 to 11 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur Groups such as 8 to 10 membered heteroarylheterocycloalkyls having 8 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples include 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, [1,3]dioxolane[4,5-b]pyridine, 2,3-dihydro -1H-pyrido[3,4-b][1,4]oxazine, 2,3,4,6-tetrahydropyrrolo[3,4-b][1,4]oxazine, 2,4 , 5,6-tetrahydropyrano[2,3-c]pyrazole, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, etc.

"Alkoxy" refers to -O-alkyl, wherein the definition of alkyl is as above, such as C _1-8 alkoxy, in some embodiments C _1-6 alkoxy, in other embodiments is C _1-3 alkoxy. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, pentyloxy, and the like.

"Cycloalkyloxy" means an -O-cycloalkyl group in which cycloalkyl is as defined above. For example C _3-8 cycloalkyloxy, in some embodiments C _3-6 cycloalkyloxy. Non-limiting examples of cycloalkyloxy include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

"A bond" means that the two groups connected by it are connected by a covalent bond.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Halo" refers to a group in which one or more (eg 1, 2, 3, 4 or 5) hydrogens are replaced by a halogen.

For example, "haloalkyl" means that the hydrogen on the alkyl is replaced by one or more (such as 1, 2, 3, 4 or 5) halogens, wherein the definition of alkyl is as above, such as halo C _1-8 Alkyl, more preferably haloC _1-6 alkyl, in some embodiments haloC _1-3 alkyl. Examples of haloalkyl include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monochloroethyl, Fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.

As another example, "halogenated alkoxy" means that the hydrogen on the alkoxy group is replaced by one or more (such as 1, 2, 3, 4 or 5) halogens, where the definition of alkoxy group is as above, such as halo C _1-8 alkoxy, in some embodiments halo C _1-6 alkoxy, in other embodiments halo C _1-3 alkoxy. Haloalkoxy includes, but is not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

As another example, "halocycloalkyl" means that the hydrogen on the cycloalkyl is replaced by one or more (such as 1, 2, 3, 4 or 5) halogens, wherein the definition of cycloalkyl is as above, for example, halogen Substituted C _3-8 cycloalkyl, in some embodiments is halogenated C _3-6 cycloalkyl. Halocycloalkyl includes, but is not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.

"Deuterated alkyl" means that the hydrogen on the alkyl is replaced by one or more (such as 1, 2, 3, 4 or 5) deuterium atoms, wherein the definition of alkyl is as above, for example, deuterated C _{1- 8} alkyl, in some embodiments deuterated C _1-6 alkyl, in other embodiments deuterated C _1-3 alkyl. Examples of deuteroalkyl include, but are not limited to, monodeuteromethyl, monodeuteroethyl, dideuuteromethyl, diduterioethyl, trideuteromethyl, trideuteroethyl, and the like.

"Amino" means NH ₂ , "cyano" means CN, "nitro" means NO ₂ , "benzyl" means -CH ₂ -phenyl, "oxo" means =O, "carboxy" means -C (O)OH, "acetyl" refers to -C(O)CH ₃ , "hydroxymethyl" refers to -CH ₂ OH, "hydroxyethyl" refers to -CH ₂ CH ₂ OH or -CHOHCH ₃ , "hydroxyl" refers to -OH, "mercapto" refers to SH, and the structure of "cyclopropylene" is:

"Saturated or partially unsaturated monocyclic ring" means a saturated or partially unsaturated all-carbon monocyclic ring system, where "partially unsaturated" means a ring portion that includes at least one double or triple bond, and "partially unsaturated" is intended to encompass Rings with multiple sites of unsaturation, but are not intended to include aryl or heteroaryl moieties as defined herein. In certain embodiments, saturated or partially unsaturated monocyclic rings contain one or more carbonyl groups, such as oxo groups. A "3 to 7 membered saturated or partially unsaturated monocyclic ring" has 3 to 7 ring carbon atoms, for example a saturated or partially unsaturated monocyclic ring having 3 to 6 ring carbon atoms, in some embodiments 3 to 6 A saturated monocyclic ring with ring carbon atoms. Non-limiting examples of saturated or partially unsaturated monocyclic rings include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, Cycloheptyl ring, cycloheptatrienyl ring, cyclopentanone ring, cyclopentane-1,3-dione ring, etc.

"Saturated or partially unsaturated monoheterocyclic ring" means that 1, 2 or 3 ring carbon atoms in a saturated or partially unsaturated monocyclic ring are selected from nitrogen, oxygen or S(O) _t (where t is an integer 0, 1 or 2), but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. "3 to 7 membered saturated or partially unsaturated monoheterocyclic ring" has 3 to 7 ring atoms, of which 1, 2 or 3 ring atoms are the above-mentioned heteroatoms, for example has 3 to 6 ring atoms, of which 1 or 2 3 to 6 membered saturated or partially unsaturated monoheterocyclic rings having 5 to 6 ring atoms, 1 or 2 of which are 5 to 6 membered saturated heteroatoms described above Or a partially unsaturated monoheterocycle, in other embodiments a 5- or 6-membered saturated monoheterocycle. Non-limiting examples of saturated monoheterocyclic rings include propylene oxide rings, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydrothiophene rings, tetrahydropyrrole rings, piperidine rings, pyrroline rings , oxazolidine ring, piperazine ring, dioxolane, dioxane, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring, nitrogen Heterocyclobutane-2-one ring, oxetane-2-one ring, pyrrolidin-2-one ring, pyrrolidine-2,5-dione ring, piperidin-2-one ring, dihydro Furan-2(3H)-one ring, dihydrofuran-2,5-dione ring, tetrahydro-2H-pyran-2-one ring, piperazin-2-one ring, morpholin-3-one ring . Non-limiting examples of partially unsaturated monoheterocyclic rings include 1,2-dihydroazetidinium rings, 1,2-dihydrooxetidine rings, 2,5-dihydro-1H- Pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2, 3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4 ,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazosin ring, 1,6-dihydropyrimidine ring, 4,5,6, 7-tetrahydro-1H-1,3-diazepine Cyclo, 2,5,6,7-tetrahydro-1,3,5-oxadiazepine Ring etc.

"Substituted" refers to one or more hydrogen atoms in the group, for example, 1 to 5 hydrogen atoms are independently substituted by the corresponding number of substituents, in some embodiments, 1 to 3 hydrogen atoms are independently substituted by each other Substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

Unless otherwise defined, the "substituents independently selected from ..." described in this application means that when more than one hydrogen on the group is replaced by a substituent, the types of substituents may be the same or different, so The selected substituents are each independent species.

Unless otherwise defined, "...the same or different, and each independently being..." in this application means that when there are more than one identical substituent groups in the general formula, the groups may be the same or different, and are each separate species. For example L is (CR ₀₁ R ₀₂ ) _s , when s is 2, that is, L is (CR ₀₁ R ₀₂ )-(CR ₀₁ R ₀₂ ), where two R ₀₁ can be the same or different, and two R ₀₂ can be the same or different , are independent species, for example L can be C(CH ₃ )(CN)-C(CH ₂ CH ₃ )(OH), C(CH ₃ )(CN)-C(CH ₃ )(OH) or C (CN) _{( CH2CH3} )-C(OH) _{( CH2CH3} ).

Unless otherwise defined, any group herein may be substituted or unsubstituted. When the above-mentioned groups are substituted, the substituents can optionally be 1 to 5 following groups independently selected from cyano, halogen (such as fluorine or chlorine), C _1-8 alkyl (such as C _1-6 alkyl , in some embodiments C _1-3 alkyl), C _1-8 alkoxy (such as C _1-6 alkoxy, in some embodiments C _1-3 alkoxy), halogenated C _{1- 8} Alkyl (such as halogenated C _1-6 alkyl, in some embodiments halogenated C _1-3 alkyl), C _3-8 cycloalkyl (such as C _3-6 cycloalkyl), halogenated C _1-8 alkoxy (such as halo C _1-6 alkoxy, in some embodiments halo C _1-3 alkoxy), C _1-8 alkyl substituted amino, halo C _1-8 Alkyl-substituted amino, acetyl, hydroxyl, hydroxymethyl, hydroxyethyl, carboxyl, nitro, C _6-10 aryl (such as phenyl), C _3-8 cycloalkyloxy (such as C _{3 -6} cycloalkyloxy), C _2-8 alkenyl (such as C _2-6 alkenyl, in some embodiments C _2-4 alkenyl), C _2-8 alkynyl (such as C _2-6 alkyne group, in some embodiments C _2-4 alkynyl), -CONR _a0 R _b0 , -C(O)OC _1-10 alkyl (such as -C(O)OC _1-6 alkyl, in some embodiments Examples are -C(O)OC _1-3 alkyl), -CHO, -OC(O)C _1-10 alkyl (such as -OC(O)C _1-6 alkyl, in some embodiments is -OC(O)C _1-3 alkyl), -SO ₂ C _1-10 alkyl (such as -SO ₂ C _1-6 alkyl, in some embodiments -SO ₂ C _1-3 alkane base), -SO ₂ C _6-10 aryl (such as -SO ₂ C ₆ aryl, in some embodiments -SO ₂ -phenyl), -COC _6-10 aryl (such as -COC ₆ aryl, in some embodiments -CO-phenyl), 4 to 6 membered saturated or unsaturated monoheterocyclic ring, 4 to 6 membered saturated or unsaturated monocyclic ring, 5 to 6 membered monocyclic heteroaryl ring, 8- to 10-membered bicyclic heteroaryl ring, spiro ring, spiro heterocyclic ring, bridged ring or bridged heterocyclic ring, wherein R _a0 and R _b0 are each independently hydrogen or C _1-3 alkyl.

In the present application, when the number of substituents is greater than 1, any two substituents may be the same or different. For example, it can be substituted by two identical or different halogens, and can be substituted by one halogen and one hydroxyl.

The various substituent groups described herein above may themselves be substituted by groups described herein.

When the 4- to 6-membered saturated monoheterocycles described herein are substituted, the positions of the substituents can be in their possible chemical positions, and the representative substitution situations of the exemplary monoheterocycles are as follows:

Where "Sub" represents various substituents described herein; Indicates the position of attachment to other atoms.

pharmaceutical composition

Usually, the compound of the present application or its pharmaceutically acceptable salt or its stereoisomer can be administered in a suitable dosage form with one or more pharmaceutical carriers. These dosage forms are suitable for oral, rectal, topical, buccal and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, syrups and the like. The compound of the present application contained in these formulations may be solid powder or granule; solution or suspension in aqueous or non-aqueous liquid; water-in-oil or oil-in-water emulsion and the like. The above-mentioned dosage forms can be made from the active compound and one or more carriers or excipients through common pharmaceutical methods. The aforementioned carriers need to be compatible with the active compound or other excipients. For solid preparations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like. The active compounds can form solutions or suspensions with the above-mentioned carriers.

"Pharmaceutically acceptable carrier" means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary preparation or excipient of any type, which is compatible with the patient, in some embodiments A mammal, such as a human, is suitable for delivering an active agent to a target of interest without terminating the activity of the agent.

"The active substance of the present application" or "the active compound of the present application" refers to the compound of formula (I) of the present application, or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer, or its prodrug , which has PI3Kγ selective inhibitory activity.

The compositions of the present application are formulated, dosed and administered in a manner consistent with medical practice. The "therapeutically effective amount" of a compound to be administered is determined by factors such as the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

"Therapeutically effective amount" refers to the amount of the compound of the present application that will cause the individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing down or delaying disease progression or preventing diseases, etc.

The pharmaceutical composition of the present application or the therapeutically effective amount of the compound of the present application contained in the pharmaceutical composition or its pharmaceutically acceptable salt or its stereoisomer is, for example, 0.1 mg/kg-5 g/kg ( weight).

"Patient" means an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.

"Treating" means alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing its development, or alleviating to some extent one or more symptoms of a disease or disorder.

The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. A pharmaceutically acceptable acid addition salt refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salts" include, but are not limited to, salts of inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salts, triethylamine salts, lysine salts, arginine salts and the like. These salts can be prepared by methods known in the art.

When the compound represented by formula (I) of the present application contains one or more chiral centers, it can exist in different optically active forms. When a compound of formula (I) contains one chiral center, the compound contains a pair of enantiomers. The two enantiomers of the compound and the mixture of the pair of enantiomers, such as the racemic mixture, are also within the protection scope of the present application. Enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of formula (I) contains more than one chiral center, the compound includes enantiomers and diastereomers. All enantiomers and diastereomers of the compound, and mixtures of enantiomers, mixtures of diastereomers, and mixtures of enantiomers and diastereomers Also within the protection scope of the present application. Enantiomers and diastereomers may be resolved by methods known in the art, such as crystallization and preparative chromatography.

Preparation

The present application provides the preparation method of the compound of formula (I), and the compound of formula (I) can be synthesized by using the standard synthetic technique known to those skilled in the art or using the method known in the art in combination with the method described in the present application. Solvents, temperatures and other reaction conditions given in this application can be varied according to the skill in the art. The reactions can be used in sequence to provide the compounds of the application, or they can be used to synthesize fragments which are subsequently added by methods described herein and/or methods known in the art.

The compounds described in this application can be synthesized using appropriate alternative starting materials using methods similar to those described below or the exemplary methods described in the Examples, or relevant publications used by those skilled in the art. Starting materials for the synthesis of compounds described herein can be synthesized or can be obtained from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using techniques and starting materials known to those skilled in the art. General methods for preparing compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties in the molecules provided herein.

The main advantages of this application include:

A series of six-membered aromatic ring pyrrolidone derivatives are provided, which have high selective inhibitory activity on PI3Kγ and improved pharmacokinetic properties in vivo, and the inhibitory activity IC ₅₀ value on PI3Kγ kinase is less than 100nM, in some embodiments Having an IC ₅₀ value of less than 50 nM, in some embodiments less than 10 nM, is therefore useful as a medicament for the treatment and/or prevention of _diseases associated with or mediated by PI3K gamma activity.

The present application will be further elaborated below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. The experimental method that does not indicate specific condition in the following examples, usually according to conventional conditions such as people such as Sambrook, molecular cloning: the condition described in the laboratory handbook (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer suggested conditions. Percentages and parts are by weight unless otherwise indicated. Unless otherwise defined, terms used herein have the same meanings as those skilled in the art are familiar with. In addition, any methods and materials similar or equivalent to those described can be applied to this application.

Known starting materials can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc) and Darui Chemicals, etc. company.

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

DCM: dichloromethane, TEA: triethylamine, _Et3N : triethylamine, DIPEA: N,N-diisopropylethylamine, NaOH: sodium _hydroxide , _K2CO3 : potassium carbonate, _CCl4 : Carbon Tetrachloride, ACN: Acetonitrile, _CHCN : Acetonitrile, MeCN: Acetonitrile, n-BuLi: n-Butyl Lithium, _CDCl3 : Deuterochloroform, _CuBr2 : Copper Bromide, Pd/C: Palladium/Carbon, H ₂ O: water, CuI: cuprous iodide, t-BuONO: tert-butyl nitroso, HCl: hydrogen chloride, TsOH: p-toluenesulfonic acid, N ₂ H ₄ H ₂ O: hydrazine hydrate, POCl ₃ : Phosphorus oxychloride, H ₂ : hydrogen, N ₂ : nitrogen, NH ₄ HCO ₃ : ammonium bicarbonate, Cs ₂ CO ₃ : cesium carbonate, NH ₃ .H ₂ O: ammonia water, MeOH: methanol, DAST: diethylamine Sulfur trifluoride, CO: carbon monoxide, LiOH: lithium hydroxide, TFA: trifluoroacetic acid, NaHMDS: sodium bis(trimethylsilyl)amide, DMF: dimethylformamide, DMSO: dimethyl sulfoxide , DMSO-d ₆ : deuterated dimethyl sulfoxide THF: tetrahydrofuran, DIEA: N,N-diisopropylethylamine, EA: ethyl acetate, EtOAc: ethyl acetate; PE: petroleum ether, DMAP: 4 -Dimethylaminopyridine, TsCl: 4-toluenesulfonyl chloride, HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, DMF -DMA: N,N-dimethylformamide dimethyl acetal, LDA: lithium diisopropylamide, MCPBA: m-chloroperoxybenzoic acid, TMSCN: trimethylnitrile silane, TMSCl: trimethyl chloride Silane, BINAP: (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl, NBS: N-bromosuccinimide, NCS: N-chlorosuccinyl Imine, Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone) dipalladium, Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, Pd(dppf )Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, PdCl ₂ (dppf):[1,1'-bis(diphenylphosphino)ferrocene]di Palladium chloride, Pd(PPh ₃ ) ₂ Cl ₂ : bis(triphenylphosphine)palladium(II) chloride, DPPA: diphenylphosphoryl azide, Selectfluor: 1-chloromethyl-4-fluoro-1, 4-Diazotized bicyclo[2.2.2]octane bis(tetrafluoroborate) salt. (t-Bu) ₃ PHBF ₄ : tri-tert-butylphosphonium tetrafluoroborate, TLC: thin layer chromatography, MeMgBr: methylmagnesium bromide, NaI: sodium iodide, K ₂ OsO ₄ : potassium osmate, BAST : 2-methoxy-N-(2-methoxyethyl)-N-(trifluorosulfonyl)ethylamine, Zn(CN) ₂ : zinc cyanide.

The percentage content involved in this application, unless otherwise specified, refers to mass percentage for solid-liquid mixing and solid-solid phase mixing, and refers to volume percentage for liquid-liquid phase mixing.

As used herein, room temperature means about 20-30°C.

Preparation of Intermediate 1

The compound N-(4-methylthiazol-2-yl)acetamide (500mg, 3.20mmol) was dissolved in acetic acid (15mL), and NBS (854.57mg, 4.80mmol) was added with stirring at room temperature, and stirred overnight at room temperature. The target product was found by LC-MS detection. The reaction solution was poured into water, extracted with ethyl acetate (30ml*2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified by silica gel column (EA:PE=0～50%) to obtain white solid intermediate 1 (450mg, 1.91 mmol, yield 59.80%). MS (ESI): 235.2 [M+H] ⁺ .

Preparation of intermediate 2

Step 1: Mix 4-chloro-2-methylbenzoic acid (30g, 175.86mmol), palladium acetate (1.97g, 8.79mmol), iodobenzenediacetic acid (113.29g, 351.71mmol) and iodine (66.95g, 263.79mmol ) was dissolved in DMF (300 mL), heated to 100° C., and reacted overnight under nitrogen protection. The system was cooled to room temperature, quenched with saturated sodium thiosulfate solution, and extracted with ethyl acetate. The extract phase was washed with 10% NaOH solution, the aqueous phase was adjusted to acid, extracted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a brown oily crude product 4-chloro-2-iodo-6- Toluic acid (43 g, yield 82.47%).

Step 2: Dissolve 4-chloro-2-iodo-6-methylbenzoic acid (35g, 118.05mmol), methyl iodide (30.16g, 212.49mmol) in DMF (60mL), potassium carbonate (32.63g, 236.10 mmol) was added to the system, and reacted at room temperature for 2 hours. Dilute with water (300 mL), extract with ethyl acetate (200 mL), wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, and spin dry to obtain a crude product. The crude product was separated by Combiflash column (80g, 0-50%PE/EtOAc) to obtain the product 4-chloro-2-iodo-6-methylbenzoate (22g, yield 60.02%).

Step 3: Methyl 4-chloro-2-iodo-6-methylbenzoate (22g, 70.85mmol), N-bromosuccinimide ((22.70g, 127.53mmol) and azobisisobutyl Nitrile (1.16g, 7.09mmol) was dissolved in carbon tetrachloride (300mL), heated to 90°C, and reacted for 24 hours. Added saturated sodium bisulfite to the system, diluted with water, extracted with dichloromethane, and the organic phase was washed with saturated Wash twice with brine, dry over anhydrous sodium sulfate, and spin dry to obtain the crude product. The crude product is separated by Combiflash through a column (0-80% EA/PE) to obtain the yellow oily product 2-(bromomethyl)-4-chloro-6- Methyl iodobenzoate (25 g, yield 90.61%). MS (ESI): 388.7 [M+H] ⁺ .

Step 4: Dissolve methyl 2-(bromomethyl)-4-chloro-6-iodobenzoate (25g, 64.20mmol) in acetonitrile (120mL), and dissolve (S)-1-cyclopropylethyl Amine hydrochloride (7.81g, 64.20mmol) was added to the system, then boric acid (4.76g, 77.04mmol) was added to the system, and finally potassium carbonate (17.75g, 128.40mmol) was added to the system in batches, and then Stir at 40 °C for 20 h. The reaction solution was filtered, the filtrate was washed with acetonitrile, the organic phase was spin-dried, and the crude product was separated through a Combiflash column (4g, 0-50%PE/EtOAc) to obtain a light yellow solid product Intermediate 2 (9.5g, yield 40.92%) . MS (ESI): 361.9 [M+H] ⁺ .

Preparation of Intermediate 3

Step 1: Mix (S)-1-cyclopropylethane-1-amine hydrochloride (4.5g, 37.00mmol) and 4-chloro-2-(trifluoromethyl)benzoic acid (9.14g, 40.70mmol ) was dissolved in DMF (40 mL), then DIPEA (14.35 g, 111.01 mmol, 19.34 mL), HATU (27.92 g, 74.01 mmol) were added thereto. The reaction was stirred at 21°C for 4 hours. After the reaction is completed, pour the reaction solution into saturated ammonium chloride aqueous solution, extract three times with ethyl acetate, wash once with saturated aqueous sodium bicarbonate solution, wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, and spin dry the solvent under reduced pressure crude product was obtained. Combiflash was separated by column (80g, 0-40% EA/PE). The product (S)-4-chloro-N-(1-cyclopropylethyl)-2-(trifluoromethyl)benzamide (9.8 g, 91%) was successfully obtained as a white solid. MS(ESI):292.1[M+H] ⁺ .

Step 2: Dissolve (S)-4-chloro-N-(1-cyclopropylethyl)-2-(trifluoromethyl)benzamide (8.8 g, 30.17 mmol) in THF (100 mL), The reaction temperature was lowered to -78°C, then sec-butyllithium (1.3M, 58.02mL) was added dropwise therein, and the dropwise addition was completed in about 20 minutes, then stirred for 10 minutes, and DMF (11.03g, 150.84 mmol), the dropwise addition was complete, and the reaction was stirred at this temperature for 1.5 hours. After the reaction was completed, slowly drop saturated aqueous ammonium chloride solution into the reaction solution at low temperature, extract three times with ethyl acetate, dry over anhydrous sodium sulfate, filter, and spin dry the solvent under reduced pressure to obtain a light yellow solid product 5-chloro-2 -((S)-1-Cyclopropylethyl)-3-hydroxy-7-(trifluoromethyl)isoindol-1-one (12.1 g, 100.00%). MS(ESI):320.1[M+H] ⁺ .

Step 3: 5-Chloro-2-((S)-1-cyclopropylethyl)-3-hydroxy-7-(trifluoromethyl)isoindol-1-one (12.1g, 37.85mmol) Dissolved in DCM (130 mL), then lowered the temperature to 0 °C, added triethylsilane (4.40 g, 37.85 mmol, 6.04 mL) and TFA (87.50 g, 767.35 mmol, 57 mL) sequentially. The reaction was allowed to warm to room temperature and stirred for 0.5 hours. After the reaction was completed, the reaction was concentrated, neutralized with saturated sodium bicarbonate, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain a crude product. Combiflash (0 ~ 30%, ethyl acetate/petroleum ether) separation, successfully obtained yellow solid product (S)-5-chloro-2-(1-cyclopropylethyl)-7-(trifluoromethyl)iso Indol-1-one (8.9 g, 77%). MS(ESI):304.1[M+H] ⁺ .

Step 4: Dissolve (S)-5-chloro-2-(1-cyclopropylethyl)-7-(trifluoromethyl)isoindol-1-one (5.15g, 16.96mmol) in dioxygen Hexacyclic (85mL), then pinacol diboronate (4.74g, 18.67mmol), potassium acetate (5.83g, 59.40mmol), chloro[(tricyclohexylphosphine)-2-(2-aminobi Benzene)]palladium(II) (999.63mg, 1.70mmol) was added thereto. The reaction was stirred at 100°C for 1 hour. The raw material reacted completely. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product. Combiflash (0-40%, ethyl acetate/petroleum ether) isolated. Intermediate 3 (6.1 g, 91%) was successfully obtained as a light yellow solid product. MS(ESI):396.2[M+H] ⁺ .

Preparation of Intermediate 4

Step 1: Dissolve 4-bromo-2-fluoro-6-methylbenzoic acid (15g, 64.37mmol) in DMF (107mL), then K ₂ CO ₃ (26.72g, 193.30mmol), iodomethane (18.28 g, 128.76mmol, 8mL) was added to it. The reaction was stirred at 80°C for 1 hour. After the reaction was completed, it was cooled to room temperature (20°C), quenched with 500ML aqueous solution, extracted three times with ethyl acetate, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered and The crude product was obtained after the solvent was spin-dried under reduced pressure. Combiflash was separated by column (8g, 0-20% EA/PE). The product, methyl 4-bromo-2-fluoro-6-methylbenzoate (12.7 g, 80%) was successfully obtained as a colorless oil. MS(ESI):247[M+H] ⁺ .

Step 2: Dissolve methyl 4-bromo-2-fluoro-6-methylbenzoate (12.7g, 51.40mmol) in CCl ₄ (322mL), then NBS (18.30g, 102.81mmol), benzene peroxide Formyl (794.45 mg, 10.28 mmol, 80% purity) was added. The reaction was stirred at 90°C for 18 hours. After the reaction was completed, it was cooled to room temperature, the aqueous solution was quenched, and the solvent was extracted The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain light yellow oily crude product 4-bromo-2-(dibromomethyl)-6-fluorobenzoic acid methyl ester (21.5g, Yield 103%). MS(ESI):405[M+H] ⁺ .

Step 3: Dissolve methyl 4-bromo-2-(dibromomethyl)-6-fluorobenzoate (21.5g, 53.11mmol) in ACN (200mL), cool down to 0-5°C, add DIPEA ( 6.86g, 53.11mmol, 9.25mL) and diethyl phosphite (5.10g, 37.17mmol), then react at 0-5°C for 0.5 hours. At 0-5°C, add saturated sodium bicarbonate, dilute with water, and extract with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The ombiFlash column separation (120 g, 0-50% PE/EtOAc) successfully obtained the pale yellow oily product 4-bromo-2-(bromo Methyl)-6-fluorobenzoic acid methyl ester (12.9 g, 74.). MS(ESI):825[M+H] ⁺ .

Step 4: Add (S)-1-cyclopropylethane-1-amine hydrochloride (4.80g, 39.48mmol) into CH ₃ CN (250mL), then add K ₂ CO ₃ (24.80g, 179.47mmol ) was stirred for 5 minutes, then a solution of boronic acid (2.44g, 39.48mmol) and methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (11.7g, 35.89mmol) in CH ₃ CN (250mL) Added to the reaction liquid, stirred at room temperature for 20 hours. Water was added, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Combiflash was separated by column (40g, 0-20% EA/PE). The product Intermediate 4 (7.1 g, 66) was obtained as a white solid. MS(ESI):298[M+H] ⁺ .

Preparation of Intermediate 5

Step 1: Dissolve 2,6-dichloro-4-methylnicotinic acid (40.00g, 194.15mmol) and potassium carbonate (67.08g, 485.38mmol) in DMF (200mL), add iodomethane (41.34g , 291.23mmol), then reacted at 24°C for 1 hour, poured the reaction solution into water, extracted with ethyl acetate, washed the organic phase twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate to obtain a brown crude product 2, Methyl 6-dichloro-4-methylnicotinate (39.00 g, 91.29%). MS(ESI):220.0[M+H] ⁺ .

Step 2: the crude product 2,6-dichloro-4-methyl nicotinic acid methyl ester (39.00g, 177.23mmol) and N-bromosuccinimide (47.32g, 265.85mmol) and benzyl peroxide The acyl (47.32g, 265.85mmol) was dissolved in _CCl4 (300mL), then the reaction was warmed to 90°C and the reaction was stirred at 90°C for 48 hours. Water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Combiflash (0 ~ 30%, ethyl acetate/petroleum ether) separation, successfully obtained yellow oily mixed product 4-(bromomethyl)-2,6-dichloronicotinic acid methyl ester and 2,6-dichloro-4- A mixture of methyl (dibromomethyl)nicotinate (50 g). MS(ESI):299.8[M+H] ⁺ ，MS(ESI):379.7[M+H] ⁺ .

Step 3: a mixture (50 g) of the crude product 4-(bromomethyl)-2,6-dichloronicotinic acid methyl ester and 2,6-dichloro-4-(dibromomethyl)nicotinic acid methyl ester was dissolved In ACN (300mL), the temperature was lowered to 5°C under the protection of _N2 , and N,N-diisopropylethylamine (34.20g, 264.66mmol) was added dropwise at this temperature, followed by diethyl phosphite (18.14 g, 132.33mmol), reacted at 5°C for 0.5 hours, the raw materials were completely reacted, added saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, Combiflash (0～ 20%, ethyl acetate/petroleum ether) separation. The yellow oily product 4-(bromomethyl)-2,6-dichloronicotinic acid methyl ester (28.00 g, 70.78%) was successfully obtained. MS(ESI):299.9[M+H] ⁺ .

Step 4: Combine -(bromomethyl)-2,6-dichloronicotinic acid methyl ester (28.00g, 93.66mmol) and (S)-1-cyclopropylethylamine hydrochloride (11.39g, 93.66mmol) Dissolve in acetonitrile (200 mL), then add boronic acid (5.79 g, 93.66 mmol) and potassium carbonate (25.89 g, 187.32 mmol). The reaction was stirred at 24°C for 12 hours. The suspension was filtered, and the filtrate was spin-dried to obtain a crude product. Combiflash (0-50%, ethyl acetate/petroleum ether) was separated to obtain intermediate 5 (22.60 g, 88.99%) as a white solid product. MS(ESI):271.0[M+H]+;

Preparation of intermediate 6

Take n-BuLi (2.5M in THF, 5.12mL, 12.8mmol), dropwise add diisopropylamine (1.29g, 12.8mmol) in THF (20mL) solution at 0°C, keep 0°C for 30 minutes. At -78°C, the above solution was slowly added dropwise into a THF (5 mL) solution of N-(4-methylthiazol-2-yl)acetamide (500 mg, 3.2 mmol), and the reaction was continued for 30 minutes. Slowly drop 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.19g, 6.4mmol) into the above reaction solution, keeping- React at 78°C for two hours. Quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed the organic phase twice with brine, dried over sodium sulfate, and concentrated by filtration to obtain intermediate 6 (410 mg, yield 45%) as a pale yellow solid. ¹ H-NMR (400MHz, CDCl ₃ ) δ2.53(s, 3H), 2.25(d, J=2.4Hz, 3H), 1.25(s, 12H).

Preparation of Intermediate 7

Step 1: Intermediate 4 (500mg, 1.68mmol) and (4-methoxyphenyl)methanamine (690.15mg, 5.03mmol) were dissolved in dioxane (10mL), and potassium carbonate (695.31mg ,5.03mmol) was added to it. The reaction was stirred in microwave at 150°C for 2 hours. The solvent was spin-dried under reduced pressure, and the resulting crude product was separated by a Combiflash column (0-70% EA/PE) to obtain a yellow solid (S)-5-bromo-2-(1-cyclopropylethyl)-7-((4 -Methoxybenzyl)amino)isoindolin-1-one (650 mg, yield 93.32%). MS (ESI): 415.1 [M+H] ⁺ .

Step 2: Add (S)-5-bromo-2-(1-cyclopropylethyl)-7-((4-methoxybenzyl)amino)isoindolin-1-one (1.3g, 3.13mmol) was dissolved in trifluoroacetic acid (20mL). The reaction was stirred at 20°C for 20 hours. The solvent was spin-dried under reduced pressure, neutralized to basicity by adding saturated sodium bicarbonate, extracted with DCM, dried over anhydrous sodium sulfate, spin-dried the solvent, and the crude product was separated by Combiflash (0-80% EA/PE) to obtain yellow solid intermediate 7 ( 920mg, yield 99.58%). MS (ESI): 295.1 [M+H] ⁺ .

Preparation of intermediate 8

Step 1: tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (25g, 89.88mmol), thiourea (7.54g, 99.00mmol) and DIPEA (27.29g, 269.65mmol, 37.61mL) Dissolve in DMF (220 mL) and heat to 110°C. The reaction was stirred at 110°C for 12 hours. After the reaction of the raw materials is completed, the reaction solution is lowered to room temperature, and poured into water (1000mL), the solid in it is filtered, and the solid is washed with a small amount of water, and the solid is vacuum-dried to obtain the crude product 2-amino-6,7-di Hydrothiazolo[4,5-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (17 g, 74%). MS(ESI):256.1[M+H] ⁺ .

Step 2: Mix tert-butyl 2-amino-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate (6g, 23.50mmol) and tert-butyl nitrite (2.91g , 28.20mmol) was dissolved in CH ₃ CN (50mL), cooled to 0°C, CuBr ₂ (6.31g, 11.53mmol) was added to the reaction solution, and stirred at 0°C for 2 hours. After the reaction of the raw materials was completed, the reaction liquid was diluted with DCM, filtered, and the filtrate was concentrated. The crude product was isolated by Combiflash (24 g, 0-50% PE/EtOAc) to give the product 2-bromo-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylic acid tert Butyl ester (2.2 g, 29%). MS(ESI):318.9[M+H] ⁺ .

Step 3: tert-butyl 2-bromo-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate (2.2g, 6.89mmol) and Pd/C (502mg, 50% H ₂ O), potassium hydroxide (541mg, 9.65mmol) was dissolved in methanol (40mL), and the reaction was carried out at 50°C Stir for 3 hours. After the reaction of the raw materials was completed, the reaction solution was filtered and concentrated. The crude product was isolated by Combiflash (24 g, 0-30% PE/EtOAc) to successfully give the product tert-butyl 6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate as a light yellow solid (521 mg, 31%). MS(ESI):241.1[M+H] ⁺ .

Step 4: tert-butyl 6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate (521mg, 2.17mmol) was dissolved in EA (10mL), then hydrogen chloride (4M in EA, 5.42 mL) was added thereto. The reaction was stirred at room temperature for 3 hours. After the reaction of the raw materials was completed, the reaction solution was concentrated to obtain the crude product 8 (383 mg, 100.00%) as a pale yellow solid. MS(ESI):141.1[M+H] ⁺ .

Preparation of Intermediate 9

Step 1: tert-butyl 3,3-difluoro-4-oxo-piperidine-1-carboxylate (4.7g, 19.98mmol), and cyanamide (1.68g, 39.96mmol) were dissolved in pyridine (2mL) , sulfur (1.28g, 39.96mmol) was added, and the mixture was heated to 130°C and stirred for 1.5 hours. The starting material was completely reacted, the reaction liquid was poured into water, extracted with EA, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and separated by Combiflash (40 g, 0-50% PE/EtOAc), and a yellow solid product was successfully obtained tert-butyl 2-amino-7,7-difluoro-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (5.82 g, 100%). MS (ESI): 292 [M+H] ⁺ .

Step 2: tert-butyl 2-amino-7,7-difluoro-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (2.8g, 9.61mmol) and Tert-butyl nitrite (1.19g, 11.53mmol) was dissolved in CH ₃ CN (30mL), cooled to 0°C, CuBr ₂ (2.58g, 11.53mmol) was added to the reaction solution, and stirred at 0°C 2 hours. After the reaction of the raw materials was completed, the reaction liquid was diluted with DCM, filtered, and the filtrate was concentrated. The crude product was isolated by Combiflash (24 g, 0-50% PE/EtOAc) to successfully give the product 2-bromo-7,7-difluoro-6,7-dihydrothiazolo[5,4-c]pyridine as a light yellow solid - tert-butyl 5(4H)-carboxylate (2.12 g, 62%). MS(ESI):354.9[M+H] ⁺ .

Step 3: tert-butyl 2-bromo-7,7-difluoro-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (2.8g, 7.88mmol) and Pd /C (957 mg, 50% H ₂ O), potassium hydroxide (619 mg, 11.04 mmol) was dissolved in methanol (70 mL), and the reaction was stirred at 35° C. for 18 hours. After the reaction of the raw materials was completed, the reaction solution was filtered and concentrated. The crude product was isolated by Combiflash (24 g, 0-30% PE/EtOAc) to give the product 7,7-difluoro-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)- tert-Butyl carboxylate (800 mg, 37%). MS(ESI):277.0[M+H] ⁺ .

Step 4: Dissolve tert-butyl 7,7-difluoro-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (800 mg, 2.90 mmol) in EA (10 mL) , then added hydrogen chloride (4M in EA, 14.48 mL). The reaction was stirred at room temperature for 3 hours. After the reaction of the starting materials was completed, the reaction solution was concentrated to obtain the crude product 9 (510 mg, 100%) as a white solid. MS(ESI):177.1[M+H] ⁺ .

Preparation of intermediate 10

Step 1: tert-butyl 2-amino-6,7-dihydro-5(4H)-thiazolo[4,5-c]pyridine-5-carboxylate (500 mg, 1.96 mmol) was dissolved in DCM (10 mL) , then Et ₃ N (1.39 g, 13.71 mmol) was added thereto. Acetyl chloride (307.43 mg, 3.92 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was stirred at 20°C for 5 hours. After the reaction was completed, it was quenched with saturated aqueous sodium bicarbonate, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure to obtain a crude product. Combiflash (12g, 0-70% EA/PE) was isolated and purified. The product tert-butyl 2-acetamido-6,7-dihydro-5(4H)-thiazolo[4,5-c]pyridine-5-carboxylate (450 mg, 77%) was obtained as a pale yellow solid. MS(ESI):298.1[M+H] ⁺ .

Step 2: Dissolve tert-butyl 2-acetamido-6,7-dihydro-5(4H)-thiazolo[4,5-c]pyridine-5-carboxylate (450 mg, 1.52 mmol) in EA (10 mL ), then hydrogen chloride (4M in EA, 10 mL) was added thereto. The reaction was stirred at room temperature for 3 hours When the reaction of the raw materials was completed, the reaction solution was concentrated to obtain the crude product 10 (353 mg, 100%) as a white solid. MS(ESI):198.1[M+H] ⁺ .

Preparation of intermediate 11

Step 1: Dissolve tert-butyl 2-bromo-6,7-dihydro-5(4H)-thiazolo[4,5-c]pyridine-5-carboxylate (500 mg, 1.57 mmol) in DMF (6 mL) , then CuI (596.62 mg, 3.13 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (902.74 mg, 4.70 mmol) were added thereto. The reaction was stirred in the microwave at 100°C for 2 hours. After the reaction of the raw materials was complete, the reaction solution was diluted with dichloromethane, the insoluble matter was removed by filtration, and the filtrate was concentrated to obtain a crude product. Combiflash (24g, 0-20% EA/PE) was isolated and purified. The product tert-butyl 2-(trifluoromethyl)-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate (320 mg, 56%) was obtained as an oil. MS(ESI):309.1[M+H] ⁺ .

Step 2: tert-butyl 2-(trifluoromethyl)-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate (320 mg, 1.04 mmol) was dissolved in EA ( 10 mL), then hydrogen chloride (4M in EA, 10 mL) was added thereto. The reaction was stirred at room temperature for 3 hours. After the reaction of the starting materials was complete, the reaction solution was concentrated to give the crude product 11 (254 mg, 100%) as a white solid. MS(ESI):209.1[M+H] ⁺ .

Preparation of intermediate 12

Step 1: tert-butyl 2-amino-6,7-dihydro-5(4H)-thiazolo[4,5-c]pyridine-5-carboxylate (2500 mg, 9.79 mmol) was dissolved in MeCN (250 mL) , then cuprous cyanide (1.83g, 19.58mmol), t-BuONO (2.02g, 19.58mmol) were added thereto. The reaction was at room temperature for 1 hour, then heated to reflux and stirred for 6 hours. Cooled to room temperature, the reaction solution was concentrated, diluted with ethyl acetate and water, filtered to remove insoluble substances, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. Combiflash (12g, 0%-40% EA/PE) was isolated and purified. The product tert-butyl 2-cyano-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate (700 mg, 27%) was obtained as a pale yellow solid. MS(ESI):266.1[M+H] ⁺ .

Step 2: Dissolve tert-butyl 2-cyano-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate (300mg, 1.13mmol) in EA (10mL), Hydrogen chloride (4M in EA, 10 mL) was then added. The reaction was stirred at room temperature for 3 hours. After the reaction of the starting materials was completed, the reaction solution was concentrated to obtain the crude product 12 (228 mg, 100%) as a white solid. MS(ESI):166.1[M+H] ⁺ .

Preparation of intermediate 13

Step 1: Dissolve tert-butyl 2-bromo-6,7-dihydro-5(4H)-thiazolo[4,5-c]pyridine-5-carboxylate (800 mg, 2.51 mmol) in THF (10 mL) , then sodium methylthiolate (1.08 g, 15.04 mmol) was added thereto. The reaction was stirred in the microwave at 50°C for 4 hours. An aqueous solution of sodium hypochlorite was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Combiflash (12g, 0%-30% EA/PE) was isolated and purified. The light yellow oily product tert-butyl 2-methylsulfanyl-6,7-dihydro-5(4H)-thiazolo[4,5-c]pyridine-5-carboxylate (500mg, 70%) was successfully obtained . MS(ESI):287.1[M+H] ⁺ .

Step 2: tert-butyl 2-methylsulfanyl-6,7-dihydro-5(4H)-thiazolo[4,5-c]pyridine-5-carboxylate (500mg, 1.75mmol) Dissolved in EA (10 mL), then added HCl (4M, 10 mL). The reaction was stirred at room temperature for 3 hours. After the reaction of the raw materials was completed, the reaction solution was concentrated to give the crude intermediate 13 (353 mg, 100%) as a white solid. MS(ESI):187.1[M+H] ⁺ .

Preparation of intermediate 14

Dissolve tert-butyl N-(4-methylthiazol-2-yl)carbamate (1g, 4.67mmol) in tetrahydrofuran (15mL), cool to -78°C, and add lithium diisopropylamide (2M ,7.00mL), react for 1h. Then tributyltin chloride (1.52g, 4.67mmol) was added to react at -78°C for 1h. The completion of the reaction was detected by LCMS, water and ethyl acetate were added for extraction, and the organic phase was spin-dried to obtain a crude product. The crude product was passed through the column to obtain intermediate 14 (1.5 g, 2.98 mmol, yield 63.86%) as a yellow oily product. MS (ESI): 505 [M+H] ⁺ .

Preparation of Intermediate 15

Step 1: tert-butyl 3-oxopiperidine-1-carboxylate (26 g, 130 mmol), tetrahydropyrrole (11.05 g, 156 mmol) and p-toluenesulfonic acid monohydrate (0.78 g, 3.9 mmol) were dissolved in 150 mL of anhydrous In toluene, the system was heated to reflux, and the water generated by the reaction was removed through a water separator. After 3 hours of reaction, the system was cooled to room temperature, and directly proceeded to the next step.

Step 2: Add p-toluenesulfonic acid monohydrate (0.78g, 3.9mmol) and ethyl glyoxylate (50% solution in toluene) (29.12mL, 143mmol) to the system in step 1, and heat the system to reflux for two hours After the reaction was stopped, the system was cooled to room temperature, concentrated, and separated by column. The product 2-oxo-4,5-dihydrofuro[2,3-c]pyridine-6(2H)-carboxylic acid tert-butyl ester (12.6g) and (E)-4-(2-ethoxy -2-Oxoethylene)-5-pyrrolidin-1-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.8 g).

Step 3: (1) Dissolve tert-butyl 2-oxo-4,5-dihydrofuro[2,3-c]pyridine-6(2H)-carboxylate (12.6g, 53.11mmol) in 54mL of anhydrous Ethanol, then hydrazine hydrate (5.7g, 91.2mmol, 80%) and acetic acid (13.5mL) were added to the system, heated to reflux for 16 hours, and the reaction mixture was concentrated.

(2) (E)-4-(2-ethoxy-2-oxoethylene)-5-pyrrolidin-1-yl)-3,4-dihydropyridine-1(2H)-carboxyl Tert-butyl acid ester (3.8g, 11.30mmol) was dissolved in 11mL of absolute ethanol, then hydrazine hydrate (11.8g, 188.8mmol, 80%) and acetic acid (3mL) were added to the system, heated to reflux for 8 hours, and the mixture was concentrated.

The concentrates in (1) and (2) were combined and purified by column to obtain the product 3-oxo-2,5,6,8-tetrahydropyrido[3,4-c]pyridazine-7(3H) - tert-butyl carboxylate (638 mg, white solid), yield: 3.67%. MS (ESI): 252.2/503.3 [M+H] ⁺ .

Step 4: Dissolve tert-butyl 3-oxo-2,5,6,8-tetrahydropyrido[3,4-c]pyridazine-7(3H)-carboxylate (50mg, 0.2mmol) in tris Phosphorus oxychloride (3 mL), protected by N ₂ , reacted at 100°C for 1 hour. The reaction solution was dried directly to obtain 3-chloro-5,6,7,8-tetrahydropyrido[3,4-c]pyridazine (80mg). The product was directly used in the next reaction. MS (ESI): 170.2 [M+H] ⁺ .

Step 5: Dissolve 3-chloro-5,6,7,8-tetrahydropyridin[3,4-c]pyridazine (330mg, 1.95mmol) in ethyl acetate (10ml), then add Pd/C ( 33 mg), the reaction solution was reacted under _H2 atmosphere at room temperature and pressure for 30 hours. After filtration, the filtrate was concentrated to obtain 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine (Intermediate 15, 200mg, colorless oil). MS (ESI): 136.2 [M+H] ⁺ .

Preparation of intermediate 16

Step 1: The compound N-(4-methylthiazol-2-yl)carbamate tert-butyl ester (3.4g, 15.87mmol) was dissolved in tetrahydrofuran (50mL), the temperature was lowered to -78 degrees under the protection of argon, and two Lithium isopropylamide (2.0M, 31.73mL), stirred at -78°C for 2 hours, added dropwise 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborin Cyclopentane (5.90 g, 31.73 mmol), then continued stirring at -78°C for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate (30ml×2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified by silica gel column to obtain intermediate 16 (1.2g, white solid), yield 75.58%, MS ( ESI): 341[M+H] ⁺ .

Embodiment 1: the preparation of compound S-1

Step 1: Intermediate 2 (300 mg, 829.63 μmol) and ethynyl(triisopropyl)silane (151.31 mg, 829.63 μmol) were dissolved in N,N-dimethylformamide (10 mL) under argon protection Add cuprous iodide (31.60 mg, 165.93 μmol), bistriphenylphosphine palladium dichloride (116.46 mg, 165.93 μmol) and triethylamine (418.97 mg, 4.15 mmol) in sequence, heat up to 100°C and stir for 30 minutes. LC-MS detected that the reaction was complete and the target product was formed. The reaction solution was poured into water, extracted with dichloromethane (30ml*2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified by silica gel column (EA:PE=0～50%) to obtain off-white solid compound S-1- a (280 mg, 672.96 μmol, yield 81.12%). MS(ESI):416.2[M+H] ⁺ .

Step 2: Dissolve compound S-1-a (230mg, 552.79μmol) and diboronic acid pinacol ester (280.75mg, 1.11mmol) in 1,4-dioxane (10mL), successively under the protection of argon Add tris(dibenzylideneacetone)dipalladium (50.62mg, 55.28μmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (52.70mg, 110.56μmol), acetic acid Potassium (108.50mg, 1.11mmol), heated to 120°C in microwave and stirred for 30 minutes. LC-MS detection found that the reaction solution of the target product was poured into water, extracted with ethyl acetate (30ml*2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified on a silica gel column (EA:PE=0～50%) to obtain a yellow solid Compound S-1-b (180mg, 354.62μmol, yield 64.15%). MS (ESI): 508.2[M+H] ⁺ .

Step 3: Compound S-1-b (400 mg, 788.04 μmol) and Intermediate 1 (240.85 mg, 1.02 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL), argon Potassium carbonate (108.91 mg, 788.04 μmol), bis(2-diphenylphosphinocyclopentane-2,4-dien-1-yl)iron dichloropalladium (115.32 mg, 157.61 μmol) were added under gas protection, heat up Stir overnight at 80°C. The target product was found by LC-MS detection. The reaction solution was poured into water, extracted with dichloromethane (30ml*2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified by silica gel column (EA:PE=0～50%) to obtain yellow solid compound S-1-c (300mg, 559.90μmol, yield 71.05%). MS (ESI): 536.1[M+H] ⁺ .

Step 4: Dissolve compound S-1-c (10 mg, 18.66 μmol) in methanol (5 mL), add ammonium fluoride (13.81 mg, 373.26 μmol) and dissolve in water (0.5 mL), and heat up to Stir overnight at 75 degrees. LC-MS detected that the reaction was complete, the reaction solution was poured into water, extracted with DCM (30ml*2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified by HPLC to obtain compound S-1 (1.65mg, 4.35μmol, yield 23.3 %,100%).MS(ESI):380[M+H] ^{+ .1} H-NMR(400MHz,DMSO-d ₆ )δ7.68(s,1H),7.53(s,1H),4.53(s ,2H),4.47(s,1H),3.60–3.48(m,1H),2.37(s,3H),2.13(s,3H),1.26(d,J＝6.8Hz,3H),1.15–1.04( m,1H),0.62–0.51(m,1H),0.45–0.29(m,2H),0.25–0.16(m,1H).

Embodiment 2: the preparation of compound S-2

Dissolve compound S-1 and azide(trimethyl)silane (136.62mg, 1.19mmol) in a mixed solvent of tetrahydrofuran (5mL) and tert-butanol (5mL), and add aqueous copper sulfate (29.61mg Copper sulfate pentahydrate was dissolved in 3 mL of water), sodium ascorbate aqueous solution (23.49 mg of sodium ascorbate was dissolved in 3 mL of water), then heated to 70 degrees and stirred overnight. LC-Ms detection found the target product. The reaction solution was poured into 2.0M hydrochloric acid, stirred for 2 hours, extracted with dichloromethane (30ml*2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified by HPLC to obtain compound S-2 (2.39mg, 5.56μmol, harvested Yield 4.69%, purity 98.34%). MS (ESI): 423[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.26(s, 1H), 8.84(s, 1H), 8.14(s,1H),7.67(s,1H),4.62(s,2H),3.71–3.53(m,1H),2.42(s,3H),2.14(s,3H),1.28(d,J= 6.8Hz,3H),1.17–1.07(m,1H),0.63–0.52(m,1H),0.46–0.32(m,2H),0.28–0.18(m,1H).

Embodiment 3: the preparation of compound S-3

Step 1: Intermediate 7 (640 mg, 2.17 mmol) was dissolved in pyridine (15 mL), and then dimethylsulfamoyl chloride (8 g, 55.71 mmol) was added thereto. The reaction was stirred at 80°C for 2 hours. Water was added to the reaction liquid, extracted with DCM, dried over anhydrous sodium sulfate, and spin-dried to dry the solvent. The resulting crude product was separated by Combiflash (0-30% EA/PE) to obtain the white solid product S-3-a (176mg, yield 20.18% ). MS (ESI): 402.1 [M+H] ⁺ .

Step 2: Mix N-(4-methylthiazol-2-yl)acetamide (46.59 mg, 298.28 μmol) with cesium carbonate (194.37 mg, 596.56 μmol), palladium acetate (13.39 mg, 59.66 μmol) and tetrafluoroboric acid Tri-tert-butylphosphine (17.31mg, 59.66μmol) was dissolved in DMF (5mL), replaced by nitrogen, at 100°C, a solution of compound S-3-a (80mg, 198.85μmol) in DMF (1ml) was added dropwise, The mixed solution was stirred and reacted at 100° C. for 2 hours. The solvent was spin-dried and purified by Combiflash (MeOH:DCM=0-10%) to obtain the crude product. The crude product was prepared by alkaline method to obtain compound S-3 (15.45 mg, yield 16.27%). MS (ESI): 478.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.22(s,1H), 9.63(s,1H), 7.41(s,1H), 7.35(s,1H), 4.62(s,2H), 3.56 -3.52(m,1H), 2.80(s,6H), 2.40(s,3H), 2.16(s,3H), 1.31(m,3H), 1.17-1.14(m,1H),0.58-0.56(m ,1H), 0.43-0.37(m,2H),0.26-0.24(m,1H).

Embodiment 4: the preparation of compound S-4

Step 1: Dissolve Intermediate 3 (500mg, 1.27mmol) and sodium hydroxide (151.80mg, 3.80mmol) in tetrahydrofuran (20mL), cool to 0°C, and then dissolve hydrogen peroxide (430.32mg, 3.80mmol, 30%purity ) into it. The reaction was stirred at room temperature for 2 hours. Water was added to the reaction liquid, extracted with EA, the organic phase was washed with sodium sulfite solution, dried, and the solvent was spin-dried, and the obtained crude product was separated by Combiflash column (0-70% EA/PE) to obtain intermediate 17 (360 mg, yield 99.75%) . MS (ESI): 286.1 [M+H] ⁺ .

Step 2: Intermediate 17 (360 mg, 1.26 mmol) and pyridine (311.12 mg, 3.93 mmol) were dissolved in dichloromethane (10 mL), then trifluoromethanesulfonic anhydride (721.32 mg, 2.56 mmol) was added thereto. The reaction was stirred at 0°C for 0.5 hours. Add water to the reaction solution, extract with DCM, dry over anhydrous sodium sulfate, and spin dry under reduced pressure. The obtained crude product is separated by Combiflash column (0-80% EA/PE) to obtain yellow solid intermediate 18 (380 mg, yield 46.30%) . MS (ESI): 418.1 [M+H] ⁺ .

Step 3: Intermediate 18 (200 mg, 0.48 mmol) and tert-butyl N-(4-methyl-5-tributyltinthiazol-2-yl)carbamate (Intermediate 14, 361.83 mg, 0.72 mmol) were dissolved in dioxane (10 mL), then tetrakis(triphenylphosphinepalladium) (55.35 mg, 0.048 mmol) was added thereto. The reaction was stirred at 150°C for 0.5 hours. The solvent was spin-dried under reduced pressure, and the obtained crude product was separated by Combiflash column (0-100% EA/PE) to obtain yellow solid compound S-4-a (160 mg, yield 87.53%). MS (ESI): 382.1 [M+H] ⁺ .

Step 4: Compound S-4-a (160mg, 0.42mmol) and triethylamine (254.69mg, 2.52mmol) were dissolved in dichloromethane (10mL), cooled to 0°C, and then acetyl chloride (131.72mg, 1.68mmol) was added thereto. The reaction was stirred at 0°C for 2 hours. Add water to the reaction liquid, extract with DCM, dry over anhydrous sodium sulfate _, and _{spin dry} the solvent under reduced pressure. : 254/214nm; Gradient: 0%-60% change in acetonitrile) purification to obtain compound S-4 (11.10mg, yield 6.22%). MS (ESI): 424.1 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.21(s,1H), 7.99(s,1H), 7.77(s,1H), 4.66(s,2H), 3.62-3.58(m,1H) , 2.42(s,3H),2.17(s,3H),1.30-1.14(m,4H),0.60-0.57(m,1H),0.44-0.37(m,2H),0.28-0.24(m,1H) .

Embodiment 5: the preparation of compound S-5

Step 1: Dissolve 5,6,7,8-tetrahydro-1,7-naphthyridine (250 mg, 1.86 mmol) and Et ₃ N (942 mg, 9.32 mmol) in DMF (5 mL), then intermediate 5 (505 mg, 1.86 mmol) was added, and the reaction solution was heated to 65°C and stirred for 18 hours. The raw materials were completely reacted, the reaction liquid was concentrated, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was separated by Combiflash (0-30%, ethyl acetate/petroleum ether) to obtain light Red solid product Compound S-5-a (340 mg, 49%). MS(ESI):369.0[M+H] ⁺ .

Step 2: Mix N-(4-methylthiazol-2-yl)acetamide (264mg, 1.69mmol) and Cs ₂ CO ₃ (688mg, 2.11mmol), diacetoxypalladium (76mg, 338μmol), (t -Bu) ₃ PHBF ₄ (86mg, 295μmol) was dissolved in DMF (10mL), heated to 100°C under nitrogen protection, and compound S-5-a (311mg, 844.20μmol) in DMF (10mL) was added dropwise. The reaction was stirred at 100°C for 1.5 hours. Concentrate to remove solvent, add dichloromethane to dissolve and dilute, filter to remove insoluble matter, and concentrate again. The crude product was prepared by basic method to obtain compound S-5 (84 mg, 20%). ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.14 (1H, s), 8.35 (1H, d, J = 3.3), 7.58 (1H, d, J = 7.7), 7.24 (1H, s), 7.18 (1H, dd, J = 7.5, 4.8), 4.83 (2H, s), 4.52 (2H, s), 3.99 (2H, t, J = 8.9), 3.61–3.50 (1H, m), 3.03 (2H ,d,J=3.5),2.58(3H,s),2.14(3H,s),1.23(3H,d,J=6.8),1.13–1.02(1H,m),0.53(1H,d,J= 5.5), 0.36 (2H, dd, J = 13.3, 6.6), 0.22 (1H, d, J = 5.3). MS (ESI): 489.2 [M+H] ⁺ .

The compounds of the following examples were synthesized with reference to the preparation method of compound S-5.

Embodiment 14: Preparation of Compound S-14

Step 1: Intermediate 2 (300mg, 829.63μmol) and 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (173.22mg , 1.08mmol) was dissolved in dioxane (6mL), then tris(dibenzylideneacetone)dipalladium (37.99mg, 41.48μmol), 4,5-bisdiphenylphosphine-9,9-di Methylxanthene (48.00 mg, 82.96 μmol) and cesium carbonate (810.93 mg, 2.49 mmol) were added. The reaction was stirred in microwave at 150°C for 0.5 hours. The solvent was spin-dried under reduced pressure, and the resulting crude product was separated by Combiflash column (0-15% MeOH/DCM) to obtain compound S-14-a (45 mg, yield 15.16%) as a yellow solid. MS (ESI): 402.1 [M+H] ⁺ .

Step 2: Combine N-(4-methylthiazol-2-yl)acetamide (58.93mg, 377.27μmol) and cesium carbonate (163.89mg, 503.02μmol), palladium acetate (16.94mg, 75.45μmol), tetrafluoroboric acid Tri-tert-butylphosphine (21.89 mg, 75.45 μmol) was dissolved in DMF (6 mL), replaced by nitrogen, at 100 ° C, a solution of compound S-14-a (90 mg, 251.51 μmol) in DMF (2 ml) was added dropwise, The mixed solution was stirred and reacted at 100° C. for 2 hours. The solvent was spin-dried and purified by Combiflash (MeOH:DCM=0-10%) to obtain the crude product, which was prepared by alkaline method to obtain compound S-14 (8.39 mg, yield 6.58%). MS (ESI): 478.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.16(s,1H), 8.51(s,1H), 7.26(s,1H), 7.01(s,1H), 4.62(s,2H), 4.53 (s,2H), 4.29-4.26(m,2H), 3.73-3.70(m,2H), 3.59-3.55(m,1H), 2.41(s,3H), 2.16(s,3H),1.27-1.25 (m,3H), 1.12-1.07(m,1H), 0.57-0.55(m,1H), 0.41-0.36(m,2H), 0.23-0.20(m,1H).

Embodiment 15: Preparation of Compound S-15

Prepared according to the method of compound S-14. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.16(s,1H), 7.99(s,1H), 7.26(s,1H), 7.01(s,1H), 4.61(s,2H), 4.53 (s,2H), 4.29-4.26(m,2H), 3.85-3.82(m,2H), 3.60-3.55(m,1H), 2.41(s,3H), 2.16(s,3H),1.28-1.26 (m,3H), 1.12-1.09(m,1H), 0.57-0.55(m,1H), 0.39-0.36(m,2H), 0.23-0.20(m,1H).

Embodiment 19: Preparation of compound 19

Step 1: Dissolve Intermediate 2 (500 mg, 1.4 mmol) in DMF (15 mL), add tributyl(1-ethoxyethylene) tin (600 mg, 1.66 mmol), bistriphenylphosphine palladium dichloride (100mg, 0.14mmol), triethylamine (353mg, 3.5mmol), replaced with argon three times, and the temperature of the oil bath was raised to 100°C for 16 hours. After cooling the reaction solution, add water (30ml) to dilute, filter, rinse the filter cake with a small amount of ethyl acetate, extract with ethyl acetate (50mL X 3), separate the layers, dry the organic phase with anhydrous sodium sulfate, filter and spin dry to obtain compound S -19-a (430 mg, brown oil). The product was directly used in the next reaction. MS (ESI): 306.1 [M+H] ⁺ .

Step 2: Dissolve compound S-19-a (150mg, 0.49mmol) in acetone (15ml), add hydrochloric acid (0.5ml, 2mol/L), protect with argon, and stir at 0°C for 1 hour. Product formation was monitored by LCMS. The reaction solution was poured into 100ml saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (30ml x 3), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by a normal phase column to obtain compound S- 19-b (110 mg), yield: 81%. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ7.83(d, J=1.7Hz, 1H), 7.46(d, J=1.8Hz, 1H), 4.60(s, 2H), 3.55(dd, J =9.2,6.9Hz,1H),2.63(d,J=2.9Hz,3H),1.28(d,J=6.8Hz,3H),1.15–1.06(m,1H),0.59–0.21(m,4H) .

Step 3: Dissolve compound S-19-b (100mg, 0.36mmol) in tetrahydrofuran (3ml), under argon protection, under ice bath, add methylmagnesium bromide (0.36ml, 1.08mol, 3mol/L) dropwise ), and stirred for 1 hour. Product formation was monitored by LCMS. The reaction solution was poured into 30ml of ice-water mixture, adjusted to pH 6 with acetic acid, extracted with dichloromethane (30ml x 3), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound S-19 -c (88 mg). MS (ESI): 294.3 [M+H] ⁺ .

Step 4: Dissolve compound S-19-c (2.6g, 8.8mmol) in DMF (35mL), add N-(4-methylthiazol-2-yl)acetamide (2.08mg, 13.3mmol), four Tri-tert-butylphosphine fluoroborate (1.02g, 3.52mmol), cesium carbonate (5.72g, 17.6mmol), palladium acetate (394mg, 1.76mmol) were strictly replaced with argon three times, and the oil bath was heated to 100°C for 3 hours. After cooling the reaction solution, add water (30ml) to dilute, filter, rinse the filter cake with a small amount of ethyl acetate, extract with ethyl acetate (50mL X3), separate the layers, dry the organic phase with anhydrous sodium sulfate, filter and spin dry, add a small amount of diethyl acetate to the crude product Methylformamide was dissolved and prepared (preparative column: Welch Xtimate C ₁₈ , elution phase: 10mM NH ₄ .HCO ₃ aqueous solution/acetonitrile, elution gradient: start 45% acetonitrile-end 50% acetonitrile, flow rate: 30mL/min) Separation, purification, and freeze-drying gave compound S-19 (1.1 g), yield: 30.3%. MS(ESI):414.2[M+H] ⁺ ; ¹ H-NMR(400MHz,DMSO-d ₆ )δ12.19(s,1H),7.59(d,J=1.1Hz,1H),7.45(d, J=1.2Hz,1H),7.17(s,1H),4.66(s,2H),3.64(dd,J=9.2,6.8Hz,1H),2.51–2.49(m,3H),2.16(s,3H ),1.56(s,6H),1.31(d,J＝6.8Hz,3H),1.16(dd,J＝10.9,6.6Hz,1H),0.72–0.53(m,1H),0.48–0.33(m, 2H), 0.26 (d, J=5.5Hz, 1H).

Embodiment 20: Preparation of Compound S-20

Step 1: Dissolve Intermediate 2 (350mg, 967.91μmol) in THF (5mL), add isopropylmagnesium bromide (2.8M, 1.04mL) under ice bath (0°C), and stir the mixed solution at 0°C After reacting for 0.5 hour, continue to add 3-oxetanone (209.25 mg, 2.90 mmol) at 0°C, and the mixed solution was stirred and reacted at room temperature for 1 hour, and the raw materials were completely reacted. The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The spin-dried product was subjected to Combiflash (MeOH:DCM=0-10%) to obtain an oily substance, and the oily substance was subjected to TLC (EA:PE=1:4) to obtain a white solid compound S-17-a (202mg, 67.81%). MS(ESI):308.1[M+H] ⁺ .

Step 2: Mix N-(4-methylthiazol-2-yl)acetamide (76.13mg, 487.37μmol) and cesium carbonate (317.59mg, 974.75μmol), palladium acetate (21.88mg, 97.47μmol), tetrafluoroboric acid Tri-tert-butylphosphine (28.28mg, 97.47μmol) was dissolved in DMF (3mL), replaced by nitrogen, at 100°C, the DMF (1ml) solution of compound S-17-a was added dropwise, and the mixed solution was heated at 100°C Continue to stir and react for 3 hours, and the reaction of raw materials is complete. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The spin-dried product was purified by Combiflash (MeOH:DCM=0-20%) to obtain a crude product, which was prepared by alkaline method to obtain compound S-17 (58.48mg, 41.72%). MS (ESI): 285.1 [M+H] ⁺ . Purity: 99.09%. 1H-NMR(400MHz,DMSO-d ₆ )δ12.20(s,1H),7.67(s,1H),7.55(s,1H),7.02(s,1H),4.97–4.85(m,2H), 4.74(d, J=7.0Hz, 2H), 4.66(s, 2H), 3.63–3.55(m, 1H), 2.42(s, 3H), 2.16(s, 3H), 1.29(d, J=6.8Hz ,3H),1.14(d,J=8.2Hz,1H),0.58(s,1H),0.41(dd,J=13.5,6.4Hz,2H),0.24(d,J=5.3Hz,1H).

Step 3: Compound S-17 (15mg, 35.09μmol) was dissolved in DCM (5mL), cooled to (-10°C), and DAST (16.97mg, 105.26μmol) was slowly added dropwise, and the mixed solution was naturally warmed to room temperature ( 22° C.) and stirred for 3 hours, and the raw materials were completely reacted. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was prepared by alkaline method to obtain compound S-20 (5.93 mg, 39.35%). MS(ESI):430.2[M+H] ^{+ .1} H-NMR(400MHz,DMSO-d ₆ )δ12.19(s,1H),7.57(s,1H),7.50(dd,J＝4.7,1.5 Hz,1H),7.15(dd,J=7.9,1.5Hz,1H),6.77(dd,J=7.9,4.8Hz,1H),4.58(s,2H),4.38(s,2H),4.02(s ,2H),3.44–3.38(m,1H),2.59(s,3H),2.15(s,3H),1.22(d,J＝6.8Hz,3H),1.06(s,1H),0.54(s, 1H), 0.34(d, J=32.7Hz, 2H), 0.16(s, 1H).

Embodiment 22: Preparation of compound S-22

Step 1: Intermediate 2 (300mg, 0.83mmol) and cuprous cyanide (300mg, 3.35mmol) were dissolved in DMSO (5mL), and microwaved at 100°C for 5 hours. LCMS and TLC monitor, add water after the reaction of the raw material is complete, and extract with ethyl acetate, the organic phase is dried with anhydrous sodium sulfate, filter and concentrate the filtrate, the crude product is passed through Combiflash (0～50%, ethyl acetate/petroleum ether) Separation and purification gave light yellow solid intermediate 19 (150 mg, 70%), MS (ESI): 261.0 [M+H] ⁺ .

Step 2: Mix N-(4-methylthiazol-2-yl)acetamide (60mg, 0.38mmol) and Cs ₂ CO ₃ (124mg, 0.38mmol), diacetoxypalladium (10mg, 44μmol), (t -Bu) ₃ PHBF ₄ (15mg, 51μmol) was dissolved in DMF (5mL), heated to 100°C under the protection of nitrogen, and then the DMF (5mL) solution of intermediate 10 (50mg, 0.19mmol) was slowly added dropwise, about 1 The hour dropwise addition was completed. The reaction was stirred for an additional 1.5 hours at 100°C. After the reaction was complete, water was added and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The crude product was separated and purified by Combiflash (20-85%, ethyl acetate/petroleum ether) to obtain compound S -22 (5.58 mg, 38%), MS (ESI): 381.0 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.27(s, 1H), 7.99(d, J=0.9Hz, 2H), 4.63(s, 2H), 3.57(dd, J=9.3, 6.8Hz ,1H),2.39(s,3H),2.15(s,3H),1.29(d,J＝6.8Hz,3H),1.16–1.05(m,1H),0.57(ddd,J＝10.6,5.5,3.4 Hz,1H),0.39(ddd,J=9.6,6.6,3.7Hz,2H),0.24(q,J=5.3Hz,1H).

The following examples were synthesized with reference to the preparation method of compound S-5 or S-14.

Embodiment 26: Preparation of compound S-26

Step 1: Intermediate 5 (271mg, 1.0mmol) and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (123mg, 1.0mmol) Dissolve in DMF (5 mL), add 1 ml of triethylamine, and heat at 90° C. for 16 hours. LCMS and TLC monitor, after the raw material reacts completely, the reaction solution is concentrated, water is added, and extracted with ethyl acetate, the organic phase is dried with anhydrous sodium sulfate, filtered and the filtrate is concentrated, and the crude product is passed through Combiflash (15～100%, ethyl acetate ester/petroleum ether) to obtain compound S-26-a (200 mg, 56%) as a light yellow solid product, MS (ESI): 358.0 [M+H] ⁺ .

Step 2: Compound S-26-a (200mg, 0.56mmol) and sodium carbonate (118mg, 1.12mmol), Pd(dppf)Cl ₂ (25mg, 34.2μmol), intermediate 6 (316mg, 1.12mmol) were dissolved in 1,4-dioxane (5 mL), then added 0.5 ml of water, heated to 100° C. under nitrogen protection, and continued to stir for 1.5 hours. After the reaction, water was added and extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated, the crude product was separated and purified by Combiflash (20-100%, ethyl acetate/petroleum ether) to obtain the product compound S-26 (50 mg, 18.7%), MS (ESI): 478.0 [M+H] ⁺ . ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.21–12.09(m,1H),7.45(s,1H),7.21(s,1H),4.62(s,2H),4.50(s,2H) ,3.92(d,J=6.2Hz,2H),3.61–3.49(m,1H),2.90(d,J=5.6Hz,2H),2.57(s,3H),2.14(s,3H),1.23( d,J=6.8Hz,4H),0.55(dt,J=8.6,5.3Hz,1H),0.36(td,J=10.3,9.8,6.3Hz,2H),0.21(q,J=4.7Hz,1H ).

Embodiment 27: Preparation of compound S-27

Step 1: Intermediate 5 (600mg, 2.21mmol), 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (545.05mg, 4.43mmol) and DIPEA (286.00mg, 2.21mmol, 385.44μL) was dissolved in dioxane (8mL), and after nitrogen replacement, stirred and reacted in a Weibo reactor at 185°C for 0.75 hours. The basic reaction of raw materials is complete. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by Combiflash (MeOH:DCM=0-10%) to obtain compound S-27-a (453 mg, 1.27 mmol, yield 57.21%) as a yellow oil. MS(ESI):358.1[M+H] ⁺ .

Step 2: Compound S-27-a (70mg, 195.62μmol), intermediate 6 (60.72mg, 215.18μmol), sodium carbonate (103.67mg, 978.10μmol) and PdCl ₂ (dppf) (21.29mg, 29.34μmol) It was dissolved in dioxane (10 mL) and water (1 mL), and the mixed solution was replaced with nitrogen, then stirred and reacted in a microwave reactor at 100° C. for 0.5 hour, and the raw materials were completely reacted. The reaction solution was concentrated to dryness under reduced pressure, and subjected to Combiflash (MeOH:DCM=0-15%) to obtain a crude yellow solid. The crude product was prepared by column chromatography to obtain compound S-27 (3.26 mg, 3.29%). MS(ESI):478.2[M+H] ⁺ .1H-NMR(400MHz,DMSO-d ₆ )δ12.15(s,1H),12.11–11.74(m,1H),7.49(s,1H),7.21 (s,1H),4.57(s,2H),4.50(s,2H),3.93(dd,J=14.1,5.7Hz,2H),3.55(s,1H),2.82(s,2H),2.57( s,3H),2.14(s,3H),1.23(d,J=6.8Hz,3H),1.08(s,1H),0.54(s,1H),0.36(dd,J=13.1,6.5Hz,2H ),0.21(d,J=5.4Hz,1H).

Embodiment 28: Preparation of Compound S-28

Compound S-28 can be synthesized according to the method of compound S-5. MS(ESI):475.2[MH] ^- . ¹ H-NMR(400MHz,DMSO-d ₆ )δ12.14(s,1H),8.63(s,1H),8.47(d,J＝4.7Hz,1H) ,7.47(d,J=4.9Hz,1H),7.15(s,1H),5.19(q,J=16.6Hz,4H),4.52(s,2H),3.62–3.51(m,1H),2.59( s,3H),2.13(s,3H),1.24(d,J＝6.8Hz,3H),1.13–1.03(m,1H),0.61–0.51(m,1H),0.45–0.30(m,2H) ,0.28–0.19(m,1H).

Embodiment 29: Preparation of Compound S-29

Step 1: Intermediate 5 (300mg, 1.11mmol), 7,7-difluoro-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine (275mg, 1.44mmol ) and DIPEA (1.43g, 11.06mmol, 1.5mL) were dissolved in 1,4-dioxane (3.5mL), and stirred under microwave conditions at 180°C for 0.5 hours. The raw materials were completely reacted, and the reaction solution was dichloromethane Diluted, filtered to remove insoluble material, concentrated the filtrate, and separated by Combiflash (0-80% EA/PE). Compound S-29-a (190 mg, 40%) was successfully obtained as a white solid product. MS(ESI):426.1[M+H] ⁺ .

Step 2: Dissolve compound S-29-a (100mg, 234.81μmol) and intermediate 6 (66mg, 234.81μmol) in water (0.5mL), 1,4-dioxane (2mL), then carbonic acid Sodium (99 mg, 939.23 μmol), Pd(dppf)Cl ₂ (34.36 mg, 46.96 μmol) were added. The reaction was stirred in the microwave at 100°C for 0.5 hours. After the reaction of raw materials was completed, it was cooled to room temperature, diluted with dichloromethane, filtered, and the filtrate was concentrated under reduced pressure. The product compound S-29 (2.97 mg, 2.30%) was successfully obtained by Combiflash crude separation (4 g, 0-10% MeOH/DCM), and then prepared by alkaline method. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.17(s,1H),7.31(s,1H),7.17(s,2H),4.90(dd,J=31.6,16.0Hz,2H),4.70 (td,J=26.2,14.4Hz,2H),4.55(s,2H),3.56(dq,J=14.0,7.0Hz,1H),2.55(s,3H),2.14(s,3H),1.24( d,J=6.8Hz,3H), 1.07(dt,J=12.2,6.1Hz,1H),0.58–0.50(m,1H),0.43–0.32(m,2H),0.26–0.16(m,1H) .MS(ESI):546.2[MH] ^- .

Embodiment 30: Preparation of compound S-30

Step 1: Intermediate 5 (150 mg, 553.22 μmol), 4,5,6,7-tetrahydro-2H-pyrazol[3,4-c]pyridine (132.45 mg, 829.82 μmol, HCl) and DIPEA (742.00 mg, 5.74mmol, 1mL) was dissolved in dioxane (4mL), and the mixed solution was replaced with nitrogen, then stirred and reacted in a Weibo reactor at 100°C for 0.75 hours, and the raw materials were completely reacted. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was subjected to Combiflash (MeOH:DCM=0-10%) to obtain Compound S-30-a (180 mg, 90.93%) as a yellow oil. MS(ESI):358.1[M+H] ⁺ .

Step 2: Compound S-30-a (60 mg, 167.67 μmol), Intermediate 6 (50 mg, 177.20 μmol), PdCl (dppf) (24.33 mg, 33.53 μmol) and sodium carbonate (88.86 mg, 838.37 μmol) were dissolved in In dioxane (5 mL) and water (0.5 mL), the mixed solution was replaced with nitrogen, then stirred and reacted in a microwave reactor at 100° C. for 0.75 hours, and the raw materials were completely reacted. The reaction solution was concentrated to dryness under reduced pressure, and the spin-dried product was purified by Combiflash (MeOH:DCM=0-15%) to obtain a crude yellow oil, which was prepared by column chromatography to obtain compound S-30 (5.21 mg, 6.45%). MS(ESI):478.2[M+H] ⁺ .1H-NMR(400MHz,DMSO-d ₆ )δ12.50(s,1H),12.18(s,1H),7.45(s,1H),7.24(s ,1H),4.73(s,2H),4.53(s,2H),3.98–3.79(m,2H),3.62–3.51(m,1H),2.83(s,2H),2.60(s,3H), 2.16(s,3H),1.26(d,J=6.8Hz,3H),1.10(s,1H),0.56(s,1H),0.44–0.33(m,2H),0.24(d,J=5.1Hz ,1H).

Embodiment 31: Preparation of compound S-31

Step 1: Intermediate 5 (500 mg, 1.84 mmol) and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (272.53 mg, 2.21 mmol) were dissolved in DMF (10 mL), Triethylamine (559.80 mg, 5.53 mmol) was then added. The reaction was stirred at 80°C for 20 hours. The solvent was spin-dried under reduced pressure, and the obtained crude product was separated by Combiflash column (0-15% MeOH/DCM) to obtain compound S-31-a (210 mg, yield 31.82%) as a yellow solid product. MS(ESI):358.0[M+H] ⁺

Step 2: Compound S-31-a (100mg, 0.28mmol) and Intermediate 6 (104.59mg, 0.31mol) were dissolved in dioxane (8mL) and water (1mL), then PdCl ₂ (dppf) (20.45 mg, 0.028 mmol) and sodium carbonate (59.24 mg, 0.56 mmol) were added thereto. The reaction was stirred in the microwave at 100°C for 45 minutes. The solvent was spin-dried under reduced pressure, and the crude product was separated by Combiflash column (0-80% EA/PE) to obtain a yellow solid, which was further analyzed by preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH ₄ HCO ₃ H ₂ O; wavelength: 254/214nm; gradient: 0%-60% change in acetonitrile) purification to obtain the target compound S-31 (11.76mg, yield 8.78%). MS (ESI): 478.2 [M+H] ⁺ . ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.20(s,1H),7.34(s,1H),7.14-7.10(m,1H),6.91-6.89(m,1H),4.82(s,1H) 2H), 4.57(s,2H), 4.22-4.15(m,4H), 3.59-3.55(m,1H), 2.61(s,3H), 2.16(s,3H), 1.27-1.26(m,3H) , 1.13-1.09 (m, 1H), 0.57-0.55 (m, 1H), 0.40-0.36 (m, 2H), 0.26-0.22 (m, 1H).

Embodiment 32: Preparation of Compound S-32

Step 1: Dissolve compound S-22 (30mg, 0.078mmol) in toluene (2mL), add azidotributylstannane (270mg, 0.87mmol), react at 120°C for 24 hours, filter, and send the filter cake to prepare to obtain Compound S-32 (1.51 mg, white solid, purity: 97%). ¹ H-NMR(400MHz,DMSO-d ₆ )δ12.30(s,1H),8.21(s,1H),7.95(s,1H),4.79(s,2H),3.67(s,1H),2.18 (s,3H),1.35(d,J=6.5Hz,3H),1.23(s,3H),0.85(s,1H),0.61(s,1H),0.44(s,2H),0.30(s, 1H).

Embodiment 33: Preparation of compound S-33

Step 1: Dissolve Intermediate 2 (400mg, 1.11mmol) in THF (10mL), add isopropylmagnesium bromide (2.8M, 987.66μL) under ice bath (0°C), and mix the solution at room temperature (22 ℃) stirring reaction for 1 hour, continued to add dicyclopropyl ketone (609.25 mg, 5.53 mmol) under ice bath (0 ℃), and the mixed solution continued to stir and react at room temperature (22 ℃) for 1 hour. The raw material reacted completely. The reaction solution was concentrated to dryness under reduced pressure, and passed through Combiflash (MeOH:DCM=0～15%) get crude. The crude product was purified by TLC (EA:PE=1:4) to give white solid product Compound S-33-a (125 mg, 32.67%) MS (ESI): 328.2[M+H] ⁺ .

Step 2: Combine 2-acetylamino-4-methylthiazole (108.39mg, 693.92μmol), cesium carbonate (282.61mg, 867.40μmol), palladium acetate (23.37mg, 104.09μmol) and tri-tert-butylphosphine tetrafluoroborate (30.20mg, 104.09μmol) was dissolved in DMF (3mL), and after nitrogen replacement, the DMF (2ml) solution of compound S-33-a (120mg, 346.96μmol) was slowly added dropwise at 100°C, and the mixed solution continued to The reaction was stirred at 100°C for 3 hours. The raw material reacted completely. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude product, which was subjected to Combiflash (EA:PE=40-80%) to obtain light yellow solid compound S-51 (122 mg, 75.52%). MS(ESI):448.2[M+H] ⁺ .

Step 3: Compound S-51 (90mg, 193.30μmol) was dissolved in DCM (10mL), DAST (155.79mg, 966.48μmol) was added dropwise at -20°C, and the mixed solution was naturally warmed to room temperature (22°C) and stirred for reaction 18 hours. The raw material reacted completely. The reaction solution was concentrated to dryness under reduced pressure, and the spin-dried product was subjected to Combiflash (EA:PE=0-80%) to obtain a crude product. The crude product was prepared by column chromatography to obtain the product compound S-33 (3.40 mg, 3.76%). MS(ESI):468.3[M+H] ⁺ .1H-NMR(400MHz,DMSO-d ₆ )δ12.20(s,1H),7.57(s,1H),7.00(s,1H),5.40(t ,J=7.1Hz,1H),4.61(t,J=6.5Hz,1H),4.53(s,2H),4.49(t,J=6.5Hz,1H),3.60–3.52(m,1H),2.80 –2.67(m,2H),2.38(s,3H),2.15(s,3H),2.06(s,1H),1.26(d,J=6.8Hz,3H),1.09(s,1H),0.63( d,J=8.4Hz,2H),0.56(s,1H),0.43–0.32(m,2H),0.22(d,J=5.1Hz,1H),0.11(d,J=3.9Hz,2H).

Embodiment 34: Preparation of compound S-34

Step 1: Dissolve compound S-38 (30 mg, 0.079 mmol), azidotributylstannane (261 mg, 0.79 mmol) in toluene (2 mL), replace argon three times, and react in an oil bath at 120° C. for 36 hours. The reaction solution was brought to room temperature, filtered, and the filter cake was washed twice with dichloromethane. The filter cake was dissolved in dimethyl sulfoxide (5 mL) and purified by alkaline preparation to obtain compound S-34 (1.21 mg, white solid, purity 99%). ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.29(s,1H),8.10(s,1H),5.33(t,J=4.9Hz,1H),4.82(s,2H),3.68–3.53 (m,1H),2.69(s,3H),2.19(s,3H),1.33(d,J=6.8Hz,3H),0.86(t,J=6.7Hz,1H),0.61(t,J= 6.8Hz, 1H), 0.44(d, J=5.4Hz, 2H), 0.28(d, J=5.5Hz, 1H).

Embodiment 35: Preparation of compound S-35

Step 1: Dissolve Intermediate 2 (800mg, 2.16mmol) in anhydrous methanol (50mL), then add TEA (800mg, 7.92mmol), Pd(PPh ₃ ) ₂ Cl ₂ (160mg, 0.16mmol), carbon monoxide was passed through, autoclave reaction, 4M Pa, 80°C for 16 hours. LCMS detection, the reaction is complete. The reaction solution was transferred to 100 mL of water, extracted with ethyl acetate (100 mL×3), the combined organic phase was washed with saturated sodium chloride solution (100 mL×1), dried with anhydrous sodium sulfate, spin-dried, and passed through a normal phase column Purified to obtain compound S-35-a (500mg), yield: 76.94%. MS (ESI): 294.0 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ7.64(d, J=1.7Hz, 1H), 7.44(d, J=1.8Hz, 1H), 4.36(s, 2H), 3.61(s, 3H ), 3.30 (dd, J=9.2, 6.9Hz, 1H), 1.04 (d, J=6.8Hz, 3H), 0.92–0.84 (m, 1H), 0.38–0.04 (m, 4H).

Step 2: Dissolve compound S-35-a (450mg, 1.53mmol) in 1,4-dioxane (20mL) and water (4mL), then add intermediate 6 (1.729g, 6.13mmol), carbonic acid Sodium (487 mg, 4.60 mmol), replaced with argon. Then Pd(dppf)Cl ₂ (168mg, 0.23mmol) was added, replaced by argon, protected by argon, stirred at 100°C for 3 hours, and detected by LCMS, the reaction was complete. The reaction solution was transferred to water, extracted with ethyl acetate (100 mL×3), the combined organic phases were washed with saturated aqueous sodium chloride (100 mL×1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purified by normal phase column to obtain compound S-35-b (277mg), yield: 40.77%. MS (ESI): 414.1 [M+H ^]+ . ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.23(s,1H),7.81(s,1H),7.59(d,J=1.5Hz,1H),4.62(s,2H),3.84(s ,3H),3.62–3.48(m,1H),2.40(s,3H),2.16(s,3H),1.28(d,J＝6.8Hz,3H),1.12(dd,J＝8.8,3.6Hz, 1H), 0.40 (dddd, J=54.9, 17.9, 8.8, 4.0Hz, 4H).

Step 3: Dissolve compound S-35-b (277mg) in 15mL of tetrahydrofuran, protect by argon displacement, add lithium hydroxide aqueous solution (1M) (2.5mL), stir and react at room temperature for 1 hour after the addition is complete. LCMS detection, the reaction is complete. The reaction solution was spin-dried and purified by reverse-phase column to obtain compound S-35-c (268mg), yield: 98.22%. MS (ESI): 400.0 [M+H] ⁺ . ¹ H-NMR (400MHz,DMSO-d ₆ )δ7.63(s,1H),7.56(s,1H),4.58(s,2H),3.61–3.55(m,1H),2.39(s,3H) ,2.14(s,3H),1.29(d,J=6.6Hz,3H),1.13(s,1H),0.63–0.55(m,1H),0.41(dd,J=12.3,5.8Hz,2H), 0.26 (dd, J = 9.9, 4.2 Hz, 1H).

Step 4: Dissolve compound S-35-c (220mg, 0.55mmol) in DMF (10mL), then add formic hydrazide (36mg, 0.61mmol), N-methylmorpholine (167mg, 1.65mmol), HATu (251 mg, 0.66 mmol), argon replacement, argon protection, stirring reaction at room temperature for 16 hours, LCMS detection, the reaction was complete. The reaction solution was transferred to water (100 mL), extracted with dichloromethane (100 mL × 3), the combined organic phase was washed with saturated sodium chloride solution (100 mL × 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and over Purified by normal phase column to obtain compound S-35-d (300mg). MS (ESI): 442.2 [M+H] ⁺ . ¹ H-NMR (400MHz,DMSO-d ₆ )δ13.82(s,1H),12.26(s,1H),10.57(s,1H),8.30(d,J=1.2Hz,1H),8.09(s ,1H),7.97(s,1H),4.76(s,2H),3.67(dd,J=9.1,6.9Hz,1H),2.45(s,3H),2.17(s,3H),1.34(d, J＝6.8Hz, 3H), 1.19(dd, J＝8.2, 4.4Hz, 1H), 0.62(dd, J＝11.7, 6.4Hz, 1H), 0.45(dd, J＝12.7, 7.0Hz, 2H), 0.32–0.27 (m,1H).

Step 5: Dissolve compound S-35-d (270 mg, 0.61 mmol) in DCM (20 mL), then add Burgess reagent (432 mg, 1.83 mmol), replace with argon, protect with argon, and stir at room temperature for 48 hours . LCMS detection, the reaction is complete. Spin-dried, sent to preparation and purification, and then went through Prep-TLC to obtain compound S-35 (0.91 mg, white solid), yield: 0.29%. MS (ESI): 424.3 [M+H] ⁺ . ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.25(s,1H),9.43(s,1H),7.97(s,1H),7.82(s,1H),4.68(s,2H),3.53 (s,1H),2.43(s,3H),2.17(s,3H),1.29(d,J＝6.8Hz,3H),1.15–1.05(m,1H),0.58(s,1H),0.35( s,2H), 0.22(s,1H).

Embodiment 37: Preparation of Compound S-37

Step 1: Dissolve compound S-47-a (500mg, 1.28mmol) and trimethyl((tributyltin)ethynyl)silane (995mg, 2.56mmol) in toluene (20ml), then add tetrakistriphenylphosphine Palladium (45mg, 0.03mmol), argon Protected and reacted in an oil bath at 120°C for 16 hours. The reaction solution was cooled to room temperature, extracted three times with ethyl acetate and water, combined the organic phases, backwashed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound S-37-a (500 mg, crude product, yellow solid).

Step 2: Compound S-37-a (450mg, 0.99mmol) was dissolved in dichloromethane (9ml) and methanol (3mL), then potassium carbonate (206mg, 1.49mmol) was added, and the reaction solution was reacted at room temperature for 2h. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (silica, petroleum ether-ethyl acetate system), and then sent to prepare compound S-37 (6.09 mg, light yellow solid, purity 91%). ¹ H-NMR (400MHz,DMSO-d ₆ )δ11.87(s,1H),7.68(s,1H),4.40(s,1H),4.35(d,J=20.7Hz,2H),3.33(dq ,J=13.7,6.9Hz,1H),2.43–2.32(m,3H),1.94(s,3H),1.04(d,J=6.8Hz,3H),0.94–0.82(m,1H),0.41– 0.28(m,1H),0.24–0.10(m,2H),0.06–0.06(m,1H).

Embodiment 38: Preparation of Compound S-38

Step 1. Dissolve compound S-47-a (100mg, 0.256mmol) in N,N-dimethylformamide (3ml), add zinc cyanide (150mg, 1.28mmol), 1,1'-bis (Diphenylphosphine)ferrocene (56.7mg, 0.1mmol), activated zinc powder (16.6mg, 0.256mmol), blowing argon into the reaction solution for 30 seconds, adding tris(dibenzylideneacetone)dipalladium (46.6mg, 0.05mmol), continue to blow argon into the reaction solution for one minute. Microwave at 125°C for one hour. The reaction solution was brought to room temperature, filtered, and the filter cake was washed twice with dichloromethane. The filter cake was further beaten with dimethyl sulfoxide (5 mL) for 30 minutes, filtered and dried with an oil pump to obtain compound S-38 (50 mg, gray solid), yield: 51%. ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.92–11.68(m,1H),8.20(s,1H),4.71(s,2H),3.71–3.49(m,1H),2.63(s, 3H),2.18(s,3H),1.31(d,J=6.8Hz,3H),1.24(s,1H),0.59(t,J=7.0Hz,1H),0.48–0.35(m,2H), 0.27 (d, J=4.9Hz, 1H).

Example 41: Preparation of Compound S-41

Step 1: Intermediate 2 (1.6g, 4.42mmol) was dissolved in tetrahydrofuran (30mL), the temperature was lowered to 0°C under the protection of argon, and bromo(isopropyl)magnesium (3.0M, 2.21mL) was added dropwise, and the addition was completed After 2 minutes, acetone (1.28 g, 22.12 mmol) was added dropwise, and the reaction was worked up for 3 minutes. The reaction solution was poured into water, extracted with dichloromethane (30ml×2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified by silica gel column (EA:PE=0～30%) to obtain compound S-41-a (750mg , yellow solid), yield: 57.70%, MS (ESI): 294[M+H] ⁺ .

Step 2: Compound S-41-a (650mg, 2.21mmol) was dissolved in dichloromethane (10mL), cooled to 0°C under argon protection, and 2-methoxy-N-(2-methoxyethyl base)-N-(trifluorosulfonyl)ethylamine (978.98mg, 4.42mmol), stirred at 0°C for 2 hours, then at room temperature overnight. The reaction solution was poured into water, extracted with dichloromethane (30ml×2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified on a silica gel column (EA:PE=0～50%) to obtain compound S-41-b ( 35mg, white solid), yield: 5.35%. MS (ESI): 298 [M+H] ⁺ .

Step 3: Compound S-41-b (30 mg, 101.43 μmol) and Intermediate 6 (143.10 mg, 507.14 μmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (0.5 mL), argon Pd(dppf)Cl ₂ (37.11 mg, 50.71 μmol) and sodium carbonate (53.75 mg, 507.14 μmol) were added under air protection, and the temperature was raised to 120°C by microwave and stirred for 1.5 hours. The reaction solution Poured into water, extracted with dichloromethane (30ml×2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified by HPLC to obtain compound S-41 (1.50mg, white solid, purity 97.11%), yield: 3.46 %. MS (ESI): 416 [M+H] ⁺ .

Embodiment 49: Preparation of Compound S-49

Step 1: Intermediate 5 (300mg, 1.11mmol) and 3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine (764.38mg , 5.53mmol) was dissolved in 1,4-dioxane (5mL), N,N-diisopropylethylamine (714.99mg, 5.53mmol) was added under the protection of argon, and the microwave was heated to 100°C and stirred for 1 hour . The reaction solution was directly concentrated to dryness under reduced pressure, separated and purified by silica gel column to obtain S-49-a (350 mg, yellow oil), yield: 84.84%. MS (ESI): 373 [M+H] ⁺ .

Step 2: Compound S-49-a (175 mg, 469.36 μmol) and Intermediate 16 (479.09 mg, 1.41 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL) under argon Under protection, Pd(dppf)Cl ₂ (103.03 mg, 140.81 μmol) and sodium carbonate (129.74 mg, 938.71 μmol) were sequentially added, heated to 100°C by microwave and stirred for 20 minutes. The reaction solution was poured into water, extracted with dichloromethane (30ml*2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and separated and purified on a silica gel column to obtain compound S-49-b (200mg, yellow solid). Rate: 77.38%. MS (ESI): 551 [M+H] ⁺ .

Step 3: Compound S-49-b (250 mg, 453.99 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (16.55 mg, 145.17 μmol) was added with stirring at room temperature, and stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain compound S-49-c (150 mg, yellow solid), yield: 73.33%. MS(ESI):451[M+H] ⁺ .

Step 4: Dissolve compound S-49-c (60mg, 133.17μmol) in DCM (10mL), cool down to 0°C under argon protection, add diisopropylethylamine (86.06mg, 665.84μmol), acetyl chloride (15.68mg, 199.75μmol), stirred at 0°C for 1 hour. The reaction solution was poured into water, extracted with dichloromethane (30ml*2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified by HPLC to obtain compound S-49 (3.92mg, yellow solid, purity 95.34%), yield : 5.70%. MS (ESI): 493 [M+H] ⁺ . ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.20(s,1H),7.34(s,1H),4.91(s,2H),4.55(s,2H),4.22–4.02(m,4H) ,3.61–3.48(m,1H),2.59(s,3H),2.30(s,3H),2.14(s,3H),1.25(d,J＝6.8Hz,3H),1.13–1.02(m,1H ), 0.59–0.51(m,1H), 0.42–0.29(m,2H), 0.26–0.18(m,1H).

Compound S-36 can be synthesized by referring to the preparation method of compound S-2. S-39 can be synthesized by referring to the preparation method of compound S-20. S-40, S-45, S-46, S-48, and S-52 can be synthesized by referring to the preparation method of compound S-5 or S-14. S-42 can be synthesized by referring to the preparation method of compound S-20.

Embodiment 47: Preparation of Compound S-47

Step 1: Intermediate 5 (1.200g, 4.43mmol) and Intermediate 6 (3.75g, 13.28mmol) were dissolved in N,N-dimethylformamide (20mL), and bis(2-bis Phenylphosphinocyclopentane-2,4-dien-1-yl)iron dichloropalladium (323.83mg, 442.57μmol), sodium carbonate (1.41g, 13.28mmol), heated to 100°C and stirred for 10 hours. The target product was found by LC-MS detection. The reaction solution was poured into water, extracted with dichloromethane (50ml*2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified by silica gel column (EA:PE=0～100%) to obtain yellow solid compound S-47-a (380mg, 972.15μmol, yield 21.97%). MS(ESI):391[M+H] ⁺ .

Step 2: Compound S-47-a (380 mg, 972.15 μmol) was dissolved in 1,4-dioxane (15 mL), cooled to -78 ° C under argon protection, and tetrakistriphenylphosphine palladium (101.99 mg, 97.21 μmol), stirred at -78°C for 2 hours, added dibutyl-(1-ethoxyvinyl)-propyltin (674.91mg, 1.94mmol) dropwise, and continued to stir at -78°C for 2 hours. The target product was found by LC-MS detection. The reaction solution was directly concentrated to dryness under reduced pressure, separated and purified on a silica gel column (EA:PE=0-100%) to obtain yellow solid compound S-47-b (230 mg, 539.23 μmol, yield 55.47%). MS(ESI):427[M+H] ⁺ .

Step 3: Compound S-47-b (230 mg, 539.23 μmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (19.66 mg, 172.43 μmol, 1 mL) was added with stirring at room temperature, and stirred at room temperature for 1 hour. The target product was found by LC-MS detection. The reaction solution was poured into a 1:1 mixture of saturated sodium bicarbonate solution and ice, extracted with dichloromethane (100ml*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a red solid compound S-47-c (214.87mg , 539.23 μmol, yield 100.00%).

Step 4: Compound S-47-c (214mg, 537.04μmol) was dissolved in tetrahydrofuran (10mL), cooled to 0°C under the protection of argon, and methylmagnesium bromide (1.0M, 1.61mL) was added dropwise, then 0°C Stir for 25 minutes before processing. The target product was found by LC-MS detection. The reaction solution was poured into water, extracted with DCM (50ml*3), dried over anhydrous sodium sulfate, and subjected to HPLC (preparative column: Welch Xtimate C ₁₈ , elution phase: 10mM NH ₄ .HCO ₃ aqueous solution/acetonitrile, elution gradient: start 43% acetonitrile-end 48% acetonitrile, flow rate: 30 mL/min) separation and purification to obtain compound S-47 (51.32 mg, 123.81 μmol, yield 23.05%). MS(ESI):415[M+H] ⁺ . ¹ H-NMR(400MHz,DMSO-d ₆ )δ12.21(s,1H),7.77(s,1H),7.26(s,1H),4.72( s,2H),3.60(dq,J=14.0,7.0Hz,1H),2.59(s,3H),2.14(s,3H),1.5(s,6H),1.29(d,J=6.8Hz,3H ),1.18–1.06(m,1H),0.63–0.49(m,1H),0.47–0.31(m,2H),0.30–0.18(m,1H).

Embodiment 53: Preparation of compound S-53

Step 1: Intermediate 5 (500mg, 1.84mmol), Intermediate 13 (325mg, 1.75mmol), DIPEA (2.23g, 17.22mmol, 3.00mL) were dissolved in 1,4-dioxane (8mL), Stir under microwave conditions at 130° C. for 1 hour. The raw material reacted completely, the reaction solution was diluted with dichloromethane, filtered to remove insoluble matter, the filtrate was concentrated, and separated by Combiflash (0-80% EA/PE). The white solid product compound S-53-a (320 mg, 41%) was successfully obtained. MS(ESI):421.1[M+H] ⁺ .

Step 2: Compound S-53-a (220 mg, 522.59 μmol) was dissolved in DCM (20 mL), and m-chloroperoxybenzoic acid (270.54 mg, 1.57 mmol) was added thereto. The reaction was stirred at 20°C for 3 hours. After completion, quenched with aqueous sodium bicarbonate, extracted with ethyl acetate, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, and spin-dried the solvent under reduced pressure to obtain a crude product. Combiflash (12g, 0-50% EA/PE) was separated and purified. Compound S-53-b (160 mg, 68%) was successfully obtained as a light yellow solid product. MS(ESI):421.1[M+H] ⁺ .

Step 3: Dissolve compound S-53-b (100mg, 234.81μmol) and intermediate 6 (186.87mg, 662.28μmol) in water (0.5mL) and 1,4-dioxane (4mL), and then Sodium carbonate (116.99 mg, 1.10 mmol), Pd(dppf)Cl ₂ (19.38 mg, 26.49 μmol) were added. The reaction was stirred in the microwave at 120°C for 45 minutes. After the reaction of raw materials was completed, it was cooled to room temperature, diluted with dichloromethane, filtered, and the filtrate was concentrated under reduced pressure. The crude product was prepared by alkaline method to obtain compound S-53 (22.46 mg, 17.76%). ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.13(s,1H),7.29(s,1H),5.04(s,2H),4.53(s,2H),4.08(s,2H),3.62 –3.50(m,1H),3.40(s,3H),3.09(s,2H),2.56(s,3H),2.14(s,3H),1.23(t,J＝7.5Hz,3H),1.08( s,1H),0.54(s,1H),0.37(d,J=6.3Hz,2H),0.22(d,J=5.7Hz,1H).MS(ESI):573.2[M+H] ⁺ .

The compounds of the following examples were synthesized with reference to the preparation method of compound S-53.

Preparation of Example 58 Compound S-58

Step 1: Compound S-47-a (200mg, 0.51mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-di Oxaborolane (104 mg, 0.61 mmol) was dissolved in dioxane (10 mL) and water (1 mL), then [1,1'-bis(diphenylphosphino)ferrocene] dichloride was added Palladium dichloromethane complex (42mg, 0.05mmol) and potassium carbonate (142mg, 1.02mmol), and the reaction solution was stirred at 90°C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, the filtrate was extracted three times with ethyl acetate and water, the organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound S- 58-a (110 mg, colorless oil), yield: 54.1%. MS (ESI): 397.0 [M+H] ⁺ .

Step 2: Compound S-58-a (80 mg, 0.20 mmol) and N-methylmorpholine-N-oxide (24 mg, 0.20 mmol) were dissolved in tetrahydrofuran (8 mL) and water (8 mL), then osmium was added Potassium acid (3mg, 0.008mmol). The reaction solution was stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was quenched with saturated sodium sulfite solution, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparation to obtain compound S-58 (6.48 mg, white solid), yield: 7.4%. MS(ESI):431.1[M+H] ⁺ . ¹ H-NMR(400MHz,DMSO-d ₆ )δ12.19(s,1H),7.79(s,1H),7.43(s,1H),4.74( s,2H),4.62(d,J=4.6Hz,1H),3.62(d,J=5.6Hz,3H),2.61(s,3H),2.16(s,3H),1.50(s,3H), 1.31 (d, J = 6.8Hz, 3H), 1.16 (s, 1H), 0.60 (s, 1H), 0.43 (d, J = 6.0Hz, 2H), 0.26 (s, 1H).

Preparation of Example 59 Compound S-59

Step 1: Dissolve compound S-47-a (200mg, 0.51mmol) in acetonitrile (10mL), then add trimethylchlorosilane (56mg, 0.51mmol) and sodium iodide (231mg, 1.53mmol), the reaction solution 80°C under nitrogen protection Stir for 2 hours. The reaction solution was extracted twice with ethyl acetate and water, the organic phases were combined, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound S-59-a (100 mg, colorless oil) , Yield: 40.4%. MS (ESI): 483.0 [M+H] ⁺ .

Step 2: Compound S-59-a (250mg, 0.51mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.0g, 15.5mmol) were dissolved in N,N-dimethyl Formamide (50 mL), then added cuprous iodide (3.0 g, 15.5 mmol) and tris[dibenzylideneacetone]dipalladium (96 mg, 0.10 mmol). The reaction solution was directly stirred at 80° C. for 0.5 hours under the protection of nitrogen. Filtrate, extract the filtrate with ethyl acetate and water three times, combine the organic phases, backwash with water three times, then backwash once with saturated brine, dry on anhydrous sodium sulfate, filter, concentrate the filtrate and obtain compound S- 59 (3.45 mg, white solid), yield: 1.5%. MS(ESI):483.0[M+H] ^{+ .1} H-NMR(400MHz,DMSO-d ₆ )δ12.32(s,1H),8.16(s,1H),4.70(d,J＝21.1Hz, 2H),3.69–3.50(m,1H),2.66(d,J＝8.4Hz,3H),2.18(s,3H),1.29(d,J＝6.8Hz,4H),1.18–1.08(m,1H ), 0.57 (d, J=5.8Hz, 1H), 0.42 (dd, J=12.9, 6.2Hz, 2H), 0.26 (d, J=5.4Hz, 1H).

The preparation of embodiment 60 compound S-60

Step 1: Intermediate 2 (500 mg, 1.38 mmol) and pinacol isopropenylboronate (243.97 mg, 1.45 mmol) were dissolved in dioxane (6 mL) and water (2 mL). Then 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (101.17 mg, 0.14 mmol) and sodium carbonate (293.11 mg, 2.77 mmol) were added thereto. The reaction was stirred under microwave conditions at 120°C for 45 minutes. The solvent was spin-dried under reduced pressure, and the resulting crude product was purified by Combiflash column separation (0-80% EA/PE) to obtain compound S-60-a (365 mg, white solid), yield: 95.72%. MS (ESI): 276.1 [M+H] ⁺ .

Step 2: Dissolve compound S-60-a (240mg, 0.87mmol) and 2-acetamido-4-methylthiazole (203.91mg, 1.31mmol) in DMF (8mL), then cesium carbonate (567.11mg, 1.74 mmol), palladium acetate (58.62 mg, 0.26 mmol) and tri-tert-butylphosphine tetrafluoroborate (75.75 mg, 261.08 μmol) were added thereto. The reaction was stirred at 100°C under argon for 2 hours. The solvent was spin-dried under reduced pressure, and the resulting crude product was purified by Combiflash column separation (0-100% EA/PE) to obtain compound S-60-b (20 mg, yellow solid), yield: 392.97%. MS (ESI): 396.0 [M+H] ⁺ .

Step 3: Compound S-60-b (130mg, 0.33mmol) was dissolved in tetrahydrofuran (6mL) and water (3mL), then potassium osmate dihydrate (1.21mg, 3.29μmol) and N-methylmorpholine The oxide (46.20 mg, 0.39 mmol) was added. The reaction was stirred at 20°C for 20 hours. Saturated sodium sulfite solution was added to the reaction solution, the solvent was spin-dried under reduced pressure, and the obtained crude product was subjected to preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH ₄ HCO ₃ H ₂ O; wavelength: 254/214nm; gradient: 0%-60% acetonitrile) Purify the obtained crude product to obtain the target compound S-60 (22.22 mg), yield: 15.70%. MS (ESI): 430.2 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.16(s,1H), 7.59(s,1H), 7.47(s,1H), 7.32(s,1H), 4.76-4.66(m,3H) , 3.64-3.59(m,3H), 2.40(s,3H), 2.16(s,3H), 1.50(s,3H), 1.32-1.29(m,3H), 1.16-1.12(m,1H), 0.60 -0.58(m,1H), 0.45-0.40(m,2H), 0.27-0.24(m,1H).

The preparation of embodiment 61 compound S-61

Step 1: Intermediate 5 (5 g, 18.44 mmol), Intermediate 6 (9.366 g, 33.19 mmol), anhydrous sodium carbonate (3.9 g, 36.88 mmol) were dissolved in 1,4-dioxane (50 mL) , replaced by argon. Then Pd(dppf)Cl ₂ (675mg, 0.922mmol) was added, replaced by argon, and stirred at 100°C for 2 hours under the protection of argon. A large amount of yellow solid was obviously precipitated. Send LCMS to detect that the reaction is complete. The reaction solution was cooled to room temperature. The reaction solution was filtered, the filter cake was drained, a small amount of dichloromethane (15 mL) was added to rinse the filter cake, and the filter cake was dried to obtain S-47-a (4.1 g, light yellow solid), yield: 56.88%. MS (ESI): 391.1 [M+H] ⁺ .

Step 2: Dissolve S-47-a (2.2g, 5.63mmol) in N,N-dimethylformamide (20ml), add triethylamine (1.5g, 14.2mmol), bis(triphenylphosphine ) palladium dichloride (360mg, 0.5mmol), tributyl (1-ethoxyethylene) tin (2.4g, 6.8mmol), strictly replace the argon, and react with stirring at 100°C for 16 hours. Product formation was monitored by LCMS. The reaction solution was cooled to room temperature. Add ethyl acetate (30mL) to dilute, wash with water (20ml x 3), and saturated brine (20mL x 2), separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Add an appropriate amount of dichloromethane to dissolve the crude product (about three times the volume of the crude product), slowly add petroleum ether (about five times the volume of dichloromethane) under stirring, until a large amount of light yellow solid precipitates, and continue stirring for 30 minutes. After filtering, the filter cake was rinsed with a mixed solvent of DCM:PE=1:6 (10ml x 3), and the filter cake was dried to obtain compound S-47-b (2g, light yellow solid powder). MS(ESI):427.2[M+H] ⁺ . ¹ H-NMR(400MHz,DMSO-d ₆ )δ12.20(s,1H),7.85(s,1H),4.60(s,2H),4.52( d,J=3.4Hz,2H),3.93(dd,J=13.6,6.7Hz,2H),3.65–3.49(m,1H),2.61(s,3H),2.16(s,3H),1.29–1.26 (m, 3H), 1.12 (s, 1H), 0.56 (s, 1H), 0.39 (d, J=6.6Hz, 2H), 0.24 (d, J=5.8Hz, 1H).

Step 3: Dissolve compound S-47-b (2g, 4.7mmol) in acetone (50ml), put in an ice-water bath, add hydrochloric acid (8ml, 2mol/L), protect with argon, and stir at 0°C for 1 hour. Product formation was monitored by LCMS. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (100mL) containing ice, extracted with dichloromethane (100mL x 3), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound S- 47-c (1.5 g, yellow solid, purity: 94.9%). MS (ESI): 399.1 [M+H] ⁺ .

Step 4: Dissolve compound S-47-c (300mg, 0.753mmol), 2-methylpropane-2-sulfonamide (547mg, 4.52mmol) in tetrahydrofuran (20mL), then add tetraethyl titanate (515mg , 2.26mmol), argon replacement, under the protection of argon, stirred and reacted at 70°C for 16 hours. LCMS detection, the reaction is complete. After the reaction solution was cooled, water (100 mL) and dichloromethane (200 mL) were added, stirred for 5 minutes, filtered, and the filter residue was washed with dichloromethane (100 mL×3). The collected filtrate was separated with a separatory funnel, and the organic phase was washed with 100 mL of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Spin dry and purify by normal phase column to obtain compound S-61-a (300 mg, purity: 93.32%). MS (ESI): 502.2 [M+H] ⁺ .

Step 5: Compound S-61-a (300 mg, 0.598 mmol) was dissolved in dichloromethane (20 ml), replaced with argon, and protected by argon. The reaction system was lowered to -48°C, and methylmagnesium bromide (1M, 2 mL) was slowly added dropwise. After the addition, it was returned to room temperature, and the reaction was stirred for 4 hours. LCMS detection, the reaction was successful. The reaction solution was poured into ice water (50 mL), extracted with dichloromethane (100 mL×3), and the organic phase collected by liquid separation was washed with saturated aqueous sodium chloride solution (50 mL), and dried over anhydrous sodium sulfate. Spin to dryness and purify by normal phase column to obtain compound S-61-b (212mg). ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.29(s,1H),9.00(s,2H),7.96(s,1H),4.80(s,2H),3.64(dd,J=9.0, 6.9Hz, 1H), 2.63(s, 3H), 2.18(s, 3H), 1.77(d, J=1.6Hz, 6H), 1.32(d, J=6.8Hz, 3H), 1.17(dd, J= 4.2, 2.6Hz, 1H), 0.65–0.58(m, 1H), 0.46–0.39(m, 2H), 0.30–0.24(m, 1H).

Step 6: Dissolve compound S-61-b (212mg, 0.409mmol) in 1,4-dioxane (15ml) under argon protection, add hydrochloric acid-1,4-dioxane (1mL), The reaction was stirred for 10 minutes, and the reaction was completed. Pour the reaction solution into 20mL water , extracted with dichloromethane/methanol mixed solution (volume ratio 10:1) (30mL×8). The organic phase was dried over anhydrous sodium sulfate. Concentrate under reduced pressure and purify by preparative column to obtain compound S-61 (11.65 mg, light yellow solid), yield: 6.88%. ¹ H-NMR (400MHz,DMSO-d ₆ )δ8.36(s,1H),7.82(s,1H),4.70(s,2H),3.66–3.62(m,1H),2.62(s,3H) ,2.16(s,3H),1.59(d,J=1.2Hz,6H),1.30(d,J=6.8Hz,3H),1.15(dt,J=12.3,5.9Hz,1H),0.63–0.56( m, 1H), 0.46–0.38 (m, 2H), 0.27 (dd, J=9.5, 4.4Hz, 1H).

The preparation of embodiment 62 compound S-62

Step 1: Dissolve compound S-19-b (800mg, 2.88mmolq), 2-methylpropane-2-sulfonamide (2.094g, 17.28mmol) in tetrahydrofuran (30mL), and then add tetraethyl titanate ( 1.970g, 8.64mmol), replaced with argon, under the protection of argon, stirred and reacted at 70°C for 16 hours. Sent to LCMS for detection, the reaction was complete. After the reaction solution was cooled, water (100 mL) and dichloromethane (200 mL) were added, stirred for 5 minutes, filtered, and the filter residue was washed with dichloromethane (100 mL×3). Combine the filtrates, separate the filtrates with a separatory funnel, wash the organic phase with saturated aqueous sodium chloride solution, and dry over anhydrous sodium sulfate. After spin-drying and column purification, compound S-62-a (800 mg, purity: 83.43%) was obtained, yield: 60.83%. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ7.81(s, 1H), 7.37(s, 1H), 4.58(d, J=10.3Hz, 2H), 4.09(q, J=5.3Hz, 1H ),2.69(s,2H),2.47(s,1H),1.31–1.09(m,13H),0.61–0.53(m,1H),0.44–0.34(m,2H),0.23(d,J＝5.3 Hz, 1H).

Step 2: Compound S-62-a (600mg, 1.31mmol, purity: 83.43%), 4-methylthiazol-2-ylacetamide (307mg, 1.97mmol), cesium carbonate (854mg, 2.62mmol), ( t-Bu) ₃ PHBF ₄ (152mg, 0.524mmol) was dissolved in DMF (10ml), argon was replaced, and palladium (II) acetate (117mg, 0.524mmol) was added, argon was replaced, under the protection of argon, 100 The reaction was stirred at °C for 10 hours. Sent to LCMS for detection, the reaction was complete. After the reaction solution is cooled, add water (100mL) and dichloromethane (100mL), stir and then use a separatory funnel to separate the liquid. The aqueous phase is re-extracted with dichloromethane (100mL×2). Wash with aqueous sodium chloride solution, and dry the organic phase over anhydrous sodium sulfate. Spinning to dryness and column purification gave compound S-62-b (550 mg, purity: 65.90%), yield: 22.59%.

Step 3: Compound S-62-b (550 mg, 0.724 mmol, purity: 65.90%) was dissolved in dichloromethane (200 ml), replaced with argon, and protected by argon. The reaction system was lowered to -48°C, and methylmagnesium bromide (1M, 2mL) was slowly added dropwise, and returned to room temperature after the addition, and stirred for 4 hours. Sent to LCMS for detection, the reaction was successful. The reaction solution was poured into ice water (50 mL), extracted with dichloromethane (100 mL×3), the organic phase collected by liquid separation was washed with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. After spin-drying and column purification, compound S-62-c (180 mg, purity: 85.29%) was obtained, yield: 41.04%.

Step 4: Dissolve compound S-62-c (180mg, 0.297mmol, purity: 85.29%) in 1,4-dioxane (15ml), protect with argon, add hydrochloric acid-1,4-dioxane ring (1 mL), stirred for 10 minutes, and the reaction was complete. The reaction solution was poured into water (20 mL), and extracted with dichloromethane/methanol mixed solution (volume ratio 10:1) (30 mL×8). The organic phase was dried over anhydrous sodium sulfate. Spin-dried and sent to preparation and purification to obtain compound S-62 (15.60 mg, white solid), yield: 12.73%. ¹ H-NMR (400MHz,DMSO-d ₆ )δ8.37(s,1H),7.67(s,1H),7.49(s,1H),4.68(s,2H),3.66(d,J＝9.2Hz ,1H),2.42(s,3H),2.16(s,3H),1.64(s,6H),1.32(d,J＝6.8Hz,3H),1.18–1.13(m,1H),0.63–0.58( m, 1H), 0.41 (dd, J = 8.7, 5.3 Hz, 2H), 0.26 (dd, J = 10.5, 5.1 Hz, 1H).

The preparation of embodiment 63 compound S-63

Compound S-47-a (578mg, 1.48mmol) and Intermediate 15 (15, 200mg, 1.48mmol) were dissolved in toluene (20ml), then tris(dibenzylideneacetone)dipalladium (136mg, 0.014mmol) was added ), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (139mg, 0.29mmol) and cesium carbonate (966mg, 2.96mmol). The reaction solution was reacted at 110° C. for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, extracted three times with ethyl acetate and water, the organic phases were combined, backwashed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was prepared and purified to obtain compound S -63 (6.61 mg, white solid), yield: 1%. MS(ESI):490.2[M+H] ⁺ ; ¹ H-NMR(400MHz,DMSO-d ₆ )δ12.25(s,1H),8.44(d,J=6.0Hz,1H),7.80(s, 1H), 6.69(d, J=6.1Hz, 1H), 4.65(s, 2H), 3.91–3.85(m, 2H), 3.50(d, J=6.8Hz, 3H), 3.12(t, J=6.4 Hz,2H),2.58(s,3H),2.15(s,3H),1.26(d,J＝6.8Hz,3H),1.14–1.07(m,1H),0.59–0.53(m,1H),0.43 –0.32(m,2H),0.21(td,J=9.0,4.7Hz,1H).

The preparation of embodiment 64 compound S-64

Put compound S-47-c (50mg, 0.125mmol, 1eq) in a 25ml clean three-neck flask, add 2mL of tetrahydrofuran, cool down to 0°C, slowly add sodium borohydride (14mg, 0.376mmol, 3eq), stir at 0°C 1 hour. The reaction of the raw material was detected by LCMS to be complete. Add the reaction solution to ice water, add dichloromethane (10mL×3) to extract and separate the layers, combine the organic phases, wash with saturated brine, separate the layers, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, Purified by column chromatography with eluent (petroleum ether/ethyl acetate=7:1) to obtain compound S-64 (20 mg, white solid). Yield: 40%. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.02(s,1H),7.79(s,1H),6.01(t,J=7.5Hz,1H),5.22(m,1H),4.70(s, 2H), 3.60(dq, J=13.7, 6.8Hz, 1H), 2.61(s, 3H), 2.16(s, 3H), 1.46(d, J=6.6Hz, 3H), 1.30(d, J=6.8 Hz, 3H), 1.14(dt, J=12.6, 6.4Hz, 1H), 0.59(m, 1H), 0.41(m, 2H), 0.26(m, 1H).

Test Example 1: Inhibition of Akt S473 Phosphorylation Level in Raw264.7 Cells

This experiment was detected by ELISA method.

1. Raw264.7 cell treatment

Raw264.7 cells (PI3Kγ) in the logarithmic growth phase were seeded in a 96-well plate (Falcon353072) at an appropriate concentration of 90 μL, cultured at 37 ° C, 5% CO ₂ , and after the cells adhered overnight, 10 μL of different DMSO solution of the test compound at a concentration of 37°C (only DMSO was added to the control well), cultured at 37°C under 5% CO ₂ conditions, and after 2 hours, 5 μL of mC5a in DMEM serum-free medium solution (R&D 2150-C5) was added (blank well Only add medium), incubate at room temperature for 5 minutes, remove the medium, add 100 μL 1X cell lysate (CST 9806S) (CST 5872S), shake at 800 rpm for 1 minute, store at -80°C until use.

2. Detection steps

The Capture solution was prepared according to the phosphorylated Akt S473 ELISA detection kit (R&D DYC887BE), 100 μL per well was added to a high binding 96-well plate (Costar 42592), and incubated overnight at room temperature. Wash with 300 μL PBST three times, add blocking solution (PBS solution containing 1% (w/v) BSA) (Genview FA016-100G), incubate at room temperature for 2 Add 90 μL cell samples, incubate at room temperature for 2 hours, wash three times with 300 μL PBST; add 100 μL anti-pAkt S473 dilution, incubate at room temperature for 2 hours, wash three times with 300 μL PBST; add 100 μL Streptavidin-HRP (horseradish over Oxidase-labeled streptavidin) diluent, incubate at room temperature for 40 minutes, wash three times with 300 μL PBST; add 100 μL ELISA reaction substrate TMB (tetramethylbenzidine), incubate at room temperature for 20 minutes, add 50 μL 2N H ₂ SO ₄ solution terminated the reaction. The OD value was read on an Infinite M1000 fluorescent microplate reader (Tecan), and the absorption wavelengths were 450 nm and 570 nm.

3. Data Analysis

Add DMSO without mC5a as the background, add DMSO and mC5a as the blank control.

Inhibition%＝[1-(Total mean(Inhibitor)-total mean(background))/(Total mean(blank)-total mean(background))]×100％

2.4 The calculated inhibition rate was calculated with XLFIT 5.0 software to calculate the IC ₅₀ value, and the test results are shown in Table 1.

Table 1: IC ₅₀ values of compounds for the inhibition of RAW264.7 cell activity

Test Example 2: Inhibition of Akt S473 Phosphorylation Levels in T47D and PC3 Cells

This experiment was detected by Incell ELISA method.

1. Treatment of T47D and PC3 cells

T47D (PI3Kα) and PC3 (PI3Kβ) cells in the logarithmic growth phase were planted in a 96-well plate (Falcon 353072) at an appropriate concentration of 90 μL, and cultured at 37°C and 5% CO2. After the cells adhered overnight, Add 10 μL of DMSO solutions of test compounds at different concentrations (only DMSO is added to the blank, and 10 μM YZJ-0673 is added to the background), and cultured at 37°C and 5% CO2. After 2 hours, add 100 μL of 4% paraformaldehyde (Biosharp BL539A) After incubating at room temperature for 45 minutes, take it out, add 100 μL of 0.1% Triton X-100 solution, and continue to incubate for 30 minutes.

2. Detection steps

Take out the Triton X-100 solution, wash twice with 200 μL PBS (300 rpm, 1 minute), add blocking solution (1% BSA in PBS solution) (Genview FA016-100G), incubate at room temperature for 2 hours, take it out, and wash once with PBS (300 rpm, 1 minute). minutes), add 30 μL Ser473-p-Akt antibody 0.1% BSA dilution (cell signaling 4060L), and incubate overnight at 4°C. Take out the Ser473-p-Akt antibody, wash twice with PBS (300rpm, 1 minute), add 100 μL of HRP anti-rabbit IgG 0.1% BSA dilution (CST 7074S), and incubate at room temperature for 1.5 hours. Wash twice with PBS (300rpm, 1 minute), add 100μL ELISA reaction substrate TMB, incubate at room temperature for 0.5 hours, add 50μL 2N sulfuric acid to terminate the reaction, incubate at room temperature for 20min, and read on Infinite M1000 fluorescence microplate reader (Tecan) OD value, the absorption wavelength is 450nm.

Take out the TMB solution, wash with PBS three times (300rpm, 1 minute), add 100 μL 0.1% Janus aqueous solution (Abcam ab111622), incubate at room temperature for 10 minutes, take out the Janus solution, wash 5 times with double water (300rpm, 1 minute), add 100 μL 1.5M Hydrochloric acid, incubate at room temperature for 10 minutes, read the OD value on an Infinite M1000 fluorescence microplate reader (Tecan), and the absorption wavelength is 595 nm.

3. Data Analysis

Add 10 μM YZJ-0673 as the background, and add DMSO as the blank control. Ratio=OD450/OD595.

Inhibition%=[1-(Ratio(Inhibitor)-Ratio(background))/(Ratio(blank)-Ratio(background))]×100%. The calculated inhibition rate was calculated with XLFIT 5.0 software to calculate the IC ₅₀ value, and the test results are shown in Table 2.

Test Example 3: Inhibition of Akt S473 Phosphorylation Level in Raji Cells

This experiment was detected by ELISA method.

1. Raji cell treatment

Take Raji cells (PI3Kδ) in the logarithmic growth phase, plant them in 96-well V-plates (Costar 3894) at an appropriate concentration of 45 μL, add 5 μL of DMSO solutions of test compounds at different concentrations (control wells only add DMSO), and incubate at 37 °C. After 2 hours, add 10 μL of anti-Human IgM 1640 serum-free medium solution (Sigma I0759-5X1MG) (blank wells only add medium), incubate at room temperature for 10 minutes, remove the medium, Add 60 μL 2X cell lysate (CST 9806S) (CST 5872S), shake at 800 rpm for 1 minute, and store at -80°C until use.

2. Detection steps

The Capture solution was prepared according to the phosphorylated Akt S473 ELISA detection kit (R&D DYC887BE), 100 μL per well was added to a high binding 96-well plate (Costar 42592), and incubated overnight at room temperature. Wash three times with 300 μL PBST, add blocking solution (1% BSA in PBS) (Genview FA016-100G), incubate at room temperature for 2 hours, wash three times with 300 μL PBST; add 90 μL cell samples, incubate at room temperature for 2 hours, wash three times with 300 μL PBST; add 100 μL anti - pAkt S473 dilution, incubate at room temperature for 2 hours, wash three times with 300 μL PBST; add 100 μL Streptavidin-HRP dilution, incubate at room temperature for 40 minutes, wash three times with 300 μL PBST; add 100 μL ELISA reaction substrate TMB, incubate at room temperature for 20 minutes, add 50 μL 2N H ₂ SO ₄ solution to terminate the reaction. The OD value was read on an Infinite M1000 fluorescent microplate reader (Tecan), and the absorption wavelengths were 450 nm and 570 nm.

3. Data Analysis

OD=OD450-OD570. Add DMSO without anti-Human IgM as the background, add DMSO and anti-Human IgM as the blank control. Inhibition%=[1-(OD(Inhibitor)-OD(background))/(OD(blank)-OD(background))]×100%. The calculated inhibition rate was calculated with XLFIT 5.0 software to calculate the IC ₅₀ value, and the test results are shown in Table 2.

Table 2 Compounds inhibit the activity of T47D, PC3 and Raji cells with _IC50 value

Test Example 4: In vivo pharmacokinetic test in mice

The LC/MS/MS method was used to measure the drug concentration in the plasma of mice at different times after intravenous injection and oral gavage administration of the compound of the present application. The existing compound D1 and the compound S-19 and S- 47. Taking S-64 as an example, study the pharmacokinetic behavior of the compound of this application in mice, and evaluate its pharmacokinetic characteristics.

Among them, the structure of compound D1 (CAS No. 2504036-13-7) is shown below, which can be prepared by referring to the existing literature or purchased from the market.

Experimental program:

Experimental animals: healthy adult male ICR mice (weight 25-40g, 12 mice, the mice in the intravenous injection group were free to drink water and food, and the intragastric administration group was fasted overnight, and free to drink water and food after 4 hours of administration), provided by Beijing Vital Provided by River Laboratory Animal Co.LTD;

Administration method and dose: select animals that meet the experimental requirements before administration, and weigh the marks. ICR mouse tail vein administration (2mg/kg, 5% DMSO+30% (10% Solutol HS15) + 65% (20% Captisol, pH 7.4)) and intragastric administration (10mg/kg, 5% DMSO+ 30% (10% Solutol HS15) + 65% (20% Captisol, pH 7.4)).

Blood sample collection: Before collecting blood samples, bind the mice, each administered mouse at the scheduled blood collection time point (intravenous administration: respectively at 0.083, 0.25, 0.5, 1, 2, 4, 7 days after administration) , 24h blood collection, a total of 8 time points; intragastric administration: blood collection at 0.083, 0.25, 0.5, 1, 2, 4, 7, 24h after administration, a total of 8 time points), blood collection through the canthus vein About 100 μL. The whole blood was transferred to a 1.5mL test tube pre-added with K ₂ EDTA (Sigma-ACDRICH, WXBB0768), centrifuged for 6min (8000rpm, 4°C), and the plasma was separated. The whole process was completed within 15min after blood collection. All samples need to be stored in a -20°C freezer until sample analysis.

Analysis method: Plasma samples were analyzed by liquid chromatography-tandem mass spectrometry (model: Triple QuadTM 4000), and the chromatographic column was Waters XBridge-C18 (2.1×50mm, 3.5μm).

Preparation of standard curve samples: Prepare standard curve samples with a linear range of 1.00-3000 ng/mL of the compound to be tested in blank ICR mouse plasma matrix, and prepare low, medium and high concentration quality controls with concentrations of 3, 500, and 2400 ng/mL sample.

Processing of biological samples: thaw the frozen plasma samples on wet ice, and vortex for 5 minutes after the samples are thawed. Take 20 μL of plasma samples, standard curve samples and quality control samples and add them to a 96-well plate, then add 200 μL of acetonitrile protein precipitation containing internal standard dexamethasone (brand: NIFDC, batch number: 6TUC-T4C2, prepared concentration 2000ng/mL), Vortex and mix for 5 minutes, then centrifuge at 3700 rpm, 4°C for 15 minutes, extract the supernatant and centrifuge twice under the same conditions, and finally add 2 μL of the supernatant solution for LC-MS/MS analysis. The test results are shown in Table 3.

Table 3 Pharmacokinetic data of compounds in mice

All documents mentioned in this application are incorporated by reference in this application as if each individual document were individually indicated to be incorporated by reference. In addition, it should be understood that after reading the above teaching content of the application, those skilled in the art can make various changes or modifications to the application, and these equivalent forms also fall within the scope defined by the appended claims of the application.

The technical features of the above-mentioned embodiments can be combined arbitrarily. To make the description concise, all possible combinations of the technical features in the above-mentioned embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, should be considered as within the scope of this specification.

The above-mentioned embodiments only express several implementation modes of the present application, and the description thereof is relatively specific and detailed, but should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the scope of protection of the patent application should be based on the appended claims.

Claims (21)

1. A compound having a structure shown in formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
   

   in,

   Ring A is a 5 or 6 membered heteroaryl ring;

   (R ₀ ) _n means that the hydrogen on the ring A is replaced by n R ₀ , n is 0, 1, 2, 3 or 4; each R ₀ is the same or different, each independently deuterium, halogen, cyano, hydroxyl , carboxyl, C _1-3 alkyl, C _1-3 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, halogenated C _1-3 alkyl, halogenated C _1-3 alkoxy , NR _a1 R _b1 , -N(R _a3 )-C(O)C _1-3 alkyl, -N(R _a3 )-C(O)-deuterated C _1-3 alkyl, -N(R _a3 )-C(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -SO ₂ C _3-6 cycloalkyl, -C(O)NR _a1 R _b1 , -C(O)OC _1-3 alkyl, -OC(O)C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkyl, phenyl or 5 to 6-membered heteroaryl; wherein the 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are each independently unsubstituted or 1, 2 or 3 each independently selected from substituents Substituents of group Q are substituted;

   Z is N or CR _z ; R _z is hydrogen, halogen or C _1-8 alkyl;

   U is N or CH;

   W is cyano, ethynyl, -NHSO ₂ N(CH ₃ ) ₂ , 5 or 6 membered heteroaryl, or the structure shown in formula (Ia), formula (Ib), formula (Ic) or formula (Id) :
   

   R _a and R _b are each independently halogen, C _1-8 alkyl, C _1-8 alkyl substituted by hydroxy, or C _3-6 cycloalkyl;

   R _c is hydroxyl, halogen, C _1-3 alkyl, deuterated C _1-3 alkyl, C _3-6 cycloalkyl, halogenated C _1-3 alkyl or NR _a1 R _b1 ;

   Y is C or N;

   is a 5- or 6-membered heteroaryl ring, or a benzene ring;

   p, q are each independently 0, 1, 2 or 3;

   R _w1 , R _w2 , R _w3 , and R _w4 are each independently hydrogen, cyano, halogen, C _1-3 alkyl, halogenated C _1-3 alkyl, -N(R _a3 )-C(O)C _1-3 alkyl, -SO ₂ C _1-3 alkyl, -C(O)NR _a1 R _b1 or NR _a1 R _b1 ;

   p1, p2, q1, q2 are each independently 1, 2 or 3;

   _R is halogen;

   L ₂₁ and L ₂₂ are each independently -(CR _e2 R _f2 ) _m2 -; m ₂ is 1, 2 or 3;

   _Y2 is NR _g2 or O;

   R _e2 and R _f2 are each independently hydrogen, hydroxyl, oxo, C _1-3 alkyl or -C(O)C _1-3 alkyl;

   R _g2 is hydrogen, C _1-3 alkyl or -C (O) C _1-3 alkyl;

   R ₁ and R ₂ are each independently C _1-8 alkyl, halogenated C _1-8 alkyl or C _3-6 cycloalkyl; the C _3-6 cycloalkyl is unsubstituted or replaced by 1 or 2 substituents independently selected from halogen and C _1-3 alkyl are substituted;

   Substituent group Q is selected from halogen, cyano, hydroxyl, carboxyl, C _1-3 alkyl, C _1-3 alkoxy, C _2-4 alkenyl, C _2-4 alkyne base, halogenated C _1-3 alkyl, halogenated C _1-3 alkoxy, NR _a1 R _b1 , -SO ₂ C _1-3 alkyl, -S(O)C _1-3 alkyl, -C (O)NR _a1 R _b1 , -C(O)OC _1-3 alkyl, -OC(O)C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkyl, phenyl and 5 to 6 membered heteroaryl;

   R _a1 and R _b1 are each independently hydrogen, C _1-3 alkyl or acetyl, or R _a1 and R _b1 together with the connected nitrogen atom form a 4 to 6-membered saturated monoheterocycle; the 4 to 6-membered saturated The single heterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C _1-3 alkyl, C _1-3 alkane Oxygen, C _2-4 alkenyl, C _2-4 alkynyl, halogenated C _1-3 alkyl, halogenated C _1-3 alkoxy, -SO ₂ C _1-3 alkyl, -S(O )C _1-3 alkyl, -C(O)NH ₂ , -C(O)NH(C _1-3 alkyl), -C(O)N(C _1-3 alkyl) ₂ , -C( O) OC _1-3 alkyl, -OC (O) C _1-3 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;

   R _a3 is hydrogen or C _1-8 alkyl.
2. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein W is cyano, ethynyl, -NHSO ₂ N(CH ₃ ) ₂ or selected from the following group 5- or 6-membered heteroaryl: thienyl, furyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4 -Triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4 -oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazine.
3. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the 5 or 6-membered heteroaryl group in the W is selected from one of the following structures:
   
4. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the formula (Ia) is selected from one of the following structures:
   
5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, is a benzene ring or a 5- or 6-membered heteroaryl ring selected from the group consisting of thiophene ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, 1,2, 3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, 1,2,3 -Oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring , pyrimidine ring, pyrazine ring, triazine ring and tetrazine ring.
6. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the formula (Ib) is selected from one of the following structures:
   
7. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the structure shown in formula (Ic) is selected from the following structures:
   
8. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the structure shown in formula (Id) is selected from the following structures:
   
9. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein ring A is selected from the group consisting of 5 or 6 membered heteroaryl rings: thiophene ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, and tetrazine ring.
10. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, in formula (I), For the structure shown in formula (a):
    

    R ₀₁ and R ₀₂ are each independently deuterium, halogen, cyano, hydroxyl, carboxyl, C _1-3 alkyl, C _1-3 alkoxy, C _2-4 alkene Base _, C _2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C _1-3 alkoxy, NR _a1 R _b1 , -N(R _a3 )-C(O)C _1-3 alkyl , -N(R _a3 )-C(O)-deuterated C _1-3 alkyl, -N(R _a3 )-C(O)OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -SO ₂ C _3-6 cycloalkyl, -C(O)NR _a1 R _b1 , -C(O)OC _1-3 alkyl, -OC(O)C _1-3 alkyl, C _3-6 ring Alkyl, C _3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkyl, phenyl or 5 to 6 membered heteroaryl; wherein the 3 to 6 membered heterocycloalkyl, phenyl, 5 to 6 The 6-membered heteroaryl groups are each independently unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from Substituent Group Q.
11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R ₀₁ is halogen, cyano, hydroxyl, carboxyl, C _1-3 alkyl, C _1-3 Alkoxy, halogenated C _1-3 alkyl or halogenated C _1-3 alkoxy; R ₀₂ is -NH-C(O)C _1-3 alkyl, -NH-C(O)-deuterated C _1-3 alkyl or -NH-C(O)OC _1-3 alkyl.
12. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein _R is monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-Dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, monofluorosubstituted cyclopropyl or monofluorosubstituted cyclobutyl; _R2 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, monofluoro-substituted cyclopropyl or monofluoro-substituted cyclobutyl.
13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, in formula (I), Choose from one of the following structures:
    
14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, in formula (I), Choose from one of the following structures:
    
15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein Z is N or CH.
16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound of formula (I) is selected from one of the following structures:
    
    
    
    
    
17. A pharmaceutical composition, comprising the compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.
18. A compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition according to claim 17 in the preparation of treating or preventing diseases related to PI3Kγ activity Or in the medicine of diseases mediated by PI3Kγ activity.
19. The use according to claim 18, wherein the disease related to or mediated by PI3Kγ activity is inflammation, metabolic disease or cancer.
20. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for treating or preventing diseases related to or mediated by PI3Kγ activity, Or according to the pharmaceutical composition described in claim 17.
21. A method for treating or preventing a disease associated with PI3Kγ activity or mediated by PI3Kγ activity, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1-16, or its pharmaceutically An acceptable salt, or a stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition according to claim 17.