A pi3k inhibitor and methods of making and using the same

Abstract

This invention provides a PI3K inhibitor, its preparation method, and its uses, belonging to the field of chemical pharmaceuticals. The PI3K inhibitor of this invention is a compound as shown in Formula I, or a salt thereof, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a prodrug thereof. The compounds prepared by this invention can be used to prepare selective PI3K inhibitors, as well as drugs for the prevention and / or treatment of PI3K-related diseases, such as drugs for the prevention and / or treatment of cancer. This invention provides a new option for clinical cancer treatment and has promising application prospects.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceuticals, specifically relating to a PI3K inhibitor, its preparation method, and its uses. Background Technology

[0002] Phosphatidylinositol 3-kinase (PI3K) is an intracellular phosphatidylinositol kinase and an important intracellular signal transduction molecule. PI3K mainly participates in regulating physiological processes such as cell proliferation, apoptosis, and differentiation, specifically phosphorylating the 3-hydroxyl group on the phosphatidylinositol ring. As a major downstream effector of receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR), PI3K transduces signals from various growth factors and cytokines to intracellular messengers by generating phospholipids that can activate serine and threonine protein kinases (Akt) and other downstream effectors. The signaling pathway composed of PI3K and its downstream molecule Akt can activate downstream signaling molecules and is closely related to the occurrence and development of tumors such as breast cancer, gastric cancer, colon cancer, rectal cancer, ovarian cancer, and prostate cancer. Studies have shown that excessive activation of PI3K is associated with various proliferative, inflammatory, or cardiovascular diseases, including cancer, inflammation, and cardiovascular diseases.

[0003] PI3K has been proven to be a promising therapeutic target. Using selective PI3K inhibitors as anti-tumor drugs can increase treatment selectivity and reduce adverse reactions and toxicities. Currently, the number and types of selective PI3K inhibitors reported are still quite limited, and their efficacy needs further improvement. Researching a highly effective PI3K inhibitor with fewer adverse reactions and toxicities is of great significance for the clinical treatment of cancer. Summary of the Invention

[0004] The purpose of this invention is to provide a PI3K inhibitor, its preparation method, and its uses.

[0005] This invention provides compounds of Formula I, or salts thereof, or stereoisomers thereof, or solvates thereof, or hydrates thereof, or prodrugs thereof, or deuterated compounds thereof:

[0006]

[0007] in,

[0008] R1 represents a substituent on ring A, and the number of substituents is m; each R1 is independently selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, hydroxy, carboxyl, -NHR groups. 15 , -NHR8, -C(O)NHR8, -C(O)NHR 15, substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, substituted or unsubstituted 4- to 10-membered heterocycloalkyl, substituted or unsubstituted 5- to 10-membered heteroaryl; m is 0, 1, 2 or 3;

[0009] R 15 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, hydroxyl, carboxyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 4-10 membered heterocycloalkyl, and substituted or unsubstituted 5-10 membered heteroaryl.

[0010] Y1 and Y2 are independently selected from none, CR4R5, and NR4, respectively;

[0011] R4 and R5 are independently selected from hydrogen and C1-C8 alkyl groups; or R4 and R5 form a ketone group with carbon.

[0012] R3 is selected from hydrogen, 6-10 aryl groups substituted with n R6 groups, 5-10 heteroaryl groups substituted with n R6 groups, 4-10 heterocyclic alkyl groups substituted with n R6 groups, or...

[0013] Each R6 is independently selected from substituted or unsubstituted C1–C8 alkyl, C1–C8 alkoxy, halogen, cyano, nitro, amino, hydroxyl, -C(O)OR. 81 -C(O)R 81 , Acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boric acid group, -NHR8 or -C(O)NHR8; or two R6 groups on the same atom to form =O; n is 0, 1, 2, 3 or 4;

[0014] R 81 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0015] R8 is selected from substituted or unsubstituted C1-C8 alkyl, hydroxyl,

[0016] R7 and R9 are independently selected from C1-C8 alkyl and 6-10 aryl groups, respectively;

[0017] X1 is selected from C or N; when X1 is selected from C, ring A is a benzene ring; when X1 is selected from N, ring A is dihydropyridine.

[0018] X2 is selected from C or N; when X2 is selected from C, the bond between X2 and O is a double bond, and the bond between X2 and X3 is a single bond; when X2 is selected from N, the bond between X2 and O is a single bond, and the bond between X2 and X3 is a double bond, and N carries a positive charge and O carries a negative charge.

[0019] X3 is selected from N and CR. 10 or NR 10 ;

[0020] X4 is selected from C;

[0021] X5 is selected from O, N, NR 10 or CR 10 ;

[0022] R 10 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups;

[0023] When X3 is selected from CR 10 When X5 is selected from O, the bond between X3 and X4 is a double bond, the bond between X4 and X5 is a single bond, and the bond between X5 and a carbon atom is a single bond.

[0024] When X3 is selected from NR 10 When X5 is selected from N, the bond between X3 and X4 is a single bond, the bond between X4 and X5 is a double bond, and the bond between X5 and a carbon atom is a single bond.

[0025] When X3 is selected from CR 10 X5 is selected from CR 10 In this case, the bond between X3 and X4 is a single bond, the bond between X4 and X5 is a double bond, and the bond between X5 and the carbon atom is a single bond; or the bond between X3 and X4 is a double bond, the bond between X4 and X5 is a single bond, and the bond between X5 and the carbon atom is a double bond.

[0026] When X3 is selected from CR 10 When X5 is selected from N, the bond between X3 and X4 is a double bond, the bond between X4 and X5 is a single bond, and the bond between X5 and a carbon atom is a double bond.

[0027] When X3 is selected from N and X5 is selected from NR 10 At that time, the bond between X3 and X4 is a double bond, the bond between X4 and X5 is a single bond, and the bond between X5 and the carbon atom is a single bond;

[0028] R2 is selected from substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 3-8 membered cycloalkyl groups, substituted or unsubstituted 6-10 membered aryl groups, substituted or unsubstituted 4-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, and -NR. 11 R 12 , -SR 11 ;

[0029] R 11 R 12 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0030] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, 4- to 10-membered heterocyclic alkyl groups, or -NR. 13 R 14 ;

[0031] R 13 R 14 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0032] The substituents of the cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups are selected from halogens, hydroxyl groups, amino groups, carboxyl groups, nitro groups, cyano groups, and -C(O)NR groups. 16 R 17 -C(O)OR 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy groups;

[0033] R 16 R 17 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxyl groups;

[0034] The heteroaryl or heterocyclic alkyl group has a heteroatom that is N, O, or S, and the number of heteroatoms is 1, 2, or 3.

[0035] Furthermore,

[0036] The aryl group of R1 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, or pyrroleyl.

[0037] R 15 The aryl group is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, or pyrroleyl.

[0038] The aryl group of R3 is selected from phenyl, the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl or pyrrolithyl, and the heterocyclic alkyl group is selected from piperidinyl;

[0039] The aryl groups in R7 and R9 are selected from phenyl or naphthyl groups;

[0040] The aryl group of R2 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindolinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, furanyl, pyrazolyl, imidazoleyl, pyrroleyl, isoxazolyl, or...

[0041] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR.13 R 14 ;

[0042] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0043] Furthermore, the compound is as shown in Formula II:

[0044]

[0045] in,

[0046] R1 represents a substituent on the benzene ring, and the number of substituents is m; each R1 is independently selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, hydroxy, carboxyl, -NHR groups. 15 , -NHR8, -C(O)NHR8, -C(O)NHR 15 , substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, substituted or unsubstituted 4- to 10-membered heterocycloalkyl, substituted or unsubstituted 5- to 10-membered heteroaryl; m is 0, 1, 2 or 3;

[0047] R 15 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, hydroxyl, carboxyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 4-10 membered heterocycloalkyl, and substituted or unsubstituted 5-10 membered heteroaryl.

[0048] Y1 and Y2 are independently selected from none, CR4R5, and NR4, respectively;

[0049] R4 and R5 are independently selected from hydrogen and C1-C8 alkyl groups; or R4 and R5 form a ketone group with carbon.

[0050] R3 is selected from 6-10 aryl groups substituted with n R6 groups, 5-10 heteroaryl groups substituted with n R6 groups, 4-10 heterocyclic alkyl groups substituted with n R6 groups, or...

[0051] Each R6 is independently selected from substituted or unsubstituted C1–C8 alkyl, C1–C8 alkoxy, halogen, cyano, nitro, amino, hydroxyl, -C(O)OR. 81 -C(O)R 81 , Acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boric acid group, -NHR8 or -C(O)NHR8; or two R6 groups on the same atom to form =O; n is 0, 1, 2, 3 or 4;

[0052] R 81 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0053] R8 is selected from substituted or unsubstituted C1-C8 alkyl, hydroxyl,

[0054] R7 and R9 are independently selected from C1-C8 alkyl and 6-10 aryl groups, respectively;

[0055] R2 is selected from substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 3-8 membered cycloalkyl groups, substituted or unsubstituted 6-10 membered aryl groups, substituted or unsubstituted 4-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, and -NR. 11 R 12 , -SR 11 ;

[0056] When R6 is selected from a carboxyl group, R2 is not selected from substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl.

[0057] R 11 R 12 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0058] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, 4- to 10-membered heterocyclic alkyl groups, or -NR. 13 R 14 ;

[0059] R 13 R 14 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0060] The substituents of the cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups are selected from halogens, hydroxyl groups, amino groups, carboxyl groups, nitro groups, cyano groups, and -C(O)NR groups. 16 R 17 -C(O)OR 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy groups;

[0061] R 16 R 17 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxyl groups;

[0062] The heteroaryl or heterocyclic alkyl group has a heteroatom that is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0063] Preferably,

[0064] The aryl group of R1 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, or pyrroleyl.

[0065] R 15 The aryl group is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, or pyrroleyl.

[0066] The aryl group of R3 is selected from phenyl, the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl or pyrrolithyl, and the heterocyclic alkyl group is selected from piperidinyl;

[0067] The aryl groups in R7 and R9 are selected from phenyl or naphthyl groups;

[0068] The aryl group of R2 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindolinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, furanyl, pyrazolyl, imidazoleyl, pyrroleyl, isoxazolyl, or...

[0069] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0070] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0071] Furthermore, the compound is as shown in Formula II-1:

[0072]

[0073] in,

[0074] R1 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, hydroxy, carboxyl, -NHR 15 , -NHR8, -C(O)NHR8, -C(O)NHR 15 Substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, substituted or unsubstituted 4- to 10-membered heterocycloalkyl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0075] R 15Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, hydroxyl, carboxyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 4-10 membered heterocycloalkyl, and substituted or unsubstituted 5-10 membered heteroaryl.

[0076] R3 is selected from 6-10 aryl groups substituted with n R6 groups, 5-10 heteroaryl groups substituted with n R6 groups, 4-10 heterocyclic alkyl groups substituted with n R6 groups, or...

[0077] Each R6 is independently selected from substituted or unsubstituted C1–C8 alkyl, C1–C8 alkoxy, halogen, cyano, nitro, amino, hydroxyl, -C(O)OR. 81 -C(O)R 81 , Acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boric acid group, -NHR8 or -C(O)NHR8; or two R6 groups on the same atom to form =O; n is 0, 1, 2, 3 or 4;

[0078] R 81 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0079] R8 is selected from substituted or unsubstituted C1-C8 alkyl, hydroxyl,

[0080] R7 and R9 are independently selected from C1-C8 alkyl and 6-10 aryl groups, respectively;

[0081] R2 is selected from substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 3-8 membered cycloalkyl groups, substituted or unsubstituted 6-10 membered aryl groups, substituted or unsubstituted 4-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, and -NR. 11 R 12 , -SR 11 ;

[0082] When R6 is selected from a carboxyl group, R2 is not selected from substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl.

[0083] R 11 R 12 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0084] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, 4- to 10-membered heterocyclic alkyl groups, or -NR. 13 R 14 ;

[0085] R 13 R 14 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0086] The substituents of the cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups are selected from halogens, hydroxyl groups, amino groups, carboxyl groups, nitro groups, cyano groups, and -C(O)NR groups. 16 R 17 -C(O)OR 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy groups;

[0087] R 16 R 17 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxyl groups;

[0088] The heteroaryl or heterocyclic alkyl group has a heteroatom that is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0089] Preferably,

[0090] The aryl group of R1 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, or pyrroleyl.

[0091] R 15 The aryl group is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, or pyrroleyl.

[0092] The aryl group of R3 is selected from phenyl, the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl or pyrrolithyl, and the heterocyclic alkyl group is selected from piperidinyl;

[0093] The aryl groups in R7 and R9 are selected from phenyl or naphthyl groups;

[0094] The aryl group of R2 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindolinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, furanyl, pyrazolyl, imidazoleyl, pyrroleyl, isoxazolyl, or...

[0095] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0096] R 13 R14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0097] Furthermore, the compound is as shown in Formula II-2:

[0098]

[0099] in,

[0100] Z1 is selected from CH or N;

[0101] R1 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, hydroxy, carboxyl, -NHR 15 , -NHR8, -C(O)NHR8, -C(O)NHR 15 Substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, substituted or unsubstituted 4- to 10-membered heterocycloalkyl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0102] R 15 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, hydroxyl, carboxyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 4-10 membered heterocycloalkyl, and substituted or unsubstituted 5-10 membered heteroaryl.

[0103] n is 0, 1, 2, 3 or 4;

[0104] Each R6 is independently selected from substituted or unsubstituted C1–C8 alkyl, C1–C8 alkoxy, halogen, cyano, nitro, amino, hydroxyl, -C(O)OR. 81 -C(O)R 81 , Acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boric acid group, -NHR8 or -C(O)NHR8; or two R6 groups on the same atom to form =O;

[0105] R 81 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0106] R8 is selected from substituted or unsubstituted C1-C8 alkyl, hydroxyl,

[0107] R9 is selected from C1-C8 alkyl and 6-10 aryl groups;

[0108] R2 is selected from substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 3-8 membered cycloalkyl groups, substituted or unsubstituted 6-10 membered aryl groups, substituted or unsubstituted 4-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, and -NR. 11 R 12 , -SR 11 ;

[0109] When R6 is selected from a carboxyl group, R2 is not selected from substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl.

[0110] R 11 R 12 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0111] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, 4- to 10-membered heterocyclic alkyl groups, or -NR. 13 R 14 ;

[0112] R 13 R 14 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0113] The substituents of the cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups are selected from halogens, hydroxyl groups, amino groups, carboxyl groups, nitro groups, cyano groups, and -C(O)NR groups. 16 R 17 -C(O)OR 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy groups;

[0114] R 16 R 17 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxyl groups;

[0115] The heteroaryl or heterocyclic alkyl group has a heteroatom that is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0116] Preferably,

[0117] The aryl group of R1 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, or pyrroleyl.

[0118] R 15The aryl group is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, or pyrroleyl.

[0119] The aryl group in R9 is selected from phenyl or naphthyl;

[0120] The aryl group of R2 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindolinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, furanyl, pyrazolyl, imidazoleyl, pyrroleyl, isoxazolyl, or...

[0121] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0122] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0123] Furthermore, the compound is as shown in Formula II-3:

[0124]

[0125] in,

[0126] Z1 is selected from CH or N;

[0127] R1 is selected from substituted or unsubstituted C1-C8 alkyl groups and halogens;

[0128] R 61 R 62 Each of the following groups is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxyl, -C(O)OR 81 -C(O)R 81 , Acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boric acid group, -NHR8 or -C(O)NHR8;

[0129] R 81 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0130] R8 is selected from substituted or unsubstituted C1-C8 alkyl, hydroxyl,

[0131] R9 is selected from C1-C8 alkyl and 6-10 aryl groups;

[0132] R2 is selected from substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 3-8 membered cycloalkyl groups, substituted or unsubstituted 6-10 membered aryl groups, substituted or unsubstituted 4-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, and -NR. 11 R 12 , -SR 11 ;

[0133] When R6 is selected from a carboxyl group, R2 is not selected from substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 6- to 10-membered aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl.

[0134] R 11 R 12 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0135] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, 4- to 10-membered heterocyclic alkyl groups, or -NR. 13 R 14 ;

[0136] R 13 R 14 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0137] The substituents of the cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups are selected from halogens, hydroxyl groups, amino groups, carboxyl groups, nitro groups, cyano groups, and -C(O)NR groups. 16 R 17 -C(O)OR 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy groups;

[0138] R 16 R 17 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxyl groups;

[0139] The heteroaryl or heterocyclic alkyl group has a heteroatom that is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0140] Preferably,

[0141] The aryl group in R9 is selected from phenyl or naphthyl;

[0142] The aryl group of R2 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindolinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, furanyl, pyrazolyl, imidazoleyl, pyrroleyl, isoxazolyl, or...

[0143] The substituents of the alkyl group are selected from halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0144] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0145] Furthermore, the compound is as shown in Formula II-4:

[0146]

[0147] in,

[0148] Z1 is selected from CH or N;

[0149] R1 is selected from C1-C8 alkyl, halogen, and trifluoromethyl;

[0150] R 61 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxyl, -C(O)OR 81 -C(O)R 81 , Acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boric acid group, -NHR8 or -C(O)NHR8;

[0151] R 81 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0152] R8 is selected from substituted or unsubstituted C1-C8 alkyl, hydroxyl,

[0153] R9 is selected from C1-C8 alkyl and 6-10 aryl groups;

[0154] R2 is selected from substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 4-10 membered heterocyclic alkyl groups, and -NR groups. 11 R 12 , -SR 11 ;

[0155] R 11 R 12 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0156] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, 4- to 10-membered heterocyclic alkyl groups, or -NR. 13 R 14 ;

[0157] R13 R 14 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0158] The substituents of the cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups are selected from halogens, hydroxyl groups, amino groups, carboxyl groups, nitro groups, cyano groups, and -C(O)NR groups. 16 R 17 -C(O)OR 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy groups;

[0159] R 16 R 17 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxyl groups;

[0160] The heteroaryl or heterocyclic alkyl group has a heteroatom that is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0161] Preferably,

[0162] The aryl group in R9 is selected from phenyl or naphthyl;

[0163] The aryl group of R2 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindolinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, furanyl, pyrazolyl, imidazoleyl, pyrroleyl, isoxazolyl, or...

[0164] The substituents of the cyclic group are selected from halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholino, or -NR. 13 R 14 ;

[0165] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0166] Furthermore, the compound is as shown in Formula II-5:

[0167]

[0168] in,

[0169] Z1 is selected from CH or N;

[0170] R1 is selected from C1-C8 alkyl, halogen, and trifluoromethyl;

[0171] R 61 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxyl, -C(O)OR 81 -C(O)R 81, Acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boric acid group, -NHR8 or -C(O)NHR8;

[0172] R 81 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0173] R8 is selected from substituted or unsubstituted C1-C8 alkyl, hydroxyl,

[0174] R9 is selected from C1-C8 alkyl or phenyl groups;

[0175] R2' represents a substituent on the benzene ring, and the number of substituents is a; each R2' is independently selected from halogen, hydroxyl, amino, carboxyl, nitro, cyano, -C(O)NR 16 R 17 -C(O)OR 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy; a is 0, 1, 2 or 3;

[0176] R 16 R 17 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxyl groups;

[0177] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0178] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0179] Furthermore, the compound is as shown in Formula III-1:

[0180]

[0181] in,

[0182] R1 is selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy or carboxyl groups;

[0183] R3 is selected from 6-10 aryl groups substituted with n R6 groups, 5-10 heteroaryl groups substituted with n R6 groups, 4-10 heterocyclic alkyl groups substituted with n R6 groups, or...

[0184] Each R6 is independently selected from substituted or unsubstituted C1–C8 alkyl, C1–C8 alkoxy, halogen, cyano, nitro, amino, hydroxyl, -C(O)OR. 81-C(O)R 81 , Acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boric acid group, -NHR8 or -C(O)NHR8; or two R6 groups on the same atom to form =O; n is 0, 1, 2, 3 or 4;

[0185] R 81 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0186] R8 is selected from substituted or unsubstituted C1-C8 alkyl, hydroxyl,

[0187] R7 and R9 are independently selected from C1-C8 alkyl and 6-10 aryl groups, respectively;

[0188] R 10 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups;

[0189] R2 is selected from substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 3-8 membered cycloalkyl groups, substituted or unsubstituted 6-10 membered aryl groups, substituted or unsubstituted 4-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, and -NR. 11 R 12 , -SR 11 ;

[0190] R 11 R 12 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0191] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, 4- to 10-membered heterocyclic alkyl groups, or -NR. 13 R 14 ;

[0192] R 13 R 14 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0193] The substituents of the cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups are selected from halogens, hydroxyl groups, amino groups, carboxyl groups, nitro groups, cyano groups, and -C(O)NR groups. 16 R 17 -C(O)OR 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy groups;

[0194] R 16 R 17 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxyl groups;

[0195] The heteroaryl or heterocyclic alkyl group has a heteroatom that is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0196] Preferably,

[0197] The aryl group of R3 is selected from phenyl, the heteroaryl group is selected from isoindololinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl or pyrrolithyl, and the heterocyclic alkyl group is selected from piperidinyl;

[0198] The aryl groups in R7 and R9 are selected from phenyl or naphthyl groups;

[0199] The aryl group of R2 is selected from phenyl, anthracene, or naphthyl; the heterocyclic alkyl group is selected from piperidinyl or morpholinyl; and the heteroaryl group is selected from isoindolinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, furanyl, pyrazolyl, imidazoleyl, pyrroleyl, isoxazolyl, or...

[0200] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0201] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0202] Furthermore, the compound is as shown in Formula III-2:

[0203]

[0204] in,

[0205] X 11 Selected from CH or N;

[0206] R1 is selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy or carboxyl groups;

[0207] R 61 R 62 Each of the following groups is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxyl, -C(O)OR 81 -C(O)R 81 , Acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boric acid group, -NHR8 or -C(O)NHR8;

[0208] R 81 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0209] R8 is selected from substituted or unsubstituted C1-C8 alkyl, hydroxyl,

[0210] R9 is selected from C1-C8 alkyl and 6-10 aryl groups;

[0211] R 10 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups;

[0212] R2 is selected from substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 3-8 membered cycloalkyl groups, substituted or unsubstituted 6-10 membered aryl groups, substituted or unsubstituted 4-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, and -NR. 11 R 12 , -SR 11 ;

[0213] R 11 R 12 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0214] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, 4- to 10-membered heterocyclic alkyl groups, or -NR. 13 R 14 ;

[0215] R 13 R 14 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0216] The substituents of the cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups are selected from halogens, hydroxyl groups, amino groups, carboxyl groups, nitro groups, cyano groups, and C(O)NR groups. 16 R 17 -C(O)OR 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy groups;

[0217] R 16 R 17 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxyl groups;

[0218] The heteroaryl or heterocyclic alkyl group has a heteroatom that is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0219] Preferably,

[0220] The aryl group in R9 is selected from phenyl or naphthyl;

[0221] The aryl group of R2 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindolinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, furanyl, pyrazolyl, imidazoleyl, pyrroleyl, isoxazolyl, or...

[0222] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0223] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0224] Furthermore, the compound is as shown in Formula III-3:

[0225]

[0226] in,

[0227] X 11 Selected from CR 71 Or N;

[0228] R 71 Selected from hydrogen, halogens, and C1-C8 alkyl groups;

[0229] R1 is selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy or carboxyl groups;

[0230] R 61 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxyl, -C(O)OR 81 -C(O)R 81 , Acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boric acid group, -NHR8 or -C(O)NHR8;

[0231] R 81 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0232] R8 is selected from substituted or unsubstituted C1-C8 alkyl, hydroxyl,

[0233] R9 is selected from C1-C8 alkyl and 6-10 aryl groups;

[0234] R 10 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups;

[0235] R2 is selected from substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted 3-8 membered cycloalkyl groups, substituted or unsubstituted 6-10 membered aryl groups, substituted or unsubstituted 4-10 membered heterocycloalkyl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, and -NR. 11 R 12 , -SR 11 ;

[0236] R 11 R 12 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0237] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, 4- to 10-membered heterocyclic alkyl groups, or -NR. 13 R 14 ;

[0238] R 13 R 14 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0239] The substituents of the cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups are selected from halogens, hydroxyl groups, amino groups, carboxyl groups, nitro groups, cyano groups, and C(O)NR groups. 16 R 17 -C(O)OR 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy groups;

[0240] R 16 R 17 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxyl groups;

[0241] The heteroaryl or heterocyclic alkyl group has a heteroatom that is N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0242] Preferably,

[0243] The aryl group in R9 is selected from phenyl or naphthyl;

[0244] The aryl group of R2 is selected from phenyl or naphthyl, the heterocyclic alkyl group is selected from piperidinyl or morpholinyl, and the heteroaryl group is selected from isoindolinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, furanyl, pyrazolyl, imidazoleyl, pyrroleyl, isoxazolyl, or...

[0245] The substituents of the cyclic group are selected from halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholino, or -NR. 13 R 14 ;

[0246] R 13 R14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0247] Furthermore, the compound is as shown in Formula III-4:

[0248]

[0249] in,

[0250] X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 Selected independently from CR 71 Or N;

[0251] R 61 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy, carboxyl, acetonitrile, phosphonic, sulfonic, sulfonamide, boric, -NHR8 or -C(O)NHR8;

[0252] R 71 Selected from hydrogen, halogens, and C1-C8 alkyl groups;

[0253] R 81 Selected from hydroxyl, C1-C8 alkoxy, and amino groups;

[0254] R8 is selected from hydroxyl groups,

[0255] R9 is selected from C1-C8 alkyl or phenyl groups;

[0256] R1 is selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy or carboxyl groups;

[0257] R 10 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups;

[0258] R2' represents a substituent on the ring, and there are a substituents; each R2' is independently selected from halogen, hydroxyl, amino, carboxyl, nitro, cyano, -C(O)NR 16 R 17 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy; a is 0, 1, 2 or 3;

[0259] R 16 R 17 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0260] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0261] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0262] Furthermore, the compound is as shown in Formula III-5:

[0263]

[0264] in,

[0265] X 14 Selected from CH or N;

[0266] R 61 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy, carboxyl, acetonitrile, phosphonic, sulfonic, sulfonamide, boric, -NHR8 or -C(O)NHR8;

[0267] R8 is selected from hydroxyl groups,

[0268] R9 is selected from C1-C8 alkyl or phenyl groups;

[0269] R1 is selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy or carboxyl groups;

[0270] R 10 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups;

[0271] R2' is selected from halogen, hydroxyl, amino, carboxyl, nitro, cyano, C1-C8 alkyl or C1-C8 alkoxy; a is 0, 1, 2 or 3;

[0272] The substituents of the alkyl group are selected from halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0273] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0274] Furthermore, the compound is as shown in Formula III-6:

[0275]

[0276] in,

[0277] R 61 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy, carboxyl, acetonitrile, phosphonic, sulfonic, sulfonamide, boric, -NHR8 or -C(O)NHR8;

[0278] R8 is selected from hydroxyl groups,

[0279] R9 is selected from C1-C8 alkyl or phenyl groups;

[0280] R 10 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups;

[0281] R2' is a substituent on the benzene ring, and the number of substituents is a; each R2' is independently selected from halogen, hydroxyl, amino, carboxyl, nitro, cyano, C1-C8 alkyl or C1-C8 alkoxy; a is 0, 1, 2 or 3;

[0282] The substituents of the alkyl group are selected from halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0283] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0284] Furthermore, the compound is as shown in Formula III-7:

[0285]

[0286] in,

[0287] X 11 X 12 X 13 Selected independently from CR 71 Or N;

[0288] R 61 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy, carboxyl, acetonitrile, phosphonic, sulfonic, sulfonamide, boric, -NHR8 or -C(O)NHR8;

[0289] R 71 Selected from hydrogen, halogens, and C1-C8 alkyl groups;

[0290] R 81 Selected from hydroxyl, C1-C8 alkoxy, and amino groups;

[0291] R8 is selected from hydroxyl groups,

[0292] R9 is selected from C1-C8 alkyl or phenyl groups;

[0293] R1 is selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy or carboxyl groups;

[0294] R 10 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups;

[0295] R2 is selected from

[0296] R 11 Each is independently selected from hydrogen, substituted or unsubstituted C1 to C8 alkyl groups;

[0297] Each R2' is independently selected from halogen, hydroxyl, amino, carboxyl, nitro, cyano, -C(O)NR 15 R 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy; a is 0, 1, 2 or 3;

[0298] O is an integer selected from 1 to 3;

[0299] R 15 R 16 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0300] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0301] R 13 R 14 Each is independently selected from hydrogen, C1-C8 alkyl; or R 13 R 14 Connection formation

[0302] Furthermore, the compound is as shown in Formula III-8:

[0303]

[0304] in,

[0305] X 14 X 15 X 16 X 17 X 18 Selected independently from CR 71 Or N;

[0306] R 71 Selected from hydrogen, halogens, and C1-C8 alkyl groups;

[0307] R1 is selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy or carboxyl groups;

[0308] R 10 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups;

[0309] R2' represents a substituent on the ring, and there are a substituents; each R2' is independently selected from halogen, hydroxyl, amino, carboxyl, nitro, cyano, -C(O)NR 15 R 16 substituted or unsubstituted C1-C8 alkyl or C1-C8 alkoxy; a is 0, 1, 2 or 3;

[0310] R 15 R 16 Each is independently selected from hydrogen and C1-C8 alkyl groups;

[0311] R3 is selected from Phenyl group substituted with n R6, pyridyl group substituted with n R6, pyrimidinyl group substituted with n R6, pyridazinyl group substituted with n R6, thiophenyl group substituted with n R6, furanyl group substituted with n R6, pyrazolyl group substituted with n R6, imidazolyl group substituted with n R6, or pyrroleyl group substituted with n R6;

[0312] Each R6 is independently selected from substituted or unsubstituted C1–C8 alkyl, C1–C8 alkoxy, halogen, cyano, nitro, amino, hydroxyl, -C(O)OR. 81 -C(O)R 81 , Acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boric acid group, -NHR8 or -C(O)NHR8; or two R6 groups on the same atom to form =O; n is 0, 1, 2, 3 or 4;

[0313] R 81 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, and amino groups;

[0314] R8 is selected from substituted or unsubstituted C1-C8 alkyl, hydroxyl,

[0315] R9 is selected from C1-C8 alkyl and 6-10 aryl groups;

[0316] The substituents of the alkyl group are selected from deuterium, halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R14 ;

[0317] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0318] Furthermore, the compound is shown in Formula IV:

[0319]

[0320] in,

[0321] Z2 is selected from CH or N;

[0322] R 62 Selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, cyano, nitro, amino, hydroxy, carboxyl, acetonitrile, phosphonic, sulfonic, sulfonamide, boric, -NHR8 or -C(O)NHR8;

[0323] R8 is selected from hydroxyl groups,

[0324] R9 is selected from C1-C8 alkyl or phenyl groups;

[0325] R2' is a substituent on the benzene ring, and the number of substituents is a; each R2' is independently selected from halogen, hydroxyl, amino, carboxyl, nitro, cyano, C1-C8 alkyl or C1-C8 alkoxy; a is 0, 1, 2 or 3;

[0326] The substituents of the alkyl group are selected from halogen, hydroxyl, cyano, nitro, carboxyl, piperidinyl, morpholinyl, or -NR. 13 R 14 ;

[0327] R 13 R 14 Each is independently selected from hydrogen and C1 to C8 alkyl groups.

[0328] Furthermore, the compound is one of the following compounds:

[0329]

[0330]

[0331]

[0332]

[0333] The present invention also provides the use of the aforementioned compounds, or salts thereof, or stereoisomers thereof, or solvates thereof, or hydrates thereof, or prodrugs thereof, or deuterated compounds thereof, in the preparation of PI3K inhibitors;

[0334] Preferably, the PI3K inhibitor is a selective PI3K inhibitor.

[0335] The present invention also provides the use of the aforementioned compounds, or salts thereof, or stereoisomers thereof, or solvates thereof, or hydrates thereof, or prodrugs thereof, or deuterated compounds thereof, in the preparation of preventive and / or therapeutic drugs for diseases related to PI3K.

[0336] Furthermore, the diseases mentioned are PI3K-related cancers, inflammations, and cardiovascular diseases;

[0337] Preferably, the cancer is breast cancer, colorectal cancer, stomach cancer, colon cancer, rectal cancer, ovarian cancer, or prostate cancer.

[0338] The present invention also provides a drug which is prepared by adding pharmaceutically acceptable excipients or auxiliary ingredients to the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug, or its deuterated compound as the active ingredient.

[0339] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0340] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0341] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0342] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a ~C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C1 to C8 alkyl" refers to an alkyl group containing 1 to 8 carbon atoms; "C1 to C8 alkoxy" refers to an alkoxy group containing 1 to 8 carbon atoms.

[0343] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of carbon atoms. For example, C1 to C8 alkyl groups refer to alkyl groups with 1 to 8 carbon atoms, that is, alkyl groups with 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, etc.

[0344] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0345] In this invention, cycloalkyl refers to a saturated or partially saturated non-aromatic cyclic group consisting of a carbon atom, without heteroatoms, and having a single or multiple rings (including fused, bridged, and spirocyclic systems). Heterocyclic refers to a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom; including a single or multiple rings (including fused, bridged, and spirocyclic systems); wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. Examples of heterocyclic groups include, for example, piperidinyl, piperazineyl, and morpholinyl.

[0346] In this invention, aryl refers to an aromatic unsaturated group containing a single ring or multiple rings (including fused, bridged, and spirocyclic systems) without a heteroatom, such as phenyl, anthracene, or naphthyl. Heteroaryl refers to an aromatic unsaturated ring containing at least one heteroatom; including single rings or multiple rings (including fused, bridged, and spirocyclic systems); wherein the heteroatom refers to a nitrogen atom, oxygen atom, or sulfur atom. Examples include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazoleyl, pyrroleyl, furanyl, thiopheneyl, oxazolyl, and isoindolineyl.

[0347] In this invention, the structure in -CR4R5- where R4 and R5 form a ketone group with carbon is as follows:

[0348] In this invention, the structure of the phosphonic acid group is as follows: The structure of the sulfonic acid group is The structure of sulfonamide is The structure of the borate group is

[0349] The compounds prepared in this invention can be used to prepare selective PI3K inhibitors, as well as drugs for the prevention and / or treatment of PI3K-related diseases, such as drugs for the prevention and / or treatment of cancer. This invention provides a new option for clinical cancer treatment and has promising application prospects.

[0350] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0351] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0352] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0353] Synthesis of general intermediate: (R)-8-(1-aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-indoline-4-one (4-7)

[0354]

[0355] Synthesis of the first-step intermediate: 8-bromo-2-mercapto-6-methyl-4H-indoline-4-one (4-1)

[0356]

[0357] Procedure: 1-(3-bromo-2-hydroxy-5-methylphenyl)ethyl ketone (1.3 g; 5.6 mmol) was added to THF (4 mL), purged three times with nitrogen, and t-BuOK (1 M in THF; 17 mL) was added dropwise under stirring in an ice-water bath. After the addition was complete, the mixture was brought to room temperature and stirred for 30 minutes. Then, carbon disulfide (1.06 g; 14 mmol) in THF (10 mL) was slowly added dropwise under stirring in an ice-water bath. After the addition was complete, the mixture was allowed to return to room temperature naturally and stirred overnight. The pH was adjusted to 2 with HCl (1 N) under an ice-water bath, and the mixture was extracted with EA (20 mL × 3). The extract was dried over anhydrous sodium sulfate, concentrated, and then hot-beaten with EA. The mixture was filtered, dried, and the resulting compound 4-1 (1.3 g; 4.8 mmol) was obtained; yield 86%. Ms: 271(M+H + )

[0358] Synthesis of the second-step intermediate: 8-bromo-2-(ethio)-6-methyl-4H-indoline-4-one (4-2)

[0359]

[0360] Procedure: 4-1 (1.3 g; 4.8 mmol) was added to acetone (6.5 mL), followed by potassium carbonate (0.86 g; 6.2 mmol) and iodoethane (1.1 g; 7.2 mmol). The mixture was stirred at room temperature and monitored by TLC. After the reaction was complete, water (10 mL) and dichloromethane (10 mL) were added, followed by filtration. The filter cake was washed with dichloromethane (10 mL × 2) and extracted. The extract was dried, concentrated, and subjected to column chromatography to give intermediate 4-2 (950 mg; 3.2 mmol), with a yield of 66%. Ms: 299 (M + H) + )

[0361] The third step intermediate: Synthesis of 8-acetyl-2-(ethio)-6-methyl-4H-indoline-4-one (4-3)

[0362]

[0363] Procedure: 4-2 (299 mg; 1 mmol), tin reagent (541 mg; 1.5 mmol), DIPEA (258 mg; 2 mmol), and tetraphenylphosphine palladium (173 mg; 0.15 mmol) were added to dioxane (6 mL) under nitrogen protection and stirred overnight at 95 °C. After the reaction solution cooled to room temperature, concentrated hydrochloric acid (0.5 mL) was added, and the mixture was stirred for 30 minutes. Then, saturated potassium fluoride solution (3 mL) was added, and the mixture was stirred for one hour. The mixture was filtered, extracted with ethyl acetate, and subjected to column chromatography to give intermediate 4-3 (200 mg; 0.76 mmol), with a yield of 76%. Ms: 263 (M+H) + )

[0364] Synthesis of the fourth intermediate: 8-acetyl-2-(2,4-difluorophenyl)-6-methyl-4H-indoline-4-one (4-4)

[0365]

[0366] Procedure: Dissolve 4-3 (200 mg; 0.63 mmol) in dioxane (2 mL), bubble under nitrogen for three minutes, then add 2,4-difluorophenylboronic acid (1.26 g; 5.06 mmol), CuTc (202 mg; 3.17 mmol), tetrakis(triphenylphosphine)palladium (146 mg; 0.13 mmol), cesium carbonate (412 mg; 1.27 mmol), and molecular sieve (200 mg). Seal the tube and stir at 80 °C for eight hours. Add water and ethyl acetate, filter, extract with ethyl acetate, and column chromatography to give intermediate 4-4 (198 mg; 0.63 mmol), yield 63%. Ms: 315 (M+H) + )

[0367] Synthesis of the fifth intermediate: (R,Z)-N-(1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-indoline-8-yl)ethylidene)-2-isobutyl-2-sulfinamide (4-5)

[0368]

[0369] Procedure: 4-4 (198 mg; 0.63 mmol) and (R)-(+)-tert-butylsulfinamide (191 mg; 1.58 mmol) were added to tetrahydrofuran (1.1 ml), followed by the addition of tetraethyl titanate (718 mg; 3.15 mmol). The mixture was stirred overnight at 90 °C. Water and ethyl acetate were added, the mixture was filtered, extracted with ethyl acetate, and subjected to column chromatography to give intermediate 4-5 (217 mg; 0.52 mmol), in 82% yield. Ms: 418(M+H + )

[0370] Synthesis of intermediate (R)-N-(1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-indoline-8-yl)ethyl)-2-isobutane-2-sulfinamide (4-6)

[0371]

[0372] Procedure: 4-5 (217 mg; 0.52 mmol) and cerium chloride heptahydrate (97 mg; 0.26 mmol) were added to methanol (6.6 mL) under nitrogen protection. After dissolution, the solution was cooled to -78 °C. Sodium borohydride (49 mg; 1.3 mmol) was added under low-temperature stirring, and the mixture was stirred overnight. After the reaction was complete, ethyl acetate was added, the mixture was filtered, and column chromatography was performed to give intermediate 4-6 (170 mg; 0.4 mmol), yield 78%. Ms: 420 (M+H) + )

[0373] Synthesis of the seventh intermediate: (R)-8-(1-aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-indoline-4-one (4-7)

[0374]

[0375] Procedure: Dissolve 4-6 (170 mg; 0.4 mmol) in dichloromethane (3 mL), add 1 mL of dioxane solution of hydrogen chloride, and stir at room temperature. Monitor the reaction by TLC. After completion, evaporate to dryness, add water, extract with ethyl acetate, adjust the pH of the aqueous phase to alkaline, extract with ethyl acetate, dry and evaporate to dryness to give intermediate 4-7 (114 mg; 0.36 mmol), yield 90%. Ms: 316(M+H + )

[0376] Example 1: Synthesis of compound N-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-oxo-4H-chromen-8-yl)indoline-1-carboxamide (compound 1)

[0377]

[0378] Step 1: Synthesis of intermediate 8-bromo-2-mercapto-6-methyl-4H-chromen-4-one (1-1)

[0379]

[0380] Compound 1-(3-bromo-2-hydroxy-5-methylphenyl)ethane-1-one (8.1 g, 35.4 mmol) and tetrahydrofuran (100 mL) were added to a 500 mL reaction flask. The mixture was cooled to -70 °C in a dry ice bath. NaHMDS (2.0 M in THF, 53 mL, 106 mmol) was added dropwise. After the addition was complete, the mixture was allowed to rise naturally to 0 °C and stirred for 1 hour. Then, the mixture was cooled to -20 °C, and carbon disulfide (8.1 g, 106 mmol) was added dropwise. The reaction was allowed to rise naturally overnight. After the reaction was complete, the mixture was cooled to 0 °C, and the pH was adjusted to 4-5 with 1 N dilute hydrochloric acid. The mixture was stirred for 1 hour, and the mixture was extracted with ethyl acetate (50 mL x 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and then slurried with ethyl acetate. The mixture was filtered to give intermediate 1-1 (6.6 g), with a yield of 69%. Ms: 271.1, 273.1 (M+H + )

[0381] Step 2: Synthesis of intermediate 8-bromo-2-(ethio)-6-methyl-4H-chromen-4-one (1-2)

[0382]

[0383] Compound 1-1 (6.6 g, 24.4 mmol), potassium carbonate (5.1 g, 36.6 mmol), and acetone (70 mL) were added to a 250 mL reaction flask. Iodoethane (4.5 g, 29 mmol) was added with stirring, and the mixture was heated to reflux. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give compound 1-2 (4.5 g), yield 62%. Ms: 299.1, 301.1 (M+H) + )

[0384] Step 3: Synthesis of intermediate 8-bromo-2-(ethylsulfonyl)-6-methyl-4H-chromene-4-one (1-3)

[0385]

[0386] Compound 1-2 (1 g, 3.3 mmol) and dichloromethane (20 mL) were added to a 100 mL reaction flask. While stirring, m-chloroperoxybenzoic acid (2.3 g, 13.3 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered. The filtrate was washed with an aqueous sodium thiosulfate solution, and then the organic layer was washed with a saturated aqueous sodium carbonate solution. The organic layer was dried and concentrated to give crude compound 1-3 (1.3 g), with a yield of 118%. Ms: 331.1, 333.1 (M+H) + )

[0387] Step 4: Synthesis of intermediate 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4H-chromen-4-one (1-4)

[0388]

[0389] Compound 1-3 (1.3 g, 3.9 mmol), diisopropylethylamine (1.5 g, 11.7 mmol), 4,4-dimethylpiperidine hydrochloride (0.6 g, 3.9 mmol), and dichloromethane (20 mL) were added to a 100 mL reaction flask. The reaction was allowed to proceed overnight. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give compound 1-4 (1 g), yield 74%. Ms: 350.1, 352.1 (M+H) + )

[0390] Step 5: Synthesis of intermediate 2-(4,4-dimethylpiperidin-1-yl)-8-(diphenylmethylene)amino)-6-methyl-4H-chromen-4-one (1-5)

[0391]

[0392] Compounds 1-4 (1 g, 2.9 mmol), diphenylmethylimine (0.68 g, 3.7 mmol), cesium carbonate (1.4 g, 4.3 mmol), and toluene (20 mL) were added to a 100 mL reaction flask. Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.36 g, 0.6 mmol) and palladium acetate (0.13 g, 0.6 mmol) were added. The mixture was heated to 100 °C and reacted overnight. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a mixture that was used directly in the next step.

[0393] Step 6: Synthesis of intermediate 8-amino-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4H-chromen-4-one (1-6)

[0394]

[0395] The mixture from the previous step was added to a 100 mL reaction flask, dissolved in tetrahydrofuran (20 mL), followed by 15 mL of 2N dilute hydrochloric acid. The mixture was stirred at room temperature until the reaction was complete. The pH was adjusted to 8-9 with sodium carbonate aqueous solution. The mixture was extracted with ethyl acetate (20 mL x 3 times), and the organic layers were combined. The extract was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give compound 1-6 (0.7 g), yield 84%. Ms: 287.2 (M+H) + )

[0396] Step 7: Synthesis of compound N-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-oxo-4H-chromen-8-yl)indoline-1-carboxamide (compound 1)

[0397]

[0398] Compounds 1-6 (50 mg, 0.18 mmol) and dichloromethane (3 mL) were added to a 25 mL reaction flask. Triphosgene (27 mg, 0.09 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for one hour. Then, triethylamine (71 mg, 0.7 mmol) and indoline (25 mg, 0.21 mmol) were added sequentially. After the reaction was complete, water (3 mL) was added, and the mixture was extracted with ethyl acetate (3 mL x 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by plate preparation to obtain compound 1 (40 mg), with a yield of 52%. Ms: 432.2 (M+H) + ), 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H),7.84(d,J=8.0Hz,1H),7.52(d,J=3.0Hz,2H),7.21(d,J=7.4Hz,1H),7.11(t,J=7.8Hz,1H),6.91(t,J=7.4H z,1H),5.48(s,1H),4.14(t,J=8.6Hz,2H),3.45(dd,J=6.9,4.7Hz,4H),3.20(t,J=8.6Hz,2H),2.38(s,3H),1.30(t,J=5.8Hz,4H),0.91(s,6H).

[0399] Example 2: Synthesis of compound (R)-2-((1-(2-((2-hydroxy-2-methylpropyl)amino)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid (compound 7)

[0400]

[0401] Step 1: Synthesis of intermediate 8-acetyl-2-(ethio)-6-methyl-4H-chromen-4-one (2-1)

[0402]

[0403] To a 100 mL reaction flask, add compound 8-bromo-2-(ethylthio)-6-methyl-4H-chromen-4-one (700 mg, 2.3 mmol), tributyl(1-ethoxyethylene)tin (1 g, 2.8 mmol), and dioxane (15 mL). After purging with nitrogen, add 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (168 mg, 0.23 mmol). Heat the reaction to 95 °C for approximately 3-4 hours. After the reaction is complete, cool to room temperature, add 6N dilute hydrochloric acid (5 mL), stir for 1 hour, then add saturated potassium fluoride aqueous solution (15 mL), stir for 1 hour, filter, wash the filter cake three times with ethyl acetate (20 mL), separate the layers, dry the organic layer with anhydrous sodium sulfate, concentrate, and pass through a silica gel column to give intermediate 2-1 (400 mg), yield 66%. Ms: 263(M+H + )

[0404] Step 2: Synthesis of intermediate (R,Z)-N-(1-(2-(ethylthio)-6-methyl-4-oxo-4H-chromene-8-yl)ethylene)-2-methylpropane-2-sulfonamide (2-2)

[0405]

[0406] Compound 2-1 (400 mg, 1.5 mmol), (R)-tert-butylsulfinamide (370 mg, 3 mmol), tetraisopropyl titanate (870 mg, 3.1 mmol), and tetrahydrofuran (10 mL) were added to a 100 mL reaction flask. The mixture was purged with nitrogen and heated under reflux overnight. After the reaction was complete, the mixture was cooled to room temperature, and saturated brine (10 mL) was added. The mixture was stirred for 0.5 hours, filtered, and the filter cake was washed three times with ethyl acetate (10 mL). The layers were separated, combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give crude intermediate 2-2 (700 mg), yield 128%. Ms: 366 (M+H + )

[0407] Step 3: Synthesis of intermediate (R)-N-((R)-1-(2-(ethio)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfonamide (2-3)

[0408]

[0409] Compound 2-2 (375 mg, 1 mmol), cerium trichloride heptahydrate (187 mg, 0.5 mmol), and methanol (10 mL) were added to a 50 mL reaction flask. The mixture was cooled to -70 °C with stirring. A methanol solution of sodium borohydride (114 mg, 3 mmol) was added dropwise. After the addition was complete, the mixture was allowed to warm naturally overnight. Ethyl acetate was added, and the mixture was filtered. The filtrate was rotary evaporated, and ethyl acetate was added again. The filtrate was then concentrated and passed through a silica gel column to give intermediate 2-3 (80 mg), with a yield of 22%. Ms: 368 (M+H) + )

[0410] Step 4: Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(ethylthio)-6-methyl-4H-chromen-4-one (2-4)

[0411]

[0412] Compound 2-3 (80 mg, 0.22 mmol) and ethyl acetate (3 mL) were added to a 25 mL reaction flask. A solution of dioxane chloride (3 mL) was added with stirring. The reaction was stirred at room temperature until complete. The solvent was concentrated, and an aqueous sodium bicarbonate solution (5 mL) was added. The mixture was extracted with dichloromethane (5 mL x 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give intermediate 2-4 (50 mg), yield 86%. Ms: 264 (M+H) + )

[0413] Step 5: Synthesis of intermediate (R)-2-((1-(2-(ethio)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid (2-5)

[0414]

[0415] Compound 2-4 (50 mg, 0.19 mmol), o-iodobenzoic acid (39 mg, 0.29 mmol), triethylamine (38 mg, 0.38 mmol), and N,N-dimethylacetamide (1 mL) were added to a 25 mL reaction flask. The mixture was purged with nitrogen, and copper powder (12 mg, 0.19 mmol) was added. The mixture was heated to 110 °C and reacted for approximately 1-2 hours. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 4-5 with 1 N hydrochloric acid aqueous solution. Ethyl acetate (5 mL) was added, and the mixture was separated. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by plate preparation to obtain intermediate 2-5 (45 mg), with a yield of 62%. Ms: 384(M+H) + )

[0416] Step 6: Synthesis of intermediate 2-(((1R)-1-(2-(ethylsulfinyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid (2-6)

[0417]

[0418] Compound 2-5 (45 mg, 0.12 mmol) and dichloromethane (3 mL) were added to a 25 mL reaction flask. While stirring, m-chloroperoxybenzoic acid (31 mg, 0.18 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered. The filtrate was washed with an aqueous sodium thiosulfate solution, the organic layer was dried, and the solution was concentrated to give crude compound 2-6 (60 mg), yield 125%. Ms: 400 (M+H) + )

[0419] Step 7: Synthesis of compound (R)-2-((1-(2-((2-hydroxy-2-methylpropyl)amino)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid (compound 7)

[0420]

[0421] Compound 2-6 (30 mg, 0.08 mmol), 1-amino-2-methyl-2-propanol (10 mg, 0.11 mmol), diethylpropyl ethylamine (39 mg, 0.3 mmol), and dichloromethane were added to a 25 mL reaction flask. The reaction was heated to 40 °C overnight. After the reaction was complete, the compound (compound 7, 7 mg) was directly purified by preparative chromatography, yielding 21%. Ms: 411(M+H + ), 1 H NMR (400MHz, DMSO-d6) δ12.8(s,1H),8.67(s,1H),7.97(d,J=7.0Hz,1H),7.79(dd,J=7 .9,1.7Hz,1H),7.56(d,J=2.2Hz,1H),7.32(d,J=2.2Hz,1H),7.17(t,J=7.8Hz,1H),6. 50(t,J=7.5Hz,1H),6.44(d,J=8.4Hz,1H),5.33(s,1H),5.15(d,J=7.0Hz,1H),3.39(s ,1H),3.17(d,J=6.2Hz,2H),2.28(s,3H),1.55(d,J=6.6Hz,3H),1.16(d,J=7.6Hz,6H).

[0422] Example 3: Synthesis of compound (R)-2-(2,4-difluorophenyl)-6-methyl-8-(1-(1-methyl-1H-pyrazol-5-yl)amino)ethyl)-4H-methylene-4-one (compound 42)

[0423]

[0424] Intermediate 4-7 (synthesis described in Synthesis of General Intermediates, 20 mg, 0.06 mmol), 5-bromo-1-methyl-1H-pyrazole (21 mg, 0.13 mmol), sodium tert-butoxide (18 mg, 0.19 mmol), and toluene (2 mL) were added to a 25 mL reaction flask. The mixture was purged with nitrogen, and then tris(dibenzylacetone)dipalladium (12 mg, 0.01 mmol) and 2-di-tert-butylphospho-2',4',6'-triisopropylbiphenyl (6 mg, 0.01 mmol) were added. The reaction mixture was heated to 100 °C and reacted overnight. After the reaction was complete, water (2 mL) was added, and the mixture was extracted with ethyl acetate (3 mL x 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by a preparative plate to obtain compound 42 (6 mg), yield 25%. Ms: 396.1 (M+H) + ), 1H NMR(400MHz, DMSO-d6)δ7.78(d,J=2.2Hz,1H),7.70(d,J=2.2Hz,1H),7.61-5.52(m,1H),7.37–7.30(m,2H ),6.81(s,1H),6.75–6.61(m,3H),5.41(t,J=6.7Hz,1H),3.25(s,3H),2.37(s,3H),1.71(d,J=6.7Hz,3H).

[0425] Example 4: Synthesis of compound (R)-6-chloro-3-((1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)pyridinecarboxylic acid (compound 37)

[0426]

[0427] Synthesis of intermediate: 2-amino-3-bromo-N,5-dimethylbenzamide (5-1)

[0428]

[0429] 2-Amino-3-bromo-5-methylbenzoic acid (200 g, 0.87 mol) was dissolved in THF (2 L), and CDI (156 g, 0.96 mol) was added in portions. The system gradually bubbled, and after reacting for 2 h, TLC showed that the starting material had reacted completely. The system was then cooled to 0-10 °C, and 800 mL of methylamine aqueous solution was added dropwise. After the addition was complete, the ice bath was removed, and the reaction was allowed to continue for 1 h. TLC showed that the intermediate reaction was complete. During post-treatment concentration, when solid precipitated, it was poured into 10 times the volume of tetrahydrofuran in water and stirred. The mixture was filtered, and the filter cake was washed with water and anhydrous ethanol. The filter cake was then evaporated to dryness to obtain a white solid 5-1 (204 g, 0.84 mol), with a yield of 96%. M / S: 243 / 245 (M+H + ).

[0430] Synthesis of intermediate: 8-bromo-2-(2,6-difluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (5-2)

[0431]

[0432] 5-1 (2.0 g, 8.26 mmol), 2,6-difluorobenzaldehyde (1.4 g, 9.91 mmol), and elemental iodine (2.51 g, 9.91 mmol) were sequentially added to DMSO (20 mL), and stirred at 100 °C for 4 h. The reaction was monitored by LCMS until the starting materials were completely reacted. After cooling, the system was added to an ice-water solution of sodium thiosulfate. After filtration, the filter cake was washed with ethanol and evaporated to dryness to obtain a white solid 5-2 (2.2 g, 6.04 mmol), with a yield of 73%. M / S: 365 / 367 (M+H + ).

[0433] Synthesis of intermediate: 8-acetyl-2-(2,6-difluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (5-3)

[0434]

[0435] 5-2 (2.2 g, 6.04 mmol), tributyl(1-ethoxyethylene)tin (2.6 g, 7.25 mmol), and bis(triphenylphosphine)palladium dichloride (0.48 g, 0.60 mmol) were sequentially added to anhydrous dioxane (11 mL). The mixture was purged with nitrogen three times and reacted at 90 °C for 6 h. TLC monitoring showed complete reaction of the starting material. After cooling, DCM (20 mL) was added, and the pH was adjusted to 2–3 with 2N HCl. The mixture was stirred for 1–2 h, and TLC monitoring showed complete reaction of the intermediate. KF was added to saturate the solution, and the mixture was stirred for 1 h. The mixture was filtered, and the filtrate was extracted with DCM (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was pulped and filtered using EA. The filter cake was evaporated to dryness to obtain a light yellow solid 5-3 (1.7 g, 5.18 mmol), with a yield of 87%. M / S: 329(M+H) + ).

[0436] Synthesis of intermediate: (R,Z)-N-(1-(2-(2,6-difluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylene)-2-methylpropane-2-thioamide (5-4)

[0437]

[0438] 5-3 (1.7 g, 5.18 mmol), (R)-(+)-tert-butylsulfinamide (1.3 g, 10.36 mmol), and tetraethyl titanate (4.7 g, 20.72 mmol) were added sequentially to tetrahydrofuran (8.5 mL). The mixture was stirred at 90 °C for 12 h, and the reaction was monitored by TLC until the starting materials were fully reacted. After cooling, the reaction mixture was poured into ice water (85 mL), filtered, and the filter cake was pulped using DCM (50 mL × 4). The organic phase was collected, and the filtrate was extracted using DCM (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness. A yellow oily crude product of 5-4 (1.5 g, 3.48 mmol) was obtained, which could be used directly in the next step. M / S: 432 (M+H + ).

[0439] Synthesis of intermediate: N-((R)-1-(2-(2,6-difluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfonamide (5-5)

[0440]

[0441] Crude 5-4 (1.5 g, 3.48 mmol) and cerium trichloride heptahydrate (0.6 g, 1.74 mmol) were added sequentially to methanol (22 mL). The mixture was purged with nitrogen three times and cooled to -60 to -70 °C. Sodium borohydride (0.4 g, 10.44 mmol) was added in portions. After the addition was complete, the mixture was kept at this temperature for 30 min and then allowed to return to room temperature. The reaction was monitored by TLC until complete. The reaction was then quenched with water and extracted with DCM (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness, and then subjected to column chromatography to obtain a yellow solid 5-5 (0.8 g, 1.85 mmol). The two-step yield was 36%. M / S: 434 (M + H) + ).

[0442] Synthesis of intermediate: (R)-8-(1-aminoethyl)-2-(2,6-difluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (5-6)

[0443]

[0444] 5-5 (0.8 g, 1.85 mmol) was dissolved in dichloromethane (4 mL), and a dioxane solution of HCl (4 N, 2 mL) was added. The mixture was stirred at room temperature, and the reaction was monitored by TLC until the starting material was completely reacted. Water (50 mL) was added for post-treatment, and the pH was adjusted to 7–8 with sodium bicarbonate. Extraction was performed using DCM (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give solid 5-6 (0.58 g, 1.75 mmol). Yield: 95%. M / S: 317 (M + H) + ).

[0445] Synthesis of compound: (R)-2-((1-(2-(2,6-difluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (compound 37)

[0446]

[0447] Add 5-6 (70 mg, 0.21 mmol), o-iodobenzoic acid (79 mg, 0.32 mmol), copper powder (21 mg, 0.32 mmol), and triethylamine (43 mg, 0.42 mmol) to DMA (1 mL). Stir at 110 °C for 4 hours. Monitor the reaction progress by TLC. After finishing, add water (10 mL), extract with EA (10 mL × 3), dry the organic phase with anhydrous sodium sulfate, concentrate, and then column chromatography to give a white solid compound 37 (35 mg, 0.078 mmol), yield 37%. M / S: 450 (M + H + ).

[0448] 1H NMR(400MHz,Chloroform-d)δ8.04(d,J=2.0Hz,1H),7.97(dd,J=8.0,1.7Hz,1H),7.78(s,1H),7.61(d,J=2.1Hz,1H),7.57–7.45(m,1H),7.18(t,J= 7.3Hz,1H),7.11(td,J=8.2,2.5Hz,2H),6.54(s,1H),6.49(d,J=8.6Hz,1H ),5.59(q,J=6.6Hz,1H),3.50(s,3H),2.44(s,3H),1.60(d,J=6.6Hz,3H).

[0449] Example 5: Synthesis of compound (R)-2-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzenesulfonamide (compound 27)

[0450]

[0451] (R)-8-(1-aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-chromene-4-one (synthesis described in Synthesis of General Intermediates, 30 mg, 95.14 μmol), 2-fluorobenzenesulfonamide (25 mg, 142.71 μmol), and potassium carbonate (26 mg, 190.28 μmol) were added to NMP (1 mL). The mixture was stirred at 130 °C for 4 hours. TLC monitoring showed that the reaction was complete. Afterwards, water (20 mL) was added, and the mixture was extracted with EA (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to give a white solid compound 27 (20 mg, 45.51 μmol), yielding 45%. M / S: 471 (M+H + ).

[0452] 1 H NMR(400MHz,Chloroform-d)δ8.01(s,1H),8.02–7.92(m,1H),7.74(dd,J=8.5,5.2Hz,2H),7.61–7.57(m,1H),7.23(d,J =8.5Hz,2H),7.19(s,1H),6.45(d,J=8.6Hz,1H),5.63(q,J=6.6Hz,1H),3.66(s,4H),2.43(s,3H),1.60(d,J=6.7Hz,3H).

[0453] Example 6: Synthesis of 2-(2,4-difluorophenyl)-8-(1-(indolin-1-yl)ethyl)-6-methyl-4H-benzopyran-4-one (compound 116)

[0454]

[0455] Step 1: Synthesis of intermediate 2-(2,4-difluorophenyl)-8-(1-hydroxyethyl)-6-methyl-4H-indoline-4-one (8-5)

[0456]

[0457] Procedure: Compound 4-4 (synthesis details in Synthesis of General Intermediates, 314 mg; 1 mmol) was dissolved in methanol (5 mL). Sodium borohydride (114 mg; 3 mmol) was added under an ice-water bath. The mixture was allowed to return to room temperature naturally and stirred overnight. TLC monitoring was performed. After the reaction was complete, the mixture was poured into a saturated ammonium chloride solution, extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, and evaporated to dryness. Pure compound 8-5 (273 mg; 0.86 mmol) was obtained, in 86% yield. Ms: 317 (M + H + )

[0458] Step 2: Synthesis of intermediate 8-(1-chloroethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-indoline-4-one (8-6);

[0459]

[0460] Procedure: Compound 8-5 (273 mg; 0.86 mmol) was dissolved in DCM (3 ml), and thionyl chloride (113 mg; 0.95 mmol) was added with stirring at room temperature. The mixture was stirred overnight. TLC monitoring was performed. After the reaction was complete, the sample was stirred and subjected to column chromatography. Pure compound 8-6 (280 mg; 0.86 mmol) was obtained, with a yield of 84%. Ms: 335 (M+H) + )

[0461] Step 3: Synthesis of the target compound 2-(2,4-difluorophenyl)-8-(1-(indolin-1-yl)ethyl)-6-methyl-4H-benzopyran-4-one (compound 116);

[0462]

[0463] Procedure: Compound 8-6 (50 mg; 0.15 mmol) was dissolved in DCM (1 ml). Indoline (20 mg; 0.17 mmol) and triethylamine (18 mg; 0.18 mmol) were added sequentially with stirring at room temperature, and the mixture was stirred overnight. The reaction was monitored by TLC. After completion, column chromatography was performed. Pure compound 116 (30 mg; 0.07 mmol) was obtained, in 48% yield. Ms: 418 (M+H) + ); 1 H NMR(400MHz, DMSO-d6)δ8.02(td,J=8.9,6.5Hz,1H),7.83-7.77(m,1H),7.74(d,J=2.2Hz, 1H),7.54(ddd,J=11.9,9.2,2.6Hz,1H),7.15(td,J=8.5,2.6Hz,1H),7.04-6.96(m,1H),6. 93-6.84(m,1H),6.77(d,J=0.9Hz,1H),6.59-6.47(m,1H),6.39(d,J=7.8Hz,1H),5.37(q,J =6.9Hz,1H),3.44(t,J=9.5Hz,2H),2.91-2.77(m,2H),2.44(s,3H),1.54(d,J=6.9Hz,3H).

[0464] Example 7: Synthesis of compound (R)-3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)-N-(methyl-d3)pyridineamide (compound 48)

[0465]

[0466] Step 1: Synthesis of intermediate (R)-3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)pyridinecarboxylate (9-1)

[0467]

[0468] Procedure: (R)-8-(1-aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-chromene-4-one (200 mg, 0.63 mmol), methyl 3-fluoropyridinecarboxylate (197 mg, 1.27 mmol), and N,N-diisopropylethylamine (246 mg, 1.90 mmol) were added to N-methylpyrrolidone (2 mL). The mixture was heated to 120 °C and stirred overnight. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 110 mg of the product (intermediate 9-1), yield: 38.5%. Ms: 451.1 (M+H + ).

[0469] Step 2: Synthesis of intermediate (R)-3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)pyridinecarboxylic acid (9-2)

[0470]

[0471] Procedure: Intermediate 9-1 (90 mg, 0.2 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium hydroxide monohydrate (84 mg, 2.0 mmol), water (1 mL), and methanol (1 mL) were added. The mixture was stirred at room temperature for 4 hours. The pH was adjusted to approximately 3 with 0.5 N hydrochloric acid. The mixture was extracted with dichloromethane (15 mL × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 60 mg of the product (intermediate 9-2), with a yield of 68.8%. Ms: 437.2 (M + H + ).

[0472] Step 3: Synthesis of compound (R)-3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)-N-(methyl-d3)pyridineamide (compound 48)

[0473]

[0474] Procedure: Intermediate 9-2 (24 mg, 0.06 mmol) was dissolved in N,N-dimethylacetamide (0.5 mL), and N,N'-carbonyldiimidazole (10 mg, 0.06 mmol) was added. The mixture was heated to 60 °C and reacted for 1 hour. The mixture was then cooled to room temperature, and N,N-diisopropylethylamine (14 mg, 0.11 mmol) and deuterated methylamine hydrochloride (12 mg, 0.17 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (10 mL), washed with water (20 mL × 2), and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated and purified by column chromatography to give 13 mg of the product (compound 48), yield: 52.2%. Ms: 453.2 (M + H) + ). 1 H NMR(400MHz, DMSO-d6)δ9.11(d,J=6.6Hz,1H),8.72(s,1H),8.14(td,J=8.8,6.4Hz,1H),7.79–7.73(m,2H),7.61–7.53(m,2H),7.36–7.30(m,1 H),7.18(dd,J=8.6,4.3Hz,1H),6.90(dd,J=8.8,1.3Hz,1H),6.80(d,J=0.8Hz,1H),5.20(p,J=6.6Hz,1H),2.35(s,3H),1.62(d,J=6.6Hz,3H).

[0475] Example 8: Synthesis of compound (R)-2-((1-(2-(2,4-difluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (compound 41)

[0476]

[0477] Synthesis of intermediate: 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (12-1)

[0478]

[0479] 2-Amino-3-bromo-5-methylpyridine (1.87 g, 10.0 mmol) and 2,4,6-trichlorophenylmaleic acid diester (5.56 g, 12.0 mmol) were added sequentially to toluene (19 mL), and the mixture was reacted at 90 °C for 4 hours. The reaction was confirmed to be complete by TLC. After cooling to room temperature, the mixture was filtered, and the solid was washed with petroleum ether (20 mL). The solid was then evaporated to dryness to give 12-1 (2.00 g, 0.79 mol), with a yield of 79%. M / S: 255.0 (M+H) + ).

[0480] Synthesis of intermediate: 9-bromo-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yltrifluoromethanesulfonate (12-2)

[0481]

[0482] 12-1 (2.00 g, 7.9 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (5.64 g, 15.8 mmol), and triethylamine (1.60 g, 15.8 mmol) were added sequentially to DMA (20 mL). The reaction was carried out at room temperature for 4 hours. The reaction was confirmed to be complete by TLC. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was concentrated to dryness and purified by column chromatography to obtain 12-2 (2.2 g, 5.7 mmol), with a yield of 72%. M / S: 386.9 (M+H) + ).

[0483] Synthesis of intermediate: 9-bromo-2-(2,4-difluorophenyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (12-3)

[0484]

[0485] 12-2 (2.2 g, 5.7 mmol), 2,4-difluorophenylboronic acid (1.8 g, 11.4 mmol), potassium carbonate (1.6 g, 11.4 mmol), and tetraphenylphosphine palladium (0.7 g, 0.6 mmol) were sequentially added to 1,4-dioxane (22 mL). The mixture was reacted overnight at 90 °C. The reaction was monitored by TLC until complete. After cooling to room temperature, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was concentrated to dryness and purified by column chromatography to obtain 12-3 (1.5 g, 4.3 mmol), with a yield of 75%. M / S: 351.0 (M+H) + ).

[0486] Synthesis of intermediate: 9-acetyl-2-(2,4-difluorophenyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (12-4)

[0487]

[0488] 12-3 (1.5 g, 4.3 mmol), tributyl(1-ethoxyethylene)tin (2.3 g, 6.5 mmol), Pd(PPh3)Cl2 (0.28 g, 0.4 mmol), and DIPEA (1.1 g, 8.6 mmol) were sequentially added to anhydrous DMA (15 mL). Under nitrogen protection, the reaction was carried out at 100 °C for 2 h, and TLC was used to confirm complete reaction. After cooling to room temperature, the pH was adjusted to 2-3 with 4N HCl / dioxane, followed by the addition of water (1 mL). The mixture was stirred for 2 h, and TLC was used to confirm complete reaction. KF was added to saturate the solution and stirred for 2 h. The mixture was filtered, extracted with ethyl acetate (20 mL × 2), and the solid was slurried with ethyl acetate (20 mL). The solid was filtered, and the combined organic layers were dried over anhydrous sodium sulfate. The organic layers were concentrated to dryness and purified by column chromatography to obtain 12-4 (1.3 g, 4.1 mmol), with a yield of 95%. M / S: 315.1 (M + H + ).

[0489] Synthesis of intermediate: (R,Z)-N-(1-(2-(2,4-difluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethylene)-2-methylpropane-2-sulfonamide (12-5)

[0490]

[0491] 12-4 (1.3 g, 4.1 mmol), (R)-(+)-tert-butylsulfinamide (1.0 g, 8.2 mmol), and tetraethyl titanate (4.7 g, 20.5 mmol) were added sequentially to THF (13 mL), and the mixture was reacted overnight at 90 °C. The reaction was monitored by TLC until complete. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL), and water (10 mL) was added. The mixture was filtered, and the aqueous layer was extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to give 12-5 (1.6 g, 3.8 mmol), in 93% yield. M / S: 418.1 (M+H) + ).

[0492] Synthesis of intermediate: (R)-N-((R)-1-(2-(2,4-difluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)-2-methylpropane-2-sulfonamide (12-6)

[0493]

[0494] 12-5 (1.6 g, 3.8 mmol) and CeCl3·7H2O (0.6 g, 1.9 mmol) were added sequentially to MeOH (32 mL) under nitrogen protection and cooled to -60 to -70 °C. NaBH4 (0.4 g, 11.4 mmol) was added in portions. After the addition was complete, the mixture was allowed to warm naturally to room temperature. The reaction was monitored by TLC to ensure completeness. The mixture was extracted with water (20 mL) and ethyl acetate (40 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to obtain 12-6 (1.0 g, 2.4 mmol), with a yield of 63%. M / S: 420.1 (M + H2O) + ).

[0495] Synthesis of intermediate: (R)-9-(1-aminoethyl)-2-(2,4-difluorophenyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (12-7)

[0496]

[0497] 12-6 (1.0 g, 2.4 mmol) was dissolved in DCM (2 mL), and a dioxane solution of HCl (4 N, 2 mL) was added. The mixture was stirred at room temperature, and the reaction was monitored by TLC until complete. Water (10 mL) was added, and the mixture was separated. The organic layer was removed, and the pH of the aqueous phase was adjusted to 7–8 with saturated sodium bicarbonate solution. The mixture was extracted with DCM (2 mL × 2), and the combined organic layers were dried over anhydrous sodium sulfate. The mixture was filtered, and the organic layer was concentrated to obtain 12-7 (0.63 g, 2.0 mmol). Yield: 83%. M / S: 316.1 (M + H) + ).

[0498] Synthesis of compound: (R)-2-((1-(2-(2,4-difluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (compound 41)

[0499]

[0500] 12-7 (63 mg, 0.2 mmol), o-iodobenzoic acid (99 mg, 0.4 mmol), copper powder (25 mg, 0.4 mmol), and triethylamine (60 mg, 0.6 mmol) were added to DMA (1 mL). Under nitrogen protection, the mixture was stirred at 110 °C for 4 hours. The reaction was monitored by TLC until complete. Water (2 mL) was added, and the mixture was extracted with ethyl acetate (1 mL × 2). The combined organic layers were concentrated to dryness, and purified by column chromatography to give compound 41 (60 mg, 0.14 mmol), with a yield of 70%. M / S: 436.1 (M + H) + ).

[0501] HNMR:1 H NMR (400MHz, DMSO-d6) δ12.78(s,1H),8.76(s,1H),8.54(s,1H),8.34–8.26(m,1H),7.84–7.78(m,2H),7.51–7.43(m,1H),7.34–7.27(m,1H),7. 18(t,J=7.8Hz,1H),6.83(d,J=1.5Hz,1H),6.54(t,J=7.5Hz,1H),6.38(d,J=8.5Hz,1H),5.55–5.44(m,1H),2.35(s,3H),1.64(d,J=6.6Hz,3H).

[0502] Example 9: Synthesis of compound 3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-indoline-8-yl)ethyl)amino)piperidine-2,6-dione (compound 117)

[0503]

[0504] Step 1: Synthesis of the target compound 3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-indoline-8-yl)ethyl)amino)piperidine-2,6-dione (compound 117)

[0505] Procedure: Compound 8-6 (synthesis described in Example 6, intermediate 8-6 synthesis, 50 mg; 0.15 mmol) was dissolved in acetonitrile (1 ml). 3-Amino-2,6-piperidinedione (22 mg; 0.17 mmol) and triethylamine (18 mg; 0.18 mmol) were added sequentially with stirring at room temperature. The mixture was then heated to 90 °C and stirred overnight. TLC monitoring was performed. After the reaction was complete, column chromatography was used to obtain pure compound 117 (35 mg; 0.08 mmol), yield 55%. Ms: 427 (M+H) + ); 1 H NMR (400MHz, DMSO-d6) δ10.67 (s, 1H), 8.08 (tdd, J = 9.0, 6.3, 3.1Hz, 1H), 7.82 ( s,1H),7.74(s,1H),7.57(ddd,J=11.6,8.8,2.5Hz,1H),7.38(tt,J=8.4,3.1Hz ,1H),6.75(s,1H),4.87–4.38(m,1H),3.21(m,1H),2.47–2.38(m,1H),2.06(m, 1H),1.87(m,1H),1.71(m,1H),1.42(m,1H),2.44(s,3H),1.54(d,J=6.9Hz,3H).

[0506] Example 10: Synthesis of compound 2-(2,4-difluorophenyl)-6-methyl-8-((1R)-1-((2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)ethyl)-4H-methylene-4-one (compound 57)

[0507]

[0508] Step 1: Synthesis of (R)-2-(2,4-difluorophenyl)-6-methyl-8-(1-((2-(2,2,2-trifluoroacetyl)phenyl)amino)ethyl)-4H-methylene-4-one (16-1)

[0509]

[0510] Procedure: 4-7 (synthesis details in General Intermediate Synthesis, 0.1 g, 317.14 μmol), 2,2,2-trifluoro-1-(2-fluorophenyl)ethane-1-one (121.85 mg, 634.28 μmol), and N-ethyl-N-isopropylpropyl-2-amine (81.98 mg, 634.28 μmol) were dissolved in N,N-dimethylacetamide (5.0 mL). The reaction was carried out under nitrogen protection at 95 °C with stirring for 48 hours. TLC monitoring was performed. After the reaction was complete, 10.0 mL of brine was added, and the mixture was extracted with EA (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, evaporated to dryness, and the crude product was purified by column chromatography to obtain 16-1 (76.0 mg, 155.92 μmol), yield 49%. Ms: 488.1 (M + H + )

[0511] Step 2: Synthesis of compound 2-(2,4-difluorophenyl)-6-methyl-8-((1R)-1-((2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)ethyl)-4H-methylene-4-one (compound 57)

[0512]

[0513] Procedure: 16-1 (70.0 mg, 143.61 μmol) was dissolved in methanol (5.0 mL), and sodium borohydride (10.87 mg, 287.22 μmol) was added. The reaction was stirred at room temperature for 2 hours, and monitored by TLC. After the reaction was complete, the reaction solution was directly purified by column chromatography to give compound 57 (30.0 mg, 61.29 μmol), yield 42%. Ms: 490.1 (M+H) + )

[0514] HNMR: 1H NMR (400MHz, DMSO-d6) δ8.11 (td, J=8.9, 6.5Hz, 1H), 7.73 (dd, J=2.3, 1.0Hz, 1H),7.62–7.54(m,2H),7.38–7.23(m,2H),6.97(q,J=6.5,5.4Hz,2H),6.81(s ,1H),6.56(t,J=7.4Hz,1H),6.32(d,J=8.3Hz,1H),6.13(d,J=7.1Hz,1H),5.5 5(d,J=8.9Hz,1H),5.16(t,J=6.8Hz,1H),2.33(s,3H),1.57(d,J=6.6Hz,3H).

[0515] Example 11: Synthesis of compound (R)-2-((1-(2-(4,4-difluorocyclohexyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid (compound 58)

[0516]

[0517] Step 1: Synthesis of intermediate 1-(3-bromo-2-hydroxy-5-methylphenyl)-3-(4,4-difluorocyclohexyl)propane-1,3-dione (17-1)

[0518]

[0519] Add compound 1-(3-bromo-2-hydroxy-5-methylphenyl)ethane-1-one (1.3 g, 5.7 mmol) and tetrahydrofuran (15 mL) to a 100 mL reaction flask, and add bis(trimethylsilylaminolithium) (1 M, 34.2 mL, 34.2 mmol) dropwise at -70 °C. React at this temperature for one hour. In a 50 mL reaction flask, compound 4,4-difluorocyclohexane-1-carboxylic acid (1.1 g, 6.8 mmol), N,N-dimethylformamide (1 drop), and dichloromethane (20 mL) were added. Oxaloyl chloride (0.73 g, 8.6 mmol) was added dropwise under ice bath conditions. The reaction was carried out at room temperature for 1 hour. After concentration, tetrahydrofuran (10 mL) was added dropwise to the reaction solution at -70 °C, and the reaction was allowed to proceed overnight. After the reaction was complete, the pH was adjusted to 5-6 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL x 3 times), and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give intermediate 17-1 (0.97 g), yield 45%. Ms: 375.1, 377.1 (M+H) + )

[0520] Step 2: Synthesis of intermediate 8-bromo-2-(4,4-difluorocyclohexyl)-6-methyl-4H-chromen-4-one (17-2)

[0521]

[0522] Compound 17-1 (970 mg, 2.6 mmol), concentrated sulfuric acid (2 mL), and acetic acid (10 mL) were added to a 50 mL reaction flask. The reaction mixture was heated to 100 °C and reacted. After the reaction was complete, it was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give intermediate 17-2 (870 mg), yield 94%. Ms: 357.1, 359.1 (M+H) + )

[0523] Step 3: Synthesis of intermediate 8-acetyl-2-(4,4-difluorocyclohexyl)-6-methyl-4H-chromen-4-one (17-3)

[0524]

[0525] Compound 17-2 (870 mg, 2.5 mmol), tributyl(1-ethoxyethylene)tin (1.3 g, 3.7 mmol), diethylpropylethylamine (945 mg, 7.3 mmol), and dioxane (10 mL) were added to a 100 mL reaction flask. After purging with nitrogen, tetra(triphenylphosphine)palladium (282 mg, 0.24 mmol) was added. The reaction was heated to 95 °C and carried out overnight. After the reaction was completed, the mixture was cooled to room temperature, and 6N dilute hydrochloric acid (5 mL) was added. The mixture was stirred for 1 hour, and then saturated potassium fluoride aqueous solution (15 mL) was added. The mixture was stirred for 1 hour, filtered, and the filter cake was washed three times with ethyl acetate (20 mL). The layers were separated, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the mixture was passed through a silica gel column to obtain intermediate 17-3 (670 mg), with a yield of 84%. Ms: 321.1 (M+H + )

[0526] Step 4: Synthesis of intermediate (R,Z)-N-(1-(2-(4,4-difluorocyclohexyl)-6-methyl-4-oxo-4H-chromene-8-yl)ethylene)-2-methylpropane-2-sulfonamide (17-4)

[0527]

[0528] Compound 17-3 (670 mg, 2.1 mmol), (R)-tert-butylsulfinamide (507 mg, 4.2 mmol), tetraisopropyl titanate (2.4 g, 8.4 mmol), and tetrahydrofuran (15 mL) were added to a 50 mL reaction flask. The mixture was purged with nitrogen and heated under reflux overnight. After the reaction was complete, the mixture was cooled to room temperature, and saturated brine (10 mL) was added. The mixture was stirred for 0.5 hours, filtered, and the filter cake was washed three times with ethyl acetate (10 mL). The layers were separated, combined, dried over anhydrous sodium sulfate, concentrated, and column-secreting to give intermediate 17-4 (780 mg), yield 88%. Ms: 424.1 (M+H + )

[0529] Step 5: Synthesis of intermediate (R)-N-((R)-1-(2-(4,4-difluorocyclohexyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfonamide (17-5)

[0530]

[0531] Compound 17-4 (780 mg, 1.8 mmol), cerium trichloride heptahydrate (343 mg, 0.9 mmol), and methanol (10 mL) were added to a 50 mL reaction flask. The mixture was cooled to -70 °C with stirring. A methanol solution of sodium borohydride (210 mg, 5.5 mmol) was added dropwise. After the addition was complete, the mixture was allowed to warm naturally overnight. Ethyl acetate was added, and the mixture was filtered. The filtrate was rotary evaporated, and ethyl acetate was added again. The filtrate was then concentrated and passed through a silica gel column to give intermediate 17-5 (500 mg), with a yield of 65%. Ms: 426.1 (M+H) + )

[0532] Step 6: Synthesis of intermediate ((R)-8-(1-aminoethyl)-2-(4,4-difluorocyclohexyl)-6-methyl-4H-chromene-4-one (17-6)

[0533]

[0534] Compound 17-5 (500 mg, 1.2 mmol) and ethyl acetate (5 mL) were added to a 25 mL reaction flask. A solution of dioxane chloride (5 mL) was added with stirring. The reaction was stirred at room temperature until complete. The solvent was concentrated, and an aqueous sodium bicarbonate solution (5 mL) was added. The mixture was extracted with dichloromethane (5 mL x 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give intermediate 17-6 (250 mg), yield 65%. Ms: 322.1 (M+H) + )

[0535] Step 7: Synthesis of compound (R)-2-((1-(2-(4,4-difluorocyclohexyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid (compound 58)

[0536]

[0537] Compound 17-6 (60 mg, 0.19 mmol), o-iodobenzoic acid (72 mg, 0.29 mmol), triethylamine (38 mg, 0.38 mmol), and N,N-dimethylacetamide (1 mL) were added to a 25 mL reaction flask. The mixture was purged with nitrogen, and copper powder (12 mg, 0.19 mmol) was added. The mixture was heated to 110 °C and reacted for approximately 1-2 hours. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 4-5 with 1 N hydrochloric acid aqueous solution. Ethyl acetate (5 mL) was added, and the mixture was separated. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by plate preparation to obtain compound 58 (18 mg), with a yield of 21%. Ms: 442.1 (M+H) + ), 1 H NMR (400MHz, DMSO-d6) δ12.78(s,1H),8.43(s,1H),7.81(dd,J=7.9,1.7Hz,1H),7.69(d,J=2.1Hz,1H),7.54(d,J=2.2Hz,1H),7.28–7.16(m, 1H), 6.54 (t, J = 7.5Hz, 1H), 6.46 (d, J = 8.4Hz, 1H), 6.25 (s, 1H), 5.13 (d, J = 6.7Hz, 1H), 2.34 (s, 3H), 2.22–1.64 (m, 9H), 1.60 (d, J = 6.6Hz, 3H).

[0538] Example 12: Synthesis of methyl (R)-3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)furan-2-carboxylate (compound 63)

[0539]

[0540] Step 1: Synthesis of intermediate (R)-N-((R)-1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfonamide (18-1)

[0541]

[0542] (R)-N-((R)-1-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfonamide (2.0 g, 5.45 mmol), (2,4-difluorophenyl)boronic acid (6.9 g, 43.59 mmol), cesium carbonate (3.6 g, 10.91 mmol), cuprous thiophene-2-carboxylate (I) (5.2 g, 27.25 mmol), tetrakis(triphenylphosphine)palladium (1.2 g, 1.09 mmol), 4A molecular sieve (200 mg), and 1,4-dioxane (40 mL) were sequentially added to a sealed container. Under nitrogen protection, the container was sealed and reacted at 100 °C until the reaction was complete. Cooled to room temperature, the product was directly concentrated using silica gel. The concentrate was then subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give (R)-N-((R)-1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfonamide (1.0 g, 2.4 mmol), yield 44%. M / S: 420 (M+H) + ).

[0543] Step 2: Synthesis of intermediate ((R)-8-(1-aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-chromene-4-one (18-2)

[0544]

[0545] 18-1 (1.0 g, 2.38 mmol) was dissolved in ethyl acetate (20 mL), cooled in an ice-water bath, and a dioxane solution of HCl (4N, 5 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, water (30 mL) was added, and the mixture was separated. The pH of the aqueous phase was adjusted to 7–8 with sodium carbonate, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated to give (R)-8-(1-aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-chromene-4-one (700 mg, 2.2 mmol). Yield: 93%. M / S: 316 (M+H+).

[0546] Step 3: Synthesis of compound (R)-3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)furan-2-carboxylic acid methyl ester (compound 63)

[0547]

[0548] 18-2 (100 mg, 0.32 mmol), methyl 3-bromofuran-2-carboxylate (162 mg, 0.79 mmol), cesium carbonate (310 mg, 0.95 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (55 mg, 0.09 mmol), and tris(dibenzylene-BASE-acetone)palladium (58 mg, 0.09 mmol) were added to 1,4-dioxane (2 mL). The mixture was reacted at 120 °C under nitrogen protection. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature and then directly mixed with silica gel. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give methyl (R)-3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)furan-2-carboxylate (20 mg, 0.05 mmol), yield 17%. M / S: 440 (M+H + ).

[0549] 1 H NMR (400 MHz, Chloroform-d) δ7.93 (dd, J = 2.4, 0.8 Hz, 1H), 7.84 (d, J = 6.2 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 2.2 Hz,1H),7.11–7.07(m,1H),7.02(s,1H),6.84(s,1H),5.89(d,J=2.0 Hz,1H),5.11(q,J=6.6 Hz,1H),3.91(s,3H),2.43(s,3H),1.67(d,J=6.8 Hz,3H).

[0550] Example 13: Synthesis of compound (R,E)-2-(2,4-difluorophenyl)-6-methyl-8-(1-((2-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)phenyl)amino)ethyl)-4H-methylene-4-one (compound 64)

[0551]

[0552] Step 1: Synthesis of (R)-2-(2,4-difluorophenyl)-6-methyl-8-(1-((2-(2,2,2-trifluoroacetyl)phenyl)amino)ethyl)-4H-methylene-4-one (19-1)

[0553]

[0554] Procedure: 4-7 (synthesis details in the section on synthesis of general intermediates, 0.1 g, 317.14 mmol), 2,2,2-trifluoro-1-(2-fluorophenyl)ethane-1-one (121.85 mg, 634.28 mmol), and N-ethyl-N-isopropylpropyl-2-amine (81.98 mg, 634.28 mmol) were dissolved in N,N-dimethylacetamide (2.0 mL). The reaction was carried out under nitrogen protection with stirring at 80 °C and monitored by TLC. After the reaction was complete, brine (5.0 mL) was added, and the mixture was extracted with EA (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, evaporated to dryness, and the crude product was purified by column chromatography to give 19-1 (80 mg, 164.13 mmol), yield 51%. Ms: 488.1 (M + H + )

[0555] Step 2: Synthesis of compound (R, E)-2-(2,4-difluorophenyl)-6-methyl-8-(1-((2-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)phenyl)amino)ethyl)-4H-methylene-4-one (compound 64);

[0556]

[0557] Procedure: 19-1 (20.0 mg, 47.19 μmol) was dissolved in ethanol (4.0 mL), and hydroxylamine hydrochloride (29.84 mg, 441.56 mmol) was added. The reaction was stirred at 80 °C for 12 hours, and monitored by TLC. After the reaction was complete, the reaction solution was directly purified by column chromatography to give compound 64 (9.0 mg, 17.91 mmol), yield 43%. Ms: 503.1 (M+H) + )

[0558] HNMR: 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),9.03(d,J=6.5Hz,1H),7.96(td,J=8.9,6.5Hz,1H),7.70(d,J=8.4Hz,1H),7.59(dd,J=2.1,0.9Hz,1H ),7.53–7.41(m,2H),7.29(d,J=2.2Hz,1H),7.04(s,1H),6.76–6.68(m,2H),5.26(h,J=6.6,6.2Hz,1H),2.28(s,3H),1.63(d,J=6.7Hz,3H).

[0559] Example 14: Synthesis of compound (R)-6-chloro-3-((1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuterated methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (compound 88)

[0560]

[0561] Step 1: Synthesis of intermediate 2-amino-3-bromo-5-fluoro-N-deuterated methylbenzamide (20-1)

[0562]

[0563] 2-Amino-3-bromo-5-fluorobenzoic acid (4.50 g, 19.2 mmol) was dissolved in anhydrous THF (50 mL). CDI (4.67 g, 28.8 mmol) was added in portions. The system gradually bubbled, and after reacting for 2.0 h, the system was cooled to 0–10 °C. DIEA (7.95 g, 79.2 mmol) and deuterated methylamine hydrochloride (5.58 g, 79.2 mmol) were added, and the reaction was allowed to proceed for 1.0 h. TLC analysis showed the reaction was complete. The mixture was extracted with 100 mL of water and EA (40 mL × 2), the organic phase was concentrated, slurried with ethanol, and filtered to obtain 20-1 (3.20 g, 9.14 mmol), with a yield of 66%. M / S: 250 / 252 (M+H) + ).

[0564] Step 2: Synthesis of the intermediate 8-bromo-6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuterated methylquinazolin-4(3H)-one (20-2)

[0565]

[0566] 20-1 (3.00 g, 12.0 mmol), 5-fluoropyridine-2-aldehyde (1.80 g, 14.4 mmol), and elemental iodine (3.65 g, 14.4 mol) were successively dissolved in DMSO (45 mL). The mixture was stirred at 100 °C and monitored by TLC. After the reaction was complete, 100 mL of ice water was added to the system, followed by 5.0 mL of saturated sodium thiosulfate solution. The mixture was filtered to obtain the crude product, which was then slurried and filtered with ethanol to obtain 20-2 (4.20 g, 11.8 mmol), with a yield of 98%. M / S: 355 / 357 (M+H + ).

[0567] Step 3: Synthesis of the intermediate 8-acetyl-6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuterated methylquinazolin-4(3H)-one (20-3)

[0568]

[0569] 20-2 (4.20 g, 11.8 mmol), tin reagent (6.37 g, 17.7 mmol), DIEA (4.52 g, 35.2 mol), and Pd(PPh3)Cl2 (0.82 g, 0.12 mmol) were added sequentially to Dioxane (45 mL). Under nitrogen protection, the reaction was carried out at 95 °C for 12 h. The reaction was monitored by TLC until complete. After cooling, DCM (40 mL) was added, and the pH was adjusted to 2-3 with 6 M HCl. After stirring for 1-2 h, TLC was monitored again. A saturated KF solution was added and stirred for 1.0 h (pH = 7). The mixture was filtered, and the filter cake was washed with DCM. The aqueous phase was extracted with DCM (30 mL × 2), dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was pulped with MTBE to obtain 20-3 (3.20 g, 10.1 mmol), with a yield of 85%. M / S: 319 (M + H + ).

[0570] Step 4: Synthesis of intermediate (R,Z)-N-(1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuterated methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylene)-2-methylpropane-2-sulfonamide (20-4)

[0571]

[0572] 20-3 (3.20 g, 10.1 mmol), (R)-(+)-tert-butylsulfinamide (3.06 g, 25.2 mmol), and tetraethyl titanate (11.0 g, 50.5 mmol) were added sequentially to anhydrous THF (32 mL), and stirred at 85 °C for 12 h. The reaction was monitored by TLC until complete. The reaction mixture was poured into 100 mL of water, filtered, the filter cake was washed with DCM, separated, extracted with DCM (30 mL × 2), dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain crude 20-4 (3.50 g, 7.55 mmol), which was used directly in the next step. M / S: 422 (M+H + ).

[0573] Step 5: Synthesis of intermediate N-((R)-1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuterated methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfonamide (20-5)

[0574]

[0575] Crude 20-4 (3.50 g, 7.55 mmol) and CeCl3·7H2O (1.32 g, 3.77 mmol) were added sequentially to MeOH (70 mL). The reaction system was cooled to -60 to -70 °C, and NaBH4 (0.63 g, 15.1 mmol) was added in portions. After the addition was complete, the temperature was slowly raised to room temperature, and the reaction was monitored by TLC to confirm completion. Saturated ammonium chloride aqueous solution (200 mL) was added, and the mixture was extracted with DCM (80 mL × 2). The organic phase was concentrated to obtain the crude product, which was purified by column chromatography to obtain 20-5 (1.90 g, 4.48 mmol). The overall yield of the two steps was 44%. M / S: 424 (M + H + ). 1 H-NMR (400MHz, DMSO-d6) δ8.75(t,J=1.8Hz,1H),8.04(dd,J=6.7,1.8Hz,2H),7.87(dd,J=9.8,3.1Hz,1H), 7.78(dd,J=8.4,3.0Hz,1H),6.00(d,J=8.9Hz,1H),5.31–5.19(m,1H),1.43(d,J=6.8Hz,3H),1.09(s,9H).

[0576] Step 6: Synthesis of intermediate (R)-8-(1-aminoethyl)-6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuterated methylquinazolin-4(3H)-one (20-6)

[0577]

[0578] 20⁻⁵ (1.90 g, 4.48 mmol) was dissolved in DCM / THF (10 mL / 20 mL), and a dioxane solution of HCl (4 N, 3.0 mL) was added dropwise. The mixture was stirred at room temperature, and a solid precipitated. The reaction was monitored by TLC until complete. The solid was filtered and dissolved in water. The pH was adjusted to 7–9 with saturated sodium bicarbonate solution, and a solid precipitated. The solid was filtered and dried to give 20⁻⁶ (1.00 g, 3.13 mmol), with a yield of 70%. M / S: 320 (M + H₂) + ).

[0579] Step 7: Synthesis of intermediate (R)-5-chloro-2-((1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuterated methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate tert-butyl ester (20-7)

[0580]

[0581] 20-6 (150 mg, 0.47 μmol), tert-butyl 2-bromo-5-chlorobenzoate (120 mg, 1.41 μmol), Pd2(dba)3 (43.0 mg, 0.04 μmol), Xantphos (54.0 mg, 0.09 μmol), and Cs2CO3 (450 mg, 1.41 μmol) were added to dioxane (2.0 mL). Under nitrogen protection, the mixture was stirred at 110 °C for 12 hours. The reaction was monitored by TLC. After cooling, 20 mL of water was added, and the mixture was extracted with EA (10 mL × 3). The organic phase was concentrated to obtain the crude product, which was purified by column chromatography to obtain 20-7 (170 mg, 0.32 μmol), with a yield of 68%. M / S: 531 (M+H) + ).

[0582] Step 8: Synthesis of compound (R)-5-chloro-2-((1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuterated methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (compound 88)

[0583]

[0584] 20-7 (170 mg, 0.32 μmol) was dissolved in FA (2.0 mL), and the reaction was stirred at 60 °C for 1.0 h. The reaction was monitored by TLC. After completion, the pH was adjusted to approximately 3 with HCl (1 N), and the mixture was extracted with EA. The organic phase was concentrated to obtain the crude product, which was then purified by Pre-TLC to give compound 88 (101 mg, 0.213 μmol), with a yield of 66%. M / S: 474 (M+H) + ). 1 H-NMR (400MHz, DMSO-d6) δ13.16(s,1H),8.76(d,J=2.8Hz,1H),8.42(d,J=6.7H z,1H),8.12(dd,J=8.8,4.5Hz,1H),8.03(td,J=8.7,2.9Hz,1H),7.77(dd,J=8.3 ,3.0Hz,1H),7.73(d,J=2.6Hz,1H),7.60(dd,J=9.4,3.0Hz,1H),7.21(dd,J=9.0 ,2.7Hz,1H),6.42(d,J=9.1Hz,1H),5.46(t,J=6.5Hz,1H),1.59(d,J=6.7Hz,3H)

[0585] Example 15: Synthesis of compound (R)-6-chloro-3-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl)amino)pyridinecarboxylic acid (compound 115):

[0586]

[0587] Synthesis of intermediate: 2-amino-3-bromo-N,5-dimethylbenzamide (Int. C-115-1):

[0588]

[0589] 2-Amino-3-bromo-5-chloro-N-methylbenzoic acid (SM, 10 g, 43.5 mmol) was dissolved in anhydrous THF (40 mL). CDI (9.2 g, 0.565 mol) was added in portions. The system gradually bubbled, and after 2 h of reaction, the system was cooled to 0 °C. A methylamine aqueous solution (30 mL) was added dropwise, and the reaction was allowed to proceed for 1 h. TLC analysis confirmed the reaction was complete. Water (500 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, and the solid was washed with tertiary methyl ether (30 mL × 2) and dried to give 7.8 g of a white solid, Int. 115-1. Yield: 73.9%, M / S: 243, 245 (M + H₂). + ).

[0590] Synthesis of intermediate: 8-bromo-3,6-dimethyl-2-phenylquinazoline-4(3H)-one (Int. C-115-1):

[0591]

[0592] Int. 115-1 (5 g, 20.6 mmol), benzaldehyde (2.8 g, 26.7 mmol), and elemental iodine (6.8 g, 26.7 mmol) were dissolved sequentially in DMSO (50 mL). The reaction was carried out at 100 °C for 6 h, monitored by TLC. After the reaction was complete, the system was added to ice water, and saturated sodium thiosulfate solution was slowly added until the system became colorless. The mixture was stirred for 2 h, filtered, and the solid was washed with methyl ether (20 mL × 2) and dried to give 5.9 g of white solid Int. 115-2, yield 87.2%, M / S: 329, 331 (M+H+).

[0593] Synthesis of intermediate: 8-acetyl-3,6-dimethyl-2-phenylquinazoline-4(3H)-one (Int. 115-3):

[0594]

[0595] Weigh Int. 115-2 (5.9 g, 17.9 mmol), tin reagent (9.8 g, 26.9 mmol), DIPEA (4.7 g, 35.8 mmol), and Pd(PPh3)Cl2 (1.9 g, 2.7 mmol) sequentially into Dioxane (60 mL). Under nitrogen protection, react at 95 °C for 8 h, monitored by TLC. After cooling, add 20 mL of 6N HCl, stir at room temperature for 0.5 h, monitor by TLC. Add 100 mL of water (15.6 g KF), stir for 2 hours, add EA (100 mL), filter, wash the solid with EA (50 mL × 2), separate, extract with EA (30 mL) in aqueous phase, combine the EA, wash with saturated brine (30 mL × 2), dry to anhydrous sodium sulfate, concentrate, and column chromatography to obtain 4.3 g solid Int. C115-3, yield 81.8%, M / S: 293 (M + H). + ).

[0596] Synthesis of intermediate: (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethylene)-2-methylpropane-2-sulfonamide (Int. 115-4):

[0597]

[0598] Int. 115-3 (4.3 g, 14.7 mmol), (R)-(+)-tert-butylsulfinamide (3.6 g, 29.4 mmol), and tetraethyl titanate (10.1 g, 44.1 mmol) were added sequentially to anhydrous THF (21 mL), and stirred at 80 °C for 6 h, monitored by TLC. After cooling, EA (100 mL) was added for dilution, and the mixture was poured into water (200 mL) and stirred for 30 min. The mixture was filtered, separated, extracted with EA (50 mL × 2), washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain 4.9 g of pale yellow solid Int. 115-4, yield 84.5%, M / S: 396.1 (M + H). + ).

[0599] Synthesis of intermediate: (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfonamide (Int. 115-5)

[0600]

[0601] Int.C115-4 (4.9 g, 12.4 mmol) and CeCl3·7H2O (2.3 g, 6.2 mmol) were added sequentially to MeOH (25 mL) and THF (25 mL) under nitrogen protection. After dissolution, the solution was cooled to -78 to -20 °C. NaBH4 (706 mg, 18.6 mmol) was dissolved in 5 mL of DMA and slowly added dropwise to the reaction solution. The solution was allowed to warm naturally to room temperature (4 H) and monitored by TLC. The solution was cooled to 0 °C, and the pH was adjusted to 3-4 with 1 N HCl. DCM (100 mL) and water (150 mL) were added. The solution was separated, and the aqueous phase was extracted with DCM (50 mL × 2). The DCMs were combined, washed once with saturated sodium chloride solution (50 mL), dried, concentrated, and column chromatography was performed to obtain 3.6 g of solid Int.115-5. Yield: 73.1%, M / S: 397.1 (M+H+), de value: 98.2%.

[0602] Synthesis of intermediate: (R)-8-(1-aminoethyl)-3,6-dimethyl-2-phenylquinazoline-4(3H)-one (Int. 115-6): Int. 115-5 (3.6 g, 9.1 mmol) was dissolved in DCM (20 mL), and HCl-Dioxane (4 N, 20 mL) was added. The reaction was carried out at room temperature for 3 h, monitored by TLC. The reaction solution was concentrated to dryness, and DCM was used once. EA (30 mL) and water (30 mL) were added to dissolve the solid. The mixture was separated, and EA (20 mL) was used for extraction once. The aqueous phase was adjusted to pH 8-9 with sodium bicarbonate, and then extracted with DCM (50 mL × 4). The solution was dried and concentrated to give 2.1 g of white solid Int. 115-6, yield 78.9%, M / S: 294 (M+H+). Synthesis of intermediate: methyl(R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl)amino)pyridinecarboxylic acid (Int. 115-7): Int. 115-6 (400 mg, 1.36 mmol), methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (337 mg, 1.77 mmol), and DIPEA (351 mg, 2.72 mmol) were added to DMA (5 mL). The mixture was stirred at 90 °C for 6 hours and monitored by TLC. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with EA (10 mL × 3). The EA was combined, washed with water (20 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give 450 mg of solid (Int. 115-7), yield 71.4%. M / S: 463 (M+H+). Synthesis of compound (R)-6-chloro-3-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl)amino)pyridinecarboxylic acid (compound 115).

[0603] Int. 115-7 (450 mg, 0.97 mmol) was dissolved in THF (5 mL), and potassium trimethylsilanolate (250 mg, 1.84 mmol) was added. The reaction was carried out at room temperature for 15 min, monitored by TLC, and water (20 mL) was added. The pH was adjusted to 2-3 with 1 N HCl. The mixture was extracted with DCM (20 mL × 3). The DCM samples were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to give 360 ​​mg of solid (compound 115), yield 82.5%, M / S: 449 (M + H). + )

[0604] 1H NMR(400MHz,Chloroform-d)δ8.55(d,J=2.9Hz,1H),8.23(d,J=2.4Hz,1H),8.07(dd,J=8.7,4.4Hz,1H),7.68 –7.61(m,2H),5.13(p,J=6.7Hz,1H),4.70(d,J=6.6Hz,1H),3.66(s,3H),1.60(d,J=6.8Hz,3H),1.16(s,9H).

[0605] Example 16: Synthesis of compound (R)-6-chloro-3-((1-(2-(5-fluoropyridin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)pyridinecarboxylic acid (compound 66)

[0606]

[0607] Step 1: Synthesis of intermediate 2-amino-3-bromo-N,5-dimethylbenzamide (25-1)

[0608] 2-Amino-3-bromo-5-methylbenzoic acid (230 g, 1.0 mol) was dissolved in THF (2 L), and CDI (178 g, 1.1 mol) was added in portions. The system gradually bubbled, and after reacting for 2 hours, the system was cooled to 10 °C, and methylamine aqueous solution (920 mL) was added dropwise, with the temperature controlled below 15 °C during the addition. The reaction was allowed to proceed for 1 hour after the addition was complete. TLC confirmed that the reaction was complete. The reaction solution was concentrated to remove some of the solvent until a solid precipitated, which was then poured into water (2 L) and stirred for 1 hour. The mixture was filtered and dried under reduced pressure to constant weight to obtain 230 g of product (intermediate 25-1), with a yield of 94.6%. Ms: 243.0 / 245.0 (M+H + ).

[0609] Step 2: Synthesis of intermediate 8-bromo-2-(5-fluoropyridin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (25-2)

[0610]

[0611] Intermediate 25-1 (60.0 g, 0.25 mol), 5-fluoropyridine-2-carboxaldehyde (37.0 g, 0.30 mol), and iodine (75.2 g, 0.30 mol) were sequentially added to dimethyl sulfoxide (900 mL) at room temperature. The mixture was heated to 95 °C and reacted overnight. The reaction solution was cooled to room temperature and slowly poured into water (3000 mL). A saturated sodium thiosulfate aqueous solution (300 mL) was added, and the mixture was stirred for 2 hours. The mixture was filtered, and the filter cake was washed once with water (100 mL), once with anhydrous ethanol (100 mL), and once with methyl tert-butyl ether (100 mL). The product (intermediate 25-2) was obtained by vacuum drying, yielding 74.7 g of the product (intermediate 25-2), with a yield of 86.9%. Ms: 243.0 / 245.0 (M+H) + ).

[0612] Step 3: Synthesis of intermediate 8-acetyl-2-(5-fluoropyridin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (25-3)

[0613]

[0614] Intermediate 25-2 (74.7 g, 0.21 mol), tributyl(1-ethoxyethylene)tin (116.2 g, 0.32 mol), N,N-diisopropylethylamine (83.2 g, 0.64 mol), and Pd(PPh3)2Cl2 (15.0 g, 0.02 mol) were sequentially added to N,N-dimethylacetamide (800 mL) at room temperature. The mixture was purged with nitrogen three times, heated to 100 °C, and reacted overnight. The reaction solution was then cooled to room temperature, and a dioxane solution of hydrogen chloride (4 mol / L) was slowly added to adjust the temperature. Adjust the pH to 1-2, add a small amount of water (20 mL), stir for 1 hour, dilute with ethyl acetate (2000 mL), add water (4000 mL), adjust the pH to greater than 7 with potassium fluoride aqueous solution, stir for 2 hours, filter, and slurry the filter cake with ethyl acetate (500 mL × 3). Combine the filtrates and separate the layers. Extract the aqueous layer with ethyl acetate (500 mL), combine the organic layers, dry with anhydrous sodium sulfate, concentrate the residue, and slurry with methanol (500 mL) to obtain 60.8 g of product (intermediate 25-3), yield 91.0%. Ms: 312.0 (M+H) + )

[0615] Step 4: Synthesis of intermediate (R,Z)-N-(1-(2-(5-fluoropyridin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylene)-2-methylpropane-2-sulfinamide (25-4)

[0616]

[0617] Intermediate 25-3 (60.8 g, 0.20 mol), (R)-(+)-tert-butylsulfinamide (47.3 g, 0.39 mol), and tetraethyl titanate (222.7 g, 0.98 mol) were sequentially added to 300 mL of dry tetrahydrofuran at room temperature. The mixture was heated to 90 °C and reacted overnight. The reaction solution was cooled to room temperature, diluted with 2000 mL of dichloromethane, and then water (4000 mL) was added. The mixture was stirred for 0.5 hours, filtered, and the filter cake was slurried with 500 mL × 3 of dichloromethane. The filtrates were combined and separated into two layers. The aqueous layer was extracted with 500 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 90.0 g of crude yellow oil (intermediate 25-4), which was directly used in the next reaction. Ms: 415.1 (M+H + ).

[0618] Step 5: Synthesis of intermediate (R)-N-((R)-1-(2-(5-fluoropyridin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (25-5)

[0619]

[0620] Intermediate 25-4 (90.0 g, 0.20 mol) and cerium chloride heptahydrate (36.4 g, 0.10 mol) were added sequentially to methanol (2000 mL) at room temperature. The mixture was cooled to -65°C in a dry ice bath. Sodium borohydride (22.2 g, 0.58 mol) was dissolved in methanol in portions and added dropwise to the reaction system, keeping the temperature below -60°C for approximately 30 minutes. The dry ice bath was removed, and the mixture was allowed to warm naturally to room temperature. Diluted with dichloromethane (2000 mL), then water (4000 mL) was added. The pH was adjusted to 6 with 1 N hydrochloric acid. The mixture was allowed to separate into two layers. The aqueous layer was extracted with dichloromethane (500 mL), and the organic layers were combined. The mixture was washed once with saturated sodium bicarbonate aqueous solution (500 mL), dried over anhydrous sodium sulfate, concentrated, purified by column chromatography, and recrystallized from methanol / water (1:1) to give 50.8 g of the product (intermediate 25-5). The two-step yield was 62.4%. Ms: 417.1 (M+H) + ). 1HNMR(400MHz,Chloroform-d)δ8.55(d,J=2.8Hz,1H),8.06(dt,J=5.5,4.4Hz,2H),7.63(td,J=8.4,2.9Hz,1H),7.53(d,J =2.0Hz,1H),5.08(p,J=6.8Hz,1H),4.91(d,J=6.8Hz,1H),3.65(s,3H),2.50(s,3H),1.60(d,J=6.8Hz,3H),1.15(s,9H).

[0621] Step 6: Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(5-fluoropyridin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (25-6)

[0622]

[0623] Intermediate 25-5 (50.8 g, 0.12 mol) was added to dichloromethane (1000 mL) at room temperature, and a dioxane solution of hydrogen chloride (4 mol / L, 500 mL) was added dropwise. The mixture was stirred for 2 hours, concentrated, and the residue was dissolved in water (1000 mL). Extraction was performed with ethyl acetate (500 mL). The ethyl acetate layer was washed once with 1N hydrochloric acid (100 mL) and discarded. The combined acidic aqueous layers were adjusted to a pH greater than 7, and extracted with dichloromethane (1000 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and the residue was slurried with methyl tert-butyl ether (300 mL) to give 33.4 g of product (intermediate 25-6), yield: 87.7%. Ms: 313.1 (M + H + ). 1 H NMR(400MHz,Chloroform-d)δ8.55(d,J=2.8Hz,1H),8.03(dd,J=2.1,1.0Hz,1H),7.97(dd,J=8.7,4.4Hz,1 H),7.66–7.57(m,2H),4.85(q,J=6.7Hz,1H),3.67(s,3H),2.50(s,3H),2.12(s,2H),1.52(d,J=6.7Hz,3H).

[0624] Step 7: Synthesis of intermediate (R)-6-chloro-3-((1-(2-(5-fluoropyridin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)pyridinecarboxylic acid methyl ester (25-7)

[0625]

[0626] Intermediate 25-6 (200 mg, 0.64 mmol), methyl 6-chloro-3-fluoropyridinecarboxylate (243 mg, 1.28 mmol), and DIPEA (248 mg, 1.92 mmol) were added to N,N-dimethylacetamide (4 mL). The mixture was heated to 100 °C and stirred overnight. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with water (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 210 mg of the product (intermediate 25-7), yield: 68.0%. Ms: 482.1 (M+H) + ).

[0627] Step 8: Synthesis of compound (R)-6-chloro-3-((1-(2-(5-fluoropyridin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)pyridinecarboxylic acid (compound 66)

[0628]

[0629] Intermediate 25-7 (210 mg, 0.44 mmol) was dissolved in dry tetrahydrofuran (4 ml), and potassium trimethylsilanolate (168 mg, 1.31 mmol) was added. The mixture was stirred at room temperature for 20 minutes, and the pH was adjusted to approximately 3 with 0.5 N hydrochloric acid. Extraction was performed with dichloromethane (15 ml × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 180 mg of the product (compound 66), with a yield of 88.3%. Ms: 468.1 (M + H + ). 1 H NMR (400MHz, DMSO-d6) δ12.99(s,1H),8.75(d,J=2.9Hz,1H),8.43(d,J=7.0H z,1H),8.12(dd,J=8.7,4.5Hz,1H),8.01(td,J=8.7,2.9Hz,1H),7.91(dd,J=2 .1,1.0Hz,1H),7.64(d,J=2.1Hz,1H),7.29(d,J=8.9Hz,1H),7.02(d,J=9.1Hz ,1H),5.46(p,J=6.7Hz,1H),3.49(s,3H),2.41(s,3H),1.59(d,J=6.6Hz,3H).

[0630] Example 17: Synthesis of compound (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (compound 4):

[0631]

[0632] Synthesis of intermediate 2-amino-3-bromo-N,5-dimethylbenzamide (4-1)

[0633]

[0634] 2-Amino-3-bromo-5-methylbenzoic acid (SM, 100 g, 435 mmol) was dissolved in anhydrous THF (300 mL). CDI (91.6 g, 565 mmol) was added in portions. The system gradually bubbled, and the reaction proceeded for 1 h. The mixture was cooled to 0 °C, and ammonia (500 mL) was added dropwise. The reaction proceeded for 2 h, monitored by TLC. The reaction solution was poured into water (4 L), stirred for 1 h, filtered, and the solid was washed with tertiary methyl ether (30 mL × 2). The solid was dried to give 87.5 g of a white solid (4-1), yield 87.9%. MS: 228, 231 / (M+H) + ).

[0635] Synthesis of intermediate 8-bromo-3,6-dimethylquinazoline-2,4(1H,3H)-dione (4-2):

[0636]

[0637] 4-1 (31 g, 135 mmol) and triethylamine (27.4 g, 271 mmol) were dissolved in anhydrous THF (300 mL). The mixture was cooled to 0 °C, and triphosgene (20 g, 68 mmol) was slowly added in portions. The ice bath was removed, and the mixture was stirred for 30 min. The temperature was raised to 80 °C and the reaction was carried out for 12 h. The reaction was monitored by TLC. Most of the THF was concentrated, and water (1 L) was added. The mixture was stirred for 1 h, filtered, and the solid was washed with methyl tert-ethyl ether (30 mL × 2) and dried to give 23.2 g of white solid (4-2). MS: 255, 257 / (M+H) + )

[0638] Synthesis of intermediate 8-bromo-2,4-dichloro-6-methylquinazoline (4-3):

[0639]

[0640] Dissolve 4-2 (23.2 g, 91 mmol) in toluene (116 mL), add phosphorus oxychloride (70 g, 455 mmol) dropwise, react at 100 °C for 12 h, monitor by TLC, concentrate the reaction solution to dryness, and perform DCM twice to obtain crude product (4-3), which can be directly used for the next synthesis.

[0641] Synthesis of intermediate 8-bromo-2-chloro-6-methylquinazoline-4(3H)-one (4-4):

[0642]

[0643] 4-3 (crude product) was dissolved in THF (116 mL), and NaOH (2 N, 116 mL) aqueous solution was added dropwise. The system gradually dissolved completely. The solution was monitored by TLC. The pH was adjusted to 6-7 with dilute HCl (1 N), filtered, and dried to obtain 16.5 g of solid (4-4). The two-step yield was 66.3%. MS: 273, 275 / (M+H) + ).

[0644] Synthesis of intermediate 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazoline-4(3H)-one (4-5):

[0645]

[0646] 4-4 (16.5 g, 60 mmol) was dissolved in NMP (90 mL), and 4,4-dimethylpiperidine hydrochloride (10.8 g, 72 mmol) was added. DIPEA (38.7 g, 300 mmol) was added dropwise. The reaction was carried out at 120 °C for 3 h under TLC monitoring. The mixture was then cooled, and the pH was adjusted to 6-7 with dilute HCl (1 N). Extraction was performed using DCM (200 mL × 3), and the extract was dried over anhydrous sodium sulfate. The extract was concentrated and column chromatography was used to obtain 15 g of a yellow solid (4-5), yield 71.4%, MS: 350 / 352 (M+H+).

[0647] Synthesis of intermediate 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-dimethylquinazolin-4(3H)-one (4-6)

[0648]

[0649] Add 4-5 (2.1g, 6mmol), tin reagent (3.3g, 9mmol), and DPIEA (1.5g, 12mmol).

[0650] Pd(PPh3)Cl2 (630 mg, 0.9 mmol) was added sequentially to Dioxane (10 mL). Under nitrogen protection, the reaction was carried out at 95 °C for 8 h, monitored by TLC. The mixture was then cooled, and HCl (6 N, 10 mL) was added. The mixture was stirred for 30 min, monitored by TLC, and water (30 mL, 5.3 g KF) was added. The mixture was stirred for 3 h, and EA (30 mL) was added. The mixture was filtered, and the filter cake was washed with EA (30 mL × 3). The EA mixtures were combined, washed once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to give 1.5 g of solid (4-6), yield 79.9%, MS: 314 (M+H+).

[0651] Synthesis of intermediate (R,E)-N-(1-2-(4,4-dimethylpiperidin-1-yl)-6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylene)-2-methylpropane-2-thioamide (4-7):

[0652]

[0653] 4-6 (1.5 g, 4.8 mmol), (R)-(+)-tert-butylsulfinamide (1.2 g, 9.6 mmol), and tetraethyl titanate (3.3 g, 14.4 mmol) were added sequentially to a THF-free solution (5 mL). The mixture was stirred at 85 °C for 6 h and monitored by TLC. After cooling, EA (30 mL) was added for dilution, and the solution was poured into water (30 mL) and stirred for 30 min. The mixture was filtered, extracted with EA (20 mL × 2) in two separate layers, washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain 1.8 g of pale yellow solid (4-7), yield 75.4%, M / S: 417 (M+H+).

[0654] Synthesis of compound (R)-N-((-R-)1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfonamide (4-8):

[0655]

[0656] Dissolve 4-7 (1.5 g, 3.6 mmol) in DCM / MeOH (7.5 mL / 7.5 mL), add glacial acetic acid (1.3 g, 21.6 mmol) dropwise, cool to -10 °C, and add in portions (680 mg, 10.8 mmol). Allow the mixture to rise naturally for 12 h, monitor by TLC, adjust pH to 9-10 with saturated sodium carbonate solution, extract with EA (20 mL × 3), combine the EA extracts, wash once with saturated sodium chloride solution (10 mL), dry, concentrate, and column chromatography to obtain 1.2 g of white solid (4-8) (79.6% yield, M / S: 419 (M+H)). + ), de value: 98%.

[0657] Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (4-9):

[0658]

[0659] Dissolve 4-8 (1.2 g 2.9 mmol) in DCM (6 mL), add dropwise HCl-Dioxane (6 mL), react at room temperature, monitor by TLC, concentrate the reaction solution to dryness, add water (10 mL) and EA (10 mL), dissolve thoroughly, separate the layers, extract once with EA (10 mL), adjust the pH of the aqueous phase to 8-9 with NaHCO3, extract with DCM (15 mL × 3), dry, concentrate to obtain 0.8 g pale yellow solid (4-9), yield 88.8%, MS: 315 / (M+H) + ).

[0660] Synthesis of compound (R)2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)yl)benzoic acid (compound 4)

[0661]

[0662] Compounds 4-9 (70 mg, 0.22 mmol), 2-iodobenzoic acid (83 mg, 0.33 mmol), TEA (45 mg, 0.44 mmol), and nano-copper powder (14 mg, 0.22 mmol) were added sequentially to DMAc (1 mL). The reaction was carried out at 115 °C for 3 h, monitored by TLC. Water (15 mL) was added, and the pH was adjusted to 3-4 with dilute HCl (1 N). Extraction was performed with EA (10 mL × 3). The EA extracts were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain 35 mg of solid (compound 4), yield 37.9%, MS: 435 / (M+H). + ).

[0663] 1 H NMR (400MHz, CDCl3) δ7.99(d,J=7.9Hz,1H),7.89(s,1H),7.57(s,1H),7.22(t,J=7.8Hz,1H),6.67(s,1H),6.60(dd,J =10.6,8.2Hz,1H),5.56(d,J=6.8Hz,1H),3.22(s,4H),2.39(s,3H),1.72(d,J=6.5Hz,3H),1.26(s,4H),1.03(s,6H).

[0664] Example 18: Synthesis of compound (R)-2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (compound 6):

[0665]

[0666] Synthesis of intermediate 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (6-1):

[0667]

[0668] Intermediate 4-5 (1.5 g, 0.43 mmol, synthesis as described in Example 17, synthesis of intermediate 4-5) and K2CO3 (0.6 g, 8.6 mmol) were added sequentially to DMA (15 mL), followed by dropwise addition of MeI (1.9 g, 12.9 mmol). The reaction was carried out at room temperature and monitored by TLC. Water (30 mL) was added, and the mixture was extracted with EA (30 mL × 3). The EA samples were combined, washed with water (20 mL × 3), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give 1.1 g of solid (6-1), yield 70.5%. MS: 364, 366 / (M+H) + )

[0669] Synthesis of intermediate 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (6-2)

[0670]

[0671] 6-1 (1.1 g, 3 mmol), tin reagent (1.7 g, 4.5 mmol), DIPEA (0.8 g, 6 mmol), and Pd(PPh3)Cl2 (0.3 g, 0.45 mmol) were added sequentially to Dioxane (10 mL). The mixture was reacted under nitrogen protection at 95 °C for 8 h, monitored by TLC. The mixture was then cooled, and HCl (4N, 5 mL) was added. The mixture was stirred for 30 min, monitored by TLC, and water (30 mL, 2.7 g KF) was added. The mixture was stirred for 3 h, filtered, and the filter cake was washed with EA (20 mL × 3). The EA solutions were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and column chromatographically extracted to give 0.7 g of solid (6-2), yield 70.7%. MS: 328 / (M+H) + ).

[0672] Synthesis of intermediate (R,E)-N-(1,2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylene)-2-methylpropane-2-thioamide (6-3)

[0673]

[0674] 6-2 (0.7 g, 2.1 mmol), (R)-(+)-tert-butylsulfinamide (0.5 g, 4.3 mmol), and tetraethyl titanate (1.5 g, 0.64 mmol) were added sequentially to anhydrous THF (5 mL), and stirred at 85 °C for 6 h, monitored by TLC. After cooling, EA (30 mL) was added for dilution, and the mixture was poured into water (30 mL) and stirred for 30 min. The mixture was filtered, extracted with EA (20 mL × 2) in two separate layers, washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain 0.7 g of pale yellow solid (6-3), yield 76%, M / S: 431 (M + H). + ).

[0675] Synthesis of compound (R)-N-((-R-)1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfonamide (6-4):

[0676]

[0677] Dissolve 6-3 (0.7 g, 1.6 mmol) in DCM / MeOH (3.5 mL / 3.5 mL), add glacial acetic acid (0.6 g, 10 mmol) dropwise, cool to -10 °C, and add in portions (0.3 g, 4.9 mmol). Allow the mixture to react naturally for 12 h, monitor with TLC, adjust pH to 9-10 with saturated sodium carbonate solution, extract with EA (20 mL × 3), combine the EA extracts, wash once with saturated sodium chloride solution (10 mL), dry, concentrate, and column chromatography to obtain 0.6 g of white solid (6-4), yield 85.3%, M / S: 433 (M + H₂O). + de value: 98%.

[0678] Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (6-5):

[0679]

[0680] Dissolve 0.6 g (1.4 mmol) of 6-4 in 3 mL of DCM, add 3 mL of HCl-Dioxane dropwise, and react at room temperature under TLC monitoring. Concentrate the reaction solution to dryness, add 10 mL of water and 10 mL of EA, dissolve thoroughly, separate the layers, extract once with 10 mL of EA, adjust the pH of the aqueous phase to 8-9 with NaHCO3, extract with 15 mL × 3 of DCM, dry, and concentrate to obtain 0.4 g of pale yellow solid (6-5), yield 87.8%, MS: 329 / (M+H + ).

[0681] Synthesis of compound (R)2-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)yl)benzoic acid (compound 6)

[0682]

[0683] 6-5 (70 mg, 0.22 mmol), 2-iodobenzoic acid (83 mg, 0.33 mmol), TEA (43 mg, 0.43 mmol), and nano copper powder (14 mg, 0.21 mmol) were added sequentially to DMAc (1 mL). The reaction was carried out at 115 °C for 3 h, monitored by TLC. Water (15 mL) was added, and the pH was adjusted to 3-4 with dilute HCl (1 N). Extraction was performed with EA (10 mL × 3). The EA samples were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain 35 mg of solid (compound 6), yield 36.6%, MS: 489 / (M+H). + ).

[0684] 1 H NMR(400MHz,Chloroform-d)δ7.99(d,J=7.9Hz,1H),7.89(s,1H),7.57(s,1H),7.22(t,J=7.8Hz,1H),6.67(s,1H),6.60(dd,J=1 0.6,8.2Hz,1H),5.56(d,J=6.8Hz,1H),3.57(s,3H),3.22(s,4H),2.39(s,3H),1.72(d,J=6.5Hz,3H),1.26(s,4H),1.03(s,6H).

[0685] Example 19 Synthesis of compound (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(pyridin-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)pyridinecarboxylic acid (compound 109)

[0686]

[0687] Step 1: Synthesis of intermediate 8-bromo-3,6-dimethyl-2-(pyridin-4-yl)quinazolin-4(3H)-one (19-1)

[0688]

[0689] 2-Amino-3-bromo-N,5-dimethylbenzamide (2.4 g, 10.0 mmol), 4-pyridinecarboxaldehyde (1.3 g, 12.0 mmol), and iodine (3.0 g, 12.0 mmol) were sequentially added to dimethyl sulfoxide (25 mL) at room temperature. The mixture was heated to 95 °C and reacted overnight. The reaction solution was cooled to room temperature and slowly poured into water (50 mL). A saturated sodium thiosulfate aqueous solution (10 mL) was added, and the mixture was stirred for 2 hours. The mixture was filtered, and the filter cake was washed once with water (20 mL), once with anhydrous ethanol (20 mL), and once with methyl tert-butyl ether (20 mL). The product was dried under vacuum to obtain 2.9 g of product (intermediate 19-1), with a yield of 87.9%. Ms: 330.0 (M+H) + ).

[0690] Step 2: Synthesis of intermediate 8-acetyl-3,6-dimethyl-2-(pyridin-4-yl)quinazolin-4(3H)-one (19-2)

[0691]

[0692] Intermediate 19-1 (2.9 g, 8.8 mmol), tributyl(1-ethoxyethylene)tin (4.8 g, 13.2 mmol), N,N-diisopropylethylamine (3.4 g, 26.4 mmol), and Pd(PPh3)2Cl2 (0.6 g, 0.9 mmol) were added sequentially to N,N-dimethylacetamide (40 mL) at room temperature. The mixture was purged with nitrogen three times, heated to 100 °C, and reacted overnight. The reaction solution was then cooled to room temperature, and a 4 mol / L solution of dioxane chloride was slowly added. Adjust the pH to 1-2, add a small amount of water (1 mL), stir for 1 hour, dilute with ethyl acetate (20 mL), add water (20 mL), adjust the pH to greater than 7 with potassium fluoride aqueous solution, stir for 2 hours, filter, slurry the filter cake with ethyl acetate (20 mL × 3), combine the filtrates and separate the layers, extract the aqueous layer with ethyl acetate (20 mL), combine the organic layers, dry with anhydrous sodium sulfate, concentrate the residue and slurry with methanol (20 mL) to obtain 2.5 g of product (intermediate 19-2), yield 96.6%. Ms: 294.1 (M+H + )

[0693] Step 3: Synthesis of intermediate (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-4-yl)-3,4-dihydroquinazolin-8-yl)ethylene)-2-methylpropane-2-sulfonamide (19-3)

[0694]

[0695] Intermediate 19-2 (2.5 g, 8.5 mmol), (R)-(+)-tert-butylsulfinamide (2.1 g, 17.0 mmol), and tetraethyl titanate (9.7 g, 42.5 mmol) were sequentially added to dry tetrahydrofuran (25 mL) at room temperature. The mixture was heated to 90 °C and reacted overnight. The reaction solution was cooled to room temperature, diluted with dichloromethane (25 mL), and water (50 mL) was added. The mixture was stirred for 0.5 hours, filtered, and the filter cake was slurried with dichloromethane (20 mL × 3). The filtrates were combined and separated into two layers. The aqueous layer was extracted with dichloromethane (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 3.0 g of product (intermediate 19-3), with a yield of 88.6%. Ms: 397.2 (M+H) + ).

[0696] Step 4: Synthesis of intermediate (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-4-yl)-3,4-dihydroquinazolin-8-yl)ethylene)-2-methylpropane-2-sulfonamide (19-4)

[0697]

[0698] Intermediate 19-3 (3.0 g, 7.5 mmol) and cerium chloride heptahydrate (1.4 g, 3.8 mmol) were added sequentially to methanol (30 mL) at room temperature. The mixture was cooled to -65°C in a dry ice bath. Sodium borohydride (0.6 g, 15.0 mmol) was dissolved in methanol in portions and added dropwise to the reaction system, keeping the temperature below -60°C for approximately 30 minutes. The dry ice bath was removed, and the mixture was allowed to warm naturally to room temperature. Diluted with dichloromethane (30 mL), followed by water (60 mL). The mixture was allowed to separate into two layers. The aqueous layer was extracted with dichloromethane (50 mL), and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography, and recrystallized from methanol / water (1:1) to give 2.0 g of the product (intermediate 19-4), yield: 66.7%. Ms: 399.2 (M+H) + ).

[0699] Step 5: Synthesis of intermediate (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-4-yl)quinazolin-4(3H)-one (19-5)

[0700]

[0701] Intermediate 19-4 (2.0 g, 5.0 mmol) was added to dichloromethane (20 mL) at room temperature, and a dioxane solution of hydrogen chloride (4 mol / L, 10 mL) was added dropwise. The mixture was stirred for 2 hours, concentrated, and the residue was dissolved in water (10 mL). Extraction was performed with ethyl acetate (5 mL). The ethyl acetate layer was washed once with 1N hydrochloric acid (10 mL) and discarded. The combined acidic aqueous layers were adjusted to a pH greater than 7, and extracted with dichloromethane (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 1.2 g of product (intermediate 19-5), yield: 81.3%. Ms: 295.1 (M+H) + ).

[0702] Step 6: Synthesis of intermediate (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(pyridin-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)pyridinecarboxylate (19-6)

[0703]

[0704] Intermediate 19-5 (59 mg, 0.2 mmol), methyl 6-chloro-3-fluoropyridinecarboxylate (76 mg, 0.4 mmol), and DIPEA (77 mg, 0.6 mmol) were added to N,N-dimethylacetamide (1 mL). The mixture was heated to 100 °C and stirred overnight. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (2 mL), and washed with water (2 mL × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 60 mg of the product (intermediate 19-6), yield: 64.7%. Ms: 464.1 (M + H + ).

[0705] Step 7: Synthesis of compound (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-(pyridin-4-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)pyridinecarboxylic acid (compound 109)

[0706]

[0707] Intermediate 19-6 (46 mg, 0.1 mmol) was dissolved in dry tetrahydrofuran (1 ml), and potassium trimethylsilanolate (26 mg, 0.2 mmol) was added. The mixture was stirred at room temperature for 20 minutes, and the pH was adjusted to approximately 2 with 0.5 N hydrochloric acid. Extraction was performed with dichloromethane (1 ml × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 30 mg of the product (compound 109), with a yield of 66.7%. Ms: 450.1 (M + H + ). 1HNMR(400MHz, DMSO-d6)δ12.99(s,1H),8.88–8.73(m,2H),8.31(d,J=7.4Hz,1H),7.92(d,J=1.9Hz,1H),7.84–7.74(m,2H),7.68(d, J=2.1Hz,1H),7.32(d,J=9.0Hz,1H),7.11(d,J=9.1Hz,1H),5.41(p,J=6.7Hz,1H),3.82(s,3H),2.42(s,3H),1.59(d,J=6.6Hz,3H).

[0708] Using a method similar to that described in the foregoing examples, with suitable reagents and under suitable reaction conditions, the following compounds can be synthesized.

[0709] Table 1. Compounds of the present invention

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0728] Experimental Example 1: Enzymatic Activity Assay Method for PI3Kα[WT] / [E542K] / [E545K] / [H1047R] / PI3Kβ / γ / δ

[0729] The PI3Kα[WT], PI3Kα[E542K], PI3Kα[E545K], PI3Kα[H1047R], PI3Kβ, PI3Kγ, and PI3Kδ kinase reactions were performed in 384-well plates (PerkinElmer, #6008280) with a reaction volume of 4 μL. PI3Kα[WT] enzyme solution (Promega, #V1721), PI3Kα[E542K] enzyme solution (CarnaBio, #11-413-20N), PI3Kα[E545K] enzyme solution (CarnaBio, #11-414-20N), PI3Kα[H1047R] enzyme solution (Promega, #V1741), or PI3Kβ enzyme solution (Pro Promega (#V1751) or PI3Kγ enzyme solution (ThermoFisher (#PV4786) or PI3Kδ enzyme solution (ThermoFisher (#PV6451)) was used, followed by serially diluted compounds (starting at a final concentration of 10 μM, 3-fold dilution, 10 doses). Then, PIP2:3PS (Promega (#V1701) and ATP solution (Promega (#V915B)) were added to the plate. After incubating at 25°C for 1 hour, ADP-Glo ​​reagent buffer (Promega (#V9102) was added to each well. The plate was sealed and incubated at 25°C for 40 minutes, then 10 μL of ADP-Glo ​​detection buffer (Promega (#V9102)) was added to each well. After incubating at 25°C for 40 minutes, the chemiluminescence values ​​were read using an instrument.

[0730] The experimental results are shown in the ADP-Glo ​​IC50 column of Table 2.

[0731] Experiment Example 2: MCF-10A Cell Anti-proliferation Experiment

[0732] MCF-10A cells (Cobioer Bio.#CBP60419MCF) were diluted with complete culture medium (Cobioer Bio.#CBP60419) and seeded at 500 cells / well in 96-well cell culture plates (Corning#3599) for 24 h. Then, serially diluted compounds were added (starting at 10 μM, with 3-fold gradients and 9 concentrations) to a final volume of 100 μl / well, and cultured at 37°C and 5% CO2 for 6 days. After culture, CCK8 reagent (SignalwayAntibody Bio.#CP002) was added at 10 μl / well and incubated at 37°C and 5% CO2 for 2–3 hours. OD values ​​were read using a microplate reader. 450nm value.

[0733] The results are shown in column MCF-10A IC50 of Table 2.

[0734] Experiment Example 3: T47D Cell Anti-proliferation Experiment

[0735] T47D cells (ATCC.#HTB-133) were diluted with RPMI 1640 (Gibco#22400-089) containing 10% FBS (Hyclone#SH30084.03) and seeded at 1000 cells / well in 96-well cell culture plates (Biosharp#BS-MP-96W) for 24 h. Then, serially diluted compounds were added (starting at 10 μM, with 3-fold increments and 9 concentrations) to a final volume of 150 μl / well, and the cells were cultured at 37°C and 5% CO2 for 7 days. After culture, CellTiter-Glo reagent (Promega#G7573) was added at 75 μl / well and incubated at 25°C for 10 min, after which the chemiluminescence value was read.

[0736] The results are shown in column T47D IC50 of Table 2.

[0737] Table 2. Effects of the compounds of the present invention

[0738]

[0739]

[0740]

[0741] Where XXX represents IC 50 >5μM, XX indicates 1μM <IC 50 <5μM, X indicates IC 50 <1μM.

[0742] Experimental Example 4: Rat Pharmacokinetics of the Compounds of the Invention

[0743] 1. Experimental Methods

[0744] Nine healthy adult male SD rats (three rats for each compound administration route) were gavaged and fasted overnight (>12 h) but allowed free access to water. Four hours after administration, the rats were fed, and the compounds were administered via tail vein injection or gavage, respectively. At different time points, blood samples were collected intravenously and anticoagulated (EDTA-K2 was used as the anticoagulant; blood samples were placed on ice after collection). Plasma was separated by centrifugation at 6000g for 5 min at 4℃ and stored at -70℃ for analysis. The concentrations of the compounds in the plasma were determined using LC-MS / MS.

[0745] Plasma compound concentration data at all time points were used to calculate the main pharmacokinetic parameters using a Winnolin 8.3 non-compartmental model.

[0746] Area under the curve (AUC) during drug administration all Value: Calculated using the trapezoidal rule; AUC inf =AUC all +C t / ke, C t The plasma drug concentration is the last measurable time point, and ke is the elimination rate constant.

[0747] Elimination half-life t 1 / 2 =0.693 / ke;

[0748] Sweep rate CL = D / AUC inf (D represents the dosage);

[0749] Steady-state distributed volume Vss = CL x MRT, mean residence time MRT = AUMC / AUC;

[0750] Absolute bioavailability F = (AUCi.g x Di.v.) / (AUCi.v x Di.g.) × 100%

[0751] 2. Experimental Results

[0752] Table 3. Pharmacokinetic results of the compounds of this invention in rats.

[0753]

[0754] Note: In the table, "iv(1mpk)" indicates administration via tail vein injection at a dose of 1 mg per kilogram; "ig(3mpk)" indicates administration via gavage at a dose of 3 mg per kilogram; and "ig(50mpk)" indicates administration via gavage at a dose of 50 mg per kilogram.

[0755] The above experimental results demonstrate that the compound of this invention has good pharmacokinetics.

[0756] Experimental Example 5: Beagle Pharmacokinetics of the Compounds of the Invention

[0757] 1. Experimental Methods

[0758] Nine healthy adult male beagle dogs (three animals for each compound administration route) were gavaged and fasted overnight (>12h) but allowed free access to water. They were fed 4 hours after administration and administered the compound via intravenous injection or gavage. Blood was collected from the forelimb vein at different time points, and after anticoagulation with EDTA-K2 (blood samples were placed on ice after collection), plasma was separated by centrifugation at 3200g for 10 min. Plasma samples were stored at -70℃ before analysis, and the concentrations of the compounds in the plasma were determined using LC-MS / MS.

[0759] Plasma compound concentration data at all time points were used to calculate the main pharmacokinetic parameters using a Winnolin 8.3 non-compartmental model.

[0760] Area under the curve (AUC) during drug administration all Value: Calculated using the trapezoidal rule; AUCinf = AUC all +C t / ke, C t The plasma drug concentration is the last measurable time point, and ke is the elimination rate constant.

[0761] Elimination half-life t 1 / 2 =0.693 / ke;

[0762] Sweep rate CL = D / AUC inf (D represents the dosage);

[0763] Steady-state distributed volume Vss = CL x MRT. Mean residence time MRT = AUMC / AUC;

[0764] Absolute bioavailability F = (AUCi.g x Di.v.) / (AUCi.v x Di.g.) × 100%

[0765] 2. Experimental Results

[0766] Table 4. Pharmacokinetic results of the compounds of this invention in beagle dogs

[0767]

[0768] Note: In the table, "iv(1mpk)" means intravenous injection, with a dose of 1 mg per kilogram; "ig(3mpk)" means gavage, with a dose of 3 mg per kilogram; and "ig(10mpk)" means gavage, with a dose of 10 mg per kilogram.

[0769] The above experimental results demonstrate that the compound of this invention has good pharmacokinetics.

[0770] Experimental Example 6: Pharmacodynamic evaluation of the compounds of the present invention in a mouse model of NOD SCID tumor subcutaneously transplanted into MDA-MB-453 cells:

[0771] 1. Experimental Methods

[0772] (1) Cell culture and inoculation:

[0773] MDA-MB-453 cell line was cultured in Leibovitz's L-15 medium with 10% fetal bovine serum and 1% penicillin-drug antibiotics at 37°C with 5% CO2, and passaged once a week. When the cell saturation reached 80%–90% and the required number was achieved, the cells were harvested, counted, and seeded.

[0774] When the number of cells in the logarithmic growth phase reached the required experimental quantity, the cells were collected, centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in culture medium. Cells were counted using a cell counter, and based on the counting results, the original solution was diluted to a viable cell concentration of 1*10⁸ cells / mL, with a cell viability of 94.55% (P14 passage). The diluted cell suspension was then diluted with Matrigel at a 1:1 ratio. After mixing, the mixture was placed on ice, and 0.2 mL of the cell suspension was subcutaneously inoculated into the right axilla of each mouse using a 1 mL sterile syringe. This equates to 1*10⁷ MDA-MB-453 cells per mouse.

[0775] (2) Grouping method:

[0776] After inoculation, tumor growth was observed daily, with an average tumor volume of approximately 157.14 mm. 3 Mice were randomly assigned to groups based on tumor size and body weight. A control group received the same dose of solvent. Day 0 was defined as the day of tumor cell inoculation.

[0777] (3) Experimental observation and data measurement:

[0778] The animals' health and mortality are monitored daily. Routine checks include tumor growth, activity level, diet, weight, eyes, coat, and any abnormal behaviors. Weight is measured daily, and tumor volume is measured twice weekly. Tumor volume is measured using calipers, with the formula TV = 0.5a × b. 2 Where a is the long diameter of the tumor and b is the short diameter of the tumor. After reaching the experimental endpoint, plasma samples were collected from each group at specific time points for blood drug concentration detection. After euthanasia of the mice, tumors were collected, photographed, weighed, and flash-frozen.

[0779] (4) Evaluation indicators of antitumor drug efficacy:

[0780] The relative tumor proliferation rate, T / C (%), is the percentage of tumor volume or weight in the treatment group and control group at a given time point. The calculation formula is: T / C% = TTRTV / CRTV × 100%

[0781] Wherein, TRTV: mean relative tumor volume (RTV) in the treatment group; CRTV: mean relative tumor volume in the control group; (RTV): RTV = V t / V0, where V0 is the tumor volume of the animal at the time of grouping, V t The tumor volume of the animal after treatment.

[0782] Or T / C% = TTW / CTW × 100%; where TTW: average tumor weight at the end of the experiment in the treatment group; CTW: average tumor weight at the end of the experiment in the control group.

[0783] The relative tumor inhibition rate, TGI (%), is calculated using the formula: [TGI% = (1-T / C) × 100%; where T and C are the relative tumor volume (RTV) or tumor weight (TW) of the treatment group and the control group at a specific time point, respectively.

[0784] 2. Experimental Results

[0785] Table 5. Pharmacodynamic evaluation results of the compounds of the present invention in a mouse model of NOD SCID tumor subcutaneous xenografted MDA-MB-453 cells.

[0786]

[0787] The above experimental results demonstrate that the compound of this invention has a good inhibitory effect on breast cancer tumors.

[0788] In summary, the compounds prepared by this invention can be used to prepare selective PI3K inhibitors, as well as drugs for the prevention and / or treatment of PI3K-related diseases, such as drugs for the prevention and / or treatment of cancer. This invention provides a new option for clinical cancer treatment and has promising application prospects.

Claims

1. A compound, or a salt thereof, or a stereoisomer thereof, characterized in that: The compound is shown in Formula III-2: Formula III-2 in, X 11 selected from N; R1 is selected from C1~C8 alkyl groups and halogens; R 61 selected from halogen; R 62 selected from -C(O)OR 81 , -C(O)R 81 ; R 81 selected from the group consisting of hydrogen, C1-C8alkyl, amino; R 10 selected from hydrogen, substituted or unsubstituted Ci-C8alkyl; substituents of the alkyl groups are selected from deuterium; R2 is selected from substituted or unsubstituted pyridinyl groups; the substituents of the pyridinyl group are selected from halogens.

2. The compound of claim 1, or a salt thereof, or a stereoisomer thereof. The compound is shown in Formula III-3: Formula III-3 in, X 11 selected from N; R1 is selected from C1~C8 alkyl groups and halogens; R 61 selected from halogen; R 10 selected from hydrogen, substituted or unsubstituted Ci-C8alkyl; substituents of the alkyl groups are selected from deuterium; R2 is selected from substituted or unsubstituted pyridinyl groups; the substituents of the pyridinyl group are selected from halogens.

3. A compound, or a salt thereof, or a stereoisomer thereof, characterized in that: The compound is shown in Formula III-4: Formula III-4 in, X 11 selected from N; X 12 , X 13 selected from CR 71 ; X 14 selected from N; X 15 , X 16 , X 17 , X 18 selected from CR 71 ; R 71 selected from hydrogen; R 61 selected from halogen; R 81 selected from the group consisting of hydroxy, C1-C8alkoxy, amino; R1 is selected from C1~C8 alkyl groups and halogens; R 10 selected from hydrogen, substituted or unsubstituted Ci-C8alkyl; substituents of the alkyl groups are selected from deuterium; R2' is a substituent on the ring, and the number of substituents is a; each R2' is independently selected from halogens; a is 0, 1, 2 or 3.

4. The compound, or its salt, or its stereoisomer according to claim 3, characterized in that: The compound is shown in Formula III-5: Formula III-5 in, X 14 selected from N; R 61 selected from halogen; R1 is selected from C1~C8 alkyl groups and halogens; R 10 selected from hydrogen, substituted or unsubstituted Ci-C8alkyl; substituents of the alkyl groups are selected from deuterium; R2' is selected from halogens.

5. A compound, or a salt thereof, or a stereoisomer thereof, characterized in that: The compound is one of the following compounds: 。 6. Use of the compound, salt thereof, or stereoisomer thereof according to any one of claims 1 to 5 in the preparation of PI3K inhibitors.

7. The use according to claim 6, characterized in that: The PI3K inhibitor is a selective PI3K inhibitor.

8. Use of the compound, salt thereof, or stereoisomer thereof according to any one of claims 1 to 5 in the preparation of a medicament for the prevention and / or treatment of PI3K-related diseases.

9. The use according to claim 8, characterized in that: The diseases mentioned are PI3K-related cancers, inflammations, and cardiovascular diseases.

10. The use according to claim 9, characterized in that: The cancers mentioned are breast cancer, colorectal cancer, stomach cancer, colon cancer, rectal cancer, ovarian cancer, and prostate cancer.

11. A drug, characterized in that: It is prepared by adding pharmaceutically acceptable excipients to the active ingredient of any one of the compounds described in claims 1 to 5, or their salts or stereoisomers.

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