PI3K inhibitor, method for producing the same, and use thereof

Abstract

The present invention provides a PI3K inhibitor, a method for producing the same, and uses thereof, belonging to the field of chemical drugs. The PI3K inhibitor of the present invention is a compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof. The compound prepared according to the present invention can be used for the production of a selective inhibitor of PI3K, and for the production of a drug for the prevention and / or treatment of diseases related to PI3K, for example, a drug for the prevention and / or treatment of cancer. The present invention provides a new option for cancer treatment in clinical practice and has good prospects for the future. TIFF2025520857000327.tif51170

Description

Technical Field

[0001] The present invention belongs to the field of chemical drugs, and specifically relates to a PI3K inhibitor, a method for producing the same, and uses thereof.

Background Art

[0002] Phosphatidylinositol 3-kinase (PI3K) is an intracellular phosphatidylinositol kinase and an important signal transduction molecule in cells. PI3K is mainly involved in the regulation of physiological processes such as cell proliferation, apoptosis, and differentiation, and specifically phosphorylates the 3-position hydroxyl group on the phosphatidylinositol ring. As a major downstream effector of receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR), PI3K produces phospholipids that activate serine / threonine protein kinase (Akt) and other downstream effectors, thereby transmitting signals from various growth factors and cytokines to intracellular messengers. The signal pathway composed of PI3K and its downstream molecule Akt can activate downstream signal molecules and is closely related to the occurrence and progression of tumors such as breast cancer, gastric cancer, colon cancer, rectal cancer, ovarian cancer, and prostate cancer. Studies have revealed that the overactivation of PI3K is associated with various hyperproliferative, inflammatory, or cardiovascular diseases, including cancer, inflammation, and cardiovascular diseases.

[0003] PI3K has been proven to be a drug treatment target with great potential. By using a selective PI3K inhibitor as an antitumor drug, the selectivity of treatment can be enhanced, and the occurrence of adverse reactions and toxic side effects can be reduced. The number of currently reported selective PI3K inhibitors and the types of compound structures are still quite limited, and there is still room for further improvement in terms of efficacy. Studying PI3K inhibitors with excellent effects and few adverse reactions and toxic side effects and treating cancer clinically has important significance.

Summary of the Invention

[0004] An object of the present invention is to provide a PI3K inhibitor, a method for producing the same, and uses thereof.

[0005] The present invention provides a compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof. TIFF2025520857000002.tif51170

[0006] However, R1 is a substituent on the A ring, the number of substituents is m, and each R1 is independently a substituted or unsubstituted C1-C8 alkyl group, C1-C8 alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, -NHR 15 , -NHR8, -C(O)NHR8, -C(O)NHR 15 , a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, m is 0, 1, 2 or 3, R 15 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, C1-C8 alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, Y1 and Y2 are each independently selected from none, CR4R5, NR4, R4 and R5 are each independently selected from hydrogen, a C1-C8 alkyl group, or R4 and R5 together with carbon form a ketone group, R3 is selected from hydrogen, a 6- to 10-membered aryl group substituted with n R6s, a 5- to 10-membered heteroaryl group substituted with n R6s, a 4- to 10-membered heterocycloalkyl group substituted with n R6s or TIFF2025520857000003.tif16170 Each R6 is independently a substituted or unsubstituted C1-C8 alkyl group, C1-C8 alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR 81 , -C(O)R 81 , TIFF2025520857000004.tif13170, acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR8 or -C(O)NHR8, or two R6 on the same atom form =O, n is 0, 1, 2, 3 or 4, R 81 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl group, amino group, R8 is selected from substituted or unsubstituted C1-C8 alkyl group, hydroxy group, TIFF2025520857000005.tif20170, R7 and R9 are each independently selected from C1-C8 alkyl group, 6-10 membered aryl group, 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, X2 is selected from C or N. When X2 is selected from C, the bond connecting X2 to O is a double bond, and the bond connecting X2 to X3 is a single bond. When X2 is selected from N, the bond connecting X2 to O is a single bond, the bond connecting X2 to X3 is a double bond, and N has a positive charge and O has a negative charge, X3 is selected from N, CR 10 or NR 10 , X4 is selected from C, X5 is selected from O, N, NR 10 or CR 10 , R 10 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl group, When X3 is CR 10selected from, when X5 is selected from O, the bond by which X3 is linked to X4 is a double bond, the bond by which X4 is linked to X5 is a single bond, and the bond by which X5 is linked to a carbon atom is a single bond, X3 is NR 10 selected from, when X5 is selected from N, the bond by which X3 is linked to X4 is a single bond, the bond by which X4 is linked to X5 is a double bond, and the bond by which X5 is linked to a carbon atom is a single bond, X3 is CR 10 selected from, when X5 is selected from CR 10 selected from, the bond by which X3 is linked to X4 is a single bond, the bond by which X4 is linked to X5 is a double bond, and the bond by which X5 is linked to a carbon atom is a single bond, or the bond by which X3 is linked to X4 is a double bond, the bond by which X4 is linked to X5 is a single bond, and the bond by which X5 is linked to a carbon atom is a double bond, X3 is CR 10 selected from, when X5 is selected from N, the bond by which X3 is linked to X4 is a double bond, the bond by which X4 is linked to X5 is a single bond, and the bond by which X5 is linked to a carbon atom is a double bond, X3 is selected from N, and when X5 is selected from NR 10 selected from, the bond by which X3 is linked to X4 is a double bond, the bond by which X4 is linked to X5 is a single bond, and the bond by which X5 is linked to a carbon atom is a single bond, R2 is a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 4-10 membered heterocycloalkyl group, a substituted or unsubstituted 5-10 membered heteroaryl group, -NR 11 R 12 , TIFF2025520857000006.tif17170, -SR 11 selected from, R 11 R 12 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group, The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4- to 10-membered heterocycloalkyl group or -NR 13 R 14 selected from, R 13 R 14 each independently selected from hydrogen and C1-C8 alkyl groups, The substituent of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group is selected from halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR 16 R 17 , -C(O)OR 16 , a substituted or unsubstituted C1-C8 alkyl group or C1-C8 alkoxy group, R 16 R 17 each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group and hydroxy group, The heteroatom in the heteroaryl group and heterocycloalkyl group is N, O or S, and the number of the heteroatoms is 1, 2 or 3.

[0007] Furthermore, The aryl group of R1 is selected from phenyl group and naphthyl group, the heterocycloalkyl group is selected from piperidyl group and morpholinyl group, and the heteroaryl group is selected from isoindolinyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, thienyl group, furyl group, pyrazolyl group, imidazolyl group or pyrrolyl group. R 15 The aryl group of R The aryl group of R3 is selected from phenyl groups, and the heteroaryl group is selected from isoindolinyl groups, pyridyl groups, pyrimidinyl groups, pyridazinyl groups, thienyl groups, furyl groups, pyrazolyl groups, imidazolyl groups or pyrrolyl groups, and the heterocycloalkyl group is selected from piperidyl groups, The aryl groups of R7 and R9 are selected from phenyl groups or naphthyl groups, The aryl group of R2 is selected from phenyl groups or naphthyl groups, the heterocycloalkyl group is selected from piperidyl groups or morpholinyl groups, and the heteroaryl group is selected from isoindolinyl groups, pyridyl groups, pyrimidinyl groups, pyridazinyl groups, thienyl groups, furyl groups, pyrazolyl groups, imidazolyl groups, pyrrolyl groups, isoxazolyl groups or selected from 13170 of TIFF2025520857000007.tif, The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR 13 R 14 selected from, R 13 、R 14 are each independently selected from hydrogen and C1-C8 alkyl groups.

[0008] Furthermore, the compound is as shown in formula II. 52170 of TIFF2025520857000008.tif

[0009] However, R1 is a substituent on the benzene ring, the number of substituents is m, and each R1 is independently a substituted or unsubstituted C1-C8 alkyl group, C1-C8 alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, -NHR 15 、-NHR8、-C(O)NHR8、-C(O)NHR 15, selected from a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, m is 0, 1, 2 or 3, R 15 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, a halogen, a cyano group, a nitro group, a hydroxy group, a carboxy group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, Y1 and Y2 are each independently selected from none, CR4R5, NR4, R4 and R5 are each independently selected from hydrogen, a C1-C8 alkyl group, or R4 and R5 together with carbon form a ketone group, R3 is a 6- to 10-membered aryl group substituted with n R6s, a 5- to 10-membered heteroaryl group substituted with n R6s, a 4- to 10-membered heterocycloalkyl group substituted with n R6s or selected from TIFF2025520857000009.tif16170, each R6 is independently a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, a halogen, a cyano group, a nitro group, an amino group, a hydroxy group, -C(O)OR 81 -C(O)R 81 , TIFF2025520857000010.tif13170, an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR8 or -C(O)NHR8, or two R6s on the same atom form =O, n is 0, 1, 2, 3 or 4, R 81 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, an amino group, R8 is a substituted or unsubstituted C1-C8 alkyl group, a hydroxy group, selected from TIFF2025520857000011.tif20170, R7 and R9 are each independently selected from a C1-C8 alkyl group and a 6-10 membered aryl group, R2 is a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 4-10 membered heterocycloalkyl group, a substituted or unsubstituted 5-10 membered heteroaryl group, -NR 11 R 12 , TIFF2025520857000012.tif17170, -SR 11 and is selected from, when R6 is selected from a carboxy group, R2 is not selected from a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl group, R 11 , R 12 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group, the substituent of the alkyl group is selected from deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4-10 membered heterocycloalkyl group or -NR 13 R 14 and is selected from, R 13 , R 14 are each independently selected from hydrogen and a C1-C8 alkyl group, the substituent of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group is selected from halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR 16 R 17 , -C(O)OR 16 , a substituted or unsubstituted C1-C8 alkyl group or a C1-C8 alkoxy group, R 16 , R 17 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and a hydroxy group, The heteroatoms in the heteroaryl group and the heterocycloalkyl group are N, O or S, and the number of the heteroatoms is 1, 2 or 3. Preferably, the aryl group of R1 is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group. R 15 the aryl group of which is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group. the aryl group of R3 is selected from a phenyl group, the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, and the heterocycloalkyl group is selected from a piperidyl group. the aryl groups of R7 and R9 are selected from a phenyl group or a naphthyl group. the aryl group of R2 is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or TIFF2025520857000013.tif13170. the substituent of the alkyl group is selected from deuterium, halogen, a hydroxy group, a cyano group, a nitro group, a carboxy group, a piperidyl group, a morpholinyl group or -NR 13 R 14 selected from. R 13 R 14are each independently selected from hydrogen and C1-C8 alkyl groups.

[0010] Furthermore, the compound is as shown in Formula II-1. TIFF2025520857000014.tif47170

[0011] However, R1 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, cyano, nitro, hydroxy, carboxy, -NHR 15 , -NHR8, -C(O)NHR8, -C(O)NHR 15 , a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, and a substituted or unsubstituted 5- to 10-membered heteroaryl group, R 15 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, cyano, nitro, hydroxy, carboxy, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, and a substituted or unsubstituted 5- to 10-membered heteroaryl group, R3 is selected from a 6- to 10-membered aryl group substituted with n R6 groups, a 5- to 10-membered heteroaryl group substituted with n R6 groups, a 4- to 10-membered heterocycloalkyl group substituted with n R6 groups, or TIFF2025520857000015.tif16170, each R6 is independently selected from a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, cyano, nitro, amino, hydroxy, -C(O)OR 81 , -C(O)R 81 , TIFF2025520857000016.tif13170 is selected from an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR8 or -C(O)NHR8, or two R6 on the same atom form =O, and n is 0, 1, 2, 3 or 4. R 81 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group. R8 is a substituted or unsubstituted C1-C8 alkyl group, a hydroxy group. TIFF2025520857000017.tif20170 is selected from. R7 and R9 are each independently selected from a C1-C8 alkyl group and a 6-10 membered aryl group. R2 is selected from a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 4-10 membered heterocycloalkyl group, a substituted or unsubstituted 5-10 membered heteroaryl group, -NR 11 R 12 , TIFF2025520857000018.tif17170, -SR 11 is selected from. When R6 is selected from a carboxy group, R2 is not selected from a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl group. R 11 R 12 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group. The substituents of the alkyl group are selected from deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4-10 membered heterocycloalkyl group or -NR 13 R 14 is selected from. R 13 R 14 are each independently selected from hydrogen and a C1-C8 alkyl group. The substituents of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group are halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR 16 R 17 、-C(O)OR 16 、selected from a substituted or unsubstituted C1-C8 alkyl group or C1-C8 alkoxy group, R 16 、R 17 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and a hydroxy group, The heteroatoms in the heteroaryl group and heterocycloalkyl group are N, O or S, and the number of the heteroatoms is 1, 2 or 3, Preferably, the aryl group of R1 is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, R 15 the aryl group of is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, the aryl group of R3 is selected from a phenyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, and the heterocycloalkyl group is selected from a piperidyl group, the aryl groups of R7 and R9 are selected from a phenyl group or a naphthyl group, The aryl group of R2 is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from TIFF2025520857000019.tif13170, The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR 13 R 14 selected from, R 13 and R 14 are each independently selected from hydrogen and a C1-C8 alkyl group.

[0012] Furthermore, the compound is as shown in formula II-2. TIFF2025520857000020.tif47170

[0013] However, Z1 is selected from CH or N, R1 is hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, -NHR 15 , -NHR8, -C(O)NHR8, -C(O)NHR 15 , a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, R 15 is hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, n is 0, 1, 2, 3 or 4, and each R6 is independently selected from a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, a cyano group, a nitro group, an amino group, a hydroxy group, -C(O)OR 81 , -C(O)R 81 , TIFF2025520857000021.tif13170, an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR8 or -C(O)NHR8, or two R6s on the same atom form =O, and R 81 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group, R8 is selected from a substituted or unsubstituted C1-C8 alkyl group and a hydroxy group, TIFF2025520857000022.tif20170, R9 is selected from a C1-C8 alkyl group and a 6-10 membered aryl group, R2 is selected from a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 4-10 membered heterocycloalkyl group, a substituted or unsubstituted 5-10 membered heteroaryl group, -NR 11 R 12 , TIFF2025520857000023.tif17170, -SR 11 , and when R6 is selected from a carboxy group, R2 is not selected from a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl group, R 11 , R 12 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group, the substituents of the alkyl group are deuterium, halogen, a hydroxy group, a cyano group, a nitro group, a carboxy group, a 4-10 membered heterocycloalkyl group or -NR 13R 14 selected from R 13 and R 14 are each independently selected from hydrogen and C1-C8 alkyl groups, The substituents of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group are halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR 16 R 17 , -C(O)OR 16 , and selected from substituted or unsubstituted C1-C8 alkyl groups or C1-C8 alkoxy groups, R 16 and R 17 are each independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxy groups, The heteroatoms in the heteroaryl group and heterocycloalkyl group are N, O or S, and the number of the heteroatoms is 1, 2 or 3, Preferably, the aryl group of R1 is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, R 15 the aryl group of which is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, the aryl group of R9 is selected from a phenyl group or a naphthyl group, The aryl group of R2 is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from TIFF2025520857000024.tif13170, the substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR 13 R 14 selected from, R 13 and R 14 are each independently selected from hydrogen and a C1-C8 alkyl group.

[0014] Furthermore, the compound is as shown in formula II-3. TIFF2025520857000025.tif52170

[0015] However, Z1 is selected from CH or N, R1 is selected from a substituted or unsubstituted C1-C8 alkyl group and halogen, R 61、 R 62 are each independently hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR 81 -C(O)R 81 , TIFF2025520857000026.tif13170, acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR8 or -C(O)NHR8, R 81 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group and amino group, R8 is a substituted or unsubstituted C1-C8 alkyl group, hydroxy group, Selected from TIFF2025520857000027.tif20170, R9 is selected from a C1-C8 alkyl group and a 6-10 membered aryl group, R2 is a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 4-10 membered heterocycloalkyl group, a substituted or unsubstituted 5-10 membered heteroaryl group, -NR 11 R 12 , TIFF2025520857000028.tif17170, -SR 11 selected from, When R6 is selected from carboxy groups, R2 is not selected from a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl group, R 11 , R 12 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group, The substituents of the alkyl group are selected from deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4-10 membered heterocycloalkyl group or -NR 13 R 14 selected from, R 13 , R 14 are each independently selected from hydrogen and a C1-C8 alkyl group, The substituents of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group are selected from halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR 16 R 17 , -C(O)OR 16 , a substituted or unsubstituted C1-C8 alkyl group or a C1-C8 alkoxy group selected from, R 16 , R 17 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and a hydroxy group, The heteroatoms in the heteroaryl group and heterocycloalkyl group are N, O, or S, and the number of the heteroatoms is 1, 2, or 3. Preferably, the aryl group of R9 is selected from a phenyl group or a naphthyl group, the aryl group of R2 is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group, or selected from TIFF2025520857000029.tif13170, the substituent of the alkyl group is halogen, a hydroxy group, a cyano group, a nitro group, a carboxy group, a piperidyl group, a morpholinyl group, or -NR 13 R 14 selected from R 13 and R 14 are each independently selected from hydrogen and a C1-C8 alkyl group.

[0016] Furthermore, the compound is as shown in Formula II-4. TIFF2025520857000030.tif55170

[0017] However, Z1 is selected from CH or N, R1 is selected from a C1-C8 alkyl group, halogen, and a trifluoromethyl group, R 61 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, a cyano group, a nitro group, an amino group, a hydroxy group, -C(O)OR 81 -C(O)R 81 and TIFF2025520857000031.tif13170, an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR8, or -C(O)NHR8. R 81 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group, R8 is a substituted or unsubstituted C1-C8 alkyl group, a hydroxy group, selected from TIFF2025520857000032.tif20170, R9 is selected from a C1-C8 alkyl group and a 6-10 membered aryl group, R2 is a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted 4-10 membered heterocycloalkyl group, -NR 11 R 12 , TIFF2025520857000033.tif17170, -SR 11 selected from, R 11 R 12 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group, The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4-10 membered heterocycloalkyl group or -NR 13 R 14 selected from, R 13 R 14 are each independently selected from hydrogen and a C1-C8 alkyl group, The substituent of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group is halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR 16 R 17 , -C(O)OR 16 , selected from a substituted or unsubstituted C1-C8 alkyl group or a C1-C8 alkoxy group, R 16 R 17 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and a hydroxy group, The heteroatom in the heteroaryl group and heterocycloalkyl group is N, O or S, and the number of the heteroatoms is 1, 2 or 3, Preferably, the aryl group of R9 is selected from a phenyl group or a naphthyl group, the aryl group of R2 is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from TIFF2025520857000034.tif13170, the substituent of the cyclic group is halogen, a hydroxy group, a cyano group, a nitro group, a carboxy group, a piperidyl group, a morpholinyl group or -NR 13 R 14 selected from R 13 and R 14 are each independently selected from hydrogen and a C1-C8 alkyl group.

[0018] Furthermore, the compound is as shown in formula II-5. TIFF2025520857000035.tif60170

[0019] However, Z1 is selected from CH or N, R1 is selected from a C1-C8 alkyl group, halogen, and a trifluoromethyl group, R 61 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, a cyano group, a nitro group, an amino group, a hydroxy group, -C(O)OR 81 -C(O)R 81 and TIFF2025520857000036.tif13170, an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR8 or -C(O)NHR8, R 81 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group, R8 is a substituted or unsubstituted C1-C8 alkyl group, a hydroxy group, selected from TIFF2025520857000037.tif20170, R9 is selected from a C1-C8 alkyl group, a phenyl group, R2’ is a substituent on the benzene ring, the number of substituents is a, and each R2’ is, independently of one another, halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR 16 R 17 , -C(O)OR 16 , selected from a substituted or unsubstituted C1-C8 alkyl group or a C1-C8 alkoxy group, and a is 0, 1, 2 or 3, R 16 , R 17 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a hydroxy group, The substituent of the alkyl group is selected from deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR 13 R 14 R R 13 , R 14 are each independently selected from hydrogen, a C1-C8 alkyl group.

[0020] Furthermore, the compound is as shown in formula III-1. TIFF2025520857000038.tif51170

[0021] However, R1 is selected from a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group or carboxy group, R3 is a 6- to 10-membered aryl group substituted with n R6s, a 5- to 10-membered heteroaryl group substituted with n R6s, a 4- to 10-membered heterocycloalkyl group substituted with n R6s or selected from TIFF2025520857000039.tif16170, Each R6 is independently a substituted or unsubstituted C1-C8 alkyl group, C1-C8 alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR 81 、-C(O)R 81 、 TIFF2025520857000040.tif13170, acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR8 or -C(O)NHR8, or two R6s on the same atom form =O, n is 0, 1, 2, 3 or 4, and R 81 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl group, amino group, R8 is selected from substituted or unsubstituted C1-C8 alkyl group, hydroxy group, TIFF2025520857000041.tif20170, R7 and R9 are each independently selected from C1-C8 alkyl group, 6-10 membered aryl group, R 10 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl group, R2 is selected from substituted or unsubstituted C1-C8 alkyl group, substituted or unsubstituted 3-8 membered cycloalkyl group, substituted or unsubstituted 6-10 membered aryl group, substituted or unsubstituted 4-10 membered heterocycloalkyl group, substituted or unsubstituted 5-10 membered heteroaryl group, -NR 11 R 12 、 TIFF2025520857000042.tif17170, -SR 11 selected from, R 11 、R 12 are each independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl group, amino group, The substituents of the alkyl group are deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4-10 membered heterocycloalkyl group or -NR 13 R 14 selected from, R 13 、R 14are each independently selected from hydrogen and C1-C8 alkyl groups, The substituents of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group are halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR 16 R 17 、-C(O)OR 16 selected from substituted or unsubstituted C1-C8 alkyl groups or C1-C8 alkoxy groups, R 16 、R 17 are each independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl groups, and hydroxy groups, The heteroatoms in the heteroaryl group and heterocycloalkyl group are N, O or S, and the number of the heteroatoms is 1, 2 or 3, Preferably, the aryl group of R3 is selected from phenyl groups, the heteroaryl group is selected from isoindolinyl groups, pyridyl groups, pyrimidinyl groups, pyridazinyl groups, thienyl groups, furyl groups, pyrazolyl groups, imidazolyl groups or pyrrolyl groups, and the heterocycloalkyl group is selected from piperidyl groups, the aryl groups of R7 and R9 are selected from phenyl groups or naphthyl groups, the aryl group of R2 is selected from phenyl groups, anthracenyl groups or naphthyl groups, the heterocycloalkyl group is selected from piperidyl groups or morpholinyl groups, and the heteroaryl group is selected from isoindolinyl groups, pyridyl groups, pyrimidinyl groups, pyridazinyl groups, thienyl groups, furyl groups, pyrazolyl groups, imidazolyl groups, pyrrolyl groups, isoxazolyl groups or selected from TIFF2025520857000043.tif13170, the substituents of the alkyl group are selected from deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR 13 R 14 selected from, R 13 、R 14is independently selected from hydrogen and C1-C8 alkyl groups respectively.

[0022] Furthermore, the compound is as shown in Formula III-2. TIFF2025520857000044.tif55170

[0023] However, X 11 is selected from CH or N, R1 is selected from a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group or carboxy group, R 61、 R 62 are each independently hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR 81 -C(O)R 81 , TIFF2025520857000045.tif13170, acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR8 or -C(O)NHR8, R 81 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, amino group, R8 is selected from a substituted or unsubstituted C1-C8 alkyl group, hydroxy group, TIFF2025520857000046.tif20170, R9 is selected from a C1-C8 alkyl group, a 6-10 membered aryl group, R 10 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, R2 is a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 4-10 membered heterocycloalkyl group, a substituted or unsubstituted 5-10 membered heteroaryl group, -NR 11 R 12 , TIFF2025520857000047.tif17170, -SR 11 selected from R 11 and R 12 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, a 4-10 membered heterocycloalkyl group or -NR 13 R 14 selected from R 13 and R 14 are each independently selected from hydrogen and a C1-C8 alkyl group The substituent of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group is halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, C(O)NR 16 R 17 , -C(O)OR 16 selected from a substituted or unsubstituted C1-C8 alkyl group or a C1-C8 alkoxy group R 16 and R 17 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and a hydroxy group The heteroatom in the heteroaryl group and heterocycloalkyl group is N, O or S, and the number of the heteroatoms is 1, 2 or 3 Preferably the aryl group of R9 is selected from a phenyl group and a naphthyl group the aryl group of R2 is selected from a phenyl group and a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group and a morpholinyl group, and the heteroaryl group is an isoindolinyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, thienyl group, furyl group, pyrazolyl group, imidazolyl group, pyrrolyl group, isoxazolyl group or TIFF2025520857000048.tif13170 selected from The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR 13 R 14 selected from, R 13 R 14 each independently selected from hydrogen and C1-C8 alkyl groups.

[0024] Furthermore, the compound is as shown in formula III-3. TIFF2025520857000049.tif54170

[0025] However, X 11 is selected from CR 71 or N, R 71 is selected from hydrogen, halogen, and C1-C8 alkyl groups, R1 is selected from a substituted or unsubstituted C1-C8 alkyl group, C1-C8 alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, or carboxy group, R 61 is hydrogen, a substituted or unsubstituted C1-C8 alkyl group, C1-C8 alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR 81 -C(O)R 81 , TIFF2025520857000050.tif13170, acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR8 or -C(O)NHR8, R 81 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and amino group, R8 is a substituted or unsubstituted C1-C8 alkyl group, hydroxy group, TIFF2025520857000051.tif20170 selected from, R9 is selected from a C1-C8 alkyl group and a 6-10 membered aryl group, R 10is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, R2 is selected from a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 4-10 membered heterocycloalkyl group, a substituted or unsubstituted 5-10 membered heteroaryl group, -NR 11 R 12 , TIFF2025520857000052.tif17170, -SR 11 and is selected from R 11 , R 12 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and an amino group, The substituents of the alkyl group are deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4-10 membered heterocycloalkyl group or -NR 13 R 14 and are selected from R 13 , R 14 are each independently selected from hydrogen and a C1-C8 alkyl group, The substituents of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group are halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, C(O)NR 16 R 17 , -C(O)OR 16 , a substituted or unsubstituted C1-C8 alkyl group or a C1-C8 alkoxy group, and are selected from R 16 , R 17 are each independently selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, and a hydroxy group, The heteroatoms in the heteroaryl group and heterocycloalkyl group are N, O or S, and the number of the heteroatoms is 1, 2 or 3, Preferably, the aryl group of R9 is selected from a phenyl group and a naphthyl group, The aryl group of R2 is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from TIFF2025520857000053.tif13170, the substituent of the cyclic group is selected from halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR 13 R 14 selected from, R 13 R 14 are each independently selected from hydrogen and C1-C8 alkyl groups.

[0026] Furthermore, the compound is as shown in Formula III-4. TIFF2025520857000054.tif55170

[0027] However, X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 are each independently selected from CR 71 or N, R 61 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, carboxy group, acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR8 or -C(O)NHR8, R 71 is selected from hydrogen, halogen, and C1-C8 alkyl groups, R 81 is selected from hydroxy group, C1-C8 alkoxy group, and amino group, R8 is a hydroxy group, Selected from TIFF2025520857000055.tif20170, R9 is selected from a C1-C8 alkyl group and a phenyl group, R1 is selected from a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, a halogen, a cyano group, a nitro group, an amino group, a hydroxy group or a carboxy group, R 10 is selected from hydrogen and a substituted or unsubstituted C1-C8 alkyl group, R2’ is a substituent on the ring, the number of substituents is a, and each R2’ is independently a halogen, a hydroxy group, an amino group, a carboxy group, a nitro group, a cyano group, -C(O)NR 16 R 17 , a substituted or unsubstituted C1-C8 alkyl group or a C1-C8 alkoxy group, and a is 0, 1, 2 or 3, R 16 , R 17 are each independently selected from hydrogen and a C1-C8 alkyl group, The substituents of the alkyl group are selected from deuterium, a halogen, a hydroxy group, a cyano group, a nitro group, a carboxy group, a piperidyl group, a morpholinyl group or -NR 13 R 14 selected from, R 13 , R 14 are each independently selected from hydrogen and a C1-C8 alkyl group.

[0028] Furthermore, the compound is as shown in formula III-5. TIFF2025520857000056.tif59170

[0029] However, X 14 is selected from CH or N, R 61is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, a halogen, a cyano group, a nitro group, an amino group, a hydroxy group, a carboxy group, an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR8 or -C(O)NHR8, R8 is a hydroxy group, is selected from TIFF2025520857000057.tif20170, R9 is selected from a C1-C8 alkyl group, a phenyl group, R1 is selected from a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, a halogen, a cyano group, a nitro group, an amino group, a hydroxy group or a carboxy group, R 10 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, R2’ is selected from a halogen, a hydroxy group, an amino group, a carboxy group, a nitro group, a cyano group, a C1-C8 alkyl group or a C1-C8 alkoxy group, and a is 0, 1, 2 or 3, the substituent of the alkyl group is selected from a halogen, a hydroxy group, a cyano group, a nitro group, a carboxy group, a piperidyl group, a morpholinyl group or -NR 13 R 14 selected from, R 13 R 14 are each independently selected from hydrogen, a C1-C8 alkyl group.

[0030] Furthermore, the compound is as shown in formula III-6. TIFF2025520857000058.tif59170

[0031] However, R 61 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, a halogen, a cyano group, a nitro group, an amino group, a hydroxy group, a carboxy group, an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR8 or -C(O)NHR8, R8 is a hydroxy group, selected from TIFF2025520857000059.tif20170, R9 is selected from a C1-C8 alkyl group and a phenyl group, R 10 is selected from hydrogen and a substituted or unsubstituted C1-C8 alkyl group, R2’ is a substituent on the benzene ring, the number of substituents is a, and each R2’ is independently selected from a halogen, a hydroxy group, an amino group, a carboxy group, a nitro group, a cyano group, a C1-C8 alkyl group or a C1-C8 alkoxy group, and a is 0, 1, 2 or 3, The substituent of the alkyl group is selected from a halogen, a hydroxy group, a cyano group, a nitro group, a carboxy group, a piperidyl group, a morpholinyl group or -NR 13 R 14 selected from R 13 and R 14 are each independently selected from hydrogen and a C1-C8 alkyl group.

[0032] Furthermore, the compound is as shown in formula III-7. TIFF2025520857000060.tif62170

[0033] However, X 11 X 12 X 13 are each independently selected from CR 71 or N, R 61 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, a halogen, a cyano group, a nitro group, an amino group, a hydroxy group, a carboxy group, an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR8 or -C(O)NHR8, R 71 is selected from hydrogen, a halogen and a C1-C8 alkyl group, R 81 is selected from a hydroxy group, a C1-C8 alkoxy group and an amino group, R8 is a hydroxy group, selected from TIFF2025520857000061.tif20170, R9 is selected from a C1-C8 alkyl group and a phenyl group, R1 is selected from a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, a halogen, a cyano group, a nitro group, an amino group, a hydroxy group or a carboxy group, R 10 is selected from hydrogen and a substituted or unsubstituted C1-C8 alkyl group, R2 is TIFF2025520857000062.tif22170, TIFF2025520857000063.tif23170, TIFF2025520857000064.tif23170, TIFF2025520857000065.tif16170, TIFF2025520857000066.tif16170, TIFF2025520857000067.tif14170, TIFF2025520857000068.tif16170, selected from TIFF2025520857000069.tif8170, R 11 is each independently selected from hydrogen and a substituted or unsubstituted C1-C8 alkyl group, Each R2' is independently selected from a halogen, a hydroxy group, an amino group, a carboxy group, a nitro group, a cyano group, -C(O)NR 15 R 16 is selected from a substituted or unsubstituted C1-C8 alkyl group or a C1-C8 alkoxy group, and a is 0, 1, 2 or 3, O is selected from integers from 1 to 3, R 15 and R 16 are each independently selected from hydrogen and a C1-C8 alkyl group, The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR 13 R 14 selected from, R 13 R 14 each independently is selected from hydrogen, a C1-C8 alkyl group, or R 13 R 14 are linked to form TIFF2025520857000070.tif14170.

[0034] Furthermore, the compound is as shown in formula III-8. TIFF2025520857000071.tif52170

[0035] However, X 14 X 15 X 16 X 17 X 18 each independently is selected from CR 71 or N, R 71 is selected from hydrogen, halogen, a C1-C8 alkyl group, R1 is selected from a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group or carboxy group, R 10 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, R2’ is a substituent on the ring, the number of substituents is a, and each R2’ is independently selected from halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR 15 R 16 R R 15 R 16 each independently is selected from hydrogen, a C1-C8 alkyl group, R3 is TIFF2025520857000072.tif24170, TIFF2025520857000073.tif24170, TIFF2025520857000074.tif29170, a phenyl group substituted with n R6s, a pyridyl group substituted with n R6s, a pyrimidinyl group substituted with n R6s, a pyridazinyl group substituted with n R6s, a thienyl group substituted with n R6s, a furyl group substituted with n R6s, a pyrazolyl group substituted with n R6s, an imidazolyl group substituted with n R6s or a pyrrolyl group substituted with n R6s, selected from each R6 is independently a substituted or unsubstituted C1-C8 alkyl group, C1-C8 alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR 81 , -C(O)R 81 , TIFF2025520857000075.tif13170, an acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR8 or -C(O)NHR8, or two R6s on the same atom form =O, and n is 0, 1, 2, 3 or 4, R 81 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, amino group, R8 is a substituted or unsubstituted C1-C8 alkyl group, hydroxy group, TIFF2025520857000076.tif20170, selected from R9 is selected from a C1-C8 alkyl group, 6-10 membered aryl group, the substituents of the alkyl group are deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR 13 R 14 , selected from R 13 , R 14 are each independently selected from hydrogen, C1-C8 alkyl group.

[0036] Furthermore, the compound is as shown in Formula IV. TIFF2025520857000077.tif59170

[0037] However, Z2 is selected from CH or N, R 62 is selected from hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkoxy group, a halogen, a cyano group, a nitro group, an amino group, a hydroxy group, a carboxy group, an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR8 or -C(O)NHR8, R8 is a hydroxy group, TIFF2025520857000078.tif20170 selected from, R9 is selected from a C1-C8 alkyl group, a phenyl group, R2’ is a substituent on the benzene ring, the number of substituents is a, and each R2’ is independently selected from a halogen, a hydroxy group, an amino group, a carboxy group, a nitro group, a cyano group, a C1-C8 alkyl group or a C1-C8 alkoxy group, and a is 0, 1, 2 or 3. The substituent of the alkyl group is selected from a halogen, a hydroxy group, a cyano group, a nitro group, a carboxy group, a piperidyl group, a morpholinyl group or -NR 13 R 14 selected from, R 13 、R 14 are each independently selected from hydrogen, a C1-C8 alkyl group.

[0038] Furthermore, the compound is one of the following compounds. TIFF2025520857000079.tif46170TIFF2025520857000080.tif46170TIFF2025520857000081.tif49170TIFF2025520857000082.tif55170TIFF2025520857000083.tif28170TIFF2025520857000084.tif105170TIFF2025520857000085.tif122170TIFF2025520857000086.tif158170TIFF2025520857000087.tif149170TIFF2025520857000088.tif37170

[0039] The present invention also provides the use of the above-mentioned compound, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, in the manufacture of a PI3K inhibitor.

[0040] Preferably, the PI3K inhibitor is a selective PI3K inhibitor.

[0041] The present invention also provides the use of the above-mentioned compound, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, in the manufacture of a drug for the prevention and / or treatment of diseases related to PI3K.

[0042] Furthermore, the diseases are cancers, inflammations, cardiovascular diseases related to PI3K, Preferably, the cancers are breast cancer, colorectal cancer, gastric cancer, colon cancer, rectal cancer, ovarian cancer, prostate cancer.

[0043] The present invention further provides a drug manufactured by using the above-mentioned compound, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary components.

[0044] The compounds and derivatives provided by the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature.

[0045] The definitions of the terms used in the present invention are as follows. Unless otherwise specified, the first definition provided by a group or term in the text applies to the said group or term throughout the specification, and for terms not specifically defined in the text, they shall represent the meanings that can be conceived by those skilled in the art based on the disclosure content and context.

[0046] "Substituted" means that a hydrogen atom in a molecule is replaced by another different atom or molecule.

[0047] The minimum and maximum values of the carbon atom content in a hydrocarbon group are represented by a prefix. For example, the prefix C a~ C b An alkyl group represents an alkyl group containing any number of carbon atoms from "a" to "b". Thus, for example, a "C1-C8 alkyl group" refers to an alkyl group containing 1 to 8 carbon atoms, and a "C1-C8 alkoxy group" refers to an alkoxy group containing 1 to 8 carbon atoms.

[0048] "Alkyl group" refers to a saturated hydrocarbon chain having a specified number of carbon atoms. For example, a C1-C8 alkyl group refers to an alkyl group having 1 to 8 carbon atoms, that is, an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. The alkyl group may be straight-chain or branched-chain. Representative branched-chain alkyl groups have one, two, or three branched chains. The alkyl group includes a methyl group, an ethyl group, a propyl group (n-propyl group and isopropyl group), a butyl group (n-butyl group, isobutyl group, and tert-butyl group), a pentyl group (n-pentyl group, isopentyl group, and neopentyl group), a hexyl group, and the like.

[0049] "Halogen" is fluorine, chlorine, bromine, or iodine.

[0050] In the present invention, the cycloalkyl group refers to a saturated or partially saturated non-aromatic cyclic group composed of carbon atoms, having no ring heteroatoms, and having a monocyclic or polycyclic (including fused, bridged, and spiro ring systems). The heterocycloalkyl group refers to a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom, including monocyclic or polycyclic (including fused, bridged, and spiro ring systems), where the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. Examples of the heterocyclyl group include, for example, a piperidyl group, a piperazinyl group, and a morpholinyl group.

[0051] In the present invention, the aryl group refers to a group containing aromatic unsaturation having no ring heteroatoms and having a monocyclic or polycyclic (including fused, bridged, and spiro ring systems), such as a phenyl group, an anthracenyl group, or a naphthyl group. The heteroaryl group refers to an aromatic unsaturated ring containing at least one heteroatom, including monocyclic or polycyclic (including fused, bridged, and spiro ring systems), and the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. For example, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, a furyl group, a thienyl group, an oxazolyl group, an isoindolinyl group, and the like.

[0052] In the present invention, the structure in which R4 and R5 together with carbon form a ketone group in -CR4R5 is TIFF2025520857000089.tif14170.

[0053] In the present invention, the structure of the phosphonic acid group is TIFF2025520857000090.tif15170, the structure of the sulfonic acid group is TIFF2025520857000091.tif20170, the structure of the sulfonamide group is TIFF2025520857000092.tif20170, and the structure of the boronic acid group is TIFF2025520857000093.tif15170.

[0054] The compounds prepared according to the present invention can be used for the manufacture of selective inhibitors of PI3K, and for the manufacture of drugs for the prevention and / or treatment of diseases related to PI3K, such as drugs for the prevention and / or treatment of cancer. The present invention provides new options for cancer treatment in clinical practice and has good prospects for the future.

[0055] Of course, based on the above content of the present invention, various other forms of modification, substitution or change can be made on the premise of not departing from the above basic technical idea of the present invention in light of the general technical knowledge and conventional means in the art.

[0056] Hereinafter, the above content of the present invention will be described in more detail by specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology realized based on the above content of the present invention belongs to the scope of the present invention.

Embodiments for Carrying Out the Invention

[0057] All the raw materials and equipment used in the "Embodiments for Carrying Out the Invention" of the present invention are existing products, which are purchased as commercially available products.

[0058] Synthesis of common intermediate: (R)-8-(1-aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-indolin-4-one (4-7) TIFF2025520857000094.tif86170

[0059] Synthesis of the first-step intermediate: 8-bromo-2-mercapto-6-methyl-4H-indolin-4-one (4-1) TIFF2025520857000095.tif31170

[0060] Procedure: Add 1-(3-bromo-2-hydroxy-5-methylphenyl)ethanone (1.3 g, 5.6 mmol) to THF (4 mL), replace with nitrogen gas three times, and while stirring in an ice-water bath, add dropwise t-BuOK (1 M in THF, 17 mL). After the addition is complete, warm to room temperature and stir for 30 minutes. Cool and stir again in an ice-water bath, and slowly add dropwise CS₂ (1.06 g, 14 mmol) in THF (10 mL). After the addition is complete, allow to return to room temperature naturally and stir overnight. Adjust the pH to 2 using HCl (1 N) under an ice-water bath, extract with EA (20 mL × 3), dry over anhydrous sodium sulfate, concentrate, then form a hot slurry with EA, filter, and dry to obtain Compound 4-1 (1.3 g, 4.8 mmol). Yield: 86%. Ms: 271 (M+H + )。

[0061] Synthesis of the second-step intermediate: 8-bromo-2-(ethylthio)-6-methyl-4H-indolin-4-one (4-2) TIFF2025520857000096.tif30170

[0062] Procedure: Add 4-1 (1.3 g, 4.8 mmol) to acetone (6.5 mL), add potassium carbonate (0.86 g, 6.2 mmol) and iodoethane (1.1 g, 7.2 mmol), then stir at room temperature and monitor by TLC. After the reaction is complete, add water (10 mL) and dichloromethane (10 mL), filter, wash and extract the filter cake with dichloromethane (10 mL × 2), dry, concentrate, and obtain the intermediate 4-2 (950 mg, 3.2 mmol) by column chromatography. Yield: 66%. Ms: 299 (M+H + )。

[0063] Synthesis of the third-step intermediate: 8-acetyl-2-(ethylthio)-6-methyl-4H-indolin-4-one (4-3) TIFF2025520857000097.tif31170

[0064] Procedure: 4-2 (299 mg, 1 mmol), tin reagent (541 mg, 1.5 mmol), DIPEA (258 mg, 2 mmol), tetrakistriphenylphosphine palladium (173 mg, 0.15 mmol) were added to dioxane (6 mL), and stirred at 95 °C overnight under the protection of nitrogen gas. After the reaction solution was cooled to room temperature, concentrated hydrochloric acid (0.5 mL) was added, stirred for 30 minutes, saturated potassium fluoride solution (3 mL) was added, and stirred for 1 hour. Filtered, extracted with ethyl acetate, and intermediate 4-3 (200 mg, 0.76 mmol) was obtained by column chromatography. Yield 76%. Ms: 263 (M+H + )。

[0065] Synthesis of the intermediate in the 4th step: 8-acetyl-2-(2,4-difluorophenyl)-6-methyl-4H-indolin-4-one (4-4) TIFF2025520857000098.tif36170

[0066] Procedure: 4-3 (200 mg, 0.63 mmol) was dissolved in dioxane (2 mL), nitrogen gas was bubbled for 3 minutes, 2,4-difluorophenylboronic acid (1.26 g, 5.06 mmol), CuTc (202 mg, 3.17 mmol), tetrakistriphenylphosphine palladium (146 mg, 0.13 mmol), cesium carbonate (412 mg, 1.27 mmol), molecular sieve (200 mg) were added, then the sealed tube was sealed and stirred at 80 °C for 8 hours. Water and ethyl acetate were added, filtered, extracted with ethyl acetate, and intermediate 4-4 (198 mg, 0.63 mmol) was obtained by column chromatography. Yield 63%. Ms: 315 (M+H + )。

[0067] Synthesis of the intermediate in the 5th step: (R,Z)-N-(1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-indolin-8-yl)ethylidene)-2-isobutyl-2-sulfinamide (4-5) TIFF2025520857000099.tif32170

[0068] Procedure: 4-4 (198 mg, 0.63 mmol) and (R)-(+)-tert-butylsulfinamide (191 mg, 1.58 mmol) were added to tetrahydrofuran (1.1 ml), and then tetraethyl titanate (718 mg, 3.15 mmol) was added. The mixture was stirred at 90 °C overnight. Water and ethyl acetate were added, and the mixture was filtered, extracted with ethyl acetate, and intermediate 4-5 (217 mg, 0.52 mmol) was obtained by column chromatography. Yield: 82%. Ms: 418 (M+H + )。

[0069] Synthesis of the intermediate in Step 6: (R)-N-(1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-indolin-8-yl)ethyl)-2-isobutane-2-sulfinamide (4-6) TIFF2025520857000100.tif37170

[0070] Procedure: 4-5 (217 mg, 0.52 mmol) and cerium(III) chloride heptahydrate (97 mg, 0.26 mmol) were added to methanol (6.6 ml), protected with nitrogen gas, dissolved until clear, and then cooled to -78 °C. While stirring at low temperature, sodium borohydride (49 mg, 1.3 mmol) was added and the mixture was stirred overnight. After the reaction was complete, ethyl acetate was added, and the mixture was filtered. Intermediate 4-6 (170 mg, 0.4 mmol) was obtained by column chromatography. Yield: 78%. Ms: 420 (M+H + )。

[0071] Synthesis of the intermediate in Step 7: (R)-8-(1-aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-indolin-4-one (4-7) TIFF2025520857000101.tif36170

[0072] Operation: 4 - 6 (170 mg, 0.4 mmol) was dissolved in dichloromethane (3 mL), and a dioxane solution of hydrogen chloride (1 mL) was added. After that, the mixture was stirred at room temperature. Monitored by TLC, after the reaction was completed, it was rotary evaporated, water was added, extracted with ethyl acetate, the pH of the aqueous phase was adjusted to alkaline, extracted with EA, dried, and rotary evaporated to obtain intermediate 4 - 7 (114 mg, 0.36 mmol). Yield 90%. Ms: 316 (M + H + )。

[0073] 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) TIFF2025520857000102.tif86170

[0074] First Step: Synthesis of Intermediate 8-bromo-2-mercapto-6-methyl-4H-chromen-4-one (1-1) TIFF2025520857000103.tif31170

[0075] Compound 1-(3-bromo-2-hydroxy-5-methylphenyl)ethan-1-one (8.1 g, 35.4 mmol) and tetrahydrofuran (100 mL) were added to a 500 mL reaction flask, cooled to -70 °C in a dry ice bath, and NaHMDS (2.0 M in THF, 53 mL, 106 mmol) was added dropwise. After the addition was complete, the temperature was allowed to rise naturally to 0 °C, stirred for 1 hour, then cooled to -20 °C, and carbon disulfide (8.1 g, 106 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and reacted overnight. After the reaction was completed, it was cooled to 0 °C, adjusted to pH = 4 - 5 with 1 N dilute hydrochloric acid, stirred for 1 hour, extracted with ethyl acetate (50 mL × 3 times), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, ethyl acetate was added to form a slurry, and filtered to obtain intermediate 1-1 (6.6 g). Yield 69%. Ms: 271.1, 273.1 (M + H + )。

[0076] Step 2: Synthesis of Intermediate 8-Bromo-2-(ethylthio)-6-methyl-4H-chromen-4-one (1-2) TIFF2025520857000104.tif35170

[0077] To a 250 mL reaction flask, add compound 1-1 (6.6 g, 24.4 mmol), potassium carbonate (5.1 g, 36.6 mmol) and acetone (70 mL). While stirring, add iodoethane (4.5 g, 29 mmol), heat under reflux. After the reaction is complete, add water (30 mL), extract with ethyl acetate (30 mL × 3 times). Combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and pass through a silica gel column to obtain compound 1-2 (4.5 g). Yield: 62%. Ms: 299.1, 301.1 (M+H + )

[0078] Step 3: Synthesis of Intermediate 8-Bromo-2-(ethylsulfonyl)-6-methyl-4H-chromen-4-one (1-3) TIFF2025520857000105.tif35170

[0079] To a 100 mL reaction flask, add compound 1-2 (1 g, 3.3 mmol) and dichloromethane (20 mL). While stirring, add meta-chloroperbenzoic acid (2.3 g, 13.3 mmol), stir at room temperature overnight. After the reaction is complete, filter, wash the filtrate with an aqueous sodium thiosulfate solution, then further wash the organic layer with a saturated aqueous sodium carbonate solution. Dry the organic layer, concentrate to obtain the crude product, compound 1-3 (1.3 g). Yield: 118%. Ms: 331.1, 333.1 (M+H + )

[0080] Step 4: Synthesis of Intermediate 8-Bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4H-chromen-4-one (1-4) TIFF2025520857000106.tif32170

[0081] To a 100 mL reaction flask, add 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), react overnight. After the reaction is complete, add water (10 mL), extract with dichloromethane (10 mL × 3 times), combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and then pass through a silica gel column to obtain compound 1-4 (1 g). Yield 74%. Ms: 350.1, 352.1 (M+H + ).

[0082] Step 5: Synthesis of intermediate 2-(4,4-dimethylpiperidin-1-yl)-8-(diphenylmethylene)amino)-6-methyl-4H-chromen-4-one (1-5) TIFF2025520857000107.tif44170

[0083] To a 100 mL reaction flask, add compound 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), protect by nitrogen gas substitution, add 1,1'-binaphthyl-2,2'-bisdiphenylphosphino (0.36 g, 0.6 mmol) and palladium acetate (0.13 g, 0.6 mmol), heat the mixture to 100 °C, react overnight. After the reaction is complete, add water (20 mL), extract with ethyl acetate (20 mL × 3 times), combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and then use the obtained mixture directly in the next step.

[0084] Step 6: Synthesis of intermediate 8-amino-2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4H-chromen-4-one (1-6) TIFF2025520857000108.tif40170

[0085] Add the mixture from the previous step to a 100 mL reaction flask, add tetrahydrofuran (20 mL) to dissolve it, then add 2N dilute hydrochloric acid (15 mL), stir at room temperature. After the reaction is complete, add an aqueous sodium carbonate solution to adjust the pH to 8 - 9, extract with ethyl acetate (20 mL × 3 times), combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and then pass through a silica gel column to obtain compound 1-6 (0.7 g). Yield 84%. Ms: 287.2 (M+H + )

[0086] 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) TIFF2025520857000109.tif52170

[0087] Add compound 1-6 (50 mg, 0.18 mmol) and dichloromethane (3 mL) to a 25 mL reaction flask, add triphosgene (27 mg, 0.09 mmol) under an ice bath, stir at room temperature for 1 hour, then add triethylamine (71 mg, 0.7 mmol) and indoline (25 mg, 0.21 mmol) in sequence. After the reaction is complete, add water (3 mL), extract with ethyl acetate (3 mL × 3 times), combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and then purify on a preparative plate to obtain the compound (compound 1, 40 mg). Yield 52%. Ms: 432.2 (M+H + ), 1 H NMR (400 MHz, DMSO-d6) δ8.52 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 3.0 Hz, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 5.48 (s, 1H), 4.14 (t, J = 8.6 Hz, 2H), 3.45 (dd, J = 6.9, 4.7 Hz, 4H), 3.20 (t, J = 8.6 Hz, 2H), 2.38 (s, 3H), 1.30 (t, J = 5.8 Hz, 4H), 0.91 (s, 6H).

[0088] 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) TIFF2025520857000110.tif71170

[0089] Step 1: Synthesis of Intermediate 8-acetyl-2-(ethylthio)-6-methyl-4H-chromen-4-one (2-1) TIFF2025520857000111.tif36170

[0090] 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-ethoxyvinyl)tin (1 g, 2.8 mmol) and dioxane (15 mL). After purging with nitrogen gas, add 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (168 mg, 0.23 mmol). Heat the reaction mixture to 95 °C and react for about 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 with ethyl acetate (20 mL) three times, separate the layers, dry the organic layer over anhydrous sodium sulfate, concentrate, and pass through a silica gel column to obtain intermediate 2-1 (400 mg). Yield 66%. Ms: 263 (M+H + )

[0091] Step 2: Synthesis of Intermediate (R,Z)-N-(1-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8-yl)ethylidene)-2-methylpropane-2-sulfonamide (2-2) TIFF2025520857000112.tif36170

[0092] To a 100 mL reaction flask, add compound 2-1 (400 mg, 1.5 mmol), (R)-tert-butylsulfinamide (370 mg, 3 mmol), titanium(IV) isopropoxide (870 mg, 3.1 mmol), and tetrahydrofuran (10 mL). Replace with nitrogen gas, heat under reflux overnight. After the reaction is complete, cool to room temperature, add saturated brine (10 mL), stir for 0.5 h, filter, wash the filter cake three times with ethyl acetate (10 mL), separate the layers, combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and pass through a silica gel column to obtain the crude product, intermediate 2-2 (700 mg). Yield: 128%. Ms: 366 (M+H + )。

[0093] Step 3: Synthesis of intermediate (R)-N-((R)-1-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropan-2-sulfonamide (2-3) TIFF2025520857000113.tif37170

[0094] To a 50 mL reaction flask, add compound 2-2 (375 mg, 1 mmol), cerium(III) chloride heptahydrate (187 mg, 0.5 mmol), and methanol (10 mL). Cool to -70 °C with stirring, and dropwise add a solution of sodium borohydride (114 mg, 3 mmol) in methanol (2 mL). After the addition is complete, allow the temperature to rise naturally and let stand overnight. Add ethyl acetate, filter, rotary evaporate the filtrate, add ethyl acetate again, filter again, concentrate the filtrate, and pass through a silica gel column to obtain intermediate 2-3 (80 mg). Yield: 22%. Ms: 368 (M+H + )。

[0095] Step 4: Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(ethylthio)-6-methyl-4H-chromen-4-one (2-4) TIFF2025520857000114.tif39170

[0096] To a 25 mL reaction flask, compound 2-3 (80 mg, 0.22 mmol) and ethyl acetate (3 mL) were added. While stirring, a hydrogen chloride dioxane solution (3 mL) was added, and the mixture was stirred at room temperature until the reaction was complete. The solvent was concentrated, an aqueous sodium bicarbonate solution (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and after concentration, intermediate 2-4 (50 mg) was obtained. Yield: 86%. Ms: 264 (M+H + )。

[0097] Step 5: Synthesis of intermediate (R)-2-((1-(2-(ethylthio)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid (2-5) TIFF2025520857000115.tif39170

[0098] To a 25 mL reaction flask, compound 2-4 (50 mg, 0.19 mmol), o-iodobenzoic acid (39 mg, 0.29 mmol), triethylamine (38 mg, 0.38 mml), and N,N-dimethylacetamide (1 mL) were added. The flask was purged with nitrogen gas, copper powder (12 mg, 0.19 mmol) was added, and the mixture was heated to 110 °C and reacted for about 1 - 2 hours. After the reaction was complete, it was cooled to room temperature, adjusted to pH = 4 - 5 with 1N hydrochloric acid aqueous solution, ethyl acetate (5 mL) was added, and the layers were separated. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and then purified by preparative plate to obtain intermediate 2-5 (45 mg). Yield: 62%. Ms: 384 (M+H + )。

[0099] Step 6: Synthesis of intermediate 2-(((1R)-1-(2-(ethylsulfinyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid (2-6) TIFF2025520857000116.tif37170

[0100] To a 25 mL reaction flask, compound 2-5 (45 mg, 0.12 mmol) and dichloromethane (3 mL) were added. While stirring, metachloroperbenzoic acid (31 mg, 0.18 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was completed, it was filtered, and the filtrate was washed with an aqueous sodium thiosulfate solution. The organic layer was dried and concentrated to obtain the crude product, compound 2-6 (60 mg). Yield: 125%. Ms: 400 (M+H + ).

[0101] 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) TIFF2025520857000117.tif37170

[0102] To a 25 mL reaction flask, compound 2-6 (30 mg, 0.08 mmol), 1-amino-2-methyl-2-propanol (10 mg, 0.11 mmol), diethylpropylamine (39 mg, 0.3 mmol) and dichloromethane were added. The reaction mixture was heated to 40 °C and left overnight. After the reaction was completed, it was purified directly on a preparative plate to obtain the compound (compound 7, 7 mg). Yield: 21%. Ms: 411 (M+H + ), 1 H NMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 8.67 (s, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.79 (dd, J = 7.9, 1.7 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.50 (t, J = 7.5 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 5.33 (s, 1H), 5.15 (d, J = 7.0 Hz, 1H), 3.39 (s, 1H), 3.17 (d, J = 6.2 Hz, 2H), 2.28 (s, 3H), 1.55 (d, J = 6.6 Hz, 3H), 1.16 (d, J = 7.6 Hz, 6H).

[0103] 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) TIFF2025520857000118.tif36170

[0104] To a 25 mL reaction flask, intermediate 4-7 (synthesis refers to the synthesis of common 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, replaced with nitrogen gas, tris(dibenzylideneacetone)dipalladium (12 mg, 0.01 mmol) and 2-di-tert-butylphosphino-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 completed, water (2 mL) was added, extracted with ethyl acetate (3 mL × 3 times), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated on a preparative plate to obtain the target compound 42 (6 mg). Yield 25%. Ms: 396.1 (M+H + ), 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 2.2 Hz, 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 = 6.7 Hz, 1H), 3.25 (s, 3H), 2.37 (s, 3H), 1.71 (d, J = 6.7 Hz, 3H).

[0105] 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)picolinate (Compound 37) TIFF2025520857000119.tif85170

[0106] Intermediate: Synthesis of 2-Amino-3-bromo-N,5-dimethylbenzamide (5-1) TIFF2025520857000120.tif29170

[0107] Dissolve 2-Amino-3-bromo-5-methylbenzoic acid (200 g, 0.87 mol) in THF (2 L), add CDI (156 g, 0.96 mol) in several portions, gradually bubble the system, react for 2 h, then detect the completion of the reaction of the raw material by TLC. Cool the system to 0 - 10 °C and dropwise add aqueous methylamine solution (800 mL). After the addition is complete, remove the ice bath and react for 1 h. Detect the complete reaction of the intermediate by TLC. For post-treatment, concentrate until a solid precipitates, then pour it into water 10 times the volume of tetrahydrofuran to form a slurry, filter, elute the filter cake with water and absolute ethanol, and rotary dry the filter cake to obtain a white solid 5-1 (204 g, 0.84 mol). Yield: 96%. M / S: 243 / 245 (M+H + )

[0108] Intermediate: Synthesis of 8-Bromo-2-(2,6-difluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (5-2) TIFF2025520857000121.tif37170

[0109] Add 5-1 (2.0 g, 8.26 mmol), 2,6-difluorobenzaldehyde (1.4 g, 9.91 mmol) and iodine (2.51 g, 9.91 mmol) to DMSO (20 mL) in sequence, stir at 100 °C for 4 h, and monitor the completion of the reaction of the raw material by LCMS. For post-treatment, after cooling, add the system to ice water of sodium thiosulfate, filter, elute the filter cake with ethanol, and rotary dry the filter cake to obtain an off-white solid 5-2 (2.2 g, 6.04 mmol). Yield: 73%. M / S: 365 / 367 (M+H + )

[0110] Intermediate: Synthesis of 8-Acetyl-2-(2,6-difluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (5-3) TIFF2025520857000122.tif29170

[0111] 5-2 (2.2 g, 6.04 mmol), tributyl(1-ethoxyethylene)tin (2.6 g, 7.25 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.48 g, 0.60 mmol) were sequentially added to anhydrous dioxane (11 mL), replaced with nitrogen gas three times, reacted at 90 °C for 6 h, monitored by TLC for complete reaction of the raw materials, and for post-treatment, after cooling, DCM (20 mL) was added, the pH was adjusted to 2 - 3 with 2N HCl, stirred for 1 - 2 h, the completion of the intermediate reaction was detected by TLC, KF was added to dissolve it to saturation and stirred for 1 h, filtered, the filtrate was extracted with DCM (50 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness, the obtained crude product was slurried with EA and filtered, and the filter cake was rotary dried to obtain a pale yellow solid 5-3 (1.7 g, 5.18 mmol). Yield 87%. M / S: 329 (M + H + )。

[0112] Intermediate: Synthesis of (R,Z)-N-(1-(2-(2,6-difluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfonamide (5-4) TIFF2025520857000123.tif32170

[0113] 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 sequentially added to tetrahydrofuran (8.5 mL), and the mixture was stirred at 90 °C for 12 h. The completion of the reaction of the raw materials was monitored by TLC. As a post-treatment, after cooling, the reaction solution was poured into ice water (85 mL), filtered, the filter cake was slurried with DCM (50 ml × 4), the organic phase was recovered, and the filtrate was extracted with DCM (50 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness. A crude product of 5-4 as a yellow oil (1.5 g, 3.48 mmol) was obtained and could be used directly in the next step. M / S: 432 (M+H + ).

[0114] 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) TIFF2025520857000124.tif37170

[0115] The crude product of 5-4 (1.5 g, 3.48 mmol) and cerium(III) chloride heptahydrate (0.6 g, 1.74 mmol) were sequentially added to methanol (22 mL), replaced with nitrogen gas three times, cooled to -60 to -70 °C, and sodium borohydride (0.4 g, 10.44 mmol) was added in several portions. After addition, the mixture was kept warm for 30 min and then returned to room temperature. The completion of the reaction of the raw materials was monitored by TLC. As a post-treatment, water was added to quench, DCM (100 ml × 3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness, and then subjected to column chromatography to obtain yellow solid 5-5 (0.8 g, 1.85 mmol). The yield of the two steps was 36%. M / S: 434 (M+H + ).

[0116] Synthesis of Intermediate: (R)-8-(1-aminoethyl)-2-(2,6-difluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (5-6) TIFF2025520857000125.tif36170

[0117] 5-5 (0.8 g, 1.85 mmol) was dissolved in dichloromethane (4 mL), a dioxane solution of HCl (4 N, 2 mL) was added, stirred at room temperature, and the completion of the reaction of the raw material was monitored by TLC. As a post-treatment, water (50 mL) was added, the pH was adjusted to 7 - 8 with sodium bicarbonate, DCM (50 ml × 3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness to obtain solid 5-6 (0.58 g, 1.75 mmol). Yield 95%. M / S: 317 (M+H + )。

[0118] 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) TIFF2025520857000126.tif36170

[0119] 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) were added to DMA (1 mL), stirred at 110 °C for 4 hours, and the completion of the reaction of the raw material was monitored by TLC. As a post-treatment, water (10 mL) was added, extracted with EA (10 ml × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness and then subjected to column chromatography to obtain white solid Compound 37 (35 mg, 0.078 mmol). Yield 37%. M / S: 450 (M+H + )。

[0120] 11H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 8.0, 1.7 Hz, 1H), 7.78 (s, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.57 - 7.45 (m, 1H), 7.18 (t, J = 7.3 Hz, 1H), 7.11 (td, J = 8.2, 2.5 Hz, 2H), 6.54 (s, 1H), 6.49 (d, J = 8.6 Hz, 1H), 5.59 (q, J = 6.6 Hz, 1H), 3.50 (s, 3H), 2.44 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H).

[0121] 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) TIFF2025520857000127.tif38170

[0122] (R)-8-(1-aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-chromen-4-one (synthesis refers to the synthesis of common intermediate, 30 mg, 95.14 μmol), 2-fluorobenzenesulfonamide (25 mg, 142.71 μmol), potassium carbonate (26 mg, 190.28 μmol) were added to NMP (1 mL), stirred at 130 °C for 4 hours, monitored by TLC. After the reaction of the raw materials was completed, for post-treatment, water (20 mL) was added, extracted with EA (10 ml × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness and then subjected to column chromatography to obtain white solid Compound 27 (20 mg, 45.51 μmol). Yield 45%. M / S: 471 (M + H + )

[0123] 11H NMR (400 MHz, Chloroform-d) δ 8.01 (s, 1H), 8.02 - 7.92 (m, 1H), 7.74 (dd, J = 8.5, 5.2 Hz, 2H), 7.61 - 7.57 (m, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.19 (s, 1H), 6.45 (d, J = 8.6 Hz, 1H), 5.63 (q, J = 6.6 Hz, 1H), 3.66 (s, 4H), 2.43 (s, 3H), 1.60 (d, J = 6.7 Hz, 3H).

[0124] Example 6: Synthesis of 2-(2,4-difluorophenyl)-8-(1-(indolin-1-yl)ethyl)-6-methyl-4H-chromen-4-one (Compound 116) TIFF2025520857000128.tif57170

[0125] Step 1: Synthesis of Intermediate 2-(2,4-difluorophenyl)-8-(1-hydroxyethyl)-6-methyl-4H-indolin-4-one (8-5) TIFF2025520857000129.tif31170

[0126] Procedure: Compound 4-4 (synthesis refers to the synthesis of common intermediate, 314 mg, 1 mmol) was dissolved in methanol (5 ml), and sodium borohydride (114 mg, 3 mmol) was added under an ice-water bath. The mixture was allowed to warm to room temperature naturally and stirred overnight. Monitored by TLC. After the reaction was completed, it was poured into a saturated ammonium chloride solution and extracted with dichloromethane (10 mL × 3). Dried over anhydrous sodium sulfate and rotary evaporated. Pure compound 8-5 (273 mg, 0.86 mmol) was obtained. Yield 86%. Ms: 317 (M + H + ).

[0127] Step 2: Synthesis of Intermediate 8-(1-chloroethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-indolin-4-one (8-6) TIFF2025520857000130.tif32170

[0128] 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 while stirring at room temperature. The mixture was stirred overnight. After monitoring by TLC and completion of the reaction, the sample was stirred and subjected to column chromatography. Pure compound 8-6 (280 mg, 0.86 mmol) was obtained. Yield 84%. Ms: 335 (M+H + ).

[0129] Step 3: Synthesis of the target compound 2-(2,4-difluorophenyl)-8-(1-(indolin-1-yl)ethyl)-6-methyl-4H-chromen-4-one (Compound 116) TIFF2025520857000131.tif30170

[0130] Procedure: Compound 8-6 (50 mg, 0.15 mmol) was dissolved in DCM (1 ml), and indoline (20 mg, 0.17 mmol) and triethylamine (18 mg, 0.18 mmol) were sequentially added while stirring at room temperature. The mixture was stirred overnight. After monitoring by TLC and completion of the reaction, it was subjected to column chromatography. Pure compound 116 (30 mg, 0.07 mmol) was obtained. Yield 48%. Ms: 418 (M+H + ); 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (td, J = 8.9, 6.5 Hz, 1H), 7.83 - 7.77 (m, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.54 (ddd, J = 11.9, 9.2, 2.6 Hz, 1H), 7.15 (td, J = 8.5, 2.6 Hz, 1H), 7.04 - 6.96 (m, 1H), 6.93 - 6.84 (m, 1H), 6.77 (d, J = 0.9 Hz, 1H), 6.59 - 6.47 (m, 1H), 6.39 (d, J = 7.8 Hz, 1H), 5.37 (q, J = 6.9 Hz, 1H), 3.44 (t, J = 9.5 Hz, 2H), 2.91 - 2.77 (m, 2H), 2.44 (s, 3H), 1.54 (d, J = 6.9 Hz, 3H).

[0131] 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)picolylamide (Compound 48) TIFF2025520857000132.tif69170

[0132] Step 1: Synthesis of Intermediate Methyl (R)-3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinate (9-1) TIFF2025520857000133.tif44170

[0133] Procedure: (R)-8-(1-Aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-chromen-4-one (200 mg, 0.63 mmol), methyl 3-fluoropicolinate (197 mg, 1.27 mmol), and N,N-diisopropylethylamine (246 mg, 1.90 mmol) were added to N-methylpyrrolidone (2 mL). The temperature was raised to 120 °C and stirred overnight for reaction. The reaction system was cooled to room temperature, diluted with ethyl acetate (10 mL), washed with water (20 mL × 2), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography to obtain 110 mg of the product (intermediate 9-1). Yield: 38.5%. Ms: 451.1 (M+H + )

[0134] Step 2: Synthesis of Intermediate (R)-3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinate (9-2) TIFF2025520857000134.tif36170

[0135] 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 to allow the reaction to proceed. The pH was adjusted to around 3 with 0.5 N hydrochloric acid, and 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). Yield: 68.8%. Ms: 437.2 (M+H+).

[0136] 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)picolinamide (Compound 48) TIFF2025520857000135.tif38170

[0137] 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 temperature was raised to 60 °C and the mixture was reacted for 1 hour, then cooled to room temperature. N,N-diisopropylethylamine (14 mg, 0.11 mmol) and methylamine hydrochloride-d3 (12 mg, 0.17 mmol) were added to the reaction system, and the mixture was stirred at room temperature for 2 hours to allow the reaction to proceed. Ethyl acetate (10 mL) was added for dilution, and the mixture was washed with water (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 13 mg of the product (Compound 48). Yield: 52.2%. Ms: 453.2 (M+H + )。 11H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 6.6 Hz, 1H), 8.72 (s, 1H), 8.14 (td, J = 8.8, 6.4 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.61 - 7.53 (m, 2H), 7.36 - 7.30 (m, 1H), 7.18 (dd, J = 8.6, 4.3 Hz, 1H), 6.90 (dd, J = 8.8, 1.3 Hz, 1H), 6.80 (d, J = 0.8 Hz, 1H), 5.20 (p, J = 6.6 Hz, 1H), 2.35 (s, 3H), 1.62 (d, J = 6.6 Hz, 3H).

[0138] 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) TIFF2025520857000136.tif63170

[0139] Intermediate: Synthesis of 9-Bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (12-1) TIFF2025520857000137.tif29170

[0140] 2-Amino-3-bromo-5-methylpyridine (1.87 g, 10.0 mmol) and bis(2,4,6-trichlorophenyl) malonate (5.56 g, 12.0 mmol) were sequentially added to toluene (19 mL), and the mixture was reacted at 90 °C for 4 hours. It was detected by TLC that the reaction was complete. After cooling to room temperature, filtration was carried out, and the solid was eluted with petroleum ether (20 mL), and the solid was rotary dried to obtain 12-1 (2.00 g, 0.79 mol). Yield 79%. M / S: 255.0 (M+H + ).

[0141] Intermediate: Synthesis of 9-Bromo-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl trifluoromethanesulfonate (12-2) TIFF2025520857000138.tif30170

[0142] 12-1 (2.00 g, 7.9 mmol), N-phenylbis(trifluoromethanesulfon)imide (5.64 g, 15.8 mmol), and triethylamine (1.60 g, 15.8 mmol) were sequentially added to DMA (20 mL), and the mixture was reacted at room temperature for 4 hours. It was detected by TLC that the reaction was complete. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction system for extraction. The organic layer was concentrated to dryness and purified by column chromatography to obtain 12-2 (2.2 g, 5.7 mmol). Yield: 72%. M / S: 386.9 (M+H + )。

[0143] Intermediate: Synthesis of 9-bromo-2-(2,4-difluorophenyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (12-3) TIFF2025520857000139.tif35170

[0144] 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 tetrakistriphenylphosphine palladium (0.7 g, 0.6 mmol) were sequentially added to 1,4-dioxane (22 mL), and the mixture was reacted at 90 °C overnight. It was detected by TLC that the reaction was complete. The mixture was cooled to room temperature, 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 12-3 (1.5 g, 4.3 mmol). Yield: 75%. M / S: 351.0 (M+H + )。

[0145] Intermediate: Synthesis of 9-acetyl-2-(2,4-difluorophenyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (12-4) TIFF2025520857000140.tif31170

[0146] 12-3 (1.5 g, 4.3 mmol), tributyl(1-ethoxyvinyl)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), protected with nitrogen gas, and reacted at 100 °C for 2 h. It was detected by TLC that the reaction was complete. After cooling to room temperature, 4N HCl / dioxane was added to adjust the pH to 2 - 3, 1 mL of water was added, and after stirring for 2 h, it was detected by TLC that the reaction was complete. KF was added to dissolve it to saturation and stirred for 2 h, filtered, extracted with ethyl acetate (20 mL × 2), the solid was slurried with ethyl acetate (20 mL), filtered, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated to dryness, and purified by column chromatography to obtain 12-4 (1.3 g, 4.1 mmol). Yield 95%. M / S: 315.1 (M + H + )。

[0147] Intermediate: Synthesis of (R,Z)-N-(1-(2-(2,4-difluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethylidene)-2-methylpropane-2-sulfonamide (12-5) TIFF2025520857000141.tif36170

[0148] 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 sequentially added to THF (13 mL), reacted at 90 °C overnight, and it was detected by TLC that the reaction was complete. After cooling to room temperature, ethyl acetate (20 mL) was added for dilution, 10 mL of water was added, filtered, separated, and the aqueous layer was extracted with ethyl acetate (20 ml × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated to dryness, and purified by column chromatography to obtain 12-5 (1.6 g, 3.8 mmol). Yield 93%. M / S: 418.1 (M + H + )。

[0149] Intermediate: Synthesis of (R)-N-((R)-1-(2-(2,4-difluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)-2-methylpropan-2-sulfonamide (12-6) TIFF2025520857000142.tif36170

[0150] 12-5 (1.6 g, 3.8 mmol) and CeCl3·7H2O (0.6 g, 1.9 mmol) were successively added to MeOH (32 mL), protected with nitrogen gas, cooled to -60~-70 °C, and NaBH4 (0.4 g, 11.4 mmol) was added in several portions. After addition, the temperature was allowed to rise naturally to room temperature, and it was detected by TLC that the reaction was complete. Water (20 mL) and ethyl acetate (40 mL×2) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated to dryness, and purified by column chromatography to obtain 12-6 (1.0 g, 2.4 mmol). Yield 63%. M / S: 420.1 (M+H + )

[0151] Intermediate: Synthesis of (R)-9-(1-aminoethyl)-2-(2,4-difluorophenyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (12-7) TIFF2025520857000143.tif37170

[0152] 12-6 (1.0 g, 2.4 mmol) was dissolved in DCM (2 mL), and a dioxane solution of HCl (4N, 2 mL) was added. The mixture was stirred at room temperature, and it was detected by TLC that the reaction was complete. Water (10 mL) was added, and the layers were separated. The organic layer was removed, and the aqueous phase was adjusted to pH 7~8 with saturated sodium bicarbonate solution and extracted with DCM (2 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated to dryness to obtain 12-7 (0.63 g, 2.0 mmol). Yield 83%. M / S: 316.1 (M+H + )

[0153] 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) TIFF2025520857000144.tif37170

[0154] 12-7 (63 mg, 0.2 mmol), o-iodobenzoic acid (99 mg, 0.4 mmol), copper powder (25 mg, 0.4 mmol), triethylamine (60 mg, 0.6 mmol) were added to DMA (1 mL), protected with nitrogen gas, stirred at 110 °C for 4 hours, detected by TLC that the reaction was complete, added water (2 mL), extracted with ethyl acetate (1 ml × 2), combined the organic layers, concentrated to dryness, and purified by column chromatography to obtain Compound 41 (60 mg, 0.14 mmol). Yield 70%. M / S: 436.1 (M+H + )

[0155] HNMR: 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (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 = 7.8 Hz, 1H), 6.83 (d, J = 1.5 Hz, 1H), 6.54 (t, J = 7.5 Hz, 1H), 6.38 (d, J = 8.5 Hz, 1H), 5.55 - 5.44 (m, 1H), 2.35 (s, 3H), 1.64 (d, J = 6.6 Hz, 3H).

[0156] Example 9: Synthesis of compound 3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-indolin-8-yl)ethyl)amino)piperidine-2,6-dione (Compound 117) TIFF2025520857000145.tif37170

[0157] Step 1: Synthesis of the target compound 3-((1-(2-(2,4-difluorophenyl)-6-methyl-4-oxo-4H-indolin-8-yl)ethyl)amino)piperidine-2,6-dione (Compound 117)

[0158] Procedure: Compound 8-6 (synthesis refer to the synthesis of Intermediate 8-6 in Example 6, 50 mg, 0.15 mmol) was dissolved in acetonitrile (1 ml), and while stirring at room temperature, 3-amino-2,6-piperidinedione (22 mg, 0.17 mmol) and triethylamine (18 mg, 0.18 mmol) were added in sequence. Then the temperature was raised to 90 °C and stirred overnight. Monitored by TLC, after the reaction was completed, it was subjected to column chromatography. Pure Compound 117 (35 mg, 0.08 mmol) was obtained. Yield 55%. Ms: 427 (M+H + ); 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.08 (tdd, J = 9.0, 6.3, 3.1 Hz, 1H), 7.82 (s, 1H), 7.74 (s, 1H), 7.57 (ddd, J = 11.6, 8.8, 2.5 Hz, 1H), 7.38 (tt, J = 8.4, 3.1 Hz, 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 = 6.9 Hz, 3H).

[0159] 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) TIFF2025520857000146.tif36170

[0160] 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) TIFF2025520857000147.tif48170

[0161] Operation: 4 - 7 (For synthesis, refer to the synthesis of the common intermediate, 0.1 g, 317.14 μmol), dissolve 2,2,2 - trifluoro - 1 - (2 - fluorophenyl)ethan - 1 - one (121.85 mg, 634.28 μmol) and N - ethyl - N - isopropylpropan - 2 - amine (81.98 mg, 634.28 μmol) in N,N - dimethylacetamide (5.0 mL), stir the reaction mixture at 95 °C for 48 h under the protection of nitrogen gas, monitor by TLC. After the reaction is complete, add brine (10.0 mL), extract with EA (10 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and purify the crude product by column chromatography to obtain 16 - 1 (76.0 mg, 155.92 μmol). Yield 49%. Ms: 488.1 (M + H + )。

[0162] Second step: 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) TIFF2025520857000148.tif48170

[0163] Operation: Dissolve 16 - 1 (70.0 mg, 143.61 μmol) in methanol (5.0 mL), add sodium borohydride (10.87 mg, 287.22 μmol). Stir at room temperature for 2 h to react, monitor by TLC. After the reaction is complete, directly purify the reaction solution by column chromatography to obtain compound 57 (30.0 mg, 61.29 μmol). Yield 42%. Ms: 490.1 (M + H + )。

[0164] HNMR: 11H NMR (400 MHz, DMSO-d6) δ 8.11 (td, J = 8.9, 6.5 Hz, 1H), 7.73 (dd, J = 2.3, 1.0 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.38 - 7.23 (m, 2H), 6.97 (q, J = 6.5, 5.4 Hz, 2H), 6.81 (s, 1H), 6.56 (t, J = 7.4 Hz, 1H), 6.32 (d, J = 8.3 Hz, 1H), 6.13 (d, J = 7.1 Hz, 1H), 5.55 (d, J = 8.9 Hz, 1H), 5.16 (t, J = 6.8 Hz, 1H), 2.33 (s, 3H), 1.57 (d, J = 6.6 Hz, 3H).

[0165] 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) TIFF2025520857000149.tif63170

[0166] Step 1: Synthesis of Intermediate 1-(3-bromo-2-hydroxy-5-methylphenyl)-3-(4,4-difluorocyclohexyl)propane-1,3-dione (17-1) TIFF2025520857000150.tif31170

[0167] To a 100 mL reaction flask, add compound 1-(3-bromo-2-hydroxy-5-methylphenyl)ethan-1-one (1.3 g, 5.7 mmol) and tetrahydrofuran (15 mL). Dropwise add bis(trimethylsilyl)aminolithium (1 M, 34.2 mL, 34.2 mmol) at -70 °C and react at this temperature for 1 hour. To a 50 mL reaction flask, add compound 4,4-difluorocyclohexane-1-carboxylic acid (1.1 g, 6.8 mmol), 1 drop of N,N-dimethylformamide, and dichloromethane (20 mL). Dropwise add oxalyl chloride (0.73 g, 8.6 mmol) under an ice bath and react at room temperature for 1 hour. After concentration, add tetrahydrofuran (10 mL) and dropwise add it to the reaction solution at -70 °C and react overnight. After the reaction is complete, adjust the pH to 5 - 6 with 1 N hydrochloric acid, extract with ethyl acetate (30 mL × 3 times), combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and pass through a silica gel column to obtain intermediate 17-1 (0.97 g). Yield 45%. Ms: 375.1, 377.1 (M + H + ).

[0168] Step 2: Synthesis of intermediate 8-bromo-2-(4,4-difluorocyclohexyl)-6-methyl-4H-chromen-4-one (17-2) TIFF2025520857000151.tif31170

[0169] To a 50 mL reaction flask, add compound 17-1 (970 mg, 2.6 mmol), concentrated sulfuric acid (2 mL), and acetic acid (10 mL). Heat the reaction solution to 100 °C to react. After the reaction is complete, cool to room temperature, add water (10 mL), extract with ethyl acetate (10 mL × 3 times), combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and pass through a silica gel column to obtain intermediate 17-2 (870 mg). Yield 94%. Ms: 357.1, 359.1 (M + H + ).

[0170] Step 3: Synthesis of intermediate 8-acetyl-2-(4,4-difluorocyclohexyl)-6-methyl-4H-chromen-4-one (17-3) TIFF2025520857000152.tif31170

[0171] To a 100 mL reaction flask, add compound 17-2 (870 mg, 2.5 mmol), tributyl(1-ethoxyvinyl)tin (1.3 g, 3.7 mmol), diethylpropylamine (945 mg, 7.3 mmol) and dioxane (10 mL). After purging with nitrogen gas, add tetrakis(triphenylphosphine)palladium (282 mg, 0.24 mmol). Heat the reaction mixture to 95 °C and react overnight. 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 with ethyl acetate (20 mL) three times, separate the layers, dry the organic layer over anhydrous sodium sulfate, concentrate, and pass through a silica gel column to obtain intermediate 17-3 (670 mg). Yield: 84%. Ms: 321.1 (M+H + )。

[0172] Step 4: Synthesis of intermediate (R,Z)-N-(1-(2-(4,4-difluorocyclohexyl)-6-methyl-4-oxo-4H-chromen-8-yl)ethylidene)-2-methylpropane-2-sulfonamide (17-4) TIFF2025520857000153.tif37170

[0173] To a 50 mL reaction flask, add compound 17-3 (670 mg, 2.1 mmol), (R)-tert-butylsulfinamide (507 mg, 4.2 mmol), titanium tetraisopropoxide (2.4 g, 8.4 mmol) and tetrahydrofuran (15 mL). After purging with nitrogen gas, heat under reflux overnight. After the reaction is complete, cool to room temperature, add saturated brine (10 mL), stir for 0.5 hour, filter, wash the filter cake with ethyl acetate (10 mL) three times, separate the layers, combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and pass through a silica gel column to obtain intermediate 17-4 (780 mg). Yield: 88%. Ms: 424.1 (M+H + )。

[0174] 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) TIFF2025520857000154.tif37170

[0175] Compound 17-4 (780 mg, 1.8 mmol), cerium(III) chloride heptahydrate (343 mg, 0.9 mmol) and methanol (10 mL) were added to a 50 mL reaction flask, cooled to -70 °C with stirring, and a solution of sodium borohydride (210 mg, 5.5 mmol) in methanol (2 mL) was added dropwise. After the addition was complete, the temperature was allowed to rise naturally and the mixture was left overnight. Ethyl acetate was added, and the mixture was filtered. After the filtrate was rotary evaporated, ethyl acetate was added again, and the mixture was filtered again. After the filtrate was concentrated, it was passed through a silica gel column to obtain Intermediate 17-5 (500 mg). Yield 65%. Ms: 426.1 (M+H + )

[0176] Step 6: Synthesis of Intermediate ((R)-8-(1-Aminoethyl)-2-(4,4-difluorocyclohexyl)-6-methyl-4H-chromen-4-one (17-6) TIFF2025520857000155.tif37170

[0177] Compound 17-5 (500 mg, 1.2 mmol) and ethyl acetate (5 mL) were added to a 25 mL reaction flask, and a hydrogen chloride dioxane solution (5 mL) was added with stirring. The mixture was stirred at room temperature until the reaction was complete, the solvent was concentrated, an aqueous sodium bicarbonate solution (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain Intermediate 17-6 (250 mg). Yield 65%. Ms: 322.1 (M+H + )

[0178] 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) TIFF2025520857000156.tif38170

[0179] To a 25 mL reaction flask, add 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), replace with nitrogen gas, add copper powder (12 mg, 0.19 mmol), heat to 110 °C and react for about 1 - 2 hours. After the reaction is complete, cool to room temperature, adjust the pH to 4 - 5 with 1N hydrochloric acid aqueous solution, add ethyl acetate (5 mL), separate the layers, combine the organic layers, dry over anhydrous sodium sulfate, concentrate, and purify by preparative plate to obtain the compound (Compound 58, 18 mg). Yield 21%. Ms: 442.1 (M+H + ), 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.43 (s, 1H), 7.81 (dd, J = 7.9, 1.7 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.28 - 7.16 (m, 1H), 6.54 (t, J = 7.5 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 6.25 (s, 1H), 5.13 (d, J = 6.7 Hz, 1H), 2.34 (s, 3H), 2.22 - 1.64 (m, 9H), 1.60 (d, J = 6.6 Hz, 3H).

[0180] Example 12: 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) TIFF2025520857000157.tif103170

[0181] 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) TIFF2025520857000158.tif47170

[0182] (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), copper(I) thiophene-2-carboxylate (5.2 g, 27.25 mmol), tetrakistriphenylphosphine palladium (1.2 g, 1.09 mmol), 4A molecular sieve (200 mg) and 1,4-dioxane (40 mL) were added to a sealed container in sequence, protected with nitrogen gas, and then sealed and reacted at 100 °C until the reaction was complete. After cooling to room temperature, silica gel was added directly and concentrated, and the concentrate was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain (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 + ).

[0183] Step 2: Synthesis of Intermediate ((R)-8-(1-aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-chromen-4-one (18-2) TIFF2025520857000159.tif39170

[0184] 18-1 (1.0 g, 2.38 mmol) was dissolved in ethyl acetate (20 mL), cooled in an ice-water bath, HCl dioxane solution (4 N, 5 mL) was added, and the mixture was stirred at room temperature for 2 hours to react. After spotting on a plate and monitoring that the reaction was complete, water (30 mL) was added and the layers were separated. The aqueous phase was adjusted to pH 7 - 8 with sodium carbonate, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain (R)-8-(1-aminoethyl)-2-(2,4-difluorophenyl)-6-methyl-4H-chromen-4-one (700 mg, 2.2 mmol). Yield 93%. M / S: 316 (M + H+).

[0185] Step 3: 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) TIFF2025520857000160.tif47170

[0186] 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(diphenylphosphino)-9,9-dimethylxanthene (55 mg, 0.09 mmol), tris(dibenzylideneacetone)dipalladium (58 mg, 0.09 mmol) were added to 1,4-dioxane (2 mL), protected with nitrogen gas, and then reacted at 120 °C. After spotting on a plate and monitoring that the reaction was complete, it was cooled to room temperature, silica gel was directly added and the sample was stirred. The concentrate was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 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 + )

[0187] 11H NMR (400 MHz, Chloroform-d) δ 7.93 (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).

[0188] 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) TIFF2025520857000161.tif29170

[0189] 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) TIFF2025520857000162.tif45170

[0190] Procedure: 4-7 (synthesis refers to the synthesis of common intermediates, 0.1 g, 317.14 mmol), 2,2,2-trifluoro-1-(2-fluorophenyl)ethan-1-one (121.85 mg, 634.28 mmol) and N-ethyl-N-isopropylpropan-2-amine (81.98 mg, 634.28 mmol) were dissolved in N,N-dimethylacetamide (2.0 mL). The reaction mixture was stirred at 80 °C under nitrogen gas protection and monitored by TLC. After the reaction was completed, 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 and rotary evaporated. The crude product was purified by column chromatography to obtain 19-1 (80 mg, 164.13 mmol). Yield 51%. Ms: 488.1 (M+H + )

[0191] 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) TIFF2025520857000163.tif44170

[0192] 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 mixture was stirred at 80 °C for 12 h and monitored by TLC. After the reaction was completed, the reaction solution was directly purified by column chromatography to obtain Compound 64 (9.0 mg, 17.91 mmol). Yield: 43%. Ms: 503.1 (M+H + )

[0193] HNMR: 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.03 (d, J = 6.5 Hz, 1H), 7.96 (td, J = 8.9, 6.5 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 2.1, 0.9 Hz, 1H), 7.53 - 7.41 (m, 2H), 7.29 (d, J = 2.2 Hz, 1H), 7.04 (s, 1H), 6.76 - 6.68 (m, 2H), 5.26 (h, J = 6.6, 6.2 Hz, 1H), 2.28 (s, 3H), 1.63 (d, J = 6.7 Hz, 3H).

[0194] Example 14: Synthesis of compound (R)-6-chloro-3-((1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuteromethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound 88) TIFF2025520857000164.tif63170

[0195] Step 1: Synthesis of intermediate 2-amino-3-bromo-5-fluoro-N-deuteromethylbenzamide (20-1) TIFF2025520857000165.tif31170

[0196] 2-Amino-3-bromo-5-fluoro-benzoic acid (4.50 g, 19.2 mmol) was dissolved in anhydrous THF (50 mL), and CDI (4.67 g, 28.8 mmol) was added in several portions. The system was gradually bubbled and reacted for 2.0 h. Then the system was cooled to 0 - 10 °C, and DIEA (7.95 g, 79.2 mmol) and deuterated methylamine hydrochloride (5.58, 79.2 mmol) were added and reacted for 1.0 h. It was detected by TLC that the reaction was complete. 100 mL of water was added and extracted with EA (40 mL × 2). The organic phase was concentrated, slurried with ethanol, filtered, and 20-1 (3.20 g, 9.14 mmol) was obtained. Yield 66%. M / S: 250 / 252 (M+H + )。

[0197] Step 2: Synthesis of intermediate 8-bromo-6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuteromethylquinazolin-4(3H)-one (20-2) TIFF2025520857000166.tif32170

[0198] 20-1 (3.00 g, 12.0 mmol), 5-fluoropyridine-2-aldehyde (1.80 g, 14.4 mmol) and iodine (3.65 g, 14.4 mol) were successively dissolved in DMSO (45 mL), stirred at 100 °C, monitored by TLC. After the reaction was completed, the system was added to 100 mL of ice water, 5.0 mL of saturated sodium thiosulfate solution was added, filtered to obtain the crude product, slurried with ethanol, filtered, and 20-2 (4.20 g, 11.8 mmol) was obtained. Yield 98%. M / S: 355 / 357 (M+H + )。

[0199] Step 3: Synthesis of intermediate 8-acetyl-6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuteromethylquinazolin-4(3H)-one (20-3) TIFF2025520857000167.tif29170

[0200] 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 successively added to dioxane (45 mL), protected with nitrogen gas, and the reaction mixture was reacted at 95 °C for 12 h. The completion of the reaction was monitored by TLC. After cooling, DCM (40 mL) was added, and the pH was adjusted to 2 - 3 with 6M HCl. After stirring for 1 - 2 h, it was detected by TLC, a saturated KF solution was added and stirred for 1.0 h (pH = 7), filtered, eluted with DCM for the filter cake, the aqueous phase was extracted with DCM (30 mL × 2), dried over anhydrous sodium sulfate, the organic phase was concentrated, and the crude product was slurried with MTBE to obtain 20 - 3 (3.20 g, 10.1 mmol). Yield 85%. M / S: 319 (M + H + )。

[0201] Step 4: Synthesis of intermediate (R,Z)-N-(1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuteromethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropan-2-sulfonamide (20 - 4) TIFF2025520857000168.tif31170

[0202] 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 successively added to anhydrous THF (32 mL), stirred at 85 °C for 12 h, and the completion of the reaction was monitored by TLC. The reaction solution was poured into 100 mL of water, filtered, eluted with DCM for the filter cake, separated, extracted with DCM (30 ml × 2), dried over anhydrous sodium sulfate, the organic phase was concentrated to obtain the crude product 20 - 4 (3.50 g, 7.55 mmol), which was used directly in the next step. M / S: 422 (M + H + )。

[0203] Step 5: Synthesis of Intermediate N-((R)-1-(6-Fluoro-2-(5-fluoropyridin-2-yl)-3-deuteromethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan-2-sulfonamide (20-5) TIFF2025520857000169.tif35170

[0204] The crude product 20-4 (3.50 g, 7.55 mmol) and CeCl3·7H2O (1.32 g, 3.77 mmol) were successively added 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 several portions. After addition, the temperature was slowly raised to room temperature, and it was detected by TLC that the reaction was complete. Saturated aqueous ammonium chloride solution (200 mL) was added, and extraction was performed with DCM (80 mL × 2). The organic phase was concentrated to obtain a crude product, which was purified by column chromatography to obtain 20-5 (1.90 g, 4.48 mmol). The total yield of the two steps was 44%. M / S: 424 (M+H + ). 1 1H-NMR (400 MHz, DMSO-d6) δ 8.75 (t, J = 1.8 Hz, 1H), 8.04 (dd, J = 6.7, 1.8 Hz, 2H), 7.87 (dd, J = 9.8, 3.1 Hz, 1H), 7.78 (dd, J = 8.4, 3.0 Hz, 1H), 6.00 (d, J = 8.9 Hz, 1H), 5.31 - 5.19 (m, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.09 (s, 9H).

[0205] Step 6: Synthesis of Intermediate (R)-8-(1-Aminoethyl)-6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuteromethylquinazolin-4(3H)-one (20-6) TIFF2025520857000170.tif37170

[0206] 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 to precipitate a solid, and TLC was used to monitor the completion of the reaction. The solid obtained by filtration was dissolved in water until it became clear, and the pH was adjusted to 7 - 9 with saturated sodium bicarbonate solution. A solid was precipitated, and the solid was filtered and dried to obtain 20-6 (1.00 g, 3.13 mmol). Yield: 70%. M / S: 320 (M+H + )。

[0207] Step 7: Synthesis of intermediate (R)-5-chloro-2-((1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuteromethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)benzoic acid tert-butyl ester (20-7) TIFF2025520857000171.tif39170

[0208] 20-6 (150 mg, 0.47 μmol), 2-bromo-5-chlorobenzoic acid tert-butyl ester (120 mg, 1.41 μmol), Pd2(dba)3 (43.0 mg, 0.04 μmol), Xantphos (54.0 mg, 0.09 μmol), Cs2CO3 (450 mg, 1.41 μmol) were added to dioxane (2.0 mL), protected with nitrogen gas, stirred at 110 °C for 12 hours, monitored by TLC. After the reaction was completed and cooled, 20 mL of water was added, and the mixture was extracted with EA (10 ml×3). The organic phase was concentrated to obtain a crude product, which was purified by column chromatography to obtain 20-7 (170 mg, 0.32 μmol). Yield: 68%. M / S: 531 (M+H + )。

[0209] Step 8: Synthesis of compound (R)-5-chloro-2-((1-(6-fluoro-2-(5-fluoropyridin-2-yl)-3-deuteromethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Compound 88) TIFF2025520857000172.tif52170

[0210] 20-7 (170 mg, 0.32 μmol) was dissolved in FA (2.0 ml), and the reaction mixture was stirred at 60 °C for 1.0 h and monitored by TLC. After the reaction was completed, the pH was adjusted to around 3 with HCl (1N), extracted with EA, the organic phase was concentrated to obtain a crude product, and purified by Pre-TLC to obtain compound 88 (101 mg, 0.213 μmol). Yield 66%. M / S: 474 (M+H + )。 1 H-NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.76 (d, J = 2.8 Hz, 1H), 8.42 (d, J = 6.7 Hz, 1H), 8.12 (dd, J = 8.8, 4.5 Hz, 1H), 8.03 (td, J = 8.7, 2.9 Hz, 1H), 7.77 (dd, J = 8.3, 3.0 Hz, 1H), 7.73 (d, J = 2.6 Hz, 1H), 7.60 (dd, J = 9.4, 3.0 Hz, 1H), 7.21 (dd, J = 9.0, 2.7 Hz, 1H), 6.42 (d, J = 9.1 Hz, 1H), 5.46 (t, J = 6.5 Hz, 1H), 1.59 (d, J = 6.7 Hz, 3H).

[0211] Example 15: Synthesis of compound (R)-6-chloro-3-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid (compound 115) TIFF2025520857000173.tif46170

[0212] Intermediate: Synthesis of 2-amino-3-bromo-N,5-dimethylbenzamide (Int.C-115-1) TIFF2025520857000174.tif30170

[0213] 2-Amino-3-bromo-5-chloro-N-methylbenzoic acid (SM, 10 g, 43.5 mmol) was dissolved in anhydrous THF (40 mL), and CDI (9.2 g, 56.5 mol) was added in several portions. The system was gradually bubbled and reacted for 2 h. Then the system was cooled to 0 °C, and aqueous methylamine solution (30 mL) was added dropwise and reacted for 1 h. It was detected by TLC that the reaction was complete. Water (500 mL) was added, and the mixture was stirred at room temperature for 2 h, filtered under reduced pressure, and the solid was washed with methyl tert-butyl ether (30 mL × 2) and dried by heating to obtain 7.8 g of white solid Int.115-1. Yield 73.9%, M / S: 243, 245 (M + H + ).

[0214] Intermediate: Synthesis of 8-bromo-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (Int.C-115-1) TIFF2025520857000175.tif38170

[0215] Int.115-1 (5 g, 20.6 mmol), benzaldehyde (2.8 g, 26.7 mmol) and iodine (6.8 g, 26.7 mmol) were successively dissolved in DMSO (50 mL) and reacted at 100 °C for 6 h. Monitored by TLC. After the reaction was completed, ice water was added to the system, and saturated sodium bicarbonate solution was slowly added until the system became colorless. Stirred for 2 h, filtered under reduced pressure, and the solid was washed with methyl tert-butyl ether (20 mL × 2) and dried by heating to obtain 5.9 g of white solid Int.115-2. Yield 87.2%, M / S: 329, 331 (M + H+).

[0216] Intermediate: Synthesis of 8-acetyl-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (Int.115-3) TIFF2025520857000176.tif37170

[0217] 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) were weighed and added to dioxane (60 mL) in turn, protected with nitrogen gas, reacted at 95 °C for 8 h, monitored by TLC, cooled, 20 mL of 6N HCl was added, stirred at room temperature for 0.5 h, monitored by TLC, 100 mL of water (15.6 g KF) was added, stirred for 2 h, then EA (100 mL) was added, filtered under reduced pressure, the solid was washed with EA (50 mL × 2), separated, the aqueous phase was extracted with EA (30 mL), the EA was combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, concentrated, and by column chromatography, 4.3 g of solid Int.C115-3 was obtained. Yield 81.8%, M / S: 293 (M+H + )。

[0218] Intermediate: Synthesis of (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfonamide (Int.115-4) TIFF2025520857000177.tif39170

[0219] 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 to anhydrous THF (21 mL) in turn, stirred at 80 °C for 6 h, and monitored by TLC. After cooling, EA (100 mL) was added for dilution, poured into water (200 mL), stirred for 30 min, filtered, separated, extracted with EA (50 ml × 2), washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and by column chromatography, 4.9 g of pale yellow solid Int.115-4 was obtained. Yield 84.5%, M / S: 396.1 (M+H + )。

[0220] Synthesis of Intermediate: (R)-N-((R)-1-(3,6-Dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropan-2-sulfonamide (Int.115-5) TIFF2025520857000178.tif46170

[0221] Int.C115-4 (4.9 g, 12.4 mmol) and CeCl3·7H2O (2.3 g, 6.2 mmol) were successively added to MeOH (25 mL) and THF (25 mL), protected with nitrogen gas, dissolved until clear, then cooled to -78~-20 °C. NaBH4 (706 mg, 18.6 mmol) was dissolved in 5 mL of DMA and slowly added dropwise to the reaction solution, and the temperature was allowed to rise naturally to room temperature (4H). It was monitored by TLC, cooled to 0 °C, the pH was adjusted to 3~4 with 1N HCl, DCM (100 mL) and water (150 mL) were added, separated, the aqueous phase was extracted with DCM (50 mL×2), the DCM layers were combined, washed once with saturated sodium chloride solution (50 mL), dried, concentrated, and 3.6 g of solid Int.115-5 was obtained by column chromatography. Yield 73.1%, M / S: 397.1 (M+H+), de value: 98.2%.

[0222] Synthesis of Intermediate: (R)-8-(1-Aminoethyl)-3,6-dimethyl-2-phenylquinazolin-4(3H)-one (Int.115-6) TIFF2025520857000179.tif44170

[0223] Int.115-5 (3.6 g, 9.1 mmol) was dissolved in DCM (20 mL), HCl-dioxane (4N, 20 mL) was added, and the reaction was carried out at room temperature for 3 h. It was monitored by TLC, the reaction solution was concentrated to dryness, washed once with DCM, EA (30 mL) and water (30 mL) were added, dissolved until clear, separated, extracted once with EA (20 mL), the aqueous phase was adjusted to pH 8~9 with sodium bicarbonate, extracted with DCM (50 mL×4), dried, concentrated, and 2.1 g of white solid Int.115-6 was obtained. Yield 78.9%, M / S: M / S: 294 (M+H+).

[0224] Intermediate: Synthesis of Methyl (R)-6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (Int.115-7) TIFF2025520857000180.tif45170

[0225] Int.115-6 (400 mg, 1.36 mmol), methyl 6-chloro-3-fluoropyridine-2-carboxylate (337 mg, 1.77 mmol), and DIPEA (351 mg, 2.72 mmol) were added to DMA (5 mL), stirred at 90 °C for 6 hours, monitored by TLC. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with EA (10 ml × 3). The combined EA layers were washed with water (20 ml × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 450 mg of a solid (Int.115-7). Yield: 71.4%. M / S: 463 (M+H+).

[0226] Synthesis of Compound (R)-6-chloro-3-(1-(3,6-dimethyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinate (Compound 115) TIFF2025520857000181.tif46170

[0227] Int.115-7 (450 mg, 0.97 mmol) was dissolved in THF (5 mL), potassium trimethylsilanolate (250 mg, 1.84 mmol) was added, and the mixture was reacted at room temperature for 15 min, monitored by TLC. Water (20 mL) was added, and the pH was adjusted to 2 - 3 with 1N HCl. The mixture was extracted with DCM (20 ml × 3). The combined DCM layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 360 mg of a solid (Compound 115). Yield: 82.5%, M / S: 449 (M+H + )

[0228] 1H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 2.9 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.07 (dd, J = 8.7, 4.4 Hz, 1H), 7.68 - 7.61 (m, 2H), 5.13 (p, J = 6.7 Hz, 1H), 4.70 (d, J = 6.6 Hz, 1H), 3.66 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.16 (s, 9H).

[0229] 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)picolinic Acid (Compound 66) TIFF2025520857000182.tif63170

[0230] Step 1: Synthesis of Intermediate 2-Amino-3-bromo-N,5-dimethylbenzamide (25-1)

[0231] Dissolve 2-Amino-3-bromo-5-methylbenzoic acid (230 g, 1.0 mol) in THF (2 L), add CDI (178 g, 1.1 mol) in several portions, gradually bubble the system, react for 2 hours, then cool the system to 10 °C, dropwise add aqueous methylamine solution (920 mL), control the temperature below 15 °C during the dropping process, and react for 1 hour after the dropping is complete. It was detected by TLC that the reaction was complete. Concentrate the reaction solution to remove part of the solvent until a solid precipitates, pour it into water (2 L), and stir for 1 hour. Filter and dry under reduced pressure until the weight is constant to obtain 230 g of the product (Intermediate 25-1). Yield 94.6%. Ms: 243.0 / 245.0 (M+H + )

[0232] Step 2: Synthesis of Intermediate 8-Bromo-2-(5-fluoropyridin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (25-2) TIFF2025520857000183.tif30170

[0233] Intermediate 25-1 (60.0 g, 0.25 mol), 5-fluoropyridine-2-carboxaldehyde (37.0 g, 0.30 mol), iodine (75.2 g, 0.30 mol) were sequentially added to dimethyl sulfoxide (900 mL) at room temperature, heated to 95 °C and reacted overnight. The reaction solution was cooled to room temperature, slowly poured into water (3000 mL), saturated aqueous sodium thiosulfate solution (300 mL) was added and stirred for 2 hours, filtered, the filter cake was eluted once with water (100 mL), eluted once with absolute ethanol (100 mL), eluted once with methyl tert-butyl ether (100 mL), and dried under vacuum to obtain 74.7 g of the product (Intermediate 25-2). Yield 86.9%. Ms: 243.0 / 245.0 (M+H + )。

[0234] Step 3: Synthesis of Intermediate 8-acetyl-2-(5-fluoropyridin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (25-3) TIFF2025520857000184.tif29170

[0235] Intermediate 25-2 (74.7 g, 0.21 mol), tributyl(1-ethoxyvinyl)tin (116.2 g, 0.32 mol), N,N-diisopropylethylamine (83.2 g, 0.64 mol), Pd(PPh3)2Cl2 (15.0 g, 0.02 mol) were sequentially added to N,N-dimethylacetamide (800 mL) at room temperature, replaced with nitrogen gas three times, heated to 100 °C and reacted overnight, the reaction solution was cooled to room temperature, a dioxane solution of hydrogen chloride (4 mol / L) was slowly added, the pH was adjusted to 1-2, a small amount of water (20 mL) was added, stirred and reacted for 1 hour, ethyl acetate (2000 mL) was added for dilution, water (4000 mL) was added, an aqueous potassium fluoride solution was added to adjust the pH to be greater than 7, stirred for 2 hours, filtered, the filter cake was slurried with ethyl acetate (500 mL x 3), the filtrates were combined for liquid separation, the aqueous layer was extracted with ethyl acetate (500 mL), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was slurried with methanol (500 mL) to obtain 60.8 g of the product (Intermediate 25-3), yield 91.0%. Ms: 312.0 (M+H + )。

[0236] Step 4: Synthesis of Intermediate (R,Z)-N-(1-(2-(5-fluoropyridin-2-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfinamide (25-4) TIFF2025520857000185.tif36170

[0237] 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 dry tetrahydrofuran (300 mL) at room temperature, heated to 90 °C, and reacted overnight. The reaction solution was cooled to room temperature, diluted with dichloromethane (2000 mL), water (4000 mL) was added, and the mixture was stirred for 0.5 h, filtered, and the filter cake was slurried with dichloromethane (500 mL x 3). The filtrates were combined and separated into layers. The aqueous layer was extracted with dichloromethane (500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 90.0 g of a crude product (Intermediate 25-4) as a yellow oil, which was used directly in the next reaction. Ms: 415.1 (M+H + ).

[0238] 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) TIFF2025520857000186.tif36170

[0239] Intermediate 25-4 (90.0 g, 0.20 mol) and cerium(III) chloride heptahydrate (36.4 g, 0.10 mol) were sequentially added to methanol (2000 mL) at room temperature. The temperature was lowered to -65 °C in a dry ice bath. Sodium borohydride (22.2 g, 0.58 mol) was dissolved in methanol in several portions and added dropwise to the reaction system while controlling the temperature not to exceed -60 °C. It took about 30 minutes. The dry ice bath was removed, and the temperature was allowed to rise naturally to room temperature. Dichloromethane (2000 mL) was added for dilution, water (4000 mL) was added, and the pH was adjusted to 6 with 1N hydrochloric acid. Layer separation was performed, the aqueous layer was extracted with dichloromethane (500 mL), the organic layers were combined, washed once with a saturated aqueous sodium bicarbonate solution (500 mL), dried over anhydrous sodium sulfate, concentrated, purified by column chromatography, and recrystallized from methanol / water (1:1) to obtain 50.8 g of the product (Intermediate 25-5). The yield of the two steps: 62.4%. Ms: 417.1 (M+H + ). 1 H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 2.8 Hz, 1H), 8.06 (dt, J = 5.5, 4.4 Hz, 2H), 7.63 (td, J = 8.4, 2.9 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 5.08 (p, J = 6.8 Hz, 1H), 4.91 (d, J = 6.8 Hz, 1H), 3.65 (s, 3H), 2.50 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.15 (s, 9H).

[0240] Step 6: Synthesis of Intermediate (R)-8-(1-aminoethyl)-2-(5-fluoropyridin-2-yl)-3,6-dimethylquinazolin-4(3H)-one (25-6) TIFF2025520857000187.tif36170

[0241] 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 to react, concentrated, and the residue was dissolved in water (1000 mL). It was extracted with ethyl acetate (500 mL), and the ethyl acetate layer was washed once with 1N hydrochloric acid (100 mL) and discarded. The acidic aqueous layers were combined and adjusted to a pH greater than 7, then extracted with dichloromethane (1000 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was slurried with methyl tert-butyl ether (300 mL) to obtain 33.4 g of the product (Intermediate 25-6). Yield: 87.7%. Ms: 313.1 (M+H+). 1 H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 2.8 Hz, 1H), 8.03 (dd, J = 2.1, 1.0 Hz, 1H), 7.97 (dd, J = 8.7, 4.4 Hz, 1H), 7.66 - 7.57 (m, 2H), 4.85 (q, J = 6.7 Hz, 1H), 3.67 (s, 3H), 2.50 (s, 3H), 2.12 (s, 2H), 1.52 (d, J = 6.7 Hz, 3H).

[0242] 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)picolinic acid methyl ester (25-7) TIFF2025520857000188.tif38170

[0243] Intermediate 25-6 (200 mg, 0.64 mmol), methyl 6-chloro-3-fluoropicolinate (243 mg, 1.28 mmol), and DIPEA (248 mg, 1.92 mmol) were added to N,N-dimethylacetamide (4 mL). The temperature was raised to 100 °C and stirred overnight to react. The reaction system was cooled to room temperature, diluted with ethyl acetate (20 mL), washed with water (20 mL x 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+ )。

[0244] 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)picolinate (Compound 66) TIFF2025520857000189.tif38170

[0245] Intermediate 25-7 (210 mg, 0.44 mmol) was dissolved in dry tetrahydrofuran (4 ml), potassium trimethylsilanolate (168 mg, 1.31 mmol) was added, and the mixture was stirred at room temperature for 20 minutes for reaction. The pH was adjusted to around 3 with 0.5 N hydrochloric acid, extracted 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). Yield: 88.3%. Ms: 468.1 (M+H + )。 1 H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.75 (d, J = 2.9 Hz, 1H), 8.43 (d, J = 7.0 Hz, 1H), 8.12 (dd, J = 8.7, 4.5 Hz, 1H), 8.01 (td, J = 8.7, 2.9 Hz, 1H), 7.91 (dd, J = 2.1, 1.0 Hz, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 7.02 (d, J = 9.1 Hz, 1H), 5.46 (p, J = 6.7 Hz, 1H), 3.49 (s, 3H), 2.41 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H).

[0246] 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) TIFF2025520857000190.tif79170

[0247] Synthesis of intermediate 2-amino-3-bromo-N,5-dimethylbenzamide (4-1) TIFF2025520857000191.tif35170

[0248] 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 was gradually bubbled, reacted for 1 h, cooled to 0 °C, aqueous ammonia (500 mL) was added dropwise, reacted for 2 h, monitored by TLC, the reaction solution was poured into water (4 L), stirred for 1 h, filtered under reduced pressure, the solid was washed with methyl tert-butyl ether (30 mL × 2), and dried by heating to obtain 87.5 g of a white solid (4-1). Yield 87.9%, MS: 228, 231 / (M+H + ).

[0249] Synthesis of intermediate 8-bromo-3,6-dimethylquinazoline-2,4(1H,3H)-dione (4-2): TIFF2025520857000192.tif32170

[0250] 4-1 (31 g, 135 mmol), triethylamine (27.4 g, 271 mmol) were dissolved in anhydrous THF (300 mL), cooled to 0 °C, triphosgene (20 g, 68 mmol) was slowly added in portions, the ice bath was removed, stirred for 30 min, heated to 80 °C and reacted for 12 h, monitored by TLC, most of the THF was concentrated, water (1 L) was added, stirred for 1 h, filtered under reduced pressure, the solid was washed with methyl tert-butyl ether (30 mL × 2), and dried by heating to obtain 23.2 g of a white solid (4-2). MS: 255, 257 / (M+H+).

[0251] Synthesis of intermediate 8-bromo-2,4-dichloro-6-methylquinazoline (4-3) TIFF2025520857000193.tif30170

[0252] 4-2 (23.2 g, 91 mmol) was dissolved in toluene (116 mL), phosphorus oxychloride (70 g, 455 mmol) was added dropwise, and the mixture was reacted at 100 °C for 12 h. It was monitored by TLC, and the reaction solution was concentrated to dryness, washed twice with DCM to obtain the crude product (4-3), which was directly used in the synthesis of the next step.

[0253] Synthesis of intermediate 8-bromo-2-chloro-6-methylquinazolin-4(3H)-one (4-4): TIFF2025520857000194.tif32170

[0254] 4-3 (crude product) was dissolved in THF (116 mL), an aqueous solution of NaOH (2N, 116 mL) was added dropwise, and it was gradually dissolved until the system became transparent. It was monitored by TLC, adjusted to pH 6-7 with dilute HCl (1N), filtered under reduced pressure, and dried by heating to obtain 16.5 g of a solid (4-4). The yield of the two steps was 66.3%, MS: 273, 275 / (M+H + ).

[0255] Synthesis of intermediate 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4(3H)-one (4-5) TIFF2025520857000195.tif32170

[0256] 4-4 (16.5 g, 60 mmol) was dissolved in NMP (90 mL), 4,4-dimethylpiperidine hydrochloride (10.8 g, 72 mmol) was added, DIPEA (38.7 g, 300 mmol) was added dropwise, and the mixture was reacted at 120 °C for 3 h. It was monitored by TLC, cooled, adjusted to pH 6-7 with dilute HCl (1N), extracted with DCM (200 mL×3), dried over anhydrous sodium sulfate, concentrated, and 15 g of a yellow solid (4-5) was obtained by column chromatography. The yield was 71.4%, MS: 350 / 352 (M+H+).

[0257] Synthesis of intermediate 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4(3H)-one (4-6) TIFF2025520857000196.tif32170

[0258] 4-5 (2.1 g, 6 mmol), tin reagent (3.3 g, 9 mmol), DPIEA (1.5 g, 12 mmol), Pd(PPh3)Cl2 (630 mg, 0.9 mmol) were successively added to dioxane (10 mL), protected with nitrogen gas, reacted at 95 °C for 8 h, monitored by TLC, cooled, HCl (6N, 10 mL) was added, stirred for 30 min for reaction, monitored by TLC, water (30 mL, 5.3 g KF) was added, stirred for 3 h, EA (30 mL) was added, filtered under reduced pressure, the filter cake was washed with EA (30 mL × 3), the EA was combined, washed once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated, and 1.5 g of solid (4-6) was obtained by column chromatography. Yield 79.9%, MS: 314 (M+H+).

[0259] Synthesis of intermediate (R,E)-N-(1-2-(4,4-dimethylpiperidin-1-yl)-6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfonamide (4-7) TIFF2025520857000197.tif37170

[0260] 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 successively added to anhydrous THF (5 mL), stirred at 85 °C for 6 h, and monitored by TLC. After cooling, EA (30 mL) was added for dilution, poured into water (30 mL), stirred for 30 min, filtered, separated, extracted with EA (20 ml × 2), washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and 1.8 g of pale yellow solid (4-7) was obtained by column chromatography. Yield 75.4%, M / S: 417 (M+H+).

[0261] 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) TIFF2025520857000198.tif37170

[0262] 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, add (680 mg, 10.8 mmol) in several portions, allow to warm to room temperature and react for 12 h, monitor by TLC, adjust the 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 obtain 1.2 g of a white solid (4-8) by column chromatography. Yield 79.6%, M / S: 419 (M+H + ), de value: 98%.

[0263] Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (4-9) TIFF2025520857000199.tif37170

[0264] Dissolve 4-8 (1.2 g, 2.9 mmol) in DCM (6 mL), add HCl-dioxane (6 mL) dropwise, react at room temperature, monitor by TLC, concentrate the reaction solution to dryness, add water (10 mL) and EA (10 mL), dissolve until clear, 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, and obtain 0.8 g of a pale yellow solid (4-9). Yield 88.8%, MS: 315 / (M+H + ).

[0265] Synthesis of Compound (R)-2-((1-(2-(4,4-Dimethylpiperidin-1-yl)-6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl))benzoic acid (Compound 4) TIFF2025520857000200.tif37170

[0266] 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 sequentially added to DMAc (1 mL), and the reaction was carried out at 115 °C for 3 h. Monitoring was performed by TLC. Water (15 mL) was added, and the pH was adjusted to 3 - 4 with dilute HCl (1 N). Extraction was carried out with EA (10 mL × 3). The combined EA was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, concentrated, and 35 mg of solid (Compound 4) was obtained by column chromatography. Yield 37.9%, MS: 435 / (M + H + ).

[0267] 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.9 Hz, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.67 (s, 1H), 6.60 (dd, J = 10.6, 8.2 Hz, 1H), 5.56 (d, J = 6.8 Hz, 1H), 3.22 (s, 4H), 2.39 (s, 3H), 1.72 (d, J = 6.5 Hz, 3H), 1.26 (s, 4H), 1.03 (s, 6H).

[0268] 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) TIFF2025520857000201.tif62170

[0269] Synthesis of Intermediate 8-Bromo-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (6-1) TIFF2025520857000202.tif37170

[0270] 4 - 5 (1.5 g, 0.43 mmol, for synthesis, refer to the synthesis of Intermediate 4 - 5 in Example 17), K2CO3 (0.6 g, 8.6 mmol) were successively added to DMA (15 mL), MeI (1.9 g, 12.9 mmol) was added dropwise, reacted at room temperature, monitored by TLC, water (30 mL) was added, extracted with EA (30 mL × 3), the combined EA was washed with water (20 mL × 3), dried over anhydrous sodium sulfate, concentrated, and 1.1 g of solid (6 - 1) was obtained by column chromatography. Yield 70.5%, MS: 364, 366 / (M + H + )。

[0271] Synthesis of Intermediate 8 - acetyl - 2 - (4,4 - dimethylpiperidin - 1 - yl) - 3,6 - dimethylquinazolin - 4(3H) - one (6 - 2) TIFF2025520857000203.tif38170

[0272] 6 - 1 (1.1 g, 3 mmol), tin reagent (1.7 g, 4.5 mmol), DIPEA (0.8 g, 6 mmol), Pd(PPh3)Cl2 (0.3 g, 0.45 mmol) were successively added to dioxane (10 mL), protected with nitrogen gas, reacted at 95 °C for 8 h, monitored by TLC, cooled, HCl (4N, 5 mL) was added, stirred for 30 min to react, monitored by TLC, water (30 mL, 2.7 g KF) was added, stirred for 3 h, filtered under reduced pressure, the filter cake was washed with EA (20 mL × 3), the combined EA was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and 0.7 g of solid (6 - 2) was obtained by column chromatography. Yield 70.7%, MS: 328 / (M + H + )。

[0273] Synthesis of Intermediate (R,E) - N - (1 - 2 - (4,4 - dimethylpiperidin - 1 - yl) - 3,6 - dimethyl - 4 - oxo - 3,4 - dihydroquinazolin - 8 - yl)ethylidene) - 2 - methylpropane - 2 - sulfamide (6 - 3) TIFF2025520857000204.tif39170

[0274] 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 successively added to anhydrous THF (5 mL), stirred at 85 °C for 6 h, and monitored by TLC. After cooling, EA (30 mL) was added for dilution, poured into water (30 mL), stirred for 30 min, filtered, separated, extracted with EA (20 ml × 2), washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated, and 0.7 g of a pale yellow solid (6-3) was obtained by column chromatography. Yield 76%, M / S: 431 (M+H + )

[0275] 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) TIFF2025520857000205.tif38170

[0276] 6-3 (0.7 g, 1.6 mmol) was dissolved in DCM / MeOH (3.5 mL / 3.5 mL), glacial acetic acid (0.6 g, 10 mmol) was added dropwise, cooled to -10 °C, and (0.3 g, 4.9 mmol) was added in several portions, allowed to warm to room temperature, and reacted for 12 h, monitored by TLC, adjusted the pH to 9-10 with saturated sodium carbonate solution, extracted with EA (20 mL × 3), combined the EA, washed once with saturated sodium chloride solution (10 mL), dried, concentrated, and 0.6 g of a white solid (6-4) was obtained by column chromatography. Yield 85.3%, M / S: 433 (M+H + ) de value: 98%.

[0277] Synthesis of intermediate (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethylquinazolin-4(3H)-one (6-5) TIFF2025520857000206.tif37170

[0278] Dissolve 6-4 (0.6 g, 1.4 mmol) in DCM (3 mL), dropwise add HCl-dioxane (3 mL), react at room temperature, monitor by TLC, concentrate the reaction solution to dryness, add water (10 mL) and EA (10 mL), dissolve until clear, 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, and obtain 0.4 g of a pale yellow solid (6-5). Yield 87.8%, MS: 329 / (M+H + )。

[0279] 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) TIFF2025520857000207.tif37170

[0280] Add 6-5 (70 mg, 0.22 mmol), 2-iodobenzoic acid (83 mg, 0.33 mmol), TEA (43 mg, 0.43 mmol), and nanocopper powder (14 mg, 0.21 mmol) to DMAc (1 mL) in sequence, react at 115 °C for 3 h, monitor by TLC, add water (15 mL), adjust the pH to 3 - 4 with dilute HCl (1 N), extract with EA (10 mL × 3), combine the EA, wash with saturated sodium chloride solution (10 mL × 3), dry with anhydrous sodium sulfate, concentrate, and obtain 35 mg of a solid (compound 6) by column chromatography. Yield 36.6%, MS: 489 / (M+H + )。

[0281] 11H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 7.9 Hz, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.67 (s, 1H), 6.60 (dd, J = 10.6, 8.2 Hz, 1H), 5.56 (d, J = 6.8 Hz, 1H), 3.57 (s, 3H), 3.22 (s, 4H), 2.39 (s, 3H), 1.72 (d, J = 6.5 Hz, 3H), 1.26 (s, 4H), 1.03 (s, 6H).

[0282] 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)picolinic Acid (Compound 109) TIFF2025520857000208.tif74170

[0283] Step 1: Synthesis of Intermediate 8-Bromo-3,6-dimethyl-2-(pyridin-4-yl)quinazolin-4(3H)-one (19-1) TIFF2025520857000209.tif30170

[0284] 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 temperature was raised to 95 °C and the reaction was carried out overnight. The reaction solution was cooled to room temperature, slowly poured into water (50 mL), saturated sodium thiosulfate aqueous solution (10 mL) was added, and the mixture was stirred for 2 hours. It was filtered, and the filter cake was eluted once with water (20 mL), once with absolute ethanol (20 mL), and once with methyl tert-butyl ether (20 mL), and then dried under vacuum to obtain 2.9 g of the product (Intermediate 19-1). The yield was 87.9%. Ms: 330.0 (M+H + )

[0285] Step 2: Synthesis of Intermediate 8-acetyl-3,6-dimethyl-2-(pyridin-4-yl)quinazolin-4(3H)-one (19-2) TIFF2025520857000210.tif30170

[0286] Intermediate 19-1 (2.9 g, 8.8 mmol), tributyl(1-ethoxyvinyl)tin (4.8 g, 13.2 mmol), N,N-diisopropylethylamine (3.4 g, 26.4 mmol), Pd(PPh3)2Cl2 (0.6 g, 0.9 mmol) were successively added to N,N-dimethylacetamide (40 mL) at room temperature, replaced with nitrogen gas three times, heated to 100 °C and reacted overnight, the reaction solution was cooled to room temperature, a dioxane solution of hydrogen chloride (4 mol / L) was slowly added, the pH was adjusted to 1-2, a small amount of water (1 mL) was added, stirred for 1 hour to react, ethyl acetate (20 mL) was added for dilution, water (20 mL) was added, an aqueous potassium fluoride solution was added to adjust the pH to be greater than 7, stirred for 2 hours, filtered, the filter cake was slurried with ethyl acetate (20 mL x 3), the filtrates were combined for liquid separation, the aqueous layer was extracted with ethyl acetate (20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was slurried with methanol (20 mL) to obtain 2.5 g of the product (Intermediate 19-2). Yield 96.6%. Ms: 294.1 (M+H + )

[0287] Step 3: Synthesis of Intermediate (R,Z)-N-(1-(3,6-dimethyl-4-oxo-2-(pyridin-4-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropane-2-sulfonamide (19-3) TIFF2025520857000211.tif37170

[0288] 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, heated to 90 °C, and reacted overnight. The reaction solution was cooled to room temperature, diluted with dichloromethane (25 mL), water (50 mL) was added, stirred for 0.5 h, filtered, the filter cake was slurried with dichloromethane (20 mL x 3), the filtrates were combined and separated into 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 the product (Intermediate 19-3). Yield 88.6%. Ms: 397.2 (M+H + )。

[0289] Step 4: Synthesis of Intermediate (R)-N-((R)-1-(3,6-dimethyl-4-oxo-2-(pyridin-4-yl)-3,4-dihydroquinazolin-8-yl)ethylidene)-2-methylpropan-2-sulfonamide (19-4) TIFF2025520857000212.tif36170

[0290] Intermediate 19-3 (3.0 g, 7.5 mmol) and cerium(III) chloride heptahydrate (1.4 g, 3.8 mmol) were sequentially added to methanol (30 mL) at room temperature, cooled to -65 °C in a dry ice bath, and sodium borohydride (0.6 g, 15.0 mmol) was dissolved in methanol and added dropwise to the reaction system in several portions while controlling the temperature not to exceed -60 °C. It took about 30 minutes, the dry ice bath was removed, and the temperature was allowed to rise naturally to room temperature. Dichloromethane (30 mL) was added for dilution, water (60 mL) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane (50 mL), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography, and recrystallized from methanol / water (1:1) to obtain 2.0 g of the product (Intermediate 19-4). Yield 66.7%. Ms: 399.2 (M+H + )。

[0291] Step 5: Synthesis of Intermediate (R)-8-(1-aminoethyl)-3,6-dimethyl-2-(pyridin-4-yl)quinazolin-4(3H)-one (19-5) TIFF2025520857000213.tif36170

[0292] 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 to react, concentrated, and the residue was dissolved in water (10 mL). It was extracted with ethyl acetate (5 mL), and the ethyl acetate layer was washed once with 1N hydrochloric acid (10 mL) and discarded. The acidic aqueous layers were combined and adjusted to a pH greater than 7, then extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and 1.2 g of the product (Intermediate 19-5) was obtained. The yield was 81.3%. Ms: 295.1 (M+H + )

[0293] 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)picolinate methyl ester (19-6) TIFF2025520857000214.tif44170

[0294] Intermediate 19-5 (59 mg, 0.2 mmol), methyl 6-chloro-3-fluoropicolinate (76 mg, 0.4 mmol), and DIPEA (77 mg, 0.6 mmol) were added to N,N-dimethylacetamide (1 mL). The temperature was raised to 100 °C and stirred overnight to react. The reaction system was cooled to room temperature, diluted with ethyl acetate (2 mL), washed with water (2 mL x 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). The yield was 64.7%. Ms: 464.1 (M+H + )

[0295] 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)picolinic acid (Compound 109) TIFF2025520857000215.tif38170

[0296] Intermediate 19-6 (46 mg, 0.1 mmol) was dissolved in dry tetrahydrofuran (1 ml), potassium trimethylsilanolate (26 mg, 0.2 mmol) was added, and the mixture was stirred at room temperature for 20 minutes to react. The pH was adjusted to around 2 with 0.5 N hydrochloric acid, and the mixture was extracted 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). Yield: 66.7%. Ms: 450.1 (M+H + ). 1 H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.88 - 8.73 (m, 2H), 8.31 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.84 - 7.74 (m, 2H), 7.68 (d, J = 2.1 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.11 (d, J = 9.1 Hz, 1H), 5.41 (p, J = 6.7 Hz, 1H), 3.82 (s, 3H), 2.42 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H).

[0297] The following compounds can be synthesized by a method similar to the above examples using appropriate reagents under appropriate reaction conditions.

[0298]

Table 1

[0299] The beneficial effects of the present invention are demonstrated by the following specific experimental examples.

[0300] Experimental Example 1: Test method for PI3Kα[WT] / [E542K] / [E545K] / [H1047R] / PI3Kβ / γ / δ enzyme activity PI3Kα[WT], PI3Kα[E542K], PI3Kα[E545K], PI3Kα[H1047R], PI3Kβ, PI3Kγ, and PI3Kδ kinase reactions were performed in a 384-well plate (PerkinElmer, #6008280) with a 4 μL reaction volume. To the 384-well plate, PI3Kα[WT] enzyme solution (Promega, #V1721), or PI3Kα[E542K] enzyme solution (CarnaBio, #11-413-20N), or PI3Kα[E545K] enzyme solution (CarnaBio, #11-414-20N), or PI3Kα[H1047R] enzyme solution (Promega, #V1741), or PI3Kβ enzyme solution (Promega, #V1751), or PI3Kγ enzyme solution (ThermoFisher, #PV4786), or PI3Kδ enzyme solution (ThermoFisher, #PV6451) was added, followed by the addition of serially diluted compounds (starting at a final concentration of 10 μM, 3-fold dilution, 10 doses), and then PIP2:3PS (Promega, #V1701) and ATP solution (Promega, #V915B) were added to the plate. After incubation at 25 °C for 1 hour, ADP-Glo reagent buffer (Promega, #V9102) was added to each well. After sealing the plate and incubating at 25 °C for 40 minutes, 10 μL of ADP-Glo detection buffer (Promega, #V9102) was added to each well. After incubation at 25 °C for 40 minutes, the chemiluminescence value was read using a device.

[0301] The experimental results are shown in the ADP-Glo IC50 column of Table 2.

[0302] Experimental Example 2: Anti-proliferation experiment of MCF-10A cells MCF-10A cells (Cobioer Bio. #CBP60419MCF) were diluted with complete medium (Cobioer Bio. #CBP60419), seeded into a 96-well cell culture plate (Corning #3599) at a cell density of 500 cells / well, and cultured for 24 h. Subsequently, serially diluted compounds (starting from a final concentration of 10 μM, 3-fold gradient, 9 concentration doses) were added to make the final volume 100 μl / well, and the cells were cultured at 37 °C and 5% CO2 for 6 days. After the culture, CCK8 reagent (Signalway Antibody Bio. #CP002) was added at 10 μl / well, and the cells were incubated at 37 °C and 5% CO2 for 2 - 3 h, and then the OD 450nm value was read using a microplate reader.

[0303] The results are shown in the MCF-10A IC50 column of Table 2.

[0304] Experimental Example 3: Anti-proliferation experiment of T47D cells T47D cells (ATCC. #HTB-133) were diluted with RPMI 1640 (Gibco #22400-089) containing 10% FBS (Hyclone #SH30084.03), seeded into a 96-well cell culture plate (Biosharp #BS-MP-96W) at 1000 cells / well, and cultured for 24 h. Subsequently, serially diluted compounds (starting from a final concentration of 10 μM, 3-fold gradient, 9 concentration doses) were added at a final volume of 150 μl / well, and the cells were cultured at 37 °C and 5% CO2 for 7 days. After the culture, CellTiter-Glo reagent (Promega #G7573) was added at 75 μl / well, incubated at 25 °C for 10 min, and then the chemiluminescence value was read using a device.

[0305] The results are shown in the T47D IC50 column of Table 2.

[0306]

Table 2

[0307] Here, XXX is an IC 50 >5 μM represents, and XX is 1 μM < IC 50 <5 μM represents, and X is IC 50 <1 μM represents.

[0308] Experimental Example 4: Pharmacokinetics of the Compounds of the Present Invention in Rats 1. Experimental Method Nine healthy adult male SD rats (three rats for each compound administration method) were fasted overnight (>12 h), water was not restricted, and food was given 4 h after administration. They were administered by tail vein injection and forced oral administration, respectively. Blood was collected from the vein at different time points and anticoagulated. The anticoagulant was EDTA-K2 (placed in an ice bath after blood sample collection), and then centrifuged at 4 °C and 6000 g for 5 min to separate plasma. The plasma was stored at -70 °C for measurement. The compound concentration in plasma was measured using the LC-MS / MS method.

[0309] From the data of the compound concentration in plasma at all time points, the main pharmacokinetic parameters were calculated using the Winnolin 8.3 non-compartment model. Area under the blood concentration-time curve AUC all Value: Calculated as follows using the trapezoidal method. AUC inf = AUC all + C t / ke, C t is the blood concentration at the last measurable time point, and ke is the elimination rate constant. Elimination half-life t 1 / 2 = 0.693 / ke. Clearance CL = D / AUC inf (D is the administered dose). Steady-state volume of distribution Vss = CL × MRT, mean residence time MRT = AUMC / AUC. Absolute bioavailability F = (AUCi.g. x Di.v.) / (AUCi.v. x Di.g.) × 100%.

[0310] 2. Experimental Results

[0311]

Table 3

[0312] Remarks: “iv(1mpk)” in the table represents administration by intravenous injection into the tail vein, and the administration dose is 1 milligram per kilogram. “ig(3mpk)” represents forced oral administration, and the administration dose is 3 milligrams per kilogram. “ig(50mpk)” represents forced oral administration, and the administration dose is 50 milligrams per kilogram.

[0313] The above experimental results indicate that the compound of the present invention has good pharmacokinetics.

[0314] Experimental Example 5: Pharmacokinetics of the compound of the present invention in beagle dogs 1. Experimental method Nine healthy adult male beagle dogs (3 dogs for each compound administration method) were fasted overnight (>12 h), with water unrestricted, and fed 4 h after administration. They were administered by intravenous injection and forced oral administration respectively. Blood was collected from the veins of the forelimbs at different time points and anticoagulated. The anticoagulant was EDTA-K2 (placed in an ice bath after blood sample collection), and then centrifuged at 3200 g for 10 min to separate plasma. The plasma samples were stored in a freezer at -70°C until analysis, and the compound concentration in plasma was measured using the LC-MS / MS method.

[0315] From the data of the compound concentration in plasma at all time points, the main pharmacokinetic parameters were calculated using the Winnolin 8.3 non-compartment model. Area under the blood concentration-time curve AUC all Value: Calculated as follows using the trapezoidal method. AUC inf =AUC all +C t / ke, C t is the blood concentration at the last measurable time point, and ke is the elimination rate constant. Elimination half-life t 1 / 2 =0.693 / ke. Clearance CL = D / AUC inf (D is the administration dose). Steady-state distribution volume Vss = CL × MRT. Mean residence time MRT = AUMC / AUC. Absolute bioavailability F = (AUCi.g.xDi.v.) / (AUCi.v.xDi.g.) × 100%.

[0316] 2. Experimental results

[0317]

Table 4

[0318] Remarks: “iv(1mpk)” in the table represents administration by intravenous injection, and the administration dose is 1 milligram per kilogram. “ig(3mpk)” represents forced oral administration, and the administration dose is 3 milligrams per kilogram. “ig(10mpk)” represents forced oral administration, and the administration dose is 10 milligrams per kilogram.

[0319] The above experimental results indicate that the compound of the present invention has good pharmacokinetics.

[0320] Experimental Example 6: Pharmacodynamic evaluation of the compound of the present invention in a subcutaneous xenograft tumor NOD SCID mouse model of MDA-MB-453 cells 1. Experimental method (1) Cell culture and inoculation: The MDA-MB-453 cell line was cultured at 37°C and 5% CO2 using Leibovitz’s L-15 medium + 10% fetal bovine serum + 1% double antibody, and subcultured once a week. When the cell saturation reached 80% - 90% and the quantity reached the requirement, the cells were collected, counted, and inoculated.

[0321] When the number of cells in the logarithmic growth phase reached the number required for the experiment, the cells were collected, centrifuged at 1000 rpm for 5 min to remove the supernatant, resuspended in the medium, counted with a cell counter, and based on the counting results, the original solution was diluted to a cell suspension with a viable cell concentration of 1×108 cells / mL. The cell viability was 94.55% and it was the P14 generation. The diluted cell suspension was diluted at a ratio of 1:1 with Matrigel. After mixing uniformly, it was placed on ice, the suspension was aspirated with a 1 mL sterile syringe, and 0.2 mL of the cell suspension was subcutaneously inoculated into the right axilla of each mouse. That is, 1×107 MDA-MB-453 cells were inoculated per mouse.

[0322] (2) Method of grouping: After the inoculation was completed, the growth state of the tumor was observed daily. When the average volume of the tumor reached about 157.14 mm 3 , the mice were randomly grouped and administered according to the size of the tumor and the body weight of the mice. Also, the same dose of solvent was given as a control group. The day of tumor cell inoculation was defined as day 0.

[0323] (3) Experimental observation and data measurement: The health status and death status of the animals were checked daily, and the growth status of the tumors, activity ability, diet, body weight, eyes, hair, and other abnormal behaviors of the animals were regularly examined. The body weight was measured daily, and the volume of the tumor was measured twice a week. The volume of the tumor was measured with calipers, and the formula was TV = 0.5a×b 2 , where a is the major axis of the tumor and b is the minor axis of the tumor. When the experiment reached the end, plasma samples were collected for each group according to the time point for use in detecting the blood concentration. After the mice were euthanized, the tumors were collected, photographed, weighed, and snap-frozen.

[0324] (4) Evaluation index for the effect of the anti-tumor drug: The relative tumor growth rate T / C(%) is the percentage value of the relative tumor volume or tumor weight between the treatment group and the control group at a certain time point. The calculation formula is T / C% = TRTV / CRTV×100%.

[0325] Here, TRTV is the average relative tumor volume (RTV) of the treatment group, CRTV is the average relative tumor volume of the control group, (RTV)=V t / V0, where V0 is the tumor volume of the animal at the time of grouping, and V t is the tumor volume of the animal after treatment.

[0326] Or T / C% = TTW / CTW × 100%, where TTW is the average tumor weight at the end of the experiment in the treatment group and CTW is the average tumor weight at the end of the experiment in the control group.

[0327] The calculation formula for the relative tumor inhibition rate TGI(%) is [TGI%=(1 - T / C)×100%, where T and C are the relative tumor volumes (RTV) or tumor weights (TW) of the treatment group and the control group at a specific time point, respectively.

[0328] 2. Experimental results

[0329]

Table 5

[0330] The above experimental results indicate that the compound of the present invention has a good inhibitory effect on breast cancer tumors.

[0331] As described above, the compound prepared according to the present invention can be used for the manufacture of PI3K selective inhibitors and drugs for the prevention and / or treatment of diseases related to PI3K, such as drugs for the prevention and / or treatment of cancer. The present invention provides a new option for cancer treatment in clinical practice and has good prospects.

Claims

1. The compound shown in Formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof (provided that R １ is a substituent on the A ring, the number of substituents is m, and each R １ is independently, a substituted or unsubstituted C １ to C ８ alkyl group, C １ to C ８ alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, -NHR １５ , -NHR ８ , -C(O)NHR ８ , -C(O)NHR １５ , a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, and m is 0, 1, 2 or 3, R １５ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, and a substituted or unsubstituted 5- to 10-membered heteroaryl group. Y １ 、 Y ２ is each independently none, CR ４ R ５ 、 NR ４ selected from, R ４ and R ５ are each independently selected from hydrogen, C １ to C ８ alkyl groups, or R ４ and R ５ together with carbon form a ketone group. R ３ is hydrogen, n R ６ substituted 6- to 10-membered aryl group, n R ６ substituted 5- to 10-membered heteroaryl group, n R ６ substituted 4- to 10-membered heterocycloalkyl group or selected from Each R ６ is, independently of one another, a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR ８１ , -C(O)R ８１ , , an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR ８ or -C(O)NHR ８ selected from, or two Rs on the same atom ６ form =O, and n is 0, 1, 2, 3 or 4, R ８１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and an amino group, R ８ is a substituted or unsubstituted C １ -C ８ alkyl group, hydroxy group, selected from R ７ 、R ９ each independently represents a C １ -C ８ alkyl group or a 6- to 10-membered aryl group, and is selected from X １ is selected from C or N, and when X １ is selected from C, ring A is a benzene ring, and when X １ is selected from N, ring A is dihydropyridine, X ２ is selected from C or N, and when X ２ is selected from C, the bond connecting X ２ to O is a double bond, and when X ２ is X ３ the bond connecting to X ２ is a single bond. When X ２ is selected from N, the bond connecting X ２ to O is a single bond, and when X ３ the bond connecting to X has a double bond, and N has a positive charge and O has a negative charge. X ３ is N, Cr １０ or NR １０ selected from, X ４ is selected from C and X ５ is selected from O, N, NR １０ or CR １０ and is selected from R １０ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, X ３ is CR １０ selected from, X ５ when is selected from O, X ３ is X ４ the bond connecting to is a double bond, X ４ is X ５ the bond connecting to is a single bond, X ５ the bond connecting to a carbon atom is a single bond, X ３ is NR １０ selected from, when X ５ is selected from N, X ３ is X ４ the bond connecting to X is a single bond, X ４ is X ５ the bond connecting to X is a double bond, X ５ the bond connecting to a carbon atom is a single bond, X ３ is selected from CR １０ , and when X ５ is selected from CR １０ , the bond connecting X ３ to X ４ is a single bond, and the bond connecting X ４ to X ５ is a double bond, and the bond connecting X ５ to a carbon atom is a single bond, or the bond connecting X ３ to X ４ is a double bond, and the bond connecting X ４ to X ５ is a single bond, and the bond connecting X ５ to a carbon atom is a double bond X ３ is CR １０ selected from, X ５ is selected from N, when X ３ is X ４ the bond connecting with is a double bond, X ４ is X ５ the bond connecting with is a single bond, X ５ the bond connecting with a carbon atom is a double bond, X ３ is selected from N, and X ５ is NR １０ when selected from, the bond connecting X ３ to X ４ is a double bond, and X ４ is X ５ the bond connecting to X ５ is a single bond, and the bond connecting X to a carbon atom is a single bond, R ２ is a substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted 3- to 8-membered cycloalkyl group, substituted or unsubstituted 6- to 10-membered aryl group, substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, substituted or unsubstituted 5- to 10-membered heteroaryl group, -NR １１ R １２ , , -SR １１ selected from R １１ 、 R １２ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or an amino group The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4- to 10-membered heterocycloalkyl group or -NR １３ R １４ selected from, R １３ and R １４ are each independently selected from hydrogen, C １ to C ８ alkyl groups, The substituent of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group is halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR １６ R １７ , -C(O)OR １６ , a substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, and is selected from them, R １６ 、R １７ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or a hydroxy group In the heteroaryl group and heterocycloalkyl group, the heteroatom is N, O or S, and the number of the heteroatoms is 1, 2 or 3.).

2. R １ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, R １５ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, R ３ wherein the aryl group is selected from phenyl groups, the heteroaryl group is selected from isoindolinyl groups, pyridyl groups, pyrimidinyl groups, pyridazinyl groups, thienyl groups, furyl groups, pyrazolyl groups, imidazolyl groups or pyrrolyl groups, and the heterocycloalkyl group is selected from piperidyl groups, R ７ 、R ９ wherein the aryl group of R and R is selected from a phenyl group or a naphthyl group, R ２ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ 、R １４ are each independently selected from hydrogen, C １ -C ８ alkyl groups, and the compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof.

3. The compound according to Claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, characterized in that the compound is as shown in Formula II (provided that R １ is a substituent on the benzene ring, and the number of substituents is m, and each R １ is independently selected from a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, -NHR １５ , -NHR ８ , -C(O)NHR ８ , -C(O)NHR １５ , a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, and m is 0, 1, 2 or 3. R １５ is selected from hydrogen, a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, and a substituted or unsubstituted 5- to 10-membered heteroaryl group, Y １ , Y ２ are each independently none, CR ４ R ５ , NR ４ selected from, R ４ and R ５ are each independently selected from hydrogen, C １ to C ８ alkyl groups, or R ４ and R ５ together with carbon form a ketone group R ３ is a 6- to 10-membered aryl group substituted with n R ６ groups, a 5- to 10-membered heteroaryl group substituted with n R ６ groups, a 4- to 10-membered heterocycloalkyl group substituted with n R ６ groups or selected from Each R ６ is, independently of one another, a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR ８１ or -C(O)R ８１ , , an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR ８ or -C(O)NHR ８ selected from, or two Rs on the same atom ６ form =O, and n is 0, 1, 2, 3 or 4, R ８１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and an amino group, R ８ is a substituted or unsubstituted C １ -C ８ alkyl group, hydroxy group, selected from R ７ 、R ９ each independently represents a C １ -C ８ alkyl group or a 6- to 10-membered aryl group, and is selected from R ２ is a substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted 3- to 8-membered cycloalkyl group, substituted or unsubstituted 6- to 10-membered aryl group, substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, substituted or unsubstituted 5- to 10-membered heteroaryl group, -NR １１ R １２ , , -SR １１ selected from R ６ When R is selected from carboxy groups, ２ R is not selected from substituted or unsubstituted 3- to 8-membered cycloalkyl groups, substituted or unsubstituted 6- to 10-membered aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, R １１ 、R １２ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or an amino group The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4- to 10-membered heterocycloalkyl group or -NR １３ R １４ selected from, R １３ 、R １４ are each independently selected from hydrogen, C １ -C ８ alkyl groups, The substituents of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group are halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR １６ R １７ , -C(O)OR １６ , substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, and are selected from R １６ 、 R １７ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or a hydroxy group In the heteroaryl group and heterocycloalkyl group, the heteroatom is N, O or S, and the number of the heteroatoms is 1, 2 or 3, preferably R １ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, R １５ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, or a pyrrolyl group, R ３ wherein the aryl group is selected from phenyl groups, the heteroaryl group is selected from isoindolinyl groups, pyridyl groups, pyrimidinyl groups, pyridazinyl groups, thienyl groups, furyl groups, pyrazolyl groups, imidazolyl groups or pyrrolyl groups, and the heterocycloalkyl group is selected from piperidyl groups, R ７ 、 R ９ wherein the aryl group of R and R is selected from a phenyl group or a naphthyl group, R ２ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ 、 R １４ are each independently selected from hydrogen, C １ -C ８ alkyl groups.).

4. The compound according to Claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, characterized in that the compound is as shown in Formula II-1 (provided that R １ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ -C alkyl group, a C １ -C ８ -C alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, -NHR １５ , -NHR ８ , -C(O)NHR ８ , -C(O)NHR １５ , a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, R １５ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, and a substituted or unsubstituted 5- to 10-membered heteroaryl group, R ３ is a 6- to 10-membered aryl group substituted with n R ６ groups, a 5- to 10-membered heteroaryl group substituted with n R ６ groups, a 4- to 10-membered heterocycloalkyl group substituted with n R ６ groups or selected from Each R ６ is, independently of one another, a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR ８１ , -C(O)R ８１ , , an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR ８ or -C(O)NHR ８ is selected from, or two Rs on the same atom ６ form =O, and n is 0, 1, 2, 3 or 4, R ８１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and an amino group, R ８ is a substituted or unsubstituted C １ -C ８ alkyl group, hydroxy group, selected from R ７ 、R ９ are each independently selected from C １ to C ８ alkyl groups and 6- to 10-membered aryl groups, R ２ is a substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted 3- to 8-membered cycloalkyl group, substituted or unsubstituted 6- to 10-membered aryl group, substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, substituted or unsubstituted 5- to 10-membered heteroaryl group, -NR １１ R １２ , , -SR １１ selected from R ６ When R is selected from carboxy groups, ２ R is not selected from substituted or unsubstituted 3- to 8-membered cycloalkyl groups, substituted or unsubstituted 6- to 10-membered aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, R １１ 、R １２ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or an amino group The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4- to 10-membered heterocycloalkyl group or -NR １３ R １４ selected from, R １３ 、R １４ are each independently selected from hydrogen, C １ -C ８ alkyl groups, The substituents of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group are halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR １６ R １７ , -C(O)OR １６ , substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, and are selected from R １６ 、R １７ are each independently selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and a hydroxy group In the heteroaryl group and heterocycloalkyl group, the heteroatom is N, O or S, and the number of the heteroatoms is 1, 2 or 3, preferably R １ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, R １５ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, R ３ the aryl group of R is selected from phenyl groups, the heteroaryl group is selected from isoindolinyl groups, pyridyl groups, pyrimidinyl groups, pyridazinyl groups, thienyl groups, furyl groups, pyrazolyl groups, imidazolyl groups or pyrrolyl groups, and the heterocycloalkyl group is selected from piperidyl groups, R ７ 、 R ９ wherein the aryl group of R is selected from a phenyl group or a naphthyl group, R ２ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ 、 R １４ is, independently, hydrogen, C １ -C ８ alkyl group. ).

5. The compound according to Claim 4, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, characterized in that the compound is as shown in Formula II-2 (provided that Z １ is selected from CH or N, R １ is selected from hydrogen, a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, -NHR １５ , -NHR ８ , -C(O)NHR ８ , -C(O)NHR １５ , a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, R １５ is selected from hydrogen, a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, cyano group, nitro group, hydroxy group, carboxy group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, and a substituted or unsubstituted 5- to 10-membered heteroaryl group, n is 0, 1, 2, 3 or 4, Each R ６ is, independently of one another, a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR ８１ , -C(O)R ８１ , , an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR ８ or -C(O)NHR ８ is selected from, or two Rs on the same atom ６ form =O, R ８１ is selected from hydrogen, a substituted or unsubstituted C １ to C ８ alkyl group, and an amino group, R ８ is a substituted or unsubstituted C １ -C ８ alkyl group, hydroxy group, selected from R ９ is selected from C １ to C ８ alkyl groups and 6- to 10-membered aryl groups, R ２ is a substituted or unsubstituted C １ -C ８ alkyl group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, -NR １１ R １２ , , -SR １１ selected from R ６ When R is selected from carboxy groups, ２ R is not selected from substituted or unsubstituted 3- to 8-membered cycloalkyl groups, substituted or unsubstituted 6- to 10-membered aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, R １１ and R １２ are each independently selected from hydrogen, a substituted or unsubstituted C １ to C ８ alkyl group, and an amino group The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4- to 10-membered heterocycloalkyl group or -NR １３ R １４ selected from, R １３ 、 R １４ are each independently selected from hydrogen, C １ to C ８ alkyl groups, The substituent of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group is halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR １６ R １７ , -C(O)OR １６ , a substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, and is selected from R １６ 、 R １７ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or a hydroxy group In the heteroaryl group and heterocycloalkyl group, the heteroatom is N, O or S, and the number of the heteroatoms is 1, 2 or 3, preferably R １ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, R １５ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is selected from an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group or a pyrrolyl group, R ９ wherein the aryl group of R is selected from a phenyl group or a naphthyl group, R ２ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ , R １４ are each independently selected from hydrogen, C １ to C ８ alkyl groups.).

6. The compound according to Claim 5, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, characterized in that the compound is as shown in Formula II-3 (provided that Z １ is selected from CH or N, R １ is selected from a substituted or unsubstituted C １ -C ８ alkyl group, halogen, and is R ６１、 R ６２ Each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR ８１ -C(O)R ８１ , , an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR ８ or -C(O)NHR ８ selected from, R ８１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and an amino group, R ８ is a substituted or unsubstituted C １ -C ８ alkyl group, hydroxy group, selected from R ９ is selected from C １ to C ８ alkyl groups and 6- to 10-membered aryl groups, R ２ is a substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted 3- to 8-membered cycloalkyl group, substituted or unsubstituted 6- to 10-membered aryl group, substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, substituted or unsubstituted 5- to 10-membered heteroaryl group, -NR １１ R １２ , , -SR １１ selected from R ６ When R is selected from carboxy groups, ２ R is not selected from substituted or unsubstituted 3- to 8-membered cycloalkyl groups, substituted or unsubstituted 6- to 10-membered aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups, R １１ 、 R １２ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or an amino group, The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4- to 10-membered heterocycloalkyl group or -NR １３ R １４ selected from and R １３ 、R １４ are each independently selected from hydrogen, C １ -C ８ alkyl groups, The substituents of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group are halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR １６ R １７ , -C(O)OR １６ , substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, and are selected from, R １６ 、 R １７ are each independently selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and a hydroxy group In the heteroaryl group and heterocycloalkyl group, the heteroatom is N, O or S, and the number of the heteroatoms is 1, 2 or 3, preferably R ９ wherein the aryl group is selected from a phenyl group or a naphthyl group, R ２ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from The substituent of the alkyl group is halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ 、R １４ is, independently, hydrogen, C １ -C ８ alkyl group. ).

7. The compound according to claim 6, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is as shown in Formula II-4 provided that Z １ is selected from CH or N, R １ is selected from C １ to C ８ alkyl groups, halogens, and trifluoromethyl groups, R ６１ is hydrogen, a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR ８１ or -C(O)R ８１ or , an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR ８ or -C(O)NHR ８ selected from, R ８１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and an amino group, R ８ is a substituted or unsubstituted C １ -C ８ alkyl group, hydroxy group, selected from R ９ is selected from C １ to C ８ alkyl groups and 6- to 10-membered aryl groups, R ２ is a substituted or unsubstituted C １ -C ８ alkyl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, -NR １１ R １２ , , -SR １１ selected from R １１ 、R １２ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or an amino group The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4- to 10-membered heterocycloalkyl group or -NR １３ R １４ selected from, R １３ 、R １４ each independently represents hydrogen, C １ ~C ８ selected from alkyl groups, The substituent of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group is halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR １６ R １７ , -C(O)OR １６ , a substituted or unsubstituted C １ -C ８ alkyl group or C １ -C ８ alkoxy group, and is selected from among them, R １６ 、 R １７ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or a hydroxy group the heteroatom in the heteroaryl group or heterocycloalkyl group is N, O or S, and the number of the heteroatoms is 1, 2 or 3 preferably R ９ wherein said aryl group is selected from a phenyl group or a naphthyl group, R ２ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from The substituent of the cyclic group is halogen, a hydroxy group, a cyano group, a nitro group, a carboxy group, a piperidyl group, a morpholinyl group or -NR １３ R １４ selected from, R １３ 、R １４ are each independently selected from hydrogen, C １ -C ８ alkyl groups.).

8. The compound according to claim 7, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is as shown in Formula II-5 provided that Z １ is selected from CH or N, R １ is selected from C １ to C ８ alkyl groups, halogen, and trifluoromethyl groups, R ６１ is hydrogen, a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR ８１ or -C(O)R ８１ or , an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR ８ or -C(O)NHR ８ selected from, R ８１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and an amino group, R ８ is a substituted or unsubstituted C １ -C ８ alkyl group, hydroxy group, selected from R ９ is selected from C １ to C ８ alkyl groups and phenyl groups, R ２ ' is a substituent on the benzene ring, the number of substituents is a, and each R ２ ' is, independently of one another, halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR １６ R １７ , -C(O)OR １６ , substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, a is 0, 1, 2 or 3, R １６ 、R １７ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or a hydroxy group The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from and R １３ and R １４ are each independently selected from hydrogen, C １ to C ８ alkyl groups.).

9. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is as shown in Formula III-1 provided that R １ is selected from a substituted or unsubstituted C １ -C ８ alkyl group, C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group or carboxy group, R ３ is a 6- to 10-membered aryl group substituted with n R ６ groups, a 5- to 10-membered heteroaryl group substituted with n R ６ groups, a 4- to 10-membered heterocycloalkyl group substituted with n R ６ groups or selected from Each R ６ is, independently of one another, a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR ８１ , -C(O)R ８１ , , an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR ８ or -C(O)NHR ８ selected from, or two Rs on the same atom ６ form =O, n is 0, 1, 2, 3 or 4, R ８１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and an amino group, R ８ is a substituted or unsubstituted C １ -C ８ alkyl group, hydroxy group, selected from R ７ 、R ９ each independently represents a C １ -C ８ alkyl group or a 6- to 10-membered aryl group, and is selected from among them R １０ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, R ２ is a substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted 3- to 8-membered cycloalkyl group, substituted or unsubstituted 6- to 10-membered aryl group, substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, substituted or unsubstituted 5- to 10-membered heteroaryl group, -NR １１ R １２ , , -SR １１ selected from R １１ 、R １２ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or an amino group The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4- to 10-membered heterocycloalkyl group or -NR １３ R １４ selected from, R １３ 、R １４ are each independently selected from hydrogen, C １ to C ８ alkyl groups, The substituent of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group is halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR １６ R １７ , -C(O)OR １６ , substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, and is selected from them, R １６ 、R １７ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or a hydroxy group the heteroatom in the heteroaryl group or heterocycloalkyl group is N, O or S, and the number of the heteroatoms is 1, 2 or 3 preferably R ３ wherein the aryl group is selected from phenyl groups, the heteroaryl group is selected from isoindolinyl groups, pyridyl groups, pyrimidinyl groups, pyridazinyl groups, thienyl groups, furyl groups, pyrazolyl groups, imidazolyl groups or pyrrolyl groups, and the heterocycloalkyl group is selected from piperidyl groups, R ７ 、 R ９ wherein the aryl group of R and R is selected from a phenyl group or a naphthyl group, R ２ the aryl group is selected from a phenyl group, an anthracenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ 、 R １４ is, independently, hydrogen, C １ -C ８ alkyl group. ).

10. The compound according to claim 9, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is as shown in Formula III-2 provided that X １１ is selected from CH or N, R １ is selected from a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group or carboxy group, R ６１、 R ６２ Each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR ８１ -C(O)R ８１ , , an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR ８ or -C(O)NHR ８ selected from, R ８１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and an amino group, R ８ is a substituted or unsubstituted C １ -C ８ alkyl group, hydroxy group, selected from R ９ is selected from a C １ -C ８ alkyl group or a 6- to 10-membered aryl group, R １０ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, R ２ is a substituted or unsubstituted C １ to C ８ alkyl group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, -NR １１ R １２ , , -SR １１ selected from R １１ 、R １２ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or an amino group The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4- to 10-membered heterocycloalkyl group or -NR １３ R １４ selected from, R １３ 、R １４ are each independently selected from hydrogen, C １ - C ８ alkyl groups, The substituent of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group is halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, C(O)NR １６ R １７ , -C(O)OR １６ , substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, and is selected from them, R １６ 、 R １７ are each independently selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and a hydroxy group the heteroatom in the heteroaryl group or heterocycloalkyl group is N, O or S, and the number of the heteroatoms is 1, 2 or 3 preferably R ９ wherein the aryl group is selected from a phenyl group or a naphthyl group, R ２ wherein the aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ 、 R １４ are each independently selected from hydrogen, C １ -C ８ alkyl groups.).

11. The compound according to claim 9, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is as shown in Formula III-3 provided that X １１ is selected from CR ７１ or N, and R ７１ is selected from hydrogen, halogen, C １ to C ８ alkyl groups, R １ is selected from a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group or carboxy group, R ６１ is hydrogen, a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR ８１ or -C(O)R ８１ or , an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR ８ or -C(O)NHR ８ selected from, R ８１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and an amino group, R ８ is a substituted or unsubstituted C １ -C ８ alkyl group, hydroxy group, selected from R ９ is selected from C １ to C ８ alkyl groups and 6- to 10-membered aryl groups, R １０ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, R ２ is a substituted or unsubstituted C １ -C ８ alkyl group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, -NR １１ R １２ , , -SR １１ selected from R １１ 、 R １２ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or an amino group The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, 4- to 10-membered heterocycloalkyl group or -NR １３ R １４ is selected from, R １３ 、R １４ are each independently selected from hydrogen, C １ - C ８ alkyl groups, The substituents of the cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group are halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, C(O)NR １６ R １７ , -C(O)OR １６ , substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, and are selected from R １６ 、R １７ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, or a hydroxy group the heteroatom in the heteroaryl group or heterocycloalkyl group is N, O or S, and the number of the heteroatoms is 1, 2 or 3 preferably R ９ wherein the aryl group of R is selected from a phenyl group or a naphthyl group, R ２ The aryl group is selected from a phenyl group or a naphthyl group, the heterocycloalkyl group is selected from a piperidyl group or a morpholinyl group, and the heteroaryl group is an isoindolinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, an isoxazolyl group or selected from The substituent of the cyclic group is halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ 、 R １４ is independently selected from hydrogen, C １ to C ８ alkyl groups, respectively.).

12. The compound according to claim 9, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is as shown in formula III-4 (provided that X １１ , X １２ , X １３ , X １４ , X １５ , X １６ , X １７ , X １８ is independently selected from CR ７１ or N, R ６１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ -C alkyl group, a C １ -C ８ -C alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, carboxy group, acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR ８ or -C(O)NHR ８ and is selected from the group consisting of R ７１ is selected from hydrogen, halogen, C １ to C ８ alkyl groups, R ８１ is selected from a hydroxy group, a C １ -C ８ alkoxy group, and an amino group, R ８ is a hydroxy group, selected from R ９ is selected from C １ to C ８ alkyl groups and phenyl groups, R １ is selected from a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group or carboxy group, R １０ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, R ２ ' is a substituent on the ring, the number of substituents is a, and each R ２ ' is independently selected from halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR １６ R １７ , substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, a is 0, 1, 2 or 3, R １６ 、R １７ are each independently selected from hydrogen, C １ -C ８ alkyl groups, The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ and R １４ are each independently selected from hydrogen, C １ to C ８ alkyl groups.).

13. The compound according to claim 12, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is as shown in formula III-5 (provided that X １４ is selected from CH or N, R ６１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ -C alkyl group, a C １ -C ８ -C alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, carboxy group, acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR ８ or -C(O)NHR ８ and is selected from the group consisting of: R ８ is a hydroxy group, selected from R ９ is selected from C １ to C ８ alkyl groups and phenyl groups, R １ is selected from a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group or carboxy group, R １０ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, R ２ ' is selected from a halogen, a hydroxy group, an amino group, a carboxy group, a nitro group, a cyano group, C １ to C ８ alkyl group or C １ to C ８ alkoxy group, a is 0, 1, 2 or 3, The substituent of the alkyl group is halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ and R １４ are each independently selected from hydrogen, C １ to C ８ alkyl groups.).

14. The compound according to claim 9, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is as shown in formula III-6 (provided that R ６１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, carboxy group, acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR ８ or -C(O)NHR ８ and is selected from the group consisting of R ８ is a hydroxy group, selected from R ９ is selected from C １ to C ８ alkyl groups and phenyl groups, R １０ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, R ２ ' is a substituent on the benzene ring, the number of substituents is a, and each R ２ ' is independently selected from halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, a is 0, 1, 2 or 3, The substituent of the alkyl group is halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from and R １３ 、 R １４ are each independently selected from hydrogen, C １ - C ８ alkyl groups.).

15. The compound according to claim 9, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is as shown in formula III-7 (provided that X １１ 、 X １２ 、 X １３ are each independently selected from CR ７１ or N, R ６１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, carboxy group, acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR ８ or -C(O)NHR ８ and is selected from the group consisting of R ７１ is selected from hydrogen, halogen, C １ to C ８ alkyl groups, R ８１ is selected from a hydroxy group, a C １ -C ８ alkoxy group, and an amino group, R ８ is a hydroxy group, selected from R ９ is selected from C １ to C ８ alkyl groups and phenyl groups, R １ is selected from a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group or carboxy group, R １０ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, R ２ is 、 、 、 、 、 、 、 selected from R １１ each independently represents hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and Each R ２ ’ is independently selected from halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR １５ R １６ , substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, a is 0, 1, 2 or 3, O is selected from integers of 1 to 3, R １５ and R １６ are each independently selected from hydrogen, C １ to C ８ alkyl groups, The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ and R １４ are each independently selected from hydrogen, C １ to C ８ alkyl groups, or R １３ and R １４ are linked forming.).

16. The compound according to claim 9, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is as shown in formula III-8 (provided that X １４ 、 X １５ 、 X １６ 、 X １７ 、 X １８ are each independently selected from CR ７１ or N, R ７１ is selected from hydrogen, halogen, C １ ~C ８ alkyl group, and R １ is selected from a substituted or unsubstituted C １ -C ８ alkyl group, a C １ -C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group or carboxy group, R １０ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and R ２ ' is a substituent on the ring, the number of substituents is a, and each R ２ ' is independently selected from halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, -C(O)NR １５ R １６ , substituted or unsubstituted C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, a is 0, 1, 2 or 3, R １５ 、 R １６ are each independently selected from hydrogen, C １ to C ８ alkyl groups, R ３ is 、 、 , n R's ６ phenyl group substituted with n R's ６ pyridyl group substituted with n R's ６ pyrimidinyl group substituted with n R's ６ pyridazinyl group substituted with n R's ６ thienyl group substituted with n R's ６ furyl group substituted with n R's ６ pyrazolyl group substituted with n R's ６ imidazolyl group substituted with n R's or n R's ６ pyrrolyl group substituted with, and is selected from, Each R ６ is, independently of one another, a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, -C(O)OR ８１ , -C(O)R ８１ , , an acetonitrile group, a phosphonic acid group, a sulfonic acid group, a sulfonamide group, a boronic acid group, -NHR ８ or -C(O)NHR ８ is selected from, or two Rs on the same atom ６ form =O, and n is 0, 1, 2, 3 or 4, R ８１ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, and an amino group, R ８ is a substituted or unsubstituted C １ -C ８ alkyl group, hydroxy group, selected from R ９ is selected from a C １ -C ８ alkyl group or a 6- to 10-membered aryl group, The substituent of the alkyl group is deuterium, halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ and R １４ are each independently selected from hydrogen, C １ to C ８ alkyl groups.).

17. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is as shown in formula IV (provided that Z ２ is selected from CH or N, R ６２ is selected from hydrogen, a substituted or unsubstituted C １ -C ８ -C alkyl group, a C １ -C ８ -C alkoxy group, halogen, cyano group, nitro group, amino group, hydroxy group, carboxy group, acetonitrile group, phosphonic acid group, sulfonic acid group, sulfonamide group, boronic acid group, -NHR ８ or -C(O)NHR ８ and is selected from the group consisting of R ８ is a hydroxy group, selected from R ９ is selected from C １ to C ８ alkyl groups and phenyl groups, R ２ ' is a substituent on the benzene ring, the number of substituents is a, and each R ２ ' is independently selected from halogen, hydroxy group, amino group, carboxy group, nitro group, cyano group, C １ ~C ８ alkyl group or C １ ~C ８ alkoxy group, a is 0, 1, 2 or 3, The substituent of the alkyl group is halogen, hydroxy group, cyano group, nitro group, carboxy group, piperidyl group, morpholinyl group or -NR １３ R １４ selected from, R １３ , R １４ are each independently selected from hydrogen, C １ -C ８ alkyl groups.).

18. The compound according to any one of claims 1 to 17, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, wherein the compound is one of the following compounds

19. Use of the compound according to any one of claims 1 to 18, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof, in the manufacture of a PI3K inhibitor Use preferably of the PI3K inhibitor being a selective PI3K inhibitor.

20. Use in the manufacture of a medicament for the prevention and / or treatment of a disease associated with PI3K of the compound according to any one of claims 1 to 18, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof.

21. The disease being a cancer, inflammation, cardiovascular disease associated with PI3K, Use according to claim 19, characterized in that preferably the cancer is breast cancer, colon cancer, gastric cancer, colorectal cancer, rectal cancer, ovarian cancer, prostate cancer.

22. A medicament characterized by being manufactured by adding a pharmaceutically acceptable auxiliary material or auxiliary component, with the compound according to any one of claims 1 to 18, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, or a deuterated compound thereof as an active ingredient.

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